Guide To Gastrointestinal Oncology The Clinician Guide To GI Series
Guide To Gastrointestinal Oncology The Clinician Guide To GI Series
Guide To Gastrointestinal Oncology The Clinician Guide To GI Series
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DEDICATION
This book is dedicated to my family: my wife, Mary, and my children Elyse and
Sidney, without their indulgence this book would not have been possible.
Over the years a number of key individuals sparked and nurtured my interest in gastrointestinal oncology. Thomas Lad, MD and Jay Goldstein, MD were critical early on
in demonstrating to me the need for better diagnostics and additional effective therapies.
Tachi Yamada, MD and Chung Owyang, MD had the foresight to allow me the specialized training, which I hope I have put to good use. Drs. Rick Boland, John DelValle,
Grace Elta, Robert Hawes, Peter Traber, and Maurits Wiersema were instrumental in
helping me acquire and define my skillset and in facilitating my clinical research. My
current colleagues at the University of Pennsylvania have been instrumental, with Dan
Haller, MD at the forefront.
Clifford Pilz, MD deserves special mention as Chief of Medicine during my medical
school, residency, and Chief Residency; he clearly defined the epitome of the all-knowing physician; no question was too small to deserve an answer, no sign or symptom too
subtle to be ignored.
CONTENTS
Dedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
About the Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x
Contributing Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Chapter 1:
Chapter 2:
Chapter 3:
Chapter 4:
Chapter 5:
Chapter 6:
Chapter 7:
Chapter 8:
Chapter 9:
viii
Contents
ACKNOWLEDGMENTS
I would like to thank the chapter authors who clearly did a phenomenal job conveying their expertise in their respective areas. It is difficult in these times to have genuine experts write chapters due to the complex time demands placed upon them; they
are to be congratulated.
The staff at SLACK Incorporated was superb and demonstrated great professionalism; their guidance and expertise shows in the polish of the final product. An individual thanks is due to Carrie Kotlar, without her persistence (and perseverance) this handbook would not have come to fruition.
ABOUT
THE
EDITOR
CONTRIBUTING AUTHORS
Jordan Berlin, MD
Vanderbilt University
Nashville, Tennessee
Lynn A. Brody, MD
Memorial Sloan-Kettering Cancer Center
New York, New York
John C. Kucharczuk, MD
University of Pennsylvania Health System
Philadelphia, Pennsylvania
Karen T. Brown, MD
Memorial Sloan-Kettering Cancer Center
New York, New York
Linda S. Lee, MD
Harvard Medical School
Boston, Massachusetts
Allen W. Burton, MD
UT MD Anderson Cancer Center
Houston, Texas
Najjia N. Mahmoud, MD
University of Pennsylvania Health System
Philadelphia, Pennsylvania
Navtej Buttar, MD
Mayo Clinic
Jacksonville, Florida
Arnold J. Markowitz, MD
Memorial Sloan-Kettering Cancer Center
New York, New York
Robert J. Canter, MD
University of Pennsylvania Health System
Philadelphia, Pennsylvania
Patrick M. McQuillan, MD
Penn State College of Medicine
Hershey, Pennsylvania
Bapsi Chak, MD
Vanderbilt University
Nashville, Tennessee
Carla L. Nash, MD
Memorial Sloan-Kettering Cancer Center
New York, New York
Anne Covey, MD
Memorial Sloan-Kettering Cancer Center
New York, New York
Patrick R. Pfau, MD
University of Wisconsin, Madison
Madison, Wisconsin
Kristoffel R. Dumon, MD
University of Pennsylvania Health System
Philadelphia, Pennsylvania
John M. Poneros, MD
Brigham and Womens Hospital
Boston, Massachusetts
xii
Contributing Authors
Niraja Rajan, MD
Penn State College of Medicine
Hershey, Pennsylvania
Janak N. Shah, MD
San Francisco General Hospital
San Francisco, California
Richard E. Sampliner, MD
University of Arizona Health Sciences
Center
Tucson, Arizona
James S. Scolapio, MD
Mayo Clinic
Jacksonville, Florida
Ilias Scotiniotis, MD
Department of Gastroenterology
Hygeia Hospital
Athens, Greece
Weijing Sun, MD
University of Pennsylvania Health System
Philadelphia, Pennsylvania
Noel N. Williams, MD
University of Pennsylvania Health System
Philadelphia, Pennsylvania
PREFACE
The area of gastrointestinal oncology is an active one. Both clinical research and basic
research have come together and changed the diagnostic and treatment protocols for a
number of deadly malignancies. A multidisciplinary approach to the diagnosis and treatment appears to be the best paradigm; it allows for each individual medical specialty to
apply their knowledge and expertise in an expeditious and effective manner.
Some of the cancers with which we deal are unfortunately all too often ultimately
fatal. Our roles are changing; the boundaries between the medical subspecialties are
blurring, with progressive leadership we are better able to make the patients feel that
their team is truly in sync and providing cutting edge therapy. To this end, I have gathered a nationally and internationally recognized group of clinical researchers and clinicians to provide a balanced and multidisciplinary approach to the treatment of the most
common of the gastrointestinal malignancies.
It is intended that this book will serve as a resource for trainees and clinicians in the
medical and surgical fields. Those that infrequently diagnose or take care of patients
with these neoplasms should be able to find enough easily accessible information to be
able to converse with their patients and their families, and those who are routinely
involved in the care of these patients will gain a better understanding of the capabilities
of the other specialties and gain insight into the thought processes behind the often difficult treatment decisions that must be made.
chapter
Management of Premalignant
Diseases of the Esophagus:
Barretts Esophagus
Richard E. Sampliner, MD
DEFINITION
The current working definition of BE is based on endoscopic assessment (Table 11). The distal esophagus has an abnormal liningsalmon-colored rather than the normal pearl-colored squamous lining. In addition, intestinal metaplasia is present on biopsy. Intestinal metaplasia is a change like the intestinegoblet cellsbut in the esophagus. This is the specific epithelium at risk for development of dysplasia and ultimately
EAC.
This definition of BE has evolved over the last 3 decades. It is important to differentiate BE from intestinal metaplasia of the gastric cardia. This differentiation requires
careful targeting of biopsies by the gastroenterologist and clear communication with the
pathologist about the origin of the biopsy. The targeting of biopsies is guided by the
recognition of essential endoscopic landmarks (Table 1-2). Missed targeting or mislabeling of the site of biopsy may lead to an incorrect diagnosis. According to one group,
BE has a greater concentration of glands than intestinal metaplasia of the gastric cardia
and lacks well developed adjacent cardiac mucosa, thus basing the distinction between
BE and intestinal metaplasia of the gastric cardia on histologic criteria.
The definition of BE includes patients with intestinal metaplasia of any length in an
abnormal distal esophagus. An older definition of BE as columnar lined esophagus
greater than 3 cm has led to the current arbitrary classification of short segment BE
(<3 cm) and long segment BE (3 cm).
Chapter 1
Table 1-1
Table 1-2
EPIDEMIOLOGY
The epidemiology of BE is incompletely identified and derived mostly from cohort
studies of patients with BE. These studies are retrospective, prospective, and subject to
the variability of disease definition, referral bias, and the specifics of the population
served at the study site. The mean age of diagnosis is 63 years and the estimated mean
age of onset is 40 years.2 Patients with BE are predominantly male2:1 male to female
ratio.3 The frequency of BE differs dramatically among ethnic groups. The prevalence of
BE in adults undergoing endoscopy ranges from 7.8% of Whites to 4.8% of Hispanic
Americans and 1.1% of African Americans. A longer duration of reflux symptoms separates BE from non-Barretts GERD patients as a group, but there is a great overlap of
individual patients. An earlier age of onset of GERD may also be a characteristic of BE.
Reports of families with generations of patients with BE suggest familial aggregation.
First-degree relatives of patients with BE and EAC are more likely to have a history of
GERD than first-degree relatives of patients with reflux esophagitis.4 Familial aggregation of BE, EAC and adenocarcinoma of the esophagogastric junction has been demonstrated in White adults.
Hiatal hernia is commonly associated with BE and contributes to the pathophysiology. Ninety-six percent of patients with long segment BE have a hiatal hernia.5 In fact,
a predictive model for the length of BE uses the length of the hiatal hernia and the duration of esophageal acid exposure.6 On average, patients with BE have greater esophageal
acid and bile acid exposure than GERD patients without mucosal disease.
SCREENING
FOR
BARRETTS ESOPHAGUS
The rationale for screening for BE is that it is the premalignant lesion for EAC.
Recognition of BE allows an opportunity for early recognition of EAC to enable intervention and improvement of outcome. The rising incidence of EAC has been docu-
Table 1-3
Gender: Male
Ethnicity:White
Older age
Chronic GERD
High body mass index
Cigarette smoking
LES relaxing drugs
mented since 1975 and continues to climb. EAC has increased from 5% of esophageal
cancers to more than 50% in the last 30 years. Unfortunately, less than 5% of patients
with EAC have been previously identified with BE. Only prior detection of BE allows
for early intervention.
The annual incidence of EAC in patients with BE has been controversial. A funnel
analysis demonstrated publication bias with series with smaller numbers of patients with
shorter follow-up having a higher incidence of cancer.7 This analysis as well as a prospective cohort study suggests the annual incidence to be 0.5%.8 Even these data are subject
to bias from an inadequate length of follow-up. A young patient with BE does not have
a greater risk of EAC than an older one just because he has a much longer life expectancy. A more realistic estimate of mortality from EAC can be derived from a population
based and a cohort study demonstrating a mortality from EAC in patients with BE of
4.7% and 2.5% respectively.9,10 The lifetime risk of dying from EAC may be a concept
that can be grasped by patients more readily than annual incidence. Patients with BE are
usually surprised and reassured that this risk is less than 5%.
The epidemiology of BE and EAC provides information on who is at higher risk for
having these diseases (Table 1-3). Who should we screen for BE? Older White males
with chronic reflux symptoms will have the highest yield of BE. Evidence-based thresholds for a specific age and years of reflux symptoms are not established. A Veterans
Affairs Medical Center study found an age of more than 40 years with heartburn at least
weekly to be predictive of BE.11 There is a 2 phase risk stratification that is necessary:
those patients at risk for BE and those with BE at risk for EAC. The risk factors for EAC
are similar to those for BE85% of patients with EAC are White men. Increased frequency, severity, and duration of reflux symptoms are risk factors for EAC. This was documented in a Swedish population-based study. Combining long duration with severity
of reflux symptoms has an odds ratio of EAC of 43.5 compared to controls lacking
GERD.12
Trials of screening a random sample of the population for BE do not exist. BE can
even occur in patients lacking evident GERD symptoms. This provides a formidable
challenge for screening. In a predominantly male (90%), veteran, and White (73%)
group with a mean age of 61 undergoing sigmoidoscopy screening, 7% had long segment BE and 17% short segment.13 These surprising findings were not substantiated in
a larger study of patients with a mean age of 59, 60% male, and 78% White undergoing colonoscopy. Only 0.36% had long segment and 5.2% short segment BE.14 Long
segment BE is uncommon in patients lacking reflux symptoms.
Chapter 1
Table 1-4
Evaluation
Endoscopy Frequency
None
LGD
2 endoscopies
Highest grade on second
endoscopy
Repeat endoscopy with
intensive large forceps
biopsy protocol
Expert pathologist interpretation
3 to 4 years
Annual until no dysplasia x 2
HGD
Individualize intervention
SURVEILLANCE ENDOSCOPY
Once BE is diagnosed, the next step is surveillance in an effort to detect high grade
dysplasia (HGD) and EAC for effective intervention. Dysplasia is the currently available
clinical biologic marker predicting cancer. Dysplasia is the first step of the neoplastic
process. It is characterized by cytologic and architectural changes in intestinal metaplasia that typically involve the surface epithelium. Although a higher grade of dysplasia is
associated with a greater risk of EAC, even HGD may apparently regress and may not
progress to cancer over even a decade. Progression from HGD to cancer ranges from
59% in 5 years15 to 16% in 7 years.16 However, eliminating patients referred for HGD
and cancer that develop within the first year of follow-up (prevalence EAC) reduces the
higher rate to 24% at 5 years, a still significant risk. All patients with BE and HGD do
not inevitably progress to cancer over their lifetime.
The problem with dysplasia as the basis for surveillance is the interobserver variability. Even expert gastrointestinal (GI) pathologists have only a fair agreement in differentiating HGD from intramucosal cancerkappa value of 0.56.17 This interobserver
variability is not overcome by training. Unfortunately, this basis of clinical decision making is not a clear cut endpoint.
Surveillance endoscopy is intrinsically reasonable and uniformly practiced in the
United States,18 although proof of efficacy is lacking. Retrospective surgical series document a significantly greater survival in patients with cancer found at surveillance
endoscopy than patients clinically presenting with EAC (62% to 90% vs 20%). Recent
case-control studies also suggest that endoscopy is associated with earlier stage cancer
and improved survival.19,20 The frequency of surveillance endoscopy is based on the
grade of dysplasia (Table 1-4).21 The intervals are derived from prospectively followed
patient cohorts and the biopsy protocol is based on modeling studies. With no dysplasia on two consecutive endoscopies, an interval of at least 3 years is recommended. With
low grade dysplasia (LGD) after a second endoscopy confirming no higher grade of dysplasia in the esophagus, endoscopy is recommended annually until no dysplasia is
detected in 2 consecutive endoscopies. The standard biopsy protocol includes biopsies
of any mucosal irregularities and four-quadrant every 2 cm. HGD will be discussed next.
Symptom Control
Unrelieved Symptoms
Long-term maintenance
BID dosing
Surveillance endoscopy
Regurgitation: Consider
fundoplication
MEDICAL TREATMENT
The mainstay of medical therapy is proton pump inhibitor therapy. The goal of therapy for patients with BE is control of reflux symptoms and healing of accompanying
erosive esophagitis. Symptom control often requires BID dosing (Figure 1-1). Even with
appropriate timing prior to meals, esophageal pH is still abnormal in 25% of patients
with BE.22 Patients with postprandial and supine regurgitation may benefit from metoclopramide prior to a late meal. Additionally, intermittent H2 receptor antagonist use
may be of benefit.
Patients with refractory regurgitation and volume reflux, are candidates for surgical
fundoplication. Currently, this is performed less invasively and with shorter hospital stay
by laparoscopy. Although short term effectiveness is to be expected, a longer term median follow-up of 5 years in 85 BE patients demonstrated recurrent symptoms in 20%.23
The long term symptomatic durability of surgery is a concern, especially in patients with
BE.
Resectional surgery has a definitive role in patients with EAC. It is the only therapy
resulting in long-term cancer-free survival. The long-term survival is excellent for early
stage disease. TNM staging is utilized (ie, tumor, nodal involvement, and distant metastases) (see Appendix A). Endosonography provides the most accurate assessment of
depth of wall invasion and mediastinal involvement can be directly determined with fine
needle aspiration. Intramucosal EAC cancer in the lamina propria and above the muscularis mucosa has less than 5% risk of regional lymph node spread in contrast to submucosal cancer with a 25% risk. With the recognition of the dependence of operative
mortality on the institutional volume of esophagectomy, there has been increased motivation to send patients for surgery to high volume centers.24,25 The role of surgery in the
management of HGD will be discussed below.
MANAGEMENT
OF
The management of HGD is complicated by problems including endoscopic sampling, histologic interpretation, variable natural history, coexistence of unrecognized
EAC, patient comorbidity, and inconsistent institutional expertise (Figure 1-2). HGD is
commonly not visible at endoscopy so that even though a biopsy protocol is systematic,
the specific site involved may not be targeted. Therefore, the first step in managing a
patient with HGD is to repeat the endoscopy using a therapeutic endoscope and a large
Chapter 1
Patient
Lesion
Institution
capacity biopsy forceps to obtain larger samples. Four-quadrant biopsies are performed
every 1 cm. Biopsies from each level are placed in a separate container to help localize
the HGD. Any mucosal irregularity should also be separately biopsied. HGD found in
the biopsy of a nodule should be considered a cancer until proven otherwise. This is the
ideal setting to apply the new technique of endoscopic mucosal resection. This provides
a large sampleusually 1 cmto more effectively stage the disease for therapeutic decision making. The finding of intramucosal cancer could lead to topical (endoscopic) therapy. Invasion of the muscularis mucosa would lead to an esophageal resection in a
patient who is a good surgical candidate because of the risk of regional lymph node
spread.
An expert GI pathologist should then confirm the reading of HGD. At this point, it
is worthwhile to sit down with the patient and his or her partner to discuss the
optionsintensive endoscopic surveillance, endoscopic ablation therapy, or esophagectomy. This decision should be individualized based on the patients age, medical condition, and preferences. A year of surveillance endoscopy every 3 months should not pose
a risk of delayed diagnosis in a patient without mucosal irregularities. The finding of
cancer at any endoscopy usually simplifies decision making. Factors favoring surgery
include younger age, good cardiopulmonary condition, multifocal HGD, recurrently
identified HGD, and the availability of a high volume surgical center. Favoring endoscopic surveillance or therapies include an aged patient, major comorbidity, and local
endoscopic expertise.
Photodynamic therapy using porfimer sodium as the photosensitizer has been
recently approved by the FDA for patients with BE and HGD. A multicenter randomized trial with a 2-year follow-up documented significant improvement in eradication of
HGD (77% vs 39% in the nonendoscopically-treated control group) and development
of EAC (13% vs 28%).26 This option offers no procedural mortality and retained
esophageal function. One third of patients do develop strictures and patients can still
develop EAC. Endoscopic therapy may include a combination of endoscopic mucosal
resection of mucosal irregularities and photodynamic therapy of the entire segment of
BE.
The patient has to weigh the risk of operative mortality and morbidity against the
opportunity for cancer-free survival. In contrast, the patient choosing endoscopic therapy balances the avoidance of procedural mortality and maintenance of esophageal func-
tion for the continuing risk of developing EAC and the need to maintain endoscopic
surveillance. The risk of developing EAC after endoscopic therapy has been documented to continue for as long as 6 years.
Chapter 1
REFERENCES
1. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the
United States. Surg Oncol Clin N Am. 2002;11:235-256.
2. Cameron AJ, Lomboy CT. Barretts esophagus: age, prevalence and extent of columnar
epithelium. Gastroenterology. 1992;103:1241-1245.
3. OConnor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in
Barretts esophagus. Am J Gastroenterol. 1999;94(8):2037-2042.
4. Romero Y, Cameron AJ, Locke GR, et al. Familial aggregation of gastroesophageal
reflux in patients with Barretts esophagus and esophageal adenocarcinoma.
Gastroenterology. 1997;113:1449-1456.
5. Cameron AJ. Barretts esophagus: prevalence and size of hiatal hernia. Am J
Gastroenterol. 1999;94(8):2054-2059.
6. Wakelin DE, Al-Mutawa TS, Wendel CS, et al. A predictive model for length of
Barretts esophagus with hiatal hernia length and duration of esophageal acid exposure.
Gastrointest Endosc. 2003;58:350-355.
7. Shaheen NJ, Crosby MA, Bozymski EM. Is there publication bias in the reporting of
cancer risk of Barretts esophagus? Gastroenterology. 2000;119:333-338.
8. Drewitz DJ, Sampliner RE, Garewal HS. The incidence of adenocarcinoma in Barretts
esophagusa prospective study of 170 patients followed 4.8 years. Am J Gastroenterol.
1997;92(2):212-215.
9. Anderson LA, Murray LJ, Murphy SJ, et al. Mortality in Barretts esophagus: results
from a population based study. Gut. 2003;52:1081-84.
10. VanDerBurgh A, Doos J, Hop WJC, VanBlankenstein M. Esophageal cancer is an
uncommon cause of death in patients with Barretts oesophagus. Gut. 1996;39:5-8.
11. Eloubeide MA, Provenzale D. Clinical and demographic predictors of Barretts esophagus among patients with gastroesophageal reflux disease. J Clin Gastroenterol. 2001;
33(4):306-309.
12. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux
as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340(11):825-831.
10
Chapter 1
32. Wallace MB, Perelman LT, Backman V, et al. Endoscopic detection of dysplasia in
patients with Barretts esophagus using light-scattering spectroscopy. Gastroenterology.
2000;119:677-682.
33. Kendall C, Stone N, Shepherd NA, et al. Raman spectroscopy, a potential tool for the
objective identification and classification of neoplasia in Barretts oesophagus. J Pathol.
2003;200:602-609.
34. Poneros JM, Nishioka NS. Diagnosis of Barretts esophagus using optical coherence
tomography. Gastrointest Endosc Clin N Am. 2003;13:309-323.
35. Shirvani VN, Ouatu-Lascar R, Kaur B, Omary B, Triadafilopoloulos G. Cyclooxygenase
2 expression in Barretts esophagus and adenocarcinoma: ex vivo induction by bile salts
and acid exposure. Gastroenterology. 2000;118:487-496.
36. Buttar NS, Wang KK, Leontovich O, et al. Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barretts esophagus.
Gastroenterology. 2002;122:1101-1112.
37. Corley DA, Kerlikowske K, Verma R, Buffler PA. Protective association of
aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis.
Gastroenterology. 2003;124:47-56.
chapter
Surgical Approaches to
Esophageal Neoplasms
John C. Kucharczuk, MD
INTRODUCTION
Several important factors influence the surgical approach to an esophageal neoplasm. These include the nature of the neoplasm (benign vs malignant), the overall
health of the patient, and the expertise of the surgeon. The intent of this chapter is to
familiarize the reader with the different approaches available for resection of esophageal
neoplasms. Special emphasis will be placed on the expected benefits as well as potential
risk of each operative approach to aide in the dialogue between the gastroenterologist
and surgeon. This dialogue is vital in providing an individual patient with the surgical
approach that is most likely to be safe and effective.
12
Chapter 2
13
14
Chapter 2
Figure 2-3. (A) Typical small esophageal leiomyoma appropriate for extramucosal enucleation. (B) A longitudinal myotomy is performed exposing the leiomyoma. C) The
leiomyoma is gently dissected away from the esophageal mucosa. (D) The myotomy is
closed to prevent pseudodiverticulum formation. (Reprinted from Atlas of Surgery, 2e,
Cameron JL, pp 73-75, Copyright 1994 with permission from Elsevier.) For full color version, see pages CA-II and CA-III of the Color Atlas.
15
uncontrollable bleeding, and very large cervical esophageal lesions should usually be
approached via a left cervical esophagotomy.8
16
Chapter 2
protected throughout the dissection as this will become the major blood supply to the
gastric tube. As dissection is continued along the greater curvature of the stomach, the
short gastric vessels are individually identified and ligated. If there are dense adhesions
in the left upper quadrant, the spleen is at risk for injury and bleeding. On rare occasion, a splenectomy is required. On the lesser curvature side, the left gastric artery is
identified, ligated, and divided. Lymph nodes around the celiac axis are dissected away
and brought up with the mobilized stomach. A Kocher maneuver is performed to
mobilize the duodenum, providing more mobility to the gastric remnant. At this point
the transhiatal dissection is begun.
The hiatus is opened and a Penrose drain is passed around the distal esophagus for
retraction. Although some have referred to this operation as a blind esophagectomy,
this is a misnomer. The transhiatal dissection is actually performed under direct vision
by placing Deaver retractors in the hiatus (Figure 2-5). The first move is to identify the
right and left vagus nerves running along the distal esophagus and to divide them. This
move provides a significant amount of esophageal mobility. Next, the posterior dissection along the spine is performed. All attachments are dissected, clipped, and divided.
Care is taken with the lateral attachments containing the blood supply to the esophagus
directly from the thoracic aorta. Avulsion of branches coming directly from the aorta can
lead to significant bleeding and must be avoided. Often, the patient will experience
hypotension during dissection due to compression of the heart by anteriorly directed
hiatal retraction. In these circumstances, close communication between the surgeon and
the anesthesiologist is vital as simple intermittent relaxation of retraction allows for
recovery of blood pressure. Often the dissection is completed with multiple short
episodes or retraction followed by recovery to minimize the effects of prolonged
hypotension. Finally, the anterior portion of the dissection is performed. In moving
more proximally on the anterior surface of the esophagus, special care must be taken to
avoid injury to the membranous portions of the airway, especially the left mainstem
bronchus. One also needs to be aware of potential disruption of the azygous vein as the
dissection proceeds higher on the right side. Both injuries can be life threatening and
require conversion to a right thoracotomy for repair (note that for the thoracic surgeon,
17
the proximal left mainstem bronchus is approached from the right chest; approaching
through the left chest obstructs access).
Next, a cervical incision is made along the border of the left sternocleidomastoid
muscle. The platysma is divided, the sternocleidomastoid is retracted, and the omohyoid muscle is identified. The omohyoid is divided and dissection is carried down directly onto the prevertebral fascia, which is incised; at this point, a dissecting finger can easily palpate the posterior cervical esophagus. The esophagus is gently mobilized (Figure
2-6). No deep retractors are placed in the incision to avoid damage to the recurrent
laryngeal nerve. The recurrent nerve is identified in the tracheal esophageal groove and
protected throughout the dissection. A Penrose drain is placed around the cervical
esophagus and used for retraction. The esophagus is mobilized from above to meet the
mobilization already completed through the hiatus. Once mobilized, the esophagus is
divided in the neck and the distal esophagus is brought down through the hiatus. The
gastric tube creation is completed in the abdomen with multiple firings of a stapling
device. The resected specimen is oriented and forwarded to pathology. A pyloromyotomy or pyloroplasty is performed to aid in gastric tube emptying since the vagus nerves
have been divided. Finally, the gastric tube is delivered into the neck in an oriented fashion through the bed of the resected esophagus (Figure 2-7). Multiple techniques have
been described for the cervical esophagogastric tube anastomosis. At present, the modified stapled anastomosis17 appears to have the lowest leak rate, about 2% as compared
to sutured techniques, which are as high as 15%. The final reconstruction is shown in
Figure 2-8.
The transhiatal approach can be utilized in the majority of patients with very good
results. The reported hospital mortality rates are under 5% and major morbidity, including hemorrhage, recurrent nerve damage, chylothorax, and tracheal laceration, is less
than 1%.18 Despite concerns regarding the lack of a complete lymph node dissection
with the transhiatal approach, review of the published English literature revealed no difference in the 3 or 5 year survival when comparing transthoracic versus the transhiatal
18
Chapter 2
Figure 2-6. View through the hiatus after the stomach has been mobilized. Retractors are
placed in the hiatus which has been enlarged. This allows for direct visualization of the
lateral attachments that contain the blood supply to the esophagus. A small clip applier
is used to control the vessels prior to division. (Reprinted from Atlas of General Thoracic
Surgery, Kaiser LR, Copyright 1997, with permission from Elsevier.)
Figure 2-7. The gastric tube has been
completed and is supplied by the gastroepiploic artery. It is pulled up orthotopically through the mediastinum
and delivered into the cervical incision for completion of the cervical
esophagogastric anastomosis. (Reproduced with permission from Skinner
DB. Atlas of Esophageal Surgery. New
York: Churchill Livingstone; 1991.)
19
approach; however, the early pulmonary complications appear higher in the transthoracic approach.19
20
Chapter 2
REFERENCES
1. Seremetis MG, Lyons WS, deGuzman VC, Peabody JW Jr. Leiomyomata of the esophagus. An analysis of 838 cases. Cancer. 1976;38:2166-2177.
2. Hatch GF 3rd, Wertheimer-Hatch L, Hatch KF, et al. Tumors of the esophagus. World
J Surg. 2000;24:401-411.
3. Zuccaro G Jr, Rice TW. Tumors of the esophagus. In: Brandt LJ, ed. Clinical Practice of
Gastroenterology. Philadelphia: Churchill Livingstone; 1999:131-134.
21
4. Lee LS, Singhal S, Brinster CJ, et al. Current management of esophageal leiomyoma. J
Am Coll Surg. 2004;198:136-146.
5. Bonavina L, Segalin A, Rosati R, et al. Surgical therapy of esophageal leiomyoma. J Am
Coll Surg. 1995;181:257-262.
6. Hatch GF III, Wertheimer-Hatch L, Hatch KF, et al. Tumors of the esophagus. World J
Surg. 2000;24:401-411.
7. Bardini R, Segalin A, Ruol A, et al. Videothoracoscopic enucleation of esophageal
leiomyoma. Ann Thorac Surg. 1992;54:576-577.
8. Eberlin TJ, et al. Benign schwannoma of the esophagus presenting as a giant fibrovascular polyp. Ann Thorac Surg. 1992;53:343.
9. Orringer MB. Substernal gastric bypass of the excluded esophagusresults of an illadvised operation. Surgery. 1984;96:467.
10. Orringer MB, Sloan H. Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg.
1978;76:643-654.
11. Lewis I. The surgical treatment of carcinoma of the esophagus with special reference to
a new operation for growths of the middle third. Br J Surg. 1946;34:18.
12. McKeown KC. Total three-stage oesphagectomy for cancer of the esophagus. Br J Surg.
1976;51:259.
13. Bolten JS. Teng S. Transthoracic or transhiatal esophagectomy for cancer of the esophagusdoes it matter. Surg Oncol Clin N Am. 2002; 11(2)365-375.
14. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA. Surgical volume and quality of care
for esophageal resection: do high-volume hospitalshavehospitals have fewer complications? Ann Thor Surg. 2003;75(2):337-341.
15. Rizk NP, Bach PB, Schrag D, et al. The impact of complications on outcomes after
resection for esophageal and gastroesophageal junction carcinoma. J Am Coll Surg.
2004; 42-50.
16. Davis PA, Law S, Wong J. Colonic Interposition after esophagectomy for cancer. Arch
Surg. 2003;138(3):303-8.
17. Orringer MB, Marshall B, Iannettoni MD. Eliminating the cervical esophagogastric
anastomotic leak with a side-to-side stapled anastomosis. J Thorac Cardiovasc Surg.
2000;119(2);277-285.
18. Orringer MB, Marshall B, Iannettoni MD. Transhiatal esophagectomy: clinical experience and refinements. Ann Surg. 1999;230(3):392-400.
19. Hulscher JB, Tijissen JG, Obertop H, van Lanschot JJ. Transthoracic versus transhiatal
resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg. 2001;
72(1):306-313.
20. Altorki N, Kent M, Ferrara C, Port J. Three-field lymph node dissection for squamous
cell and adenocarcinoma of the esophagus. Ann Surg. 2002;236:177-183.
21. Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. NEJM.
2002;374(21):1662-1669.
22. Luketich JD, Alvelo-Rivera M, Buenaventura PO, Christie NA, McCaughan JS, Little
VR, Schauer PR, Close JM, Fernando HC. Minimally invasive esophagectomy: outcomes in 222 patients. Ann Surg. 2003:238(4):486-494.
chapter
Approach to Chemotherapy
and Radiation for Gastric
and Esophageal Cancer
Diane Hershock, MD, PhD
INTRODUCTION
Both gastric and esophageal cancers remain amongst the 10 most common cancers
in the world with variations in incidence and survival based on geographic sites. Gastric
cancer is the second most common tumor worldwide with 60% of cases in developing
countries.1 It appears gastric cancer worldwide is second to lung cancer with a reported
798, 300 new cases in 1990 and is more common than breast and colorectal cancers in
other areas of the world. The highest incidences are in Japanese men; rates are also
increased in Eastern Europe, South America, and Eastern Asia, but lower in the United
States, North Africa, and Australia.1 Esophageal cancer is the seventh leading cause of
death in men in the United States and unfortunately 90% of patients diagnosed with
this cancer will die from their disease.2 Metastatic disease is seen in approximately 50%
of patients at the time of diagnosis. The effectiveness of surgery, chemotherapy, radiation therapy, or the combination of the above modalities has been investigated for
decades with varied results. This chapter will discuss the strategies and dilemmas in
treating both gastric and esophageal cancers, which are often included together in many
clinical trials. The reasons for this are similar clinical behavior, histology, and responses
to various chemotherapeutic agents. Additionally, eligibility criteria for clinical trials,
particularly in this country, typically include both cancers.
GASTRIC CANCER
INCIDENCE/EPIDEMIOLOGY
The pattern of occurrence of gastric cancer has changed over the years with population migration. Although it remains the second most common tumor in the world, the
incidence of gastric cancer has declined dramatically since 1930 in developed countries,
particularly the United States.3 This decline may be attributed to reclassification of adenocarcinoma of the gastric cardia and the lower third of the esophagus as gastro-
24
Chapter 3
esophageal junction cancers since both behave in a similar biologic and clinical fashion.
Additionally, there has been a decline in the well-differentiated adenocarcinomas of the
fundus and antrum.4
CLASSIFICATION/PROGNOSTIC INDICATORS
Suspected causative agents in gastric cancer include dietary factors such as poor
nutrition, salted and smoked foods, alcohol, decreased intake of fruits/vegetables, and
nitrates.24,25 Lifestyle issues such as smoking and low socioeconomic status have been
noted. Vitamin E, vitamin C, beta-carotene, selenium, and other micronutrients have
been reported to be protective but data are relatively inconsistent.26,27
Gastroesophageal junction tumors (GEJ) appear to differ significantly in their etiology as compared to gastric cancers. GEJ tumors arise from GERD resulting in esophagitis, gastric metaplasia and BE. It appears also that obese people are at increased risk of
GERD.28 It may be related to increased intra-abdominal pressure from an increased
body mass index. Tobacco, alcohol, and low socioeconomic status may also be risk factors for GES tumors.29,30
Helicobacter pylori (H. Pylori) has been investigated as an etiological agent in nonGEJ gastric cancer. Helicobacter has been listed as a known carcinogen and has been postulated initially as inducing an inflammatory response that leads to the release of proinflammatory cytokines, many of which cause a reactive oxygen species, leading to
oxidative stress and a milieu conducive to carcinogen development.31-33 Controversy
remains, however, and it may be the cytotoxin, CagA, causing an increased risk. Those
25
individuals positive for both CagA and Helicobacter appear to have an increased risk of
developing gastric cancer.34-36
Histologically, gastric cancers are classified as diffuse or intestinal. Diffuse gastric cells
are small cells that grow diffusely into the surrounding gastric tissue; intestinal type is
more glandular in appearance and is delimited. Linitis plastica is an antomicpathological entity due to diffuse infiltration by the small, diffuse type which appears rigid and
tubular. The diffuse type appears to have an overall worse prognosis even after TMN
staging is considered. WHO classifies gastric cancer cells histologically into mucinous,
tubular, signet ring, and papillary.37
Immunohistochemistry and molecular prognostic indicators are now coming into
investigation. p53 has been evaluated to the greatest extent. One study reported an
inverse relationship between p53 protein overexpression and survival, but a multivariate
analysis was not performed and only 120/427 patients were evaluable.38-40 Serum antibodies to p53 were measured in 501 patients with gastric cancer and were associated
with a poor prognosis, lymph node metastasis, and poorly differentiated nuclear grade.41
Other prognostic markers include Bcl-2, c-met, c-erb, vascular endothelial growth factor (VEGF), urokinase plasminogen activator, DNA ploidy, CD44 expression, and
nm23.42-50 Large trials investigating their utility in predicting outcome have not been
done.
In general, gastric cancers have a poor outcome and thus prognosis. The overall survival rate, particularly in the United States, has been reported to be 37%, 18%, 11% and
5% for Stage II, IIIA, IIIB, and IV diseases.51 The survival rates are thought to be so
poor in this country due to late detection. However, rates are similar to European data.
In Japan, Stage IA and IB cancers are more frequently found due to screening programs
and thus the five year survival is reported to be 75%.52-53
Until the last decade, the management of gastric cancer for curative intent was with
surgery; chemotherapy and radiotherapy were generally used for palliation. With newer
chemotherapy and radiotherapy techniques, multimodality approaches are now coming
into existence, with newer data suggesting curative benefit. These therapies will be discussed subsequently.
SURGICAL MANAGEMENT
Surgery has been the mainstay of treatment of gastric cancers for curative intent for
the past century. Debate now exists as to the optimum surgical technique in terms of
total vs subtotal gastrectomy, the extensive lymph node dissection done by Japanese surgeons, and the approach to early gastric cancers.
Two randomized trials in Western Europe were designed to address the question of
total vs subtotal gastrectomy. The French Association for Surgical Research randomized
169 patients with adenocarcinoma to total or subtotal gastrectomy.54 The 5-year survival
rate in both groups was the same at 48% with a higher surgical mortality in the subtotal group. A second study conducted by the Italian Gastrointestinal Tumor Study Group
randomized 624 patients with gastric cancer in the distal half of the stomach to subtotal or total gastrectomy.55 Again, 5-year survival rates were similar at 65% and 62%
respectively, but those with subtotal gastrectomy and lymphadenectomy of compartments one and two had a better quality of life and nutritional status.
Lymph node metastasis clearly affects prognosis in gastric cancer. The issue of performing extensive lymph node dissection when performing a gastrectomy has been a
huge debate over the past 30 years.56-59 Removal of the perigastric lymph nodes only is
26
Chapter 3
SYSTEMIC CHEMOTHERAPY
In order to understand the current literature in the neoadjuvant and adjuvant settings, a review of chemotherapy agents in the metastatic disease will be discussed. As
with many cancers, gastric cancer was thought to be relatively insensitive to chemotherapy. Most agents used in gastric cancer did not induce a complete response as is the
norm in most cancers. Responses in general were poor, and time to progression was
short. Table 3-1 contains a list of single agent drugs with some activity in gastric cancer.
27
Table 3-1
Patients Studied
(First Line/Second Line)
Responses (%)
392
211
14/115
14
124/78
28
29
55
21
30
36/20
21
17/17
11
7
20
Adapted from Roth AD. Curative treatment of gastric cancer: towards a multidisciplinary
approach? Critical Rev in Oncology Hematology. 2003;46:59-100.
The standard first line salvage regimen through the 1980s was FAM for 5-fluorouracil (5-FU), adriamycin and mitomycin C with an initial reported response rate of
50%.77 This combination, though, was subsequently evaluated by multiple investigators
with less convincing response rates.78-81 Randomized trials subsequently followed, the
largest from the European Organization for Research and Treatment of Cancer
(EORTC). Response rates were reported at 9% with a median survival of 6.5 months.82
In the United States, 252 patients were evaluated comparing 5-FU to FAM as well as
other combinations such as CCNU with FAM and low dose cisplatin with 5-FU and
adriamycin.83 None of these combination agents had any advantage.
Attempts to evaluate more aggressive multiple drug combinations were then pursued. FAMTX or the addition of high dose methotrexate to the standard FAM with leucovorin rescue (LV) was compared to FAM alone.82,84,85 FAM again demonstrated a 9%
response compared to 42% with FAMTX; additionally, a median survival of 29 vs 42
weeks with FAMTX was reported. Thus, FAMTX became the standard of care in
metastatic gastric cancer.
Cisplatin (CDDP) in single agent trials had a mediocre response and thus was subsequently studied. Synergy was known to exist between 5-FU and cisplatin and thus trials were designed to exploit this. Regimens such as FUP (5-FU/CDDP), FLP (5FU/LV/CDDP), PELF (CDDP/Epirubicin/LV/5-FU), and ELF (Etoposide/LV/5-FU)
had responses ranging from 37% to 72% with duration of response reported between 4
and 7 months (see Table 3-2).86-91
Phase III trials compared the above regimens to each other. FAM vs 5-FU vs FUP,
which is 5-FU/CDDP, suggested responses of 25%, 51%, and 26% in 166 patients with
measurable disease.93 Time to progression was 21 weeks in the FUP arm compared to
12 weeks for either 5-FU or FAM; however, no statistical significance was found. FAM
was compared to PELF with PELF nonstatistically superior in terms of median time to
28
Chapter 3
Table 3-2
Patients
Response Rate
(RR%)
Survival
(Months)
FAMTX
FUP/FLP
PELF
ELF
317
226
85
63
25
44
43
49
6 to 1084-85,92
8 to 1189,93
891
7 to 1188
progression.91 FAMTX was compared to etoposide, adriamycin, and CDDP (EAP) but
suspended due to unacceptable toxicities.92 The EORTC did a multicenter trial comparing FAMTX, FUP and ELF with responses of 12%, 20%, and 9% respectively with
median survivals of 6.7 to 7.2 months.94 Thus, other drugs found their way into therapy in the metastatic setting.
Continuous infusion 5-FU was investigated based on new knowledge of the pharmacokinetics of the drug and method of administration. Bolus 5-FU appears to favor
binding of the drug into RNA, leading to disruption of maturation of nuclear RNA.
Infusional 5-FU on the other hand favors inhibition of thymidylate synthetase (TS) after
its conversion to 5-fluoro-2-deoxy-5 monophosphate (FdUMP) and thus DNA synthesis. Based on data derived from colon cancer, response rates with the infusional form
were noted to be 32% vs 7% for the bolus arm with no survival advantage to either
arm.95 This led to the evolution of ECF or 5-FU continuous infusion with epirubicin
and CDDP with responses of 71%.96-98 Responses compared to FAMTX were 45% vs
21% with a superior median time to progression of 7.4 vs 3.4 months and a significant
survival advantage (8.9 vs 5.7 months).99
Many of the above regimens have been given on the every 3 to 4 week cycling due
to various toxicities. High dose weekly regimens have been investigated such as EPFL or
epirubicin, CDDP, 5-FU, and LV with 62% response rates but unacceptable neutropenia.100 Another study looked at an additional drug, etoposide with the EPFL regimen
with responses of 71% again with considerable toxicity.101
Other active agents have now been looked at in the past 5 to 10 years, including the
taxanes-paclitaxel or docetaxel as well as irinotecan (CPT11) as single agents and in
combination. Other newer agents include Oxaliplatin and Xeloda or oral 5-FU.
Paclitaxel or Taxol (Bristol-Myers Squibb, New York, NY) is an antimitotic agent
that binds microtubules that promote microtubular assembly and stabilize microtubules.102 Taxol as a single agent in gastric cancer has reported response rates of 5 to
17%, as well as 20%.103-105 Taxol in combination with 5-FU, or CDDP, or both have
reported responses of 32% to 64% with time to progression of 4 to 8 months and overall median survival from 6 to 11 months.106-109 Paclitaxel with CDDP and etoposide was
evaluated in 25 chemotherapy nave patients with locally advanced, unresectable, or
metastatic gastric and esophageal cancer with a high response rate; both adenocarcinoma and squamous cell were included and thus differences may have been due to histology as well as the inclusion of locally advanced but nonmetastatic patients.110
29
ADJUVANT CHEMOTHERAPY
It is well known that despite complete resections for curative intent, locoregional failures have been noted in gastric cancers. Patients can subsequently present with local disease, peritoneal carcinomatosis, or distant disease. Over the years, various neoadjuvant
and adjuvant strategies have been investigated with the intent of treating microscopic
residual disease postsurgery. Meta analysis have suggested benefit to adjuvant
30
Chapter 3
chemotherapy but more recently, the Intergroup 0116 Study reported information with
improved disease-free and overall survival with combination chemoradiotherapy, which
will be discussed in detail subsquently.127
Initial adjuvant chemotherapy trials revealed less than encouraging data. The
Gastrointestinal Tumor Study Group published a positive trial looking at methylCCNU with 5-FU.128 The median survival was reported at 33 months in those who did
not receive postoperative chemotherapy; the median survival in the chemotherapy arm
was more than 4 years. Unfortunately, these results were not confirmed in a larger trial
setting. Mitomycin C was used by the Japanese Surgical Adjuvant Chemotherapy Group
with various dosing schedules; all trials but one were negative.129
Multiple adjuvant trials have been conducted in Japan; unfortunately, few had surgery alone as a control arm and many of these trials merely compared chemotherapy regimens. Several studies in the United States and Europe looked at regimens such as FAM
and did compare surgery alone as the control; most were negative trials with sufficient
numbers of patients enrolled.
Several meta-analyses have attempted to prove or disprove the use of adjuvant
chemotherapy by creating larger sample sizes. One study published by the Dutch, based
on 14 randomized trials including 2096 patients, did not suggest a survival advantage
from adjuvant chemotherapy.130 Another meta-analysis in 1999 analyzed 13 trials
demonstrating a small but significant survival benefit for patients receiving postoperative chemotherapy.131 There was an absolute risk reduction from 65 to 61% in relapsefree survival after postoperative chemotherapy. A third meta-analysis based on 20 trials
was published by the Gruppo Italiano per lo Studio dei Carcinomi dellApparato
Digerente (GISCAD). Patients received either 5-FU alone or in combination with adriamycin-based chemotherapy with a reduced risk of death of 18% in the chemotherapy
arm.132 This translated to an overall absolute risk reduction of about 4% in 5-year survival.
Thus, from the above trials and published meta-analyses, many negative trials appear
to exist in the adjuvant setting, none of which were powered to show a 5-year survival
advantage. The few positive trials published were too small in sample size to suggest
validity. The effectiveness of adjuvant chemotherapy alone remains controversial at best;
if a benefit exists in terms of survival, it needs to be evaluated in terms of acceptable toxicity and quality of life.
RADIOTHERAPY
The rationale for adjuvant radiation therapy is similar to chemotherapy; it is used to
decrease the locoregional relapse rate observed after surgery. Based on tissue
tolerance/toxicity to the local area, such as spinal cord, pancreas, small bowel, liver, and
kidneys, the dose of external beam is limited to 45 Gy.133-134
Many of the radiation studies published in the literature were retrospective in nature
and had methods, issues making evaluation and interpretation difficulty. Issues include
underpowered studies, variations in doses of radiation, no control arm (no treatment),
or inadequate randomization. Only one study using chemotherapy in one arm, radiation in another arm, and surgery alone suggested a benefit from radiation.135 In general,
none of the studies suggested a true survival benefit to radiation alone in the adjuvant
setting.
Intraoperative radiation therapy (IORT) is another modality in which a single dose
of radiation is given directly into the operative field at the time of surgery. The initial
31
theory is based on immediate local treatment of any residual microscopic disease that
may remain in that operative bed, sparing normal tissue from field effects. There are
technical difficulties associated with this type of treatment in that a radiation setup must
be available in the sterile arena of the operative suite, which is not necessarily practical.
The Japanese have conducted several nonrandomized trials in which single doses of
30 to 35 Gy were given to the local area, particularly lymph nodes less than 3 cm; if no
nodes were noted, 28 Gy was given to the operative bed alone.136,137 Further data suggested that doses of 30 to 40 Gy decreased primary tumor size but was insufficient to
eradicate all disease.138 Many of the above studies were feasibility studies; little has been
determined regarding improvement in overall survival. Patterns of local recurrence after
this type of radiation were assessed and felt to be of little to no benefit if surgical margins were positive.139
Two randomized trials in the United States have been published with varied results.
One study conducted at the National Cancer Institute (NCI) compared surgery alone
in Stage I/II disease vs single dose 50 Gy/surgery in those with Stage III/IV disease.140
Forty-one patients were evaluable; locoregional failure occurred in 44% of IORT
patients and 92% of surgery alone patients. No difference in median survival was documented. The second study reviewed 211 patients with no comment on staging or type
of surgical resection performed; patients were randomized at the time of the procedure.141 This report suggested a significant survival benefit but again, major flaws appear
to exist based on the information published.
Based on local and regional recurrence rates at the tumor bed, the anastomosis site
or regional lymph nodes 40% to 65% of the time in those undergoing surgery for curative resection and the unsatisfying data from adjuvant chemotherapy and radiation trials alone, the SWOG/ECOG/RTOG/CALGB/NCCTG cooperative groups designed
the landmark Intergroup 0116 trial.127 This study demonstrated that adjuvant chemoradiotherapy after surgical resection of high-risk localized gastric cancer resulted in an
improved relapse-free survival from 31% to 48% at 3 years. Overall survival at 3 years
was 52% vs 41%. The treatment arm consisted of the Mayo Clinic method of administration of one cycle of 5-FU/LV (425 mg/m2 plus 20 mg/m2 LV daily times 5 days) followed 1 month later by combined 5-FU/LV days 1 to 4 as above with 180 cGy/day of
external beam radiation and the same chemotherapy again in the last week of radiation
for 3 days. The total fraction of radiation was 4500 Gy. Two subsequent cycles of adjuvant chemotherapy alone at the above doses were given thereafter. There was a 44% relative improvement in relapse-free survival and a 28% relative improvement in survival
with median survival of 42 and 27 months, respectively. Radiotherapy techniques were
closely monitored due to variations in target volume. Flaws in this study included the
initial requirement that all patients have D2 resections; 54% of the patients ultimately
only received a D1 resection, which is less than standard. Thus, the issue of benefit from
chemoradiation may have been because of inadequate surgery.
NEOADJUVANT CHEMOTHERAPY
The rationale for preoperative neoadjuvant chemotherapy is based on treating an
intact vascular tumor with no reason for treatment-induced resistance for a better
response rate de novo. There have always been arguments that responses are improved
with the fibrotic remodeling of the tumor bed following surgical removal. Additionally,
surgery may be less invasive if an adequate response occurs prior to that procedure and
thus issues of organ preservation are considered.
32
Chapter 3
There have been extensive debates in the literature as to the utility of neoadjuvant
chemotherapy in the treatment of any cancer. In locoregionally advanced rectal cancers,
neoadjuvant radiotherapy has been considered superior to surgery alone or followed by
adjuvant radiotherapy in terms of risk of locoregional relapse.142,143 Neoadjuvant
chemotherapy is also used in inflammatory breast cancer as well as osteosarcoma.144,145
Arguments exist about its use in esophageal cancer which will be discussed later in this
chapter.
There are several issues as to the use of neoadjuvant chemotherapy in gastric cancer.
The decision for adjuvant treatment is often made based on the final pathological diagnosis and features postoperatively; the decision to perform or not perform a preoperative intervention relies on clinical staging, which is not as accurately known without the
benefit of surgery. The primary tumor extension is not necessarily obvious on routine
CT scans or MRIs and the invaded lymph nodes may not be detectable on conventional scans. Endoscopic ultrasonography is the only option for estimating the T and N stage
with a known diagnostic accuracy of 70%.146 Peritoneal carcinomatosis is also difficult
to determine without surgical exploration and thus many trials investigating neoadjuvant therapy have suggested laparoscopic staging.
Few randomized studies have been done comparing neoadjuvant chemotherapy followed by surgery vs surgery alone. One study looked at 107 patients after receiving 2 to
3 cycles of CDDP/VP16/5-FU with surgery vs surgery alone.147 A higher curative resection rate was noted in the investigative arm, with evidence of downstaging after
chemotherapy. As with many studies, though, no survival advantage was reported.
Another randomized trial looked at 2 to 4 cycles of FAMTX/surgery vs surgery alone.148
Fifty-nine patients were studied and the study was ultimately suspended due to toxicity
and poor accrual.
Two randomized trials with neoadjuvant radiation have been published as well.
Three hundred seventeen patients with adenocarcinoma of the cardia were randomized
to radiation therapy/surgery vs surgery alone.149 Forty Gy were administered as 2
Gy/day; surgery was done 2 to 4 weeks later. The reported 5-year survival was 30% vs
20% in the XRT/surgery arm vs surgery. Issues with this study include inadequate staging and the variation in the radiation fields. Another randomized study investigated
XRT/surgery, XRT/local hyperthermia followed by surgery vs surgery alone.150 Again,
20 Gy were given. The 5-year survival rates were 45%, 52%, and 30%, respectively.
The MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, a UK-driven
trial, is investigating the role of pre- and postoperative epirubicin, CDDP and 5-FU
chemotherapy in combination with surgery compared with surgery alone; results are
pending. The EORTC is comparing neoadjuvant systemic therapy with surgery vs surgery alone using weekly CDDP and high dose 5-FU/LV. The French have a similar trial
to the EORTC using infusional 5-FU/CDDP every 3 to 4 weeks. Taxotere with 5FU/CDDP is currently in trial in Italy with 4 neoadjuvant cycles followed by surgery.
MULTIMODALITY THERAPY
The treatment of gastric cancer with potential curative resection has become a question of multidisciplinary management. The roles of surgery, radiation, and chemotherapy and their sequence in treatment are still evolving. New treatment regimens based on
novel cytotoxic agents such as docetaxel, paclitaxel, irinotecan, and biologic agents such
as epidermal growth factor receptor inhibitors and antiangiogenesis may find a role in
the management of gastric cancer, either in the neoadjuvant, adjuvant, or combined
33
modality setting. The limited benefit from adjuvant therapy in many trials to date might
be due to residual tumor burden after surgery, delay in the administration of chemotherapy, insufficient activity of current chemotherapy, inadequate sample sizes of treatable
patients, or the need for better local therapies with combination radiation/chemotherapy. Optimal surgical intervention needs to be better defined as well. Thus, much work
remains in determining the best strategies for the treatment of gastric cancer.
ESOPHAGEAL CANCER
INCIDENCE/EPIDEMIOLOGY
Carcinoma of the esophagus, including the gastroesophageal junction, remains relatively uncommon in the United States, with approximately 13,000 new cases and almost
an equal number of deaths in 2003.151 As with gastric cancer, surgery has generally been
considered the standard of care for local regionally confined esophageal cancer; the survival, though, has remained poor, with 6% to 24% of patients in the Western world alive
at 5 years.152 The Japanese report 5-year survival rates around 24% as well.153 The lifetime risk of developing this cancer is 0.8% for men and 0.3% for women with risk
increasing with age.154-155 In the United States, Black men are more affected than White
males and is the seventh leading cause of cancer death; it is the sixth leading cause worldwide.156
PATHOGENESIS
There are 2 major histological classifications of esophageal cancer; 90% are either
squamous cell or adenocarcinomas.155 Less than 10% are of other subtypes such as GI
stromal tumors, lymphomas, carcinoids, or melanoma. Squamous cell carcinomas are
generally noted in the middle to lower third of the esophagus whereas adenocarcinomas
are located predominantly in the distal esophagus.155,157 The cervical esophagus generally involves squamous cell histology and is usually treated in a similar fashion to those of
the head/neck region.
The pathogenesis remains uncertain, and epidemiologic studies have investigated
potential causes for the rise in esophageal cancer. Data suggest risk factors such as smoking, oxidants, reflux (which causes inflammation), and esophagitis. This will be discussed subsequently. More than 50% of patients at the time of diagnosis have locally
advanced unresectable disease or distant metastatic disease. Fourteen percent to 21% of
T1b or submucosal lesions and 38% to 60% of T2 lesions metastasize to regional lymph
nodes.
Smoking remains a significant risk factor for both squamous cell carcenoma and adenocarcinoma. The inhalation and ingestion of tobacco carcinogens, particularly
nitrosamines, from direct contact with the mucosa of the esophagus and risk correlates
with the number and duration of cigarettes smoked.158,159 Both subtypes can be seen in
patients with prior cancers treated with radiation such as those with a history of primary
breast, non-Hodgkins and Hodgkins lymphoma and lung cancers. These generally
occur more than 10 years from primary radiotherapy.160
The initial cause of SC carcinoma may be related to chronic surface irritation and
inflammation. Leading agents of causality include alcohol, tobacco, and the incidences
with the combination of alcohol/tobacco. Ninety percent of cases worldwide are associ-
34
Chapter 3
ated with alcohol and/or tobacco etiologies.159 This is the same association as with head
and neck cancers. In fact 1% to 2% of those with esophageal cancer have head and neck
cancer as well.161 Additionally, other irritants can include esophageal diverticuli with
retained bacterial decomposition, which release local chemical irritants, and achalasia.162
Caustic fluids and lye can initiate this cancer as can the chronic consumption of very hot
beverages.163,164 Generally, squamous cell histology is linked to a lower socioeconomic
status.159 Nutritional deficiencies were linked to this cancer in the past but diseases such
as Plummer-Vinson syndrome, characterized by dysphagia, iron-deficiency anemia, and
esophageal webs, is now rare worldwide. There is only one recognized familial syndrome
that predisposes patients to squamous cell esophageal cancernonepidermolytic palmoplantar keratoderma (tylosis).165 This is a rare autosomal dominant disorder defined
by a genetic abnormality at chromosome 17q25. It is diagnosed in those with hyperkeratosis of the palms and soles and thickening of the oral mucosa. Lifetime risk of developing this disease in those affected is 95% by age 70.166
There are several risk factors associated with the development of adenocarcinoma,
which has increased in incidence to almost epidemic numbers in the United States. In
fact, during the 1990s, this had become the predominant histology for esophageal cancer in this country.167 The reason for this may be related to chronic reflux (GERD), a
cause of BE. Those people with recurrent symptoms of reflux appear to have an 8-fold
increase in risk of esophageal cancer.168 Other factors which suggest risk include hiatal
hernia; ulcers; frequent use of H2 blockers and drugs that relax the gastroesophageal
sphincter, such as anticholingergics, aminophylline, and beta blockers.169-170
There is ongoing debate as to the role of H. pylori in the development of esophageal
cancer. Certain strains of H. pylori, in particular those that are positive for the CagA protein, may decrease the risk of severe GERD and thus be protective against esophageal
cancer development.171-173 The literature suggests that H. pylori infection leads to
atrophic gastritis and reduced gastric acidity and a decline in infection by this bacteria
may actually lead to increased GERD, BE, and esophageal cancer.174
Another risk factor for adenocarcinoma of the esophagus is obesity.158,170 The basis
for this is increased intra-abdominal pressure leading to chronic GERD. Again, there is
little data to support this etiology but there is literature suggesting this mechanism as a
viable agent in women.175,176
BE has been found in 5 to 8% of people with GERD.177 Changes in the epithelium
have been histologically documented with replacement of stratified squamous cell
epithelium with specialized columnar epithelium similar to that in the intestine/stomach areas. Mutations may develop within this tissue, leading to dysplasia. The risk of
neoplastic transformation in patients with BE has been reported at 0.5%.178 Frequent
chromosomal aberrations have been noted although not distinguished as definitive causes of transformation to esophageal cancer in those with BE. Cancers that have arisen
from BE have chromosomal losses in 4q, 5q, 9p, and 18q and gains in 8q, 17q, and
20q.179-181 The gene products that may be involved in the development of this cancer
include COX-2, Bcl-2, p53, p16, p27, cyclin D1, retinoblastoma protein, epidermal
growth factor and receptor, erb-b2, E-cadherin, catenin, and catenin.181-188
PREVENTION/SURVEILLANCE/PROGNOSTIC INDICATORS
Tobacco and alcohol use are major risk factors in the development of squamous cell
esophageal cancers; cessation of tobacco and alcohol do significantly decrease risk of this
cancer.189 This, however, does not apply to adenocarcinoma development. Fresh fruit
35
SURGICAL MANAGEMENT
Localized esophageal cancer is resected and is covered in more surgical detail in
Chapter 2. The right transthoracic approach combines a laparotomy and right-sided
thoractomy leading to an esophagogastric anastomosis either in the upper chest (the
Ivor-Lewis) or in the neck (the three-field technique). A laparotomy with blunt dissection of the thoracic esophagus and anastomosis in the neck is the transhiatal approach.
Greater morbidity and mortality exists when using the transthoracic approach due to
cardiopulmonary complications. However, the tumor is better visualized and the lymphatics are more thoroughly dissected. The Ivor-Lewis technique places the patient at an
even higher risk of anastomotic leak into the chest. Although no trial has demonstrated
a significant difference in overall survival, the transhiatal approach has a lower rate of
perioperative complications and lower incidence of a thoracic duct leak.199-201 Patients
undergoing surgery as the only method of treatment independent of stage had a median survival rate of 13 to 19 months, a 2-year survival rate of 35% to 42%, and a 5-year
survival rate of 15% to 24%.202
RADIOTHERAPY
The use of radiotherapy as an alternative to surgery was evaluated in patients found
to be poor surgical risks. A review of noncontrolled patients treated with radiotherapy
alone to doses of 5000 to 6800 cGy demonstrated survival data similar to that with surgery alone.203 There appears to be less perioperative morbidity but the effectiveness of
this modality is questionable. Primary radiotherapy alone does not appear to be a successful mode for palliation as compared to surgery. It does not provide significant relief
of dysphagia/odynophagia and has a real risk of local complications independent of
recurrence such as esophagotracheal fistula development.
Radiation, whether given either preoperatively or postoperatively has, to date, not
demonstrated a survival advantage. Six randomized trials involving more than 100
36
Chapter 3
patients have been reported comparing preoperative radiotherapy followed by immediate surgery. Patients received probably inadequate dosing ranging from 2000 to 4000
cGy and the predominant histology reported was squamous cell; no survival advantage
was noted.204 Adjuvant or postoperative radiotherapy has also failed to improve survival.
Detrimental effects on survival have been noted except in the setting of recurrence rates
for node-negative patients.205,206 RTOG 8501, in which radiation was given in combination with chemotherapy, was reported to have a significant advantage over radiation
alone.207 Thus, chemotherapy may play a role in management of esophageal cancer and
will be discussed subsequently.
SYSTEMIC CHEMOTHERAPY
Currently available chemotherapy agents have modest activity in esophageal cancer.
The traditional active agents have included CDDP, 5-FU, and mitomycin with response
rates of 15% to 28% as single agents. Initial combination agents in the metastatic setting included CDDP, bleomycin and vindesine with reported responses of 33% and
29% in two respective studies.208-209 The most commonly used combination regimen
has included 5-FU and CDDP with reported responses of 50% to 60% with a toxicity
profile including myelosuppression and mucositis.210-212 This combination is considered
standard based on common practice in the community, synergism between the 2
agents, and radio-sensitizing properties.213-215 Only one trial has compared single agent
CDDP to CDDP/5-FU in a phase II setting with a higher response rate in the combined
arm of 35% and median survival of 33 weeks.216 The CDDP arm reported responses of
19% with a median survival of 28 weeks which was not statistically different. Patients
included in this trial were those with esophageal, GEJ, and gastric cancer of either adenocarcinoma or squamous cell histology. In GEJ and gastric adenocarcinoma, a trial was
published included epirubicin (E) combined with a protracted, 6-week infusion of 5FU/CDDP known as the ECF regimen and compared to 5-FU/doxorubicin and
methotrexate (FAMTX).217 The median survival in the ECF arm was 8.9 months compared to 5.7 months for FAMTX with a response rate of 45% vs 21% and less toxicity.
As described previously, another trial in GEJ/gastric cancer compared CDDP with 5-day
infusional 5-FU to FAMTX or etoposide, leucovorin, and 5-FU (ELF) with responses
of 10% to 20% and a median survival of less than 8 months.94 Thus, controversy
remains as to the benefit of CDDP/5-FU or in combination with other agents.
Thus, newer agents such as paclitaxel and irinotecan (CPT11) have been used in
combination with CDDP or 5-FU or as single agents in the metastatic setting.
Responses of 15 to 30% have been noted with either 5-FU or CDDP.218-225 In general
as previously explained, chemotherapy is essentially used for palliation of symptoms
with responses to chemotherapy lasting several months, with little influence on overall
survival. Thus, the therapeutic benefit of combination chemotherapy with its associated
toxicity must be weighed against single agent regimens.
Paclitaxel is a very active agent, alone and in combinations, for esophageal cancer.
Initially, paclitaxel was given as a 24-hour infusion at a dose of 250 mg/m2 every 3 weeks
with granulocyte support; response rates were reported at 32% in either squamous or
adenocarcinoma.226 Three hour infusional paclitaxel, which is the standard method of
administration, has not been tested as a single agent in this cancer. Weekly paclitaxel has
been demonstrated in a multicenter national trial to have a 17% response rate in
chemotherapy nave patients.227 Docetaxel as mentioned in the gastric cancer section has
been used as a single agent every 3 weeks in gastric cancer; 8 patients on that study had
esophageal cancer with a response rate of 25%.228
37
Paclitaxel has also been investigated in combination trials. In a phase II, multicenter
trial, paclitaxel was given over 3 hours with infusional 5-FU over 96 hours and CDDP
every 28 days in patients with either squamous or adenocarcinoma of the esophagus
with a reported 48% response rate.229 Significant toxicity was reported. Twenty-four
hour infusional paclitaxel was evaluated with CDDP and no 5-FU with less toxicity and
an overall response rate of 44%.230 Biweekly scheduling of paclitaxel and CDDP has
been reported from Europe where 3 hour paclitaxel is given with CDDP every 14
days.231 Forty percent responses were noted with less myelosuppression and neurotoxicity. Increased doses of paclitaxel to 200mg/m2 biweekly with CDDP rendered a 52%
objective response rate.232 Carboplatin (AUC5) with 3-hour infusional paclitaxel (200
mg/m2) every 3 weeks has been reported with an approximate 40% response rate.233
Another active drug is the topoisomerase II inhibitor, irinotecan or CPT-11. Single
agent use on a weekly schedule has reported response rates of 15%.234,235 A recently published phase II trial from New York with CDDP 30 mg/m2 and CPT-11 65 mg/m2
weekly for 4 weeks demonstrated a 57% response rate with myelosuppression as the rate
limiting factor.236 Patients quality of life appeared improved, with less dysphagia reported. Studies are ongoing looking at alterations in the dosing schedule to weekly for 2
weeks vs 4 weekly therapies. CPT-11 has been used with mitomycin C and also in a randomized phase II trial comparing it to infusional 5-FU/CPT-11 with CDDP/CPT11.237,238 The CDDP/CPT-11 combination is now being investigated in the combined
modality setting with radiation.
Other active drugs in metastatic esophageal cancer include the vinca alkaloid,
vinorelbine, and a new platinum agent, nedaplatin. Vinorelbine as a single agent at 25
mg/m2 weekly has reported response rates of 20%.239 Nedaplatin is being investigated
in Japan in those with metastatic squamous cell with reported single agent responses of
52% but dose limited by thrombocytopenia.240 Gemcitabine and oxaliplatin are also
being investigated in this disease as with gastric cancer.241-245
NEOADJUVANT CHEMOTHERAPY
The role of preoperative chemotherapy alone has been investigated in 2 multicenter
trials.246,247 Both studies used CDDP/5-FU as the chemotherapy regimen. The first
study conducted in North America showed no benefit, with 35% of patients alive at 2
years who received chemotherapy/surgery compared to 37% of patients who underwent
surgery alone. A similar British study revealed a 34% response rate for surgery alone
compared to 43% in the chemotherapy/surgery arm. The differences in these studies
include more intensive chemotherapy in the American arm, delaying surgery as well as
staging prechemotherapy CT scans.
38
Chapter 3
Table 3-3
Nygaard, et al249
S
41
CRS
47
LePrise, et al250
S
41
CRS
41
Apinop, et al251
S
34
CRS
35
Walsh, et al248
S
55
CRS
58
Bosset, et al252
S
139
CRC
143
Law, et al253
S
30
CRS
30
Urba, et al254
S
50
CRS
50
Burmeister, et al255
S
128
CRS
128
Diagnosis Chemo
(cGy)
Radiation
Months
3 Year
Survival
(%)
SCC
CDDP/
Bleomycin
3500
9
17
SCC
CDDP/5-FU 2000
10
10
14
19
SCC
CDDP/5-FU 4000
7
10
20
26
CDDP/5-FU 4000
11
16
6*
32
SCC
CDDP
3700
19
19
3
39
SCC
CDDP/5-FU 4000
27
26
SCC/A
CDDP/5-FU/ 4500
Vinblastine
18
17
16
30
SCC/A
CDDP/5-FU 3500
22
19
from historical controls. Thus, 6 of the above trials were negative; one was questionably
positive.248-255 The Nygaard trial used one chemotherapy agent other than 5-FU
(bleomycin) with no significant difference in either arm.249 Squamous cell histology
alone was looked at in the trial by Bosset, et al with CDDP at 80 mg/m2 given 2 days
prior to the initiation of radiotherapy; median follow-up of 55 months revealed no survival differences.252 Urba et al employed three chemotherapy drugs, CDDP/5-FU and
39
TARGETED THERAPIES
Because of the significant challenge of treating esophageal cancer and the less than
satisfying outcomes to chemotherapy, radiation, surgery, or the combination, novel
molecular targets may play a greater role in treatment. Additionally, markers assessing
chemo- or radiotherapy resistance may help tailor treatment.
As mentioned in the section on gastric cancer, growth factor pathway inhibitors,
inhibitors of tyrosine kinase involved in signaling and antiangiogenesis inhibitors may
take on a greater role in this cancer as well. The monoclonal antibody, C225, which is
an EGF-R inhibitor, has synergy with both chemotherapy and radiotherapy in phase I
and II trials in head/neck squamous cell cancer and colon cancer and may have a role in
esophageal cancer as well.259,260 OSI 774 and ZD 1839 with activity in both lung and
head/neck cancer is being investigated in esophageal cancer.
Markers of resistance to chemotherapy are also under investigation. One potential
marker of response to chemotherapy is the degree of expression of the target enzyme for
5-FU, thymidylate synthase. There may be some correlation between response to 5-FU
in gastric cancer based on thymidylate synthase expression.261 The DNA excision repair
gene, ERCC-1, may be a marker of response to CDDP.261
40
Chapter 3
CONCLUSIONS
Both gastric and esophageal cancers remain a challenge in terms of surgical, radiotherapy, chemotherapy or combined modality therapy. Progress with newer chemotherapy agents and optimal radiotherapy techniques may improve responses to combined
modality treatment with more limited toxicities. The advent of molecular targets may
also play a key role in therapeutic options. Quality of life indices now need to be considered, especially in patients with such a short median life expectancy. Potential markers of response or resistance may come into play as well that may aid in developing targeted therapies to improve patient response.
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256. Herskovic A, Martz K, Al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992;
326:1593-1598.
52
Chapter 3
chapter
Cancers of the esophagus and stomach are relatively uncommon neoplasms, together accounting for an estimated 3% of newly diagnosed cancers in the United States in
2003.1 While the incidence of gastric cancer has seen a decline over the past several
decades, esophageal adenocarcinoma, now the most common type of esophageal cancer, has increased over the past 3 decades. Both cancers, particularly in advanced stages,
have a generally dismal prognosis and 5-year survival, although several advancements
have been made in recent years toward treatment of these diseases. Surgical resection has
historically been a critical component of therapy for localized gastroesophageal neoplasms, and while it remains integral for curative treatment, it finds itself increasingly
in the evolving context of a multimodal approach with adjuvant or neoadjuvant
chemoradiation. This chapter aims to review esophageal and gastric cancer adenocarcinomas separately, outlining the epidemiology, risk factors, and diagnostic and preoperative evaluation of these entities, with particular attention to their management and surgical treatment.
CANCERS
OF THE
ESOPHAGUS
EPIDEMIOLOGY
Nearly 14,000 new cases of esophageal cancer were estimated in the United States
in 2003 and 13,000 esophageal cancer related deaths, making it responsible for an estimated 2% of all cancer deaths.1 The mean age of diagnosis is 67.3 years,2 and while relatively uncommon in patients under 40 years of age, increases in occurrence in an agerelated manner. Squamous cell carcinoma of the esophagus accounted for the majority
of esophageal cancers, but has been supplanted over the past couple of decades by adenocarcinoma. The lifetime risk for esophageal cancer is approximately 2- to 3-fold higher in males than in females, and this risk is nearly doubled when one considers
esophageal adenocarcinomas separately. Esophageal cancer is the seventh most common
54
Chapter 4
cause of cancer death in United States men, accounting for an estimated 4% of all cancer deaths in this population.1 With regard to race, esophageal squamous cell cancers are
more common (approximately 5-fold) in Blacks in the United States whereas adenocarcinoma occurs more frequently in Whites. Other malignancies of the esophagus include
leiomyosarcoma, lymphoma, small cell cancer, melanoma, and others, although combined these are responsible for less than 10% of all esophageal malignancies.
55
provide tissue diagnosis. Minimally invasive techniques including laparoscopy, laparoscopic ultrasound, and thoracoscopy have increased the accurate staging of esophageal
cancer to greater than 95%.10 The role of positron-emission tomography (PET) with
flu-deoxyglucose 18, whose sensitivity in detecting metastatic disease may be quite high
and may identify metastases in as many as 14% of patients11 otherwise thought to have
localized disease by conventional imaging techniques is expanding. In our practice,
endoscopy/endoscopic ultrasound with CT scan of the chest, abdomen and pelvis are
routinely obtained for diagnosis and determining surgical resectability.
56
Chapter 4
tive pulmonary and other complications associated with a thoracotomy incision. They
also point to the generally shorter intraoperative time of THE and the potentially devastating consequences of a leak from an intrathoracic anastomosis whose mortality can
be as high as 50%.
Several randomized prospective studies and retrospective meta-analyses to date have
shown no significant differences in 5-year survival rates between the transhiatal and
transthoracic approaches to esophagectomy.25 One larger randomized trial with 220
patients with esophageal adenocarcinoma12 demonstrated a statistically significant
increase in the number of postoperative pulmonary complications associated with TTE
(50%) as compared to THE (25%), but again no statistical difference in median or 5year survival.
The same randomized trial demonstrated a statistically significant difference between
the 2 surgical approaches in terms of the number of lymph nodes resected with the
esophagectomy specimen, with almost twice as many obtained from the TTE approach
as compared to THE. The clinical significance of this result is unclear however. While
the incidence of positive lymph nodes in the neck may be as high as 30%13 for mid- and
distal esophageal neoplasms, which would support the extended lymphadenectomy
approach (entailing resection of celiac, superior mediastinal, and cervical lymph nodes),
the finding of similar 5-year survival rates between THE and TTE despite their difference in lymph node dissection suggests there may not be increased benefit from more
radical resections.
The operative mortality of patients undergoing esophagectomy can range from less
than 5% to over 25% in some reports (recent Phase III trials report mortality rates of 0
to 9%).14,15 While variability in patient selection may play a role in these differences,
there seems to be a clear decrease in mortality rates in high volume centers where the
surgical and intensive care staff have frequent exposure to and experience with these
patients.
With relatively low 5-year survival rates (25%) in patients undergoing THE and
TTE, there is impetus for the development of less invasive and potentially less morbid
operative methods. The use of laparoscopy, hand-assisted laparoscopy, and/or videoassisted thoracoscopy for various portions of the operation from gastric to esophageal
mobilization has been successfully employed in several centers. The most frequent combination is the use of video-assisted thoracoscopy for esophageal dissection with an open
incision for gastric mobilization and cervical anastomosis. Theoretically, these minimally invasive approaches could combine the benefits (and reduce the risks) of THE and
TTE by allowing good visualization of intrathoracic structures and for extensive lymphadenectomy while at the same time reducing the potential complications of a large
thoracotomy incision. Indeed, the extent of lymphadenectomy by thoracoscopic methods (as measured by lymph nodes resected) has been found to be similar to that achieved
by TTE. Despite this, there has been no established significant difference found in morbidity and mortality between thoracoscopic and open methods, although some reports
indicate a small benefit in postoperative pulmonary function and decreased pulmonary
morbidity. Other considerations with minimally invasive techniques include the learning curve and training required for time-efficient performance of the surgery and operative costs. A multi-institutional trial would help sort out these various issues and critically examine any benefits that may exist with these methods.
57
58
Chapter 4
molecular level can help guide more effective treatment strategies whose true benefit can
be assessed by large multi-institutional trials.
CANCERS
OF THE
STOMACH
EPIDEMIOLOGY
Approximately 22,400 new cases of gastric cancer were estimated for 2003 with an
estimated 12,100 deaths for that year.1 The overwhelming majority of these malignancies (>95%) are adenocarcinomas, followed by lymphoma. Gastric sarcomas, of which
leiomyosarcoma is the most common, account for 1% to 3% and occur most frequently in the proximal portion of the stomach. Interestingly, the incidence of gastric cancer
related deaths has steadily decreased in the United States in both males and females since
the 1930s. The reasons for this are not entirely clear although dietary and other environmental influences may be involved. The incidence of gastric cancer is higher in males
than females (1.5:1), and the peak age incidence is in the seventh and eighth decades of
life, with a median age of 65 years.29 There is considerable geographic variation in the
incidence (and survival statistics) of gastric cancer, suggesting environmental and/or
genetic factors in the etiology of the disease. Gastric cancer has the greatest incidence in
Japan where survival rates are also the highest. Of interest, while the overall incidence of
gastric cancer has decreased, there is an increase in the number of proximal tumors in
the past 2 decades.
59
60
Chapter 4
61
postoperative mortality or 5-year survival between patients receiving a total versus subtotal gastrectomy for gastric antral tumors.45 This study was corroborated more recently
by an Italian randomized trial with 624 patients which demonstrated the 5-year survival
probability for subtotal and total gastrectomy was 65.3% and 62.4%, respectively.46
A total gastrectomy is generally performed through either a midline or bilateral subcostal incision. After assessing for metastatic disease, attention is then turned toward
mobilizing the stomach, which generally entails dissecting the omentum from the mesocolon, dividing the short gastric arteries, ligating the left gastric artery, and kocherizing
the proximal duodenum. The duodenum is divided a couple of centimeters distal to the
pylorus and the esophagus is transected several centimeters proximal to the GE junction.
Negative surgical margins are confirmed by frozen sections. Regional lymphadenectomy
is performed, and if there is evidence of encroachment into adjacent organs, these organs
are resected. We do not routinely perform a splenectomy, as this has not been shown to
improve survival outcome and increases morbidity.47 Indications for a splenectomy
include splenic involvement by the tumor or some locally advanced tumors on the
greater curvature in the proximal third of the stomach. If splenectomy is indicated, the
pancreas should be preserved (pancreatic resection is only indicated for tumor invasion
of this organ).
A subtotal gastrectomy is performed in a similar manner to total gastrectomy,
although approximately 20% to 25% of the proximal stomach is preserved (at least 6 cm
proximal margins), with some short gastrics preserved to supply the remnant stomach.
In both subtotal and total gastrectomy, the goal for curative intent is to achieve an R0
dissection (no residual macroscopic or microscopic disease).
There are several mechanisms of reconstruction following subtotal and total gastrectomy. Reconstruction following distal gastrectomy can be achieved by Billroth I or
Billroth II procedures, which were found to have no significant difference in hospital
mortality or 5-year survival outcome by randomized trial.48 The standard reconstruction
for a total gastrectomy is a Roux-en-Y esophagojejunostomy. Various more involved
reconstructions with Hunt-Lawrence pouch replacement for the stomach have been
developed with or without maintaining duodenal passage in efforts to reduce symptoms
of early satiety, bloating, and weight loss, although no convincing data support them to
have a significant benefit long-term. We generally recommend Roux-en-Y esophagojejunostomy reconstruction and frequently place a jejunostomy feeding tube for postoperative alimentary feeding.
One of the largest controversies in the surgical management of gastric cancer is the
extent of lymph node dissection. Surgeons in Japan largely support a more radical lymphadenectomy, pointing to literature that shows a significant survival benefit for patients
undergoing more extensive dissection involving not only perigastric nodes (N1), but
nodes of the celiac axis and the major branches (N2) and hepatoduodenal ligament, celiac plexus, superior mesenteric artery (N3), and even in some instances of the periaortic
area (N4). These encouraging results from Japanese literature have unfortunately failed
to be consistently reproduced in Western studies. The reasons for this are unclear,
although the possibility that differential staging practices and even differences in tumor
biology may contribute to this phenomenon is raised. A recent large Dutch multicenter
trial49 with 996 patients found no significant survival difference at 5 years between
patients undergoing removal of nodal tissue within 3 cm of the primary tumor (D1) and
those also undergoing resection of splenic, hepatic, left gastric, and celiac nodes (D2)
(45% vs 47%). The study, however, demonstrated a higher morbidity and postoperative
62
Chapter 4
mortality in the group undergoing the D2 dissection. In our practice, we generally perform gastrectomy with D1 dissection with an attempt to obtain at least 15 lymph nodes.
Five-year overall survival rates for patients with gastric cancer range from 10% to
20%, with survival rates for patients undergoing surgical resection with curative intent
reported as high as 47%.50 Higher survival figures have been reported in the Japanese literature where more aggressive screening programs may lead to earlier cancer detection.
A recent large randomized Italian study51 comparing morbidity and mortality from D1
and D2 dissections in experienced centers found overall postoperative morbidity to be
about 13.6%, with overall postoperative mortality less than 1%. Complications after
gastrectomy include anastomotic leak, which can be associated with significant morbidity and mortality. In a large series of 1114 patients who underwent total gastrectomy and
esophagojejunostomy, the leak rate was 7.5%.52 The majority of these were managed
conservatively, although of the 30% that required re-exploration, the mortality was
noted to be 64%.
63
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21. Minsky BD, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III
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24. Enzinger PC, Mayer, RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241-2252.
25. Wu PC, Posner MC. The role of surgery in the management of oesophageal cancer.
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26. Hulscher JB, van Sandwick JW, et al. Extended transthoracic resection compared with
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27. Wong JEL, Ito Y, et al. Therapeutic strategies in gastric cancer. J Clin Oncology. 2003;
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28. Norton J, et al. Essential Practice of Surgery: Basic Science and Clinical Evidence. New
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29. Wanebo HJ, et al. Cancer of the stomach. A patient care study by the American College
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30. Botet JF, et al. Preoperative staging of gastric cancer: comparison of endoscopic US and
dynamic CT. Radiology. 1991;181(2):426-432.
31. Habermann CR, Weiss F, Riecken R, et al. Preoperative staging of gastric adenocarcinoma: comparison of helical CT and endoscopic US. Radiology. 2004;230(2):465-471.
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33. Willis, S. et al. Endoscopic ultrasonography in the preoperative staging of gastric cancer: accuracy and impact on surgical therapy. Surg Endosc. 2000;14(10):951-954.
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38. Fujimoto T, et al. Evaluation of intraoperative intraperitoneal cytology for advanced gastric carcinoma. Oncology. 2002;62(3):201-208.
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antrum. A French prospective controlled study. Ann Surg. 1989;209(2):162-166.
46. Bozzetti F, et al. Subtotal versus total gastrectomy for gastric cancer: five-year survival
rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study
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47. Brady MS, et al. Effect of splenectomy on morbidity and survival following curative gastrectomy for carcinoma. Arch Surg. 1991;126(3):359-364.
48. Chareton B, et al. Prospective randomized trial comparing Billroth I and Billroth II procedures for carcinoma of the gastric antrum. J Am Coll Surg. 1996;183(3):190-194.
49. Bonenkamp JJ, et al. Extended lymph-node dissection for gastric cancer. Dutch Gastric
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51. Degiuli M, et al. Morbidity and mortality after D1 and D2 gastrectomy for cancer:
Interim analysis of the Italian Gastric Cancer Study Group (IGCSG) randomised surgical trial. Eur J Surg Oncol. 2004;30(3):303-308.
52. Lang H, et al. Management and results of proximal anastomotic leaks in a series of 1114
total gastrectomies for gastric carcinoma. Eur J Surg Oncol. 2000;26(2):168-171.
53. Hermans J, et al. Adjuvant therapy after curative resection for gastric cancer: metaanalysis of randomized trials. J Clin Oncol. 1993;11(8):1441-1447.
54. Hermans J, Bonenkamp JJ.. Meta-analysis of adjuvant chemotherapy in gastric cancer:
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56. MacDonald JS et al. Chemoradiotherapy after surgery compared with surgery alone for
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chapter
Identification and
Management of Familial
Pancreatic Cancer
Stephen J. Rulyak, MD, MPH
INTRODUCTION
Epidemiologic studies have demonstrated that family history is an important risk
factor for the development of pancreatic cancer. Families with multiple members diagnosed with pancreatic cancer are not infrequently encountered in clinical practice, and
recent estimates suggest that up to 10% of pancreatic carcinomas may be inherited. In
some families, the risk of pancreatic cancer may approach 50%. However, the identification of families predisposed to pancreatic cancer can be difficult, and the absence of
a widely accepted screening test for pancreatic cancer presents a formidable challenge to
the clinicians caring for members of these families. This chapter will review current
knowledge about the etiology of familial pancreatic cancer, and provide insight into the
clinical management of these high-risk patients with an emphasis on evolving approaches to screening and surveillance.
EPIDEMIOLOGY
The incidence of pancreatic cancer in the United States is 30,700 cases per year, and
pancreatic cancer is the fourth leading cause of cancer death among both men and
women, with a mortality rate nearly equal to its incidence rate. The cause of most pancreatic cancer cases remains unknown, and rapid and nearly uniform fatality of the disease presents a significant obstacle to epidemiologic investigation. However, studies
have identified several risk factors for pancreatic cancer (Table 5-1). Tobacco smoking
is the most consistently identified epidemiologic risk factor for pancreatic cancer,
although the approximately 2-fold increase in risk associated with smoking is modest.
Pancreatic cancer is also more common with advancing age, and male gender and Black
race appear to be associated with a slight increase in risk. Dietary factors such as
increased caloric intake, increased carbohydrate intake, and decreased dietary fiber have
been associated with pancreatic cancer, although these epidemiologic relationships have
been inconsistent. The association with other environmental factors such as occupation
68
Chapter 5
Table 5-1
is even less certain. Diabetes mellitus does appear to be associated with pancreatic cancer. However, despite multiple epidemiologic studies, it remains difficult to conclude
whether diabetes is cause or effect of the disease as glucose intolerance can result from
pancreatic cancer by several mechanisms, including peripheral insulin resistance or
impaired insulin release from islet cells. Early epidemiologic studies suggested an
increase in the risk of pancreatic cancer associated with alcohol, but subsequent studies
controlling for concurrent tobacco use have found no increase in the risk of pancreatic
cancer. Nonetheless, heavy consumption may increase the risk of pancreatic cancer in
some individuals if they develop chronic pancreatitis.
A family history of pancreatic cancer has been identified as a risk factor for pancreatic cancer in several epidemiologic studies. At least 5 cross-sectional studies report a sig-
69
nificantly increased risk associated with family history, with risk estimates ranging from
1.5-fold to 15-fold depending on the population studied. One population-based case
control study including 247 cases found that a family history of pancreatic cancer was
associated with a 2.5-fold increase in the risk of pancreatic cancer, and that risk was further magnified by either smoking or by having a family member who was diagnosed
with pancreatic cancer before age 60. Another study using the National Familial
Pancreas Tumor Registry found an 18-fold increase in risk among persons with 2 or
more first-degree relatives diagnosed with pancreatic cancer. Thus, while the magnitude
of risk associated with family history varies from study to study, a family history appears
to be one of the strongest and most consistently identified risk factors for pancreatic cancer.
GENETICS
OF
PANCREATIC CARCINOMA
Pancreatic adenocarcinomas are believed to arise from ductal epithelium, and there
is increasing evidence that neoplastic transformation progresses through a precursor
lesion known as pancreatic intraepithelial neoplasia (PanIN). It also appears that tumorigenesis occurs via a multistep process whereby oncogenes are activated and tumor suppressor genes are inactivated, similar to the adenoma-carcinoma that results in colorectal cancer. A number of molecular genetic alterations have been identified in pancreatic
adenocarcinomas, and many of these same alterations are also present in PanIN although
the sequence in which they occur has yet to be fully characterized. Some inherited pancreatic cancers are the result of germline mutations in the genes associated with sporadic
pancreatic cancer.
70
Chapter 5
Table 5-2
Function
Proportion of Pancreatic
Adenocarcinomas With
Mutation or Alteration
K-ras
CDKN2A (p16)
p53
SMAD4 (DPC4)
MLH1, MSH2
Telomere shortening
oncogene
tumor suppressor
tumor suppressor
tumor suppressor
DNA mismatch repair
chromosomal stability
>95%
63% to 100%
50% to 75%
30% to 50%
13%
>90%
mal bridges during anaphase of mitosis, with subsequent breakage of those bridges, and
repeat fusion in an ongoing cycle. Telomere shortening and activation of the associated
enzyme telomerase are relatively common findings in pancreatic cancer. Telomere shortening is also an early and very common finding in PanIN.
Still other molecular events may have the potential to result in pancreatic carcinoma.
For example, one recent study identified high-frequency microsatellite instability (MSI)
among a subset of patients with pancreatic cancers but without hereditary nonpolyposis
colorectal cancer. Interestingly, patients with MSI-positive tumors had a significantly
improved survival compared to patients with MSI-negative tumors.
CDKN2A
APC
CFTR
FAMMM
Peutz-Jeghers syndrome
FAP
HNPCC
Hereditary pancreatitis
Cystic fibrosis
7q31.2
7q35
2p21-22;3p21-23;
2p16
5q21-22
9p21
13q12-13
BRCA2
Locus
Gene(s)
Syndrome
32 (5-205)
53 (23-105)
n/a
4 (1.2-11)
132 (44-261)
22 (9-45)
7 (n/a)
Increase in Pancreatic
Cancer Risk (RR or OR [95% CI])
Table 5-3
72
Chapter 5
pancreatic cancer is considerably lower than for breast or ovarian cancers, as only about
5% of BRCA2 mutation carriers will develop pancreatic cancer. The explanation for
reduced penetrance is not yet known, although there is some evidence to suggest that
BRCA2 mutations are a late event in pancreatic tumorigenesis and that other molecular
alterations may be required to initiate pancreatic neoplasia. It is also possible that interactions with other genes or environmental factors may be required for BRCA2 mutations
to result in pancreatic cancer.
Members of FAMMM kindreds inherit a predisposition to develop multiple (>50)
atypical cutaneous nevi and melanomas, and a subset of these families also appears to
inherit pancreatic cancer. The most common mutations in FAMMM kindreds are found
in the CDKN2A gene on chromosome 9p21. Mutations in CDKN2A are also frequently identified in sporadic pancreatic adenocarcinomas. CDKN2A encodes p16,
which acts as a tumor suppressor protein by inhibition of the cyclin D1-cyclin-dependent kinase complex (CDK4). If not inhibited, the CDK4 complex in turn phosphorylates the retinoblastoma protein, allowing a cell to progress unchecked through the G1
phase of the cell cycle, resulting in unregulated cell growth. Lynch and colleagues first
reported a melanoma kindred predisposed to PC in 1968, and a number of additional
families have since been identified. Several studies of FAMMM kindreds have found a
10- to 40-fold increase in the risk of nonmelanoma cancers, and the cumulative risk of
pancreatic cancer has been estimated to be 17% by age 75. Growing epidemiologic evidence supports the observation that pancreatic cancer is inherited as an autosomal dominant trait in at least some families that inherit CDKN2A mutations.
Peutz-Jeghers syndrome is an autosomal dominant disease that results in hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. The disease is
caused by germline mutations in the serine threonine kinase 11 gene (STK11), and
patients are predisposed to a variety of cancers, including pancreatic cancer. There
appears to be more than a 100-fold increase in the relative risk of pancreatic cancer in
these families (RR=132; 95% CI 44-261) and the lifetime risk of pancreatic cancer in
these patients may exceed 36%.
FAP and HNPCC are cancer syndromes most closely associated with increased risk
of colorectal adenomas and cancers, but affected patients are also predisposed to a number of extracolonic cancers, including pancreatic cancer. FAP results from a mutation in
the tumor suppressor gene APC, which normally controls cell proliferation by inhibition of beta-catenin. In addition to colorectal cancers, affected patients can develop
small intestinal cancers, desmoid tumors, and papillary thyroid carcinoma. The risk of
pancreatic cancer in FAP patients is increased approximately 4-fold, although the
absolute risk of pancreatic cancer seems to be lower than the risk of other extracolonic
cancers. HNPCC is the most common form of hereditary colorectal cancer and is caused
by defects in DNA mismatch repair genes. Mutations in 2 mismatch repair genes
(MSH2 and MLH1) may account for up to 90% of cases, although defects in other mismatch repair genes result in a similar phenotype. Patients with HNPCC are also predisposed to a number of extracolonic cancers of the endometrium, ovary, small intestine,
stomach, and genitourinary tract. One study suggests that HNPCC families may also be
predisposed to pancreatic cancers, but population-based data to support this association
are lacking.
In addition to cancer syndromes, other hereditary diseases can predispose affected
individuals to pancreatic cancer. Hereditary pancreatitis is an autosomal dominant disorder associated with mutations in the cationic trypsinogen gene, PRSS1. Patients with
73
hereditary pancreatitis are among those at greatest risk of pancreatic cancer, as they have
been found to have a 50-fold increase in the risk of pancreatic cancer with a lifetime
cumulative incidence of pancreatic cancer in excess of 40%. Epidemiologic studies suggest that patients with cystic fibrosis are also at increased risk to develop digestive cancers, including cancer of the pancreas, although the absolute risk of pancreatic cancer in
these patients appears to be low. One recent study has identified mutations in the genes
associated with Fanconis anemia in apparently sporadic pancreatic cancers, although the
importance of these mutations in either sporadic or familial pancreatic cancers remains
to be defined. Finally, there are preliminary data to suggest mutations in the ATM gene
that results in ataxia-telangiectasia may play a role in pancreatic cancer.
74
Chapter 5
Figure 5-1. Earlier onset and increased risk of pancreatic cancer in members of familial
pancreatic cancer kindreds who smoke. (Reprinted from Gastroenterology, Vol. 124(5),
1292-9, Rulyak SJ, et al, Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds, Copyright 2003, with permission from the American
Gastroenterological Association.)
20 years. The roles of other potential risk factors such as race, gender, diet, or occupation have yet to be examined in the familial setting. Nonetheless, all patients with a family history of pancreatic cancer should be advised not to smoke.
75
Table 5-4
include 2 or more first degree relatives with pancreatic cancer should be considered to
have familial pancreatic cancer until proven otherwise. Families that include multiple
second-degree relatives with pancreatic cancer and/or those with an unusually young age
of onset (<50 years of age) may also be at increased risk, although these criteria are more
controversial. These latter criteria may be most useful in evaluating small families and/or
those with limited family history data.
It is important for the clinician to recognize that the risk to an individual patient
varies by both the number and relationship of affected relatives. For example, a patient
whose mother and brother have been diagnosed with pancreatic cancer is likely to be at
much higher risk of developing pancreatic cancer than if his or her uncle or first cousin
were affected. Table 5-4 gives criteria that may prompt a clinician to consider the diagnosis of familial pancreatic cancer, although it is important to emphasize that estimation
of risk for an individual patient is likely to be imprecise and that listed criteria have not
been validated prospectively.
76
Chapter 5
Figure 5-2. Histology of PanIN. (A) PanIN-1 (open arrow) is characterized by elongation
of epithelial cells with abundant supranuclear mucin and PanIN-2 (solid arrow) is defined
by nuclear abnormalities including enlargement and crowding, hyperchromatism, and
stratification. (B) In PanIN-3, there are lush papillary projections, loss of nuclear polarity,
and nuclear atypia with mitoses. (Photomicrographs courtesy of Dr. Teresa Brentnall.) For
a full-color version, see page CA-IV of the Color Atlas.
77
There are several important limitations in the literature regarding PanIN lesions and
their progression to cancer. First, the absolute risk of pancreatic cancer in patients with
pancreatic dysplasia has yet to be determined, as does the prevalence of PanIN in the
general population. Second, the time course for progression from PanIN to cancer is as
yet unknown. In one series of 3 patients who underwent pancreatic surgery for nonmalignant indications and were found to have dysplasia at the resection margins, all
patients progressed to cancer within 10 years. Clearly, larger studies of the natural history of PanIN are needed to confirm this finding. Finally, it is important to note that
the accurate pathologic diagnosis of PanIN can be difficult. In one study, interobserver
agreement among expert gastrointestinal pathologists was found to be only fair for
PanIN 1 and PanIN 3 (kappa=0.43 and kappa=0.42, respectively) and poor for PanIN
2 lesions (kappa=0.14). Accurate diagnosis of PanIN is critical because PanIN is a multifocal or diffuse process and total pancreatectomy is necessary to ensure removal of all
dysplastic tissue. It is likely that the accuracy of PanIN diagnoses will improve as pathologists accrue additional experience with this lesion.
While the natural history of pancreatic dysplasia is difficult to study and incompletely characterized, PanIN represents a curable precursor lesion and thus it is possible
that effective screening tests can be developed. Potential screening methods may involve
the use of imaging modalities such as endoscopy or radiography. Ultimately, a biomarker in serum or pancreatic juice may be most attractive option for screening. PanINs share
many of the molecular genetic alterations found in adenocarcinomas. Because these
molecular alterations appear to be acquired in a step-wise fashion, it may eventually be
possible to detect the highest risk precursor lesions shortly before cancer develops.
78
Chapter 5
Table 5-5
p-value
Nodules*
Prominent septae
Dilated side branch
Echogenic foci
Echogenic strands
Mass
Irregular main duct
Echogenic duct wall
46
33
33
70
67
10
17
7
0.0001
0.003
0.03
0.09
0.09
0.08
0.14
0.62
1
10
14
52
48
2
7
4
*These findings, also known as "lobules," are multifocal hypoechoic areas throughout the
pancreatic parenchyma measuring between 2 mm and 8 mm. The term lobule is used to
distinguish these findings from those of a discrete mass lesion within the pancreas
Adapted from Jagannath S, et al. Endoscopic ultrasound abnormalities in at-risk relatives
from familial pancreatic cancer kindreds: a prospective, controlled pilot cohort study.
Gastrointest Endosc. 2002;56(Suppl):S120.
ERCP may also have utility in detecting pancreatic dysplasia, although few would
advocate this as a first-line screening test given the potential for complications, including pancreatitis. As with EUS findings, the ERCP findings associated with dysplasia can
also be seen in patients with chronic pancreatitis. However, in selected members of
familial pancreatic cancer kindreds without clinical evidence for pancreatitis, several
ERCP findings have been associated with dysplasia. These include irregularity of main
79
pancreatic duct or side branches, ectasia of pancreatic duct side branches, sacculations of
pancreatic ducts, and early acinarization of pancreatic head during pancreatic duct injection with inability to completely fill the pancreatic tail (Figure 5-4). ERCP should be
used primarily as a confirmatory test when abnormalities on EUS are identified,
although one potential advantage of ERCP is ability to obtain pure pancreatic juice or
pancreatic duct brushings, which may provide material for screening if an accurate
molecular screening assay can be developed. It is important to emphasize that the use of
endoscopic screening tests in familial pancreatic cancer is a field under development, and
all screening should be conducted in the context of an approved clinical protocol.
80
Chapter 5
identified from pancreatic juice, but one recent study suggests that testing for these
mutations adds little additional diagnostic information to the detection of K-ras. It is
possible that combinations of screening markers may improve the accuracy of molecular testing for pancreatic cancers. There has been one study to suggest that combining
assays for K-ras and p53 may improve diagnostic accuracy for pancreatic adenocarcinoma. However, no published studies have utilized combinations of molecular tests for the
diagnosis of PanIN lesions.
Telomere dysfunction is another promising molecular marker for screening of familial pancreatic cancer kindreds because it is an early and nearly ubiquitous alteration in
PanIN. Telomere length shortening has been reported to be present in 96% in PanIN
specimens. Assays of telomere length currently require histologically normal tissue as a
control, and such tissue cannot be readily obtained by sampling pancreatic juice or by
fine needle aspiration because PanIN is a diffuse and frequently multifocal process.
However, telomerase activity is a surrogate for telomere shortening, and preliminary
reports suggest that telomerase activity can be determined from either pancreatic juice
or fine needle aspirates. It is important to recognize that telomere dysfunction is presently not only seen in low grade dysplasia (PanIN-2) and high grade dysplasia (PanIN-3),
but also in pancreatic duct hyperplasia (PanIN-1). Therefore, any potential assay for
telomere dysfunction is likely to have high sensitivity but low specificity for the diagnosis of dysplasia, although sensitivity is arguably the most important feature of a screening assay. If a suitable assay for telomere dysfunction can be developed, it may be most
useful to select a subset of patients who warrant more intensive screening with EUS or
other modalities.
In patients with a family history suggestive of one of the defined cancer syndromes
that result in pancreatic cancer, testing for germline mutations may represent an important tool for identifying family members at risk for pancreatic cancer. The yield of routine testing of familial pancreatic cancer kindreds for most of these mutations is likely to
be low. One exception may be testing for BRCA2, as recent studies suggest that up to
19% of familial pancreatic cancer kindreds may harbor a BRCA2 mutation in the
absence of a family history of breast or ovarian cancer. However, future studies to confirm the prevalence of BRCA2 mutations among familial pancreatic cancer kindreds are
needed before such testing can be widely recommended.
As the pathways that lead to pancreatic adenocarcinoma are better understood,
molecular approaches may assume an increasing role in screening and surveillance of
high-risk family members. With the advent of proteomic technology, it is likely that
newer markers with improved sensitivity and specificity will become available. While
molecular techniques hold great promise, there are presently few studies to suggest that
testing for single molecular genetic alterations or combinations thereof have utility in
clinical detection of PanIN or early pancreatic cancer. As with other screening modalities, their use should be restricted to investigational protocols.
APPROACH
TO
The management of members of familial pancreatic cancer kindreds presents a formidable challenge to the clinician because clinical experience with screening among
high-risk pancreatic cancer patients is limited and currently evolving. However, several
centers across the United States have initiated protocols to study the role of screening
81
and surveillance for high-risk family members, and early results from these studies are
promising. One protocol using endoscopic screening has been developed at the
University of Washington Medical Center in Seattle. To date, 73 patients from 50 different familial pancreatic cancer kindreds have been enrolled and follow-up extends to 9
years. From this cohort, 9 patients have been diagnosed with PanIN 3 and 7 have been
diagnosed with PanIN 2. Thirteen of these patients have elected to undergo total pancreatectomy, with no operative deaths. Most importantly, no patient enrolled in the protocol has developed pancreatic cancer while under surveillance.
While these results are encouraging, it must be emphasized that experience with
endoscopic screening is limited, and endoscopic tests such as EUS are operator dependent. Therefore, screening with EUS should only be entertained in patients at greatest risk
for pancreatic dysplasia, and patients should be well-informed, active participants in the
decision to proceed with screening. The findings of EUS should be corroborated by
other studies, including ERCP and ultimately laparoscopic biopsy of the pancreatic tail,
prior to proceeding with total pancreatectomy. Finally, it cannot be overemphasized that
the natural history of pancreatic dysplasia is uncertain and the performance characteristics of endoscopic tests such as EUS and ERCP have yet to be determined. However, a
recent decision analysis that assumed a 90% sensitivity of EUS for dysplasia suggested
that a strategy employing EUS to screen members of familial pancreatic cancer kindreds
is cost-effective, although the benefit appears to be limited to patients with a pre-test
probability of pancreatic dysplasia of 16% or greater.
In all patients with a family history of pancreatic cancer, evaluation should begin
with a careful history and physical examination in order to determine if alarm symptoms
such as abdominal or back pain, diarrhea, weight loss, or recent onset diabetes are present. A history of smoking, alcohol consumption, or occupational exposures should also
be elicited. All patients with a family history of pancreatic cancer should be counseled
not to smoke. A careful family history should be obtained in order to construct a
detailed family pedigree, which can then be used to select patients who may be candidates for screening. Patients with 2 or more first-degree family members diagnosed with
pancreatic cancer are considered at increased risk of pancreatic cancer, as are patients
who are known to harbor a germline mutation associated with pancreatic cancer.
Patients with less compelling family histories may also be at increased risk of pancreatic
cancer, although the utility of screening in such patients is far less certain. Table 5-4 lists
proposed criteria for pancreatic cancer risk stratification, with the understanding that
such criteria have yet to be prospectively validated. Patients with hereditary or acquired
chronic pancreatitis represent a particular challenge, because the EUS and ERCP findings in patients with these conditions are indistinguishable from the findings of dysplasia. Therefore, endoscopic screening patients with chronic pancreatitis cannot be widely recommended, although experience with this population of patients is limited.
Once a patient is deemed to be at increased risk for pancreatic cancer, extensive
counseling regarding the uncertainties about the natural history of PanIN and lack of
clearly validated methods for screening and surveillance for pancreatic neoplasia should
then be undertaken. Counseling must include a frank discussion about the outcome of
screening if abnormalities are uncovered, specifically total pancreatectomy. In patients
with family histories suggestive of a known cancer syndrome, genetic counseling and
mutational analysis should be considered. Patients who remain interested after a thorough discussion of risks and benefits are then offered screening.
82
Chapter 5
Figure 5-5. Approach to screening for pancreatic cancer in familial pancreatic cancer
kindreds.
The algorithm used at the University of Washington for screening patients who meet
criteria for familial pancreatic cancer is shown in Figure 5-5. Interested patients are
offered EUS as the initial screening test, beginning either at the age of 50 years or 10
years prior to the earliest age at which pancreatic cancer was diagnosed in an affected
family member. If EUS is abnormal and there is no recent history of alcohol use, the
patient is then offered ERCP to confirm the pancreatic abnormalities noted on EUS.
However, if the patient actively consumes alcohol, he or she is advised to abstain from
alcohol for 6 months and the EUS is repeated to confirm that abnormalities persist. If
both EUS and ERCP display characteristic abnormalities, the patient is referred for
83
CONCLUSION
Approximately 10% of pancreatic cancers are inherited. A number of genetic syndromes can predispose mutation carriers to pancreatic cancer, including FAP, FAMMM,
Peutz-Jeghers syndrome, hereditary breast/ovarian cancer syndrome, hereditary pancreatitis, and possibly HNPCC. However, the gene or genes involved in the majority of
inherited pancreatic cancers have yet to be determined, although the molecular pathways
of pancreatic tumorigenesis are beginning to be better understood. Smoking appears to
be an important modifier of familial pancreatic cancer risk, but the role of other environmental factors in such families has yet to be determined. Screening and surveillance
protocols using endoscopic techniques such as EUS and ERCP have been developed, but
their use should be restricted to approved research protocols. Molecular genetic testing
may have the greatest potential for screening and surveillance, although tests with
improved sensitivity and specificity will need to be developed. Most importantly, what
is learned from familial pancreatic cancer kindreds will have important implications for
screening and prevention of pancreatic cancer in the general population.
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Brat DJ LK, Yeo CJ, Warfield PB, Hruban RH. Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol. 1998;22:163169.
Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB. Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann
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Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers
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Giardiello FM, Offerhaus GJ, Lee DH, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34(10):1394-1396.
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Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst. 2000;92(12):1006-1010.
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Lowenfels AB, Maisonneuve P, Whitcomb DC, Lerch MM, DiMagno EP. Cigarette smoking
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Lynch HT, Brand RE, Hogg D, et al. Phenotypic variation in eight extended CDKN2A
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Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4,
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chapter
Surgical Approach to
Ampullary and Pancreatic
Neoplasia
Kristoffel R. Dumon, MD; Robert J. Canter, MD;
and Noel N. Williams, MD
INTRODUCTION
Carcinoma of the exocrine pancreas is a significant health problem in the United
States and other Western nations. It is one of the most lethal malignancies with an overall 5-year survival rate of approximately 3% and an incident rate nearly equivalent to its
mortality rate. Although a minority of patients are resectable at the time of diagnosis,
surgical resection offers the only potentially curative treatment, and surgical treatment
clearly provides the best long-term results. For patients in whom curative resection is
not possible, surgical intervention remains important as a means of palliation, particularly in patients with locally advanced disease.
This chapter reviews the various roles of surgical intervention in the curative and
palliative treatment of patients with pancreatic cancer, focusing on patients with carcinoma of the exocrine pancreas. Preoperative evaluation, with an emphasis on the controversial and evolving approaches to preoperative staging and determination of
resectability, is discussed.
PANCREATIC NEOPLASIA
Pancreatic neoplasia can be subdivided into 3 clinical entities: 1) pancreatic duct cell
adenocarcinomafrequently referred to as adenocarcinoma of the pancreas; 2) nonpancreatic periampullary cancer, which includes distal bile duct tumors, tumors originating in the ampulla of Vater, and periampullary duodenal tumors; and 3) rare pancreatic neoplasms, which include acinus cell carcinoma (a tumor that occurs more frequently in the tail of the pancreas), primary pancreatic lymphoma, cystic neoplasms of
the pancreas including intraductal papillary mucinous tumors (IPMT), solid and papillary pancreatic neoplasms, and pancreatic neuroendocrine tumors. The clinical presentation of these various entities is frequently similar. Since the decision for resection is
often made without a tissue diagnosis, the surgical approach to these different neoplasms is generally the same, although the prognosis and role for adjuvant therapy varies
depending on the histology.
88
Chapter 6
Table 6-1
Percent of
Patients
5-Year
Survival
9.8%
28%
62.2%
100%
17%
7%
2%
4%
Median
Survival
12
8
4
6
to
to
to
to
20 months
9 months
6 months
8 months
89
Table 6-2
Yeo
Sohn
Conlon
Richter
Billingsley
Year
No. of patients
Morbitity (%)
Mortality (%)
5-year survival
Median survival
(months)
1999
650
1.4
20
2000
564
31
2.3
17
17
2001
409
54
3
17.2
2003
194
30
3
25
2003
462
45.9
9.3
mimic so-called mucinous cystic neoplasm (MCN). Because the incidence of invasive
cancer at surgery is 25 to 50%, it is important to distinguish this entity from chronic
pancreatitis. This is usually done on the basis of typical changes evident on CT and
ERCP. The ERCP examination may reveal mucus exuding from the papilla or characteristic intraductal filling defects. The lesion, even if it does not contain invasive cancer,
is premalignant, and benign lesions contain several genetic mutations associated with
pancreatic cancer. Because of their favorable prognosis, an extensive diagnostic workup
for IPMTs should be performed in patients presenting with cystic lesions of the pancreas. Surgical resection is the therapy of choice for IPMTs. The type of resection
depends upon the extent of the ductal involvement. Total pancreatectomy is currently
the recommended treatment for an IPMT that comprises the entire main duct.
PREOPERATIVE EVALUATION
Accurate preoperative assessment of resectability is the most critical aspect of the
diagnostic and treatment sequence for patients with pancreatic cancer. Imaging includes
nonoperative techniques, such as abdominal ultrasonography, CT scan, MRI, angiography, and a variety of invasive techniques, such as laparoscopy and laparoscopic or intraoperative ultrasonography.
The studies for the diagnosis and staging of pancreatic cancer differ considerably
from center to center. The challenge to this process is that a high percentage of patients
who currently undergo surgery with curative intent have unresectable disease. The goal
of preoperative imaging is to spare patients a nontherapeutic laparotomy in those with
unresectable pancreatic cancer. However, this must be taken in the context of possible
palliative surgery.
90
Chapter 6
91
Genetic markers may be used to detect pancreatic cancer, but the clinical value of
these markers remains unproven. The most common gene abnormality (90%) described
in pancreatic cancer is a K-ras mutation. Mutations of the p53 tumor cell suppressor
gene are found in 50% to 70% of pancreatic cancers, and approximately 50% have
reduced expression of the DCC gene. A number of other gene deletions are less frequent
in pancreatic cancer, including alterations of tumor suppressor genes FHIT, 16/MTS1
and p15/MTS2.
K-ras mutation is the most widely studied genetic marker. K-ras in pancreatic secretions may be an early marker for pancreatic cancer, but whether K-ras mutations found
in duodenal or pancreatic juice or stools of patients with chronic pancreatitis herald pancreatic cancer is not clear.
ULTRASOUND
Abdominal ultrasonography (US) is the initial screening technique because of its low
cost and easy availability. US will confirm the presence of gallstones, assess the liver for
metastatic deposits, detect abdominal ascites, and identify the level of biliary obstruction. In certain patients, US can enable one to manage the patient without any further
investigation. Patients with malignant ascites and liver deposits require confirmatory
biopsy and no further investigation.
In addition, patients presenting with biliary obstruction are usually evaluated with
abdominal US to confirm the mechanical nature of the obstruction and to determine
whether the site of obstruction is the intrahepatic or extrahepatic portion of the biliary
tree. Obstruction of the intrapancreatic portion of the bile duct is then evaluated with a
combination of CT, ERCP, and EUS/MRCP.
However, there remain many limitations to abdominal US in the evaluation of
patients with pancreatic cancer. Bowel gas obscures the image in up to 15% of patients.
US is notoriously operator-dependent and not accurate in assessing central abdominal
and retroperitoneal structures.
92
Chapter 6
Table 6-3
Sensitivity (%)
Specificity (%)
Accuracy (%)
67 to 74
72
85 to 92
95
84
70
75 to 87
84 to 92
85 to 93
40 to 87
80
87 to 95
93
97
95
77
96 to 100
84 to 88
69
70 to 76
80
85
85 to 91
A patient is deemed to have locally advanced, unresectable disease when there is clear
evidence on CT scans of the following:
93
94
Chapter 6
ENDOSCOPIC ULTRASONOGRAPHY
EUS allows an ultrasound probe to be placed in close proximity to the pancreas. This
eliminates interference from overlying bowel gas and allows higher frequencies to be
used, resulting in markedly improved resolution of images of the pancreas and surrounding structures. EUS is not as widely available as spiral CT and requires extensive
experience and knowledge of pancreatic ultrasonographic anatomy. Although EUS gives
superior results compared with conventional CT scan, it appears to be equivalent to spiral CT scan in detecting tumors >3 cm and in assessing venous invasion and lymph node
involvement. However, its assessment of arterial invasion is limited. Although it allows
the pancreas to be assessed for small tumors (<3 cm) that may be missed on CT scan,
EUS is an invasive procedure that requires sedation and is highly operator dependent.
Moreover, it is the most reliable method to obtain accurate tissue for histologic diagnosis.
95
DIAGNOSTIC LAPAROSCOPY
For the past decade, laparoscopy has been used in patients who have radiologic evidence of localized pancreatic cancer to detect extrapancreatic tumor not visualized on
CT scan. This allows laparotomy to be limited to patients who truly have localized disease. In a recent study of 398 patients with pancreatic or periampullary cancer evaluated preoperatively with high-quality CT, ERCP, and angiography, 194 of the 398 patients
had tumors that were deemed to have a high probability of being resectable. Of the 194
patients, 172 (89%) underwent successful pancreaticoduodenectomy, and only 9 (5%)
of the 194 patients thought to have resectable tumors were found to have occult metastatic disease at laparotomy. This indicates that only a small group of patients would benefit from laparoscopy.
The extent to which laparoscopy should be used remains controversial. Laparoscopy
is reasonable to consider prior to laparotomy (during the same anesthesia induction) in
patients with biopsy-proven or suspected potentially resectable pancreatic cancer in
whom a decision has been made to proceed with pancreaticoduodenectomy. However,
we do not recommend the routine use of laparoscopy as a staging procedure under a separate anesthesia induction.
TECHNIQUES
OF
PRIMARY RESECTION
96
Chapter 6
Clinical Suspicion of Pancreatic Tumor
Contrast-Enhanced Thin-Section CT
Metastatic
Disease
Mass Lesion
Unresectable
Resectable
EUS-ERCP
MRCP
Unresectable
Resectable Mass
Malignant Structure
No Mass
Lesion
MRI/MRCP
No Evidence
of Tumor
EUS-ERCP
No Evidence
of Tumor
Palliative Intervention
Endo Biliary Stenting
Figure 6-1. Diagnostic approach to assess surgical management.
remains a formidable procedure, and as extensive outcomes data have demonstrated, one
that should only be performed by well-trained surgeons at high-volume centers.
Anatomically, the pancreas is divided into 4 sections: the head, neck, body, and tail.
The head lies within the C loop of the duodenum and extends to the border of the superior mesenteric vein (Figure 6-2). The head also includes the uncinate process, which
passes caudad and to the left and is the only part of the gland that lies posterior to the
mesenteric vessels. The neck typically refers to the portion of the gland that lies directly
over the superior mesenteric artery and vein. The body and tail of the pancreas lie to the
left of the superior mesenteric artery and extend to the splenic hilum. Despite these
anatomic boundaries, in practice, the key clinical distinction is whether a tumor is located to the right or left of the mesenteric vessels, since tumors to the right are typically
treated by pancreaticoduodenectomy and tumors to the left by distal pancreatectomy.
97
98
Chapter 6
There exists even fewer data regarding the long-term nutritional outcome for
patients following classic versus pylorus-preserving pancreaticoduodenectomy. There are
no randomized trials, and the few published series are limited by significant numbers of
patients lost to follow-up. Moreover, the nutritional data that are available are confounded by the inclusion of patients with disease progression who have significant
weight loss and malnutrition secondary to their advanced disease rather than the type of
resection that was performed. Consequently, insufficient evidence exists to definitively
favor one surgical technique over another. The classic Whipple procedure (Figure 6-3)
likely leads to a more rapid return of bowel function with a consequent shorter postoperative hospital stay, but there is probably little long-term difference between the 2 operations. Ultimately, the choice of procedure becomes one of the surgeons experience, and
as with other aspects of surgical outcomes, surgeon and hospital volume are the overriding factors to obtain the best results.
Pancreaticoduodenectomy (Figure 6-4) can be performed through either a subcostal
or midline incision. Some surgeons routinely begin the operation with laparoscopy to
rule out occult intraperitoneal spread of cancer and thereby spare patients unnecessary
laparotomy. The number of patients who may be spared laparotomy by this approach
varies among series from 4% to 25%, largely because of differences in preoperative staging algorithms and because of institutional differences in approaches to palliative procedures. However, even in institutions where resectability rates are high because of extensive preoperative cross-sectional imaging or where an aggressive approach to surgical palliation is adopted, laparoscopy prior to formal laparotomy is quick to perform and will
identify the occasional patient with carcinomatosis or unsuspected liver metastases who
is unresectable and therefore not an appropriate candidate for surgical palliation. These
patients will benefit from avoiding unnecessary laparotomy.
99
VASCULAR INVOLVEMENT
For those patients who do undergo abdominal exploration, pancreaticoduodenectomy is begun by mobilizing the second and third portions of the duodenum from its
retroperitoneal attachments in the so-called Kocher maneuver. This permits the head of
the pancreas to be elevated from the retroperitoneum, thereby exposing the vena cava,
the aorta, and the origin of the superior mesenteric artery. This maneuver allows the
mesenteric vessels, in particular the superior mesenteric artery, to be assessed for tumor
encasement and enables the surgeon to make a decision regarding resectability for cure.
Arterial encasement or invasion is generally accepted as an absolute contraindication to
resection. In contrast, many authors do not consider venous involvement by local tumor
extension to be a contraindication to pancreatic resection. Although the published series
involve relatively few patients, resection of the portal and/or superior mesenteric vein has
been shown to be technically possible and safe in experienced hands. In addition, patient
survival in these studies has been comparable to patients undergoing standard pancreaticoduodenectomy without venous reconstruction, suggesting that venous invasion is
100
Chapter 6
not an independent risk factor for a worse prognosis and should not be considered a
contraindication to resection.
Following inspection of the mesenteric vessels, the gastrohepatic omentum and the
porta hepatis are then examined to determine if lymph node metastases outside the field
of resection are present. It is also very important to identify or confirm (since many
patients will have preoperative magnetic resonance or CT angiography) aberrant arterial anatomy since these variations are not uncommon, and ligation of incorrectly identified hepatic arteries can lead to devastating postoperative complications. The peritoneum overlying the superior and inferior portion of the gland is then incised so that
the surgeon may place his or her fingers around the dorsal aspect of the gland and establish a potential plane for transection. If the tumor is deemed resectable, the pancreas is
typically transected at this point. The exact line of transection varies from surgeon to
surgeon, but typically lies to the left of the superior mesenteric artery so that an adequate
margin of non-neoplastic pancreatic tissue can be obtained.
101
PALLIATIVE INTERVENTION
Although surgical resection offers the only potential chance for cure in patients with
pancreatic cancer, the majority of patients are not candidates for resection because of the
presence of locally advanced or metastatic disease at the time of presentation. For those
patients with unresectable disease, the question becomes how to best palliate the symptoms of biliary obstruction, gastric outlet obstruction, and persistent abdominal pain.
Different approaches to these entities depend on the overall clinical picture of the
patient as well as institutional variation toward palliation.
Patients who are diagnosed with metastatic disease on preoperative imaging or at the
time of diagnostic laparoscopy are not considered candidates for curative resection.
Although chemotherapy has limited efficacy in this setting, it is often the only therapeutic modality available to patients. Since recovery from a laparotomy delays initiation
of this treatment, many surgeons are reluctant to perform surgical palliative procedures
in the setting of metastatic disease. Palliation of biliary obstruction can be successfully
accomplished in these patients by the placement of expandable metal stents. These
stents, which can be placed either endoscopically or percutaneously by interventional
radiology, are effective. Randomized trials have shown similar overall survival between
patients undergoing biliary stenting and those undergoing surgical biliary-enteric
bypass. Stented patients have a higher incidence of later morbidity such as stent occlusion with recurrent jaundice and cholangitis, while biliary-enteric bypass patients have a
higher procedure-related morbidity and mortality. For example, in one recent series, palliative bypass carried a 3% mortality and 22% morbidity rate.
Many surgeons adopt a somewhat more aggressive approach to the palliation of jaundice for patients who undergo abdominal exploration for possible resection and are
found to be unresectable based on locally advanced disease, such as vascular invasion.
These patients have already been subjected to the greater short-term morbidity of a
laparotomy, so the completion of a more durable biliary-enteric bypass, usually in the
form of a choledochojejunostomy, seems indicated. This is illustrated by a recent randomized trial comparing endoscopic stent insertion with surgical biliary bypass where
102
Chapter 6
recurrent jaundice developed in only 2% of the bypass patients compared to 36% of the
stented patients.
Another advantage of surgical bypass is the ability to perform a concomitant gastrojejunostomy to treat or prevent gastric outlet obstruction. Patients who have symptoms
of gastric outlet obstruction at the time of exploration should be treated with therapeutic gastrojejunostomy. Prophylactic gastrojejunostomy is more questionable since fewer
than 20% of patients with pancreatic cancer will develop duodenal obstruction, and for
most of these patients, this occurs late in the course of their disease. Endoscopicallyplaced intraluminal stents have emerged as a potential minimally-invasive method to
treat patients with gastric outlet obstruction. Although experience with these devices is
limited, they hold promise as a potentially effective palliative procedure for the minority of patients who develop late gastric outlet obstruction secondary to unresectable pancreatic cancer.
Intractable pain can be a significant problem for many patients with pancreatic cancer. Although narcotic analgesics are effective for many patients, some patients will have
unremitting abdominal and back pain with significant effects on quality of life. An
increasingly employed approach is celiac-plexus block, which involves ablation of the
intra-abdominal pain fibers usually by the injection of 98% alcohol. This can be performed surgically, percutaneously, or more recently by endoscopic ultrasound. Results of
celiac-plexus block appear to show a benefit to this approach. A randomized trial of surgical splanchnectomy in conjunction with double bypass for patients with unresectable pancreatic cancer demonstrated greater pain relief in the celiac-block group.
This translated into improved nutritional parameters for the celiac-block group with a
trend towards longer survival.
POSTOPERATIVE CARE
Although pancreatic fistula remains a relatively frequent occurrence following pancreatic resection, with fistula rates of 5% to 10% in most series, it is no longer the dreaded complication it once was. With the use of closed-suction drains placed at the time of
surgery, or alternatively with percutaneous drains placed postoperatively into suspicious
peripancreatic collections, pancreatic fistulae are easily controlled, and almost always
resolve spontaneously. In fact, many surgeons no longer consider the presence of a postoperative pancreatic fistula an absolute indication for bowel rest and total parenteral
nutrition, and patients are allowed to take a diet as tolerated as long as fistulous drainage
does not increase.
SUMMARY
Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United
States. Since surgical resection remains the only potentially curative option, an aggressive approach to surgical exploration is indicated even though only a minority of patients
are resectable. Preoperative staging should include high resolution cross-sectional imaging as well as endoscopic ultrasound for tissue sampling and assessment of locoregional
spread. Preoperative laparoscopy is used in the treatment of patients with pancreatic cancer since the occasional patient will be diagnosed with unsuspected disseminated disease
and spared the morbidity of a formal laparotomy. For patients who undergo abdominal
exploration, careful assessment of the mesenteric vessels should be performed since
extensive vascular invasion is a contraindication to resection. In the absence of dissemi-
103
nated disease or vascular invasion, en bloc pancreatic resection along with removal of the
regional lymph nodes should be undertaken with the type of resection depending on the
location of the primary tumor. For patients with unresectable disease, palliative procedures can provide significant relief, although newer minimally invasive techniques may
replace surgical palliative procedures.
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chapter
Chemotherapy and
Radiation in the Treatment
of Pancreatic Cancer
Bapsi Chak, MD and Jordan Berlin, MD
INTRODUCTION
This chapter will review neoplasms from the sites referred to by the term pancreaticobiliary malignancy. This term refers to several primary sites often considered together.
Pancreas cancer is the most common of the pancreaticobiliary malignancies representing an estimated 31,860 new cases and 31,270 deaths in the United States in 2004,
making it the fourth leading cause of cancer death in the United States.1 Finally, there
are many rare histologic subtypes that occur in the pancreas, but this chapter will only
focus on the most common cell type, adenocarcinoma.
PANCREATIC CANCER
Pancreatic cancer is a devastating illness with <5% of all patients surviving 5 years.
Clinical decision making for therapy of pancreatic cancer patients is determined by classifying these tumors into one of 3 categories: metastatic disease, locally advanced and
unresectable, and resectable disease. To introduce the chemotherapy drugs, this chapter
will work backward from metastatic disease to resectable disease.
108
Chapter 7
Table 7-1
Dose
(mg/m2)
Duration
of Infusion
Schedule
of Cycle
Duration
of Cycle
Leucovorin1
5-FU
20
425
Bolus
Bolus
Daily x 5
4 to 5 weeks
Leucovorin1
5-FU
500
500
2 hours
Bolus
Once weekly x 6
8 weeks
Leucovorin1
200
5-FU
400
5-FU
2000 to 2400
2 hours
Bolus
46 hours
Day 1
2 weeks
5-FU
24 hours
Once weekly x 4
4 weeks
2 hours
24 hours
Once weekly x 4
4 weeks
Oral
Twice daily x 2
weeks
3 weeks
2600
Leucovorin1
500
5-FU
2200 to 2600
Capecitabine*
1250
1Leucovorin
weeks, favors TS inhibition. It is clear that altering the administration schedule alters the
toxicity profile. For example, infusional schedules have higher rates of hand and foot
rash (palmar plantar erythrodysesthesia), while bolus injections have higher rates of diarrhea or hematologic toxicity. The metabolite of 5-FU (5-fluorodeoxyuridine monophosphate or FdUMP) that binds to TS requires a reduced folate as a cofactor. Therefore,
folinic acid or leucovorin is often coadministered with 5-FU. Studies demonstrated that
5-FU-based therapy significantly improved the average survival for pancreatic cancer
patients compared to palliative care alone.2,3 In addition, 5-FU maintained quality of life
better than supportive care alone.2 When using 5-FU, there are a number of doses and
schedules for administration, including an oral prodrug, capecitabine, that is converted
in vivo to 5-FU. Table 7-1 provides several schedules for 5-FU with or without leucovorin.
Gemcitabine (2,2-diflorodeoxycytidine), another pyrimidine analogue, demonstrated efficacy early in clinical trials. Although response rates on the phase II trials were
low (<10%), investigators noted that pancreatic cancer patients receiving gemcitabine
appeared to have improvements in disease-related symptoms out of proportion to objective response rates.4-6 Common and serious side effects of gemcitabine are listed in Table
7-2. When the phase III trial comparing gemcitabine to 5-FU was designed, the investigators used a new parameter called clinical benefit response as the primary endpoint.7
The clinical benefit response attempted to objectively measure the effects of gemcitabine
on symptoms common to pancreatic cancer patients: pain (pain score and analgesic con-
Side Effect
Rare (1%)
sumption), fatigue (Karnofsky performance status), and weight loss. To have clinical
benefit response, a patient had to have and maintain improvement in one parameter
without a decline in any other symptoms. Clinical benefit response evaluates specific
symptoms and is not a measure of global quality of life. The secondary parameters studied included response rate, median survival and 1-year survival. Results are shown in
Table 7-3. Gemcitabine was superior to 5-FU in terms of clinical benefit response, time
to tumor progression, overall survival, and 1-year survival. Neither regimen produced
many objective responses. With these results, gemcitabine became the standard treatment for pancreatic cancer and the control arm for future studies. However, like 5-FU,
there may be rationale for administering gemcitabine by different schedules.
Gemcitabine is a prodrug that needs to be phosphorylated for activation. The rate-limiting enzyme, deoxycytidine kinase, is saturable in laboratory studies at a rate of 10
mg/m2/min. The standard regimen infuses gemcitabine 1000 mg/m2 over 30 minutes,
which far exceeds the saturation rate. A single randomized phase II study compared a
30-minute infusion of high-dose gemcitabine to a fixed-dose rate of gemcitabine in
which the infusion rate was kept at 10 mg/m2/min.8 With a total of 92 patients enrolled,
there was a suggestion that fixed-dose rate gemcitabine had better median (8 months vs
5 months, respectively) and 1-year survival rates than the 30-minute arm. In addition,
higher levels of gemcitabine triphosphate were measured in peripheral blood mononu-
110
Chapter 7
Table 7-3
5-FU (n=63)
Gemcitabine (n=63)
4.8%
4 weeks
0%
4.4 months
2%
23.8% (p=0.0022)
9 weeks (p=0.0002)
5.4%
5.6 months (p=0.0025)
18%
Table 7-4
Study
Arms
# of
Patients
Time to
Tumor
Progress.
Median 1-Year
Survival Survival
Richards
(2004)
Moore
(2003)
Gemcitabine
Exactecan
Gemcitabine
BAY 12-9666
170
169
139
138
4.4 mos
2.8 mos
3.5 mos*
1.7 mos
(p<0.001)
Bramall
(2001)
Gemcitabine
Marimastat 5 mg
Marimastat 10 mg
Marimastat 25 mg
103
104
105
102
6.6 mos
5.0 mos
6.6 mos
3.7 mos
(p<0.001)
5.6 mos
3.7 mos
3.5 mos
4.2 mos
22.1%
17.9%
25%
10%
20%
14%
14%
19%
clear cells of patients treated with fixed-dose rate gemcitabine than those treated with a
higher total dose of gemcitabine given as a 30-minute infusion.
Current and recent randomized trials largely follow one of 2 designs: gemcitabine vs
drug X or gemcitabine + drug X vs gemcitabine alone. Results for these trials are shown
in Tables 7-4 and 7-5 and discussed in the following text. Table 7-6 provides a list of
gemcitabine-based regimens.
Adding gemcitabine to 5-FU has produced variable results. Several factors play a role,
including patient selection, small sample size, inclusion of locally advanced disease
patients with metastatic disease patients, and possibly the use of different schedules of
5-FU in combination with gemcitabine. Median survival times on some of the phase II
trials have varied from as low as 4 months to >10 months, although response rates have
remained <10% throughout.9-11 Thus far, one randomized trial has been reported comparing gemcitabine to gemcitabine + bolus 5-FU (see Table 7-5).12 There was a statisti-
111
Table 7-5
Study
Arms
Gemcitabine
Gemcitabine
+ 5-FU
Richards
Gemcitabine
(2004)
Gemcitabine
+ Pemetrexed
Louvet
Gemcitabine
(2004)
Gemcitabine
+ Oxaliplatin
Heineman Gemcitabine
(2003)
Gemcitabine
+ Cisplatin
Rocha Lima Gemcitabine
(2004)
Gemcitabine
+ Irinotecan
OReilly
Gemcitabine
(2004)
Gemcitabine
+ Exatecan
Bramall
Gemcitabine
(2002)
Gemcitabine
+ Marimastat
VanCutsem Gemcitabine
(2004)
Gemcitabine
+ Tipifarnib
# of
Patients
Time to
Tumor
Progress.
Median 1-Year
Survival Survival
162
160
119
120
2.2 mos
3.4 mos
(p<0.022)
3.6 mos
5.2 mos
(p<0.42)
3.7 mos*
5.5 mos
(p<0.04)
2.5 mos
4.6 mos
(p<0.016)
3.0 mos
3.5 mos
(p<0.35)
3.8 mos
3.7 mos
(p<0.22)
341
347
3.6 mos*
3.7 mos
5.4 mos
6.7 mos
(p<0.09)
6.3 mos
6.2 mos
(p<0.85)
7.1 mos
9.0 mos
(p<0.13)
6.0 mos
7.6 mos
(p<0.12)
6.6 mos
6.3 mos
(p<0.79)
6.2 mos
6.7 mos
(p<0.52)
5.5 mos
5.5 mos
(p<NS)
6.0 mos
6.4 mos
(p<0.75)
282
283
156
157
97
95
169
173
174
175
N/A
N/A
20.1%
21.4%
(p<0.72)
27.8%
34.7%
N/A
20%
20%
21%
23%
18%
17%
(p<NS)
24%
27%
112
Chapter 7
Table 7-6
Dose (mg/m2)
Frequency
Cycle Duration
Gemcitabine1
Weekly x 3 weeks
4 weeks
Gemcitabine
Weekly x 3 weeks
4 weeks
Gemcitabine
Leucovorin
5-FU
Weekly x 3 weeks
Weekly x 3 weeks
Weekly x 3 weeks
4 weeks
Gemcitabine
Cisplatin
Every 2 weeks
Every 2 weeks
4 weeks
Gemcitabine
Oxaliplatin
Day 1
Day 2
2 weeks
Cetuximab2
4 weeks
Gemcitabine1
Gemcitabine
Bevacizumab3
4 weeks
The first regimen only is considered standard care in pancreatic cancer. Others have been
or are being studied in phase III trials.The first drug administered is always listed on top.
1The
first cycle is usually given as 7 weekly infusions followed by 1 week of rest (total duration is 8 weeks).
2The first dose is 400 mg/m2 over 2 hours and subsequent doses are given over 60 mins.
3The first dose is given over 2 hours and infusion time is shortened to 1 hour over time.
113
BEYOND CHEMOTHERAPY
Because standard cytotoxic chemotherapy has had limited effects in pancreatic cancer, other approaches need to be sought. Rather than blocking DNA synthesis at various levels, the so-called targeted therapies inhibit proteins in signaling pathways that
promote tumorigenic phenotypes. For example, the epidermal growth factor receptor
(EGFR or HER1) is a member of the HER family of transmembrane tyrosine kinases.
It has 4 domains. The external receptor portion binds a ligand that results in homodimerization or heterodimerization with another member of the HER family.
Dimerization activates the internal tyrosine kinase portion, which initiates 2 kinase
pathways that produce cellular growth, proliferation, and metastasis. Antibodies to
EGFR block activation of the external receptor portion and small molecules inhibit the
activity of the internal tyrosine kinase domain. Cetuximab is a chimerized (70% human,
30% mouse) antibody to the EGFR that was tested in combination with gemcitabine in
a phase II trial.19 Of 41 patients enrolled, 5 (12.2%) responded and 63.4% had stable
disease. Median survival was 7.1 months with 31.7% of patients alive at 1 year. These
promising data have led to a large phase III trial in the Southwest Oncology Group
(SWOG). Of the small molecule inhibitors, erlotinib has been tested in pancreatic cancer in a phase III trial conducted by the National Cancer Institute of Canada (NCIC),
randomly assigning patients to gemcitabine alone or in combination with erlotinib.
Patients were randomized to gemcitabine + placebo vs gemcitabine + erlotinib given
orally as either 100 mg or 150 mg/day.20 Only 48 of the 569 patients enrolled were randomized to placebo vs 150 mg/day. The data have not been published or presented in a
scientific forum as of the beginning of 2005, but have been released on the Genentech
Web site (www.biooncology.com). When compared to gemcitabine alone, gemcitabine
+ erlotinib improved median survival from 5.9 to 6.4 months. One-year survival was
25.6% for gemcitabine + erlotinib compared to 19.6% for gemcitabine + placebo. When
converted to a hazard ratio of 0.81, this data was statistically significant (p=0.025).
There were no differences in response rates in the 2 arms and little is noted of extra side
effects on the erlotinib arm, although diarrhea and rash are known side effects. This trial
needs to undergo peer review to evaluate whether or not the apparent small benefits outweigh the risks of adding erlotinib to pancreatic cancer therapy.
Another cell signaling pathway that stimulates cellular growth is the ras pathway. Kras, one of the subtypes of Ras, has an activating mutation in >90% of pancreatic cancers that leaves the Ras pathway permanently on. The Ras proteins require posttranslational modification, including farnesylation, to get to the transmembrane position
required for its activity. Farnesyl transferase inhibitors were tested as inhibitors of the Ras
pathway in an attempt to improve upon gemcitabine, but tipifarnib (R115777) did not
add to the efficacy of single agent gemcitabine (see Table 7-5).21 The lack of efficacy of
114
Chapter 7
farnesyl transferase inhibitors do not prove that K-ras is not a good target, but may be
due to the fact that K-ras can undergo other forms of post-translational modification
than farnesylation.
The extracellular matrix in which cancer develops is now known to interact with the
cancer. In order to metastasize, cancer cells have to break free of their primary location,
migrate, invade, and alter the environment to allow growth. At the center of this development is an enhanced understanding of tumor angiogenesis, the process by which
tumors break down the extracellular matrix and stimulate new blood vessel growth to
allow for larger sized masses to develop.
Matrix metalloproteinases (MMPs) are proteins that degrade components of the
extracellular matrix. The activity of some of these MMPs allows for invasion and angiogenesis to occur. Two matrix metalloproteinase inhibitors (MMPIs) were tested in pancreatic cancer patients. Both marimastat and BAY 12-9566 were less effective than gemcitabine (see Table 7-4).22,23 When added to gemcitabine, marimastat did not improve
upon single-agent gemcitabine results (see Table 7-5).24 Since these trials, scientific
understanding of MMPs has continued to develop. Whether this will lead to more effective therapy is not yet known.
More recently, promise has been shown by an inhibitor of vascular endothelial
growth factor (VEGF). VEGF is produced by a variety of epithelial tumors, including
pancreatic cancers. VEGF stimulates vascular growth and permeability as well as sustains
survival of tumor vasculature. Bevacizumab is a humanized monoclonal antibody (95%
human, 5% mouse) that binds VEGF, preventing it from activating its receptor. A multiinstitutional phase II trial of bevacizumab + gemcitabine showed promising median survival of 8.7 months, 1-year survival of 29%, and an excellent response rate of 19%.25
This data led to the development of the current Cancer and Leukemia group B
(CALGB) trial randomly assigning patients to gemcitabine vs gemcitabine + bevacizumab.
Immune Therapy
The goal of immune therapy is to utilize the immune system to selectively kill cancer cells without harming normal cells. Two methods have recently shown promise in
developing immune therapy. G17DT is a fusion protein consisting of gastrin 17 and
diphtheria toxin. Through administration of G17DT, neutralizing antibodies to glycineextended gastrin 17 may be formed. pancreatic cancers can be stimulated by amidated
gastrin to increase expression of EGFR ligands, matrix metalloproteinases, and antiapoptotic factors. A phase II randomized trial of G17DT versus placebo in patients
unable to or unwilling to undergo chemotherapy was reported.26 Median survival for
G17DT was 5 months compared to 2.7 months for placebo (p=0.03). These data warrant further investigation.
An alternative immune therapy approach is to vaccinate the patient against proteins
that are preferentially expressed by tumor cells. Two examples of such proteins are
MUC-1 and CEA. A recently reported phase I trial vaccinated patients to CEA using a
vaccinia CEA vaccine for one dose then a fowlpox CEA vaccine, both of which were coadministered with 3 T-cell costimulatory molecules.27 Enhanced CEA-specific T cell
responses were seen in the majority of patients and intriguing stable diseases were seen
in a variety of cancers. This agent is currently being studied in a randomized trial vs 5FU or irinotecan as treatment for pancreatic cancer patients who have progressed on
gemcitabine.
RANDOMIZE
SWOG S0205
Target Accrual: 704
RANDOMIZE
CALGB 80303
Target Accrual: 590
RANDOMIZE
115
Figure 7-1. Cooperative group randomized trials open in the United States as
of January 1, 2005.
CONCLUSION
Systemic therapy of pancreatic cancer has had limited impact on the natural history
of disease. While oxaliplatin or altering the schedule of gemcitabine may still improve
upon the results of single agent gemcitabine, future benefits from chemotherapy are likely to be limited. Therefore, newer targeted therapies and immune therapies provide
hope for more significant improvements in disease control. Currently active United
States cooperative group trials are depicted in Figure 7-1.
116
Chapter 7
Table 7-7
CHEMORADIATION REGIMENS
Agent
Dose
Schedule
Duration
# of Courses
Days 1 to 3
During XRT
XRT
350 mg/m2
bolus
1.8 Gy/day
Daily x 5 each
week
2 weeks
2 courses
separated by a 2
week break
5-FU
200 mg/m2/day
During XRT
1 course
XRT
1.8 Gy/day
Continuous
infusion
Daily x 5 each
week
Orally BID
Daily x 5 each
week
During XRT
5.5 weeks
(50.4 Gy)
1 course
Weekly
During XRT
1 course
Daily x 5 each
week
5.5 weeks
(50.4 Gy)
Weekly x 3
During XRT
Daily x 5 each
week
3 weeks
(36 Gy)
5-FU
Gemcitabine
XRT*
1000 mg/
m2/week
2.4 Gy/day
5.5 weeks
(50.4 Gy)
1 course
size was reduced at 39.6 Gy; *Field size was much smaller than standard
In an attempt to improve upon overall disease control, chemotherapy was administered both during radiation therapy (chemoradiation) to sensitize cells to radiation for
improved local control and after radiation to improve systemic control of pancreatic cancer. The Gastrointestinal Tumor Study Group (GITSG) performed a randomized trial
comparing 60 Gy of radiation to either 40 Gy or 60 Gy of radiation in combination
with 5-FU chemotherapy.28 The radiation was given in 2-week blocks administering 2
Gy fractions 5 days per week for 2 weeks (total=20 Gy over 2 weeks) followed by 2-week
breaks (Figure 7-2A). Therefore, the 40 Gy arm had 1 break during radiation and the
60 Gy arms had 2 breaks. Both chemotherapy + radiation arms performed significantly better than the radiation alone arm. Survival times for the high dose and low dose
chemoradiation arms were 9.3 months and 9.7 months, respectively, while it was only
5.3 months for radiation alone.29 This established chemoradiation as a standard against
which to compare other treatments. In addition, using this administration schedule, this
study established that higher doses of radiation were not better than 40 Gy. The GITSG
5-FU
5-FU
SMTuWThFSa
SMTuWThFSa
2 Weeks No Treatment
Radiation Therapy
117
Radiation Therapy
Radiation Therapy
Radiation Therapy
Radiation Therapy
Figure 7-2. Graphic view of 5-FU + radiation schedules used in trials in pancreatic cancer.
118
Chapter 7
only an 8.2 month median survival at the expense of serious (grade 3 or 4) hematologic toxicity in 21% of patients and grade 3 gastrointestinal toxicity in 10% of patients.
This survival was not felt to be long enough to further pursue the regimen. An interesting phase I approach was to administer the gemcitabine at full dose then escalate the
radiation dose. In this case, weekly gemcitabine of 1000 mg/m2 was used during a 3week course of radiation therapy.34 The dose per fraction of radiation for the phase II
trial was 36 Gy over 15 fractions (2.4 Gy per fraction). This trial also employed smaller
radiation fields than used on other studies, meaning that these data are not applicable to
a standard field size. When 41 locally advanced, unresectable patients and preoperative
resectable patients were treated, two patients responded to therapy and 25 had stable disease while 20% had grade 3 gastrointestinal toxicities. The investigators have now successfully added cisplatin to this gemcitabine + radiation regimen.35 Finally, in at least one
trial, adding gemcitabine to standard infusional 5-FU + radiation was not well tolerated.36
CONCLUSION
Locally advanced disease patients are currently treated with chemotherapy alone
(included with patients on metastatic trials) or with chemotherapy + radiation. The current ECOG randomized trial will help to define the role of chemoradiation vs
chemotherapy alone by testing gemcitabine with or without radiation therapy. Other
groups are trying to improve upon chemoradiation by adding newer agents such as
cetuximab, erlotinib, and bevacizumab.
RESECTABLE DISEASE
Patients with resectable disease represent a small subset (<10% of all patients) of pancreatic cancer patients. However, even if the cancer can be completely removed with negative margins (no microscopic or macroscopic residual disease at the cut edges), the
majority still have recurrences, with only 20% of patients alive at 5 years.
Adjuvant therapy is the term used for treatment administered to patients who have
completed a definitive primary therapy such as surgery. The purpose of adjuvant therapy is to eliminate microscopic residual disease and reduce risk of cancer recurrence.
Patients with pancreatic cancer who have undergone complete resection with negative
margins (R0) or with only microscopic residual disease (R1) have been studied to learn
the benefits of either chemotherapy alone or in combination with radiation therapy for
adjuvant treatment. Data on adjuvant therapy remain limited.
The GITSG compared surgery alone to a treatment arm consisting of surgery followed first by combined chemotherapy with radiation (chemoradiation) and subsequently by 24 months of weekly bolus 5-FU chemotherapy.37 The chemoradiation consisted of bolus 5-FU on days 1 to 3 of each of two 2-week courses of 20 Gy of radiation,
totaling 40 Gy. Forty-three patients were randomized over 8 years. Survival in the control arm was 11 months compared to 20 months in the adjuvant treatment arm
(p=0.035). However, this trial was small and took a long time to accrue. To confirm the
findings of the randomized trial, the GITSG subsequently enrolled 30 patients on a
phase II adjuvant trial using the same regimen of chemoradiation followed by 2 years of
weekly bolus 5-FU.38 At 18 months, the median survival was similar to the treatment
arm of the phase III trial. These results suggest that chemoradiation followed by
chemotherapy can be considered a possible standard option for adjuvant therapy.
119
However, as discussed earlier, there is theoretical benefit for more continuous administration of both 5-FU and radiation, particularly in combination. In a large randomized
trial of rectal cancer adjuvant therapy, continuous infusion 5-FU combined with radiation therapy significantly improved disease-free and overall survival compared to bolus
administration of 5-FU. Although rectal cancer is a different disease, theoretically the
principles hold for radiation sensitization between disease sites.
The EORTC conducted a randomized trial comparing continuous infusion 5-FU
and 50.4 Gy radiation (Figure 7-2B) after surgery versus surgery alone.39 No chemotherapy was given after completing chemoradiation. This trial enrolled 207 patients, of
whom 114 were pancreatic cancer patients. The remaining patients had periampullary
tumors. For the overall group, there was no difference in median survival between the
surgery alone arm and the chemoradiation arm (19 months vs 24.5 months, respectively, p<NS). At 5 years, 28% of patients receiving chemoradiation were still alive compared to 22% of patients who did not have adjuvant therapy, which was also not statistically significant. However, when a subset analysis was performed, the pancreatic cancer patients had a trend toward improved survival favoring the chemoradiation arm
(17.1 months vs 12.6 months, p=0.099), suggesting a need for further studies to be performed.
The most recently reported randomized trial, titled ESPAC-1, was designed to evaluate the roles of both chemotherapy and chemoradiation.40,41 A 2-x-2 design was
employed in which patients were randomized to either chemotherapy or no chemotherapy and chemoradiation or no chemoradiation (referring to chemotherapy during radiation only). If patients were randomized to chemoradiation or chemotherapy, then the
chemoradiation was administered first. Chemotherapy consisted of bolus 5-FU for 6
months. Chemoradiation consisted of bolus 5-FU in combination with radiation
administered in the same split-course therapy as in the GITSG trial (see Figure 7-2A).
ESPAC-1 was designed to evaluate only the patients randomized in a 2-x-2 fashion, but
some institutions were allowed to enroll patients in only one of the two randomizations.40 These patients were never designed to be part of the primary evaluation. In the
preliminary report of ESPAC-1, the patients randomized in a 2-x-2 fashion were combined with the subsets that were only randomized once. The data suggested that benefit
came from chemotherapy compared to no chemotherapy but no benefit was derived
from the use of chemoradiation. The final report was recently released with 47 months
median follow-up for survivors.41 Because the primary analysis was designed to evaluate
only the 289 patients in the 2-x-2 randomization group, the subset randomized only
once was not included in the final report. The patients randomized to chemotherapy
had a statistically significantly longer median survival than patients not randomized to
chemotherapy (20.1 months vs 15.5 months, respectively, p=0.0009). In contrast, those
patients randomly assigned to chemoradiation had a nonsignificant shorter survival than
those randomized to no chemoradiation (15.9 months vs 17.9 months, respectively,
p<NS). Although this study suggested a possible detriment from chemoradiation,
ESPAC-1 used a split-course radiation therapy with bolus 5-FU. The trial does not
address the role of infusional 5-FU administered concurrently with a more continuous
course of radiation.
Current clinical trials are attempting to integrate other agents into the adjuvant therapy of pancreatic cancer. Gemcitabine, 2,2-difluorodeoxycytidine, is a cytidine analogue that is activated to a phosphorylated form and incorporated into DNA, resulting
in chain termination (triphosphate form) and also inhibits the enzyme ribonucleotide
reductase (diphosphate form). It is the current standard therapy for metastatic disease.
120
Chapter 7
CONCLUSION
Four randomized trials have been conducted in adjuvant therapy of pancreatic cancer thus far. ESPAC-1 has established a benefit to adjuvant chemotherapy with 5-FU
and established that split course chemoradiation is ineffective. However, questions still
remain as to the role of chemoradiation using more modern regimens, the role of neoadjuvant therapy, and the impact of newer systemic agents.
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33. Blackstock AW, Tepper JE, Niedwiecki D, et al. Cancer and leukemia group B
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34. McGinn CJ, Zalupski MM, Shureiqi I, et al. Phase I trial of radiation dose escalation
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35. Muler JH, McGinn CJ, Normolle D, et al. Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with Gemcitabine and
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776-782.
chapter
Endoscopic Retrograde
Cholangiopancreatography
in the Management of
Pancreaticobiliary Neoplasia
Ilias Scotiniotis, MD
INTRODUCTION
Pancreaticobiliary malignancies can be divided into tumors of the ampulla of Vater,
tumors of the bile ducts, tumors of the pancreas, and metastatic disease affecting the biliary system. Endoscopy had little role in the management of these conditions until
1968, when the first description of endoscopic cannulation of the ampulla of Vater was
published, thus signaling the birth of ERCP. This was followed in 1979 by the first
description of biliary stent placement, which greatly increased the therapeutic utility of
pancreaticobiliary endoscopy. In the years that followed, ERCP became the gold standard for imaging and draining the pancreaticobiliary tree. At present, a large portion
of the 30,000 cases of pancreatic cancer and 7000 cases of biliary cancer diagnosed each
year in the United States undergo ERCP at some point in the course of their illness. The
recent development of less invasive diagnostic modalities, such as dual-phase helical CT,
MRCP, and EUS, results in a fine-tuning of the application of ERCP, such that a majority of these procedures are now performed with therapeutic rather than diagnostic
intent. This chapter will discuss the role of ERCP in the evaluation and management of
pancreaticobiliary malignancies.
TECHNIQUE
OF
ERCP
126
Chapter 8
cially designed with side-viewing orientation to offer an en face view of the major
papilla. The outer diameter of a duodenoscope is 10.5 to 12.5 mm, as compared with a
diameter of 9 mm for a diagnostic upper endoscope. It should be noted that the sideviewing orientation of the endoscopes used for ERCP allows for only a cursory examination of the esophagus, stomach, and duodenal bulb. Examination of the upper gastrointestinal tract with a side-viewing duodenoscope is therefore not a substitute for
evaluation with a forward-viewing upper endoscope, except for those with experience.
In a patient with a prior gastrectomy and Billroth II anastomosis, reaching the
ampulla of Vater can be a challenge, since the duodenoscope must ascend the length of
the afferent limb in a retrograde direction. Pyloric or duodenal stenosis or a Roux-en-Y
gastrojejunostomy may make it impossible to reach the papilla. Once the major papilla
has been reached in the second portion of the duodenum, a cannulation catheter is
passed through the working channel of the endoscope. By maneuvering the tip of the
endoscope and angling the tip of the catheter with an elevator lever, selective cannulation of the bile duct or pancreatic duct is performed. Radiopaque dye is then injected
under fluoroscopic inspection. Selective cannulation of the desired duct requires considerable endoscopic skill and experience. Successful cannulation should be achieved in
more than 90% of cases. A variety of catheter designs and guidewires are available to
assist in cannulation.
ENDOSCOPIC STENTING
The technique of endoscopic stent placement across an obstructive biliary lesion is
relatively straightforward once the stricture has been traversed with a guidewire. In the
majority of cases, it is not necessary to cut through the muscular fibers of the sphincter
of Oddi (ie, sphincterotomy) prior to placing a biliary stent. On the other hand, sphincterotomy may be helpful if multiple stents are to be placed (which is sometimes done for
lesions at the hepatic duct bifurcation) or if subsequent stent exchanges are anticipated.
Similarly, dilation of the stricture is usually not performed, but may be necessary prior
to stent placement for complex, tight strictures.
The stents most commonly used in patients with malignant obstruction are made of
polyethylene and have flaps at both ends to prevent migration. They have a slightly
curved shape to conform to the course of the bile duct. Pigtail stents are rarely used
because they have been shown to have lower flow rates. The typical stent has an outside
diameter of 10 French (3.3 mm), allowing it to fit through the channel of the endo-
127
128
Chapter 8
COMPLICATIONS
OF
ERCP
Complications related to ERCP can be divided into those that are inherent to any
prolonged endoscopic procedure and those that are specific to ERCP and sphinctorotomy. The former include aspiration pneumonia, adverse cardiovascular or neurologic
events related to sedation, drug reactions, and perforation. The most common ERCPspecific complication is pancreatitis, occurring in 5% of patients and accounting for
more that half of the total complications (Table 8-1). Typical pancreatitis-like pain is
present in those cases. The mere elevation of serum levels of pancreatic enzymes is not
diagnostic of post-ERCP pancreatitis, since 75% of uncomplicated ERCPs are followed
by a transient bump in amylase or lipase levels. Sphincterotomy may be complicated
by serious bleeding in 2% of cases, and this can be managed endoscopically in the great
majority of cases. Cholangitis, occurring in about 1% of ERCP procedures, usually
results from inadequate ductal drainage following contrast injection.
Complications specific to stent placement include stent migration and stent occlusion. The clinical picture of the 2 is indistinguishable, since they both result in recurrence of obstruction and possibly cholangitis. Stent migration may be spontaneous or
caused by inappropriate placement. If a stent migrates proximally (into the bile duct), it
has to be retrieved endoscopically, since a nondraining stent will form the nidus for
infection. If a stent migrates distally, its distal end may compress and erode into the duodenal wall opposite the ampulla of Vater, causing hemorrhage or perforation. If it passes completely out of the bile duct into the duodenal lumen, it need not be retrieved and
can be left to pass spontaneously.
129
Table 8-1
Percent With
Complication
Percent With
Severe Complication
5.4
2.0
0.3
1.0
1.0
1.1
9.8
0.4
0.5
0.2
0.1
0.1
0.3
1.6
*Includes cardiopulmonary complications, ductal perforations by guidewire, stent malfunction, antibiotic-induced diarrhea, indeterminate fluid collection, and infection of pancreatic
pseudocyst.
IN
In patients who present with painless jaundice due to malignancy, 85% of tumors are
pancreatic carcinomas, 6% are cholangiocarcinomas, and 4.5% each are duodenal and
ampullary carcinomas. Making the distinction between these is important, since duodenal and ampullary lesions have a significantly better prognosis. Until fairly recently,
ERCP represented the most effective method of imaging the pancreaticobiliary system.
The emergence of helical CT in the past decade has resulted in a reassessment of that
role. A helical CT performed with a pancreatic protocol provides fine cuts through the
pancreas during both the arterial and venous phases, and is a sensitive means of detecting tumors of the pancreatic head, the most common type of pancreaticobiliary malignancy. A helical CT should therefore be obtained early in the evaluation of a patient
with suspected pancreaticobiliary malignancy, preferably with a dual-phase, fine-cut
pancreatic protocol.
In a significant number of patients, however, diagnostic uncertainty remains after the
initial CT. This may be either because a typical mass in the head of the pancreas is not
seen, which is the case in bile duct, ampullary, and duodenal cancers, or because of
inherent limitations of the CT study, such as not performing it with a pancreatic protocol. Several options exist in that setting (Figure 8-2). One is to obtain indirect cholangiopancreatography using MRI. The technique of MRCP is noninvasive and does not
expose the patient to the ERCP risk of pancreatitis and cholangitis. A second option is
to clarify any indeterminate CT findings in the pancreas through EUS. This modality is
performed by placing the tip of an ultrasound-emitting endoscope adjacent to the head
of the pancreas in the second portion of the duodenum. It uses high ultrasound frequencies to obtain high resolution images of the pancreatic parenchyma and is a highly
130
Chapter 8
Ultrasound
Biliary dilation?
Yes
No
Work-up for cholestatic liver disease
Hepatitis/drug/autoimmune screen
Consider MRCP, liver biopsy
Suspected pancreaticobiliary
malignancy
Mass?
No/Not sure
Yes
Surgical candidate and
potentially resectable?
(Consider laparoscopy)
Yes
Yes
Mass?
No
No/Not sure
Consider EUS-FNA
for tissue confirmation
Surgery
Figure 8-2. An algorithm for the evaluation of a patient with painless jaundice.
sensitive means of detecting neoplastic lesions in the pancreas. EUS can be coupled with
FNA of a suspicious lesion, with a reported sensitivity of 93% and a specificity of 100%
in the detection of pancreatic malignancy2 (Figure 8-3). EUS is thus evolving as a procedure of choice in the investigation of atypical presentations of pancreatic malignancy.
For many reasons, however, ERCP remains an important diagnostic tool in pancreaticobiliary malignancy. First, both MRCP and EUS of a high quality still remain the
purvue of large, specialized centers and are often not available to the wider medical community. Second, ERCP offers direct visualization of the duodenum and ampulla and is
the superior means of diagnosing tumors in those locations (Figure 8-4). Third, in cases
of a biliary stricture, it can provide the definitive diagnosis by tissue cytology or biopsy.
A final argument in support of ERCP for atypical presentations of malignancy is that
all experienced endoscopists have been occasionally surprised by the unexpected finding
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Chapter 8
132
Table 8-2
CONFIRMATION OF MALIGNANCY
A malignant stricture on cholangiogram typically displays an abrupt transition
between normal and abnormal bile duct, the so-called shouldering or shelflike
appearance. The location of a stricture can also determine the likelihood of malignancy,
since benign strictures are almost never found at the level of the hepatic duct bifurcation. However, the appearance of a biliary stricture on ERCP cannot be considered
pathognomonic for malignancy. Even the double-duct sign (ie, concomitant narrowing of the bile duct and the pancreatic duct with upstream dilatation), initially proposed
as a specific indicator of pancreatic cancer, may be seen in benign disease such as chronic pancreatitis. The causes of benign biliary stricture are listed in Table 8-2.
Tissue confirmation of malignancy should therefore always be sought (Figure 8-5).
Techniques of tissue confirmation on ERCP include forceps biopsy, bile or pancreatic
juice aspiration, and brush cytology.3 Forceps biopsy of the stricture generally requires a
sphincterotomy to allow passage of the forceps into the bile duct or pancreatic duct
(Figure 8-6). Bile or pancreatic juice aspiration has unacceptably low sensitivity for the
detection of malignancy, around 20%. From a practical standpoint, therefore, most
endoscopists limit tissue acquisition to brush cytology, because a brushing catheter can
easily be passed into the duct over a guidewire.
Brush cytology has been demonstrated to have a sensitivity of approximately 40% in
cases of cancer. This may be explained by the fact that pancreatic cancer often causes bile
duct obstruction by means of extrinsic compression rather than direct invasion.
Brushing a concomitant pancreatic duct stricture has not been shown to improve the
yield significantly, but may be a reasonable supplement if it can be performed easily. The
yield of brushings is even lower if obstruction is caused by hilar lymphadenopathy, local
extension from an adjacent tumor (eg, gallbladder carcinoma), or metastatic disease
within the liver parenchyma. On the other hand, if obstruction is caused by a cholan-
133
134
Chapter 8
Figure 8-6. A forceps has been advanced into the bile duct to obtain a
biopsy.
135
ERCP
IN
STAGING TOOL
PANCREATICOBILIARY MALIGNANCY
AS A
Surgery offers the only means of potential cure in malignant tumors of the pancreas
and bile duct. From the surgeons point of view, staging of pancreaticobiliary malignancy requires answers to 2 questions. First, are there distant metastases either intra-abdominally or extra-abdominally? Second, is there local spread of tumor that precludes surgical resection?
With regard to the first question, distant metastases are usually found in the liver,
lungs, and peritoneal surfaces. They are detected by CT or MRI, or laparoscopy in the
case of peritoneal lesions. ERCP clearly has no role in the evaluation of these sites of dis-
136
Chapter 8
tant metastases. With regard to the second question, surgery may be precluded by the
invasion of vascular structures (portal vein, superior mesenteric vein, superior mesenteric
artery, and hepatic artery) or lymph node metastases outside the zone of resection (such
as celiac lymph node involvement). The extent of involvement with tumor of the bile
duct or pancreatic duct itself is not a staging consideration because the tumors do not
spread to the limit of resection of the bile duct or pancreatic duct without being unresectable for other reasons. As a result, information gleaned at ERCP has little value in
the decision whether or not to operate.
One special category of tumors is that of hilar cholangiocarcinomas (also known as
Klatskin tumors). These account for about two-thirds of all cholangiocarcinomas. In
these lesions, the extent of bile duct involvement, especially in terms of the upper margin, is critical in determining resectability. Surgery is a reasonable option only for the
rare lesions that are located below the bifurcation of the hepatic ducts (Bismuth I
lesions), but not for those that extend into or above the bifucation (Bismuth II, III, or
IV lesions). Cholangiography is therefore an important part of staging. This can be performed either by ERCP or MRCP. MRCP has the advantage of providing information
about vascular staging and local hepatic extention as well. Furthermore, full delineation
of the extent of disease in both left and right hepatic ductal systems by ERCP will result
in the need for bilateral stent placement to drain the opacified ducts. For those reasons,
MRCP is the preferred diagnostic method in patients with suspected hilar cholangiocarcinoma. Thus, ERCP overall has only a limited role in the staging of most pancreaticobiliary tumors.
137
dice can be accomplished either by endoscopic stent placement or by surgical biliaryenteric bypass, the relative merits of which have been examined in a number of studies.
The most rigorous of these, published in 1994, showed that the endoscopic approach
was associated with lower morbidity and mortality.10 This study has been criticized for
the unusually high number of postoperative intra-abdominal abscesses and the surgeryrelated mortality of 14% that it reported. On the other hand, it showed that if a patient
survived surgical biliary-enteric bypass, there was rarely an episode of recurrent jaundice
down the road. Superiority of the endoscopic approach shown in this study forms the
basis for the current preference in most centers of endoscopic stent placement over surgical bypass in unresectable malignant biliary obstruction. As a result, most surgeons vigorously attempt to identify unresectable cases preoperatively, even employing
laparoscopy to rule out occult peritoneal metastases, so as to avoid an exploratory laparotomy that would result in palliative surgical bypass.
The preference for endoscopic palliation in inoperable biliary obstruction has been
strengthened by the development of SEMS, as noted earlier. These were initially
designed for percutaneous deployment, but were later modified for endoscopic placement (Figure 8-8). SEMS offer the benefit of longer patency than plastic (polyethylene)
stents because of their wider lumen. For distal bile duct malignant obstruction, the tip
138
Chapter 8
of the metal stent is left outside the papilla. For more proximal biliary tree lesions (e.g
within the common hepatic duct), it is possible to place a SEMS entirely within the bile
duct. In a multicenter, randomized trial of a common type of SEMS in comparison to
10 French plastic stents for the palliation of malignant biliary obstruction, overall complication rates were significantly lower in the SEMS group than the plastic stent group
(20% vs 31 and p <0.05), mostly accounted for by a 2.8-fold reduction in the probability of stent occlusion.11 The prolonged patency and reduced need for repeat endoscopic intervention translates into a cost benefit for the metallic stent, despite its initial
high cost. Thus, metallic stent placement is generally recommended for inoperable
patients whose life expectancy exceeds the expected patency period of 4 to 6 months of
a plastic stent. A recent randomized study suggested that absence of liver metastases
identifies the group of patients for whom metal stent placement is cost effective.12 As
endoscopists have increased their familiarity with SEMS, it has become possible to treat
large tumors that are eroding into the duodenum by simultaneous placement of separate
metal stents into the bile duct and the duodenum.13 However, if diagnostic uncertainty
exists, a plastic rather than a metal stent should be placed to avoid permanent embedding into the bile duct wall.
The palliation of jaundice in patients with hilar cholangiocarcinomas poses a special
challenge. Bilateral placement of stents is technically arduous, and not always feasible
even in the best endoscopic hands. The realization that only 25% of the liver needs to
be drained to relieve jaundice has led to a trend toward unilateral stent placement. This
has been supported by randomized studies showing no benefit for a policy of bilateral
stent placement over a simpler approach of unilateral drainage.14 One possible strategy
is the use of MRCP or CT to guide unilateral stent placement into the larger of the 2
biliary systems, thus avoiding stent placement into atrophic liver segments.15
CONCLUSION
The most sensible approach toward pancreaticobiliary malignancy combines considerations of diagnosis, staging, and therapy. There are few evidence-based studies to prove
the superiority of one single approach, and the rapid pace of change in imaging and
endoscopic techniques will likely preclude any such studies from being performed. In
synthesizing the available evidence, one hypothetical approach is the choice of a helical
CT performed on a pancreatic protocol as the best first test for patients with suspected
pancreaticobiliary malignancy. This approach will likely visualize a tumor if one is present and identify its local spread into vessels and surrounding structures, as well as hepatic metastases. Staging may then be complemented by laparoscopy for evaluation of peritoneal surfaces. If uncertainty persists, EUS or MRI with MRCP may clarify the picture.
These modalities have tended to supplant the previous role of ERCP as a crucial diag-
139
nostic tool. The current trend is toward deferring possible ERCP until after a presumptive diagnosis has been made and thorough staging has been completed (see Figure 8-2).
In this approach, ERCP is reserved for patients in whom a tissue diagnosis has to be confirmed preoperatively, for those who have a rare indication for preoperative decompression (such as cholangitis), and, most importantly, for palliation of biliary obstruction
when the tumor is deemed unresectable. Preoperative stent placement is not universally
recommended, because it does not improve surgical outcomes in malignant biliary
obstruction. If a stent is placed in an unresectable tumor, the choice of stent type is
determined on an individual basis and based largely on each patients life expectancy.
This approach has been endorsed in a statement issued by a conference recently convened by the National Institutes of Health regarding utilization of ERCP.16 Nevertheless,
ERCP maintains an important diagnostic role as one moves further from typical toward
atypical presentations (eg, when noninvasive modalities fail to reveal a malignantappearing mass). In that instance, ERCP offers the advantages of direct endoscopic visualization of the duodenum and ampulla as well as the ability to brush or biopsy a biliary
stricture.
REFERENCES
1. Schilling D, Rink G, Arnold JC, et al. Prospective, randomized, single-center trial comparing 3 different 10F plastic stents in malignant mid- and distal bile duct strictures.
Gastrointest Endosc. 2003;58:54-58.
2. Hunt GC, Faigel DO. Assessment of EUS for diagnosing, staging, and determining
respectability of pancreatic cancer: a review. Gastrointest Endosc. 2002;55:232-237.
3. De Bellis M, Sherman S, Fogel EL, et al. Tissue sampling at ERCP in suspected malignant biliary strictures (part 2). Gastrointest Endosc. 2002;56:720-730.
4. Siqueira E, Schoen RE, Silverman W, et al. Detecting cholangiocarcinoma in patients
with primary sclerosing cholangitis. Gastrointest Endosc. 2002;56:40-47.
5. Hawes RH. Diagnostic and therapeutic uses of ERCP in pancreatic and biliary tract
malignancies. Gastrointest Endosc. 2002;56.
6. Vazquez-Sequeiros E, Baron TH, Clain JE, et al. Evaluation of indeterminate bile duct
strictures by intraductal US. Gastrointest Endosc. 2002;56:372-379.
7. Strasberg SM. ERCP and surgical intervention in pancreatic and biliary malignancies.
Gastrointest Endosc. 2002;56.
8. Povoski SP, Karpeh MS Jr, Conlon KC, Blumgart LH, Brennan MF. Preoperative biliary drainage: impact on intra-operative bile cultures and infectious morbidity and mortality after pancreaticoduodenectomy. J Gastrointest Surg. 1999;3:496-505.
9. Padillo J, Puente J, Gomez M, et al. Improved cardiac function in patients with obstructive jaundice after internal biliary drainage: hemodynamic and hormonal assessment.
Ann Surg. 2001;234:652-656.
10. Smith AC, Dowsett JF, Russell RC, Hatfield AR, Cotton PB. Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet.
1994;344:1655-1660.
11. Carr-Locke DL, Ball TJ, Connors PJ et al. Multicenter randomized trial of Wallstent
biliary endoprosthesis versus plastic stents. Gastrointest Endosc. 1993;39:310.
12. Kaassis M, Boyer J, Dumas R, et al. Plastic or metal stents for malignant stricture of the
common bile duct? Results of a randomized prospective study. Gastrointest Endosc.
2003;57:178-182.
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Chapter 8
chapter
INTRODUCTION
Colorectal cancer is a common malignancy in the United States. The development
of cancer is preceded by a premalignant precursor lesion, the adenomatous polyp, or
adenoma. Screening for colorectal cancer provides the opportunity to detect and remove
the adenoma, thus interrupting its potential progression to invasive cancer. In addition,
screening also allows for the detection of colorectal cancer prior to the onset of symptoms, thus potentially allowing for cancer diagnosis at an early, more curable stage of
disease. This chapter will review currently utilized screening modalities and recommended screening and surveillance guidelines for average- and increased-risk individuals.
BACKGROUND
Colorectal cancer accounts for significant morbidity and mortality in the United
States. It is the fourth most common type of cancer, and the second most common
cause of cancer-related death among American men and women.1 In 2005, it is estimated that there will be approximately 145,000 new colorectal cancer cases diagnosed
and about 56,000 deaths from this disease. The lifetime risk of developing colorectal
cancer in the United States is approximately 6%.
Colorectal cancer is one of the few cancers that can be detected early by the presence
of a premalignant lesion, the adenomatous polyp, or adenoma. Colorectal polyps are
classified as either neoplastic (adenoma) or non-neoplastic. Although all adenomas have
malignant potential, the majority are benign when detected. Adenomatous polyps are
subcategorized histologically as tubular, villous, or tubulovillous adenomas, as well as by
the degree of dysplasia. Advanced adenomas may demonstrate HGD (dysplastic cells
limited to the epithelium, with no extension beyond the basement membrane) or contain invasive cancer (invasion through the muscularis mucosa into the submucosa). In
contrast, non-neoplastic polyps include hyperplastic, mucosal, inflammatory, and
hamartomatous polyps.
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Chapter 9
SCREENING
IN
AVERAGE-RISK INDIVIDUALS
Average-risk individuals are asymptomatic men and women over 50 years of age,
with no personal or family history of colorectal cancer or polyps, and no personal history of inflammatory bowel disease (IBD). Routine screening for colorectal cancer is
indicated in all appropriate average-risk individuals starting at age 50. Currently-used
screening tests include the fecal occult blood test (FOBT), sigmoidoscopy, barium
enema, and colonoscopy. Following are reviews these tests and the recommended screening strategies.
143
Table 9-1
Nottingham4
(UK)
Funen5
(Denmark)
N
46,551
Age of subjects
50 to 80
Test frequency
Annual or biennial
Compliance
75%
Positive tests
2.4%
Follow-up
13 to 18 years
Test rehydration
Rehydrated
Mortality reduction
21% to 33%
PPV
31%
Sensitivity
80% to 92%
Specificity
90% to 98%
152,850
45 to 74
Biennial
53%
2.3%
7.8 years
Nonrehydrated
15%
53%
72%
98%
140,000
45 to 75
Biennial
67%
1%
10 years
Nonrehydrated
18%
NR
NR
NR
Three large prospective randomized controlled trials demonstrate that FOBT screening reduces mortality from colorectal cancer2-5 (Table 9-1). Individuals with a positive
FOBT were followed up with colonoscopy. The Minnesota trial examined over 46,000
patients 50 to 80 years of age with annual or biennial FOB testing, as compared to a
control group with no screening. After 13 years of patient follow-up, the cumulative
mortality from colorectal cancer was reduced by 33%. Eighteen-year follow up data
showed a persistent 33% mortality reduction with annual FOB testing, and a 21% mortality reduction with biennial testing, as well as a reduction in the incidence of advanced
colorectal cancer.2,3
Similar results have been seen worldwide. A British study of over 152,000 patients
aged 45 to 74 years randomized to biennial screening reduced colorectal cancer mortality by 15% over a median follow-up of almost 8 years. Tumors were also detected at earlier stages as compared with the control group not offered screening.4,6 A study from
Denmark of 140,000 patients aged 45 to 75 years demonstrated an 18% reduction in
colorectal cancer mortality using biennial screening.5 In addition to decreasing mortality, FOBT screening has also been shown to reduce the incidence of colorectal cancer.7
FOBT attempts to detect blood loss from colorectal cancers and premalignant
polyps; however, these neoplastic lesions may bleed intermittently. The sensitivity of
FOBT has been estimated to range from approximately 30% to 50%.8 The positive predictive value of a positive FOBT for a colorectal cancer has been estimated to be 5% to
18%, and for early stage cancer 3% to 14%.8 Thus when used as a screening modality,
FOBT must be performed on multiple stool samples, and repeated on an annual basis
to maximize chance of detection of blood loss from colorectal neoplasia. Rehydration of
FOBT specimens is not recommended in general practice because although it increases
the sensitivity of the test, it also substantially increases false positive rates, thus reducing
test specificity.
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Advantages of FOBT include its low cost, ready availability, and noninvasive nature.
Disadvantages include need for annual testing, relatively low sensitivity and positive predictive value for detecting colorectal cancer, high false positive rates that lead to unnecessary invasive investigations and their associated risks, and need for dietary restrictions
during testing.
New immunohistochemical FOBTs have been developed that utilize monoclonal
and/or polyclonal antibodies to detect human hemoglobin in stool. Since these tests do
not react with nonhuman hemoglobin in red meat and certain vegetables and fruits that
contain peroxidase activity, dietary restrictions are not required, and an expected
decrease in false positives should result in increased test specificity.
SIGMOIDOSCOPY
Flexible sigmoidoscopy, typically performed utilizing a 60 cm scope, allows for direct
visualization of the distal segments of the large bowel, up to about the distal one-third
of the colorectum. Sigmoidoscopy provides a very sensitive examination of the distal colorectal mucosa and allows for biopsy of polyps or mass lesions identified within the segments of distal large bowel evaluated during this examination. Screening sigmoidoscopy
is performed as an outpatient procedure by gastroenterologists, surgeons, and some primary care physicians. The procedure requires preparation of the distal large bowel, generally with an enema or laxative. It is performed without sedation, and generally takes
about 10 minutes.
If an adenomatous polyp is detected during a screening sigmoidoscopy, the patient
should proceed to colonoscopy to remove the polyp and screen the more proximal large
bowel for potential additional synchronous neoplastic lesions. A finding of a distal
advanced adenoma (size 1 cm or villous histology) or multiple adenomas, patient age
>65 years, and a family history of colorectal cancer are factors associated with an
increased risk of identifying an advanced neoplasm (adenoma 1 cm, villous histology,
severe dysplasia, or invasive cancer) in the proximal large bowel.9-11 In contrast, a finding of a distal hyperplastic polyp during screening sigmoidoscopy is not associated with
increased risk of proximal advanced neoplasia, and thus does not require further
workup.
Two case-control studies demonstrate the effectiveness of screening sigmoidoscopy in
reducing distal colorectal cancer mortality.12,13 In one study from Northern California,
Selby et al. examined the records of 261 patients who had died of rectal or distal colon
cancer and compared them with 868 matched controls.12 Of the case patients, only
8.8% had undergone earlier screening with rigid sigmoidoscopy prior to cancer diagnosis, as compared to 24.2% of the control patients. Rigid sigmoidoscopy was found to be
associated with a 59% reduction in rectosigmoid cancer mortality. Furthermore, this
protection extended 10 years from the time of the sigmoidoscopy. In a second study
from Wisconsin, Newcomb et al similarly compared a case group of 66 patients who
died from colorectal cancer with 196 matched controls.13 Case patients (10%) were less
likely to have undergone prior screening sigmoidoscopy than control patients (30%).
Screening sigmoidoscopy was associated with an 80% reduction in rectosigmoid cancer
mortality.
Although there is currently no direct evidence from prospective randomized controlled trials to support the effectiveness of screening sigmoidoscopy, 2 studies are now
in progress. Only preliminary findings have been reported to date: the National Cancer
145
Institutes Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial14 and
the UK Flexible Sigmoidoscopy Screening Trial.15
Advantages of flexible sigmoidoscopy screening include direct visualization of up to
the distal one-third of colorectum; the ability to biopsy detected polyps or masses; relatively minor bowel preparation; lack of need for sedation, thus allowing the patient to
return directly to work or other daily activities, and no need for a care partner to accompany them home from the procedure; and a low risk for procedural complications.
However, the procedure does remain somewhat invasive; given the lack of sedation,
some patients may experience mild discomfort due to cramps and spasms related to air
insufflation and scope passage.
BARIUM ENEMA
A double-contrast barium enema (DCBE) is a radiographic examination of the large
bowel following administration of barium contrast followed by air per rectum. There are
no randomized studies to evaluate the effectiveness of DCBE as a colorectal cancer
screening test in average-risk individuals. Although DCBE is still included as an alternative option in standard screening guidelines, it has been demonstrated to be less sensitive than colonoscopy for the detection of neoplastic lesions. In a large prospective
study of DCBE in the surveillance setting following polypectomy, DCBE only detected
48% of adenomatous polyps >1 cm in size and 53% of adenomatous polyps 6 to 10
mm, as compared to colonoscopy.18
Advantages of DCBE include its ability to evaluate the entire large bowel, its performance without sedation, and its low complication rate. Disadvantages include the
potential for mild discomfort during the instillation of barium and air via a rectal
catheter, the inability of some elderly or incontinent patients to hold the barium/air during the study, and the need for multiple changes in body position while on the x-ray
table. Also, because DCBE is a diagnostic study, abnormal test results require further
work-up by colonoscopy for polyp removal or biopsy of mass lesions. Furthermore, false
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Chapter 9
positive findings on DCBE may occur due to retained fecal matter, anatomical differences, and benign mucosal abnormalities, resulting in unnecessary colonoscopy examinations.
DCBE allows for an alternative modality to examine the entire large bowel.
However, because of its lower sensitivity for detection of potentially clinically important
neoplastic lesions, screening guidelines recommend a 5-year interval between DCBE
examinations.
COLONOSCOPY
Colonoscopy is a procedure performed by gastroenterologists and some surgeons and
involves a complete direct examination of the entire colon and rectum. It is very sensitive for the detection of even small and flat neoplastic lesions. Colonoscopy allows for
the removal of polyps using hot biopsy forceps or snare cautery, and for biopsy of suspicious-appearing mass lesions. It involves a somewhat more extensive bowel preparation
than flexible sigmoidoscopy, and conscious sedation is used to ensure patient comfort.
With an expert endoscopist, the procedure generally takes about 20 minutes to perform.
Two large colonoscopy screening trials demonstrated a 97% completion rate to the
cecum.10,11 Incomplete examinations may be related to a particularly tortuous or redundant colon, adhesions related to prior abdominopelvic surgery, or patient intolerance
despite sedation.
Although there are currently no prospective randomized studies in average-risk individuals to demonstrate that screening colonoscopy reduces colorectal cancer mortality or
incidence, there is indirect evidence to support the effectiveness of colonoscopy as a primary screening test. Colonoscopy was utilized in the large FOBT screening trials to evaluate positive test results, and thus is felt to have played a significant role in these studies, which demonstrated a reduction in colorectal cancer mortality. Furthermore, since
screening sigmoidoscopy reduces colorectal cancer mortality, it would be expected that
colonoscopy would be at least as effective, if not more so, since it provides direct examination of the entire large bowel.
Particularly strong rationale to support the use of colonoscopy as a screening modality is that it allows for polyp removal, which has been demonstrated to decrease the incidence of colorectal cancer. In the United States National Polyp Study, Winawer et al followed a cohort of 1418 patients who had undergone prior colonoscopy and removal of
adenomatous polyps, and demonstrated that the incidence of colorectal cancer was significantly lower in the study group as compared with the expected incidence in other
reference cohorts.19
Recent screening colonoscopy trials have also provided evidence of added benefit of
direct evaluation of the proximal large bowel, beyond the reach of the flexible sigmoidoscope. In the study by Lieberman et al, screening colonoscopy performed in over
3000 asymptomatic men (97%) aged 50 to 75 years in 13 Veterans Affairs medical centers detected colorectal neoplasms in 37.5% of patients.10 An adenoma 1 cm in size or
a villous adenoma was detected in 7.9%; an adenoma with HGD in 1.6%; and an invasive cancer in 1% of patients. In this cohort, 2.7% of the 1765 patients with no distal
colorectal polyp (distal to the splenic flexure) had an advanced proximal neoplasm (adenoma 1 cm, villous histology, severe dysplasia, or invasive cancer). In addition, 52% of
the 128 patients with a proximal advanced neoplasm had no distal adenoma. Similarly,
in the trial by Imperiale et al, approximately 2000 asymptomatic patients, aged 50 years
or older underwent screening colonoscopy as part of an employer-sponsored screening
147
program.11 In this cohort, 2.5% of 1564 patients with no distal polyp had an advanced
proximal neoplasm (villous adenoma, severe dysplasia, or invasive cancer). In addition,
46% of the 50 patients with an advanced proximal neoplasm had no distal polyp. Thus,
these 2 studies demonstrated that significant proximal colonic neoplasia may have gone
undetected if patients had utilized flexible sigmoidoscopy alone as their screening strategy.
Current screening guidelines for average-risk individuals now include the option of
undergoing a screening colonoscopy starting at age 50; if negative, repeat in 10 years.
Although not determined by direct studies, the 10-year follow-up interval has been
based on several indirect lines of support. For one, the duration of time for malignant
transformation of an adenoma into a cancer has been estimated to occur, on average,
over at least 10 years.19-21 A study of 183 patients undergoing 2 back-to-back same-day
colonoscopy examinations demonstrated a low 6% miss rate for advanced adenomas 1
cm in size.22 In addition, the case-control study of screening rigid sigmoidoscopy
demonstrated a protective effect from distal colorectal cancer mortality for up to 10
years from the last examination.12 Further evidence is provided by a study of 154 asymptomatic average-risk patients with a previously negative colonoscopy examination that at
follow-up colonoscopy 5 years later were demonstrated to have a low rate of advanced
neoplasia (only 1 patient with an adenoma 1cm; no cancer, HGD, or villous histology).23
SCREENING GUIDELINES
FOR AVERAGE-RISK INDIVIDUALS
Asymptomatic average-risk individuals should undergo routine colorectal cancer
screening starting at age 50 years. Recently updated screening guidelines from a multidisciplinary panel of experts,21 and endorsed by a consortium of US GI societies and various other national organizations, recommend several different screening options for the
average-risk patient. One may choose any one of the following strategies: 1) FOBT
annually, 2) flexible sigmoidoscopy every 5 years, 3) FOBT annually plus flexible sigmoidoscopy every 5 years, 4) DCBE every 5 years, or 5) colonoscopy every 10 years. Of
note, these guidelines are also endorsed by the American Cancer Society.24
Of the various average-risk screening options, the authors preference is to recommend colonoscopy every 10 years. Alternatively, they would consider FOBT annually
with flexible sigmoidoscopy every 5 years, as the combination of 2 tests is preferable to
only performing either test alone. With any screening strategy that utilizes FOBT or
flexible sigmoidoscopy, if any one FOBT specimen is positive or if an adenomatous
polyp is detected during sigmoidoscopy, then the patient should proceed to colonoscopy
for further evaluation and management (Table 9-2).
Chapter 9
148
Table 9-2
Options
1.
2.
3.
4.
5.
FOBT annuallyA
Flexible sigmoidoscopy every 5 yearsB
FOBT annually with flexible sigmoidoscopy every 5 yearsC
DCBE every 5 yearsD
Colonoscopy every 10 yearsE
149
Table 9-3
SCREENING GUIDELINES:
INCREASED FAMILIAL RISK INDIVIDUALS21
Family History
Screening Recommendations
Average-risk guidelines
150
Chapter 9
Table 9-4
Recommended Follow-Up
151
Until recently, Crohns disease was thought to have a lower risk of colorectal cancer
development than ulcerative colitis. However, recent reports have suggested that the risk
is just as great for patients with long-standing Crohns disease, particularly those with
chronic Crohns colitis.32,33 Current surveillance guidelines for patients with Crohns disease are the same as those for ulcerative colitis.21
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Chapter 9
Table 9-5
Recommendations
FAP
Flexible sigmoidoscopy annually, beginning age 10 to 12 years*; genetic counseling and gene testing
HNPCC
*In attenuated FAP screen with colonoscopy because of increased incidence of right colon
adenomas, beginning in late teens or early 20s.
HNPCC patients are at increased risk for early onset colorectal cancer, at an average
age of diagnosis of 40 to 45 years. The colon cancers are predominantly right-sided, with
about 60% to 70% proximal to the splenic flexure. Patients often present with multiple
primary colon cancers, and are at increased risk for metachronous cancers. In HNPCC
it is believed that adenomas may progress to cancer at an accelerated rate, as compared
to sporadic adenomas. HNPCC is also associated with extracolonic cancers of the
endometrium, ovary, stomach, small intestine, renal pelvis and ureter (transitional cell
cancer), and the pancreaticobiliary system.
The diagnosis of HNPCC has been primarily based on family history. Initial
Amsterdam criteria defined an HNPCC family as one in which there are 3 or more close
relatives, one a first-degree relative of the other 2, from 2 or more generations, affected
with colorectal cancer, with at least one cancer diagnosed before age 50, and FAP is
excluded.34 Subsequently, updated Amsterdam II criteria expanded the definition to also
include several HNPCC-associated malignancies, including endometrial, small bowel,
ureter, and renal pelvis cancer.35 Genetic testing for HNPCC is available; however, a disease causing mutation may be identified in only approximately 50% to 70% of families
that meet Amsterdam criteria.
Another approach to identifying patients at risk for HNPCC is to perform testing
for microsatellite instability on the colorectal cancer tissue of an affected patient who
may be suspicious for possible HNPCC, but does not necessarily meet Amsterdam criteria. The Bethesda guidelines offer a set of multiple criteria that may be used to identify patients suspicious for HNPCC who should undergo MSI testing of their tumors.36
Patients with MSI-positive tumors can then go on to germline testing for a MMR gene
mutation.
A long-term Finnish study evaluated the effectiveness of screening in HNPCC
patients and their families.37 This study compared a group of 251 at-risk individuals
from 22 HNPCC families who had screening examinations (colonoscopy or flexible sigmoidoscopy and barium enema) every 3 years to a control group who had no screening,
153
and demonstrated a significant reduction in incidence (p=0.03) and a reduction in mortality (p=0.08) of colorectal cancer in the screened group. The reduction in colon cancer risk was likely due to the colonoscopic removal of adenomas.
A 15-year followup study evaluated the incidence of colorectal cancer and survival in
2 cohorts of at-risk members of the 22 Finnish HNPCC families by comparing a study
group of 133 at-risk patients who underwent colorectal screening every 3 years with an
unscreened control group of 119 patients.38 Colonoscopy screening reduced the rate of
colorectal cancer by 62%, prevented cancer-related death, and decreased overall mortality by 65% in HNPCC families.
Colorectal screening in HNPCC patients should be performed by colonoscopy due
to the increased incidence of proximal cancers and adenomas. At-risk individuals should
undergo colonoscopy screening every 1 to 2 years beginning at age 20 to 25, or 10 years
earlier than the youngest family member diagnosed. Special screening for HNPCC-associated extracolonic malignancies is also recommended. In addition, HNPCC patients
and their at-risk family members should also be referred for genetic counseling and possible gene testing (see Table 9-5).
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analysis. DNA abnormalities have been detected in such genes as K-ras, APC, and p53.
In one study, a blinded analysis of stool specimens from 33 patients with colorectal cancer or adenomas demonstrated that a multi-target assay panel was 91% sensitive in
detecting cancer, and 82% sensitive for detecting adenomas 1 cm in size, with a specificity of 93%.42 Another study reported similar promising results regarding the feasibility of detecting APC gene mutations utilizing a digital protein truncation assay.43
CONCLUSION
Colorectal cancer remains a prevalent disease in the United States, and continues to
account for significant premature death and life-years lost. Currently available screening
tests are effective in detecting early stage colorectal cancer and its premalignant precursor lesion, the adenoma. Evidence demonstrates that screening examinations reduce colorectal cancer mortality. Removal of adenomas by colonoscopic polypectomy has been
demonstrated to significantly reduce the incidence of colorectal cancer.
Appropriate screening and surveillance recommendations should be based on the
individuals colorectal cancer risk stratification. Average-risk individuals should begin
screening at age 50 years. Increased-risk individuals should be identified and offered
more aggressive screening recommendations beginning at an earlier age. High-risk individuals at-risk for hereditary syndromes such as FAP and HNPCC should be offered
genetic counseling and specialized screening recommendations for colorectal cancer, and
associated extracolonic malignancies.
At the present time, patients need to be encouraged to engage in and benefit from
currently proven and available screening and surveillance strategies in order to reduce
their risk of developing and dying from colorectal cancer.
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2. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by
screening for fecal occult blood. N Engl J Med. 1993;328:1365-1371.
3. Mandel JS, Church TR, Ederer F, Bond JH. Colorectal cancer mortality: Effectiveness
of biennial screening for fecal occult blood. J Natl Cancer Inst. 1999;91:434-437.
4. Hardcastle JD, Chamberlain JO, Robinson MHE, et al. Randomized controlled trial of
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a negative examination. JAMA. 2003;290:41-48.
15. UK Flexible Sigmoidoscopy Screening Trial Investigators and Atkin WS. Single flexible
sigmoidoscopy screening to prevent colorectal cancer: baseline findings of a UK multicentre randomised trial. Lancet. 2002;359:1291-1300.
16. Jorgensen OD, Kronborg O, Fenger C. A randomized study of screening for colorectal
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17. Winawer SJ, Flehinger BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer
with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst. 1993;85:13111318.
18. Winawer SJ, Stewart E, Zauber AG, et al. A comparison of colonoscopy and doublecontrast barium enema for surveillance after polypectomy. N Engl J Med. 2000;
342:1766-1772.
19. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic
polypectomy. The National Polyp Study Workgroup. N Engl J Med. 1993;329:19771981.
20. Hofstad B, Vatn M. Growth rate of colon polyps and cancer. Gastrointest Endosc Clin N
Am. 1997;7:345-363.
21. Winawer S, Fletcher R, Rex D, et al for the US Multisociety Task Force On Colorectal
Cancer. Colorectal cancer screening and surveillance: clinical guidelines and rationale update based on new evidence. Gastroenterology. 2003;124:544-560.
22. Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology. 1997;112:24-28.
23. Rex DK, Cummings OW, Helper DJ, et al. Five-year incidence of adenomas after negative colonoscopy in asymptomatic average-risk persons. Gastroenterology. 1996;111:
1178-1181.
24. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the early
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25. St. John DJ, McDermott FT, Hopper JL, et al. Cancer risk in relatives of patients with
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26. Slattery ML, Kerber RA. Family history of cancer and colon cancer risk: the Utah
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27. Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal cancer in the families of
patients with adenomatous polyps. N Engl J Med. 1996;334:82-87.
28. Burt RW. Colon cancer screening. Gastroenterology. 2000;119:837-853.
29. Winawer SJ, Zauber AG, O'Brien MJ, et al. Randomized comparison of surveillance
intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J
Med. 1993;328:901-906.
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30. Gyde SN, Prior P, Allan RN, et al. Colorectal cancer in ulcerative colitis: a cohort study
of primary referrals from three centres. Gut. 1988;29:206-217.
31. Ekbom A, Helmick C, Zack M, Adami H-O. Ulcerative colitis and colorectal cancer: a
population-based study. N Engl J Med. 1990;232:1228-1233.
32. Sachar DB. Cancer in Crohn's disease: dispelling the myths. Gut. 1994;35:1507-1508.
33. Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN. Ulcerative colitis and
Crohn's disease: a comparison of the colorectal cancer risk in extensive colitis. Gut.
1994;35:1590-1592.
34. Vasen HF, Mecklin JP, Khan PM, et al. The International Collaborative Group on
Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum.
1991;34:424-425.
35. Vasen HFA, Watson P, Mecklin JP, et al. New clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International
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36. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute
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37. Jarvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families
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38. Jarvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for
colorectal cancer in families with hereditary nonpolyposis colorectal cancer.
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39. Vining DJ, Gelfand DW, Bechtold RE, et al. Technical feasibility of colon imaging with
helical CT and virtual reality. Am J Roentgenol. 1994;62Suppl:104. abstract.
40. Fenlon HM, Nunes DP, Schroy III PC, et al. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med. 1999;341:14961503.
41. Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic virtual colonoscopy to
screen for colorectal neoplasia in asymptomatic adults. N Engl J Med. 2003;349:21912200.
42. Ahlquist DH, Skoletsky JE, Boynton KA, et al. Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multi-target assay panel.
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43. Traverso G, Shuber AP, Levin B, et al. Detection of APC mutations in fecal DNA from
patients with colorectal tumors. N Engl J Med. 2002;346:311-320.
chapter
10
Surgical Approach to
Colorectal Neoplasia and
High-Risk Conditions
Najjia N. Mahmoud, MD and J.J. Karmacharya, FRCS
INTRODUCTION
Adenocarcinoma of the colon and rectum are the third most common sites of new
cancer cases and deaths in both men and women in the United States. Although surgery remains the primary treatment for this disease, surgical and medical therapy for
colorectal and other cancers is currently in an exciting era of discovery. The rise of medical applications of molecular biology and the promise of new therapeutic and diagnostic modalities derived from this field necessarily requires a basic understanding of the
underlying genetics of the disease. A future paradigm shift in the treatment of colorectal cancer away from intervention and toward molecular therapies seems likely, and an
appreciation of the current impact of the science of colon cancer is crucial in treating
the modern colorectal cancer patient and his family. The estimated incidence of new
cases of colon cancer is actually stable from year to year, without appreciable increase or
decrease in the last century. The American Cancer Society estimates that about 106,370
new cases of colon cancer (50,400 men and 55,970 women) and 40,570 new cases of
rectal cancer (23,220 men and 17,350 women) will be diagnosed in 2004. Colorectal
cancer is expected to cause about 56,730 deaths in 2004, accounting for 10% of all cancer deaths. The lifetime risk of developing colorectal cancer in the United States is 6%,
with over 90% of cases occurring after the age of 50. Surgery is the critical treatment
modality currently, and postoperative medical treatment is predicated on pathologic
review of the surgical specimen and draining lymph nodes.
Colorectal cancer occurs in hereditary, sporadic, and familial forms. Hereditary
forms of colorectal cancer have been extensively described and are characterized by family history, young age at onset, other coexisting tumors types, extraintestinal manifestations and the presence of specific germline genetic mutations. FAP and HNPCC are the
2 major hereditary colorectal cancer syndromes and are the subject of many recent
investigations that continue to provide significant insights into the pathogenesis of colorectal cancer.
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Sporadic colorectal cancer occurs in the absence of family history, generally affects an
older population (60 to 80 years of age), and usually presents as an isolated colon or rectal lesion. Seventy percent to 80% of all colorectal cancers are sporadic (Figure 10-1).
Genetic mutations associated with the cancer are limited to the tumor itself, unlike
hereditary disease where the specific mutation is present in all cells of the affected individual. Nevertheless, the genetics of colorectal cancer initiation and progression proceed
along very similar pathways in both hereditary and sporadic forms of the disease. Studies
of the relatively rare inherited models of the disease have greatly enhanced the understanding of the genetics of the far more common sporadic form of the cancer.
The concept of familial colorectal cancer is relatively new. Lifetime risk of colorectal cancer increases for members in families in which the index case is young (less than
50 years of age) and the relative is close (first degree) (Table 10-1). The risk increases as
the number of family members with colorectal cancer rises. An individual who is a firstdegree relative of a patient diagnosed with colorectal cancer under the age of 50 is twice
as likely as the general population to develop the cancer. This more subtle form of inheritance is currently the subject of much investigation. Genetic polymorphisms, gene
modifiers, and defects in tyrosine kinases have all been implicated in various forms of
familial colorectal cancer.
159
Table 10-1
General US Population
One first-degree relative with colon cancer1
Two first-degree relatives with colon cancer1
First-degree relative with colon cancer
diagnosed at <50
One second- or third-degree relative
with colon cancer2,3
Two second-degree relatives with colon
cancer2
One first-degree relative with an
adenomatous polyp1
6%
2- to 3-fold increased
3- to 4-fold increased
3- to 4-fold increased
1.5-fold increased
2- to 3-fold increased
2-fold increased
Mismatch repair genes (MMR) are called caretaker genes because of their important role in policing the integrity of the genome and correcting DNA replication errors.
MMR genes that undergo a loss of function contribute to carcinogenesis by accelerating
tumor progression. Mutations in MMR genes (including hMLH1, hMSH2, hMSH3,
hPMS1, hPMS2, and hMSH6) result in the syndrome HNPCC. Approximately 3% of
colorectal cancers in the United States are caused by HNPCC. Mutations in MMR
genes produce microsatellite instability (MSI)a measurable characteristic of tumors
considered a marker for MMR gene mutations. Microsatellites are repetitive sequences
of DNA that seem randomly distributed throughout the genome. Stability of these
sequences is a good measure of the general integrity of the genome. MSI exists in 10%
to 15% of sporadic tumors and in 95% of tumors in patients with HNPCC. Even so,
only 50% of patients diagnosed with HNPCC have readily identifiable MMR mutations. For additional discussion and screening and surveillance recommendations, please
see Chapter 9.
Proto-oncogenes are genes that produce proteins that promote cellular growth and
proliferation. Mutations in proto-oncogenes typically produce a gain-of-function and
can be caused by mutation in only one of the 2 alleles. Following mutation, the gene is
called an oncogene. Overexpression of these growth-oriented genes contributes to the
uncontrolled proliferation of cells associated with cancer. The products of oncogenes can
be divided into categories. For example, growth factors (TGF, EGF, insulin-like growth
factor); growth factor receptors (erbB2), signal transducers (src, abl, ras); and nuclear
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proto-oncogenes and transcription factors (myc) are all oncogene products that appear
to have a role in the development of colorectal neoplasia. The ras protooncogene is located on chromosome 12 and mutations are believed to occur very early in the adenomacarcinoma sequence. Mutated ras has been found to be present in adenomatous polyps.
Activated ras leads to constitutive activity of a protein that stimulates cellular growth.
Fifty percent of sporadic colon cancers possess ras mutations, and current trials of farnesyl transferase inhibitors, which block a step in ras post-translational modification,
may hold therapeutic promise.1
161
Table 10-2
<1 cm
1 to 2 cm
>2 cm
% Total
1%
4%
10%
10%
7%
10%
35%
46%
53%
5
23
41
On average, only 5% of polyps <1cm in size harbor an invasive cancer. Size, rather than histology, is the major risk factor for cancer.
Adapted from Chang AE. Colorectal cancer. In: Greenfield LJ, ed. Surgery: Scientific Principles
and Practice. Philadelphia, Pa JB Lippincott; 1993:1007.
Larger adenomas are found to harbor cancers more often than smaller ones
the larger the polyp, the higher the risk of cancer. While the cellular characteristics of the polyp are important, with villous adenomas carrying a higher
risk than tubular adenomas, the size of the polyp is most important. The risk
of cancer in a tubular adenoma smaller than 1 cm in diameter is less than
5%, whereas the risk of cancer in a tubular adenoma larger than 2 cm is 35%.
A villous adenoma larger than 2 cm in size carries a 50% chance of containing a cancer (Table 10-2).
Residual benign adenomatous tissue is found in the majority of invasive colorectal cancers, suggesting progression of the cancer from the remaining
benign cells to the predominant malignant ones.
Benign polyps have been observed to develop into cancers. There have been
reports of the direct observation of benign polyps that were not removed progressing over time into malignancies.
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163
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Table 10-3
Colon Cancer
Rectal Cancer
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Maybe
Yes
Yes
Yes
Yes
Yes
Yes
Maybe
No
Yes
*Although no Level I or Level II evidence supports routine use of CT scan in the preoperative evaluation of colorectal cancer, it is recognized that it is a commonly ordered test and
may affect the care of a small subset of patients. Please see text for further discussion.
165
Cancers in the right colon more often present with melena, fatigue associated with
anemia, or, if the tumor is advanced, abdominal pain. Although obstructive symptoms
are more commonly associated with cancers of the left colon, any advanced colorectal
cancer can cause a change in bowel habits and intestinal obstruction. Colonoscopy is the
gold standard for establishing the diagnosis of colon cancer. It permits biopsy of the
tumor to verify the diagnosis, while allowing inspection of the entire colon to exclude
the synchronous polyps or cancers that occur in 3% to 5% of cases.
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Chapter 10
from the inferior mesenteric artery and the frequent involvement of the sigmoid with
diverticular disease.
167
largely been banished by surgeon experience, technology that allows safer specimen
delivery, and examination of the tissue through studies with large patient numbers.
Through a number of studies examining lymph node harvest, we know that oncologic
standards are being met, operative times for these complicated procedures are reduced,
and complication rates are comparable to open procedures. What remains to be definitively clarified, however, is a decisive patient benefit. While it is clear that many patients
do gain an advantage from the minimally invasive approach in general, many of the
studies designed to explore this in colorectal disease have been statistically underpowered, and answers have not been easily forthcoming. Laparoscopic colorectal surgery is
technically demanding and time consumingespecially for the low-volume surgeon. In
the near future, prospective studies from major, high volume centers will undoubtedly
demonstrate that laparoscopic colorectal surgery is at least as effective and well tolerated
as traditional open techniques. Future challenges will center on the widespread incorporation of this technology into the repertoire of surgeons everywhere and definitively
address issues directly impacting patient benefit such as length of stay, postoperative
pain, and return to work.11,12
EMERGENT PRESENTATIONS
Obstructing Cancers
Patients who are obstructed commonly present emergently, without the benefit of a
thorough preoperative evaluation. Dehydration and physiological stress complicates surgical treatment, and fluid resuscitation with close monitoring is advisable even in the
completely obstructed patient prior to operative intervention if possible. Because of the
relatively small sigmoid colon caliber, most obstructing colon cancers occur in this area,
and a plain film of the abdomen reveals a distal large bowel obstruction with a dilated,
distended proximal colon. The presence of free air under the diaphragm is a grave sign,
indicating free perforation of the colon, usually in the thin-walled cecum.
In patients with left-sided tumors causing complete obstruction, a water-soluble contrast enema is often useful to establish the anatomic level of the obstruction. Primary
anastomosis between the proximal colon and the colon distal to the tumor is usually
avoided in the presence of obstruction because of a perceived high risk of anastomotic
leak or infection associated with such an approach. Thus, such patients are usually treated by resection of the segment of colon containing the obstructing cancer, closure of the
distal sigmoid or rectum, and contruction of a colostomy (Hartmanns operation).
Intestinal continuity can be re-established later after the colon has been prepped by taking down the colostomy and fashioning a colorectal anastomosis.
One alternative to this approach is to resect the segment of left colon containing the
cancer, and then cleanse the remaining colon with saline lavage by inserting a catheter
through the appendix or ileum into the cecum and irrigating the contents from the
colon. A primary anastomosis between the prepared colon and the rectum can then be
fashioned without the need for a temporary colostomy. A loop ileostomy, easily closed a
few months later, can be used to protect the newly formed anastomosis by diverting
the fecal stream if necessary. A third approach occasionally used for obstructing cancers
of the sigmoid colon, particularly when obstruction is complicated by proximal ischemia
or perforation, is to resect the tumor and the entire colon proximal to the tumor and
fashion an anastomosis between the ileum and the distal sigmoid colon or rectum
(subtotal colectomy with ileosigmoid or ileorectal anastomosis). This approach has the
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advantage of avoiding a temporary colostomy and eliminating the need to search for
synchronous lesions in the colon proximal to the cancer. Due to loss of the absorptive
and storage capacity of the colon, however, this procedure causes an increase in stool frequency. Patients under the age of 60 years generally tolerate this well, with gradual adaptation of the small bowel mucosa, increased water absorption, and an acceptable stool
frequency of 1 to 3 movements daily. In older individuals though, subtotal colectomy
may result in significant chronic diarrhea.
Patients with obstructing right-sided tumors are rare, and present as distal small
bowel obstruction. Right hemicolectomy with primary anastomosis, even in an unprepared colon, is the usual treatment of choice. This approach, however, is predicated on
the patients presenting hemodynamic status, with resection and end ileostomy being the
most expedient, and at times, the safest alternative.
STAGING
Tumor staging describes the process by which information concerning the size, location, and extraintestinal spread of the cancer is assimilated into an overall description of
the state of the disease at the moment. The most significant data, however, arise from
the postoperative inspection of the specimen. Tumor depth, nodal metastases, and the
presence of tumor metastasis are most significant in determining prognosis. At the present time, the stage of the tumor is assessed by indicating the depth of penetration of the
tumor into the bowel wall, the extent of lymph node involvement, and the presence or
absence of distant metastases. For most of the last half century, the standard staging system was based on a system developed and modified by Cuthbert Dukes, a pathologist at
St. Marks Hospital in London.13 The Dukes classification is simple to remember, and
still frequently used. Dukes Stage A cancer is confined to the bowel wall; Stage B cancer
penetrates the bowel wall, and Stage C cancer indicates lymph node metastases. Astler
and Coller further separated the tumors that had invaded lymph nodes but did not penetrate the entire bowel wall (C1) from tumors that invaded lymph nodes and did penetrate the entire wall (C2). Turnbull and associates from the Cleveland Clinic added Stage
D for tumors with distant metastasis. All of these modifications in various combinations
are still in use and often called modified Dukes classifications.
The classification in use by most hospitals in the United States was developed by the
AJCC and was approved by the International Union Against Cancer (UICC). This classification, known as the TNM system, combines clinical information obtained preoperatively with data obtained during surgery and after histological examination of the specimen. There have been some modifications in the system since its introduction in 1987.
169
The surgeon is now encouraged to score the completeness of the resection as follows: R0
for complete tumor resection with all margins negative, R1 for incomplete tumor resection with microscopic involvement of a margin, and R2 for incomplete tumor resection
with gross residual tumor not resected (see Appendix D).
There are 4 possible stages of colorectal cancer within the AJCC system. In Stage I,
there is no lymph node metastasis and the tumor is either T1 or T2 (up to muscularis
propria). Patients who undergo appropriate resection of T Stage 1 colon cancer have a
5-year survival rate of approximately 90%. Stage II is now subdivided into IIA (if the
primary tumor is T3) and IIB (for T4 lesions), with no lymph node metastasis. The 5year survival rate for patients with Stage II colon cancer treated by appropriate surgical
resection is approximately 75%. Stage III cancer is characterized by lymph node metastasis and is now subdivided into IIIA (T1 to T2, N1, M0), IIIB (T3 to T4, N1, M0),
and IIIC (any T, N2, M0). In the current version of the staging system, smooth metastatic nodules in the pericolic or perirectal fat are considered lymph node metastasis and
should be included in N staging. The estimated survival for Stage III cancer treated by
surgery alone is approximately 50%. With the presence of distant metastasis (Stage IV),
the 5-year survival rate is less than 5%.14
The survival rates described above do not reflect the use of adjuvant chemotherapy
following curative resection of colon cancer. There is a clearly demonstrated benefit for
patients with Stage III disease treated postoperatively with 5-fluorouracil/leukovorin
(67% 5-year survival). The benefits of adjuvant chemotherapy for patients with Stage II
colon cancer have not been clearly demonstrated, and several ongoing clinical trials are
now studying chemotherapy in this group of patients. There has been no demonstrated
efficacy for adjuvant chemotherapy for patients with Stage I colon cancer.15
The presence of hepatic metastatic disease does not preclude the surgical excision of
the primary tumor. Unless the hepatic metastatic disease is extensive, excising the primary cancer can provide excellent palliation. Bleeding and obstruction caused by the
tumor can be avoided, and if the metastatic hepatic disease is resectable, the cure rate
approaches 25%.
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Abdominoperineal Resection
The complete excision of the rectum and anus by dissection through the abdomen
and perineum with suture closure of the perineum and creation of a permanent colostomy was first described by Ernest Miles and is thus sometimes referred to as the Miles
procedure.16 For many years, before the advent of neoadjuvant therapy and mechanical staplers, this procedure was considered the standard of care for tumors in the distal
half of the rectum. An abdominal perineal resection (APR) is indicated when the tumor
involves the anal sphincters, when the tumor is too close to the sphincters to obtain adequate margins, or in patients in whom sphincter-preserving surgery is not possible
171
because of unfavorable body habitus or poor preoperative sphincter control. The rectum
and sigmoid colon are mobilized along with the mesorectum through an abdominal
incision to the level of the levator ani muscles. Careful attention to the oncologic and
functional details of the resection mandates ligation of the IMA, sparing of the hypogastric nerve bundles, and resecting the mesorectum just outside its investing fascia. The
perineal portion of the operation excises the anus, the anal sphincters, and the distal rectum.
Local Excision
Local excision of a rectal cancer is an excellent operation for a small cancer in the distal rectum that has not penetrated into the muscularis propria. This is usually accomplished through a transanal approach and usually involves excision of the full thickness
of the rectal wall underlying the tumor. Other approaches less commonly utilized
include the trans-sphincteric (York-Mason) approach and posterior proctectomy
(Kraskes procedure). Local excisions do not allow complete removal of lymph nodes in
the mesorectum; therefore, operative staging is limited. The operation is indicated for
mobile tumors that are less than 4 cm in diameter, that involve less than 40% of the rectal wall circumference, and that are located within 6 cm of the anal verge. A good clinical indicator of a locally resectable tumor is a mobile tumor easily palpated via digital
rectal exam. These tumors should be Stage T1 (depth limited to the submucosa), well or
moderately differentiated histologically, and with no vascular or lymphatic invasion.
There should be no evidence of nodal disease on preoperative endorectal ultrasound or
MRI. Adherence to these principles results in acceptable local recurrence rates compared
with treatment by abdominal perineal resection. Local excision is also used for palliation
of more advanced cancer in patients with severe comorbid disease, in whom extensive
surgery carries a high risk of morbidity or mortality.
Transanal excision requires the complete excision of the cancer with adequate margins
of normal tissue. Unfortunately, as experience has accumulated with this approach, it has
become clear that close follow-up is mandatory because approximately 8% to 18% of
T1 lesions will recur, and the recurrence rate for T2 lesions has been shown in some
series to exceed 20%. Local excision is not adequate treatment for a T2 rectal cancer, and
radical excision (low anterior resection or abdominal perineal resection) is the procedure
of choice.17-20 Both the York-Mason and Kraske procedures approach the rectum posteriorly via a midline or slightly off-set incision. The York-Mason incision actually divides
the sphincter mechanism to approach the low rectum. The sphincters must be carefully
sewn back together at the end of the case. The Kraske procedure is used for slightly higher tumors and is suprasphincteric. The coccyx is usually removed using this approach
since it impedes visualization. Both of these approaches are far less commonly used
today than in the past. Technology has not only allowed us to achieve safer lower anastomoses while using good oncologic technique, it has also allowed us to operate on older,
more medically challenging patients with more confidence in their ability to tolerate the
surgery.
Fulguration
This technique, which eradicates the cancer by using an electrocautery device that
destroys the tumor by creating a full-thickness eschar at the tumor site, requires extension of the eschar into the perirectal fat, thus destroying both the tumor and the rectal
wall. The procedure is reserved for patients with a prohibitive operative risk for radical
surgery and a limited life expectancy. The procedure is used only for lesions below the
172
Chapter 10
Coloanal Anastomosis
Abdominal perineal resection is at times required because a cancer in the distal rectum cannot be resected with adequate margins while preserving the anal sphincter.
However, the use of preoperative radiation and chemotherapy has been shown, in some
instances, to shrink the tumor to an extent that acceptable margins can be achieved. If
the anal sphincters do not need to be sacrificed to achieve adequate margins based upon
173
C
D
Figure 10-4. Operative strategies for rectal
cancers. (A) Extent of resection for APR. (B)
Stapled LAR. (C) Handsewn coloanal anastomosis. (D) Exposure for a transsacral
resection. (Reprinted with permission from
Chang AE. Colorectal cancer. In:
Greenfield LJ, Mulholland MW, Oldham
KT, Zelenock GB, eds. Surgery: Scientific
Principles and Practice. Philadelphia, PA:
JB Lippincott Company; 1993:1024.
174
Chapter 10
175
Surgical Management
Surgical treatment of patients with FAP is directed at removal of all affected colonic
and rectal mucosa. Restorative proctocolectomy with ileal pouch anal anastomosis
(IPAA) has become the most commonly recommended operation, although historically,
176
Chapter 10
total proctocolectomy with end ileostomy was performed for FAP. The quality of life
advantages for IPAA over end ileostomy are great. Restoration of GI continuity allows
these typically young patients to have a fairly normal lifestyle. While this same operation
in patients with ulcerative colitis may be complicated by occasional or chronic inflammation of the pouch (pouchitis), those issues seem not to plague the FAP patient.
Function is good, with good continence, and good pouch function characterized by 5 to
7 bowel movements per day typically. The ileal pouch is really a neorectumroughly 20
cm of terminal ileum folded over and opened to create a functional reservoir that is
attached directly above the anal sphincter complex at the dentate line. Either surgical
stapling or hand suturing the connection is acceptable. An alternative approach, total
abdominal colectomy with ileorectal anastomosis, may only be used in individuals with
rectal sparing, such as patients with attenuated FAP. With this procedure, the abdominal colon is resected and an anastomosis fashioned between the ileum and top of the rectum. It is a technically simpler operation to perform, pelvic dissection is avoided, and
function is often better with fewer bowel movements and improved sensation. This
technique reduces the potential complication of injury to the autonomic nerves that
could result in impotence. In addition, there is theoretically less risk of anastomotic leak
from the relatively simple ileorectal anastomosis fashioned in the peritoneal cavity, compared to the long staple lines required to form the ileal pouch. Because the rectum
remains at high risk for the formation of new precancerous polyps, a proctoscopic examination is required every 6 months to detect and destroy any new polyps, and there is a
definite increased risk of cancer arising in the rectum with the passage of time. Patients
who choose to be treated by abdominal colectomy with ileorectal anastomosis should
realize that the risk of developing rectal cancer is real and has been shown to be 4, 5.6,
7.9, and 25% at 5, 10, 15, and 20 years after the operation, respectively. Even though
sulindac and celecoxib can produce partial regression of polyps, semiannual surveillance
of the rectal mucosa is required, and about one-third of patients treated by abdominal
colectomy and ileorectal anastomosis will develop florid polyposis of the rectum that will
require proctectomy (and either ileostomy or IPAA) within 20 years.26
As discussed above, polyps of the stomach and duodenum are not uncommon in
patients with FAP. Gastric polyps are usually hyperplastic or fundic gland polyps and do
not require surgical removal. However, duodenal and ampullary polyps are usually adenomatous and require surveillance and, if possible, excision. A reasonable surveillance
program calls for upper GI surveillance every year after the age of 30, with endoscopic
polypectomy to remove all large adenomas from the duodenum. If numerous polyps are
identified, the endoscopy may be repeated with greater frequency dependent upon
pathologic findings. If an ampullary cancer is discovered at an early stage or if duodenal
polyps appear to be rapidly enlarging, endoscopic resection or pancreatoduodenectomy
(Whipples procedure) may be indicated.
Abdominal desmoid tumor can be an especially vexing and difficult extraintestinal
manifestation of FAP. After surgical procedures, dense fibrous tissue forms in the mesentery of the small intestine or within the abdominal wall in some patients with FAP. If the
mesentery is involved, the intestine can be tethered or invaded directly by the tumor.
The locally invasive tumor can also encroach upon the vascular supply to the intestine.
Small desmoid tumors confined to the abdominal wall are appropriately treated by resection, but the surgical treatment of mesenteric desmoids is dangerous and generally futile.
Operation seems to stimulate them, causing them to grow more rapidly. There have
been sporadic reports of regression of desmoid tumors after treatment with sulindac,
177
tamoxifen, radiation, and various types of chemotherapy. The initial treatment is usually with sulindac or tamoxifen.
APC I1307K
The I1307K point mutation is an APC mutation implicated in up to 25% of familial colorectal cancers afflicting Ashkenazi Jewish descendants (6% of the general
Ashkenazi Jewish population) and is associated with a 2-fold colorectal cancer risk
increase. This mutation is now recognized as perhaps the most important cause of familial colorectal cancer in this population. It is caused by substitution of a lysine for
isoleucine at codon 1307. This mutation results in an unstable polyadenine tract causing DNA replication mechanisms to fail, thus producing somatic mutations in the APC
gene further downstream during cell division. Colorectal cancers in young (<50)
patients of Ashkenazi Jewish descent with a positive family history should arouse suspicion of this defect. Treatment is usually limited to segmental resection of the tumor and
involved lymph node basin. Close yearly surveillance in the face of a known germline
defect seems reasonable, although formal surgical and screening recommendations have
not yet been formulated.27
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Chapter 10
alization for identifying patients with HNPCC occurred with the introduction of the
Bethesda criteria.
As outlined in the genetics section, molecular biologists have demonstrated that the
increased cancer risk in these syndromes is due to mutations of MMR genes governing
DNA repair. Mutations in hMSH2 or hMLH1 account for over 90% of identifiable
mutations in patients with HNPCC. Although the difference in cancer types occurring
in Lynch I and Lynch II syndromes cannot be accounted for by mutations in specific
mismatch repair genes, the syndrome involving hMSH6 is characterized by an increased
incidence of endometrial carcinoma.28
Although the mainstay of diagnosis of HNPCC is a detailed family history, it should
be remembered that as many as 20% of newly discovered cases of HNPCC are caused
by spontaneous germline mutations, so a family history may not accurately reflect the
genetic nature of the syndrome. Colorectal cancer, or an HNPC-related cancer, arising
in a person under the age of 50 should raise the suspicion of this syndrome. Genetic
counseling and genetic testing can be offered. If the individual proves to have HNPCC
by identification of a mutation in one of the known mismatch repair genes, then other
family members can be tested after obtaining genetic counseling. However, failure to
identify a causative MMR gene mutation in a patient with a suggestive history does not
exclude the diagnosis of HNPCC. In as many as 50% of patients with a family history
that clearly demonstrates HNPCC type transmission of cancer susceptibility, DNA testing will fail to identify the causative gene.27
Surgical Management
The management of patients with HNPCC is somewhat controversial, but the need
for close surveillance in patients known to carry the mutation is obvious. It is usually
recommended that a program of surveillance colonoscopy begin between the ages of 20
and 30, repeated every 1 to 2 years until age 40, then annually thereafter. Patients with
known germline mutations should start yearly colonoscopic surveillance at age 25, or 5
years prior to the age at diagnosis of the index family member. In women, periodic vacuum curettage, as well as pelvic ultrasound and CA-125 levels, are begun at age 25 to
35. Annual tests for occult blood in the urine should also be obtained, because of the
risk of ureteral and renal pelvic cancer.27
It has been shown that annual colonoscopy and removal of polyps when found
decreases the incidence of colon cancer in patients with HNPCC. However, there have
been well-documented cases of invasive colon cancers occurring 1 year after a negative
colonoscopy. In fact, in patients with a known MMR gene defect and a history of colorectal cancer, the risk of metachronous and synchronous colorectal cancers is about
45% 10 years after resection. It is obvious that the slow evolution from benign polyp to
invasive cancer is not a feature of pathogenesis in HNPCC patients, and this phenomenon of accelerated carcinogenesis mandates frequent (annual) colonoscopic examinations.
Based on these data, the surgical treatment of HNPCC in a patient with cancer
should be subtotal colectomy with ileorectal anastomosis followed by annual sigmoidoscopic rectal surveillance. There is currently no consensus regarding prophylactic surgery
of the colon, uterus, and ovaries for HNPCC. The role of prophylactic colectomy for
patients with HNPCC has not received universal acceptance, and decisions regarding
surgery should be made on an individual basis until better data-driven recommendations
become available. Female patients with no further plans for childbearing are advised to
undergo prophylactic hysterectomy and bilateral salpingo-oophorectomy if undergoing
179
surgery for a colon cancer because the risk of endometrial and ovarian cancer reaches
39% and 9%, respectively by age 70. Other forms of cancer associated with HNPCC
are treated according to nonhereditary cancer criteria.27
ULCERATIVE COLITIS
Colorectal cancer is one of the most devastating long-term sequelae of ulcerative colitis (UC). Duration of disease is directly correlated with development of colorectal cancer, with risk beginning to increase 8 years after diagnosis. At 10 years, the risk of cancer is 0% to 3%, but by 30 years, the risk increases to 50% and then 75% after 40 years
of disease. Colonoscopic surveillance every 1 to 2 years beginning 8 years after diagnosis of UC is mandatory. This strategy is based on the premise that a dysplastic lesion or
high-grade cellular dysplasia can be detected endoscopically before invasive cancer has
developed.29 Detailed pathologic studies have confirmed the patchy nature of dysplasia
and have recommended 33 colonoscopic biopsies during yearly colonoscopy to provide
a 90% chance of detecting dysplasia. A meta-analysis of 10 prospective studies of dysplasia surveillance, with a total of 1225 patients, shows that when colectomy is performed for HGD, carcinoma is present in 42% of patients. Less than 8% of patients
undergoing colectomy with LGD or indefinite dysplasia had cancer in this and other
series. Thus, HGD is an absolute indication for colectomy. LGD is far more controversial, with most surgeons opting for frequent surveillance and rebiopsy. The diagnosis of
dysplasia is difficult to establish in the presence of active inflammation, and most
authorities recommend that the diagnosis should be confirmed independently by two
experienced GI pathologists.30
Surgical Management
The goal of surgical management of UC is excision of all affected mucosa and
reestablishment of GI continuity, if possible. Indications for surgery may differ from
patient to patient, and this greatly influences the choice of operation. Total proctocolectomy with IPAA, as previously described for familial polyposis, is the procedure of
choice for patients with HGD, or who become refractory to medical management. This
procedure involves removing the entire colon and rectum down to the dentate line and
creating an ileal reservoir (Figure 10-5). This anastomosis is particularly vulnerable to
leakage, especially in the presence of malnutrition and chronic or ongoing steroid usage.
Anastomotic leak/pelvic abscess rate is in excess of 18% if not diverted when medical
therapy includes steroid immunosuppression. In these cases, it is usually necessary to
temporarily divert the fecal stream with a loop ileostomy, thus allowing the pouch-anal
anastomosis to heal. Later closure of the ileostomy (in 8 to 10 weeks) is standard in the
absence of pelvic infection. Functionally, patients with good preoperative continence can
expect to have, on average, 7 bowel movements per day, and one to two per night.
Stapled anastomoses are significantly less likely than hand-sewn ones to cause inadvertent fecal leakage. Patients with preoperative incontinence are therefore poor candidates
for IPAA and may be good candidates for end ileostomy. Total proctocolectomy with
end ileostomy removes all of the colon, rectum, and anal canal mucosa. This procedure
was the operation of choice until the introduction of IPAA in the 1970s and is indicated for patients who are poor candidates for restorative proctocolectomy.
Ulcerative colitis patients diagnosed with colon cancer can have difficult surgical
management and reconstruction requirements. These patients require total proctocolectomy but the need for postoperative chemotherapy and the sequelae of diarrhea or
180
Chapter 10
mucositis can make pouch patients miserable at best. While there are no current guidelines, it is generally felt that small cancers, likely to be early stage (T1 and T2), may be
offered IPAA. Those with large bulky lesions, or distant metastatic disease facing months
of chemotherapy and possible re-operation, may function better with subtotal colectomy, end ileostomy and a Hartmanns pouch (the rectum is left in place). If treatment
results in cure, future reconstruction possibilities are preserved with minimal morbidity.31
Rectal cancer treatment in the patient with UC may present the most difficult surgical challenges of all. As discussed, the management of node positive and Stage III node
negative rectal tumors require either pre- or postoperative radiationa strategy that provides good control of local recurrence. A total proctocolectomy is required, but IPAA
reconstruction in this setting is controversial. In the setting of radiation, there is an
181
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137:603-612.
2. Kinzler KW, Vogelstein B. Lessons form hereditary colorectal cancer. Cell. 1996;
87:159-170.
3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;
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4. Haggitt RC, Glotzbach RE, Soffer EE, et al. Prognostic factors in colorectal carcinomas
arising in adenomas: implications for lesions removed by endoscopic polypectomy.
Gastroenterology.1985;89:328-336.
5. Simmang CL, Senatore P, Lowry A, et al. Practice parameters for the detection of colorectal neoplasms. Dis Colon Rectum. 1999;42:1123-1129.
6. Graham RA, Wang S, Catalano PJ, Haller DG. Postsurgical surveillance of colon cancer: preliminary cost analysis of physician examination, carcino-embryonic antigen testing, chest x-ray, and colonoscopy. Ann Surg. 1998;228(1):59-63.
7. Newland RC, Chapes PH, Smyth EJ. The prognostic value of substaging colorectal cancer. Cancer. 1987;60:852-857.
8. Malassagme B, Valleus P, Serra J, et al. Relationship of apical lymph node involvement
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9. Kawamura YJ, Umetani N, Sunami E. Effect of high ligation on the long-term of
patients with operable colon cancer, particularly those with limited nodal involvement.
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10. Rouffetto F, Jay JM, Vachas B, et al. Curative resection for left colonic carcinoma: hemicolectomy vs. segmental colectomy. A prospective, controlled, and multicenter trial.
French Association for Surgical Research. Dis Colon Rectum. 1994;37:651-659.
11. Hartley JE, Monson JR. The role of laparoscopy in the multimodality treatment of colorectal cancer. Surg Clin North America. 2002;82(5):1019-1033.
12. Gerritsen van der Hoop A. Laparoscopic surgery for colorectal carcinoma: an overnight
victory? European J Cancer. 2002;38:899-903.
13. Fisher ER, Sass R, Palekar A, Fisher B, Wolmark N. Dukes classification revisited.
Findings fromt he National Surgical Adjuvant Breast and Bowel Projects (Protocol R01). Cancer. 1989;64(11):2354-2360.
14. Green FL, Page DL, Fleming, et al. In: AJCC Cancer Staging Manual. 6th ed. New York,
New York: Springer-Verlag; 2002:113-23.
15. Saltz LB, Minsky B. Adjuvant therapy of cancers of the colon and rectum. Surg Clin
North Am. 2002;82:1035-1058.
16. Miles WE. Classic articles in colonic and rectal surgery. A method of performing
abdominopherineal excision for carcinoma of the rectum and of the terminal portion of
the pelvic colon. Dis Colon Rectum. 1980;23(3):202-205.
17. Garcia-Aguilar J, Mellgren A, Sirivongs P, Buie D, Madoff RD, Rothenberger DA. Local
excision of rectal cancer without adjuvant therapy: a word of caution. Ann Surg. 2000;
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231(3):345-351.
18. Chorost MI, Petrelli NJ, McKenna M, Kraybill WG, Rodriguez-Bigas MA. Local excision of rectal carcinoma. Am J. Surg. 2001;67(8):774-779.
19. Visser BC, Varma MG, Welton ML. S Local therapy for rectal cancer. Surg Oncol. 2001;
10(1-2):61-69.
20. Sengupta S, Tjandra JJ. Local excision of rectal cancer: what is the evidence? Dis Colon
Rectum. 2001;44(9):1345-1361.
21. Heald RJ, Moran BJ, Ryall RDH, et al. Rectal cancer: the Basingstoke experience of
total mesorectal excision, 1978-1997. Arch Surg. 1998;133:894-899.
22. Lazorthes F, Gamagami R, Chiotasso P, et al. Prospective, randomized study comparing
clinical results between small and large colonic J-pouch following coloanal anastomosis.
Dis Colon Rectum. 1997;40:1409-1413.
23. Brown SCW, Walsh S, Abraham JS, Sykes PA. Risk factors and operative mortality in
surgery for colorectal cancer. Am R Coll Surg Engl. 1991;73:269-272.
24. Enker WE, Paty PB. Advances in rectal cancer surgery: the combined goals of curing
cancer and reducing morbidity. In: Andersen DK, ed. Advances in Colorectal Carcinoma
Surgery. New York, NY: World Medical Press; 1993:33.
25. Kollmorgen CF, Meagher AP, Wolff BG, Pemberton JH, Martenson JA, Illstrup DM.
The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma
on bowel function. Ann Surg. 1994;220(5):676-82.
26. Heiskanen I, Jarvinen HJ. Fate of the rectal stump after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Int J Colorectal Dis. 1997;12:9-13.
27. Trimbath JD, Giardiello FM. Review article: genetic testing and counseling for hereditary colorectal cancer. Aliment Pharmacol Ther. 2002;16:1843-1857.
28. Chung DC, Rustgi AK. The hereditary nonpolyposis colorectal cancer syndrome:
genetics and clinical implications. Ann Intern Med. 2003;138(7):560-570.
29. Mayer R, Wong WD, Rothenberger DA, et al. Colorectal cancer in inflammatory bowel
disease. Dis Colon Rectum. 1999;4:343-347.
30. Wexner SD, Rosen L, Lowry A, et al. Practice parameters for the treatment of mucosal
ulcerative colitis-supporting documentation. Dis Colon Rectum. 1997;40:1277-1285.
31. Radice E, Nelson H, Devine RM, et al. Ileal pouch-anal anastomosis in patients with
colorectal cancer: long-term functional and oncologic outcomes. Dis Colon Rectum.
1998;41(1):11-7.
BIBLIOGRAPHY
Lewis WG, Holdsworth PJ, Stephenson BM, Finan PJ, Johnston D. Role of the rectum in
the physiological and clinical results of coloanal and colorectal anastomosis after anterior resection for rectal carcinoma. Br J Surg. 1992;79:1082-1062.
Neibergs HL, Hein DW, Spratt JS. Genetic profiling of colon cancer. J Surg Oncol.
2002;80:204-213.
Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor
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Willett CG. Sphincter preservation in rectal cancer. Curr Treat Options Oncol. 2000;
1(5):399-405.
chapter
11
Approach to Chemotherapy
and Radiation Therapy for
Colorectal Neoplasia
Weijing Sun, MD
INTRODUCTION
Colorectal cancer is the most common GI malignancy, and the second leading cause
of cancer-related death in North America. There are 147,500 new cases of colorectal
cancer with 57,100 deaths in 2003 based on the estimates from the American Cancer
Society.1 The overall outcome of patients with colorectal cancer has been greatly
improved over the past several decades, with better understanding of the disease process,
earlier diagnosis through screening, and the development of new and novel treatments.
It is important for clinicians to understand that the prognosis of colorectal cancer is
largely dependent on the extent of the disease at presentation, the depth of tumor penetration into the bowel wall, and the presence or absence of regional lymph node
involvement and distant metastases. The goal of therapy is to improve the chance of survival and the quality of life in patients diagnosed with colorectal cancer based upon the
extent of the disease and risk factors. If the disease is detected early, the prognosis is
excellent and further treatment may not be needed after curative intent surgical resection. However, about two-thirds of patients have lymph node involvement or distal
metastases when their disease is diagnosed. Chemotherapy or chemoradiation plays a
crucial role in increasing the chance of a cure for those patients with lymph node
involvement. Chemotherapy is the most important maneuver to improve the survival
rate for patients with distant metastatic colorectal cancer.
OF
COLORECTAL CANCER
Although the recent advances in biological and molecular characteristics of the disease have brought our understanding of the disease to a different level, pathologic staging is still the most important and reliable system for predicting the prognosis of colorectal cancer, and thereafter guiding the treatment decisions.
Two commonly-used pathological staging systems are the modified Astler-Coller
system from the original Dukes classification and the TNM-based classification of the
184
Chapter 11
AJCC (see Appendix D). Several modifications were included in the recently-edited
AJCC classification. Smooth metastatic nodules in the pericolonic or perirectal fat are
defined as lymph node metastases. Irregularly-contoured metastatic nodules in the peritumoral fat are considered vascular invasion. Stage II is subdivided into IIA (T3 lesions)
and IIB (T4 lesions) based on the depth of invasion. Stage III disease is further subdivided into IIIA (T1-2N1), IIIB (T3-4N1), or IIIC (TanyN2) depending on the depth
of invasion and the level of involvement of lymph node. The importance of cooperation
among the different medical specialties is emphasized also by the Joint Committee.
Surgeons are encouraged to score the completeness of the resection as R0 (the complete
resection with all margins negative of cancer), R1 (incomplete resection with microscopic involvement of a margin), and R2 (incomplete resection with gross residual of
cancer).
For stage I colorectal cancer, the cure rate exceeds 90% following surgery alone.
However, once a tumor invades through the bowel wall (stage II), survival at 5 years
decreases to 60% to 80%. If the pericolonic or perirectal lymph nodes are found to be
involved with cancer (stage III), 5-year survival falls to 30% to 60%, with the lower survival associated with an increasing number of lymph node metastases.3,4 The overall
prognosis of patients with distant metastases is poor, although the survival rate has been
improved dramatically in past several years because of the development of new cytotoxic chemotherapy agents and novel molecular oriented agents. The most frequent site of
metastasis for colorectal cancer is the liver, followed by lung and intra-abdominal sites.
Other clinical and pathologic features such as perforation, obstruction, adherence or
invasion of the tumor to other organs, radial (lateral) margin involvement, lymphatic
and vascular invasion, and degree of tumor differentiation may also increase the risk of
recurrence in those patients with localized diseases.5 Elevation of preoperative CEA level
may predict for prognosis, especially in patients with node-positive disease.6 The change
of CEA level is frequently used as a surrogate indicator of response in patients having
chemotherapy for their metastatic diseases. The elevation of CEA may be an early warning sign of recurrence and/or metastasis of the disease in those patients with localized
colorectal cancer with or without adjuvant therapy. A number of biological and molecular characteristics (such as mutations of p53 and p21, K-ras mutation, chromosome
18q loss of heterozygosity [LOH], MSI-related germline mismatch repair gene mutations, and high expression of thymidylate synthase [TS]) have been identified that may
be of prognostic importance,7-10 although none has yet been validated in prospective
clinical trials.
TREATMENT
OF
The chemotherapy of metastatic colorectal cancer has greatly advanced in the past
several years because of the development of new cytotoxic and novel molecular-oriented
agents. The paradigm of treatment has changed. Physicians should encourage all suitable
patients to enter clinical studies for understanding the disease better, improving the
treatment further, and achieving potentially the best outcome for enrolled patients.
For some selected patients with metastatic colorectal cancer (mainly those with limited hepatic and pulmonary lesions), there is a potential of having their diseases cured
after surgical resection (metastasectomy). It is important to evaluate the resectability first
for patients with metastatic colorectal cancer (Figure 11-1). The data have shown that
surgical resection is safe and may achieve a long-time survival depending on the size and
number of the metastases, the disease-free interval, the lymph node status of the primary
185
Metastases Disease
Resectability Assessment
Unresectable
Resectable
Surgery
Neoadjuvant
Chemotherapy
Postoperation Chemotherapy
Table 11-1
0 to 1
2 to 3
4 to 5
52%
23%
11%
tumor, and the level of CEA11 (Table 11-1). The advantage of systemic chemotherapy
with 5-FU/LV after resection of metastases has been demonstrated in both 5-year disease free survival (DFS) and 5-year overall survival (OS).12 Until now, surgical resection
of metastatic lesions followed by further chemotherapy for those with respectable diseases was accepted at most situations (see Figure 11-1). Preoperative chemotherapy with
new agents has been investigated lately. This approach may help to select patients who
will benefit from curative resection if they have good responses to the systemic
chemotherapy and to avoid unnecessary surgical procedure for those patients with no
response to chemotherapy or even with their diseases progressed during treatment.
Successful down-staging of the disease, even with complete histologic response, has been
achieved in some patients with initially unresectable metastases.13,14 It has been reported that the postmetastasectomy outcome in patients whose disease responded to neoadjuvant chemotherapy is much better than those whose disease did not.15
186
Chapter 11
Majority of patients with metastatic colorectal cancer are not candidates for metastasectomy, and surgical procedures are performed only for bypassing obstructive and
hemorrhagic lesions. The palliative systemic chemotherapy is the only maneuver for
their treatment. The median survival (MS) of individuals with metastatic disease has
dramatically improved in the past several years. As a main component of chemotherapy,
5-FU is administered intravenously either with LV as bolus fashions or as continuous
infusion. The combinations of 5-FU with oxaliplatin (a diaminocyclohexane platin that
inhibits DNA replication and transcription through the formation of intra- and interstrand DNA adducts) or irinotecan (a topoisomerase I inhibitor) are the new standard
treatments for metastatic colorectal cancer.16-19 Various regimens are available with different doses and schedules (Figure 11-2). The question of which combination (irinotecan with 5-FU/LV or oxaliplatin with 5-FU/LV) is more effective is unknown, but preliminary data suggest a rough equivalency in efficacy of each combination in first- or second-line treatment, with differences in toxicity patterns.20 It appears that the combination of irinotecan with bolus 5-FU may be more toxic, particularly in the elderly and
patients with poor performance status. It is important for physicians to realize that
patients with reasonable good performance should be treated with all 3 effective medications during their treatment courses. Capecitabine, an oral fluoropyrimidine carbamate derivative, has also been approved by the FDA as first-line therapy for patients with
metastatic colorectal cancer who are not candidates for combination therapy.
Capecitabine was shown to be as effective as a standard bolus 5-FU/LV regimen in 2 randomized trials.21,22 Based on continuous dosing, capecitabine may hold the potential to
replace infusional 5-FU in combination with irinotecan and oxaliplatin. Although phase
II trials of capecitabine in combination with irinotecan and oxaliplatin appear promising, equivalence to standard intravenous infusional therapy needs to be proven by ongoing phase III studies.
Many novel biological agents are now being tested. These new agents target the
EGFR, VEGF, and other molecular markers. Significant improvements in median survival, progression-free survival, and overall response rates have been demonstrated when
bevacizumab, a recombinant humanized monoclonal antibody against VEGF, is added
to irinotecan/5-FU/LV (IFL)23 (Table 11-2). The results of the combination of bevacizumab with oxaliplatin/5-FU/LV are expected in 2005. Encouraging results have also
been shown from phase II studies with cetuximab (C225), a monoclonal humanized
antibody directly against EGFR in previous-treated metastatic colorectal cancer
patients.24
Postmetastectomy hepatic artery infusion (HAI) of floxuridine (FUDR) with systemic 5-FU/LV chemotherapy may improve survival compared with systemic 5-FU/LV
alone25 (Table 11-3). However, with more effective systemic chemotherapy regimens
available, the potential contribution of HAI needs to be tested further. Many other
hepatic-directed treatments have been proposed for metastases of colorectal cancer,
including radiofrequency ablation (RFA), hepatic artery chemoembolization (HACE),
cryotherapy, and percutaneous ethanol injection.26-28 All of these procedures have their
limits, and local availability and expertise vary widely. While no survival benefit has been
proven to date, trials are underway comparing chemotherapy alone to chemotherapy
plus either HACE or RFA.
LV 200 mg/m2
IV over 2 hours
LV 200 mg/m2
IV over 2 hours
LV 200 mg/m2
IV over 2 hours
Day 2
Figure 11-2. Schema of common chemotherapy regimens in treatment of metastatic colorectal cancer.
Ox 100 mg/m2
IV over 2 hours
LV 400 mg/m2
IV over 2 hours
Day 1
Ox 100 mg/m2
IV over 2 hours
LV 400 mg/m2
IV over 2 hours
Day 1
LV 200 mg/m2
IV over 2 hours
Day 2
LV 200 mg/m2
IV over 2 hours
Ox 85 mg/m2
IV over 2 hours
Day 1
Day 1
Day 1
188
Chapter 11
Table 11-2
IFL/BV
(N=403)
p-value
20.3
10.6
45
10.4
3.1
9.3
0.8
10.9
0.00003
<0.00001
0.0029
0.0014
NS
NS
NS
Table 11-3
5-Year DFS
5-Year OS
82
34%
49%
74
40%
61%
FUDR=floxuridine, or fludeoxyuridine
189
Table 11-4
Dosing
Schedule
Roswell Park
LV 500mg/m2 IV over
2 hours
5-FU 500mg/m2 IV push
1 hour after LV infusion
started
Mayo Clinic
LV 20mg/m2 IV push
5-FU 425mg/m2 IV push
de Gramont
(LV5FU2)
LV=leucovorin; 5-FU=fluorouracil
ADJUVANT CHEMOTHERAPY
FOR
COLON CANCER
The benefit of adjuvant chemotherapy for colorectal cancer has become well established over the past 2 decades.29-33 The final results of Intergroup 0089 and National
Surgical Adjuvant Breast and Bowel Project (NSABP) C-04 studies confirmed that
5-FU-based therapy significantly improves disease-free and overall survival for patients
with stage III colon cancer.33,34 Neither study showed the addition of levamisole (LEV)
to 5-FU/LV providing any additional benefits. The combination of 5-FU with LV for 6
to 8 months is still the standard therapy for stage III (Dukes C) colon cancer as adjuvant setting by the time this article was written, given by a variety of different doses and
schedules that have demonstrated comparable efficacy (Table 11-4). In the United
States, the Roswell Park regimen and the Mayo Clinic regimen are commonly used with
somewhat different toxicity profiles. More leukopenia and stomatitis are associated with
the Mayo regimen, and more grade 3 to 4 diarrhea is seen in the Roswell Park regimen,
which is usually manageable with aggressive antidiarrhea medications. The infusional
regimen, LV5FU2 (also called de Gramont regimen) was compared with a bolus regime
for toxicity and efficacy in patients with stage II and III colorectal cancer.35 There was
no significant difference in disease-free or overall survival between the treatment arms;
however, toxicities were significantly lower in the infusion group (p<0.001).
Capecitabine, as an oral fluoropyrimidine, has been studied as an adjuvant treatment for
patients with resected Dukes C colon cancer (the X-ACT trial). Preliminary safety data
showed 60-day all-cause and treatment-related mortality was similar to the Mayo Clinic
Regimen at ~0.5%. Capecitabine causes significantly less diarrhea, nausea, vomiting,
stomatitis, and alopecia compared to bolus 5-FU/LV, but more hand-foot syndrome.36
The efficacy data are expected soon.
190
Chapter 11
Newer studies have been designed to prove whether the survival advantage of the
combination of 5-FU/LV with oxaliplatin or irinotecan in metastatic colorectal cancer
can be transferred to the adjuvant setting. A European study (MOSAIC) compared
LV5FU2 and the combination of oxaliplatin with infusional 5-FU/LV (FOLFOX) in
patients with stage II/III colon cancer after complete resection of the primary colon cancer.38 The results showed that the 3-years DFS in the intent-to-treat population was
77.8% in the FOLFOX arm vs 72.9% in the LV5FU2 arm (p<0.01) with a risk reduction of 23% in the FOLFOX arm. This is the first study to demonstrate the combination of oxaliplatin with 5-FU/LV superior to the current standard 5-FU/LV in adjuvant
therapy of colon cancer. The result also confirmed that FOLFOX is feasible and safe for
use in the adjuvant setting. Although there was 12.4% of grade 3 peripheral sensory neuropathy reported that was secondary to oxaliplatin, only 1% of patients had residual
neuropathy at 1 year. Other grade 3/4 toxicities were neutropenia (41%), diarrhea
(10.8%), and vomiting (5.9%). It is expected that adjuvant therapy with FOLFOX in
stage I colon cancer will be accepted as new standard. An interim analysis of the study
(C89803) comparing the combination of irinotecan with bolus 5-FU/LV (IFL) with 5FU/LV alone as adjuvant setting in patients with stage III colon cancer showed the 60day all-cause mortality was higher in patients who received the combination therapy.
Although the main causes have been identified as vascular events and GI syndromes, the
relationship of these events and the given medication is still not clear. More data from
other studies are anticipated soon. There are more studies designed to investigate the
benefits of traditional cytotoxic chemotherapy combined with molecular-oriented
agents such as bevacizumab and cetuximab as adjuvant setting in stage II/III colorectal
cancer patients.
Adjuvant treatment with monoclonal antibody 17-1A (Edrecolomab, Mab 17-1A),
a murine IgG2a monoclonal antibody that recognizes the human tumor-associated antigen Ep-CAM, has been examined extensively. However, no obvious benefit has been
shown from the available data.39,40
Adjuvant chemotherapy with 5-FU/LV in localized, node-negative disease (stage II
or Dukes B) remains controversial, even though the benefit is considered to be real, especially for those patients with high risk factors (eg, bowel obstruction, perforation, and
poorly differentiated cancer) for recurrence.41-43 However, with the availability of more
effective chemotherapy agents, significant and meaningful benefits of adjuvant
chemotherapy in the treatment of stage II colon patients are possible and very likely.
Furthermore, accurate molecular characteristic colon cancers may define those patients
with high risk, so therefore these subset stage II colon cancer patients may truly benefit
from adjuvant therapy.
ADJUVANT TREATMENT
OF
RECTAL CANCER
191
combined modality compared to TME alone in the 2-year local recurrent rate (2.4% vs
8.2%, p<0.001). However, the impact of radiation on overall survival has been minimal.
The significant improvement of overall survival with protracted venous infusion (PVI)
of 5-FU (225 mg/m2/day) during pelvic radiation (50.4 Gy) was demonstrated from an
intergroup trial.47 Although infusional 5-FU concurrent with radiation is the commonly accepted regimen as adjuvant therapy for rectal cancer, a recent published intergroup
study compared bolus 5-FU to continuous infusion 5-FU before, during, and after
pelvic radiation. The study found no significant differences between the treatment arms
in DFS, OS, or significant toxicities.48 It appeared that both bolus and infusional 5-FU
could be combined with radiation with equal efficacy and toxicity for post-operative
adjuvant therapy. The overall OS and DFS were dependent on TN stage and treatment
method.49,50 For patients with intermediate risk lesions (T1-2N1, T3N0) adjuvant
chemotherapy had equivalent results with chemoradiation therapy, which suggested that
the use of trimodality with postoperative chemoradiation for intermediate risk patients
may be excessive. For those patients with high risk (TanyN2, T3-4N1) of recurrence,
adding a new cytotoxic medication (eg, oxaliplatin to 5-FU) and radiation therapy may
decrease the risk of both locoregional and distant recurrence and metastases based on the
data from several phase II studies.51 With the advantage of more convenient than infusional 5-FU, and potential synergistic effect with radiation therapy, capecitabine has
been studied in combination with radiation, and the preliminary results are encouraging.52 Novel targeted biologic agents, including celecoxib and bevacizumab, are being
explored in combination with standard chemotherapy and radiation therapy.51
Preoperative neoadjuvant chemoradiation of localized rectal cancer may hold potential
benefit of down-staging the disease; therefore, it improves the respectability and increases the rate of salvage of the sphincter muscle. Large intergroup studies are designed to
delineate the advantage of pre- versus postoperative chemoradiation therapy in rectal
cancer.
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1. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin. 2003;
53:5-26.
2. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, eds. AJCC Cancer Staging
Manual. 6th ed. New York, NY: Springer-Verlag; 2002:113-118.
3. Macdonald JS. Adjuvant therapy of colon cancer. CA Cancer J Clin. 1999;49(4):202219.
4. Bokey EL, Ojerskog B, Cahpuis PH, et al. Local recurrence after curative excision of the
rectum for cancer without adjuvant therapy: role of total anatomical dissection. Br J
Surg. 1999;86(9):1164-1170.
5. Sun W, Haller DG. Chemotherapy for colorectal cancer. Hematol Oncol Clin N Am.
2002;16:969-994.
6. Harrison LE, Guillem JG, Paty P, et al. Preoperative carcinoembryonic antigen predicts
outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients.
J Am Coll Surg. 1997;185:55-59.
7. Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18Q and prognosis in colorectal cancer. N Engl J Med. 1994;331:213-221.
8. Allegra CJ, Paik S, et al. Prognostic value of thymidylate synthase, Ki-67, and p53 in
patients with Dukes B and C colon cancer: a National Cancer Institute-National
Surgical Adjuvant Breast and Bowel Project collaborative study. J Clin Oncol. 2003;
21(2):241-250.
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9. Allegra CJ, Parr AL, Wold LE, et al. Investigation of the prognostic and predictive value
of thymidylate synthetase, p53, and Ki-67 in patients with locally advanced colon cancer. J Clin Oncol. 2002;20(7):173543.
10. Gonen M, Hummer A, Zervoudakis A, et al. Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer. J Clin Oncol. 2003;21(3):406-412.
11. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin
Oncol. 1997;15:938-946.
12. Portier G, Rougier Ph, Milan C, et al. Adjuvant systemic chemotherapy (CT) using 5fluorouracil (FU) and folinic acid (FA) after resection of liver metastases (LM) from colorectal origin. Results of an Intergroup phase III study (trial FFCD-ACHBTH-AURC
9002). Proc Am Soc Clin Oncol. 2002;21:133a(A528).
13. Giacchetti S, Itzhaki M, Gruia G et al. Longterm survival of patients with unresectable
colorectal cancer liver metastases following infusional chemotherapy with 5-flurouracial,
leucovorin, oxaliplatin and surgery. Ann Oncol. 1999;10:663669.
14. Alberts SR, Donohue JH, Mahoney MR, et al. Liver resection after 5-fluorouracil, leucovorin and oxaliplatin for patients with metastatic colorectal cancer (MCRC) limited
to the liver: A North Central Cancer Treatment Group (NCCTG) phase II study. Pro
Am Soc Clin Oncol. 2003;22:a263 (A1053).
15. Adam R, Pascal G, Castaing D, et al. Liver resection for multiple colorectal metastases:
influence of preoperative chemotherapy. Pro Am Soc Clin Oncol. 2003;22:a296
(A1188).
16. Saltz LB, Cox JV, Blanke CB, et al. Irinotecan plus fluorouracil and leucovorin for
metastatic colorectal cancer. New Eng J Med. 2000;343:905-914.
17. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil
compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer:
a multicenter randomized trial. Lancet. 2000;355:1041-1047.
18. Rothenberg ML, Oza AM, Burger B, et al. Final results of a phase III trial of 5-FU/leucovorin versus oxaliplatin versus the combination in patients with metastatic colorectal
cancer following irinotecan, 5-FU, and leucovorin. Proc Am Soc Clin Oncol. 2003;
22:a252 (A1011).
19. Goldberg RM, Morton RF, Sargent DJ, et al. N9741: oxaliplatin (Oxal) or CPT-11 +
5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer
(CRC). Updated efficacy and quality of life (QOL) data from an Intergroup study. Proc
Am Soc Clin Oncol. 2003;22:a252 (A 1009).
20. Tournigand C, Louvet C, Quinaux E, et al. FOLFIRI followed by FOLFOX versus
FOLFOX followed by FOLFIRI in metastatic colorectal cancer (MCRC): final results
of a phase III study. Proc Am Clin Oncol. 2002;21:a124 (A494).
21. Hoff PM, Ansari R, Bastist G, et al. Comparison of oral capecitabine versus intravenous
fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001;19(8):22822292.
22. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results
of a large phase III study. J Clin Oncol. 2001;19(21):4097-4106.
23. Hurwitz H, Fehrenbacher L, Cartwright T, et al. Bevacizumab (a monoclonal antibody
to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer
(CRC): results of a phase III trial of bevacizumab in combination with bolus IFL
(irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic
CRC. Proc Am Soc Clin Oncol. 2003;22:(A 3646).
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39. Punt CJ, Nagy A, Douillard JY, et al. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet. 2002;360(9334):671-677.
40. Fields AL, Keller AM, Schwartzberg L, et al. Edrecolomab (17-1A antibody) (EDR) in
combination with 5-fluorouracil (FU) based chemotherapy in the adjuvant treatment of
stage III colon cancer: results of a randomized North American phase III study. Proc Am
Soc Clin Oncol. 2002;21:128a (A508).
41. Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant
chemotherapy in patients with Dukes B versus Dukes colon cancer: results from four
national surgical adjuvant breast and bowel project adjuvant studies (C-01, C-02, C-03,
and C-04). J Clin Oncol. 1999;17:1349-1355.
42. Efficacy of Adjuvant Fluorouracil and Folinic Acid in B2 Colon Cancer. International
Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J
Clin Oncol. 1999;17:1356-1363.
43. Marsoni S for IMPACT investigators. Efficacy of adjuvant fluorouracil and leucovorin
in Stage B2 and C colon cancer. Semin Oncol. 2001;28 (suppl 1):14-19.
44. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP protocol R-01. J Natl Cancer Inst.
1988;80:21-29.
45. Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in
resectable rectal cancer. N Eng J Med. 1997;336:980-987.
46. Kapitijin E, Marijnen CAM, Magtegaal, ID, et al. Preoperative radiotherapy combined
with total mesorectal excision for respectable rectal cancer. N Engl J Med. 2001;345:
638-646.
47. OConnell MJ, Martenson JA, Weiand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after
curative surgery. N Engl J Med. 1994; 331(8):502507.
48. Smalley SR, Benedetti J, Williamson S, et al. Intergroup 0144 - phase III trial of 5-FU
based chemotherapy regimens plus radiotherapy (XRT) in postoperative adjuvant rectal
cancer. Bolus 5-FU vs. prolonged venous infusion (PVI) before and after XRT + PVI vs.
bolus 5-FU + leucovorin (LV) + levamisole (LEV) before and after XRT + bolus 5-FU
+ LV. Proc Am Soc Clin Oncol. 2003;22:(A1006).
49. Tepper JE, OConnell M, Niedzwiecki D, et al. Adjuvant therapy in rectal cancer:
analysis of stage, sex, and local controlfinal report of Intergroup 0114. J Clin Oncol.
2002;20(7):17441750.
50. Gunderson LL, Sargent D, Tepper J, et al. Impact of TN stage and treatment on survival and relapse in adjuvant rectal cancer pooled analysis. Pro Am Soc Clin Oncol. 2003;
22:a251(A1008).
51. Zhu AX, Willett CG. Chemotherapeutic and biologic agents as radiosensitizers in rectal cancer. Semin Radiat Oncol. 2003;13(4):454-68.
52. Rodel C, Grabenbauer GG, Papadopoulos T, et al. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol. 2003;21(16):3098-104.
chapter
12
INTRODUCTION
Despite recent national attention on the assessment and treatment of cancer pain,
unrelieved pain from cancer treatment and disease progression continues to be alarming high. The complexity of cancer pain and its undertreatment are major factors attributed to poor pain control. Pain experiences that span from diagnosis to the end of life
are highly influenced by primary tumor site, stage, treatment-related factors, physiological sources of pain (somatic, visceral, and neuropathic), and psychosocial determinants. While pain represents only one dimension of the multiple symptoms experienced
by cancer patients, it is clearly a problem that has the most profound impact on healthrelated quality of life (HrQOL).
More than 70% of patients with cancer have significant pain during their course of
their illness.1 Worldwide estimates of the prevalence of cancer pain show that some 30%
to 40% of patients undergoing cancer therapy and, more discouraging, about 70% to
90% of those with advanced disease report pain.2 Other global appraisals of pain indicate that one-third to one-half of patients undergoing active treatment experience pain
and that some cancer-specific sites are associated with more severe pain. Specific data
that are available for pain associated with GI malignancies show variations in its prevalence by the primary cancer site. Through an international collaborative study of
patients with advanced cancer, moderate to severe pain was found in 51% of those with
esophageal cancer, 59% with colorectal cancer, and 43% with cancer of the stomach.3
At diagnosis, almost 75% of patients with pancreatic cancer experience pain,4 which
may persist in the later stages of the disease without aggressive interventions. Locally
recurrent rectal cancer, which occurs in up to one-third of patients, can be controlled in
about a third of these patients, but not without significant morbidity and mortality.
Whether this progression is managed with nonsurgical palliation or resection, it is associated with a significant degree of pain.5
196
Chapter 12
BARRIERS
TO
Pain management practices are highly influenced by both practitioner- and health
system-related barriers. Frequently mentioned reasons for untreated pain are inadequate
pain assessment, lack of knowledge and training in pain management, attitudes, beliefs
and biases, concern and fear over regulatory scrutiny, and health care disparities in the
treatment of vulnerable populations (eg, elderly and culturally diverse populations).
Discouraging accounts of pain were noted in a national study of over 1300 outpatients
across 54 Eastern Oncology Cooperative Group practice sites, with 36% of patients
experiencing pain so severe that it interfered with function.6 Even though a significant
number of patients reported high pain interference, over 50% of physicians treating
these patients felt that pain control in their practice was good to very good.7 They
also acknowledged their reluctance to aggressively treat pain with opioid analgesics until
patients were in the later stages of their disease.
Confusion regarding the terminology associated with opioid use continues to negatively affect prescribing patterns.8,9 Physical dependence, which is a state of physiological
adaptation that occurs from repeated exposure to a drug, is manifested by a drug class
specific withdrawal syndrome resulting from abrupt cessation of the drug, rapid dose
reduction, or administration of a reversal agent. Physical dependence inevitably develops with chronic opioid use. Abrupt withdrawal of therapy often results in physical
symptoms such as nervousness, sweating, nausea, vomiting, abdominal cramping, diarrhea, and, more seriously, seizures. Concerns about physical dependence should not
deter physicians from prescribing adequate doses of opioid analgesics because doses can
always be decreased slowly to prevent acute withdrawal. More importantly, physical
dependence is a separate entitynot to be confused with addiction or psychological
dependence, which is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors. Addiction is characterized by compulsive drug use
behaviors such as continued craving for the substance, the need to use the drug for
effects other than relieving pain, and a preoccupation with procuring the drug to get
high, despite harmful effects. A number of studies have shown that short- and longterm use of opioids to control pain is unlikely to lead to addiction.8 Patients also worry
about becoming addicted and need appropriate information and reassurance that
chronic opioid use for cancer pain seldom leads to abuse. Tolerance occurs when an
increased dose is required to maintain the original analgesic effects. Tolerance is rarely a
clinical problem, is unlikely to occur with short-term opioid use, and typically develops
in cancer patients because of disease progression and worsening of pain.
Eliminating healthcare disparities has been a major research priority for the National
Institutes of Health (NIH) and other funding agencies. Age, gender, ethnicity, and race
can negatively affect pain management practices. For example, older persons with cancer may be less likely to be referred to pain specialists for interventional pain care and
palliative care services.10 Elders, females, and minorities are at greater risk for inadequate
opioid analgesia.6
197
pain intensity is increasingly recognized as the fifth vital sign commonly used to gauge
the effectiveness of pain relieving therapies. While dissemination of these standards has
increased accountability for prompt attention and response to unrelieved pain, many
agree that more stringent laws and regulations must be imposed to overcome the prevailing reluctance to aggressively treat cancer pain. A study of Wisconsin physicians
revealed that more than 50% admitted to occasionally reducing the dose or quantity of
refills, or prescribing an opioid in a lower scheduled category for fear of regulatory
scrutiny.12 To overcome these unfounded concerns, state medical boards have adopted
guidelines to ensure that patients do not suffer needlessly because of misconceptions surrounding the prescribing of opioids. Moreover, compliance with published cancer pain
management guidelines, diligence in documenting pain outcomes and response to therapy, and appropriate patient education regarding the safe use of opioid analgesics should
alleviate these concerns. The University of Wisconsin Pain Studies Group/WHO
Collaborating Center now tracks the introduction and enactment of new state laws and
regulations. Recent data show a sustained increase in the number of states that define
accepted pain practices and penalties under code for failure to render appropriate care to
patients in pain.13 Updated progress reports in the development of national and state
pain-related health policies and legislation can be accessed from the University of
Wisconsin Pain Policy Web site: www.medsch.wisc.edu/painpolicy.
Several strategies have been proposed to increase awareness of the proper approaches to assessing and managing cancer pain. Professional societies and government agencies have developed research- and evidence-based reviews and criteria for what constitutes best practices. In July 2002, the NIH held a State-of-the-Science conference
where national experts convened to establish consensus on the best approaches to treating the symptom cluster of pain, fatigue, and depression in cancer patients.14 A summary of the panels recommendations can be accessed from the Agency for Healthcare
Research and Quality (AHRQ) evidence-based Web site: www.ahrq.gov. Other comprehensive guidelines for cancer pain are published through the AHRQ in an evidence
report/technology assessment prepared by the New England Center EPC, Boston,
Mass,15 and the National Comprehensive Cancer Network (NCCN).16 Current NCCN
pain and distress management guidelines are available on their Web site: www.nccn.org.
Few studies have actually measured the benefits to patients when clinical care guidelines are consistently incorporated in routine patient care. The earliest attempts to evaluate the impact of practice guidelines focused on cancer prevention interventions in primary care by examining single outcomes such as written orders, tests obtained, and
drugs prescribed.17 Computerized systems to facilitate patient care orders were also studied in a variety of practice settings, but none of these investigations actually linked comprehensive pain guidelines to improvements in patient care. DuPen et al were among the
first to test the effects of implementing cancer pain management clinical algorithms in
a randomized controlled clinical trial involving 26 western Washington-area oncology
outpatient sites.18 Patients whose care was directed by clinical decision tools experienced
statistically significant decreases in usual pain compared to those managed with standard
practices (controls). Others found that individualized patient educational sessions and
coaching techniques to promote self-management of pain for outpatients with cancer
pain resulted in significant improvements in average levels.19
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Chapter 12
Numerical Scale
1
2
No pain
9
10
Worst pain
Visual Scale
No
Pain
Worst
Pain
Categorical Scale
None (0) Mild (1-3) Moderate (4-6) Severe (7-10)
ASSESSMENT
OF
PAIN
AND
PAIN-RELATED OUTCOMES
Pain assessment begins with eliciting patient-reported data from reliable and valid
measures, a physical examination, and evaluation of diagnostic criteria. Self-reports of
pain intensity are most frequently obtained with the numeric rating scale (NRS) (0 to
10), 10 cm visual analogue scale (VAS) (0 no pain to 10 unbearable or worst pain imagined), and verbal rating scales (VRS) (Figure 12-1). Equally important is the ability to
diagnose the physiological sources of pain (somatic, visceral, or neuropathic) through
patient-reported information, physical exams, and radiological evaluations. The effectiveness of many treatment approaches is dependent on the origin of pain. Table 12-1
outlines the mechanisms for both acute and chronic cancer- and noncancer-related pain
syndromes, characteristics, and an overview of treatment strategies. Somatic and visceral pain arises from activation of nociceptors in the periphery, while neuropathic pain or
non-nociceptive pain results from damage to the peripheral or central nervous system.
The following criteria should be a part of the clinical assessment for chronic pain:
Etiology (cancer disease-related, cancer treatment-related, chronic nonmalignant
pain, etiology unclear or unknown)
Physiological sources of pain (somatic, visceral, neuropathic, or mixed pain)
Mechanism (eg, inflammation, muscle spasm, visceral distention, nerve compression, or infiltration)
Trajectory (progressive or stable)
Severity (mild, moderate, or severe)
Degree of physical debilitation
Location
Pain history (duration, temporal factors, patterns of pain)
Confounding psychosocial (depression; anxiety; disruptions in interpersonal,
family, or social relationships)
Cognitive impairment or mental status changes (especially important in the elderly)
Activation of
nociceptors.
Somatic
Visceral
Activation of
nociceptors.
Mechanism
Physiological
Structures
Examples of
Syndromes
Clinical Evaluation
of Pain Types
Pain Type
Table 12-1
The Assessment and Management of Acute and Chronic
199
Physiological
Structures
Nerve fibers
Spinal cord
Central nervous system
Pain Type
Neuropathic
Nonnociceptive
injury to the
nervous system
structures.
Examples of
Syndromes
Clinical Evaluation
of Pain Types
Mechanism
200
Chapter 12
201
Location, pain history (onset and duration), and temporal factors (precipitating factors) must also be included in a through pain assessment. Many patients with progressive cancer-related pain experience 2 or more sites of pain. A new pain location should
raise suspicion for possible disease progression. Information about the patterns of pain
can be useful in directing pain therapy. Patients with chronic pain often experience
episodic or breakthrough pain in addition to their continuous or usual pain. In some
circumstances, exacerbations of pain are predictable (such as pain with movement or
activity) or occur at the end the duration of their pain medication(s). A study of 200
ambulatory patients found 90% with pain on movement.20 On the other hand, pain
episodes can be unpredictable. For example, neuropathic pain is often associated with
spontaneous paroxysmal shooting pains, and cramping or stretching of hollow viscera
may be sudden and unexpected. Breakthrough pains are generally a marker of more
severe pain21 and are associated with higher direct medical costs from pain-related hospitalizations and physician office visits.22
For chronic cancer pain, it is not enough to simply obtain pain intensity levels. Since
cancer pain almost always coexists with other physical symptoms and psychosocial factors, multidimensional assessments are extremely helpful in understanding patient experiences. A critical review of the psychosocial aspects of cancer pain elucidates this strong
association between pain and psychological distress.23 Comprehensive pain assessments
should be routinely incorporated into practice by including periodic or longitudinal
evaluations of pain relief, symptom experiences, function, HrQOL, psychological distress, and satisfaction with pain care. Moreover, these variables may be independent of
one another and outcomes from pain management.24
The Brief Pain Inventory (BPI) is commonly employed in outpatient settings to
quantify patient-reported present, least, worst, and average pain levels; perceptions of
pain relief; and pain interference25 (Figure 12-2). The instrument is easy to administer
and complete and has been tested in a variety of practice settings. The BPI has been validated with several culturally diverse populations and is translated in many languages.
The 7 items measuring pain interference provide useful information on the degree to
which pain interferes with function, mood, relationships, and other important aspects
of daily living. Increased ratings of pain on the BPI have been associated with greater
functional impairments and declines in perceptions of well-being. The Karnofsky
Performance Status (KPS) Scale, which is an 11-point rating scale ranging from 0
(=dead) to 100 (=normal function), provides a unidimensional assessment of function.26
The KPS has been traditionally a part of outcome measures in numerous clinical trials
for cancer treatment.
The character and quality of pain can easily be assessed with the short form of the
McGill Pain Questionnaire (SF-MPQ), which lists 11 sensory words and 4 affective
words.27 Respondents indicate whether or not they are experiencing the sensation or
affective component and rank the severity on a scale of 1 (mild) to 3 (severe).
Information is grouped in 3 categories: Physical Symptom Distress, Psychological
Distress, and Global Distress Index. The SF-MPQ is especially useful to track the severity of sensations associated with specific pain syndromes following treatment. Since
word choices such as shooting, hot-burning, and stabbing are included and often
reported with nerve injury, the effectiveness of anticonvulsants and tricylic antidepressants commonly used to treat neuropathic pain can be evaluated. Patients with visceral
pain often describe their pain as cramping or splitting, which are also part of the SFMPQ.
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Chapter 12
Symptom experiences that coexist with cancer and cancer pain can be identified and
quantified with the Memorial Symptom Assessment Scale (MSAS).28 Patients rate 32
symptoms for presence and severity and degree to which they are bothered by the symptom on a 0-to-4 Likert Scale. HrQOL while mostly measured in the context of clinical
trials and outcome research studies has gained importance in routine clinical practice.
Additional information on the clinical utility of HrQOL is available in an extensive
review of quality of life measures and their meaningfulness in clinical care.29
Careful selection of pain assessment tools is needed for special populations such elders, terminally ill, cognitively impaired, culturally diverse, or those with language barriers. Pain instruments must be easily understood and administered, validated for use with
203
these populations and capable of identifying changes in pain over time. Item burden and
stress associated with responding to questions are reduced by prioritizing the most critical information and obtaining patient-reported data with short questionnaires or surveys. For specific recommendations for assessing pain in vulnerable patients, consult the
American Geriatrics Society clinical care guidelines,30,31 report from the Expert Working
Group of the European Association of Palliative Care32 and available data on the psychometric testing of instruments in culturally-based research.13
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Pre-Emptive Analgesia
Timing of analgesia plays an important role in the degree of effectiveness of postsurgical pain control and possibly the interruption of tissue injury responses before the surgical insult. Preemptive interventions remain controversial and the clinical benefits have
been difficult to prove. Moreover, there is little consensus as to what constitutes preemptive analgesia, but most agree that preoperative and sometimes intraoperative
administration of analgesics falls within the applied use of the concept.
In experimental models, antinociceptive strategies implemented prior to the time of
tissue injury show a reduction in the development of postinjury central sensitization.
Clinically, however, research with preemptive analgesia yields wide variations in achieving desired postoperative pain outcomes. An extensive systematic review by Moiniche,
et al37 evaluating the effects of preemptive strategies (preoperatively or intraoperatively)
analyzed the results from double-blind randomized studies of analgesia initiated before
or after surgical incision. For the most part, preemptive analgesia with NSAIDs, intravenous opioids or ketamine, peripheral local anesthetics and caudal analgesia offered no
appreciable benefit over postsurgical treatment. The greatest benefit seemed to occur
with single-dose epidural analgesia, although the same was not supported with continuous epidural infusions.
205
Table 12-2
ANALGESIC
EFFECT
Salicylic Acids
ASA
Propionic Acids
Diclofenac
Ibuprofen
Naproxen
Carbo and Heterouyclicacetic
Acids Indomethacin
Fenamates
Meclofenamate Acid
Oxicams
Piroxicam
Pyrazolines
Phenybutazone
Paracetamol
Pyrrolo-Pyrroles
Ketorolac
ANTIPYRETIC
EFFECT
ANTI-INFLAMMATORY
EFFECT
+
+
+
+
+
+
+
+
+
+
+
++
+
+
+
+
++
+
EFFECTS
CNS
Pulmonary
Headaches, nausea
Asthma/bronchospasm, pulmonary
edema
Ulceration/Hemorrhage, stomatitis
ARF, Hypertension, Interstitial Nephritis
Photosensitivity, Erythema Multiforme,
Fixed Drug Eruption, Reye's Syndrome
Aplastic Anemia, Hemolytic Anemia
Anaphylactoid Reactions
Gastric
Renal
Dermatological
Hepatic
Systemic
especially for patients with chronic cancer or nonmalignant pain syndromes. Most opioid-dependent patients require at least 100% more opioid for pain management than
their daily requirement prior to surgery. Consult Macintyre40 for an extensive review of
the safety and efficacy of PCA not only for postoperative pain, but also for other acute
pain syndromes and chronic pain.
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EPIDURAL ANALGESIA
For major thoracic and abdominal surgical procedures, epidural analgesia is superior
in its pain-relieving effects when compared to other analgesic therapy. Evidence from a
recent meta-analysis on postoperative epidural analgesia confirms that better pain control is achieved compared to parenteral opioids regardless of the analgesic agent and level
of the catheter.41 The optimal approaches for this technique are often debated as epidural analgesia can involve both single agent or combination therapy and delivery of agents
at different levels in the epidural space. Moreover, variations exist in reported failure
rates and risk/benefit analyses. Most often therapy with continuous infusions with or
without patient-controlled epidural analgesia is associated with better pain outcomes
than intermittent dosing schedules alone. Studies consistently show that combinations
of an opioid and local anesthetic provide significantly greater pain relief following upper
and lower abdominal surgery in contrast to single agent administration. The advantages
of lipophilic opioids (fentanyl and hydromorphone) alone are questionable, especially
for pain management after upper and lower abdominal procedures.42
There is definitely a role for epidural analgesia following major abdominal surgery
for GI malignancies. Despite the lack of randomized controlled trials to evaluate the
effectiveness of catheter levels with abdominal procedures, the use of thoracic epidurals
remains the standard for practice. The key is concordance of anatomic site and catheter
location (ie, thoracic dermatome incision and thoracic epidural). With opioid and local
anesthetic combinations, thoracic administration promotes the drug delivery of smaller
doses of lipophilic agents at the same level of the incision and lessens chances for motor
and sympathetic blockade from local anesthetics.42 Successful placement of thoracic
catheters requires technical expertise that is often present among pain management
trained anesthesiologists or general anesthesiologists with extensive experience.
Along with the level of catheter placement, the selection of an opioid and local anesthetic combination solution and hourly rate of administration seem to be the most
important determinants of treatment success with epidural analgesia. The mechanism of
action of epidural opioids is by mu receptor activity in the spinal cord and systemic
absorption. Fentanyl, because of its lipophilic pharmacological property, provides more
segmental pain relief and is probably effective through absorption into the systemic circulation. Epidural doses often approximate those required for systemic administration.
While fentanyl causes less pruritis and nausea compared to morphine, which has some
advantage in patients with GI malignancies already experiencing preoperative nausea, its
limited vertical distribution may lead to less effective pain control with extensive abdominal incisions when administered through lumbar catheters. Morphine, because of its
hydrophilic properties, has greater rostral (vertical) spread in the epidural space, thus it
is more appropriate for managing pain from surgical incisions that are more remote from
the catheter tip. Hydromorphone, used less often, provides similar relief as morphine
with limited side effects. Approximately one-fifth to one-fourth of the systemic dose is
required for epidural morphine and hydromorphone administration; therefore, additional systemic opioids may be needed to abate physiological withdrawal in opioiddependent patients.
Bupivacaine, in concentrations of 0.065% to 0.125%, is the most common local
anesthetic for postoperative epidural analgesia solutions, and levobupivacaine and ropivacaine are less often used. Motor blockade is more common with bupivacaine and levobupivacaine, while ropivacaine in typical doses is selective for sensory blockade only.
Patients receiving local anesthetics should be observed for sensory impairment below the
207
catheter level including routine inspection of the skin, repositioned frequently to alleviate pressure, given range of motion exercise to improve circulation and prevent thrombophelebitis, and assisted when getting out of bed. Adjustments in infusion rates, typically a decrease of 20 to 25%, changes in the concentration of local anesthetic or switching the local anesthetic to ropivacaine can prevent moderate to dense motor blockade.
Complication rates for epidural analgesia include dural puncture (0.32% to 1.23%),
direct neurological trauma (extremely rare), spinal hematoma from puncture of epidural vessels during catheter insertion (3% to 12%), catheter migration (0.15% to 0.18%),
and infection (extremely rare). Respiratory depression (respiratory rate <8 per minute),
while the most serious, is no greater than the incidence associated with systemic opioids.42 Patients closely followed by acute pain management services are less likely to
experience respiratory depression, and frequent monitoring of respiratory rate and cautious use with older patients >70 years of age and those with pre-existing respiratory diseases can often prevent its occurrence. Pruritis, which is a less serious adverse effect but
more distressing to patients, occurs in about 40% of patients, more commonly with
morphine. Small intravenous doses of naloxone (<0.1 mg) administered IV every 2 to 3
hours is the most effective treatment.
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209
NEUROPATHIC PAIN
Neuropathic pain is the most complex and challenging to treat. It results from direct
injury to peripheral nerves or central nervous system and can also occur from a disruption in the central processing of pain caused by peripheral nerve injury (central pain).
The primary mechanisms for neuropathic pain do not involve direct activation of nociceptorshence it is often referred to as non-nociceptive mediated pain. Clinically, neuropathic pain syndromes appear to be less responsive to opioid analgesics than somatic
and visceral pain. As a result, patients will often require higher doses of opioid analgesics
and may still not achieve acceptable pain relief. Opioid therapy can be slowly titrated up
to the point that patients get relief or experience intolerable toxicities (eg, sedation, nausea). Selection of opioid analgesics is critical, and nonopioid combinations should be
avoided so that doses can be escalated without added toxicities and ceiling effects.
Greater benefits may be derived from combining opioid analgesics with effective adjuvant agents such as tricyclic antidepressants and anticonvusants that have documented
efficacy in the treatment of neuropathic pain. Selective interventional techniques including temporary nerve blocks, neurolysis or nerve destruction procedures, and neuraxial
(epidural or subarachnoid) therapy have demonstrated significant benefits.
210
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211
INTERVENTIONAL TECHNIQUES
When optimal oral pharmacological therapy is ineffective or leads to unacceptable
side effects, interventional pain management techniques should be considered. The
WHO Analgesic Step Ladder for cancer pain management outlines several sequential
strategies for alleviating persistent and uncontrolled pain with Step 4, the highest level,
encompassing invasive procedures (Figure 12-3). Several interventional approaches such
as parenteral opioid infusions, neuraxial medication infusion, neurolytic blockade, and
other procedures (eg, vertebroplasty) offer effective alternatives to pain management.
Substantial progress has been made over the past two decades in elucidating appropriate
selection criteria and refining technology for these invasive techniques. Moreover,
advances in the radiological diagnostics have provided significant advantages in precise
placement of neuraxial (intraspinal) catheters and safety with the delivery of neuroablative agents (ie, phenol and alcohol). The NCCN recommendations for procedural
strategies are outlined in Figures 12-4.
1High benefits/risk ratio examples: celiac plexus, superior hypogastric plexus, and
peripheral nerves
212
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214
Chapter 12
infusion dose and the interval for patient access may vary from every 15 to 60 minutes.
PCA allows patients to gain rapid control over exacerbations of pain without the need
for family and home health nurse interventions. PCA technology is only effective if
patients have the cognitive and functional capabilities to self-administer medication.
Doses are adjusted by taking into account pain intensity, demand dose requirements and
disposition of the patient. If patients are not experiencing side effects from the opioid,
escalations of about 10 to 25% of the hourly rate can be safely done every 24 hours for
unrelieved pain.
215
Equivocal Result
IT Catheter Trial
Diffuse pain, epidural space obliterated by tumor or surgery
Need for IT-PCA or unavailability of programming for implanted pump
>50% Pain
Relief
<50% Pain
Relief
**
Further Medical
Management
Figure 12-5. Decision-making algorithm for the use of neuraxial analgesia in treating cancer pain. (Adapted from Burton AW, Rajagopal A, Shah HN, et al. Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Medicine, 5(3);239-247,
2004.)
infusion device is surgical implanted.52 The MD Anderson Cancer Center decisionmaking algorithm is shown in Figure 12-5. A recently published multi-center prospective randomized clinical trial by Smith et al compared intrathecal therapy to continued
medical management, revealing a trend toward better analgesia in the intrathecal group
with improved side effect profile and increased survival in the intrathecal group.53
Neuraxial analgesia is suitable for patients at any stage of their disease, including those
who are considered free of disease, but who are plagued with persistent unrelieved pain.
This technique is contraindicated in patients with systemic or localized infections or
those with any form of a coagulopathy.
NERVE BLOCKS
Cancer patients are often referred to pain management specialists for a quick cure
or because systemic analgesics seem to be ineffective. Many referring physicians are
under the mistaken impression that nerve blocks alleviate all types of pain. Some focal
pain syndromes are amenable to these procedures, as outlined below, but many are not.
Generally, the more focal the pain, the easier it is to locally block sensory nerves involved
in pain transmission. Unfortunately, peripheral sensory blocks also cause motor impair-
216
Chapter 12
ment as both fibers are intertwined. With peripheral blocks using local anesthetic, pain
relief and any motor impairment are temporary; however, permanent blocks or neurolysis with alcohol or phenol are much more risky and not possible without major morbidity. Some areas where neurolytic nerve blocks can be useful include pancreatic or
upper abdominal malignancy with the celiac plexus block; lower abdominal pain with
the superior hypogastric plexus block; chest wall pain with intercostal nerve blockade,
and end stage lumbosacral plexopathy with intraspinal neurolysis.54-56 Although infrequent, symptoms may arise as a result of tumor invasion of nervous system structure (eg,
brachial or lumbosacral plexopathy), in which case either local anesthetic blockade of the
stellate ganglion or lumbar sympathetic chain has been used with some success to relieve
pain.57
Neurolytic blocks play an important role in the management of intractable cancer
pain. This modality should only be offered when pain persists despite thorough trials of
aggressive pharmacological management or when drug therapy produces undesirable
and uncontrollable side effects. Patient selection is of utmost importance including some
general tenets:
Severe pain
Pain is expected to persist
Pain cannot be modified by less invasive means
Pain is well-localized
Pain is well-characterized
Pain is not multifocal
Pain is of somatic or visceral origin
Limited life expectancy
Alcohol and phenol are the only agents commonly used to produce chemical neurolysis. Ethyl alcohol is a pungent, colorless solution that can be readily injected through
small-bore needles and that is hypobaric with respect to CSF. For peripheral and subarachnoid blocks, alcohol is usually diluted (referred to as 100% alcohol, dehydrated
alcohol, or absolute alcohol), while a 50% solution is used for celiac plexus block. With
alcohol blocks, denervation and pain relief sometimes accrue over a day following injection. Phenol has a biphasic actionits initial local anesthetic action produces subjective
warmth and numbness that usually give way to chronic denervation over a days time.
Hypoalgesia after phenol is typically not as dense as after alcohol, and the quality and
extent of analgesia may diminish slightly within the first 24 hours of administration.
The average duration of all neurolytic blocks is estimated at 3 to 6 months, with a wide
variation in effectiveness. Reports of analgesia persisting 1 to 2 years are fairly common.
Subarachnoid neurolysis can be performed at any level up to the midcervical region.
Above this area, increases any risk of drug diffusion to medullary centers and the potential for cardiorespiratory collapse increases. Blocks in the region of the brachial outflow
are best reserved for patients with preexisting compromise of upper limb function.
Similarly, lumbar injections are avoided in ambulatory patients, as are sacral injections
in patients with normal bowel and bladder function.
Celiac plexus block continues to be one of the most efficacious and common nerve
blocks employed in patients with pain from pancreatic cancer and liver metastases. It is
most effective for relieving upper abdominal and referred back pain secondary to malignant neoplasm involving structures derived from the foregut (distal esophagus to midtransverse colon, liver, biliary tree, and adrenal glands). The most common indication
217
for celiac axis block is pancreatic cancer. Celiac axis block is most frequently attempted
by positioning needles bilaterally either antero- or retrocrurally via a posterior percutaneous approach (Figure 12-6). Despite the proximity of major organs (aorta, vena cava,
kidneys, pleura) and requirements for a large volume of the neurolytic agent (30 to 50
mL of 50% alcohol in the anterocrural technique and much less volume in the retrocrural) complication rates are uniformly low.
More recently, radiofrequency-generated thermal lesions are another effective means
of inducing therapeutic nerve injury and, when directed to the tumor itself, it can have
a tumoricidal effect often with salutary effects on symptoms.58 Peripheral cranial nerve
blocks have a limited role in the management of cancer pain. Control of neoplastic-related pain from locally invasive head and neck carcinomas are challenging because of rich
sensory innervations to these structures. In selected patients, blockade of involved cranial and/or upper cervical nerves is extremely helpful in treating pain. Blockade of the
trigeminal nerve within the foramen ovale at the base of skull or its branches may be
beneficial for facial pain. If neural blockade is not effective, intraspinal opioid therapy
by means of an implanted cervical epidural catheter or intraventricular opioid therapy
may be considered.
VERTEBROPLASTY
Metastatic vertebral compression fractures (VCFs) or osteoporotic VCFs are often
associated with movement-related back pain. Percutaneous vertebroplasty (PV) is a min-
218
Chapter 12
imally invasive procedure that is accomplished by injecting opacified bone cement (usually polymethymethacrylate or PMMA) into the fractured vertebral body to alleviate the
pain and perhaps enhance structural stability. This procedure is performed by placing
needles under fluoroscopic guidance with a uni- or bipedicular approach. PMMA is
injected in a carefully controlled manner to avoid unintended cement spread into the
spinal canal. The injection is stopped as soon as cement starts approaching in posterior
on third of vertebral body. PV has been shown to be highly efficacious in treating VCF
cancer-related pain.59 Complications are rare but can be serious, including paralysis and
death.
NEUROMODULATION
Spinal cord stimulation is a nonpharmacologic method used to treat refractory
chronic neuropathic pain states. Recently, investigators at MD Anderson Cancer Center
have demonstrated success in treating painful chemotherapy induced neuropathic pain
with spinal cord stimulation.60
NEUROSURGICAL INTERVENTIONS
Neurosurgical palliative techniques are seldom performed as more aggressive,
reversible, titratable, and lower risk techniques have largely replaced these procedures.
Techniques such as pituitary ablation, myelotomy, and cordotomy should only be considered in patients who have not responded to more conservative pharmacological and
interventional approaches aforementioned.
SUMMARY
Principles of interventional cancer pain management are in most respects similar to
those that apply to good medical practice. These procedures should only be considered
in collaboration with pain experts and performed by skilled pain trained anesthesiologists, neurosurgeons or neurologists. Eligibility criteria are stringent and patients should
be carefully examined prior to undertaking any procedure. A realistic, frank discussion
of the risks, benefits, alternatives, and goals of care must take place with patients and
family members so that they have a clear understanding of what the technique entails
and the expected outcomes. After the procedure, follow-up care should be maintained
as long as desired by the patient and or primary physician. While rarely eliminated altogether, pain can be controlled in the vast majority of patients, usually with the careful
application of straightforward pharmacological measures combined with diagnostic acumen and conscientious follow up. In a small but significant cohort of patients whose
pain is not readily controlled with noninvasive analgesics, a variety of alternative measures, when selected carefully, are also associated with a high degree of success.
An increasingly large cadre of anesthesiologists have come to recognize that far from
an exercise in futility, caring for patients with advanced irreversible illness can be highly
satisfying and met with considerable success. Multidisciplinary approaches to cancer
pain management yield the greatest success. Recognizing that primary care physicians
may benefit from criteria-based information for initiating referrals to pain management
specialists, the NCCN has developed indications for specialty consultations. Thus, no
patient should ever wish for death as a result of inadequate control of pain or other
symptoms, or be deprived of expert evaluation for interventional procedures or other
219
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chapter
13
Endoscopic Ultrasound in
the Diagnosis and Staging of
Gastrointestinal Malignancy
Janak N. Shah, MD
INTRODUCTION
EUS was first introduced in the United States in the late 1980s, and has since
become an important technological advance in GIs endoscopy. EUS enables the endoscopist to obtain high-resolution, detailed images of the GI luminal wall and pancreaticobiliary system. This ability has allowed EUS to make substantial contributions to the
clinical management of GI malignancies. Other technological improvements, such as
the ability to perform EUS-FNA, have led to expanded roles, and EUS is now increasingly utilized in patient care. This chapter will review the current clinical uses of EUS
in the setting of GI malignancies.
EUS: INSTRUMENTS
AND
TECHNIQUE
EUS is performed using specialized endoscopes (echoendoscopes) with radial or linear array ultrasound transducers at the instrument tip (Figure 13-1). Most echoendoscopes use ultrasound frequencies ranging from 7.5 to 12 MHz. Newer instruments
allow the operator to choose from a wider range of scanning frequencies while using the
same echoendoscope. Smaller, high-frequency (20 to 30 MHz), catheter based probes
are available to perform intraluminal and intraductal ultrasonography via the instrument channel of standard endoscopes. In general, higher frequency scanning produces
more detailed, high-resolution images, but at the cost of decreased depth of penetration.
Lower frequency scanning generates the opposite effect.
EUS is considered a technically demanding modality, as it calls for expert procedural skills, detailed knowledge of cross-sectional anatomy, and the ability to interpret
ultrasound images. EUS is not routinely performed by most gastroenterologists, and is
ideally learned under the direction of an experienced endosonographer. Although there
are no formal requirements establishing EUS proficiency, it is reasonable that endoscopists performing EUS should obtain diagnostic accuracy rates similar to those in previously published series. Diagnostic EUS is a safe procedure, with types and rates of
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Chapter 13
ESOPHAGEAL MALIGNANCY
Treatment recommendations for esophageal cancer are largely dependent on tumor
stage. For example, patients with early, localized disease are offered immediate surgery.
Patients with high operative risk superficial disease limited to the mucosa may be candidates for endoscopically-directed intraluminal therapy (eg, endoscopic mucosal resection or photodynamic therapy). The optimal management in those with locoregionally
advanced disease may include chemoradiotherapy prior to surgical resection. Therefore,
it is imperative to accurately stage esophageal cancer in order to guide appropriate therapy for each particular patient.
Once a histologic diagnosis of esophageal cancer is established (usually by forceps
biopsies during diagnostic endoscopy), further evaluation should occur in stepwise fashion (Figure 13-2). First, the presence of metastases should be ascertained. This is usually evaluated using cross-sectional imaging. Where available, positron emission tomography (PET) may be used, and may be more accurate than computerized tomography
(CT) to detect stage IV disease.1 If metastases are present, palliative measures should be
considered, and EUS examination would be unnecessary.
If there is no evidence for metastatic disease, EUS should be performed to assess
locoregional staging of the primary tumor site (see Appendix A). Tumor involvement of
the esophageal wall is seen endosonographically as a hypoechoic mass or thickening of
the wall with disruption of the normal ultrasonic wall layer pattern. The depth of abnormality and extent of wall pattern disruption guide the endosonographer in determining
T stage by EUS (Figure 13-3). For N staging, several sonographic criteria suggest malignant involvement of visualized lymph nodes: 1) homogeneous echo pattern, 2) smooth
borders, 3) circular shape, and 4) size greater than 10 mm.2 When all four features are
present (in only 25%), EUS is highly accurate (>80%) in identifying malignant lymph
nodes.3
225
Esophageal malignancy
Are metasteses
present?
Yes
Palliative measures/therapy
No
Early stage
Surgery
Consider endoscopic therapy in nonoperative candidates (eg, endoscopic mucosal resection, photodynamic therapy).
226
Chapter 13
EUS has proven to be the most accurate modality to evaluate the local extent of
esophageal malignancy, and is more accurate than CT, magnetic resonance imaging
(MRI), or PET scanning for determining T and N stage.1,4,5,6 The average overall accuracy of EUS for T and N staging of esophageal malignancy is about 85% and 77%,
respectively.6 For superficial tumors, high frequency EUS scanning may be required to
verify the precise depth of involvement, but EUS remains an accurate staging modality
for these lesions as well. EUS accuracy for determining local unresectability (T4) is
about 86%,6 and given the morbidity and mortality rates following esophagectomy,
EUS can be particularly useful in identifying inappropriate surgical candidates. Overall
T and N staging accuracy using CT scan is poorer, ranging 40% to 50% and 50% to
70%, respectively.6
EUS-FNA of periesophageal lymph nodes can be performed to confirm nodal
involvement. However, this technique is only reliable when lymph nodes can be accessed
without traversing the primary tumor (to avoid false positive contamination of the cytology specimen). When performed, EUS-FNA improves the assessment of lymph node
staging by yielding sensitivity, specificity, and accuracy of over 90% in several series, and
should be utilized when histologic confirmation of nodal involvement would alter clinical management.7,8
Complete EUS staging evaluation can be difficult in patients with stenotic tumors,
and incomplete examinations can lead to decreased staging accuracy. One published
technique that has been safely employed to allow echoendoscope passage through
stenotic segments is luminal dilation. Esophageal dilation to a diameter of 14 to 16 mm
permits complete EUS examination in the majority (>85%) of cases.9,10 Other instruments that may enable the completion of EUS examination through stenoses include
catheter based ultrasound probes and nonfiberoptic (blind), wire-guided, small diameter echoendoscopes.
Many centers treat patients with locally advanced tumors with preoperative
chemoradiotherapy, with the anticipation of improved outcomes compared to surgery
alone. Although it would be of interest to subsequently assess the tumor response to
neoadjuvant treatment prior to surgical resection, the accuracy of EUS for restaging in
this scenario is poor (about 42% and 54% for T and N stage, respectively)11,12 This is
likely due to the inability to sonographically distinguish tumor from post-treatment
inflammation (both appear hypoechoic). However, a reduction in maximal cross-sectional area (50%) following chemoradiotherapy has been associated with longer survival, and may be a helpful sonographic prognostic criteria.13
In patients who have undergone resection for esophageal malignancy, locoregional
recurrence is often difficult to detect with standard endoscopic and radiologic evaluation. As EUS can provide detailed images of the luminal wall and extraluminal tissue, it
is particularly useful in this setting, and has reported sensitivity and specificity of over
90%.14
GASTRIC MALIGNANCY
GASTRIC ADENOCARCINOMA
Gastric adenocarcinomas occur in two clinico-histologic varieties: an intestinal type
and a diffusely spreading type (linitis plastica). The intestinal type of gastric cancer is
usually detected endoscopically as a discrete polypoid mass or ulcerated lesion, and diag-
227
nosed on endoscopic forceps biopsies. In linitis plastica, the tumor may be difficult to
detect, as it infiltrates along the gastric wall and may diffusely spread to involve large
portions of the stomach. EUS plays an important role in the management of patients
with both clinical varieties of gastric cancer. For discrete masses or infiltrative tumors
that have already been diagnosed as adenocarcinoma, EUS provides local staging information. For patients suspected of having linitis plastica but are undiagnosed, EUS offers
valuable diagnostic data to help direct further evaluation and/or treatment.
As with other malignancies, accurate staging helps estimate survival and guides further treatment. Sonographic assessment of T and N staging in gastric cancer is done
similar to that of esophageal cancer (see Appendix B). In those with established malignancy and no evidence for metastases, EUS should be used to determine the locoregional involvement, and has overall accuracy rates for T and N staging of about 80%
and 70%, respectively.15,16 Patients with tumors that appear resectable by imaging are
usually offered gastrectomy. Anastomotic recurrences can occur after surgery, and EUS
has high sensitivity (95%) and specificity (80%) for detecting recurrent tumor.17
Select patients with superficial, mucosal-based tumors who are poor operative candidates may be considered for endoscopic resection at expert endoscopic centers. But to
even contemplate this mode of therapy, EUS examination is critical as it is the only nonsurgical means of accurately identifying the depth of wall invasion for superficial lesions.
EUS (with high-frequency scanning) accurately identifies T1 gastric cancers in 80% to
90% of cases.15
In evaluating patients suspected of having linitis plastica, EUS can be particularly
useful in diagnosis. Sonographically, the gastric wall is usually thickened (>3 mm).
When tumor cells have infiltrated all wall layers, by EUS there appears to be hypoechoic
thickening with complete loss of normal wall layer pattern. When the tumor has diffusely spread along intact histologic planes (eg, along the submucosa or muscularis propria), the wall layer pattern may be preserved, but the involved histologic layer is quite
thickened sonographically. In this setting, mucosal forceps biopsies obtained during
standard endoscopy may be nondiagnostic, and EUS findings provide crucial information to guide further evaluation.18 When the diagnosis of linitis plastica is clinically
entertained, sonographic findings are suspicious, and mucosal forceps biopsies are nondiagnostic, a full-thickness surgical biopsy should be considered.
GASTRIC LYMPHOMA
The most common site for primary non-Hodgkins extranodal lymphoma is the
stomach, and accounts for about 5% of all gastric neoplasms. Gastric lymphomas often
manifest as a polypoid, exophytic mass, but may also diffusely infiltrate, similar to linitis plastica. Histologically, the tumors may be high-grade lymphomas or MALT
(mucosa-associated lymphoid tissue) lymphomas, which are usually low-grade but may
have high-grade foci.
In patients with high-grade lymphomas, treatment considerations include radiation,
chemotherapy, surgical resection, or combination multimodality therapy. EUS is useful
in guiding the treatment plan by determining the local involvement of disease through
assessment of depth (partial- or full-thickness) and extent (fundus, body, and/or antrum)
of tumor, as well as regional lymph nodes. Sonographically, their appearance is usually
similar to that of gastric adenocarcinoma, with a hypoechoic mass or thickening, and
disruption of the normal wall layer pattern. EUS accurately determines the depth of
infiltration (T stage) in about 90%, and accurately detects lymph node disease (N stage)
228
Chapter 13
Rectal cancer
Yes
Palliative measures/therapy
in over 80%.19 When needed, the accuracy for detecting lymph node disease can be
improved by performing EUS-FNA with flow cytometry.20
MALT lymphomas are associated with H. pylori infection, and have an overall better
prognosis than high-grade gastric lymphomas. Some MALT lymphomas, those limited
to the mucosa or submucosa with no suspicious regional lymph nodes, may respond to
antimicrobial therapy alone, without need for more extensive treatment with surgery
and/or chemoradiotherapy. By determining an accurate depth of tumor extent, EUS has
proven helpful in identifying patients that can be appropriately treated with H. pylori
eradication as the sole initial therapy.21 Moreover, interval EUS can be used to detect
those that did not respond to antimicrobial therapy, so that appropriate further treatment can be administered.
RECTAL MALIGNANCY
Similar to the setting of esophageal cancers, the treatment options for rectal neoplasms are largely contingent on tumor stage. As an accurate means of determining the
locoregional extent of rectal tumors, EUS plays an important role in guiding the optimal therapy for these malignancies.
Rectal tumors are usually diagnosed histologically by forceps biopsies obtained during endoscopy. Further evaluation should occur in a stepwise manner (Figure 13-4). The
presence of lung and liver metastases should be excluded using a chest radiograph and/or
cross-sectional imaging. The presence of distant metastases obviates the need for local
staging. Patients with no evidence for metastases should undergo rectal EUS to deter-
229
mine the locoregional extent of tumor (see Appendix D). On EUS, tumors appear as
hypoechoic masses or thickening with loss of the normal rectal wall layer pattern. The T
stage is determined by assessing the depth of tumor involvement, and accuracy rates for
EUS range from 80% to 95%.22 EUS appears to be least accurate in correctly identifying T2 lesions; these are often incorrectly overstaged as T3, likely due to the inability to
distinguish adjacent inflammation from tumor penetration through the muscularis propria. Comparatively, overall T stage accuracy rates for CT and MRI are lower, ranging
65% to 75% and 75% to 85%, respectively.23
N stage is determined by assessing perirectal lymph nodes for suspicious sonographic criteria (large size, homogenous echo pattern, circular shape, and smooth borders).
Accuracy rates for EUS range from 70% to 75%.23 Although lymph node size is considered an important feature in identifying suspicious nodes elsewhere in the GI tract,
up to 50% of malignant perirectal nodes are less than 5 mm in diameter.24 Thus, even
small nodes should be regarded malignant. Given that nonmalignant perirectal lymph
nodes are sonographically heterogenous, small, and rarely seen by EUS, some experts
advocate that any visualized node should be considered malignant. Unlike other areas of
the GI tract, EUS-FNA does not significantly increase N stage accuracy over EUS alone,
and should not be routinely used.25 EUS-FNA is likely most useful in confirming lymph
node status in patients with early T stage tumors and sonographically visible nodes, in
which true nodal involvement is in question and the knowledge of which would impact
clinical management. Comparative N stage accuracy rates for CT and MRI are lower,
about 55% to 65% and 60% to 65%, respectively.23
Findings on rectal EUS help determine appropriate therapy for each particular
patient. For instance, individuals with locally advanced tumors (T3, T4, N1, or N2)
may be offered neoadjuvant therapy. Analogous to other sites, EUS is not useful to assess
response to neoadjuvant treatment due to the difficulty in sonographically differentiating tumor from therapy effect, and has lower accuracy rates for both T and N staging
(about 50%) following radiation therapy.26 Surgical planning is often guided by EUS
findings. For example, those with superficial tumors (T1-2, N0) in the distal rectum
may be candidates for sphincter-saving transanal excision, and sonographic evaluation
provides valuable information to select the appropriate candidate (Figures 13-5 and 136). Those with more advanced lesions in the distal rectum would likely require more
extensive surgery (abdominoperineal or mesorectal resection).
Up to 25% of patients develop local recurrence of cancer following sphincter-saving
operations.22 These can be very difficult to diagnose, as recurrences may develop extraluminally. The ability of EUS to image perirectal tissue is particularly useful in this situation, and allows better detection rates compared to CT scan.27 EUS-FNA improves
the accuracy of detecting recurrent tumor over EUS alone, from about 75% to greater
than 90%, and should be utilized when needed.28 Some advocate the routine use of
postoperative rectal EUS for surveillance of recurrent cancer.
230
Chapter 13
On endoscopy, GISTs are usually seen as submucosal lesions with normal appearing,
overlying mucosa. Occasionally, mucosal ulcerations can be seen. Unfortunately, an
accurate diagnosis is extremely difficult to make on standard endoscopy, as other submucosal lesions can produce a similar endoscopic appearance, and forceps biopsies are
usually not of adequate depth to obtain histologic confirmation.
The unique ability of EUS to provide detailed images of the luminal wall makes it a
particularly attractive modality in the evaluation of GISTs (Figure 13-7).
Sonographically, GISTs appear as hypoechoic masses that are usually located in the muscularis propria (fourth wall layer on EUS). They may also arise from the muscularis
mucosa (second wall layer). Rarely, they may appear to be in the third wall layer (sub-
231
Suspected GIST
Perform EUS:
No
Yes
Symptomatic?
Any malignant EUS
features?
Yes
Consider surgical resection
Size >4 cm
Irregular borders
Echogenic foci >3 mm
Cystic spaces >4 mm
Increased size on
repeat EUS?
No
Repeat EUS in 6 to 12 months
Figure 13-7. Algorithm for evaluation of localized GIST.
mucosa), in which case the tumor has likely extended into the submucosa from the muscularis propria or muscularis mucosa. EUS findings can additionally exclude other common lesions that look similar endoscopically, but differ in sonographic appearance, such
as lipomas (hyperechoic), duplication cysts (anechoic), gastric varices (anechoic), and
extrinsic compression from adjacent structures.
GISTs may be benign or malignant. Several EUS features appear to be helpful in
identifying malignant tumors: 1) size >4 cm, 2) irregular extraluminal border, 3)
echogenic foci >3 mm within lesion, and 4) cystic spaces >4 mm within lesion.30
Symptomatic tumors or those with malignant-appearing EUS characteristics should be
resected (Figure 13-8). Lesions that are suspected to be GISTs, but are asymptomatic
without high-risk sonographic features may be followed by repeat EUS every 6 to 12
months. Those that develop interval increase in size, suspicious EUS criteria, or become
symptomatic should undergo surgical resection. Tumors that appear unresectable or that
are metastatic may be considered for therapy with imatinib mesylate, a selective tyrosine
kinase inhibitor.29
Histologic confirmation of GISTs has been difficult short of an operation.
Endoscopic forceps biopsy may be attempted using large particle forceps, with a tunnel or bite-on-bite technique. But, specimens are often nondiagnostic due to the typ-
232
Chapter 13
ical deep location of the tumor in the luminal wall (usually in the muscularis propria).
However, EUS-FNA can be used to establish a diagnosis. Immunohistochemical analysis of FNA specimens can reveal c-kit expression, which is a highly accurate marker for
GISTs.31 One must keep in mind that the presence of c-kit identifies GISTs, but is not
useful to discriminate between benign and malignant tumors. Special stains of FNA
samples for other cell markers (eg, Ki-67) may prove useful in establishing malignancy.32
Where available, newer EUS devices that allow retrieval of tissue core specimens could
provide larger samples to more accurately assess mitotic activity and other pathologic
features.
PANCREATICOBILIARY MALIGNANCY
PANCREATIC ADENOCARCINOMA
EUS is an important modality in the evaluation of patients with known or suspected pancreatic adenocarcinoma, but its specific role may evolve with technological
advances in other, noninvasive imaging techniques (eg, helical CT and multidetector
CT). The evaluation of patients with suspected pancreatic adenocarcinoma should occur
in a stepwise manner (Figure 13-9). Where available, helical/multidetector CT or stateof-the-art MRI, tailored to examination of the pancreas (pancreatic protocol), should
be requested as these provide the most detailed, cross-sectional images possible, and may
improve the detection and evaluation of tumors compared to conventional CT.
As with other malignancies, assessment of metastases is of first priority. If metastases
are present on cross-sectional imaging, EUS for staging purposes would be unnecessary.
Where available, PET scanning may be used to clarify questionable liver lesions that are
seen on cross-sectional imaging. When histologic confirmation is desired, either a CT
guided biopsy or EUS-FNA can be used to establish a tissue diagnosis.
233
No mass identified
EUS
Normal EUS:
Clinical follow-up
Metastases
Occult metastases
by EUS
Resectable mass by
EUS:
Surgery
Consider EUS-FNA
Locally unresectable
mass by EUS:
EUS-FNA for tissue
diagnosis
Treatment considerations:
Surgical exploration?
Chemoradiotherapy?
Endoscopic palliation?
Palliative measures?
234
Chapter 13
235
committing the patient to a major operation. In the setting of obvious metastatic disease, tissue acquisition may provide the patient the satisfaction of a definite diagnosis.
Occasionally, cross-sectional imaging and/or EUS demonstrate lesions that are atypical
for pancreatic adenocarcinoma, and histologic confirmation is desirable to confirm
malignancy, exclude other types of lesions (eg, lymphoma, neuroendocrine tumor), and
guide appropriate therapy.
EUS-FNA has emerged as an important means of obtaining tissue diagnosis of pancreatic tumors, with high sensitivity for establishing malignancy (75% to 90%) and high
accuracy rates (85% to 96%).33 False negative results can occur in up to 15% to 20%,
thus EUS-FNA should not be used to preclude operative resection in an otherwise
appropriate surgical candidate with high suspicion for pancreatic cancer.35 EUS-FNA of
the pancreas is performed transgastrically or transduodenally, and can be used to target
the primary mass, lymph nodes, liver metastases, and even small areas of ascites (suggestive of peritoneal involvement). For patients with nonmetastatic, potentially
resectable tumors that require histologic confirmation, EUS-FNA is preferred to percutaneous FNA (ultrasound or CT guided), as one recent study reveals a significantly
increased association of peritoneal carcinomatosis with the latter.41
236
Chapter 13
aspirated cyst fluid is very suggestive of a mucinous cystic neoplasm. Glycogen containing cells in FNA specimens are diagnostic of serous cystadenomas. Histiocytes and elevated amylase concentrations are associated with pseudocysts. Any solid component of
cysts should be considered for EUS-FNA to assess for malignancy. There has been recent
interest in analyzing cyst fluid for tumor markers. Higher concentrations of CEA and
CA 72-4 have been found in mucinous neoplasms compared to serous cystadenomas.44
However, at this time tumor marker analysis should be interpreted with caution and
within the overall clinical context, as one recent investigation revealed poor sensitivity
(28%) and specificity (25%) for the use of CEA fluid analysis in classifying cystic
lesions.45
CHOLANGIOCARCINOMA
There are limited data on the utility of EUS for biliary tract cancers. Nevertheless,
endosonography is used at many centers to provide additional diagnostic information
for biliary neoplasms, and particularly for those tumors that are small and not well characterized by other imaging techniques. On EUS, cholangiocarcinoma typically appears
as a hypoechoic lesion or thickening that arises from or surrounds the bile duct wall,
with disruption of the normal three-layer biliary wall pattern. Sonographic images are
obtained using either echoendoscopes or ultrasound miniprobes placed into the bile
duct during ERCP (intraductal ultrasonography). For detecting extrahepatic cholangiocarcinomas, EUS appears to be as sensitive as ERCP (95%), and more sensitive than CT
(79%) or angiography (42%).50 The local staging accuracy of EUS for cholangiocarcinomas is about 86%.51 Perhaps of greater importance, one study found higher accuracy
of determining portal venous invasion by EUS (100%), compared to CT (84%) or
angiography (89%).50
Establishing a preoperative diagnosis of a biliary tract malignancy can be difficult.
Conclusive results from cytology brushings obtained at ERCP have been disappointing
and are not consistent. Although EUS is highly sensitive at identifying bile duct abnormalities, it is not useful at discriminating benign from malignant processes. EUS-FNA
has recently emerged as a useful tool in confirming biliary malignancy. An accuracy, sensitivity, and specificity of 91%, 89%, and 100% has been reported for EUS-FNA in
evaluating patients with suspected hilar cholangiocarcinoma, but negative brush cytology.52
237
238
Chapter 13
and cross-sectional imaging. On the other hand, FNA may be useful in an elderly, high
surgical risk patient, as cytology results may influence the treatment plan.
When EUS-FNA is performed, the lesion that would have the greatest impact on
subsequent management (lesion that confirms the most advanced stage) should be targeted first. In descending order of importance, these would include: suspicious metastasis (ascites/pleural fluid, peritoneal nodule, or liver mass), distant lymph node, peritumoral lymph node, and primary mass. Multiple FNA passes may be required to obtain
an adequate specimen, with pancreatic tumors generally requiring the greatest number
(3 to 5).53 Where available, on-site cytologic interpretation should be performed, as
recent data suggest improved diagnostic yield and decreased need for repeat procedures
using intraprocedural evaluation as compared to postprocedure cytology analysis.54
EUS-FNA is generally a safe procedure with complications similar to those of diagnostic EUS. Additional complications that may be unique to EUS-FNA due to the
advancement of needles extraluminally include infections, hemorrhage, and pancreatitis. Based on a large multicenter study, infectious and hemorrhagic complications seem
particularly associated with EUS-FNA for cystic lesions (14%) as compared to solid
masses (0.5%).55 Antibiotic prophylaxis is recommended for procedures involving cystic or perirectal lesions.53 Acute pancreatitis may complicate EUS-FNA of pancreatic
masses in up to 2%, and appears to be associated with FNA performance after a recent
history of pancreatitis (within 2 months).56 Malignant seeding is a concern, but EUSFNA appears to be safer for this potential risk as compared to percutaneous, image-guided biopsy techniques.41
The same needle devices that are used for EUS-FNA can be used to perform EUSguided fine needle injection (EUS-FNI), and inject pharmaceuticals into specific locations under real-time image guidance. For the management of pain due to advanced
intra-abdominal malignancies, EUS-FNI techniques have been used to perform celiac
plexus neurolysis using absolute alcohol, with significant reduction of pain scores for at
least 12 weeks.57 There has also been recent interest in using EUS-FNI to deliver anticancer drugs or direct other anticancer therapies (eg, radiofrequency ablation, photodynamic therapy) with precision targeting into tumors.58,59 Increasing applications will
likely be seen in the coming years.
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45. Sedlack R, Affi A, Vazquez-Sequeiros E, et al. Utility of EUS in the evaluation of cystic
pancreatic lesions. Gastrointest Endosc. 2002;56:543-547.
241
46. Anderson MA, Carpenter S, Thompson NW, et al. Endoscopic ultrasound is highly
accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2000;95:2271-2277.
47. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by
endoscopic ultrasonography. N Engl J Med. 1992;326:1770-1772.
48. Zimmer T, Stolzel U, Bader M, et al. Endoscopic ultrasonography and somatostatin
receptor scintigraphy in the preoperative localization of insulinomas and gastrinomas.
Gut. 1996;39:562-568.
49. Gines A, Vazquez-Sequeiros E, Soria MT, et al. Usefulness of EUS-guided fine needle
aspiration (EUS-FNA) in the diagnosis of functioning neuroendocrine tumors.
Gastrointest Endosc. 2002;56:291-296.
50. Sugiyama M, Hagi H, Atomi Y, et al. Diagnosis of portal venous invasion by pancreatobiliary carcinoma: value of endoscopic ultrasonography. Abdom Imaging. 1997;
22:434-438.
51. Tio TL, Reeders JW, Sie LH, et al. Endosonography in the clinical staging of Klatskin
tumor. Endoscopy. 1993;25:81-85.
52. Fritscher-Ravens A, Broering DC, Knoefel WT, et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology. Am J Gastroenterol. 2004;99:45-51.
53. Chang KJ. Maximizing the yield of EUS-guided fine-needle aspiration. Gastrointest
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54. Klapman JB, Logrono R, Dye CE, et al. Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol.
2003;98:1289-1294.
55. Wiersema MJ, Vilmann P, Giovannini M, et al. Endosonography-guided fine-needle
aspiration biopsy: diagnostic accuracy and complication assessment. Gastroenterology.
1997;112:1087-1095.
56. Gress F, Michael H, Gelrud D, et al. EUS-guided fine-needle aspiration of the pancreas:
evaluation of pancreatitis as a complication. Gastrointest Endosc. 2002;56:864-867.
57. Wiersema MJ, Wiersema LM. Endosonography-guided celiac plexus neurolysis.
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58. Chan HH, Nishioka NS, Mino M, et al. EUS-guided photodynamic therapy of the
pancreas: a pilot study. Gastrointest Endosc. 2004;59:95-99.
59. Chang KJ, Nguyen PT, Thompson JA, et al. Phase I clinical trial of allogeneic mixed
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chapter
14
Interventional Radiology
Karen T. Brown, MD; Anne Covey, MD;
and Lynn A. Brody, MD
INTRODUCTION
The role of interventional radiology in the care of patients with malignant disease
continues to grow. Procedures may involve diagnosis, treatment or palliation. The trend
toward minimally invasive medicine is well served by percutaneous image guided interventions (IGI). New advances in IGI, including robotics, navigation, and virtual reality, make the field ever more exciting and offer new choices in less invasive cancer treatment.
What follows is a compendium of common procedures performed by interventional radiologists that might serve to help the gastrointestinal oncology physician better
care for his or her patients.
GASTROINTESTINAL PROCEDURES
GASTROSTOMY/GASTROJEJUNOSTOMY
Patients with a functional GI tract who are unable to obtain adequate nutrition by
mouth are ideal candidates for enteral feeding via gastrostomy or transgastric jejunostomy. Percutaneous gastrostomy catheters may also be used for decompression in
patients with chronic bowel obstruction. Decompression gastrostomy is most commonly performed for patients with advanced ovarian cancer. Symptoms of nausea and
abdominal distension can be alleviated, and in some cases patients are able to resume
oral intake. Although there is no nutritional benefit, since the drainage gastrostomy
empties the stomach, most patients derive a lifestyle benefit from this.
Gastrostomy and gastrojejunostomy catheters can be placed endoscopically or surgically.1,2 Percutaneous image guided placement is safe and effective, and most useful in
cases where endoscopy in unsafe, impractical, or impossible, such as with head and neck
or esophageal cancers. In patients with ascites, endoscopic illumination may be quite
difficult. Percutaneous gastrostomy placement may be safely performed in these patients
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by using gastropexy to fix the stomach to the anterior abdominal wall. This is accomplished via metallic T-fasteners introduced through the percutaneous access needle.
Finally, percutaneous gastrostomy or gastrojejunostomy catheter placement generally
requires less sedation than endoscopic catheter placement, and may be more appropriate in cases where sedation is an issue.
Percutaneous gastrostomy catheter placement is performed using fluoroscopic guidance, though ultrasound guided gastrostomy placement has been described.3 Some
interventional radiologists administer barium (either orally or via a nasogastric tube) the
night prior to the procedure, so that the colon is filled with barium at the time of the
procedure to minimize the risk of puncturing the colon. All relevant abdominal imaging should be reviewed prior to the procedure.
Several catheters in different sizes (10 to 28 French), and with different locking
mechanisms (pigtail, mushroom, inflatable balloon) are available. Larger catheters (24 to
28 French) are preferred for decompression, especially in obstructed patients who want
to eat. Catheters may be placed using either push or pull-through techniques. Both
methods involve primary percutaneous puncture of the stomach after insufflation with
air, commonly using an 18-gauge needle. Gastropexy may be performed based on the
clinical situation or operator preference. With the push technique, the puncture tract
is serially dilated and the gastrostomy tube is advanced into the stomach through the
abdominal wall, then held in position by an inflatable balloon or locking loop on the
catheter. This technique is also employed in placing transgastric jejunostomy catheters.
In this case, after accessing the stomach, a directional catheter is advanced to the
jejunum under fluoroscopic guidance, using water soluble contrast to opacify the bowel.
In the pull-through technique, the percutaneous access needle is exchanged for a
directional catheter, which is advanced retrograde under fluoroscopic guidance from the
stomach to the mouth. A snare is then advanced through the catheter exiting the mouth.
The snare is used to pull the gastrostomy catheter to the stomach and out through the
anterior abdominal wall, similar to PEG placement. This technique is increasingly popular as it allows for large catheters (up to 28 French) to be placed primarily. The complication rates are low and the long-term patency of these large catheters is high.
Complications include site infection, peritonitis, tube malfunction, and dislodgement. When gastropexy is performed, or after a tract has been established (2 to 4 weeks),
catheter replacement may be performed without imaging guidance. Contraindications
to gastrostomy include previous gastrectomy, gastric varices, and uncorrectable coagulopathy.
GASTROINTESTINAL STENTS
Stents may be delivered per oral into the esophagus, or per rectum into the colon to
palliate patients with malignant obstruction and to treat malignant fistulae (Figure 141). These stents are most often self-expanding metallic stents covered with silicone or
PTFE to prevent tumor ingrowth in malignant obstruction and to seal fistulae or perforations. Left sided colonic stents have been used to reestablish luminal patency and
palliate bowel obstruction (as occurs in 10% to 30% cases of colorectal cancer). Colonic
stenting has also been proposed as a preoperative adjunct in patients with obstruction as
a bridge to definitive one-stage laparoscopic resection, avoiding the increased mortality
of emergent surgery4 and the need to create, and then close, a colostomy. Following
esophageal stent placement for malignant obstruction, most patients are able to resume
a near normal diet.5 When used to seal fistulae, esophageal stents offer an immediate
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success of 73% to 100%, with a 20% to 39% recurrence rate, most often due to new
fistula formation or stent migration.6
TREATMENT
OF
BILIARY DISEASE
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tree, and the polypoid intraductal tumor causes biliary obstruction, or mass effect from
the parenchymal tumor causes extrinsic compression of the bile duct. Pancreatic and
ampullary or duodenal carcinomas frequently cause low bile duct obstruction.
Metastatic disease to the bile duct epithelium may occur; most often from melanoma or
from solid tumors of the GI tract. Biliary obstruction may also be caused by masses causing extrinsic compression of the extrahepatic biliary tree, as in cases of periportal lymphadenopathy from metastatic disease or lymphoma.
Biliary obstruction may be classified based on the level of the occlusion, as either
high, mid, or low. Low obstruction typically refers to obstruction occurring at the
ampulla or distal common bile duct. High obstruction is caused by lesions at or above
the common hepatic duct. Mid bile duct obstruction is everything in between.
Obstruction at or above the confluence of the right and left hepatic ducts may result in
isolation of part or parts of the biliary tree. For example, a tumor at the hilus may cause
obstruction of both the left and right hepatic ducts. The right hepatic duct is typically
shorter than the left and, not uncommonly, the obstruction may extend from the confluence to isolate the right anterior and posterior ducts from each other, as well as from
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the left duct. With larger central tumors, isolation may progress to the subsegmental
level. This has tremendous implications for developing drainage strategies. One must
realize that a stent or catheter will only decompress the system in which it is placed, and
other ducts with which that system connects. Isolated ducts will not be effectively
drained. For example, in the case of a central mass causing isolation of the right anterior, right posterior, and left hepatic ducts, a drainage catheter or stent placed via one of
those systems will drain only that system, while the other two systems will remain
undrained. In these cases, multiple catheters or stents may be necessary for effective palliation. In some cases, adequate drainage cannot be achieved. The situation is further
complicated by issues related to contamination and cholangitis.
We refer to isolation as: 1) completethe isolated ducts are never opacified cholangiographically; 2) effectivethe isolated ducts are opacified, but the contrast that fills
them does not drain; or 3)impendingthe opacified ducts can be drained at the current
time, but there is central narrowing that is likely to progress. Particularly in cases of
effective isolation, it is almost certain that the incompletely drained ducts will become
contaminated, and may cause cholangitis and even sepsis. Not infrequently, multiple
drainage catheters or stents are necessary to individually drain each isolated system. At
times, this may not be practical or possible, and optimal drainage cannot be achieved.
The level of obstruction commonly dictates management directed toward palliation.
Management is also influenced by expected survival and lifestyle issues. Since proper
identification of the level of obstruction is so important, it is essential to have good
cross-sectional imaging prior to any intervention. Similarly, since the risks involved in
percutaneous or endoscopic access to the biliary tree are not trivial, noninvasive imaging
tools should be used for diagnostic purposes. Direct cholangiography should be used for
diagnostic purposes only under unusual circumstances.
Since biliary drainage procedures are, for the most part, palliative in nature, the
goal(s) of intervention should be well delineated at the start. Commonly accepted indications for drainage include hyperbilirubinemia precluding chemotherapy, pruritis, and
cholangitis. Preoperative drainage may be requested at the discretion of the hepatobiliary surgeon. Diminished appetite and malaise may also improve after biliary drainage,
and these symptoms should be taken into consideration when deciding whether or not
to proceed with drainage. We do not consider asymptomatic ductal dilatation, hyperbilirubinemia alone, or even jaundice a suitable reason to intervene in most cases. One
must remember that an asymptomatic patient cannot be made to feel better, but they
can be made to feel worse. Particularly as the level of obstruction gets higher, the likelihood of complete drainage decreases, the number of drainage catheters increases, and
the complexity of management grows.
Mid- and low bile duct obstruction are generally easier to palliate than disease at or
above the confluence, as a single stent or drain can successfully decompress the entire
biliary tree. Obstruction at this level is accessible to the gastroenterologist, and should
first be approached endoscopically, unless surgically altered anatomy, gastric outlet
obstruction, or a duodenal mass impair access to the ampulla. Endoscopic treatment
obviates the need for percutaneous puncture or exteriorized catheters. Tools for relieving
low bile duct obstruction available to the endoscopist include plastic and metallic stents,
as well as nasobiliary drainage catheters for very short-term use. Endoscopically placed
metallic stents are self-expanding with typical diameters of 8 to 12 mm. Covered and
bare stents are available. Patency of covered stents may be longer, but care must be taken
not to occlude the cystic duct (or any side duct), as cholecystitis has been reported in
this situation.8 Most metallic stents are not removable, and their presence may compli-
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cate or even preclude surgery. Therefore, prior to placement, care should be taken to
assure that the patient has a diagnosis of malignancy and is not a surgical candidate. The
average patency of metallic stents is 7 months. Metallic stents are particularly well-suited to patients whose survival is not likely to exceed the patency of the stent. In patients
who do not possess the aforementioned characteristics, plastic stents may sometimes be
placed. Plastic stents are typically smaller in diameter than metallic stents, and average
patency is considerably shorter, on the order of 3 months. These stents are removable,
and can be changed either as needed, or at regularly scheduled intervals.
Patients with high bile duct obstruction or those with low or midobstruction who
cannot be accessed or successfully treated endoscopically, should be treated percutaneously. Percutaneous biliary drainage is done primarily under fluoroscopic guidance.
Relevant cross-sectional imaging is reviewed to guide selection of the access site/duct.
The imaging is reviewed to assess for patency of the portal vein(s), atrophy, tumor volume, ascites, and previously placed stents or catheters. The indication for drainage is
carefully considered. It is important to discuss with the referring clinician, as well as the
patient, what the likelihood is that the goal of drainage will be met. This is typically
dependent upon the amount of functional liver that can be drained, the level of obstruction and the indication for drainage. For example, drainage of only a small amount of
functional liver, occasionally just a few ducts, is all that is necessary to ameliorate pruritis, whereas achieving a normal bilirubin typically requires drainage of at least 30% of
the liver. In patients with compromised hepatic function, and high bile duct obstruction
with isolation, this may not be possible.
Access may be into the right or left liver. The right ducts are typically accessed via a
lower intercostal approach, generally between the mid and anterior axillary line. The left
ducts are accessed from the epigastric region, though rarely a left intercostal approach
may be employed depending on the individual anatomy. At the discretion of the operator, ultrasound may be used to guide the puncture of a duct. Often it is easier to see the
left ducts sonographically. A 21- or 22-gauge needle is used for initial access, and a limited cholangiogram is then performed. The needle is converted to a larger introducer,
through which standard sized angiographic catheters and steerable guidewires can be
placed. The catheters and guidewires are used to negotiate across the occlusion and gain
access to the small bowel. The angiographic catheter can then be exchanged for a biliary
drainage catheter. These catheters range in size from 8 to 12 French, and have multiple
sideholes beginning in the distal loop of the catheter and extending proximally to a point
above the level of obstruction. The catheters are available in various lengths and with
various numbers of sideholes for applicability to a wide range of anatomy and level of
obstruction. These types of catheters are referred to as internal/external catheters, meaning that the bile can drain either internally (into the small bowel) or externally (into a
drainage bag). The catheters can function like internal stents if they are closed to external drainage. Some patients cannot tolerate closing their catheters to external drainage,
and there may then be management issues related to losing large volumes of fluid and
electrolytes.
At times, it is not possible to cross the obstruction when the patient is initially
drained. In these cases, and in other select circumstances, an external drainage catheter
is placed. These catheters must remain open to external drainage (Figures 14-2A and B).
Repeated attempts to convert an external catheter to an internal-external catheter are
warranted, and these are often successful after decompression of the bile ducts above the
level of obstruction (Figure 14-2C).
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Irrespective of the catheter type, catheter care is the same. We recommend flushing
the catheters twice daily with 10 cc of saline. The catheters are flushed internally but are
not aspirated. This helps clear debris from the side holes of the catheter. If the catheter
is attached to an external drainage system, the external tubing and drainage bags are
changed weekly. The drainage catheters themselves require routine exchange every 10 to
12 weeks. The catheters are also changed as needed if proper function ceases. This is
often manifest by leakage of bile around the catheter, difficulty flushing the catheter, and
symptoms of cholangitis. Prior to the initial drainage, and for every future procedure,
prophylactic antibiotics are recommended.
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Metallic stents are deployed through the same tract established for biliary drainage
using small (6 to 9 French) delivery systems. Most stents are self-expanding, though balloon expandable stents are used on rare occasions. Self-expanding stents have intrinsic
radial force and, once released from the delivery device, eventually expand to their stated diameter. Most percutaneously placed stents are 8 to 10 mm in diameter, but stents
from 4 to 12 mm may be placed. With a larger lumen and intrinsic radial force, these
stents have a longer primary patency than plastic stents, with a median patency of 7
months. Self-expanding metallic stents are very flexible and remain patent despite relatively acute angulation. This is a useful feature when the tumor involves the confluence
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Figure 14-3C. Removal of endoscopic stent. The stent was displaced into the duodenum using
a balloon catheter.
of hepatic ducts (Figure 14-4). In the case of high bile duct obstruction, multiple stents
may be placed simultaneously. Multiple ducts may be stented using both Y and T
configurations.
In addition to establishing biliary drainage, percutaneous access to the bile ducts
provides a means for additional diagnostic and therapeutic procedures including biopsy
of bile duct masses,9,10 stone retrieval, percutaneous choledochoscopy, and placement of
catheters for novel treatments such as local radiation (brachytherapy) or photodynamic
therapy.
When the cause of bile duct occlusion is uncertain, bile duct biopsy can be performed through the tract created for biliary drainage. Because the specimens obtained
are from the mucosa and superficial portion of the fibromuscular layer of the duct,10 this
is most effective for mucosal and intraductal lesions, including cholangiocarcinoma and
intraductal metastases, and is less effective in diagnosing extraductal lesions, such as pancreatic cancer or liver or nodal metastases causing extrinsic compression. After cholangiography is performed, a forceps, brush, or atherectomy device is advanced to the
obstruction and a specimen is obtained. Reported sensitivities of forceps biopsy range
from 30% to 100% for malignancy, but in most studies a high false negative rate effectively makes a negative biopsy nondiagnostic in most cases.
Biliary stone disease is surprisingly common in cancer patients, due to concurrent
gallstone disease or biliary stasis, particularly related to narrowing at a bilioenteric anastomosis. Small stones may pass from the gallbladder through the cystic duct into the
common bile duct. When large, these are apparent preoperatively and can be removed
endoscopically. Smaller stones, however, can be missed during surgery and identified by
cholangiography in patients with persistent symptoms or hyperbilirubinemia. After maturation of a T-tube or biliary drainage tract, these stones can be safely treated in the
majority of cases using either a basket or snare to remove them percutaneously, a balloon
to push them through the papilla into the small bowel, or a laser lithotripsy device to
disintegrate them.10 When associated with papillary stenosis or anastomotic strictures,
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balloon sphincterotomy is performed to allow stone fragments to pass. In contradistinction to endoscopic sphincterotomy, where there is a high incidence of sepsis and pancreatitis, such complications following balloon sphincterotomy are uncommon.11
Percutaneous choledochoscopy is a technique in which a fiberoptic scope similar to
a bronchoscope is advanced percutaneously along the course of a biliary drainage
catheter and used to visualize bile ducts, intraluminal masses, and stones in detail.
Currently, the most common applications are intrahepatic stone retrieval and intraductal biopsy. Choledochoscopy is performed after the maturation of a percutaneous tract
following biliary drainage, which usually takes 2 to 4 weeks. When used in concert with
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PERCUTANEOUS CHOLECYSTOSTOMY
Percutaneous cholecystostomy (PC) is indicated in patients with acute calculus or
acalculous cholecystitis who are unable to undergo urgent cholecystectomy due to comorbid disease or debilitated condition. Because of the low procedure-related morbidity, in addition to its therapeutic role, PC is commonly used as a diagnostic tool in
patients with unexplained sepsis.12
PC is performed using ultrasound or CT guidance. A transhepatic approach is generally preferred to minimize the risk of bile peritonitis and leakage during catheter placement and exchange procedures. PC allows for rapid decompression of the diseased gallbladder as well as access for cholecystography and potential further intervention.
Overdistention of the gallbladder at the time of placement is avoided because bile in diseased gallbladders is often infected, and overdistention may worsen sepsis in these
already compromised patients.12
After resolution of the acute episode, cholecystography can be very helpful in determining the presence and level of obstruction. In cases of acalculous cholecystitis, patency of the cystic duct is known to be restored when normal bile begins draining from the
catheter. Once the patients clinical condition improves, the catheter is capped and left
in place until the tract matures, at which point it can be removed. In other instances,
PC catheters are left in place until the time of definitive treatment, which is usually
cholecystectomy. Occasionally, percutaneous stone removal through the PC can be performed as a definitive procedure in high-risk patients with calculus cholecystitis.
Although recurrent stone disease will cause biliary symptoms within 5 years in 20 to
50% of cases, this less invasive treatment may be preferable in patients with limited life
expectancy.
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PC may also provide biliary drainage in some patients with mid or low bile duct
occlusion. The gallbladder is quite capacious, and in some cases it can enlarge to completely decompress the intrahepatic bile ducts, making percutaneous biliary drainage
quite difficult. In the presence of low bile duct occlusion and a distended gallbladder,
PC is technically simple and provides drainage of all bile segments. Alternatively, the
gallbladder may be accessed with a needle and cholecystography performed to delineate
the intrahepatic bile ducts, thus facilitating percutaneous transhepatic biliary drainage.
Complications of PC include bleeding, sepsis, bile peritonitis, gallbladder perforation, and catheter dislodgement. Removal of a PC prior to the formation of a mature
tract can also cause bile peritonitis. Tract maturation usually occurs within 4 weeks even
in debilitated patients, but may take longer in patients on immunosuppressive drugs.
PERCUTANEOUS TREATMENT
OF
HEPATIC NEOPLASMS
EMBOLOTHERAPY
The liver receives oxygenated blood from both the hepatic artery and the portal vein.
While the portal vein supplies the majority of the blood supply to the hepatic parenchyma, the hepatic artery is the predominant source of blood for most hepatic tumors, even
those that are not hypervascular. This allows a variety of agents designed to induce insitu cell death to be delivered to hepatic neoplasms via the hepatic artery. Embolic agents
may be delivered alone (bland embolization), or in combination with chemotherapeutic
agents (chemoembolization). In combination with embolization, the delivery of
chemotherapeutic agents via the hepatic artery has been theorized to result in both prolonged contact and higher concentrations of drug within the tumor, with few or no systemic effects.13,14 This is an attractive theory for treating chemotherapy sensitive tumors.
As an alternative to chemoembolization, chemotherapeutic agents may be administered
via hepatic artery infusion pumps to achieve high first pass extraction by the liver as
another means of achieving higher concentrations of drug within the tumor(s) with
diminished systemic effects.15 In the United States, these pumps are most often placed
surgically, but they can be placed percutaneously.
Even in cases of tumors which are thought to be insensitive to chemotherapy, such
as hepatocellular carcinoma (HCC), increased concentration and dwell time of a drug
might result in response to an agent used for chemoembolization that is not effective
when administered systemically. Some early studies demonstrated higher concentration
of doxorubicin within chemoembolized tumors, though these involved very few
patients.14 More recent biodistribution studies do suggest that the combination of doxorubicin, ethiodized oil, and an embolic agent results in the highest concentration of
doxorubicin in a treated tumor, compared to infusing doxorubicin alone or in combination with ethiodized oil.13 In vivo and in vitro laboratory studies also suggest that
ischemia promotes cellular uptake of a radio-labeled doxorubicin analogue, most likely
secondary to reduced active transport of the analogue out of the cell.16
Hypervascular tumors are known to be sensitive to ischemia; in fact early treatment
of such tumors involved hepatic artery ligation alone. There are practitioners who concentrate on maximizing the ischemic effect of embolization, rather than adding
chemotherapy to the embolic material. Bland embolization is used to treat hypervascular tumors such as HCC and metastatic neuroendocrine tumors.17,18 Other tumors
shown to be hypervascular by contrast enhanced cross sectional imaging, or angio-
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Chapter 14
toms or, occasionally, for pain related to tumor bulk). Further, there are no conclusive
data regarding the optimal mix and type of chemotherapeutic agent(s), embolic material(s), and contrast used for chemoembolization. It is our belief that for the treatment of
hypervascular tumors, bland embolization is simpler, less expensive, and obviates potential side effects related to chemotherapeutic agents. One might expect that in treating
hypovascular tumors, chemoembolization would be more efficacious. We do not treat
hypovascular tumors with any form of embolization, as patients at our institution who
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Figure 14-7A. Embolization of neuroendocrine liver metastasis. Preembolization CT demonstrates innumerable right and left hemi-liver
metastases.
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might be treated this way at other medical centers typically receive intra-arterial
chemotherapy via surgically placed pumps.
Embolization is performed from a femoral approach; almost always from the right
femoral artery. Patients receive prophylactic antibiotics, typically a first generation
cephalosporin or equivalent. In patients likely to have bile colonized with bacteria, such
as those who have undergone previous pancreaticoduodenectomy or other type of surgery producing a bilioenteric anastomosis, or even those with biliary stents, coverage
(and longer treatment) with tazobactam/piperacillin (Zosyn [Wyeth, Madison, NJ]) is
recommended because of the higher incidence of infection and abscess formation in
these patients.20 Patients also receive antinausea prophylaxis. The procedure is performed with conscious sedation.
Recent, good quality, contrast enhanced imaging is crucial prior to the embolization.
This maximizes the ability to correlate angiographic findings with cross sectional findings, and provides a basis for follow up and assessment of results. After arterial anatomy
is delineated, a catheter (or microcatheter as needed) is advanced as distally as necessary
and/or possible. The need for super-selective catheterization will vary depending on the
type, number and distribution of tumors. For focal HCC or other tumors treated to prolong survival, super-selective catheterization is preferred. For multifocal HCC or neuroendocrine metastases, typically either the right or left hemiliver is treated initially, with
the patient returning after a few weeks for treatment of the other hemiliver in the case
of HCC, or as symptoms dictate in the case of neuroendocrine metastases.
Postembolization syndrome (PES) consists of pain, fever, and nausea. Most patients
will experience PES to at least some extent. PES is self-limited, generally lasting between
1 and 3 days. Patients also typically demonstrate leukocytosis and elevation of liver function tests. Complications from embolization may be related to arterial access, such as
bleeding, vessel injury, femoral pseudoaneurysm formation, etc, or to the embolization
itself. Rarely do treated tumors become infected. Patients at greatest risk for liver abscess
are those likely to have bile colonized with bacteria, as discussed above. Cholecystitis
may also occur, though in our experience this is surprisingly infrequent, even when the
cystic artery has been embolized. Images obtained soon after the embolization may raise
the question of infection or abscess formation, as tumors typically contain gas, and the
gallbladder wall is often thickened, even when the cystic artery appeared to have been
preserved on the angiographic images. These imaging findings should be ignored in the
absence of compelling clinical evidence to the contrary.
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Some of these ablative treatments may be applied to other hepatic neoplasms or, in the
case of thermal ablation, even be used outside of the liver.
CHEMICAL ABLATION
Ethanol has been the most commonly used agent for the chemical ablation of HCC.
Absolute ethanol results in coagulative necrosis; causing cell dehydration and denaturation as well as small vessel occlusion, presumably due to endothelial cell damage.
Percutaneous ethanol injection (PEI) gained popularity in 1995 when Livraghi and his
group published a study of 746 patients with HCC treated with PEI who demonstrated survival results similar to those who underwent surgical resection.21 Small HCC
tumors are well suited to treatment with PEI, as the typical HCC is a soft tumor
occurring in the background of a hard (cirrhotic) liver. This, combined with the fact
that small HCC tumors are often encapsulated, facilitates injection and promotes uniform distribution and containment of the alcohol within the lesion. While recent studies have shown that radiofrequency ablation (RFA) is more effective and requires fewer
treatments than PEI, PEI may still be preferred for treatment of HCC tumors that might
not be safely or effectively treated with RFA based on tumor location22 (Figure 14-8).
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PEI is indicated for the treatment of patients with 1 to 3 HCC tumors, each of which
is less than 5 cm in diameter. The treatment of larger tumors may be precluded by
potential alcohol toxicity. The volume of alcohol to be injected is calculated using the
formula 4/3(r + 0.5)3, where r is the radius of the tumor in centimeters. PEI is performed using a 22-gauge needle, with either CT or ultrasound guidance. The alcohol is
well seen on CT imaging, appearing as black as air. Alcohol can only be used in soft
tumors such as HCC; because most metastases are quite hard, it is not possible to inject
them with any significant amount of ethanol. Typically, in this situation alcohol will leak
back along the course of the needle, rather than infusing into the tumor.
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THERMAL ABLATION
Tissue can be killed using either heat or cold. Percutaneous cryotherapy has recently
become possible, though probes are still larger than those used for injection of chemical
ablative materials or even radiofrequency ablation (RFA). More than one tumor can be
treated at a time, though multiple probes are often needed for each tumor. Experience
is still limited. Treatment of tumors in liver, lung, and kidney has been performed.24,25
Cryotherapy is reportedly less painful than RFA.
Radiofrequency ablation uses heat to induce coagulative necrosis of the target tissue.
Cell death occurs instantly at temperatures greater than 60C. Necrosis can be achieved
at lower temperatures if the temperature is maintained for longer times. At temperatures
between 100 and 110C vaporization, carbonization and charring may occur. RFA
involves inserting a probe with an insulated shaft and noninsulated tip into a tumor
using imaging guidance. During RFA, the patient is turned into a part of the electrical
circuit. After grounding pads are applied to the patient, the probe is attached to a generator, which produces AC current in the radiofrequency range (300 to 500 kHz). This
causes ionic agitation at the probe tip, which, in turn, causes frictional heating. Tissue
immediately adjacent to the electrode heats by resistive heating, whereas deeper tissues
heat by conduction. As the necrotic sphere (the lesions themselves are rarely perfectly
spherical) grows, the tissue desiccates and impedance rises (see Figure 14-8).
Probes range in size from 15- to 17-gauge. Coaxial and flexible systems have been
developed to combat some of the logistical issues associated with imaging guided RFA,
which typically involve trying to fit the patient in the CT gantry with the probe in place.
MRI compatible probes have also been developed.
RFA is limited in two major ways: by the size of the treated area produced by a given
probe and by heat sinks. Manufacturers have used many methods in order to increase
the size of the treated area in one burn. Since lesion size is proportional to power, the
generators have become more powerful over the last few years. Some probes are internally cooled by circulating saline, many probes are configured in arrays of multiple tines,
the size and diameter of which have continued to increase, and some employ pulsed
power. Various methods of infusing saline into the tumor during the ablation are also
being investigated.26 Currently, the largest diameter of cell death that can be created
using a single burn cycle with one probe is 7 cm. Larger lesions can be created by heating overlapping spheres of tissue.
Heat sinks refer to vessels of large enough size that the flowing blood takes away
enough heat to preclude reaching a high enough temperature adjacent to the vessel to
achieve cell death. In order to combat this problem, some have employed occlusion balloons to block regional blood flow during RFA. The use of a Pringle maneuver, in which
the hepatic vascular inflow is temporarily occluded by placement of a vascular clamp
across the porta hepatic, during laparoscopic RFA has been shown to increase the size of
ablation in a pig model.27
Another problem associated with adjacent structures involves not the efficacy but the
safety of RFA. In certain circumstances the location of a tumor relative to the bowel,
heart, bile duct, adrenal gland, or renal pelvis might preclude safely ablating the tumor.
In these cases, it might be possible to create a safe window by injecting saline to move
the tissue to be spared out of the way. Alternatively, a surgical rather than percutaneous
approach might be safer in such cases.
Results of RFA have been promising, especially in treating HCC tumors 3 cm in
diameter or less.15 While the greatest experience with RFA has been in treating liver
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tumors, it has also been used to treat tumors in the lung, adrenal gland, kidney, soft tissues, and bone.
COMBINATION THERAPY
Any of the minimally invasive treatment methods described above can be used conjunctively with one another.28,29 The two methods we routinely use together are
embolotherapy with percutaneous ethanol injection, or embolotherapy and RFA. The
biggest problem with any ablative treatment is local recurrence. It follows that the use of
two different treatment methods may reduce the recurrence rate. In the case of
embolotherapy and PEI, we found that when PEI was performed after embolotherapy
it was possible to inject higher volumes of ethanol into the target tumor, and there
appeared to be better coverage than when PEI was used alone. Embolizing the arterial
blood supply to a hypervascular tumor might be expected to shorten treatment time for
RFA by reducing the heat sink and allowing for immediate direct deposition of heat
into the target tissue. It might also enhance the effects of RFA, resulting in a larger area
of tissue destruction, as is seen with balloon occlusion of the artery at the time of RFA
or with the Pringle maneuver. RFA has also been combined with PEI in a rat model,
resulting in an increase in the extent of coagulation necrosis.30
ASCITES
Most ascites is due to liver disease, and medical management is the mainstay of therapy for this group of patients. In cases of medically refractory ascites or in ascites of other
etiologies, in particular malignant ascites (representing approximately 10% of cases),
other treatment options must be considered. There are many procedures aimed at controlling ascites now in the armamentarium of the Interventional Radiologist, and more
are no doubt forthcoming.31,32
Repeated large volume paracentesis (LVP) is the most common means of managing
refractory ascites. Safe drainage of up to 4 to 6 L per session seems relatively uncontroversial. Reports of draining more than 20 L at one time exist. The biggest problem with
LVP is the need for patients to return repeatedly for the procedure. Concerns also exist
regarding the loss of protein from the ascitic fluid.
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Control of ascites using percutaneously placed exteriorized catheters has been reported by several authors.33-35 Catheters have been used for both benign and malignant etiologies, though more reports describe their use in malignant disease. Nontunneled
catheters are easily placed, but have been reported to be associated with a high rate of
infection and catheter related sepsis. Tunneled catheters have been advocated by several
authors, and appear to provide effective relief for most patients. It is currently unclear
whether or not the Pleur-x (Denver Biomedical, Golden, Colo) offers a substantial
advantage over nonvalved cuffed catheters such as the Tenckhoff catheter. Potential complications include infection, which is thought to be less common than with nontunneled
catheters, occlusion, dislodgment, and loss of protein, as with repeated LVP. The
catheters are likely to be successfully managed by the patients and their families, though
they do carry the psycho-social issues and physical constraints associated with other
types of exteriorized catheters. There are small series describing the use of subcutaneous
peritoneal ports, which could ameliorate some of those issues. However, one study noted
a 33% infection rate. Additionally, a trained health care worker is typically needed to
access the port.
The role of percutaneous peritoneovenous shunting remains unclear. Potential benefits of shunting include the lack of repeated trips to a health care provider, lack of an
exteriorized device, and the continued reintroduction of the ascites volume and proteins
into the circulation. Reports on the success and complications associated with the procedure are quite varied. Recently, a few reports have been published describing percutaneous placement of Denver peritoneovenous shunts (Denver Biomedical) by interventional radiologists.36 However, most reports come from the surgical literature. Reported
complications include shunt malfunction from occlusion and disseminated intravascular coagulation (DIC). The occurrence of the latter appears to be reduced by completely draining the ascites at the time of shunt placement. Theoretical concern of decreasing
survival by disseminating tumor cells in cases of malignant ascites has not been reported in the literature.
Placement of a transjugular intrahepatic portosystemic shunt (TIPS) can control
ascites in patients with portal hypertension. TIPS are contraindicated in patients with
encephalopathy or heart failure, and are not well tolerated in cases of poorly compensated cirrhosis. TIPS plus medical therapy has been shown to be superior to medical
management of ascites alone. Compared with LVP, TIPS has been shown to lower the
rate of ascites recurrence and the risk of developing hepatorenal syndrome, but with an
increased incidence of encephalopathy. Many studies show no survival benefit to TIPS
compared with other therapies, though other studies have suggested improved survival
in certain populations. TIPS may take several weeks to result in resolution of ascites, and
may not be effective in all cases.
ABSCESS DRAINAGE
Image-guided percutaneous drainage techniques have had tremendous impact on the
management of fluid collections within the abdomen and pelvis, most of which are postoperative. Reoperation is obviated in most cases. Postoperative collections may result
from leaks (bowel contents, bile, urine, or pancreatic fluid), lymphatic obstruction or
injury (lymphocele), or the presence of residual blood or ascites. Drainage is most often
performed for suspected infection, typically in the setting of fever and leukocytosis.
Drainage may also be performed to relieve symptoms from mass effect, control a leak
(sometimes in conjunction with diversion of the source of the leaking fluid), or for characterization of the fluid.
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CT imaging, preferably with both oral and intravenous contrast, is our preferred
modality for diagnosing a postoperative fluid collection. It affords excellent visualization
of the fluid, and is often able to provide characterization of the fluid as well. CT scanning may demonstrate urine or bowel leaks, and is also accurate in characterizing blood.
Enhancement of the wall of a collection may support clinical concerns for infection and,
in the case of multiple collections, can be helpful in deciding which collection to drain.
CT also allows planning of the drainage, and will demonstrate rare cases where a collection cannot be safely accessed percutaneously, as in deep collections surrounded by
bowel, vessels, and/or bone.
Drainage may be performed using CT, ultrasound, or fluoroscopic guidance,
depending on the nature and location of the collection, as well as operator preference.
As with most interventional procedures, abscess drainage is performed using conscious
sedation. Depending on the nature of the fluid, locking loop catheters ranging from 8
to 12 French are placed primarily. Gram stain and culture is performed routinely.
Specimens may be sent for measurement of amylase, creatinine, bilirubin, or triglycerides, depending on the clinical situation. In managing urinomas after cystectomy or
partial nephrectomy, typically associated with a leak from the ureter, collecting system,
ileal conduit or neobladder, diverting nephrostomies are almost always necessary. Biliary
diversion may be necessary in cases of bile leak, but generally only in the setting of
obstruction.
While most catheters are placed percutaneously, a transrectal, transvaginal, or perineal approach may also be used. Management of the catheters is similar irrespective of
the source or the approach. The catheters are flushed twice daily to help ensure patency.
If postprocedure imaging shows incomplete drainage, fibrinolytic therapy is initiated.
This may be performed using tissue plasminogen activator (tPA) or urokinase. While
initial reports described benefits of lytic therapy in managing empyema, this has become
a very popular tool in the management of abdominal and pelvic fluid collections as well,
often speeding resolution of the collection and obviating additional procedures to reposition a catheter or place multiple catheters.37,38
When the output of the drain is essentially equal to the volume of daily flush, investigation is performed to determine whether the collection has resolved, or whether low
output is due to catheter malfunction. This may involve CT scanning or studying the
cavity fluoroscopically by injecting contrast material into the drainage catheter. A contrast study performed after the cavity has resolved, or at least decreased significantly in
size, may demonstrate the source of a leak. Even with a known leak from bowel, bile
duct, or urinary system, a fistula may be impossible to demonstrate if the collection of
fluid/cavity is large. It is difficult to force contrast along the fistula, since it is easier to
fill the capacious space. As the space decreases, as well as the inflammatory changes in
the wall of the cavity, it is usually possible to demonstrate the fistula. Most leaks will
close if the cavity outside the perforation closes, unless there is obstruction of the system
from which the fluid is leaking, distal to the leak. Generally, when the cavity is completely resolved, the drain can be removed.
In addition to managing postoperative fluid collections, interventional radiological
techniques may be applied to diverticular or appendiceal abscesses, as a preoperative procedure.
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PERCUTANEOUS BIOPSY
Percutaneous imaging-guided needle biopsy may be used to diagnose primary or
metastatic cancers and occasionally benign neoplasms. In the case of organ dysfunction,
needle biopsy may provide tissue (liver or kidney) for histologic evaluation. Imaging
guided aspiration may also be used to sample an abscess or infected tumor in order to
provide an organism to guide antibiotic treatment. A specific diagnosis should be made
in 80% to 95% of biopsies. Complications may occur but are generally self-limited or
easily treated. Needle tract seeding has been reported but is quite rare. It is important to
remember that there is no such thing as a negative biopsy. If malignancy is not documented then a specific benign diagnosis should be made. If nonspecific findings such as
normal site tissue, fibrous tissue, or inflammatory, reactive, or atypical cells are present
in the biopsy specimen, then a repeat biopsy or close follow-up are warranted. In certain
cases, incisional or even excisional biopsy may be warranted.
Percutaneous biopsy needles range in size from 14- to 25-gauge, and may be of either
coring or noncoring design. Larger needles (20- to 14-gauge) needles are typically used
to perform core biopsies, where pieces of tissue are obtained for pathologic evaluation.
Smaller needles (25- to 20-gauge) are commonly used to obtain specimens for cytological evaluation, or for acquisition of material for culture or chemical analysis. At our
institution, the majority of tumor biopsies are performed using 22-gauge needles to provide material for cytology. Core biopsies are generally performed to facilitate a specific
diagnosis in suspected sarcomas, hepatocellular carcinoma and lymphomas. In biopsies
performed for patients with known or suspected non-Hodgkins lymphoma, material is
also obtained for flow cytometry. Key to maximizing the likelihood of obtaining diagnostic material is onsite evaluation of each specimen by a skilled cytotechnologist or
cytopathologist. If the initial specimen is not felt to provide diagnostic material, additional tissue can be obtained immediately. It is important for the interventional radiologist to be aware of special handling instructions or tissue preparations that may be
unique to his or her institution.
Good quality imaging is essential for demonstrating the lesion and planning the
biopsy. It is optimal to have a study demonstrating the target lesion using the modality
that will be used to guide the procedure. For example, if a mass is only demonstrable by
MRI, performing the biopsy with CT or ultrasound guidance will be challenging, at
best. This is less relevant with larger lesions, where the likelihood that a mass will not be
demonstrated by multiple modalities is lower, or the mass can be biopsied based on landmarks alone. Percutaneous biopsy can be performed using CT, ultrasound, fluoroscopic, or MRI guidance, depending on available resources, operator preference and experience and the nature of target. The biopsy should be planned to minimize both potential
complications and the need for the patient to cooperate with complicated positioning or
breathing instructions.
While the basic principles of percutaneous needle biopsy apply irrespective of the target tissue, there are a few considerations that are location specific.
LUNG/MEDIASTINAL BIOPSY
Lung biopsies can be performed under CT or fluoroscopic guidance. In our experience, lung biopsies are easier and faster under fluoroscopic guidance, as the real-time
modality allows for adjustment of the needle with breathing. This is more important
with smaller lesions. Mediastinal biopsies generally require CT guidance.
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Complications related to lung and mediastinal biopsy involve hemorrhage and pneumothorax. True hemorrhagic complications are rare in biopsy of parenchymal lung
masses performed in noncoagulopathic patients. Serious bleeding complications may
occur in coagulopathic patients. Hemoptysis is not uncommon, occurring in up to 30%
of cases. This is almost uniformly self-limited, and advising the patient properly will
avoid them being frightened. True bleeding complications may occur during or after
mediastinal biopsy, and may result in hemothorax or hemopericardium. Hemorrhagic
pericardial tamponade is quite rare, but is life threatening. While hypoxemia can occur
with either pneumothorax or pericardial tamponade, tamponade can be suspected by the
concomitant development of hypotension with narrowed pulse pressure, as well as
diminished amplitude of the ECG complex. Immediate CT scanning provides diagnostic confirmation, and allows guidance for placement of a small drainage catheter into the
pericardial space, which in our experience of three cases, has provided effective treatment.
Pneumothorax occurs in 25% to 30% of patients undergoing percutaneous lung
biopsy. Treatment is required in approximately 5% of cases overall.39 The risk of pneumothorax is increased with deeper lesions and increased number of pleural surfaces traversed, but is surprisingly unrelated to the size of the needle. Treatment is more often
necessary in patients with underlying COPD. No treatment is required for stable pneumothorax in an asymptomatic patient. Once the pneumothorax has been shown to be
stable over at least 2 hours, an asymptomatic patient can be discharged. Patients who are
symptomatic, or with an enlarging pneumothorax are treated with small caliber (typically 8 French) thoracostomy catheters, typically placed in the second anterior intercostal space. Once the lung is re-expanded and the absence of an air leak can be documented, the catheter is removed. Occasionally, an air leak will persist beyond a few
hours, and admission to the hospital is then required. Rarely, a reliable patient can be
sent home with a Heimlich valve (a one way valve which allows air out but not in) and
can be managed as an outpatient.
ADRENAL BIOPSY
Adrenal adenomas are common benign tumors, occurring in as many as 10% of
patients. The adrenal gland is also a fairly common site of metastatic disease. While MRI
can often reliably distinguish an adenoma from a metastasis,40 needle biopsy is sometimes required for definitive diagnosis. It is often necessary for the needle to traverse aerated lung when performing percutaneous adrenal biopsy and pneumothorax is the most
common complication of this procedure. Adrenal biopsy is typically performed using
CT guidance.
LIVER BIOPSY
Many benign tumors such as FNH, adenoma, or hemangioma can be reliably diagnosed by high quality cross-sectional imaging. Biopsy of these lesions is rarely conclusive, though the absence of malignant tissue may further support imaging findings that
may be suggestive, but not diagnostic, of a benign entity. Metastatic disease can generally be documented using a cytologic specimen obtained from a fine needle biopsy.41
Special studies can often be performed to determine the primary tumor type when needed. A core biopsy is sometimes necessary to diagnose hepatocellular carcinoma, as welldifferentiated tumors can be difficult to distinguish from normal liver based on cytology
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alone. In patients with a liver mass in the background of cirrhosis or viral hepatitis, an
alpha-fetoprotein level >500 ng/mL is considered diagnostic for HCC. Biopsy of hepatic masses is most commonly performed using CT or ultrasound guidance, largely
depending upon operator preference.
PANCREAS BIOPSY
Most patients with pancreatic cancer still present with unresectable disease. Needle
biopsy may be requested for tissue diagnosis so that treatment can be initiated.
Pancreatic cancer often incites a scirrhous reaction and there is often abundant fibrous
tissue associated with the tumor; it is often more fruitful to biopsy peripancreatic lymph
nodes or liver metastasis, when present. Biopsy of the pancreas may be safely performed
from an anterior approach through the stomach or liver, or from a posterior approach
through the inferior vena cava when necessary. CT guidance is most common, but ultrasound guided biopsy may also be performed. Pancreatitis may occur rarely after needle
biopsy.
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guidewires, interventional radiologists can place central venous catheters more safely and
reliably than physicians relying on landmarks alone.42 Access requirements vary from
patient to patient, and as a result, many different types of catheters are available. These
are characterized by catheter size, type (implantable vs external), number of lumens, and
potential dwell time.
Central venous access should be considered when long term treatment is anticipated, or when treatment with desiccant chemotherapy or total parenteral nutrition is indicated. Complications of central venous access include pneumothorax, infection, catheter
malposition, venous stenosis, and pericatheter thrombosis. Internal jugular access for
catheter placement and proper catheter tip positioning minimize the risk of symptomatic venous thrombosis, and with ultrasound guidance, the risk of pneumothorax is
essentially eliminated. Subclavian access is associated with a higher risk of pneumothorax, development of venous stenosis, and pericatheter thrombosis causing symptomatic
upper extremity edema. The preferred site of access, therefore, is the internal jugular vein
because of the low risk of complications. Access via the right internal jugular vein is preferred over the left, because of a shorter and straighter intravascular course to the right
atrium.
In patients who have had multiple prior catheters, conventional access sites may be
occluded. Interventional radiology techniques are especially valuable in such cases, as
central venous access can often be achieved by recanalizing an occluded vein or using
collateral veins. Occasionally, alternative access sites must be employed. Catheters may
be placed from a translumbar approach into the inferior vena cava, from a trans- hepatic approach into one of the hepatics vein, or via a transfemoral approach.
Implantable ports are ideal for long-term intermittent use, as is often the case for
patients receiving chemotherapy. When not accessed, they are completely contained
under the skin; as such, these catheters have a low risk of infection and no lifestyle
restrictions (once the incision has healed patients can shower, swim, play golf, etc). As
with all central venous access, the preferred access site is the right internal jugular vein,
and the catheter is tunneled under the skin of the anterior chest wall to the port reservoir placed in a subcutaneous pocket. Because ports require an incision and the creation
of a pocket in the chest wall, as well as a needle stick for access, coagulopathy or anticoagulation is a relative contraindication. Ports may remain in place indefinitely, often
for several years, and need to be flushed only every 4 to 6 weeks. Chest wall ports can
be placed safely, even in patients who have undergone ipsilateral axillary lymph node dissections from breast cancer or melanoma surgery.43 Ports may also be placed in the arm,
via the brachial or basilic vein. However, the risk of central venous stenosis or occlusion
is higher than with jugular access for chest port placement.
Exteriorized tunneled catheters are also commonly used, including Broviac/Hickman
catheters, leukapheresis, and dialysis catheters. Most catheters are available with one, two
or three lumens, and come in many sizes. Larger catheters (13.5 French to 15.5 French)
are commonly used for dialysis or leukapheresis, where higher flow rates are required. As
with ports, these catheters are generally placed in the internal jugular vein and tunneled
to the anterior chest wall. Because the catheters are exteriorized, it is not necessary to
puncture the skin to use them. However, they are more lifestyle limiting and require
more care. Additionally, these catheters are not ideal for noncompliant patients, small
children, or patients with small children, as they may be removed inadvertently with
traction.
Peripherally inserted central catheters (PICCs) are placed in an upper extremity vein,
often at bedside by a nurse or IV team, and measured so that the tip ends centrally. They
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are nontunneled catheters, and may be used for short to intermediate term therapy.
Because they are placed in an arm vein and have a long intravascular course, complications include symptomatic venous thrombosis. They are, however, very easy for patients
to take care of at home and very acceptable cosmetically.
SVC STENTS
Malignant occlusion of the superior vena cava is a potential consequence of thoracic
malignancies, most commonly lung cancer. Obstruction may be due to direct tumor
involvement, extrinsic compression by tumor, or lymphadenopathy. Benign cases of
superior vena cava occlusion in cancer patients occur as well, most commonly due to
malpositioned venous access devices.
Often radiographic occlusion is seen in patients with no clinical symptoms, due to
abundant thoracic collateral channels predominantly draining into the azygous system
or inferior vena cava. In such cases, no treatment is indicated. In some patients, however, superior vena cava obstruction is associated with the superior vena cava syndrome,
consisting of upper extremity, head and neck swelling, headache, mental status changes,
and dyspnea.
In symptomatic patients with radiosensitive tumors, radiation has been the treatment
of choice. While this is often successful, it requires daily therapy for several weeks and
improvement occurs slowly over days to weeks. Recanalization of the superior vena cava
with balloon angioplasty or metallic stenting, on the other hand, offers rapid and often
dramatic relief of symptoms, typically within 24 hours. Although some success has been
reported with angioplasty alone, the recurrence or failure rate after percutaneous transluminal angioplasty, particularly in patients with malignant obstruction, is quite high
because of the elastic recoil that takes place secondary to the compressing tumor or fibrosis. Stent placement is the most durable method of reestablishing blood flow.
Contrast-enhanced chest CT is critical for procedure planning to define the level and
length of obstruction. CT may also suggest the presence of acute thrombus, which may
require thrombolysis prior to stenting. When venous access is also required (as is often
the case in patients with cancer), an approach via the subclavian or internal jugular vein
is preferred, and a venous access device is placed through the stent at the end of the procedure. Alternatively, a transfemoral approach may be used. Once venography is performed, the occlusion is crossed with a catheter and guidewire. If acute thrombus is present, pharmacologic thrombolysis (tPA, urokinase) is indicated prior to balloon dilation
or stent placement to minimize the risk of procedure-related pulmonary embolism and
stent occlusion by thrombus.
It is our practice to place unilateral stents from the brachiocephalic vein of the punctured side to the high right atrium. This is supported by a recent study by Dinkel, in
which 84 patients with SVC syndrome underwent either unilateral or bilateral stenting
(ie, double barreled stents into the SVC from both brachiocephalic veins) for malignant
SVC syndrome. They found no difference in technical success or clinical response, but
a trend toward longer primary patency in the unilaterally stented group.44
Pre-stent angioplasty may be performed and an appropriate diameter self-expanding
stent is then deployed across the occlusion. Technical success approaches 100%, and
symptomatic relief is seen in 80% to 99%. Peri- and postprocedure anticoagulation is
controversial and ranges from baby aspirin to full, lifetime anticoagulation with warfarin.45
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not indicated. Ideally, filters are placed immediately below the most caudal renal vein,
but they may be placed in a suprarenal portion of the IVC if the thrombus extends more
centrally. Most filters are designed to be placed in vessels of 20 to 28 mm, and in the
unusual case of a mega-IVC, a Birds Nest filter can be placed safely in IVCs up to 40
mm. Each filter has advantages and disadvantages, and selection of a specific filter often
depends on the experience of the radiologist.
Complications of filter placement include nontarget placement, recurrent pulmonary embolism, IVC occlusion, migration, contrast reactions, and access complications. The frequency of complications reported in the literature is difficult to interpret,
as ranges of 3% to 69% for filter migration, 2% to 28% access site thrombosis and 6%
to 30% IVC occlusion are reported.46 For more realistic numbers, a study of 1765 filters placed in 1731 patients over 26 years at the Massachusetts General Hospital was
reported in 2000.48 In this large cohort, symptomatic IVC thrombosis occurred in
2.7%, recurrent PE in 5.6% (fatal in 3.7%).
Recently, an optionally retrievable IVC filter was approved for use in the United
States. The term optionally retrievable refers to the fact that this filter may be removed
up to 161 days after placement, but also may function as a permanent filter if the contraindication to anticoagulation unexpectedly persists. This filter can provide short-term
mechanical filtration for patients at high-risk for pulmonary embolism and prevent the
long-term complications associated with permanent filter placement. Indications
include preoperative prophylaxis in high-risk patients who have no long-term contraindication to anticoagulation, protection during lower extremity or IVC thrombolysis, DVT in pregnancy, and trauma. An additional advantage is the ability to retrieve and
reposition malpositioned filters after deployment. Currently, the Recovery is the only
FDA-approved retrievable filter, though others are awaiting approval.
GENITOURINARY PROCEDURES
Obstruction of the urinary tract is not uncommon in cancer patients, and may be
caused by primary GU neoplasms, other pelvic masses, lymphadenopathy or other
metastases, or ureteral strictures or fibrosis. Stone disease may also occur in this patient
population. Relief of obstruction may be indicated for renal insufficiency or frank renal
failure, pyonephrosis, or pain control. Asymptomatic obstruction may also be treated to
preserve or maximize renal function. Percutaneous urinary drainage may also be required
to provide urinary diversion, in cases of fistulae or leaks.
Good quality preprocedure imaging is essential to identify the cause and level of the
obstruction and get a look at the bladder, as well as defining relevant anatomic details.
It helps determine the treatment options available, as well as whether the patient is best
approached percutaneously or cystoscopically. Generally, patients with essentially normal bladders, who are able to fill and empty their bladder, should undergo attempted
retrograde ureteral stent placement as a primary treatment approach. This obviates the
need for percutaneous catheters, with their attendant physical and psychological issues.
A percutaneous approach to urinary drainage should be undertaken in cases of unsuccessful cystoscopic, retrograde stent placement, when the bladder is filled with or compressed by tumor, or to provide urinary diversion. Urinary diversion is generally provided by a percutaneous nephrostomy catheter. For cases in which permanent diversion is
desired, nephrostomy placement may be combined with embolization of the ureter.
Ureteral occlusion may be accomplished by placement of coils, gelatin sponge pledgets,
or detachable latex balloons using the percutaneous nephrostomy site for access.49,50
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There are four main tools employed by interventional radiologists who perform percutaneous urinary drainage procedures. These are: nephrostomy, nephroureterostomy,
transloop retrograde nephrostomy, and ureteral stent. Initial percutaneous access is performed using fluoroscopic and/or sonographic guidance. A nephrostomy catheter enters
the patient via the flank and terminates in the renal pelvis. Most catheters have a locking-loop that forms a pigtail, and serves as a retention device. A nephroureterostomy
catheter is essentially a nephrostomy catheter with an attached ureteral stent, so that
the catheter enters the kidney, has a loop within the renal pelvis, then extends to the
bladder where it terminates in another pigtail. This catheter can drain both the kidney
and the bladder when allowed to drain externally. These catheters can be capped and can
act as an internal stent, allowing urine from the collecting system to drain into the bladder. This can allow a trial of internal stent use. If the patient tolerates a capped
nephroureterostomy catheter, the catheter can then be converted to an internal stent.
Occasionally, patients who cannot tolerate an internal stent may be able to cap their
nephroureterostomy intermittently. Patients who undergo conversion of a percutaneous
catheter to an internal ureteral stent are typically referred to a urologist for future cystoscopic stent exchanges. Stents can be changed by the Interventional Radiologist from a
transurethral approach using fluoroscopic guidance. This is reasonably easy in women,
but may be difficult in men.
Ureterointestinal anastomotic strictures occur in 4% to 8% of patients who have
undergone cystectomy and creation of a neobladder or ileal conduit. In these patients,
open ureteral implantation has traditionally been the treatment of choice. Balloon dilation (cutting/angiographic), however, now offers a minimally invasive treatment option
and is successful in approximately 50% of cases, obviating the need for long-term
catheter drainage.51,52 Another option for patients with an ileal conduit is to use antegrade access to the kidney to allow for crossing the obstruction into the conduit, and
then retrograde placement of a nephrostomy tube. The end of this catheter then protrudes from the patients stoma and is placed in the stoma bag. Therefore, the lumen of
the catheter does not become obstructed from mucus produced by the conduit, and the
catheter can easily be changed from below. If nephroureterostomy catheters are placed
in these patients the catheters should not be capped, as the intestinal mucosa of the conduits or neobladders, secretes mucus that will occlude the distal portion of the catheter.
These patients are not candidates for internal stent placement for the same reason. In
patients with ileal conduits, a nephroureterostomy catheter can easily be converted to a
retrograde nephrostomy, as discussed previously. This option is preferred by patients
because there is no additional external appliance to maintain (Figure 14-9).
Exteriorized urinary drainage catheters typically require routine exchange at roughly
three month intervals. Antibiotic coverage for these procedures is essential. Like all exteriorized catheters, nephrostomy and nephroureterostomy catheters will be colonized
within a few days, and thus transient bacteremia may result from even routine exchange.
If a catheter occludes, patients may develop urosepsis. Because these catheters become
colonized, when they are properly functioning there is no need to treat positive cultures
from the catheter in the absence of clinical signs or symptoms.
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INTERVENTIONS
IN THE
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CHEST
PLEURAL EFFUSIONS
Malignant pleural effusions are common in patients with cancer, most frequently in
breast carcinoma, lung carcinoma, and lymphoma. These effusions are exudative in
nature, and result from weeping of fluid from pleural metastases or lymphatic obstruction by tumor. The accumulation of fluid in the pleural space may be associated with
dyspnea, cough or chest pain.
Malignant effusions in patients with lymphoma or small cell lung cancer may
improve significantly or even resolve with systemic therapy, but the majority of symptomatic patients with malignant pleural effusions will require some form of drainage for
relief. Treatment options include repeated thoracentesis, tube thoracostomy, VATS and
pleurodesis.
Thoracentesis may be performed on an outpatient basis or at bedside, but because
malignant effusions recur in the vast majority, it does not represent a definitive treatment
option.
Several different chest tubes, made of polyurethane or silicone, are available for
drainage of pleural effusions, ranging in size from 8 to 36 French. Surgical chest tubes,
placed at the bedside or in the operating room, are usually 24 to 36 French catheters.
When placed at bedside, chest tube placement is a blind procedure relying on landmarks to access the effusion. Therefore, this technique is limited to patients with moderate to large free-flowing effusions, and poor catheter position is a common occurrence.
These catheters tend to be rather uncomfortable, as well.
Although surgical teaching is that a large catheter is required for successful drainage,
recent data suggests that smaller caliber catheters are equally effective. Large caliber tubes
are certainly associated with more pain and limitation of mobility. The small bore (8 to
15.5 French) catheters placed by interventional radiologists (and some surgeons) generally have multiple side holes, flexible pigtail locking-loops, and are able to change position within an effusion as it resolves. Several studies have demonstrated no significant
difference between large and small bore catheters in the successful management of
malignant pleural effusions.53,54
Placement of chest tubes using CT, ultrasound, or fluoroscopic imaging has the additional advantage of making it possible to place the catheter into a desirable location to
maximize drainage. In other words, using guidance, catheters can be placed where the
fluid is rather than at an external anatomic landmark. This is most important in
patients with small or loculated effusions.
Using imaging guidance, an appropriate puncture site is marked. The pleural space
is accessed with an 18- to 21-gauge needle and fluid is aspirated. A guidewire is advanced
into the pleural space, and this guidewire may be used to disrupt septations in multiloculated effusions. The tract is then dilated, and a catheter is advanced over the wire
into a dependant portion of the pleural space. One to 1.5 L may be aspirated immediately, after which the catheter is attached to a closed system water-seal device. Gravity
drainage is usually sufficient, but suction may improve drainage in a minority of
patients.
A chest radiograph is obtained immediately following drainage to provide a new
baseline and to evaluate for lung re-expansion. In chronic effusions, the lung may not
be compliant and an ex-vacuo air collection may be seen in the pleural space after
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Chapter 14
drainage of pleural fluid. This usually resolves over days to weeks, but may persist in
some cases.
Daily outputs are measured and are critical in the tube management decision making process. Low catheter output (<25 cc/day) indicates either tube malfunction or resolution, and a chest radiograph can usually differentiate between the two. If the catheter
is malpositioned or malfunctioning, it may be exchanged over a guidewire. If the effusion has resolved, as happens in a significant minority of patients with malignant pleural effusions, the catheter may be removed without further intervention.
The majority of patients with malignant pleural effusions, however, will not have a
durable, long-term response to thoracentesis or catheter placement alone. In this group
of patients, mechanical or chemical pleurodesis may be performed. Mechanical pleurodesis and/or chemical pleurodesis are performed during video-assisted thorascopy,
while chemical pleurodesis can be performed at bedside via a chest tube. While surgical
pleurodesis offers a slightly higher success rate and shorter hospital stay, it is more expensive, more invasive, and associated with higher morbidity.55,56
Chemical pleurodesis is achieved by instilling a sclerosing agent (asbestos-free talc,
bleomycin, doxycycline) into the pleural space to incite an inflammatory reaction that
ultimately causes the visceral pleura to adhere to the parietal pleura, thereby eliminating
the potential space in which fluid can accumulate. The choice of agents is operator
dependent, and each has pros and cons. Talc is inexpensive and readily available, but has
been associated with acute respiratory distress syndrome. Talc also forms a thick slurry
and can occlude smaller bore (8 to 10 French) catheters. Bleomycin is slightly less effective and quite expensive. Doxycycline is relatively effective, inexpensive, and available,
and has, therefore, been our agent of choice.
In order for pleurodesis to be successful, the pleural space should be completely
drained with good apposition of the visceral and parietal pleura. Injecting a sclerosant
into an incompletely drained effusion can turn a simple effusion into a multiloculated
effusion, often necessitating further intervention. Once adequate drainage is documented by imaging, 1% lidocaine is injected into the pleural space and intravenous analgesics
administered prior to pleurodesis. The sclerosant (5 gm of talc in 100 cc NS, 500 mg
doxycycline in 100 cc NS, 60 IU Bleomycin in 100 cc D5W) is injected into the pleural space, the catheter is clamped, and the patient is instructed to change position every
15 minutes for 2 hours to distribute the agent in the pleural space. The tube is then
reopened and removed when drainage is less than 100 cc/day.
Chemical pleurodesis is effective in 61% to 90% patients, but often requires prolonged hospitalization of 5 to 12 days to adequately drain the pleural space;56 in a
patient population with a median life expectancy of 6 to 12 months and a 30-day mortality of 29% to 50%,57 this may not be acceptable.
An alternate approach is to treat malignant pleural effusions with a long-term tunneled chest catheter (Pleur-x, Denver Biomedical). This is a 15.5 French silastic catheter
with an airtight valve in the hub, allowing the catheter to remain in place indefinitely
and be accessed for intermittent drainage using a vacuum bottle. These catheters may be
placed on an outpatient basis with appropriate teaching, and intermittent drainage may
be performed by the patient at home. Mechanical pleurodesis is spontaneously achieved
by almost 50% of patients at 30 days.58
To improve drainage of complex pleural collections, intrapleural fibrinolytic agents,
including tPA and urokinase, may be instilled into the pleural space. These agents promote enzymatic debridement of fibrinous septae in the pleural space and when injected
Interventional Radiology
279
through a chest tube can reestablish catheter patency and improve drainage of complex,
multiloculated effusions and even empyema.57,59
BRONCHIAL STENTS
Patients with occlusion of the central airways by intrinsic tumor or extrinsic compression present with dyspnea, obstructive pneumonia, and often have the sensation of
impending suffocation.60 When not amenable to resection, intraluminal malignant
lesions can be effectively palliated bronchoscopically with laser ablation, electrocautery,
brachytherapy, or photodynamic therapy. Placement of plastic or metallic stents is a useful adjuvant to reestablish and maintain airway patency in these cases, and it is the treatment of choice for endobronchial obstruction due to extrinsic compression.61-63 In fact,
78% to 98% of patients stented can be expected to have immediate relief of respiratory
symptoms related to central airway obstruction.62
As in the biliary tract, plastic stents have the advantage of being removable and
replaceable, but require rigid bronchoscopy for placement and are subject to occlusion
by inspisated mucus or granulation tissue. Self-expanding metallic stents provide a larger lumen and may be placed via flexible bronchoscopy, but they are permanent.
Successful stent deployment requires a coordinated effort by a multidisciplinary
team. CT with 3-dimensional reconstruction is useful in determining the length and
level of obstruction, as well as the anatomy of the airway. Flexible or rigid bronchoscopy
is then performed (usually by a surgeon or pulmonologist) to confirm the imaging findings and provide access to the lesion. The scope is then removed over a guidewire in the
side port and an angiographic catheter advanced central to the obstructing lesion. A selfexpanding metallic stent is then advanced over the guidewire and deployed to cover the
obstructed portion of the airway. Lastly, the bronchoscope is readvanced over the
guidewire to confirm adequate coverage by the stent prior to completion of the procedure.
Long-term follow-up data is limited because the life expectancy of these patients is
measured in weeks. Wood et al published Washington Universitys series of 53 patients
stented for malignant disease, in whom 85% had adequate palliation with a mean follow-up of 4 months, with 28% requiring additional bronchoscopic procedures to
reestablish stent patency.63 A study from Norway, in which 14 patients were treated with
endobronchial stents for malignant obstruction, had a median survival of 11 weeks, with
a range of 0.5 to 34 weeks.60
EMERGING THERAPIES
AND
FUTURE DIRECTIONS
The field of interventional radiology has undergone several metamorphoses since its
inception almost 30 years ago, when Charles Dotter performed the first percutaneous
dilation of a superficial femoral stenosis in a patient who had refused amputation.
Minimally invasive image guided techniques have replaced many open surgical procedures and provide new options for patients with previously untreatable diseases.
Progress continues and many new and exciting techniques are emerging. Gene therapy is a promising new tool based on the transfer of genetic material to a target cell population. Preclinical and clinical studies in the treatment of liver metastases in which viral
vectors containing either a suicide gene or corrective copies of a defective gene are
injected directly into the hepatic artery or portal vein to reverse the malignant phenotype and induce apoptosis or growth arrest of tumor cells are being investigated. The role
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of interventional radiology is not only to provide access for local delivery, but in the
development of maximally effective delivery systems.
Chemotherapy containing liposomes, including new stealth liposomes that evade
destruction by the immune system are currently in clinical trials for the treatment of
melanoma, breast carcinoma, ovarian carcinoma, and AIDS-related Kaposis sarcoma.
Currently delivered systemically, catheter-directed delivery has the potential to maximize
pharmacokinetics and minimize systemic toxicity.
In addition to novel treatment strategies, future trends in interventional radiology
promise to include more effective and efficient ways to perform current procedures.
Robots with arms and wrists have allowed complex open surgical procedures, including
coronary artery bypass grafting surgery (CABG) and hepatic resection, to be performed
through tiny incisions and have facilitated surgical procedures on newborns and fetuses.
The development of robotics has promised to revolutionize the field of surgery in replacing open surgical procedures with minimally invasive ones and developing entirely new
procedures to treat disease. In the arena of interventional radiology, where essentially all
procedures are minimally invasive, robotics can be used to improve accuracy of needle
placement when performing a biopsy, radiofrequency ablation, or targeted access to an
organ or vessel.
A precursor to robotics includes an electromagnetic targeting system based on the
Global Positioning System, which is commercially available for both CT and ultrasound. Using a sensor on a needle in a weak magnetic field, the exact position and orientation of a needle with respect to the target is displayed on a monitor in multiple
planes, facilitating and optimizing needle placement.
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chapter
15
Maintenance
of Luminal Patency:
Dilation, Endoprosthetics,
and Thermal Techniques
Patrick R. Pfau, MD
INTRODUCTION
Advanced malignancy may result in obstruction of the gastrointestinal lumen in
patients with esophageal, gastric, pancreatobiliary, colorectal, or metastatic cancers
resulting in significant patient morbidity and mortality. Traditional methods of relieving or bypassing malignant obstruction through surgery or chemoradiotherapy are often
difficult in patients with a poor performance status or those who need immediate relief
of obstruction.
A number of successful endoscopic methods have been developed and are used in
clinical practice that provide safe and prompt relief to patients with malignant GI
obstruction.
ESOPHAGUS
Esophageal cancer remains an infrequent disease in the United States with approximately 12,000 cases diagnosed per year. However, the incidence of adenocarcinoma of
the esophagus and gastroesophageal junction is increasing at a rate greater than any
other malignancy. Further, cancer of the esophagus remains a deadly disease with a 5year survival of less than 10%.1
Cancer of the esophagus presents often at an advanced stage and local recurrence is
a common problem post esophageal resection. Malignant dysphagia is the most common symptom, occurring in 70% of patients with esophageal cancer.2 Obstruction of
the esophagus can also lead to nausea, vomiting, anorexia, aspiration, and malnutrition.
Surgery in esophageal cancer is now primarily limited to patients thought to be
potentially resectable for cure. Radiation with or without chemotherapy is still frequently used for palliation of dysphagia but can be complicated by esophagitis, strictures, and more importantly, does not provide immediate relief of dysphagia. These limitations have led to the development of endoscopic modalities to treat the malignant
dysphagia associated with cancer of the esophagus.
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DILATION
Dilation of esophageal strictures has long been used as a temporizing endoscopic
therapy for malignant dysphagia. Dilation can provide immediate improvement in swallowing and may be used prior to more definitive therapy such as surgery, radiation, or
other endoscopic interventions. However, dilation is not a permanent solution to maintain luminal patency. Further, malignant strictures are complex and often have an unpredictable response to dilation in terms of relief of symptoms and duration of relief of
symptoms.3 Thus, endoscopic dilation of esophageal cancer should be used as a bridge
to a more permanent relief of a patients dysphagia through other methods.
Endoscopic dilation is performed with either polyvinyl wire-guided dilators or
through the scope (TTS) balloon dilators (Figure 15-1). A third type of dilator, the
Maloney dilator, is passed without endoscopic guidance, should be avoided in malignant
strictures due to the complexity of these strictures and potential increased chance for
perforation.
Savary dilators are passed over a wire that is placed under direct vision at the time of
endoscopy. The endoscope first is negotiated through the tumor and the wire is placed
through the working channel of the endoscope. The dilators are then passed over the
wire through the tumor, slowly and progressively enlarging the esophageal lumen by
using larger diameter dilators. Size of dilators used is primarily an estimation by the
endoscopist knowing that dilation of the luminal diameter to 13 to 15 mm is often
needed to provide symptomatic relief of a patients dysphagia. Tight complex strictures
and particularly strictures through which the guidewire but not the endoscope can be
passed should be performed under fluoroscopy to improve the safety of the procedure.
Radial TTS balloon dilators may be passed under endoscopic visualization through
the malignant stricture and then dilated to a predetermined size and force. Theoretical
advantages are that the force with which the TTS balloon is applied is in a radial direction without an additional longitudinal force seen in wire-guided dilation.4 As with
wire-guided dilation, more than one dilation session may be needed to stretch the luminal diameter to provide adequate improvement in swallowing.
Dilation is generally safe with complication rates of 2.5 to 10%, comparable to the
dilation of benign strictures.5 Other than as a bridge to more permanent treatment, dila-
287
THERMAL TECHNIQUES
Thermal techniques, particularly laser therapy, through the endoscope have been
used to palliate advanced cancer for over 20 years. BICAP, tumor probes, argon plasma
coagulation, and carbon dioxide lasers have been used to treat esophageal carcinoma, but
by far the most experience and data are with the neodymium:yttrium aluminum garnet
(Nd:Yag) laser.
Laser is a noncontact light treatment that is applied through the working channel of
the endoscope and has thermal and photobiochemical effects on the cancerous tissue.
The depth and degree of tumor ablation is dependent on power of the laser, duration of
exposure, tissue absorption of the light, and the distance of the laser from the tissue.6
Practically, treatment is applied with the use of a Nd:YAG probe passed through an
endoscope and the laser light is applied with direct endoscopic visualization. Treatment
that begins distal to proximal is preferred, even if dilation is needed prior to treatment.
However, proximal endoscopic laser treatment can be useful and may be the only endoscopic method possible when the lumen is nearly completely obstructed. Treatment is
applied in a circumferential manner, slowly enlarging the esophageal lumen. Total energy is recorded during treatment but endoscopic evidence of a coagulation effect and then
vaporization of the tumor tissue is the primary way that determination of adequate
treatment is made. The goal of treatment is vaporization of tumor tissue to restore luminal integrity. Repeat treatment 24 to 48 hours after the first treatment is often needed
to debride necrotic tumor tissue with the endoscope and possibly apply more therapy.
Success of laser therapy, with resumption of oral intake as the marker of success, is
approximately 85% with success rates ranging in the literature from 64% to 100%.7-10
The tumor length and circumference as well as degree of tumor obstruction affect the
ability of Nd:YAG laser to successfully palliate dysphagia secondary to esophageal cancer.8 Laser therapy is most suited for short tumors, less than 5 cm, exophytic discrete
strictures, and proximal lesions that are not suitable for other modes of endoscopic treatment, particularly esophageal stenting. Complication rates range from 1% to 15% with
perforation, creation of a tracheo-esophageal fistula, and bleeding being the most common problems associated with laser treatment.11 The greatest limitation is the need for
frequent treatment sessions with dysphagia free intervals lasting only 2 to 4 months. If
laser is the sole palliative treatment modality the patient is committed to multiple endoscopies and repeat laser applications.
Argon plasma coagulation (APC) is a relatively new endoscopic thermal technology
that causes tissue coagulation and destruction through a noncontact probe that transfers
energy via electrically charged argon gas. The largest study examining endoscopic APC
treatment of malignant dysphagia had a success rate of 84%, approaching the success
found with Nd:YAG laser.12 However, APC treatment requires even more frequent sessions and is limited in the palliative treatment of esophageal cancer because of limited
288
Chapter 15
tissue destruction depth to only 2 to 3 mm.13 No data exists directly comparing APC to
Nd:YAG laser for the palliative treatment of malignant dysphagia.
While laser or APC treatment are both limited as a primary treatment to treating
short, discrete strictures or proximal tumors, both have been found to be useful when
used as adjuvant therapy, particularly in association with esophageal stents. Laser therapy is effective in treating tumor ingrowth or tumor overgrowth at the proximal or distal
aspect of the stent by recanalizing a lumen through the stent. Laser treatment in a stent
is safe, extremely easy to perform, and possibly more cost-effective than placing a second
esophageal stent within the lumen of the original stent.
PHOTODYNAMIC THERAPY
Photodynamic therapy is another thermal technique used in the palliation of
esophageal cancer that couples the use of a photosensitizer with the delivery of light
directly to the tumor resulting in selective destruction of tumor cells. In the treatment
of advanced esophageal cancer, photosensitizers are usually porphyrin based, the most
commonly used being porfimer sodium or Photofrin II (Axcan, Birmington, Ala).
Photosensitizers are selectively taken up and concentrated in tumor cells, resulting in a
high therapeutic index. Reasons why photosensitizers are retained to a greater degree in
tumor cells is complex and not completely understood. Theories include that larger
amounts of porphyrins are thought to pass through a tumors neovasculature, the lymphatics of tumors may poorly drain the sensitizer, and transport of the sensitizer into
tumor cells may be greater because photosensitizers bind to low-density lipoproteins
which preferentially are carried into the tumor cells.14
Activation of the photosensitizer is performed by delivery of light to the area of the
tumor. In esophageal cancer this is performed via laser light carried to the tumor by a
flexible endoscope and applied with a cigar-shaped cylindrical diffusing fiber that allows
light to be transmitted circumferentially within the esophagus. The sensitizer is given
intravenously 48 hours before the delivery of the light with the endoscope. Red light
with a standardized wavelength and light dosimetry have been developed for advanced
esophageal cancer to produce a light penetration of approximately 5 mm resulting in
maximal tumoricidal efficacy while minimizing complications.15
Delivery of the light to the sensitized tissue causes generation of oxygen radicals and
molecular oxygen. The generated oxygen radicals affect cell plasma and organelle membranes particularly in mitochondria resulting in a direct cytotoxic effect. Tumor vasculature endothelium is thought to be affected greater than normal tissue resulting in vasoconstriction, thrombosis, and tumor death as a result of hypoxia.14 Besides direct tumor
cell death and tissue necrosis, PDT is thought to have other antitumor effects including
induction of apoptosis, stimulation of the immune system, and an overall increased
cytokine based inflammatory response.
The length of the tumor is treated in as many stages as needed at the first treatment
session, usually with the use of a 2.5 or 5.0 cm cylindrical fiber passed through the endoscope. The tumor is treated in a distal to proximal step-wise fashion with attempts to
ensure the length of the tumor has been exposed to the laser light. Forty-eight hours
after the first treatment an upper endoscopy is repeated to debride necrotic tumor and
retreat any residual tumor that is seen (Figure 15-2). Timing of retreatment is not standardized and should be based upon the recurrence of symptoms, the physical amount of
tumor recurrence, and other treatment options that may be available to the patient.
289
Through anecdotal experience it has been shown that multiple treatment sessions over a
period of months may be applied safely and effectively.
Multiple nonrandomized retrospective studies have stated success rates for PDT in
esophageal cancer to range from 60% to 90% with success usually defined as improvement in dysphagia scores.10,16 Multiple sessions are often required because of return of
dysphagia symptoms with duration of each treatment session ranging from 9 to 14
weeks.17,18 No definitive improvement in survival has been found with the use of PDT.
PDT has been found to be successful and safe before and after radiation/chemotherapy
and successful in treating tumor overgrowth and ingrowth within esophageal stents.19
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The most frequent toxicity associated with PDT is skin photosensitivity. This is secondary to the propensity for the photosensitizer to collect in the skin and then be activated upon exposure to sunlight. Risk for skin photosensitivity is generally limited to the
first 4 weeks post-treatment. Exposure to sunlight usually results in mild erythema and
sunburn but second degree burns and blistering burns are frequently reported. Patient
education is essential and patients should be instructed to avoid direct sunlight for the
first 30 days after each treatment with protective eyewear, headwear, and clothes to be
worn when going outside for any extended time period.
Mild procedure related toxicities with PDT include chest pain, nausea, and occasional self-limited fevers secondary to inflammation. Transient increase in dysphagia is
common secondary to debris, necrosis, and swelling immediately after therapy. This is
easily treated 48 hours after treatment by endoscopic clearance of the necrotic debris.
Major complications include esophageal stricture or fistula with incidence of postPDT stricture formation ranging from 0% to 21% and fistula formation from 0% to
14%.14 As more experience has been gained with PDT and uniform light dosimetry is
applied these complication rates have become less frequent. Fistula formation can be further lessened through correct staging with endoscopic ultrasound and bronchoscopy if
tracheal involvement is suspected. Treatment of post-PDT strictures is easily managed
with endoscopic dilation while fistulas require a covered esophageal stent for treatment.
Two randomized studies have compared PDT to Nd:YAG laser for the palliation of
advanced esophageal cancer.20,21 These studies showed better and longer relief of dysphagia with PDT (84 days vs 53 days) as compared to laser. Mild toxicities, particularly photosensitivity, were more common with PDT, but major complications (most
notably perforation) occurred more frequently with laser treatment.
Advantages of PDT are ease of use and relatively low serious complication rates.
PDT is especially useful for proximal esophageal cervical tumors and gastroesophageal
junction tumors where it is sometimes difficult to place an esophageal stent. Further, as
291
opposed to esophageal stents, previous chemoradiotherapy does not increase or affect the
complication rate of PDT. PDT is also very efficient for near complete obstruction of
the lumen in which case only the small PDT fiber needs to be advanced through or into
the tumor.
Major drawbacks of PDT include the need for multiple repeated treatments and
cost, with PDT being arguably the most expensive of modalities available for esophageal
cancer dysphagia palliation. Finally, the skin photosensitivity and the need to avoid sunlight for 4 to 6 weeks is an important aspect to consider in patients with average survival
rates of 6 months or less.
ESOPHAGEAL STENTS
The first endoscopic stenting of malignant dysphagia was performed with plastic
endosprosthesis. The originally designed plastic stents were difficult to deploy and
extremely rigid leading to an unacceptable high complication rate. Further, the original
plastic stents had a limited diameter leading to only minimal improvement in a patients
dysphagia.
Since the early 1990s, self-expanding metal stents (SEMS) have become the primary
stents used to palliate inoperable esophageal cancer. Placement of the various types of
SEMS is based on the same principles using a combination of endoscopy and fluoroscopy. Endoscopy should always be performed first to measure the length of the
tumor, determine the position of the tumor (cervical, midesophagus, or crossing the gastroesophageal junction), and estimate the luminal diameter. Selection of stent length
should be at least 2 to 3 cm above and below the proximal and distal aspects of the
tumor. Cervical tumors within a few centimeters of the upper esophageal sphincter are
thought to be a relative contraindication to stent placement because of the possibility of
respiratory compromise and permanent foreign body sensation caused by the proximal
aspect of the stent. Recently however, groups have reported acceptable success rates with
minimal complications when stenting cervical tumors.22 Stent diameters range from 16
to 24 mm with a general rule to use smaller diameter stents for midesophageal tumors
to prevent perforation and larger diameter stents in GE junction tumors to prevent stent
migration.
Esophageal stents come with or without polyurethane coverings to prevent the late
complication of tumor ingrowth through the stent. Care should be used in placing covered stents across the GE junction because of increased chance of migration without the
bare metal to embed into the esophageal mucosa and submucosa to hold the stent in
place.23 Studies have shown that the newer covered stents, which are of greater central
and proximal diameter and have areas of uncovered stent on both ends of the stent, do
not have an increased migration rate even when crossing the cardia.24
If a malignant stricture is present at the time of endoscopy, it may need to be first
dilated to 9 to 11 mm prior to the placement of the stent so that the delivery system that
measures from 7 to 11 mm can pass through the stricture. Before removing the endoscope the proximal and distal aspects of the tumor are marked to aid in placement of the
stent under fluoroscopy. This can be performed with external markers, internal clips
placed onto the esophageal mucosa, or a contrast agent that can be injected into the submucosa just above and below the tumor. A stiff guidewire is then placed through the
endoscope across the stricture into the stomach, and the endoscope is subsequently
removed leaving the wire in place. The stent is placed under fluoroscopic control, ensuring the stent extends 2 to 3 cm above and below the malignant stricture to allow com-
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plete covering of the tumor (because of the shortening that occurs in some stents after
deployment). Based upon the type of stent used repositioning of the stent can be performed during or just after deployment. The endoscope can be passed back into the
esophagus to check the proximal position of the stent (Figure 15-3). SEMS then fully
expand to their desired maximal diameter, expanding the esophageal lumen over the
next 1 to 2 days. This ensures maximal palliation while lessening the immediate complications that were seen with the rigid plastic stents. On Day 0 or 1, chest x-ray/abdominal films or barium swallow may be performed to verify correct stent location and
improvement in luminal diameter (Figure 15-4).
293
Available SEMS in the United States include the Wallstent II (Microvasive, Natick,
Mass), the Ultraflex stent (Microvasive) and the Gianturco Z-stent (Wilson Cook
Medical, Winston-Salem, NC) (Figure 15-5 and 15-6). The majority of stents are covered as this significantly decreases the rate of tumor in-growth through the stent and the
need for re-intervention because of recurrent dysphagia. Stents are still available in
uncovered versions for tumors crossing the GE junction or tumors causing external
compression to potentially lessen the migration rate. Though each patient must be individualized generally the larger stents should be placed across the GE junction to avoid
migration and the smaller diameter stents should be placed in tight midesophageal strictures to avoid the possibility of perforation with stent expansion. Finally, because of the
significant amount of reflux associated with stents placed across the GE junction a
recently developed version of the Z-stentthe Dua antireflux stenthas become available (Figure 15-7). This stent has a valve or windsock on the distal aspect of the stent,
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295
which theoretically reduces the amount of acid reflux across the stent into the esophagus post stent deployment.25
A recent study compared the various makes of esophageal stents (Ultraflex stent, Zstent, and Flamingo Wallstent [available in Europe]) for efficacy and safety in 100 consecutive patients.26 Each stent type resulted in a significant improvement in dysphagia
and similar reintervention rates of 24% to 33%. There was no statistical difference in
complication rates between the different stents, but a trend of higher major complications of 1.5 to 2 times was seen with placement of the Z-stent. A smaller comparative
study found Ultraflex stents to have lower procedure-related mortality and complication
rates when compared to esophageal Wallstents.27
A recently developed self-expanding plastic stent (Polyflex [Rusch, Duluth, Ga]) has
been shown to have similar success, complication, and re-intervention rates compared to
historical numbers reported with SEMS.28 However, data on self-expanding plastic
stents are still very limited with no direct comparison to metal stents.
Multiple series exist which examine patient outcomes using esophageal self-expanding metal stents to treat malignant dysphagia. Examining the larger studies in the literature technical deployment is successful in greater than 95% of cases. Dysphagia scores
routinely improve in 75% to 95% of patients, with dysphagia scores improving a mean
of 2 in most studies using a 4 or 6 point scale.9,10,13,29,30 Successful palliation is near
immediate in the first 24 to 48 hours poststent insertion.
Chest pain postprocedure occurs in almost 100% of patients secondary to the expansile force of the stent. Major immediate and early complications include perforation, fistula formation, bleeding, and aspiration of gastric contents. On average major complications occur in as many as 10% to 20% of patients after having an esophageal stent
placed.9,10,13 Studies have shown an increased major complication rate in patients who
have received prior or are receiving concurrent chemotherapy and/or radiation, particularly an increased perforation rate because of the presumed weakened tissues.31,32
Later complications include stent migration and tumor ingrowth and overgrowth.
Stent migration has been reported to occur in 0% to 6% of placed SEMS with increased
migration rates when the stent is placed across the cardia.9,10,13,29,30 Migration is likely
increased with covered stents, but if larger diameter covered stents are used migration
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rates of covered stents do not appear to be significantly increased. With uncovered stents
tumor ingrowth was common, 8% to 35%, with resultant recurrent dysphagia and need
for repeat intervention to maintain luminal patency.9,10,13 The problem of tumor
ingrowth has been for the most part solved with the increasing use of covered stents.
With covered stents, tumor overgrowth at the distal or proximal edge of the stent has
become the more frequent problem. This may be due to infiltration of the tumor over
the edge or through the uncovered aspect of the stent. Benign epithelial hyperplasia,
granulation tissue, and tissue fibrosis where the edge of the bare stent contacts the
esophageal mucosa can also lead to stent obstruction. Other causes of dysphagia are food
impaction within the stent and angulation of the stent as it crosses the GE junction. Reintervention with dilation, second stent placement, or application of thermal techniques
occurs at a mean of 80 days after stent placement, but with proper patient screening and
stent selection reintervention is not needed in the majority of patients for more than 120
days.
Survival poststenting has been found to be between 3 and 6 months in the majority
of studies with mortality related to the advanced state of the cancer. Thirty day mortality post-stent placement has been reported to be as high as 26%, with up to 3% to 16%
mortality directly attributed to the stent placement.13,33,34
SEMS has a distinct advantage over other endoscopic modalities in that stents can
successfully treat tracheo-esophageal fistulas and obstruction of the esophageal lumen
secondary to extrinsic compression from metastatic tumor, mediastinal masses, or lymphadenopathy. Placement of a covered metal stent with the covered aspect of the stent
sealing the fistula has become the treatment of choice in patients with esophageal cancer associated with a fistula. Studies are small but success rates in sealing a fistula have
been found to be 90% or greater with covered esophageal stents placed under combined
endoscopic and fluoroscopic control.32,34,35 Dysphagia scores decrease post-stent placement in patients with external compression, but not to as great a degree as found when
stents are placed to relieve intrinsic malignant blockage of the esophagus. The main
complication rate of placing a stent for extrinsic compression is stent migration due to
the fact that no luminal tumor is present to better anchor the stent within the esophagus.
Four studies have compared thermal therapy, primarily Nd:YAG laser to esophageal
stent therapy in treating malignant dysphagia.36-39 Two studies show a greater degree of
improvement in dysphagia with SEMS while two other studies showed no difference in
efficacy between esophageal stents and laser therapy. More complications overall were
found in patients treated with laser than stents and the use of laser therapy required
more frequent endoscopic reintervention to maintain swallowing. One of four studies
did show a survival advantage with laser and a faster decrease in health related quality of
life in patients who had SEMS placed. The stent group in this study had a median survival of only 4.7 weeks with a poor improvement in dysphagia post-stent likely secondary to selection of patients with a very poor pretreatment health and performance status.
297
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299
be deployed with overlapping of the two stents, again ensuring there is stent proximal
and distal to the tumor.
Data on outcome of SEMS placed by endoscopy in patients with malignant gastroduodenal obstruction is limited by the fact that studies in the literature are retrospective
and small (less than 50 patients).40,43-50 Technical placement of the stents is almost
always successful with success rates of 90% to 100%. Larger studies report improvement
in symptoms and improvement in diet in approximately 80% of patients. Almost all
patients are able to tolerate some oral intake after stent placement, but not necessarily a
full solid diet. Studies in which weight and Karnofsky score have been measured have
found a slight increase in both after placement of an enteral stent for malignant upper
tract obstruction.
Immediate complications are primarily bleeding and perforation. Reported rates of
immediate complications are less than 5%,40,43-50 but are likely under-reported in the literature and slightly higher in practice. Late complications include tumor overgrowth
and ingrowth. This may lead to the need for endoscopic reintervention in approximately 15% to 25% of patients with enteral stents. Reintervention usually consists of a second stent placed across the tumor or restoration of the lumen with thermal methods
such as APC or Nd:YAG laser. The other main late complication is stent migration.
SEMS migration may be asymptomatic or lead to bleeding or perforation as the
edges/ends of the stent contact normal mucosa. Obstruction because of altered angulation of the stent in the lumen may occur as the already expanded stent migrates distally
in the small intestine. Stent migration occurs in <5% of cases and is a less frequent problem than the migration seen with esophageal metallic stenting.
Two studies have compared surgical bypass with enteral stent placement for gastric
or duodenal obstruction.45,51 One study showed similar survival in both groups of 90
days. Patients who had enteral stents placed had less inpatient hospital days and lower
overall hospital charges than the surgical group. The second comparative study found a
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lower 30-day mortality rate with stents as opposed to surgery (0% vs 18%). Limitation
of these studies must be noted as both studies were retrospective and had very small
amount of patients. Likely no accurate prospective study will be performed comparing
surgical versus endoscopic palliation of upper GI obstruction as surgery remains the first
treatment of choice in a patient group with a high performance status and relatively
extended expected survival. Enteral stenting is performed more frequently in patients
who tend to be more ill, more symptomatic, have a shorter expected survival, and who
would not tolerate surgery.
Finally, survival postenteral stenting is short, with median survival ranging from 7 to
20 weeks in most studies.40,43,45-47,49 As with methods to maintain esophageal lumen
patency, enteral stenting is a palliative modality in patients with advanced gastric or pancreato-biliary malignancies who cannot undergo surgery for cure or palliation. No data
have shown that enteral stenting has a definitive impact on survival.
COLORECTAL OBSTRUCTION
Colon cancer may present with complete or near complete luminal obstruction in up
to 30% of patients.52 Patients who present with obstruction often have advanced disease
and are usually found to have Dukes stage C or D disease at the time of surgery.53
Metastatic disease, peritoneal carcinomatosis, and extrinsic compression from genitourinary tumors may also cause malignant large bowel obstruction.54 Patients with malignant obstruction of the colon will frequently present malnourished, dehydrated, and
severely ill.
The traditional therapy of malignant large bowel obstruction, like that of upper GI
obstruction, is surgery. The three-stage surgery for obstructing colon cancer decompressing colostomy, a second operation for resection of the tumor, and a third to reconnect the large intestinehas largely been discontinued because of the number of procedures, time needed for treatment, and high associated morbidity and mortality.
Presently, a two-step surgery may be performed: a Hartmanns procedure, initially performed for decompression and resection, followed by a second surgery to restore bowel
continuity. Finally, a one-step procedure can be performed with primary resection and
anastomosis on an unprepped bowel, if extensive perioperative cleansing of the bowel
can be done. However, overall morbidity is 40% in cases when surgery is performed on
an unprepped obstructing colon cancer.55 Mortality ranges from 5% to 32% for surgical procedures for these patients.55,56 Appropriate patient selection is important with
worse outcome associated with patients who have advanced disease, poor performance
status, and associated diffuse disease such as ascites or carcinomatosis.42
Due to the morbidity and mortality associated with the surgical treatment of acute
malignant large bowel obstruction less invasive modalities have been developed to deal
with the obstruction and restore luminal patency. The two main methods used are laser
therapy through the colonoscope or the placement of colonic stents via the endoscope
with fluoroscopic guidance or with fluoroscopy alone. Nonsurgical treatment, particularly stent placement, has become more frequent in both palliative treatment of colorectal obstruction and as a temporizing resolution of the obstruction so the patient may
be subsequently prepped for a one-step surgery.
Laser therapy, usually Nd:YAG has been used to recanalize the colonic lumen in a
method similar to how laser is used to palliate nonresectable esophageal cancer. A laser
probe is passed through the working channel of a colonoscope. Thermal energy provided under direct endoscopic visualization is used to partially ablate the tumor in a cir-
301
cumferential manner, creating a workable colon lumen so that the obstruction can be
relieved.
Success rates of treating obstruction in colon cancer with laser are 75% to 90% with
relief of obstructive symptoms and the ability to pass stool.54 Repetitive sessions are
almost always needed because of recurrent symptoms. Complication rates range from
2% to 15% with the most common complications being bleeding or perforation, both
of which can require urgent surgery. Limitations of laser for obstructive colon cancer are
the need for multiple sessions, often in frail patients; limited success with larger and
longer tumors; and finally, laser therapy is more technically difficult and less successful
in tumors proximal to the sigmoid colon.
SEMS are increasingly being used to acutely decompress the colon in patients with
either obstructing colon cancer or metastatic and extrinsic tumors causing large bowel
obstruction. Technique for deployment is similar to deployment in the upper digestive
tract and like upper tract tumors colonic stents were originally primarily placed by interventional radiologists because of the lack of a colonic stent that could be placed through
the colonoscope. Data concerning the placement of colonic stents are found in both the
radiology and gastroenterology literature and whether colonic stents are placed by radiologists or gastroenterologists is institution based. Three colonic stents are available in
the United States. The Enteral Wallstent is the same stent used for stent placement in
the upper GI tract and is the only colonic stent that has a delivery system that that can
pass through the working channel of a colonoscope. The colonic Z-stent (Wilson-Cook
Medical) and the Bard (Tempe, Ariz) colonic stent do not pass through the colonoscope,
but are placed under fluoroscopy sometimes with a colonoscope alongside the stent and
its delivery system to provide some endoscopic visualization. Placement of the enteral
Wallstent through the colonoscope has the advantage of direct visualization of the tumor
and the stent at deployment. TTS stents improve the mechanical advantage during
placement and allow placement of colon stents in the more proximal colon. Placement
of colonic stents without endoscopic guidance is limited to the very distal colon because
of the inability of the delivery system with fluoroscopy alone to maneuver through the
sigmoid colon.
Outcome data in the endoscopic and radiology literature derives mostly from retrospective series of 80 patients or less. Technical success in placing colonic metal stents can
be achieved in greater than 90% of patients. Clinical success, defined as relief of obstruction in palliative cases or as a temporizing measure prior to surgery, approaches
90%.44,50,54,57
The largest prospective study examining colonic stents to treat obstruction as a
bridge to surgery found that 85% of patients could undergo a primary anastomosis
without the need for a colostomy after stent placement. Only 41% of patients could be
treated successfully with one operation if surgery was performed without prior colonic
stenting.58 Further, complications and in-patient stay were less when colonic obstruction
was first treated with a SEMS. A review of all publications concerning colonic stents
published in the literature from 1990 to 2000 revealed an 85% technical success rate and
95% of stent patients able to undergo a one-stage operation.57 Clinical success rates with
relief of the obstruction for patients treated for palliation were in the range of 85% to
95%.57 Stent patency at 3 and 6 months has been found in greater than 90% of
patients59 and many reports exist of palliation secondary to colon stent lasting greater
than 1 year after the placement of the stent.
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Placing stents in the colon can be more challenging than in the upper GI tract
because of the angulation and tortuosity of the colon. Though the through the scope
Enteral Wallstent allows placement of a colonic stent in the proximal colon, the majority of data still exists on stents placed in the distal colon. Whether success and complication rates are equal for stents placed in the proximal colon is unknown. Perforation
occurs in 0% to 7% of cases either at the time of deployment due to stent expansion or
later secondary to stent migration.57 Predilation of a malignant colon stricture may
increase the rate of perforation and should be avoided. Migration occurs in 3% to 22%
of colon stents placed.57 Migration of a stent may be asymptomatic, result in perforation, or result in recurrent obstruction because the tumor is no longer stented or because
the stent itself causes physical obstruction at an acute angulation of the colon. Bleeding
secondary to stent insertion occurs in 0% to 5% of cases and reobstruction of the lumen
by tumor occurs in 0% to 15% of patients.57 Tumor ingrowth or overgrowth may be
managed with repeat stenting or with endoscopic guided laser treatment. Complications
unique to colon stents placed distally in the rectum are tenesmus and incontinence.
Since there has been a noted increased risk of perforation with dilation prior to the
placement of a colon stent, a number of researchers have found success in treating malignant colon obstruction with a combination of Nd:YAG laser and SEMS.60,61 In these
studies Nd:YAG laser photoablation was used to initially restore a completely obstructed or near completely obstructed lumen. This allowed passage of a guidewire and then
stent delivery system through the previously blocked lumen. Success rates of laser plus
stenting have equaled the success of laser or SEMS alone without any increase in complication rate.
CONCLUSION
Endoscopic palliation can provide a less invasive and highly successful means to treat
GI obstruction secondary to advanced malignant disease. The use of various endoscopic thermal treatment methods and enteral stenting has expanded from clinical tertiary
research centers to general clinical practice. Future challenges are to design and perform
prospective trials that compare the various endoscopic methods to palliate esophageal
cancer and to better compare endoscopic to surgical palliation for upper and lower tract
cancer. This will enable the practicing clinician the ability to choose the safest, most efficacious, and even most cost-efficient method to restore GI luminal patency, and provide
symptomatic palliation for their individual patient.
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59. Camunez F, Echenagusia A, Simo G, et al. Malignant colorectal obstruction treated by
means of self-expanding metallic stents: effectiveness before surgery and in palliation.
Radiology 2000;216:492-497.
60. Tack J, Gevers A, Rutgeerts P. Self-expandable metallic stents in the palliation of rectosigmoid carcinoma: a follow-up study. Gastrointest Endosc. 1998;267-271.
61. Spinelli P, Mancini A. Use of self-expanding metal stents for palliation of rectosigmoid
cancer. Gastrointest Endosc. 2001;203-206.
chapter
16
Gastrointestinal Cancer:
Diagnosis and Management
of Nutritional Issues
James S. Scolapio, MD and Alan L. Buchman, MD, MSPH
DIETARY
AND
NUTRITIONAL FACTORS
The evidence connecting food to gastrointestinal cancers is derived from epidemiological studies, case-control studies, and prospective observational studies. However, in
many of these studies, it is difficult to determine the independent effects of specific
nutrients given the many potential environmental contributors.1,2
Esophageal cancer has been linked to low intake of vitamin C, zinc, and selenium,
and a protective effect from eating fruits and vegetables has been reported in more than
one study. Meat and fish consumption has shown inconsistent associations with
esophageal cancer. Despite these positive observations, randomized controlled studies
from China have failed to show reduced esophageal cancer mortality in patients treated
with multivitamin supplements.3 As with other malignancies, obesity also appears to be
a risk factor.
It has been shown that foods high in salt or have been preserved with salt (eg, pickled, smoked foods) are associated with an increased risk of gastric cancer. Migration
studies from Japan have suggested a strong environmental component to gastric cancer.4
Preserved foods contain nitrates, which form N-nitroso compounds, including
nitrosamines, which may increase the risk of gastric cancer. There is consistent data that
fruit and vegetable consumption decreases the risk of gastric cancer. Also green tea has
been shown to be protective against gastric cancer in a number of studies.5
Pancreatic cancer has been linked to excess caloric intake and obesity. The intake of
fruits and vegetables may be protective.2 It has been widely believed that components
of the diet, including calcium,6-8 folate,9 and selenium10,11 may be protective against the
risk of colon cancer. However, diets with large components of fruits and vegetables,12,13
and fiber,14-16 as well as vitamin A, C,17 and E17,18 supplements do not appear to offer
any protective effect. Dietary fat appears to increase the risk of colon cancer in some
studies,19,20 but not in others in which the development of adenomas was used as a surrogate marker for cancer risk.14,21,22 Many case control studies have shown a link with
high animal (saturated) fat and increased total calorie intake and colon cancer,20,23,24
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although processed meats may be a higher risk.25 Several epidemiologic studies have suggested a relationship between increased body mass index (BMI) and development of
colon cancer.26,27 This association appears to be stronger for men than for women.28,29
Central obesity appears more closely linked to colon cancer risk than more peripheral fat
deposition. Insulin resistance with subsequent hyperinsulinemia may play a role.30 It
cannot be assumed the proof of association is proof of cause and effect. Establishment
of actual cause and effect for particular dietary factors in a prospective fashion is difficult and expensive. In addition, the use of adenoma development as a surrogate marker
for risk for development of more advanced carcinogenesis may be problematic.
The American Cancer Society recommends the following dietary guidelines for cancer prevention: 1) Choose most foods from plant sources, 2) Eat more than 5 servings
of fruits and vegetables each day, 3) Limit intake of high fat foods, particularly from
animal sources, 4) Achieve and maintain a healthy weight, and 5) Limit consumption of
alcoholic beverages.31
NUTRITIONAL ASSESSMENT
The nutritional management of a patient with gastrointestinal cancer first begins
with appropriate nutritional assessment. Multiple factors contribute to malnutrition in
cancer patients. Anorexia from tumor cytokines, intestinal obstruction, taste changes,
chemotherapy and radiation side effects, and depression are examples. Intestinal malabsorption also contributes to malnutrition in patients with certain types of gastrointestinal cancers. Extensive mucosal infiltrative disease, bacterial overgrowth, and surgical
resection all contribute to malabsorption and subsequent weight loss. Increased energy
expenditure has also been reported in patients with cancer.32 Nutrient deficiencies may
result in altered cellular immunity with increased risk of infection and delayed wound
healing following surgery. Therefore it is important to identify those patients that are at
potential risk of malnutrition. Management goals should then include correction of
nutritional deficits when possible. There is no gold standard or one laboratory test for
measuring the malnutrition of a patient. All current assessment methods may be affected by the underlying illness and not necessary reflect the nutritional reserve of the
patient. For example, serum albumin and prealbumin concentrations can be reduced
without a history of weight loss or other micronutrient deficiency as hepatic protein synthesis shifts to that of acute phase reactants. Likewise, extracellular fluid shifts can result
in low serum albumin and prealbumin concentrations without a clinical history to suggest weight loss or malnutrition. Delayed cutaneous hypersensitivity is an unreliable
marker of malnutrition since cancer and medications used to treat cancer can affect
results.
A complete history and physical examination is probably the best tool to access the
gross nutritional status of an individual patient (Table 16-1). Patients that have lost significant weight (defined as greater than 10%) and have had reduced oral caloric intake
over a 2- to 24-week period are at risk of both macronutrient and micronutrient deficiencies. It is known from clinical studies that cancer patients that have lost greater than
10% of their usual weight and have a reduced appetite have shorter median survival and
lower chemotherapy response.33 The important findings on physical examination,
besides an accurate weight, include loss of subcutaneous fat, muscle wasting, dependent
edema, and ascites. Subjective global assessment (SGA) is a clinical method for the evaluation of nutritional status, and includes historical, symptomatic and physical parameters of patients.34 The findings from a history and physical examination are subjectively
309
Table 16-1
NUTRITIONAL ASSESSMENT
History and Physical Examination
History
Physical examination
Anthropometrics
Ideal body weight
(IBW)
Muscle function
Midarm circumference
Triceps skin fold
Thickness
Laboratory Measurements
Nitrogen balance
Indirect calorimetry
Visceral proteins
Immune function
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Chapter 16
weighted to rank patients as well nourished (A), moderately malnourished (B), or severely malnourished (C). (Table 16-2) SGA has 80% reproducible results among multiple
observers.34
PHARMACOLOGICAL TREATMENT
Cachexia is a common and major complication of cancer. The severe loss of weight
and appetite can produce both physical and emotional disabilities. Cancer cells promote
the secretion of host-derived cytokines. Some of these cytokines can result in significant
lean tissue loss and depressed appetite. Those that have been studied more recently
include tumor necrosis factor alpha, interleukin-6 and proteolysis inducing factor.35
Medications including pentoxifylline, hydrazine sulfate, melatonin, thalidomide,
ibuprofen, and, more recently, infliximab have been used in an attempt to inhibit
cytokine-mediated cachexia. These treatments should still be regarded as experimental.
Appetite stimulants including dronabinol, corticosteroids and megestrol acetate
(Megace, Bristol-Myers Squibb, New York, NY) may be useful in some patients.36,37 The
administration of megestrol acetate (400 to 800 mg/day) may increase appetite, weight
gain (primary fat mass), and quality of life. However, improved morbidity and mortality have not been demonstrated with this treatment.37 Megestrol acetate comes in an oral
suspension that can be given once per day. It may cause adrenal suppression and exacerbate pre-existing diabetes. Thromboembolic events have also been reported in cancer
patients treated with 800 mg/day of megestrol acetate. The safest and most efficacious
dose is still somewhat controversial and therefore if used, it should be titrated to the lowest effective dose.
Cannabinoids and their derivative dronabinol may stimulate appetite and result in
weight gain in cancer patients.36 Dronabinol is approved by the FDA for treatment of
nausea and vomiting associated with chemotherapy. The dose used is 2.5 mg orally three
times daily, taken 1 hour after meals. Further controlled trails are needed to identify the
optimal dose and patient population that may derive the most benefit.
311
Table 16-2
kg
Increase
No change
Decrease
II. Physical
(for each trait specify 0=normal, 1+=mild, 2+=moderate, 3+=severe)
#
Loss of subcutaneous fat (triceps, chest)
#
Muscle wasting (quadriceps, deltoids, temporals)
#
Ankle edema, sacral edema
#
Ascites
#
Tongue or skin lesions suggesting nutrient deficiency
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NUTRITION SUPPORT
OF
313
SPECIFIC CANCERS
314
Chapter 16
Some cancers, including colorectal cancer, are treated with radiation therapy.
Although direct tumor treatment with the radiation is the goal, scatter radiation damage can occur. This is especially a nutrition concern when the small intestine is damaged.
Radiation enteritis can be classified as acute and chronic. By definition, acute is defined
as that occurring within the first 6 weeks of therapy. Acute injury to the small bowel is
usually self-limited and presents clinically with nausea and diarrhea. Acute injury does
not necessarily predict those patients that will go on to develop chronic radiation injury.
Chronic small bowel injury from radiation is marked by inflammation and fibrosis of
the small intestine. Fibrosis can result in intestinal obstruction and episodic bleeding.
Partial small bowel obstruction can result in bacterial overgrowth and diarrhea.
Treatment with broad-spectrum antibiotics may be helpful in decreasing diarrhea if bacterial overgrowth is the cause. Recurrent bowel obstructions can also result in inadequate
oral intake over time resulting in significant weight loss. The primary goal should be to
surgically correct the obstruction. Often surgeons are reluctant to operate given the
extensive damage of the bowel from the radiation, which is often not appreciated until
the time of surgery. Selection of an experienced surgeon in the area of radiation injury
is critical in the care of these patients. If patients are not surgical candidates, and they
are unable to take sufficient fluids and nutrients orally, then placement of a gastric or
jejunal feeding tube may be helpful. Often placement of a dual gastric-jejunal tube for
gastric venting and jejunal feeding is helpful. There is insufficient data to recommend
any specialized elemental formulas or glutamine for these patients. If patients cannot tolerate enteral feeding TPN may be required and can be used successfully provided
patients are monitored closely.44,45 In addition, glutamine has not generally been found
to be useful in the treatment of mucositis.46
PARENTERAL NUTRITION
Once nutritional support is deemed necessary, which route (parenteral vs enteral)
should be used? Indications for parenteral feeding usually include small bowel obstruction, which may develop in cancer patients because of tumor growth; severe diarrhea and
malabsorption during active disease and treatment; gastrointestinal hemorrhage; treatment for enterocutaneous or enteroenteric fistulae; and as supportive care in patients
that are severely malnourished (SGA C). TPN is not generally indicated in patients
that have a nonobstructive gastrointestinal tract or when the duration of nutritional
support is expected to be less than seven days.
It is thought that the gut atrophies in the absence of enteral nutrition. While this
may be the case in animal studies, the data in humans fail to support this concept.47 It
is commonly thought that in the absence of enteral nutrition, bacteria will translocate
across the intestinal epithelium, to the mesenteric lymph nodes, and into the systemic
circulationresulting in sepsis and multiorgan failure. Although this has been reported
in the rat model, it rarely occurs in humans.48 When bacterial translocation does occur
in humans, it is usually in the setting of small bowel obstruction and unrelated to the
route of feeding, and is usually clinically inconsequential.48
When is TPN appropriate for the patient with gastrointestinal cancer? TPN may be
indicated in patients with severe stomatitis from chemotherapy and/or radiation,
patients with intestinal obstruction either related to tumor or radiation therapy, and
severe malabsorption and/or diarrhea caused by radiation enteritis. Home TPN may also
be considered in such patients. However, Medicare guidelines specify that a permanently inoperative internal body organ (the intestine) be present. Permanence is defined as
315
at least 3 months. Therefore, Medicare and some insurance carriers will not pay for
home TPN in the patient when use will be less than 3 months either because of improvement in gastrointestinal function or death. There is no evidence TPN improves outcome
of chemotherapy or radiation-related treatment or patient survival with active cancer.
TPN is not appropriate in the patient that is expected to succumb within 3 months or
less. Patients who are cured of their malignancy, but left with short bowel syndrome or
severe radiation enteritis (about 5% of patients) may be candidates for lifetime TPN.45
FOR
Once it has been determined parenteral nutrition is indicated for a particular patient,
a route for delivery must be selected. Parenteral nutrition can be delivered via a peripheral or a central vein. Peripheral PN is generally used when short-term nutritional support is required (eg, <7 to 10 days). The peripheral access can sometimes be used to supply total nutritional needs (25 to 30 kcal/day), especially if a lipid emulsion is used.
Lipid emulsions are isotonic. Because of the hypertonicity of the dextrose, thrombophlebitis is a significant risk when concentrations above 10% are used. The amino
acid concentration in the TPN solution should also be 3.5% to ensure the solution has
~900mOsm. Heparin (1000 units/L) and hydrocortisone (10 mg/L) will reduce the risk
of thrombophlebitis. Central parenteral nutrition (CPN), more typically referred to as
TPN, is infused into a large central vein. Large veins such as the superior vena cava
(SVC) or the inferior vena cava (IVC) can tolerate a greater solution osmolarity (up to
1800 mOsm, typically 35% dextrose and 5% amino acids). It is important that the
catheter tip reside in either the SVC or IVC. Should the tip be located in a smaller vessel, catheter thrombosis could result when the hypertonic TPN solution is infused.
Catheter location within the right atrium may increase the risk of cardiac arrhythmia. A
catheter useful for TPN may include a percutaneously inserted central catheter (PICC)
that is typically inserted via the brachial (although occasionally the antecubital) vein,
and advance to the SVC. The risk of a pneumothorax can be avoided with this method
and therefore should be the choice of access in the authors opinion. A triple, double, or
single lumen (preferred) catheter inserted into the subclavian, internal jugular, or
femoral vain may also be used, provided the catheter tip is located within the SVC or
IVC. For longer-term use, it is typical that a single lumen Hickman, Broviac, Groshong
catheter, or a subcutaneous infusion port, be inserted. Regardless of the catheter type, it
is critical that a catheter lumen be reserved for the exclusive use of TPN to minimize
infection risk.
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IBW can be calculated using the following equations: 48 kg + 2.7 x number of inches over 60 inches in height (males) or 45 kg + 2.3 x number of inches over 60 inches in
height (females). Caloric measurement using indirect calorimetry is usually not needed.
A minimum of 200 g of dextrose is necessary daily to meet the needs of brain metabolism. The carbohydrate used in TPN solutions is dextrose monohydrate, which contains
3.4 kcal/mL.
Intravenous fat emulsion is typically used to supply 20% to 40% of the daily calories. Only 6% of daily calories are needed as lipid emulsion to prevent essential fatty acid
deficiency. Fat emulsions supply either 1.1 or 2.0 kcal/mL, dependent upon whether a
10% or 20% emulsion is selected. Fluid requirements can usually be met by using
1 mL/kcal or a 1.5 to 2.0 L TPN formula. Patients with cardiac or renal insufficiency
may require less and patients with significant diarrhea or fistula losses may require more.
Depending upon the specific order form used, one can order TPN either in terms of
absolute amounts of macromolecules (eg, dextrose, lipid, and protein) or by indicating
a total volume and final concentration of these TPN constituents. Electrolytes, minerals, trace elements, and vitamins can be written for using standard amounts (eg, multitrace elements and multiple vitamin solutions unless the addition of a specific nutrient
is required to correct or prevent a deficiency or withholding of a specific ingredient is
necessary in order to avoid potential toxicity). For example, a 70-kg man that requires
25 kcal/kg/day and 1.0 g/kg/day of protein for maintenance might receive the following
formula: 2 L of 20% dextrose (400 g, providing 1360 kcal) + 200 mL of 20% lipid
emulsion (400 kcal) with 3.5% amino acids (700 g). Again, depending upon the formulation capabilities of the hospital pharmacy, the complete solution can be provided
as a 3 (dextrose, lipid, and amino acids)-in-1 emulsion or as a 2 (dextrose, amino acids)in-1 solution, with the lipid emulsion hung in a piggybacked fashion. Initially, the TPN
rate should be relatively slow (eg, 40 mL/hour) and even slower in the malnourished
patient (see refeeding syndrome below). The rate can be advanced as rapidly as every 8
hours in a normally nourished individual without diabetes as long as the blood glucose
is <160 mg/dl. During continuous central TPN, the blood glucose should be determined every 6 hrs.
317
In general, electrolytes should be monitored daily the first few days of starting TPN
and then at least twice weekly. Acid/base disturbances can often be managed by increasing or decreasing acetate or chloride in the solution. Metabolic acidosis may be caused
by diarrhea and can usually be corrected by slightly increasing potassium acetate in the
solution. Hypochloremic metabolic alkalosis may result from nasogastric suction in the
absence of adequate replacement fluid. Elevated BUN may result because of the provision of insufficient fluid, excessive amino acid infusion, or renal insufficiency.
Mild elevations in the hepatic aminotransferases (ALT, AST), as well as the alkaline
phosphatase are often observed within 2 to 14 days of initiating TPN and should be
determined at baseline and subsequently on a weekly basis.49 These elevations are generally transient. More persistent elevation in ALT and/or AST may result from hepatic
steatosis from overfeeding or choline deficiency.49,50 Persistently elevated alkaline phosphatase may signify the development of biliary sludge, which will occur in virtually
100% of patients on TPN that are npo. It is unusual to see a rise in serum bilirubin as
a direct result of TPN.51 A rise in bilirubin is a concern, and other causes besides TPN
should be evaluated.
The serum triglyceride concentration should be monitored twice weekly during the
first week and weekly thereafter for the first 2 weeks in order to ascertain adequate clearance of the lipid emulsion. It should be obtained 4 to 6 hours after infusion of the lipid
emulsion has been completed. Although there is no clear evidence of the deleterious
effects of a serum triglyceride concentration <1000 mg/dL, it is generally recommended to decrease the infusion rate and/or volume of the lipid emulsion if the triglyceride
concentration is greater than 400 to 500 mg/dL; a concentration of >1000 mg/dL may
be associated with the development of pancreatitis.52
The human body adapts to starvation and weight loss by decreasing resting energy
expenditure. When massive amounts of carbohydrate are supplied to a malnourished
cancer patient in an overzealous attempt to renourish him or her, refeeding syndrome
may result.53 This potentially life-threatening complication of either TPN or enteral
nutritional therapy occurs when carbohydrate intake stimulates pancreatic insulin
release, which results in the flow of potassium and magnesium to the intercellular space,
which may result in cardiac arrhythmias. In addition, the demand for phosphate to produce ATP from the infused carbohydrate may result in hypophosphatemia with subsequent hemolytic anemia, seizures, rhabdomyolysis, and/or respiratory muscle dysfunction. In rare cases, respiratory failure may ensue. Prevention of refeeding syndrome can
be prevented by the slow introduction of carbohydrate, and the use of protein (amino
acids) and lipid. Small amounts of supplemental potassium phosphate and magnesium
may be helpful. Serum potassium, magnesium, and phosphate concentrations should be
determined daily or more frequently if necessary until the goal caloric support and a stable electrolyte pattern in the normal range can be achieved.
Infectious complications are also common in TPN-treated patients. There are 3 types
of catheter infections that can occur.54 The most common is catheter sepsis, whereby the
catheter tip becomes a nidus for bacterial adherence. Bacteria may reach the catheter tip
because of catheter contamination from the skin or the catheter hub (used when connecting infusion tubing to the catheter or directly injecting medications). The most
common organisms are generally skin flora, including coagulase negative staphylococci,
S. aureus, Klebsiella pneumonia, and E. coli. Such infections can often be treated without
the requirement for catheter removal using a 2-week course of systemic antibiotic therapy. Also a highly concentrated solution of vancomycin or amikacin (2 mg/mL) in 2 mL
of saline can be instilled into the catheter every 12 hours (antibiotic lock technique).55
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Should fungemia be identified, the catheter must be removed. Regardless of whether the
catheter is removed because of fungemia or refractory bacterial sepsis (sepsis syndrome
or the inability to relieve the febrile response after 48 to 72 hours of antibiotic therapy),
the patient should remain completely afebrile and have negative blood cultures prior to
insertion of a new central venous catheter.
Infection may develop surrounding the anchoring cuff of a subcutaneous tunneled
catheter. This type of infection is rarely associated with fever or leukocytosis, but is
invariably diagnosed by the presence of purulent drainage from the catheter skin exit
site. Often tenderness can be elicited over the catheter cuff. Coagulase negative staphylococci and S. aureus are the most common organisms involved. Approximately 50% of
the time, successful treatment of the infection can be achieved with 2 weeks of systemic
antibiotic therapy. If treatment of the catheter in situ is ineffective, the catheter should
be removed and a new catheter may be placed in a different site without delay in the
absence of systemic infection. Systemic antibiotics should however be continued for 5
to 7 days following catheter removal.
The subcutaneous catheter tunnel tract may also become infected. Although it is
usually difficult to culture an organism, S. aureus is most commonly recovered. Because
antibiotic penetration of the tunnel is poor, treatment consists of catheter removal in
addition to 1 week of appropriate systemic antibiotic therapy. In the absence of systemic
evidence of infection, a new catheter can be inserted in a different site without delay. In
order to help prevent the risk of infection, it is imperative that those caring for the
catheter learn appropriate catheter care technique. Virtually all catheter-related infections relate either to the skin entrance site or the catheter hub. These must be cleaned
appropriately before each use with a bactericidal agent such as povidone-iodine or
chlorhexadine; ethanol alone is insufficient. In addition, the skin surrounding the
catheter should be cleaned appropriately during dressing changes. We recommend the
use of small, sterile gauze covering, with a semipermeable dressing placed over the gauze
to anchor it to the skin. Semipermeable membranes alone have been associated with
increased infection risk in some studies. Dressings should be changed 2 to 3 times weeklymore often if the area becomes wet or dirty.
Catheter occlusion can take the form of either thrombotic or non thrombotic occlusion, and is generally manifested in difficulty with TPN or medication infusion. Routine
heparin flushes are a useful preventative measure. However, fibrin can still accumulate
and block the catheter tip. TPA 2 mg, infused in a 2 mL volume (in order to completely fill the catheter) if used within the first 24 to 48 hours, is often successful in dissolving the thrombosis.56 Following instillation of the TPA into the catheter, aspiration
should be attempted after 30 minutes. It may be necessary to repeat the procedure. In
the inpatient setting, the catheter is often simply removed and replaced. Although in the
outpatient setting, especially in the case of the short bowel patient, every attempt should
be made to preserve venous access sites.
Nonthrombotic occlusion may result from calcium-phosphate precipitates or lipid
accumulation. Either 0.2 to 0.5 mL of 0.1 N hydrochloric acid or sodium hydroxide
may be useful in clearing the obstruction, although occasionally the catheter will require
removal and replacement. Care should be taken to avoid the addition of too much supplemental calcium and phosphate simultaneously in the TPN solution. Because the solubility of calcium and phosphate in TPN is dependent on a number of factors, knowledgeable pharmacists should always prepare the formula.
319
EFFICACY
There is no gold standard or specific laboratory test to measure the efficacy of nutrition with either TPN or enteral feeding. Weight gain in the hospital during a 1- to 2week course of nutritional support is usually the result of fluid and not lean body mass.
Serum visceral proteins such as prealbumin can be measured and followed during the
course of therapy if desired. The half-life of prealbumin is 2 days, whereas the half-life
of albumin at 21 days is too long to be useful in the inpatient setting. It must be recognized that the serum concentrations of all visceral proteins, including prealbumin, may
be affected by many non-nutritional factors including intra- and extravascular fluid
shifts in the postoperative patient, or may be depressed because of the protein-losing
enteropathy seen in cancer or because of decreased synthesis as the liver turns towards
increased production of acute phase proteins during active disease. Although serum concentration of visceral proteins may guide nutritional therapy, they should be interpreted
with the caveats described above. It must also be recognized that normal visceral protein
synthesis cannot occur in the absence of sufficient energy intake because skeletal muscle
will be catabolized as a fuel source.
The nitrogen balance can also be determined if one has a laboratory to perform accurate measurements. A 24-hour urine collection is required. Total urine nitrogen (TUN)
is measured and subtracted from the nitrogen intake from TPN (or enteral nutrition for
that matter). An additional 2 g is subtracted to account for stool, sweat, and other insensible losses. It is assumed some 95% of nitrogen is generally absorbed and that the average amino acid or protein is 16% nitrogen. Therefore, in order to derive the nitrogen
intake, the grams of amino acids (or protein in the case of enteral feeding) are divided
by 6.25. If the TUN is not readily available, the urine urea nitrogen (UUN) can be
measured. If that is the case, 4 g should be added to the measured nitrogen excretion in
order to account for insensible losses and urinary nitrogen losses than are not in the form
of urea. Similar to visceral proteins, a positive nitrogen balance requires not only greater
nitrogen intake than excretion, but also an energy intake at least equal to energy expenditure. Maintaining a patient in positive nitrogen balance has been associated with better outcome and lower mortality.
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infusion gives the patient more freedom during the day to ambulate. Nocturnal infusion
may also help prevent TPN-associated liver disease and encourage eating during the normal day.
During the cycling process, the patient receives his or her prescribed TPN at a gradually increased rate over a progressively shorter period of time. For example, a patient
that receives a 3:1 emulsion containing 2 L of 20% dextrose, 3.5% amino acids, and 200
mL of 20% lipid emulsion over 24 hours (91 mL/hour) would have the same total volume infused over 10 hours (220 mL/hour) as a goal. In order to achieve that goal, the
infusion time is shortened by 2 to 4 hour increments during each subsequent 24-hour
period. For example, the TPN would be infused at 110 mL/hour for 20 hours, followed
by a tapering off of over 30 to 60 minutes. A gradual tapering off is required in order to
prevent hypoglycemia because endogenous insulin secretion increases significantly. This
can be done either by decreasing the infusion rate by 50% for 15 to 30 minutes and then
by another 50% for another 15 to 30 minutes before discontinuing the TPN.
Most pumps used in the home environment can be programmed to automatically
and gradually decrease the rate to zero over a 30 to 60 minute period. This time period
is not included in the overall infusion time calculation. During cycling of the TPN, the
blood glucose should be obtained 2 hours after starting the TPN, just before beginning
the taper period (to detect hyperglycemia) and 30 min after the TPN has been discontinued (to detect hypoglycemia). The blood glucose should always be obtained from a
peripheral vein opposite the side of the infusion in order to minimize the chance of contamination of the sample from residual dextrose, resulting in a falsely elevated concentration, and to avoid contamination of the catheter. If the blood sugar is >180 mg/dl,
regular insulin should be administered subcutaneously. The same amount can be added
to the TPN solution just prior to beginning the infusion on subsequent nights. Typically,
regular insulin is added 1 unit per 10 g of dextrose (eg, 2 L of 20% dextrose would
require 20 units/L or 40 units/bag) if necessary. If post-TPN hypoglycemia is encountered, the patient should be instructed to drink some sugar-fortified juice when the TPN
is discontinued and the taper period should be lengthened. Once the goal infusion rate
has been achieved (patients with cardiac or renal disease may not tolerate an infusion
over 10 to 12 hours and may require a slower rate), the TPN does not require ramping
up on subsequent nights.
It is strongly recommended that the home TPN patient receive his or her TPN
through a reputable home care company that has considerable experience in the care of
such patients; many do not, but welcome the care of such a patient because of the financial remuneration. It is also strongly recommended, because of the complexities involved
with HPN, that patients requiring this specialized therapy be referred to a center with a
physician experienced in the care of such patients. Because the patient at home should
be stable, minimal changes in the TPN prescription should be required. If frequent laboratory monitoring and changes in the TPN formulation are necessary, the patient is
probably not ready for discharge.
ENTERAL NUTRITION
In the absence of bowel obstruction, distal fistula, or toxic megacolon enteral nutrition is the preferred form of nutritional support for the cancer patient, provided the
patient consents to having a nasogastric or percutaneous placed feeding tube. For nasal
gastric feeding, small bore, 8 to 10 French feeding tube should be used rather than the
larger tube that is typically used for gastric decompression. Complications (discussed
321
below) are generally fewer with such a tube. Because of postoperative gastroparesis, jejunal feeding may be preferred in specific individuals. Tube placement should be verified
radiologically prior to feeding because physical examination, namely ausculatory confirmation, is often inaccurate for determining tube position. In general, feeding is begun
at a relatively slow rate (typically 40 mL/hour) and advanced every 8 hours until the goal
rate is achieved and if gastric residuals are <200 mL prior to each rate increase. However,
if a small bore feeding tube is used or if jejunal feeding is undertaken, it may be difficult
to aspirate and to determine an accurate gastric residual volume. In these patients,
abdominal pain, distention, and tenderness are used to determine enteral feeding tolerance. The presence or absence of bowel sounds may be helpful, but actually indicates
nothing more than an air-fluid interface and feeding can often be undertaken in the
absence of bowel sounds. In severely malnourished cancer patients, the formula infusion
rate should be increased more gradually to avoid refeeding syndrome (see above). In
addition, jejunal feeding in the postoperative patient should be started at as little as 10
mL/hour, although this can often be accomplished in the immediate postoperative
phase, and advanced as tolerated. Most isotonic formulas contain 1.0 to 1.5 kcal/mL
and include the protein content in this calculation.
The protein content varies among formulas. No formula provides sufficient free
water to meet the daily fluid requirement. Therefore, it is important that patients with
normal or increased fluid requirements receive at least the equivalent of 25% of the formulas volume as free water. For example, an additional 500 mL of free water should be
supplied to the patient that receives 2000 mL of formula daily. This can be provided in
2 to 4 divided doses as a bolus. This amount includes water used to flush medications
from the tube. Tap water is fine; sterile or distilled water is unnecessary.
To prevent aspiration, the patients head and shoulders should be elevated to 30 to
45 degrees at all times. The use of blue dye to detect aspiration should no longer be used,
since deaths from the blue dye have been reported.58 Gastric residuals should also be
checked every 4 hours and if <200 mL, the aspirated formula should be returned to the
tube as a bolus. The tube should be flushed with 30 mL of water after aspiration.
Accurate input and outputs should be recorded, and the patient should be weighed at
least three times weekly.
Occasionally, the nasogastric feeding tube may become clogged despite proper flushing as described. Often this is related to protein precipitates. Sugar-free decaffeinated
soda is often useful for dislodging this type of occlusion. Sometimes meat tenderizer
(papain) is necessary. One teaspoon of nonpotato flake papain meat tenderizer can be
mixed in the smallest amount of tap water required to dissolve it and instilled in the
catheter. The specific pancreatic enzyme preparations Pancrease (Ortho-McNeil,
Raritan, NJ) or Viokase (Axscan Scandipharm, Birmingham, Ala) can be mixed with
one crushed 324 mg sodium bicarbonate tablet in 5 mL of tap water, and instilled into
the feeding tube. It may be necessary to repeat the procedure. Some medications are not
compatible with enteral feedings; therefore, compatibility should be determined prior to
using the feeding tube for instillation.
Other complications of tube feeding include esophagitis, esophageal, and/or gastric
erosions or ulceration, or esophageal stricture or mucosal bridge formation. Esophageal
or gastric erosions may be evident within a week, although longer-term use is generally
required before clinically significant disease, including gastrointestinal hemorrhage, may
occur. In addition, nasal erosions and nasal cartilage sloughing may result from excessive
pressure on the nasal alae and cartilage; therefore, nasogastric feeding should be undertaken via the same nares for a maximum of 4 to 6 weeks.
322
Chapter 16
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20. Goldbohm RA, van den Brandt PA, vant Veer P, et al. A prospective cohort study on
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22. McKeown-Eyssen GE, Bright-See E, Bruce WR, et al. A randomized trial of a low fat
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23. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer. 1975;15(4):
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24. Giovannucci E, Rimm EB, Stampfer MJ, et al. Intake of fat, meat, and fiber in relation
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27. Ford ES. Body mass index and colon cancer in a national sample of adult US men and
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28. Terry P, Giovannucci E, Bergkvist L, Holmberg L, Wolk A. Body weight and colorectal
cancer risk in a cohort of Swedish women: relation varies by age and cancer site. Br J
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29. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical
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30. Giovannucci E. Insulin and colon cancer. Cancer Causes Control. 1995;6(2):164-179.
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32. Russell DM, Shike M, Marliss EB, et al. Effects of total parenteral nutrition and
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33. Dewys WD, Begg C, Lavin PT et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980;69(4):
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34. Detsky AS, McLaughlin JR, Baker JP, et al. What is subjective global assessment of
nutritional status? J Parenter Enteral Nutr. 1987;11(1):8-13.
35. Jatoi A, Jr., Loprinzi CL. Current management of cancer-associated anorexia and weight
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36. Herrington AM, Herrington JD, Church CA. Pharmacologic options for the treatment
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37. Loprinzi CL, Ellison NM, Schaid DJ, et al. Controlled trial of megestrol acetate for the
treatment of cancer anorexia and cachexia. J Natl Cancer Inst. 1990;82(13):1127-1132.
38. Kardinal CG, Loprinzi CL, Schaid DJ, et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer. 1990;65(12):2657-2662.
39. Satyanarayana R, Klein S. Clinical efficacy of perioperative nutrition support. Curr
Opin Clin Nutr Metab Care. 1998;1(1):51-58.
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41. Bozzetti F. Nutrition and gastrointestinal cancer. Curr Opin Clin Nutr Metab Care.
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42. Bae JM, Park JW, Yang HK, Kim JP. Nutritional status of gastric cancer patients after
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43. Jenkins DJ, Bloom SR, Albuquerque RH, et al. Pectin and complications after gastric
surgery: normalisation of postprandial glucose and endocrine responses. Gut. 1980;
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44. Jain G, Scolapio J, Wasserman E, Floch MH. Chronic radiation enteritis: a ten-year follow-up. J Clin Gastroenterol. 2002;35(3):214-217.
45. Scolapio JS, Ukleja A, Burnes JU, Kelly DG. Outcome of patients with radiation enteritis treated with home parenteral nutrition. Am J Gastroenterol. 2002;97(3):662-666.
46. Buchman AL. Glutamine: commercially essential or conditionally essential? A critical
appraisal of the human data. Am J Clin Nutr. 2001;74(1):25-32.
47. Buchman AL, Moukarzel AA, Bhuta S, et al. Parenteral nutrition is associated with
intestinal morphologic and functional changes in humans. J Parenter Enteral Nutr.
1995; 19(6):453-460.
48. Sedman PC, MacFie J, Palmer MD, Mitchell CJ, Sagar PM. Preoperative total parenteral nutrition is not associated with mucosal atrophy or bacterial translocation in
humans. Br J Surg. 1995;82(12):1663-1667.
49. Buchman AL, Ament ME. Liver disease and total parenteral nutrition. In: Zakim D,
Boyer TD, eds. Hepatology: A Textbook of Liver Disease. 3rd ed. Philadelphia: WB
Saunders; 1996:1812-1821.
50. Buchman AL, Ament ME, Sohel M, et al. Choline deficiency causes reversible hepatic
abnormalities in patients receiving parenteral nutrition: proof of a human choline
requirement: a placebo-controlled trial. J Parenter Enteral Nutr. 2001;25(5):260-268.
51. Scolapio JS, Tarrosa VB, Stoner GL, Moreno-Aspitia A, Solberg LA Jr., Atkinson EJ.
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325
52. Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am. 1990;19(4):783791.
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1990;14(1):90-97.
54. Buchman AL, Moukarzel A, Goodson B, et al. Catheter-related infections associated
with home parenteral nutrition and predictive factors for the need for catheter removal
in their treatment. J Parenter Enteral Nutr. 1994;18(4):297-302.
55. Messing B, Peitra-Cohen S, Debure A, Beliah M, Bernier JJ. Antibiotic-lock technique:
a new approach to optimal therapy for catheter-related sepsis in home-parenteral nutrition patients. J Parenter Enteral Nutr. 1988;12(2):185-189.
56. Atkinson JB, Bagnall HA, Gomperts E. Investigational use of tissue plasminogen activator (t-PA) for occluded central venous catheters. J Parenter Enteral Nutr. 1990;14(3):
310-311.
57. Scolapio JS, Fleming CR, Kelly DG, Wick DM, Zinsmeister AR. Survival of home parenteral nutrition-treated patients: 20 years of experience at the Mayo Clinic. Mayo Clin
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58. Maloney JP, Ryan TA. Detection of aspiration in enterally fed patients: a requiem for
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59. Sinclair JJ, Scolapio JS, Stark ME, Hinder RA. Metastasis of head and neck carcinoma
to the site of percutaneous endoscopic gastrostomy: case report and literature review. J
Parenter Enteral Nutr. 2001;25(5):282-285.
chapter
17
Chemoprevention for
Gastrointestinal Neoplasia
Paul J. Limburg, MD, MPH and Navtej Buttar, MD
INTRODUCTION
GI malignancies account for approximately 30% of all incident and 36% of all fatal
cancers reported each year.1 While early detection remains the cornerstone of prevention, chemoprevention is emerging as a complementary strategy. Within the GI tract
and elsewhere, carcinogenesis is thought to proceed through a multistep process in
which cellular growth becomes progressively dysregulated and ultimately results in
clonal evolution and expansion.2 Mutational (inherited or acquired) or non-mutational (epigenetic) events can lead to altered gene expression patterns.3 Aberrant protein
transcription or translation further disrupts normal cellular growth constraints. Once
independent in growth signaling, cells achieve limitless replicative potential. Additional
loss of usual adhesion and/or invasion controls affords the ability to breach the basement membrane.4
By definition, chemoprevention refers to the use of chemical compounds to prevent
invasion of dysplastic epithelial cells across the basement membrane (eg, blocking carcinogenesis at a preinvasive stage). In this chapter, general concepts of GI cancer chemoprevention are reviewed, followed by discussions of candidate agents by site. Basic
descriptive statistics are provided for context, and clinical trial data are emphasized
where available. Due to differences in the volume of site-specific chemoprevention
research conducted to date, esophageal and colorectal cancer chemoprevention are discussed in relatively greater detail than gastric, hepatobiliary, and pancreas cancer chemoprevention. Summary remarks are also provided that reflect the current state of the science in this rapidly evolving field.
328
Chapter 17
GENERAL CONCEPTS
AGENT IDENTIFICATION
Data from cell culture experiments, animal model systems, and epidemiological
investigations form the foundation for chemoprevention agent identification. Cell culture experiments can be used to initially screen compounds for potential effects on carcinogen synthesis, carcinogen activation, free radical scavenging, and DNA adduct formation, as well as carcinogenesis suppression at a postinitiation phase. In vitro studies
are also useful for testing the effects of candidate agents on specific molecular targets
and/or intracellular pathways. Animal model systems can be used to confirm and extend
results from cell culture experiments using several different approaches. Chemical carcinogens will induce tumor formation at most GI sites, but these highly artificial constructs are of relatively limited value for chemoprevention research. Transgenic and genemutant animals carry specific DNA alterations and more closely approximate the
human condition, at least for the subset of patients genetically predisposed to forming
GI cancers. Xenograft models permit direct evaluation of anticarcinogenic properties on
human tumor tissue, albeit in unnatural surroundings. Infectious organisms like H.
pylori) can stimulate tumorigenesis in rodents that strongly mimics human disease.
Lastly, surgically altered anatomy can promote inflammatory-mediated carcinogenesis in
select target organs, such as the esophagus. A partial listing of candidate chemoprevention agents that appear promising based on preclinical data is shown in Table 17-1.
With respect to interpreting data from epidemiological investigations, the following
factors are worthy of consideration: 1) presence or absence of a biologically plausible
rationale for the proposed anticarcinogenic effect, 2) consistency of the observed risk
association across studies, and 3) magnitude of the potential cancer prevention effect.
Study design also affects the ability to infer potentially causal associations from observational data. Cohort, nested case-cohort, and nested case-control (prospective) studies
generally provide the highest level of support, since the exposures are assessed prior to
disease onset and case status is ascertained forward in time. Case-control (retrospective)
studies are prone to several important biases (recall, survival, etc.); cross-sectional studies include only prevalent cases, obviating assessment of temporal relationships; and etiologic studies address population-specific, rather than person-specific, risk associations.
The latter study designs are useful for hypothesis generation, but do not typically form
the sole basis for moving candidate chemopreventive agents forward into clinical trials.
COHORT DEFINITION
Contrary to the traditional chemotherapy paradigm, chemopreventive interventions
are intended for generally healthy patient populations. However, because most cancer
prevention agents are not entirely devoid of potential toxicities, initial chemoprevention
trials are often conducted among high-risk subjects, who stand to benefit the most from
improved interventions. Both family cancer history and past medical history can be used
to select appropriate subject cohorts for chemoprevention trials. Other factors, such as
geographic location, may occasionally be useful in cohort selection as well, if residents
of a specific global region are known to have increased cancer rates without defined
familial, medical, or environmental associations.
Hepatobiliary tract
Pancreas
Colorectum
Farnesyl transferase
pathway
Tyrosine kinases
Perillyl alcohol,
limonene196-198
Genistein, erbstatin199-201
Colorectum
Esophagus
Colorectum
Colorectum
Colorectum
Aza-deoxycytidine, folic
acid194,195
GI Cancer Site(s)
Molecular Targets
Promoter methylation
Candidate Agents
continued
Inhibition of cancer development in xenograft models and decreased cell survival of cancer cell in vitro.
Comments
Table 17-1
Celecoxib, refecoxib,
NSAIDs, and triterpenoids78, 188, 211-214
Esophagus
Colorectum
Pancreas
S-adenosylmethionine
Polyamine biosynthesis
decarboxylase,
Difluoromethylornithine215-217
Esophagus
Colorectum
Hepatobiliary tract
Colorectum
Troglitazone208
GI Cancer Site(s)
Molecular Targets
PPAR-
Candidate Agents
continued
Comments
330
Chapter 17
Colorectum
Hepatobiliary tract
Pancreas
GI Cancer Site(s)
Colorectum
Stomach
Pancreas
Molecular Targets
Candidate Agents
Comments
332
Chapter 17
As shown in Table 17-2, several heritable syndromes are known to be associated with
increased GI cancer risk. Of these syndromes, FAP and HNPCC are sufficiently common to form the basis for defining chemoprevention trial cohorts. Among FAP patients,
APC gene mutations result in the phenotypic expression of hundreds to thousands of
colorectal adenomas, usually during adolescence. Without prophylactic colectomy, FAP
patients invariably develop colorectal cancer at a relatively young age (approximately 40
years).5 Duodenal cancer risk (especially in the periampullary region) is also elevated in
FAP and represents the leading cause of malignant death among patients who have
undergone prophylactic colectomy.6 HNPCC patients are predisposed to tumor formation at multiple GI sites (colorectal, gastric, small bowel, hepatobiliary tract, and pancreas), as well as in several non-GI target organs (uterus, genitourinary tract, and ovary),
due to mutations in any of 5 DNA mismatch repair genes (hMLH1, hMSH2, hPMS1,
hPMS2, and hMSH6).7 At present, vigilant endoscopic surveillance is the only nonsurgical option for GI cancer prevention in FAP and HNPCC kindreds. While effective,
this approach is intensive, invasive, and limited to a single organ system. Systemic interventions such as chemoprevention are therefore particularly attractive for patients with
these genetic disorders.
Comprehensive reviews regarding the spectrum of medical conditions associated
with esophageal,8-10 gastric,11 colorectal,12,13 hepatobiliary,14,15 and pancreas16 cancers
have been recently published. Patients with BE, H. pylori infection, prior colorectal adenomas, or idiopathic inflammatory bowel disease have well-defined risks for site-specific GI cancers and represent realistic cohorts for chemoprevention trials. BE, wherein
normal squamous epithelium is replaced by specialized metaplastic columnar epithelium, results from chronic exposure to refluxed gastric contents.17 In a subset of BE
patients, histologic transformation progresses beyond metaplasia, to form LGD, HGD,
and eventually adenocarcinoma. Compared to the general population, BE patients have
a 30- to 60-fold increase in esophageal adenocarcinoma risk,18 with an estimated cancer
incidence rate of approximately 0.5% to 1.0% per year.19 H. pylori is a gram-negative
bacterium that colonizes approximately one-half of the worlds population20 and has
been classified as a class I carcinogen by the International Agency for Research on
Cancer.21 Based on a recent meta-analysis of existing observational data,22 the odds ratio
for gastric cancer is 2.0 (95% CI =1.7 to 2.5) among H. pylori-positive vs H. pylori-negative patients. More strikingly, Parkin estimated that 42% of all gastric cancers may be
ascribed to this infectious organism.23
Patients with prior colorectal adenomas are approximately 3 times more likely to
develop recurrent (metachronous) neoplasia compared to average-risk patients of similar age and gender. Adenomas with the following features carry the highest risk for recurrence: 1 cm in diameter, 3 in total number, villous histology, or HGD.24 History of
colorectal cancer is also a risk factor for metachronous neoplasia, with a median time to
detection of about 24 months after curative resection.25 These patients may be particularly motivated to participate in chemoprevention trials. Idiopathic inflammatory bowel
disease (including both chronic ulcerative colitis and Crohns disease) affects approximately 400,000 patients in the United States.26 Longstanding ulcerative colitis is associated with cumulative colorectal cancer incidence rates of 2%, 8%, and 18% after 10, 20,
and 30 years of disease, respectively.27 Data for patients with Crohns disease are more
limited, but the colorectal cancer risk seems to be similarly increased.
Inheritance
Pattern
Autosomal
Recessive
Basal cell nevus
Autosomal
Dominant
Bloom
Autosomal
Recessive
Cowden (gingival
Autosomal
multiple hamartoma)
Dominant
FAP
Autosomal
Dominant
Familial gastric cancer
Autosomal
Dominant
Familal melanoma
Autosomal
Dominant
Familial pancreatic cancer Unknown
Fanconis anemia
Autosomal
Recessive
Hereditary breast/other Autosomal
cancer (BRCA2)
Dominant
Hereditary breast/
Autosomal
ovarian (BRCA1)
Dominant
Ataxia-telangiectasia
Heritable
Syndrome
Esophagus
Stomach
continued
Table 17-2
Esophagus
Stomach
Adapted from Lindor NM, Greene MH. The concise handbook of family cancer syndromes. Mayo Familiar Cancer Program. J Natl Cancer Inst. 1998;
90(14):1039-71.
Xeroderma
pigmentosum
Wilms tumor
Multiple endocrine
neoplasia I
Peutz-Jeghers
Autosomal
Dominant
Autosomal
Recessive
Autosomal
Dominant
Autosomal
Recessive
Autosomal
Dominant
Autosomal
Dominant
Autosomal
Dominant
Autosomal
Dominant
Autosomal
Dominant
(HNPCC)
Li-Fraumeni
Inheritance
Pattern
Heritable
Syndrome
334
Chapter 17
335
ENDPOINT EVALUATION
Cancer incidence and mortality remain the most definitive outcomes for judging the
effects of candidate chemoprevention agents. However, these endpoints are impractical
for early phase chemoprevention trials, since hundreds to thousands of subjects are typically needed to observe an adequate number of incident or fatal cancers, even within
high-risk subject populations. Also, years to decades of follow-up are often required to
achieve statistically meaningful results. Thus, the effects of candidate agents are commonly measured against surrogate endpoint biomarkers (SEBs) to demonstrate preliminary efficacy. Two key features of suitable SEBs are 1) level of association between the
surrogate biomarker and the GI cancer outcome (ie, the degree to which the biomarker
is on the causal pathway for disease), and 2) accuracy of the biomarker measurement
technique. At the macroscopic level, several SEBs can be assessed by endoscopy. Length
of columnar metaplasia predicts adenocarcinoma risk among BE patients28 and can be
easily measured pre- and postintervention. Colorectal adenoma size and number are
both positively correlated with colorectal cancer risk24 and have been successfully monitored in previous chemoprevention trials. Vital staining can also be used to highlight
mucosal abnormalities in both the upper and lower GI tract, but data regarding the
potential utility of chromoendoscopy-defined SEBs are only beginning to emerge.
To date, intraepithelial neoplasia has been the primary phenotypic SEB applied in
chemoprevention trials sponsored by the National Cancer Institute.29 Histologic grade
of noninvasive neoplasia (or dysplasia) predicts GI cancer risk at multiple sites and represents a potentially modifiable target for esophageal, gastric, and colorectal cancer
chemoprevention trials. In the esophagus, patients with BE-associated HGD experience
a much higher adenocarcinoma incidence rate (22%) than patients with no dysplasia
(2%) over a relatively short time interval.30-33 Similarly, esophageal biopsy specimens
with mild, moderate, and severe squamous dysplasia were associated relative risks for
incident cancer of 2.9, 9.8, and 28.3, respectively, after extended follow-up among residents of a high-risk region in China.34,35 In a prospective study of noninvasive gastric
neoplasia, Rugge et al found that invasive cancer risk was significantly correlated with
baseline histology grade over an average follow-up period of 52 months.36 Because polyp
resection convincingly decreases incident colorectal cancer,37 large bowel adenomas are
usually removed rather than monitored for signs of progression. However, cross-sectional studies have demonstrated that colorectal adenomas with LGD are less likely to contain foci of adenocarcinoma (0.3%) compared to adenomas with HGD (27%).38
Other tissue-based SEBs include assays related to growth regulation in general, such
as proliferation and apoptosis, or specific intracellular pathways of carcinogenesis. An
example of the latter group includes proteins involved in arachidonic acid metabolism.
Esophageal biopsy specimens from patients with BE show a parallel increase in cyclooxygenase-2 (COX-2) expression and neoplastic progression.39 Higher PGE2 concentration has also been observed in metaplastic BE epithelium compared to normal squamous epithelium.40 Further, PGE2 induces proliferation in BE epithelial cells41 and
inhibition of PGE2 normalizes the proliferation rate.40 These observations help form the
basis for evaluating antireflux therapy in combination with COX-2 inhibition in BE
chemoprevention trials, as discussed on page 337.
336
Chapter 17
BY
SITE
Compounds that demonstrate chemopreventive potential in preclinical studies, epidemiological investigations, or a combination of both are further developed through a
series of clinical trials designed to assess dose, bioavailability and toxicity (phase I); preliminary efficacy against molecular, imaging, or histologic SEBs (phase II); and ultimately definitive efficacy against cancer outcomes (phase III). The developmental status
of candidate chemopreventive agents for esophageal, colorectal, gastric, hepatobiliary
tract, and pancreas cancers is reviewed in the following sections.
ESOPHAGUS
Based on GLOBOCAN data, 412,327 incident and 337,501 fatal esophageal cancer
cases were recorded worldwide in 2000.1 High risk global regions include China, India,
Northern Iran, and South Africa10 for ESC and Scotland, the United Kingdom, the
Netherlands, and the United States for EAC.9,42 In the United States, age-adjusted incidence and mortality rates for esophageal cancer are 4.7/100,000 population and
4.4/100,000 population, respectively.43 Incidence rates are markedly higher for men
than for women (8.2 vs 1.9 per 100,000 population) and are also higher for AfricanAmericans than for Caucasians (6.3 vs 4.7 per 100,000 population). For cases diagnosed
in 1995 to 2000, the estimated 5-year survival rate was 14.3% overall (29.3% for localized disease). Candidate agents for esophageal cancer chemoprevention are discussed
below, with data from randomized, controlled trials presented in Table 17-3.
Selenium
Selenium may interrupt carcinogenesis through several mechanisms, including
immune modulation, decreased carcinogen activation, reduced proliferation, and
increased apoptosis.44 Cell culture and animal model studies have demonstrated few
beneficial effects from selenium compounds on esophageal carcinogenesis.44-49 In fact,
selenium administration resulted in increased EAC incidence as well as tumor volume
in a surgically altered rat model.49 However, epidemiological data are more encouraging.
Case-control and cohort studies have shown that selenium status (as measured in either
peripheral blood samples or toenail clippings) is inversely associated with incident ESC
and EAC.50-54
Two randomized, placebo-controlled trials have directly analyzed selenium as a
potential esophageal cancer chemoprevention agent. In the US Nutritional Prevention
of Cancer Study (n=1312), subjects who were treated with 200 mg/day of selenized yeast
for a mean duration of 4.5 years had a nonstatistically significant reduction in
esophageal cancer risk (RR=0.40; 95% CI=0.08 to 2.07) compared to placebo-treated
subjects.55 However, case numbers in both intervention arms were small (n=2 and n=5,
respectively) and esophageal cancer was analyzed as a secondary endpoint in this study.
Limburg et al conducted a pilot study of selenomethionine 200 mg/day (2-x-2 factorial
design) among subjects from Linxian, PRC who had histologically confirmed mild or
moderate squamous dysplasia at baseline. After a 10-month intervention period,
selenomethionine was found to have a marginally significant effect on change in squamous dysplasia grade overall (p=0.08), although subjects who began the trial with mild
dysplasia derived a statistically significant benefit (p=0.02).56
Two multinutrient intervention trials have also been conducted in Linxian, PRC.
Asymptomatic adults enrolled in the General Population Trial (n=29,584) experienced
7.4 years
Multinutrient57 29,584
Subjects enrolled
in a skin cancer
prevention trial
Intervent.
Period
Histologically10 months
confirmed squamous
dysplasia at baseline
1312
Selenium55
Risk Cohort
Selenium,
267
COX-2 inhibitor56
N1
Candidate
Agent(s)
0.40 (0.08 to
2.07)
Risk Est.
(95% CI)2
1.07 (0.92 to
1.25)
0.93 (0.92 to
1.25)
1.02 (0.87 to
1.19)
0.96 (0.78 to
1.18)
Cancer incidence
Endpoint
Cancer incidence
Selenized yeast 50
g/day
-carotene 15
Cancer mortality
g/day
-tocopherol 30 mg/
day
Retinol 5000 IU/day Cancer incidence
Zinc 22.5 mg/day
Cancer mortality
Selenomethionine
200 g/day
Celecoxib 200 mg
bid
continued
Comments
Table 17-3
Endpoint
Spectrum of histologically-defined
lesions
Cancer incidence
Ascorbic acid 120
mg/day
Molybdenum 30
Cancer mortality
g/day
Riboflavin 3.2 mg/day Cancer incidence
Niacin 40 mg/day
Cancer mortality
610
Multinutrient76
1N=number
Cytologically6 years
detected squamous
dysplasia
Residents of a high- 13.5 months
risk global region
3318
Intervent.
Period
Mutinutrient58
Risk Cohort
N1
Multinutrient57 29,584
(cont)
Candidate
Agent(s)
N/A
1.06 (0.91
1.24)
1.05 (0.85
1.29)
0.86 (0.74
1.01)
0.90 (0.73
1.11)
0.94 (0.73
1.20)
Risk Est.
(95% CI)
to
to
to
to
to
Prevalence of esophagitis
with or without atrophy or
dysplasia found to be nearly
the same in the placebo
group (45%) and the vitamin/zinc treated group
(49%).
Comments
338
Chapter 17
339
minimally reduced esophageal cancer incidence (RR=0.1.02; 95% CI=0.87 to 1.19) and
mortality (RR=0.96; 95% CI=0.78 to 1.18) rates after 5.25 years of selenium (50
mg/day as selenized yeast), -carotene (15 mg/day), and -tocopherol (30 mg/day).57 In
the smaller Dysplasia Trial, subjects with cytologically-detected dysplasia at baseline
(n=3318) had similar risks for incident (RR=0.94; 95% CI=0.73 to 1.20) and fatal
(RR=0.84; 95% CI=0.54 to 1.29) esophageal cancer regardless of whether they received
daily supplementation with 26 vitamins and minerals (including sodium selenate 50
mg/day) vs placebo over the 6-year intervention period.58
Antioxidant Vitamins
Vitamins A, C, and E (as well as their biochemical precursors) may prevent
esophageal and/or other cancers by neutralizing free radicals and blocking carcinogen
formation. Retinoids are also thought to inhibit cellular proliferation and decrease
angiogenesis. Alpha-tocopherol appears to stimulate immunosurveillance, induce apoptosis, and regulate cell signaling pathways, in addition to having other putative cancer
prevention effects.59-61 In animal models of esophageal cancer, supplementation with
vitamin A, vitamin C, and related compounds has yielded minimal cancer protective
effects (tumorigenesis was actually enhanced in Fischer 344 rats).62-65 In contrast, vitamin E has shown chemopreventive potential in both carcinogen-treated and surgically
altered rodents.49,66 Observational studies from diverse geographic regions support
inverse associations between antioxidant vitamins and esophageal cancer risk based on
either dietary data67-71 or serum/plasma levels,72-75 although not all reports are consistent.
In the Linxian General Population Trial, antioxidant vitamins in combination with
other micronutrients did not meaningfully alter the observed esophageal cancer incidence or mortality rates:
Retinol 5000 IU and zinc 22.5 mg/day (RR=1.07; 95% CI=0.92 to 1.25 and
RR=0.93; 95% CI=0.76 to 1.15, respectively)
Ascorbic acid 120 mg and molybdenum 30 mg/day (RR=1.06; 95% CI=0.91 to
1.24 and RR=1.05; 95% CI=0.85 to 1.29, respectively)
Selenium 50 mg, -carotene 15 mg, and a-tocopherol 30 mg/day (RR=1.02;
95% CI=0.87 to 1.19 and RR=0.96; 95% CI=0.78 to 1.18, respectively)
Similarly, the cadre of nutrients administered in the Linxian Dysplasia Trial, which
included vitamin A 10,000 IU, vitamin C 180 mg, and vitamin E 60 IU per day, had
no discernible effects with respect to either incident or fatal esophageal cancer. Another
randomized trial from Huixian, PRC (n=610) found that the prevalence rates for a spectrum of histologically defined esophageal lesions (including esophagitis, atrophy, dysplasia, or cancer) were not statistically different among subjects who received retinol
50,000 IU/week (along with riboflavin 200 mg/week and zinc 50 mg/week) vs placebo
after a mean intervention period of 13.5 months.76
340
Chapter 17
formed a meta-analysis of existing observational data and found that any NSAID use
was associated with a 43% risk reduction (OR=0.57; 95% CI=0.47 to 0.71).79
Moreover, frequent use appeared to be more effective than intermittent use (46% vs
18% risk reduction, respectively). By histologic subtype, NSAID use was protective for
both ESC (OR=0.58; 95% CI=0.43 to 0.78) and EAC (OR=0.67; 95% CI=0.51 to
0.87).79
In a small, uncontrolled study of BE patients (n=12), selective COX-2 inhibition
with rofecoxib 25 mg/day for 10 days resulted in a statistically significant decline in cellular proliferation (p<0.005).40 The only randomized, controlled chemoprevention trial
data reported to date are from a Linxian, PCR pilot study (see page 334) wherein celecoxib 200 mg bid for 10 months had no appreciable effect on change in histologic grade
of esophageal squamous dysplasia.56 Other esophageal cancer chemoprevention trials are
ongoing, including a large phase II trial of celecoxib 200 mg bid among subjects with
BE.80
COLORECTUM
Based on GLOBOCAN data, 944,717 incident and 492,411 fatal colorectal cancer
(CRC) cases were recorded worldwide in 2000.1 High-risk global regions include
Australia, New Zealand, North America, and Northern and Western Europe.23 In the
United States, age-adjusted incidence and mortality rates for CRC are 51.8/100,000
population and 20.0/100,000 population, respectively.43 Incidence rates are higher for
men than for women (60.6 vs 44.8 per 100,000 population) and for Blacks than for
Whites (61.4 vs 51.1 per 100,000 population). For cases diagnosed in 1995 to 2000, the
estimated 5-year survival rate was 63.4% overall (89.9% for localized disease).
Candidate agents for CRC chemoprevention are discussed below, with data from randomized, controlled trials (including at least 20 subjects and measuring at least one adenoma or cancer endpoint) presented in Table 17-4.
Fiber
Dietary fiber represents a heterogeneous class of plant-derived compounds that have
potential to reduce CRC risk by 1) diluting or adsorbing intraluminal carcinogens, 2)
reducing GI transit time, 3) altering bile acid metabolism, or 4) increasing the production of short-chain fatty acids. In a recent review of animal model data, Sengupta and
colleagues noted that 15 of 19 experimental studies found a protective effect of fiber
FAP
Prior colorectal
adenoma
58
424
1429
201
2079
Fiber,
antioxidant
vitamins100
Fiber,
antioxidant
vitamins101
Fiber102
Fiber103
Fiber104
Prior colorectal
adenoma
Prior colorectal
adenoma
Prior colorectal
adenoma
Risk
Cohort
N1
Candidate
Agent(s)
3.05 years
24 months
34 months
Dietary modification:
18 gm per 1000 kcal/day
Dietary modification:
50 gm/day
4 years
48 months
Form and
Dose
Intervent.
Period
Recurrent adenoma
Recurrent adenoma
Recurrent adenoma
Recurrent adenoma
Recurrent adenoma
Rectal adenoma
number
Endpoint
No significant
benefit from fiber
supplement.
N/A3
continued
Comments
Risk Est.
(95% CI)2
Table 17-4
255
Antioxidant
vitamins115
2 years
Prior colorectal
adenoma
Antioxidant
vitamins118
200
18 months
2 years
3 years
Intervent.
Period
Antioxidant
116
vitamins, selenium,
calcium117
Prior colorectal
adenoma
FAP
49
Antioxidant
vitamins114
Risk
Cohort
Prior colorectal
adenoma
N1
Candidate
Agent(s)
Recurrent adenoma
Polyp number
Polyp area
Recurrent adenoma
Recurrent adenoma
Endpoint
Recurrent adenoma
Recurrent adenoma
Vitamin C 150 mg/day
Vitamin E 75 mg/day
-carotene 15 mg/day
Selenium 101 mg/day
Calcium carbonate 1600 mg/day
Form and
Dose
N/A
N/A
Risk Est.
(95% CI)
continued
Recurrence rate
lower in the vitamin group (6%) vs
the placebo group
(36%).
Comments
342
Chapter 17
N1
864
29,133
25
930
Candidate
Agent(s)
Antioxidant
vitamins119
Antioxidant
vitamins121
Calcium124
Calcium128
48 months
Intervent.
Period
Prior colorectal
adenoma
FAP
48 months
6 months
Prior colorectal
adenoma
Risk
Cohort
Calcium carbonate
3000 mg/day
Calcium carbonate
1500 mg/day
-carotene 20 mg/day
Vitamin E 50 mg/day
Form and
Dose
Recurrent adenoma
Adenoma size
Adenoma number
Cancer incidence
Cancer incidence
Recurrent adenoma
Recurrent adenoma
Endpoint
Comments
N/A
continued
Risk Est.
(95% CI)
N1
22
41
635
1121
291
Candidate
Agent(s)
NSAIDs227
NSAIDs134
NSAIDs139
NSAIDs140
NSAIDs138
9 months
Intervent.
Period
Prior colorectal
adenoma
Prior colorectal
adenoma
Prior colorectal
cancer
4 years
36 months
31 months
FAP gene
4 years
mutation carriers
without adenomas
FAP
Risk
Cohort
Recurrent adenoma
Recurrent adenoma
Recurrent adenoma
Polyp incidence
Polyp size
Polyp number
Endpoint
Sulindac 75 mg BID
Sulindac 150 mg BID
Decrease in polyp
number (p=0.014)
and polyp diameter
(p<0.001) in active
compared to placcebo group.
Comments
continued
N/A
N/A
Risk Est.
(95% CI)
344
Chapter 17
1N=number
Postmenopausal
women
FAP
Health
professionals
Risk
Cohort
5.6 years
6 months
Intervent.
Period
Exogenous
16,608
hormones145
77
22,071
NSAIDs137
COX-2
inhibitors141
N1
Candidate
Agent(s)
Cancer incidence
Polyp burden
Cancer incidence
Endpoint
Comments
Significant reduction
in polyp burden
among subjects in
the higher (p=
0.001), but not the
lower (p=0.09)
dose group compared to placebo.
0.61 (0.42 to 0.87) Colorectal cancer
cases diagnosed at
a more advanced
stage among subjects in the active
arm.
N/A
Risk Est.
(95% CI)
346
Chapter 17
against tumor induction compared with controls.93 Poorly fermentable fibers, such as
wheat bran and cellulose, appeared to be more effective than soluble fibers in these systems. A meta-analysis of 16 early case-control studies by Trock et al showed that high
fiber consumption was associated with a 43% decrease in CRC risk.94 However, subsequent data from 5 cohort studies have been inconsistent95-99 and clinical trial data have
been somewhat disappointing. Among FAP patients (n=58), DeCosse et al observed
marginal benefits from a 4-year intervention of wheat bran fiber at 22 gm/ day (in combination with ascorbic acid 4 gm/day and -tocopherol 400 mg/day).100 Wheat bran
supplementation has been similarly unimpressive with respect to prevention of recurrent
sporadic colorectal adenomas.101,102 McKeown-Eyssen et al103 and Schatzkin et al104 also
noted no appreciable effects on adenoma recurrence rates from dietary modifications to
raise fiber intake, while Bonithon-Kopp et al reported that adenoma recurrence rates
were actually increased by using ispaghula husks to augment fiber consumption.105
Antioxidant Vitamins
Mechanisms for the putative anticarcinogenic effects of antioxidant vitamins are
described above. Because fecal bacteria can produce high concentrations of reactive oxygen species,106 the rationale for CRC chemoprevention with these compounds has been
particularly compelling. In carcinogen-induced animal model systems, retinoids reportedly reduce rectal aberrant foci formation, decrease cellular proliferation, and increase
apoptosis.107-109 In contrast, ascorbic acid has yielded mixed results110,111 and -tocopherol has demonstrated minimal effects.112 Associations between antioxidant vitamins
and CRC risk, based on either dietary intake (with or without inclusion of supplements)
or blood concentrations, have been evaluated in numerous observational studies with
generally favorable results, as recently reviewed.113
In an early clinical trial among FAP subjects (n=49), treatment with vitamin C
3 gm/day vs placebo for up to 2 years resulted in transiently reduced polyp number and
polyp area, but the effects were not sustained by the end of the trial.114 Five additional
trials have been performed with recurrent sporadic adenomas as the primary endpoint.
In a relatively small trial reported by Roncucci et al, subjects who were treated with vitamin A 30,000 IU/day, vitamin C 1000 mg/day, and vitamin E 70 mg/day for a mean
period of 18 months had a lower adenoma recurrence rate (6%) compared to placebotreated subjects (36%).115 However, a subsequent follow-up study from these same
investigators has revealed less striking effects from lower vitamin doses based on preliminary data analyses.116 Hofstad et al found that a 3-year intervention using vitamin C
150 mg/day and vitamin E 75 mg/day (along with -carotene 15 mg/day, selenium 101
g/day, and calcium carbonate 1600 mg/day) resulted in a 69% reduction in recurrent
adenoma risk compared to placebo.117 Conversely, the Toronto Polyp Prevention Group
(n=200) and the Antioxidant Polyp Prevention Study (n=864) reported no appreciable
chemopreventive benefits from vitamin C (400 mg/day and 1000 mg/ day, respectively)
and vitamin E (400 mg/day in each trial).118,119 Stratified analyses from the Antioxidant
Polyp Prevention Study found that -carotene 25 mg/day was associated with a 44%
reduction in recurrent adenoma risk (RR=0.56; 95% CI=0.35 to 0.89) among subjects
who were both nonsmokers and nondrinkers.120 Yet, secondary analyses of data from the
Alpha Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study of Finnish male
smokers revealed no significant benefits from 5 to 8 years of - carotene 20 mg/day with
respect to CRC incidence (RR=1.05; 95% CI=0.75 to 1.47).121 Treatment with vitamin
E 50 mg/day did result in fewer incident CRC cases in the ATBC study, but this result
was not statistically significant (RR=0.78; 95% CI=0.55 to 1.09).
347
Calcium
Calcium binds to potentially toxic bile acids within the colorectal lumen and may
also directly reduce cellular proliferation and increase apoptosis. Chemopreventive
effects have been demonstrated extensively in preclinical studies.122 A recent analysis of
pooled data from 16 case-control and 8 cohort studies yielded summary risk estimates
of 1.13 (95% CI=0.91 to 1.39) for colorectal adenomas and 0.86 (95% CI=0.74 to
0.98) for CRC among subjects with high vs low calcium intake.123 Thomas et al administered calcium 1500 mg/day vs placebo for 6 months to a small number of FAP subjects (n=25). Neither size nor number of rectal adenomas was meaningfully affected in
this trial, but a decline in the crypt cell production rate was reported.124 Conversely,
another FAP chemoprevention trial by Stern et al (n=31) detected no appreciable change
in mucosal proliferation rate from calcium 1200 mg/day for 9 months.125 Two phase II
trials conducted among HNPCC kindreds have also demonstrated mixed results on cellular proliferation from calcium doses of 1250 to 4500 mg/day for up to 3 months.126,127
With respect to sporadic CRC, Hofstad et al found no appreciable benefit on adenoma growth rate after 36 months of treatment with calcium 1600 mg/day (along with
vitamins C and E, selenium, and -carotene) vs placebo among 116 polyp-bearing subjects.117 In the large Calcium Polyp Prevention Study (n=930), 48 months of calcium
carbonate 3000 mg/day (elemental calcium 1200 mg/day) resulted in a 15% reduction
in risk for recurrent adenomas (RR=0.85; 95% CI=0.74 to 0.98).128 The European
Cancer Prevention Organization Study Group also reported a potential benefit on adenoma recurrence rate at 3 years from elemental calcium 2000 mg/day among subjects
with a history of prior colorectal adenomas (n=665). However, this result was not statistically significant (RR=0.66; 95% CI=0.38 to 1.17).105 Definitive data are anticipated from the US Womens Health Initiative Clinical Trial and Observational Study
(n=45,000), an ongoing study designed to evaluate the effects of calcium 1000 mg/day
(along with vitamin D3 400 IU/day) on several chronic disease endpoints, including
incident CRC.129
348
Chapter 17
metabolizing enzymes may have contributed to this negative result.135 NSAID chemoprevention of sporadic colorectal neoplasia has been reported in 4 randomized, controlled clinical trials.136-140 Sandler et al investigated the effects of aspirin 325 mg/day
versus placebo among subjects (n=635) with a history of curatively resected CRC.139
After a median intervention period of 31 months, the recurrent adenoma rate was significantly lower among subjects in the aspirin arm compared to the placebo arm (17%
vs 27%; p=0.004). Recurrent adenomas were also fewer in number (p=0.003) and
recurred later (p=0.02) among aspirin-treated subjects. Baron et al examined 2 aspirin
doses, 325 mg/day and 81 mg/day, among subjects with prior colorectal adenomas
(n=1121).140 After a mean follow-up period of 33 months, subjects in the aspirin 81
mg/day group were 17% less likely to develop recurrent adenomas (RR=0.8; 95%
CI=0.7 to 1.0) compared to subjects in the placebo group. For reasons that remain
incompletely defined, subjects in the aspirin 325 mg/day group had essentially the same
risk for recurrent adenomas as subjects in the placebo group. Benamouzig et al reported
interim data from the APACC trial, which showed a statistically significant decrease in
recurrent adenoma risk (RR=0.61; 95% CI=0.37 to 0.99) after 1 year of aspirin 300
mg/day vs placebo among subjects with prior colorectal adenomas.138 In the large US
Physicians Health Study (n=22,071), aspirin 325 mg every other day had no apparent
effect on CRC incidence rates, which were analyzed as a secondary endpoint, after either
5 years (RR = 1.2; 95% CI=0.8 to 1.7) or 12 years (RR = 1.03; 95% CI = 0.83 to 1.28)
of follow-up.136,137
In a chemoprevention trial of selective COX-2 inhibitors among FAP subjects (141),
Steinbach et al found that celecoxib 400 mg BID for 6 months resulted in a reduced colorectal polyp burden (30.7%; p=0.003) compared to placebo.141 This dose of the active
agent also resulted in statistically significant duodenal polyp regression (14.5%) among
subjects with >5% mucosal involvement at baseline (p=0.05 compared to placebo).142 In
a smaller (n=8), uncontrolled trial, Hallak et al detected a beneficial effect from rofecoxib 25 mg/day for 12 months on the rate of colorectal polyp formation as well.143 At
least 2 additional sporadic CRC chemoprevention trails using selective COX-2
inhibitors have been conducted. However, the overall risk-to-benefit ratio remains to be
determined.
349
STOMACH
Based on GLOBOCAN data, 876,341 incident and 646,567 fatal gastric cancer
cases were recorded worldwide in 2000.1 High risk global regions include China, Japan,
and select areas of Eastern Europe and tropical South America.23 In the United States,
age-adjusted incidence and mortality rates for gastric cancer are 7.5/100,000 population
and 4.3/100,000 population, respectively.43 Incidence rates are higher for men than for
women (10.9 vs 5.0 per 100,000 population) and for Blacks than for Whites (12.3 vs
6.3 per 100,000 population). For cases diagnosed in 1995 to 2000, the estimated 5-year
survival rate was 23.3% overall (58.4% for localized disease).
Gastric adenocarcinomas account for >95% of all stomach tumors and consist of 2
histologic subtypes (intestinal and diffuse), which are thought to arise through distinct
carcinogenic pathways.151 H. pylori infection appears to be the most important environmental risk factor for gastric cancer subtypes.152 However, dietary constituents also affect
gastric carcinogenesis. Low fruit and vegetable consumption has been consistently linked
to increased gastric cancer risk, as recently reviewed.153 Interestingly, H. pylori infection
has been associated with multiple micronutrient deficiencies, including -carotene,
ascorbic acid, and -tocopherol.154,155 Correa, et al conducted a randomized clinical trial
of H. pylori triple therapy (amoxicillin, metronidazole, and bismuth subsalicylate for 14
days) and/or -carotene 30 mg/day, ascorbic acid 1000 mg BID, or placebo among subjects with precancerous gastric lesions from a high-risk region in Colombia, South
America.156 Based on a comparison of gastric biopsy samples taken at baseline and 72
months for subjects who completed the trial (n=631), H. pylori eradication and nutritional supplementation both resulted in statistically significant histologic regression of
the precancerous lesions. Relative risks for the active versus placebo agents ranged from
3- to 8-fold in various subset analyses. Subsequent studies have shown that COX-2
expression is increased by H. pylori infection,157 suggesting a possible role for COX-2
inhibitors in gastric cancer chemoprevention as well. Indeed, administration of celecoxib to carcinogen-induced rats led to a decreased gastric cancer incidence in a recently
reported experiment, although the investigators speculated that some of the observed
chemopreventive benefit may have been derived through COX-independent pathways.158
Gastric cancer endpoints were assessed in 2 intervention trials conducted among residents of Linxian, PRC. In the Linxian General Population Trial,57 5.25 years of selenium 50 mg/day (as selenized yeast), -carotene 15 mg/day, and -tocopherol 30 mg/day
resulted in a 16% lower risk for incident gastric cancer (RR=0.84; 95% CI=0.71-1.00)
and a 21% lower risk for fatal gastric cancer (RR=0.79; 95% CI=0.64 to 0.99). None of
the other nutritional agent combinations was significantly associated with gastric cancer
risk. In the Linxian Dysplasia Trial, daily supplementation with 26 vitamins and minerals had no discernible effect on gastric cancer incidence (RR=1.17; 95% CI=0.87 to
1.58) or mortality (RR=1.18; 95% CI=0.76 to 1.85) compared to placebo.58 Another
trial using anti-H. pylori therapy combined with dietary supplementation (vitamin C,
vitamin E, selenium, and garlic derivatives) was initiated in 1995 among subjects from
350
Chapter 17
Linqu County, PRC (n=3599),159 but final results from this study have yet to be reported. In a small phase I, multiorgan chemoprevention trial, curcumin was found to be relatively nontoxic at doses up to 8000 mg/day for 3 months.160 Histologic improvement
of intestinal metaplasia was noted in gastric biopsy samples from 1 of 6 subjects as well.
Traditional NSAIDs, soy products, and DFMO have been considered for gastric cancer
chemoprevention,161-163 but clinical trial data for these compounds are currently
unavailable.
HEPATOBILIARY TRACT
Based on GLOBOCAN data, 564,336 incident and 548,554 fatal liver cancer cases
were recorded worldwide in 2000.1 High-risk global regions include Western and
Central Africa, Eastern and Southeast Asia, and Melanesia.23 In the United States, ageadjusted incidence and mortality rates for liver and bile duct cancer are 5.2/100,000
population and 4.7/100,000 population, respectively.43 Incidence rates are higher for
men than for women (8.0 vs 2.9 per 100,000 population) and for Blacks than for
Whites (7.5 vs 4.0 per 100,000 population). For cases diagnosed in 1995 to 2000, the
estimated 5-year survival rate was 8.3% overall (18.4% for localized disease).
HCC is the most common primary malignant tumor in the liver. Major HCC risk
factors include chronic hepatitis B or hepatitis C virus infection, cirrhosis of any cause
(including excess alcohol intake), previously resected HCC, and exposure to aflatoxin (a
fungal toxin). Nonalcoholic fatty liver disease has also been positively associated with
HCC164 and the rapid rise of the former condition in the United States and other industrialized countries will no doubt be an important contributor to future HCC incidence
rates. Relatively rare HCC risk factors include hereditary hemochromatosis, -1-antitrypsin deficiency, primary biliary cirrhosis, Wilsons disease, and exposure to thorium
dioxide (a contrast agent previously used in radiology studies). In select high-risk global regions, hepatitis B vaccination programs have resulted in reduced HCC incidence
rates.165,166 To date, other HCC primary prevention strategies have been minimally
effective at best. Although dysplasia is a likely precursor lesion to HCC,167 the degree of
invasiveness involved and potential for sampling error associated with liver biopsy prohibits routine application of this SEB for chemoprevention trials. More feasible SEBs
include viral load, serum protein levels (such as alpha-fetoprotein), excreted aflatoxin
metabolites, and serial imaging tests.168
Although data from clinical trials are currently limited, several candidate HCC
chemoprevention agents appear promising. Interferon-alpha therapy can eradicate hepatitis C virus and has been shown to slow the progression of fibrosis, decrease viral load,
and reduce biochemical markers of inflammation.169 Observational data further support
the potential for HCC risk reduction with interferon-alpha therapy.170 In a randomized,
prospective trial among Japanese patients with HCV-related cirrhosis (n=90), interferon-alpha 6 MU 3 times per week for 12 to 24 weeks resulted in substantially fewer incident HCC cases compared to controls (2 vs 17 cases; p=0.002).171 Lin et al reported
lower HCC recurrence rates at 1 and 4 years among subjects (n=30) randomized to
receive intermittent or continuous interferon-alpha for 24 months.172 Kubo et al also
observed beneficial effects on HCC recurrence from long-term interferon-alpha treatment (up to 104 months).173 Interferon-beta 6 MU twice per week was found to have
favorable effects on incident HCC after a median observation period of 25 months in a
relatively small clinical trial (n=20) as well.174
351
PANCREAS
Based on GLOBOCAN data, 216,367 incident and 213,462 fatal pancreas cancer
cases were recorded worldwide in 2000.1 Residents of developed countries are at greater
risk than residents of developing countries.23 In the United States, age-adjusted incidence and mortality rates for pancreatic cancer are 10.7/100,000 population and
10.5/100,000 population, respectively.43 Incidence rates are higher for men than for
women (12.4 vs 9.5 per 100,000 population) and for Blacks than for Whites (13.5 vs
10.5 per 100,000 population). For cases diagnosed in 1995 to 2000, the estimated 5year survival rate was 4.4% overall (15.2% for localized disease).
Pancreas cancer chemoprevention research has been stymied by the high case fatality rate, limited awareness of premalignant conditions, and lack of a broadly applicable
screening tool. Tobacco use has been convincingly associated with incident pancreas cancer, and smokers who consume alcohol appear to be at even greater risk.183 Emerging
data further suggest that COX-2 may be overexpressed in pancreatic adenocarcinoma
and intraepithelial neoplasia.184-187 In an experimental model of pancreatic cancer
induced by transplacental exposure to alcohol and the tobacco carcinogen NNK,
Schuller et al found that nonselective COX inhibition afforded significant cancer preventive effects.183 Other mechanistic data show that DNA adducts derived from exposure to polycyclic aromatic hydrocarbon and aromatic amines can be detected in pancreatic cancer tissue188 and the level of aromatic DNA adducts has been correlated with
K-ras mutations. Additionally, a high proportion of G to A transitions appears to be
present in pancreatic tumors, suggesting that nitrosamines and/or alkylating agents may
effect carcinogenesis in this target organ.188 Furthermore, there appears to be a gradual
decrease in antioxidant enzyme expression in normal pancreas, chronic pancreatitis, and
pancreatic cancer.189 Consistent with the latter observation, selenium supplementation
has been noted to prevent pancreatic cancer in a carcinogen-induced hamster model.190
However, neither carotene 20 mg/day nor -tocopherol 50 mg/day had a statistically
significant effect on pancreas cancer risk based on secondary analyses from the ATBC
study.191 Further insights regarding familial pancreatic cancer, as described elsewhere in
352
Chapter 17
this volume, may provide new opportunities for chemoprevention among these highrisk patients.
SUMMARY
The NCIs Division of Cancer Prevention began systematically reviewing nutritional and pharmaceutical compounds with potential to interrupt carcinogenesis at a preinvasive stage more than 2 decades ago.192 Since then, significant advances have been made
with respect to GI cancer chemoprevention. Most notably, celecoxib (a selective COX2 inhibitor) has been approved by the FDA for use as an adjunct to usual measures in
reducing the number of colorectal polyps among FAP patients.193 Ongoing trials should
yield informative data regarding the chemopreventive benefit and overall safety profile
of COX-2 inhibitors and other candidate agents among patients with BE, prior colorectal adenomas, or other conditions associated with increased GI cancer risk. Pending
further positive trial results, GI cancer chemoprevention has the potential to complement current clinical practice by allowing delayed onset of average-risk cancer screening,
prolonged intervals between high-risk screening/surveillance examinations, and
increased disease-free survival rates among curatively-resected cancer patients. Ongoing
research into synergistic agent combinations (eg, COX-2 inhibitors and DFMO), earlier SEBs (eg, rectal aberrant crypt foci), and molecularly defined risk stratification (eg,
using genetic or epigenetic characteristics to assist cohort selection) should facilitate
future progress in GI cancer chemoprevention as well.
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chapter
18
New Technologies
for the Detection of
Gastrointestinal Neoplasia
Linda S. Lee, MD and John M. Poneros, MD
INTRODUCTION
Cancers of the GI tract have a tremendous impact on society. Colorectal cancer is
the second leading cause of cancer death in the United States and accounts for 10% of
all cancer deaths. Over 57,000 deaths due to colorectal cancer were expected in the
United States in 2003.1 Although esophageal cancer is significantly less common, the
incidence of esophageal adenocarcinoma in the United States has increased dramatically over the past 2 decades.2 The prognosis for esophageal cancer is grim, with an overall 5-year survival rate of less than 10%. Both colonic and esophageal adenocarcinomas
arise from premalignant lesions; any success in their early detection could significantly
reduce their mortality rates.
Significant research efforts are being directed toward using the interaction of light
and tissue to detect precancerous lesions of the GI tract. The interaction between light
and tissue can be used to study both the chemical and physical properties of the tissue
being analyzed. The principles being studied could theoretically be applied to the early
surveillance of many different types of cancer.
The purpose of this chapter is to review the current status of various experimental
optical technologies to detect precancerous changes in the GI tract. This review will
focus on the clinical applications of these technologies for the practicing gastroenterologist.
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Chapter 18
The different distribution and concentration of fluorophores and chromophores (which absorb light without re-emission of fluorescence)
The alteration in tissue architecture, such as mucosal thickening in epithelial
tumors
The changes in the metabolic status of tumor tissue
The different biochemical microenvironments, such as the microbial activity
that occurs in necrotic tumors which can promote porphyrin synthesis
Romer et al6 studied the morphologic differences in fluorescence between normal
colonic mucosa and adenomas, specifically which tissue components contributed to fluorescence. Fluorescence mainly arose from collagen fibers in the bowel wall and
eosinophil granules in the lamina propria. Fluorescent eosinophil granules were more
numerous in adenomas, and cytoplasmic fluorescence was detected in adenomas but not
normal colonic epithelial cells. Determining which cellular components are responsible
for the differences in polyp fluorescence will help exploit these fluorescence signatures.
The wavelength of excitation light used is critical when studying tissue autofluorescence because different wavelengths excite distinct fluorophores at varying tissue depths.
The optimal excitation and emission wavelengths for various tissue types are unknown
and typically determined by ex vivo experimentation. These results may not accurately
reflect in vivo tissue properties due to changes in the microenvironment and metabolic
state.4
367
Table 18-1
Biological
Source
Wavelength of
Max. Excitation
(nm)
Wavelength of
Max. Emission
(nm)
Collagen
Elastin
Connective tissue
330
350
390
420
NADH
Respiratory chain
co-enzymes
340
450
450
515
Amino acids
280
260
275
350
280
300
Byproducts of
heme synthesis
400 to 450
635, 690
330, 340
330
400
400
340 to 395
430 to 460,
540 to 640
FAD, flavins
Tryptophan
Phenylalanine
Tyrosine
Porphyrins
Lipopigment
granules
In 1990, Kapadia et al7 reported the first use of laser-induced fluorescence spectroscopy in the GI tract. The authors examined ex vivo colonic tissue using a laser with
an excitation wavelength of 325 nm to distinguish adenomatous polyps from hyperplastic polyps. Using linear regression analysis and a training set of 70 tissue specimens
(35 normal, 35 adenomatous), a quantitative laser-induced fluorescence score was developed to discriminate adenomas from normal tissue. In the validation set, all 34 normal
mucosal specimens, 16 adenomas, and 94% of hyperplastic polyps were correctly identified. These results were confirmed in the first in vivo study by Cothren et al8 who compared the spectra from different specimens in the colon. They developed a spectrofluorometry system with an optical probe that could be passed through the accessory channel of a standard colonoscope and placed in direct contact with tissue. Using 460 and
680 nm excitation wavelengths, they distinguished adenomas from nonadenomas
(defined as normal mucosa and hyperplastic polyps) with 97% specificity, 100% sensitivity, and 94% positive predictive value.
An in vitro study to determine the optimal excitation and emission wavelengths for
distinguishing colonic adenomas from normal colonic tissue was performed by
Richards-Kortum et al.9 Excitation wavelengths of 330, 370, and 430 nm were studied
for 11 normal mucosal specimens and 16 adenomas. Using an excitation wavelength of
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Chapter 18
370 nm, the emission wavelength of 480 nm best differentiated adenomatous from normal tissue; 96% of 26 samples were correctly identified as normal or adenomatous.
Schomacker et al10 then specifically examined the discrimination of adenomas from
hyperplastic polyps in vivo. During routine colonoscopy, an optical fiber probe was
passed through the colonoscope and emission spectra collected from all polyps requiring resection. Similar to the study by Kapadia et al linear regression analysis was used to
develop a laser-induced fluorescence score to distinguish adenomas from hyperplastic
polyps.7 For an excitation wavelength of 390 nm and using histology as the reference
standard, the authors reported a slightly lower sensitivity (86%), specificity (80%), and
positive predictive value (86%) compared to previous studies. They postulated that the
use of a slightly longer excitation wavelength in vivo (390 nm vs 370 nm in the
Richards-Kortum study) and the inclusion of mixed morphology polyps might explain
the different results.
In the first blinded study published in 1996, Cothrens group11 prospectively validated a diagnostic algorithm to distinguish normal colonic mucosa from hyperplastic
and adenomatous polyps using fluorescence spectra. In vivo emission spectra were collected from 103 polypoid and 104 normal-appearing colonic mucosal sites using an
optical probe passed through the colonoscope. The diagnostic algorithm was developed
using emission spectra from 41 polyps and 43 normal-appearing colonic mucosal sites.
This algorithm was tested in a blinded fashion using the remaining polypoid and normal colonic specimens. With an excitation wavelength of 370 nm, the sensitivity, specificity, and positive predictive value for differentiating adenomas from nonadenomas
(normal mucosa and hyperplastic polyps) were 90%, 95%, and 90%, respectively. In
distinguishing adenomas from hyperplastic polyps, the sensitivity and specificity were
slightly lower at 90% and 82%. Table 18-2 summarizes several studies using endogenous
fluorescence spectroscopy to diagnose colonic adenomas.
Laser-induced fluorescence spectroscopy has also been used to examine upper GI
tract epithelia. In 1995, Panjehpour et al12 published the first use of laser-induced fluorescence spectroscopy to identify esophageal malignancy in vivo. Using linear discriminate analysis, the authors developed a diagnostic algorithm that they tested on 108 normal and 26 malignant tissue specimens. At an excitation wavelength of 410 nm, the sensitivity and specificity for detecting malignant esophageal tissue was 100% and 98%.
The investigators then examined the use of laser-induced fluorescence spectroscopy to
detect dysplasia in BE.13 They used the differential normalized fluorescence index to distinguish HGD from LGD or nondysplastic mucosa. For emission wavelengths of 480
and 660 nm at an excitation wavelength of 410 nm, 90% of HGD cases were correctly
identified; all examples of LGD and 96% of nondysplastic BE were appropriately classified. One limitation of this study was that only 28% of LGD specimens with areas of
focal HGD were correctly recognized. It should be noted that the clinical significance of
focal HGD is controversial.14,15
Light-induced fluorescence spectroscopy has been studied as an alternative to laser
excitation and appears promising.16 Mayinger et al used violet-blue light as the excitation energy in a pilot study of 11 patients (6 with esophageal squamous cell carcinoma,
3 with gastric cancer, and 2 with gastric adenomas with severe dysplasia).16 Biopsies were
obtained after spectroscopy and used as the reference standard. The illumination and
position of the probe dramatically affected the intensity of the observed spectra in this
study; therefore, the spectra were normalized before comparison. After normalization,
the spectra from normal and premalignant tissue were clearly different; the authors
369
Table 18-2
System
Studies
Excitation
Wavelength
(nm)
Tissues
Studied
Results
Kapadia et al
(1990)
Ex vivo
325
Adenoma vs
hyperplastic
polyp
94% accurate
Cothren et al
(1990)
In vivo
460, 680
Richards-Kortum
et al (1991)
In vitro
370
Adenoma vs
normal tissue
96% accurate
Schomaker et al
(1992)
In vivo
390
Adenoma vs
hyperplastic
polyp
86% sensitive
80% specific
86% PPV
Cothren et al
(1996)
In vivo,
blinded
370
Adenoma vs
90% sensitive
hyperplastic and 95% specific
normal tissue
90% PPV
found that esophageal squamous cell carcinoma and dysplastic gastric adenomas displayed significantly lower intensity compared to normal mucosa. In this study, interpretation of the biological significance of a spectrum was only possible after obtaining a reference spectrum from normal mucosa of the same patient. Compared to laser-induced
fluorescence, light-induced fluorescence spectroscopy offers the advantage of being a less
expensive technology, which would allow it to be more easily disseminated.
370
Chapter 18
optical head of a fiberoptic endoscope. The images from these 2 cameras are combined
into a real-time fluorescent image with normal tissue appearing a certain color and
abnormal tissue a different color. The endoscopist can switch back and forth between
the white-light endoscopic and real-time fluorescent imaging to image large areas of tissue rapidly. Using this system, any suspicious lesions on white-light endoscopy can be
quickly examined using fluorescent imaging.4,5 Due to the reduced signal-to-noise ratio
with fluorescent imaging, the sensitivity and specificity are thought to be less than point
spectroscopy.
In 1999, Wang et al17 studied a prototype endoscopic fluorescence imaging system
to diagnose colonic adenomas. Using histology as the reference standard and a fluorescence threshold of 80% of the average intensity of normal mucosa, this imaging system
was 83% sensitive for identifying adenomas; all hyperplastic polyps were correctly classified as nondysplastic. White-light endoscopy was compared to combination whitelight endoscopic and fluorescent imaging in differentiating nondysplastic colonic tissue
(normal or hyperplastic) from adenomatous polyps in an abstract published in 2001.18
This study demonstrated a higher sensitivity (95% vs 80%), specificity (80% vs 69%),
and positive predictive value (71% vs 59%) with fluorescent imaging when examining
62 lesions.
Fluorescence spectroscopy and imaging have several limitations. Fluorescence analyzes a relatively weak signal that results from the interaction between light and tissue
fluorophores and, therefore, necessitates sensitive and expensive instrumentation. In
addition, fluorescence spectroscopy and imaging require that the optimal excitation and
emission wavelength for each tissue be first determined through ex vivo experimentation,
which may not accurately reflect in vivo results.4 Despite these limitations, this optical
technology has shown great promise and provided the earliest experience for investigators working in this field.
371
mechanism of delivery (eg, intravenous vs topical spray), and the time delay between
sensitization and endoscopy have been studied.23
In 1996, von Holstein et al28 completed the first study using an exogenous fluorophore to perform laser-induced fluorescence spectroscopy in the GI tract. The authors
injected the photosensitizer dihematoporphyrin ether (Photofrin, [Axcan Pharma Inc,
Birmingham, Ala]) to help identify adenocarcinoma within Barretts mucosa. Photofrin
is an exogenous fluorophore with prolonged photosensitivity that can last for 6 to 8
weeks. It is less selectively concentrated in the GI mucosa than ALA. PPIX is typically
found in highest concentration in the mucosal epithelium while Photofrin diffuses
throughout the entire esophageal wall. This causes a deeper burn when using
Photofrin to perform photodynamic therapy but also leads to a higher stricture rate.2931 In this preliminary study by Von Holstein et al, the investigators used both emission
spectra from endogenous fluorophores (eg, autofluorescence) and Photofrin to create a
fluorescence ratio to identify normal mucosa, BE, dysplasia, and adenocarcinoma. The
intensity of autofluorescence at 500 nm for normal mucosa was 6.5 times higher than
adenocarcinoma or severe dysplasia, while Photofrin produced a fluorescence intensity
at 630 nm only 1.2 times higher in tumor compared to normal tissue. The authors concluded that autofluorescence was more useful than exogenous fluorescence with
Photofrin in distinguishing normal mucosa from esophageal adenocarcinoma.
The first study using ALA-enhanced fluorescence spectroscopy to detect colonic dysplasia was published by Eker et al32 in 1999. An oral dose of ALA of 5 mg/kg body
weight was administered approximately 2 to 3 hours before colonoscopy and spectroscopy. Linear regression analysis was used to create an algorithm for classifying normal mucosa, hyperplastic polyps, and adenomas. At an excitation wavelength of 337
nm, ALA did not significantly improve the ability to differentiate between adenoma and
normal or hyperplastic tissue compared to autofluorescence, but did improve discrimination using 405 and 436 nm excitation. Sensitivity was 89% with specificity of 94% at
wavelength of 405 nm with similar sensitivity (86%) and specificity (100%) using 436
nm excitation.
After these initial studies using ALA-enhanced fluorescence spectroscopy, research
has focused on ALA-enhanced fluorescence imaging. Mayinger et al33 studied 22
patients with known or suspected esophageal malignancy or BE who ingested ALA at a
dose of 15 mg/kg body weight. Fluorescence imaging, standard white-light endoscopy,
and biopsy were performed 6 to 7 hours after ingestion. Tissue histology was used as the
reference standard to determine sensitivity and specificity. While sensitivity for accurately diagnosing biopsy sites was greater with ALA-enhanced fluorescence imaging
compared to white-light endoscopy (85% vs 25%), specificity was diminished (53% vs
94%) due to PPIX accumulation in inflamed mucosa. An example of ALA-enhanced
fluorescence imaging is demonstrated in Figure 18-2.
In 2001, Endlicher et al34 investigated the optimal dose and route of administration
of ALA in fluorescence imaging to detect biopsy-proven low and high-grade dysplasia
within BE. ALA was orally ingested at doses of 5, 10, 20, or 30 mg/kg body weight or
sprayed onto Barretts epithelium using a special spray catheter at a prior endoscopy.
Imaging was performed 4 to 6 hours after systemic or 1 to 2 hours after local sensitization. At 20 and 30 mg/kg, the technique was limited by increased side effects such as
nausea, vomiting, and elevated liver enzymes. The lowest dose of 5 mg/kg failed to
detect dysplasia. Sensitivity and specificity for detecting dysplasia were similar for 10
mg/kg (80% and 56%) and 20 mg/kg (100% and 51%). Local sensitization with a spray
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Chapter 18
Figure 18-2. Endoscopic image of nodule with HGD and ALA-enhanced fluorescence imaging of identical nodule. (Courtesy of Norman Nishioka, MD,
Boston, Mass.) For a full-color version, see page CA-XV of the Color Atlas.
catheter had improved specificity (69%) but reduced sensitivity (60%) and was limited
by the need to perform 2 endoscopies. The overall high rate of false-positive fluorescence
in this study resulted from incorrectly classifying inflammatory mucosa, ulcer margins,
and bile as malignant.
Based on this work, Brand et al35 performed the first study to use quantitative ALAenhanced fluorescence point spectroscopy to differentiate nondysplastic from dysplastic
Barretts epithelium. Oral ALA at a dose of 10 mg/kg body weight was administered 3
hours before endoscopy. A standardized fluorescence intensity value was calculated by
accounting for the contribution of autofluorescence at emission wavelengths of 635 and
750 nm. Sensitivity and specificity for distinguishing HGD from non-dysplastic
Barretts mucosa and LGD were 77% and 71%, respectively.
The use of ALA-fluorescence imaging to identify colonic dysplasia was recently studied by Messmann et al.36 Previous studies had established that a higher dose of ALA is
required to sensitize the colon compared to the esophagus.37 Therefore, Messmann and
colleagues used an oral dose of 20 mg/kg, a 3 gm ALA enema, or a spray catheter to
detect dysplasia (low and high-grade) in ulcerative colitis. Endoscopy was performed 4
to 6 hours after systemic sensitization and 1 to 2 hours after local sensitization. A total
of 481 biopsies were examined from 37 patients, with 42 biopsies showing dysplasia (40
with LGD, 2 with HGD). Using histology as the reference standard, sensitivity for
detecting dysplasia ranged from 43% with oral ALA, 87% with enema, and up to 100%
with the spray catheter. However, oral ALA had a higher specificity of 73% compared
to the enema (51%) and spray catheter (62%).
Use of ALA as an exogenous fluorescent agent has shown promise in detecting dysplasia in the upper and lower GI tract, with relatively few side effects. Further studies
with other exogenous fluorescent agents and improved fluorescent imaging techniques
when using these agents are required.
373
LIGHT-SCATTERING SPECTROSCOPY
While fluorescence analyzes the biochemical properties of tissue, light-scattering
spectroscopy (LSS) interrogates structural information. The wavelength of the illuminating light and the properties of the scattering particle determine the scattering pattern.
Cell nuclei are predominately responsible for light scattering when tissue is analyzed,
specifically the nuclear size and number. Photons are typically scattered multiple times
within tissue before being emitted. LSS measures the wavelength and intensity of backreflected light. It subtracts the diffuse background caused by multiple scattering to allow
the analysis of the small amount of back-scattered light from cell nuclei. Dysplastic cells
typically have an increased nuclear-to-cytoplasmic ratio and are more crowded together.
LSS is a quantitative equivalent to the histologic markers for dysplasia of hyperchromasia and nuclear enlargement. One advantage of LSS compared to laser-induced fluorescence is that the signal intensity of light scattering dominates the fluorescent signal when
examining biological tissue.19,38,39
LSS of the GI tract involves inserting an optical probe through the accessory channel of the endoscope. The tip of the probe contacts the epithelium and emits and collects the white light from about a 1 mm2 area of tissue. In the first study of LSS in
Barretts epithelium with and without dysplasia, dysplastic epithelium was defined as at
least 30% of the nuclei being larger than 10 m.40 Using this definition and histology
as the gold standard, the sensitivity and specificity of LSS for correctly identifying highgrade and low-grade dysplasia was approximately 90%; all HGD samples and 87% of
LGD specimens were correctly classified. The appeal of this technique is that a stronger
signal is collected in real-time using white light instead of a laser source. An endoscopic
imaging system using this spectroscopic technology has not been reported.
RAMAN SPECTROSCOPY
When light interacts with tissue, incident photons cause electrons in the tissue to
oscillate and emit photons. If the emitted photons have the same energy as the incident
photons, no energy transfer occurs and the scattering is termed elastic. Although most
scattering events are elastic, some are inelastic, which refers to an energy transfer between
the photon and the molecule being illuminated. The phenomenon of inelastic light scattering is termed Raman scattering. The energy transfer causes molecules to vibrate,
which results in slight shifts in energy and wavelength of the emitted light relative to the
excitation light. Approximately 1 photon out of 1 million will scatter at a wavelength
slightly shifted from the original incident wavelength. Thus, Raman scattering is much
weaker than elastic scattering, but the signal is highly specific to the molecular composition of the tissue.19,39
Visible, UV, or near-infrared (NIR) light may be used to induce Raman scattering,
which is measured as a difference in wavelength from the excitation wavelength. When
visible light is used for excitation, autofluorescence causes severe interference with the
Raman signal, which is typically much weaker than the fluorescent signal. UV light is
not optimal for Raman spectroscopy because it can cause tissue injury and does not penetrate tissue to the same depth as visible or NIR light. NIR light for Raman spectroscopy
has the advantages of minimizing autofluorescence, penetrating more deeply to a depth
of approximately 500 mm, and being nonmutagenic.19,39
Ex vivo studies using Raman spectroscopy to examine BE reported a sensitivity and
specificity of 77% and 93%, respectively, for differentiating nondysplastic from dys-
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Chapter 18
plastic Barretts epithelium.41 Shim et al42 then designed and built a NIR device for
endoscopic in vivo Raman spectroscopy. In the first report using this device, the authors
demonstrated the feasibility of in vivo measurements, but the spectral differences
between normal tissue and HGD in the esophagus and colon were subtle.
In 2003, these authors used endoscopic NIR Raman spectroscopy to diagnose
colonic adenomas in vivo.43 They classified 19 Raman spectra from 9 polyps in 3
patients as hyperplastic or adenomatous using diagnostic algorithms. These algorithms
were developed from principal component and linear discriminant analyses in a leaveone-out cross-validation method. In this small sample, the diagnostic algorithms were
100% sensitive and 89% specific for differentiating hyperplastic from adenomatous
polyps. Raman spectroscopy is a potentially powerful tool in evaluating premalignant GI
conditions but requires further study.
TRIMODAL SPECTROSCOPY
Recently, a group of investigators combined several spectroscopic techniques in an
attempt to increase the accuracy of detecting dysplasia within BE.44 Georgakoudi et al
used a combination of fluorescence, reflectance, and light-scattering spectroscopies to
analyze the biochemical, architectural, and morphologic characteristics of Barretts
epithelium, with and without dysplasia. The simultaneous use of all 3 techniques was
named trimodal spectroscopy. The combination of fluorescence and reflectance spectroscopies was applied to remove the distortions introduced into the measured tissue fluorescence spectrum by scattering and absorption. Undistorted fluorescence was then
used to analyze the tissue biochemistry, and reflectance and light-scattering spectroscopies were used to analyze the tissue architecture and epithelial cell nuclei.
Data were collected from 40 sites in 16 patients with known BE undergoing standard surveillance endoscopy. Principal component and logistic regression analyses were
used to correlate the spectral features and histopathologic diagnosis. In this data set,
Trimodal spectroscopy classified HGD vs LGD and nondysplastic BE with 100% sensitivity and 100% specificity. HGD and LGD vs nondysplastic BE was identified with
100% sensitivity and 93% specificity. It should be noted that this study was not conducted in real time and used leave-one-out cross-validation to establish the classification algorithms. Nonetheless, Trimodal spectroscopy carries great promise for the detection of dysplastic epithelial changes by combining information regarding the biochemical and architectural characteristics of tissue.
375
uses a technique called interferometry to measure the delay. Light from a low coherence
light source is split evenly into 2 separate pathways, with one beam directed to the tissue being imaged and the other beam delivered to a reference arm. At the end of the reference arm is a mirror that oscillates at a known distance away from the detector. Each
beam of light is reflected from both the tissue and the reference mirror and recombined
at the detector. The interference created by these 2 recombined light beams is then
measured. Interference only occurs when the path lengths of both light beams are
matched to within the coherence length of the light source. The axial resolution of an
OCT image is determined by the coherence length of the light source used and is
approximately 10 mm in the infrared OCT systems. The lateral or transverse resolution
is determined by the spatial width of the light source and is approximately 30 mm. As
the position of the mirror is moved, information is collected from different tissue levels.
By scanning the optical beam across the tissue surface, a 2-dimensional picture is created.48,49
Several in vitro studies have demonstrated the feasibility of OCT imaging in the GI
tract.45,49-51 However, the clinical value of in vitro studies is limited because the optical
properties of nonliving tissue are different from in vivo tissue. In vitro OCT images have
shown esophageal squamous epithelium to be a highly scattering layer while the lamina
propria demonstrated much less backscatter.45,50 In vivo OCT images have shown the
opposite, displaying a highly scattering lamina propria and a less scattering squamous
epithelium.52-53
Multiple studies have demonstrated the characteristic findings for normal and abnormal GI tissue using OCT.52-58 In 1997 Sergeev et al54 published the first in vivo OCT
images of normal esophageal epithelium. They imaged 4 patients and demonstrated 5
esophageal wall layers composed of mucosa, lamina propria, muscularis mucosa, submucosa, and muscularis propria. Using the same OCT system, Jckle et al53,55 presented data from 48 patients, including 9 esophageal images, and confirmed their findings.
Bouma et al52 studied 32 patients using a linear scanning device that produces cross-sectional images similar to those of Jckle et al. By comparing ex vivo measurements of layer
thickness by OCT and histology in the same specimen of normal esophagus, they were
able to define precisely which OCT image layers corresponded to each esophageal wall
component. In a recent ex vivo study using a Ti:Sapphire laser as the light source, Cilesiz
et al59 clearly visualized the muscularis propria as well as lymphoid follicles.
The OCT system used by Sivak et al56 differs from other endoscopic OCT systems
in that it acquires images with a radial scanning device similar to high-frequency ultrasound. A series by Sivak et al included 72 OCT images from 38 patients taken from the
upper and lower GI tract. Zuccaro et al57 acquired 477 images of the esophagus and
stomach in 69 patients, and Li et al58 published a descriptive study of 8 patients using
both linear- and radial-scanning OCT catheter probes and spectroscopic OCT.
BE is characterized by the development of specialized intestinal metaplasia above the
esophago-gastric junction. The hallmark histologic feature of specialized intestinal metaplasia is the presence of goblet cells. Visualization of individual goblet cells is beyond the
resolution of currently available endoscopic OCT devices. However, OCT images of
Barretts epithelium have shown distinct morphologic features that enable the differentiation of Barretts epithelium from other tissue types. Pitris et al and Bouma et al45,52
identified several of these OCT features: loss of the layered esophageal structure, abnormal and disorganized glands, and increased architectural disorder and heterogeneity. The
deeper structures including the lamina propria, muscularis mucosa, and submucosa were
376
Chapter 18
Figure 18-3. OCT images of upper GI tract tissues. (A) Squamous epithelium typically
shows a 5-layered appearance. (B) Gastric mucosa demonstrates a "pit-and-crypt" morphology. (C) Barrett's epithelium, or specialized intestinal metaplasia, reveals an inhomogeneous tissue contrast, an irregular mucosal surface and submucosal glands.
(Courtesy of Brett Bouma, PhD and Gary Tearney, MD, PhD, Boston, Mass.)
not visualized due to the strong backscattering from the metaplastic epithelium. Figure
18-3 demonstrates OCT images of normal esophageal squamous epithelium, gastric
mucosa, and specialized intestinal metaplasia.
In 2001, Poneros et al60 developed and prospectively validated the first objective
OCT image criteria for diagnosing BE. These criteria were developed by examining 166
OCT-correlated biopsy specimens that served as the training set. The presence of 2 or
more of the following OCT findings was considered diagnostic for Barretts epithelium:
absence of normal esophageal layering, disorganized architecture, and the presence of
submucosal glands that look like areas of low reflectance below the tissue surface or
invaginations through the epithelium. An experienced blinded observer used these criteria to analyze 122 OCT images prospectively in the validation set. Using histology as
the standard, the OCT criteria were 97% sensitive and 92% specific for Barretts mucosa
with or without dysplasia.
This same group studied the use of OCT in identifying dysplasia in Barretts
mucosa.61 Because the degree of light reflectivity depends on nuclear size, OCT may be
able to characterize dysplasia within Barretts epithelium by quantifying the OCT signal
as a function of depth (eg, higher degrees of dysplasia characterized by larger nuclei
would be expected to cause more light scattering). This alteration in the light reflection
characteristics of dysplastic tissue may be more reliable than morphologic criteria in
identifying dysplasia.
In order to differentiate specialized intestinal metaplasia from dysplasia, the authors
used 2 parameters that are calculated from the OCT images: slope reflectivity and layer
ratio. In a preliminary retrospective study of 11 images of LGD, 4 of HGD, and 23 of
nondysplastic Barretts epithelium, sensitivity for HGD was 100% with a specificity of
82% to 85%.
Another group also recently published a study in abstract form using OCT to diagnose dysplastic Barretts epithelium.62 Isenberg et al used morphologic rather than quantitative criteria to identify dysplasia. Four endoscopists independently reviewed 152
images from 23 patients and rated them from 1 (dysplasia absent) to 5 (dysplasia present). A 2 or higher was considered positive for dysplasia. A pathologist blinded to the
OCT images reviewed the corresponding biopsies. OCT was 69% sensitive and 71%
specific with a positive predictive value of 36% and a negative predictive value of 91%.
377
Figure 18-4. (A) OCT image of esophageal adenocarcinoma. Scale bar 500 m. (B)
Corresponding histopathology (H&E, orig. mag x 40). (Courtesy of Brett Bouma, PhD and
Gary Tearney, MD, PhD, Boston, Mass.) For a full-color version, see page CA-XVI of the
Color Atlas.
The authors concluded that the high negative predictive value suggested that OCT
could be used to target biopsies to areas of higher suspicion for dysplasia in Barretts
epithelium.
OCT images of malignant GI tissue have been published by several groups. Jckle et
al55 studied 6 patients with esophageal adenocarcinoma arising from Barretts mucosa.
They described a complete loss of layering and increased heterogeneity in esophageal
adenocarcinoma when imaged by OCT. Bouma et al52 confirmed these results in two
patients and described a cellular stroma with large pockets of mucin. Figure 18-4
demonstrates an OCT image of esophageal adenocarcinoma and its corresponding histology. Because of the limited depth of penetration with OCT, the role of OCT in staging esophageal tumors is unclear. EUS accurately stages most endoscopically apparent
tumors. However, superficial esophageal squamous cell carcinomas in which the tumor
echogenicity does not differ significantly from the surrounding normal squamous
mucosa are poorly staged by EUS. OCT may be useful in this instance but experience
with OCT in esophageal squamous carcinoma is limited. Jckle et al53 and Pitris et al45
each reported one case of squamous carcinoma identified by loss of normal esophageal
layering using OCT.
Gastric tissue is very distinct and easily distinguishable from esophageal epithelium
by OCT.52-54,56-58 Instead of horizontal layering, gastric tissue displays a characteristic
vertical pit-and-crypt architecture (see Figure 18-3). The depth of penetration in the
stomach with OCT is the lowest in the GI tract, measuring approximately 0.7 mm.
Studies are lacking regarding the OCT findings in gastric dysplasia or gastritis.
In the lower GI tract, colonic mucosa is readily identified by OCT due to its narrow
and ordered crypts. Jckle et al53 reported that adenomas contain dark round areas that
represent expansion of adenomatous glands. In colonic adenocarcinoma, similar to
esophageal adenocarcinoma, there is a loss of the mucosal architecture with an uneven
surface and dilated and disorganized crypts.45,53 Mucosal inflammation is seen as areas
of high backscattering on OCT,49 and destruction of normal mucosa with ulcerative
lesions are seen in ulcerative colitis.45
OCT images of colonic adenomas were examined in a recent study by Pfau et al.63
During routine colonoscopy, OCT images were obtained from 44 polyps (30 adenomas,
14 hyperplastic polyps) and nearby normal-appearing mucosa in 24 patients. Real-time
subjective assessments of the degree of organization and light scattering were performed
378
Chapter 18
by the endoscopists who rated the images from 0 (least organization or scattering) to 5
(most organization or scattering). Digital imaging analysis was performed to quantify
the degree of light scattering, and histology was used as the reference standard.
Adenomas were significantly more disorganized, with less light scattering compared to
hyperplastic polyps; normal colonic mucosal specimens were similar to hyperplastic
polyps. The authors concluded that OCT could differentiate adenomatous from hyperplastic polyps and normal tissue based upon the degree of tissue organization and light
scattering.
OCT images of the biliary tree obtained during ERCP were published in 2002.64
OCT images of normal bile duct, cholangiocarcinoma, and a malignant biliary stricture
due to metastatic colon cancer were acquired from 5 patients. If proven sensitive for
cholangiocarcinoma, OCT would be particularly useful in this disease given the frequent
difficulty in obtaining diagnostic tissue.
OCT is an exciting technology that allows real-time tomographic visualization of tissue structures at a higher resolution than any other currently available endoscopic
modality. During OCT, an optical probe is passed down the accessory channel of the
endoscope without the need for a conducting medium. Endoscopic OCT is an evolving
technology with several current limitations, which include the length of time required
to obtain images, a shallow depth of visualization, and the inability to visualize subcellular structures. High resolution OCT imaging that is comparable to histology is closer to becoming a reality, with the development of ultrashort pulse laser technology.
Drexler et al65 published OCT images taken with a Ti:Sapphire laser system that
achieves a longitudinal resolution of ~1 m and transverse resolution of 3 m in vitro.
Subcellular structures such as nuclei are readily seen at these resolutions. As currently
configured, this system is limited in that it is not catheter-based or readily portable, and
safety data regarding its interrogating light beam lacking. However, once these limitations are overcome, high resolution OCT could provide a significant advancement in
endoscopic optical imaging of the GI tract. Figure 18-5 demonstrates an OCT image of
an African frog tadpole (Xenopus laevis) using this system.
MOLECULAR BEACONS
Recently exciting work has been published on the use of optically-based, enzymeactivatable fluorescent sensors for the in vivo detection of protease activity. Proteolytic
enzymes have been shown to play an essential role during tumor progression, specifically during high cell turnover, invasion, and angiogenesis.66 Cathepsin B, a cysteine protease, has been demonstrated to be up-regulated in areas of inflammation, necrosis,
angiogenesis, and during the focal invasion of colorectal carcinomas and dysplastic adenomas.67-69 Fluorescent sensors that operate in the NIR region have been developed to
allow noninvasive detection and monitoring of enzyme activity.70,71 These targeted NIR
fluorochromes have an advantage over other reporters such as isotopes in that they can
be silenced and activated by the enzymes they are used to identify. In their native
state, the enzymes are essentially nonfluorescent but upon enzymatic cleavage, they
become fluorescent in the NIR.
In 2002, a group of investigators reported their work using a fluorescent molecular
beacon to assess cathepsin B protease activity in adenomatous polyps.72 The authors
used a mouse model, which is heterozygous for the germ-line mutation of the mouse
homologue of the human APC gene. These animals develop multiple adenomas in the
small and large bowel that simulate adenomatous polyps in humans.73
379
Using a control set of mice injected with a nonactivatable fluorochrome, indocyanine green, the authors demonstrated that cathepsin B expression was ubiquitous in
adenomatous polyps and highest in larger polyps with higher degrees of dysplasia.
Immunohistochemistry and fluorescence confocal microscopy were used to examine the
resected murine colonic mucosa. Adenomas as small as 50 mm in diameter could be
readily identified with the aid of the fluorescent beacon. To quantify the fluorescence
signal the authors calculated a target (adenoma)-to-background (mucosa) contrast (TBC
contrast). A value of 100 represented a 100% higher fluorescence signal of the adenoma
compared with the colonic mucosa. Contrast in the large adenomas (TBC=220% +
97%) was thought to be caused by the higher amount of converting enzyme per lesion.
Adenomas in the mice that received indocyanine green showed a significantly lower
TBC contrast compared to those that received the cathepsin B sensing probe (TBC=
34% 4% vs 119 71%, p <0.01).
In humans cathepsin B-positive tumor cells have been observed in 67% of adenomas
and 100% of adenomas with HGD or adenocarcinoma.74 Optically visible activatable
fluorescent beacons could provide an important technology to screen patients for late
stage adenomas. This technology could eventually be adapted to conventional
endoscopy or even external NIR imaging of the bowel.
380
Chapter 18
CONCLUSION
The optical techniques outlined in this chapter offer an exciting, potentially powerful means of detecting premalignancy in the GI tract. The technologies being investigated to detect early GI malignancies could be transferable to other organs. The ultimate
goal of optical biopsy refers to the establishment of a tissue diagnosis based on in situ
optical measurements without the need for tissue removal. Laser-induced and ALAinduced fluorescence have demonstrated high sensitivity and specificity for detecting
colonic adenomas as well as dysplastic BE. The issue of improving fluorescence imaging
technology to visualize larger areas of tissue more rapidly without sacrificing diagnostic
accuracy remains to be solved. Determining the optimal excitation and emission wavelengths as well as the optimal dosage and route of administration of ALA-enhanced fluorescence requires further study. Light-scattering spectroscopy holds promise but is limited by the inability to survey large tissue surfaces. Raman spectroscopy offers a powerful method to visualize molecular activity, but is limited by a weak signal-to-noise ratio.
By combining fluorescence, reflectance, and light-scattering spectroscopic techniques,
Trimodal spectroscopy accurately classified nondysplastic and dysplastic Barretts
epithelium. This suggests that combining various spectroscopic techniques may be more
powerful than each technique alone. OCT offers the highest resolution endoscopic
tomographic imaging currently available. It has been shown to be a highly sensitive and
specific means of identifying BE and appears capable of grading dysplasia in Barretts
epithelium. Molecular beacons have not yet been investigated in humans but may offer
another potent method to target dysplastic and malignant cells based on the presence of
proteolytic activity. These experimental technologies offer an exciting glimpse into the
future of endoscopic diagnostic capabilities and the ever closer goal of performing an
optical biopsy.
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appendix
OF
TNM
386
Appendix A
Not applicable
Nonregional lymph nodes and/or other distant metastasis
STAGE GROUPING
Stage 0
Stage I
Stage IIA
Stage IIB
Stage III
Stage IV
Stage IVA
Stage IVB
Tis
T1
T2
T3
T1
T2
T3
T4
Any T
Any T
Any T
N0
N0
N0
N0
N1
N1
N1
Any N
Any N
Any N
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M1
M1a
M1b
Used with the permission of the American Joint Committee on Cancer (AJCC7), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, 6th edition (2002).
Springer-Verlag: New York, Inc., New York, New York.
appendix
OF
TNM
*Note: A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is
classified as T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified as T3.
**Note: The adjacent structures of the stomach include the spleen, transverse colon,
liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and
retroperitorneum.
***Note: Intramural extension to the duodenum or esophagus is classified by the depth
of the greatest invasion in any of these sites, including the stomach.
388
Appendix B
*Note: A designation of pN0 should be used if all examined lymph nodes are negative,
regardless of the total number removed and examined.
STAGE GROUPING
Stage 0
Stage IA
Stage IB
Stage II
Stage IIIA
Stage IIIB
Stage IV
Tis
T1
T1
T2a
T2b
T1
T2a
T2b
T3
T2a
T2b
T3
T4
T3
T4
T1
T2
T3
Any T
N0
N0
N1
N0
N0
N2
N1
N1
N0
N2
N2
N1
N0
N2
N1-3
N3
N3
N3
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
Used with the permission of the American Joint Committee on Cancer (AJCC7), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, 6th edition (2002).
Springer-Verlag: New York, Inc., New York, New York.
appendix
OF
TNM
390
Appendix C
STAGE GROUPING
Stage 0
Stage IA
Stage IB
Stage IIA
Stage IIB
Stage III
Stage IV
Tis
T1
T2
T3
T1
T2
T3
T4
Any T
N0
N0
N1
N2
N1
N1
N1
Any N
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M1
Used with the permission of the American Joint Committee on Cancer (AJCC7), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, 6th edition (2002).
Springer-Verlag: New York, Inc., New York, New York.
appendix
OF
TNM
The same classification is used for both clinical and pathologic staging.
*Note: Tis includes cancer cells confined within the gladular basement membrane
(intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.
**Note: Direct invasion in T4 includes invasion of other segments of the colorectum by
way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the
cecum.
***Note: Tumor that is adherent to other organs or structures, macroscopically, is classified as T4. However, if no tumor is present in the adhesion, microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence
or absence of vascular or lymphatic invasion.
392
Appendix D
Note: A tumor nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classified in
the T category and also coded as V1 (microscopic venous invasion) or as V2 (if it was
grossly evident), because there is a strong likelihood that it represents venous invasion.
STAGE GROUPING
Stage
0
I
IIA
IIB
IIIA
IIIB
IIIC
IV
T
Tis
T1
T2
T3
T4
T1-T2
T3-T4
Any T
Any T
N
N0
N0
N0
N0
N0
N1
N1
N2
Any N
M
M0
M0
M0
M0
M0
M0
M0
M0
M1
Dukes*
A
A
B
B
C
C
C
-
MAC*
A
B1
B2
B3
C1
C2/C3
C1/C2/C3
D
*Dukes B is a composite of better (T3 N0 M0) and worse (T4 N0 M0) prognostic
groups, as is Dukes C (Any TN1 M0 and Any T N2 M0). MAC is the modified
Astler-Coller classification.
Note: The y prefix is to be used for those cancers that are classified after pretreatment, whereas the r prefix is to be used for those cancers that have recurred.
Used with the permission of the American Joint Committee on Cancer (AJCC7), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, 6th edition (2002).
Springer-Verlag: New York, Inc., New York, New York.
Index
adriamycin-based chemotherapy, 31
AJCC staging
colon and rectal cancer, 168169,
391392
esophageal cancer, 385386
gastric cancer, 387388
pancreas cancer, 389390
aminotransferases, 317
ampulla of Vater, 131
analgesia, 203204, 210
epidural, 206207
intravenous patient-controlled, 204
205
neuraxial, 214215
patient-controlled, 211214
Analgesic Step Ladder, WHO, 211
angioplasty, pre-stent, 271
animal model systems, 328
antiangiogenesis inhibitors, 3233, 39
anti-AP-I retinoids, 329
antioxidants, 58, 339, 341, 343, 346,
349
APC 11307K mutation, 177
appetite stimulants, 310312
argon plasma coagulation (APC), 287
288, 299
ascites, 264265
ascorbic acid, 339, 346
Asian cholangiohepatitis, 255
394
Index
Index
chemotherapy
adjuvant, 189190
for colorectal neoplasia, 184191
for esophageal cancer, 3639, 57
for gastric cancer, 23, 2632, 62
liposomes in, 280
nutritional support in, 313
for pancreatic cancer, 107120
side effects of, 258
chest interventions, 277279
chest port placement, 270
chlorophyllin, 351
cholangiocarcinoma, 236
cholangiography, 126, 127, 136, 255
cholangiopancreatoscopy, 134
cholangioscope, baby, 134, 135
cholangioscopy, 135
cholecystitis, postembolization, 260
cholecystostomy, percutaneous, 254256
choledochojejunostomy, 101102
choledochoscopy, 253254, 255
chromosomal instability, 6970
cisplatin, 2730, 57, 62, 111, 112113
coagulative necrosis, 263
cohort definition, 328332
colectomy, subtotal, 167168
coloanal anastomosis, 172173
colon cancer, 166, 168, 300302
adjuvant chemotherapy for, 189190
familial risk and, 159
obesity and, 307308
preoperative assessment for, 164
colonic adenoma, 162, 377378, 380
colonoscopy, 146148, 153
coloplasty, 172, 174
colorectal adenocarcinoma, 157158, 162
colorectal adenoma, 141, 332, 335
colorectal cancer, 141
chemoprevention agents in, 340349
diagnosis and preoperative evaluation
of, 163165
familial, 157158
genetics of, 158162
hereditary, 151153
management of, 165167, 174
nutritional support for, 314
obstructing, 167168
screening and surveillance for, 141
154
395
sporadic, 162174
staging of, 168169, 391392
colorectal carcinoma, 161162
colorectal neoplasia
high-risk, 174181
metastatic, 184189
stage system of, 183184
surgical approach to, 157181
colorectal obstruction, luminal patency in,
300302
colorectal polyps, 161
colostomy, temporary, 167168, 172
computed tomography (CT)
in abscess drainage, 266
in colorectal cancer diagnosis, 163
165
contrast-enhanced chest, 271272
for gastric cancer, 59
for pancreatic cancer, 9193, 95
for pancreaticobiliary malignancy,
129130, 135136
thin-cut helical, 153
cordotomy, 218
coronary artery bypass grafting surgery,
280
corticosteroids, 310312
Courvoisiers sign, 8990
CPT11, 30
Crohns colitis, screening and surveillance
for, 147148, 151
cross-sectional studies, 9193, 328
cyclooxygenase-2 (COX-2) inhibitors,
78, 335, 337, 339340, 345,
347349, 351, 352
cyprohepatidine hydrochloride, 312
cytidine analogue, 119129
cytokines, host-derived, 310
cytotoxic agents, 3233, 191
D-limonene, 351
dexamethasone, 312
diagnostic technologies, 365380
dietary factors, 307308, 310
dietary guidelines, ACS, 308
difluoromethylornithine, 330, 349
dihematoporphyrin ether, 371
dilation, esophageal, 286287
diverticulitis, 164
DNA adduct formation, 328
396
Index
Index
estrogen compounds, 345, 348
ethanol, percutaneous injection of (PEI),
261262, 264
etoposide, 2730, 36
exatecan, 111
excitation light wavelength, 366, 367368
extramucosal enucleation, 11
familial atypical multiple mole melanoma
syndrome (FAMMM), 70, 72
FAMTEX, 2728, 36
Fanconis anemia, 333
FAP phenotype, 175
farnesyl transferase inhibitors, 113114
fat emulsion, intravenous, 316
fecal occult blood testing, 142145, 147
femoral stenosis, percutaneous dilation of,
279
fentanyl, 206, 210
fiber, dietary, 340346
fibrinolytic agents, intrapleural, 278279
fibroma, esophageal, 14
fibrosis, 314
fine-needle aspiration, 59
complications of, 238
endoscopic ultrasound-guided, 5455,
94, 131, 226, 229, 235, 237
238
flavopiridol, 330
floxuridine, 186
fluorescence spectroscopy, 328, 367370
laser-induced, 365369, 380
fluorescent agents, exogenous, 370372
fluorophores, 365366, 367, 371
folic acid, 329
free radicals, neutralization of, 339
fulguration, 171172
fundoplication, surgical, 5
gallbladder, drainage of, 256
gastrectomy, 2526, 6061
gastric adenocarcinoma, 226227, 349
gastric cancer, 2324, 40, 62, 333
chemoprevention agents in, 349350
classification and prognostic indicators
of, 2425
diet and, 58, 313
endpoints of, 349350
397
398
Index
Index
lymph nodes
dissection of, 6162
metastasis to, 2526, 100, 184
Lynch II Syndrome, 177
MAGIC trial, 32, 62
magnetic resonance cholangiopancreatography (MRCP), 79
magnetic resonance imaging, 93, 129130,
135136
malnutrition, 313
marimastat, 111, 331
matrix metalloproteinase inhibitors, 30,
114
McGill Pain Questionnaire (SF-MPQ),
201
mechanical pleurodesis, 278
mediastinal biopsy, 267268
megestrol acetate, 310
melanoma, familial, 333
melanotonin, 310
melena, 164
Memorial Symptom Assessment Scale
(MSAS), 202
meperidine, 209
metastasectomy, 184185
metastatic disease
incidence of, 23
in pancreaticobiliary malignancy, 135
136
treatment of, 107113, 184189
metastatic vertebral compression fractures,
217218
methotrexate, 2730
methyl-CCNU, 31
microsatellite instability (MSI), 24, 70,
151, 159
mismatch repair genes (MMR) mutations,
151, 158160, 178, 332
mitomycin C, 2730
mitomycin C and streptozocin, 117
molecular beacons, 378379, 380
molecular screening, 7980
monoclonal antibodies, 39
morphine, 206, 209210
mucinous duct ectasia, 135
mucosa-associated lymphoid tissue (MALT)
lymphoma, 227228
multimodal therapy, 57
399
400
Index
p16 mutations, 69
p53 mutations, 80, 134
p53 tumor cell suppressor genes, 91
paclitaxel, 29, 3233, 3637
pain
assessment of, 198203
pathophysiological mechanisms and
diagnosis of, 199200
pain intensity scales, 198
pain management, 195219
acute, 203207
barriers to, 196
chronic, 207210
interventional techniques in, 211218
long-term, 210
practice standards in, 196198
resources for, 219
pain-related outcomes, assessment of,
198203
pancreas
adenocarcinoma of, 133, 232235
amyloid of, 90
biopsy of, 269
cystic neoplasms of, 135
hypoechoic mass in head of, 234
mass in, 233235
surgical anatomy of, 9697
pancreatectomy, 83, 96, 100, 101
pancreatic cancer
chemoprevention agents in, 351352
chemotherapy for, 107114
diet and nutritional factors in, 307
308, 313
duodenal obstruction from, 296297
familial, 7475, 333
epidemiology and incidence of,
6769
genetics of, 73
risk factors in, 68, 7374
screening for, 7680
family history of, 6869, 8083
genetic syndrome associated with, 71
immune therapy for, 114115
locally advanced, 115118
metastatic, 107113
palliative intervention for, 101102
postoperative care for, 102
preoperative evaluation of, 8995
staging of, 88, 389390
Index
Perillyl alcohol, 329
peripheral blocks, 216
peritoneal carcinomatosis, 32
peritoneal cytology, 60
peritoneovenous shunting, percutaneous,
265
Peutz-Jeghers syndrome, 70, 72, 334
PGE2 concentration, 335
pharmacological treatment, 310312
phenol, 216
photodynamic therapy, 78, 138, 288
291
Photofrin, 288, 371
photosensitizers, 288, 370371
physical dependence, 196
pituitary ablation, 218
pleural effusions, drainage of, 277279
PMMA injection, 218
pneumothorax, 268, 270
positron emission tomography (PET), 60,
94
postembolization syndrome, 260
postoperative pain management, 203207
premalignant disease, esophageal, 18
prevention, in Barretts esophagus, 78
proctocolectomy, restorative, 175176
proctolectomy, 179181
proctosigmoidoscopy, 169
proinflammatory cytokines, 2425
propofol, 125126
proproxyphene, 209
proteolysis inducing factor, 310
proteolytic enzymes, 378
proton pump inhibitors, 340
proto-oncogenes, mutations in, 159160
protoporphyrin IX, 370371
PRSS1 mutations, 7273
pseudodiverticulum formation, 14
psychoactive drugs, 210
radiofrequency ablation, 186, 261262,
263264, 280
radiology, interventional
in abscess drainage, 265266
for ascites, 264265
in biliary disease treatment, 245256
in central venous access, 269271
in chest interventions, 277279
401
402
Index
sulindac, 176177
superior vena cava occlusion, 271272
surgical approaches
colorectal, 157181
esophageal, 1120, 35, 39
gastric, 2526, 5362
to intraductal papillary mucinous
tumor, 8889
to pancreatic neoplasia, 87103
surgical resection
esophageal, 11, 1415
pancreatic, 9596
surrogate endpoint biomarkers (SEBs), 335
surveillance procedures, 4, 78, 147153
tamoxifen, 176177
Taxol, 29
Taxotere, 30
tazobactam/piperacillin, 260
tea polyphenols, 331
telomere dysfunction, 80
thalidomide, 310
thermal ablation, 263264, 287288
thermal lesions, radiofrequency-generated,
217
thermal therapy, 296297, 300301
thoractomy, 35
tipifarnib, 111, 113114
tissue autofluorescence, 365366
tissue plasminogen antigen (tPA), 278
279
TME technique, 190191
TNM staging
for colorectal cancer, 168169, 183
184, 391392
for esophageal cancer, 5455, 385
386
for gastric cancer, 25, 60, 387388
for pancreatic cancer, 389390
total urine nitrogen (TUN), 319
transanal excision, 171
transjugular intrahepatic portosystemic
shunt (TIPS), 265
transloop retrograde nephrostomy, 274
triglycerides, 317
triterpenoids, 330
troglitazone, 330
Trouseaus syndrome, 90
TRP-MET rearrangement, 24
Index
403
vinca alkaloids, 37
vinorelbine, 37
visceral pain, cancer-related, 199, 208
209
vitamin D preparations, 329
vitamin E, 331
Von Hippel-Lindau disease, 334
Z-stent, 293295
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Figure 2-1. Endoscopic view of small mid-esophageal leiomyoma. (Photo courtesy of Michael Kochman, MD, University of
Pennsylvania Medical Center.) Also shown on page 12.
Color Atlas
Figure 15-2C. Post-treatment image demonstrating no endoscopic evidence of tumor with restoration of the esophageal
lumen. Also shown on page 290.
Figure 15-3A. Gastroesophageal junction tumor prior to placement of esophageal stent. Also shown on page 292.
CA-XI
CA-II
Figure 2-3A. Typical small
esophageal leiomyoma appropriate for extramucosal enucleation. (Reprinted from Atlas of
Surgery, 2e, Cameron JL, pp 7375, Copyright 1994 with permission from Elsevier.) Also shown
on page 14.
CA-III
Figure 2-3C. The leiomyoma is gently dissected
away from the esophageal
mucosa. (Reprinted from
Atlas of Surgery, 2e,
Cameron JL, pp 73-75,
Copyright 1994 with permission from Elsevier.) Also
shown on page 14.
CA-IV
Figure 5-2. Histology of pancreatic intraepithelial neoplasia (PanIN). (A) PanIN 1 (open
arrow) is characterized by elongation of epithelial cells with abundant supranuclear mucin
and PanIN 2 (solid arrow) is defined by nuclear abnormalities including enlargement and
crowding, hyperchromatism, and stratification. (B) In PanIN 3, there are lush papillary projections, loss of nuclear polarity, and nuclear atypia with mitoses. (Photomicrographs courtesy of Dr. Teresa Brentnall.) Also shown on page 76.
Figure 8-4A. Ampulla of Vater. Normal ampulla as seen using a sideviewing endoscope in the second portion of duodenum. A transverse
duodenal fold is seen draping over the upper margin of the papillary
mound. Also shown on page 131.
CA-V
Figure 8-4B. Bulging ampulla. This was found to harbor an adenocarcinoma arising in the very distal portion of the pancreatic duct.
Also shown on page 131.
Figure 13-11. Electronic curvilinear array echoendoscope (GFUC30P, Olympus America Corp., Melville, NY) with FNA device
(Echotip ultrasound needle, Wilson-Cook Medical, Winston-Salem,
NC) exiting the instrument channel. Also shown on page 237.
CA-VI
Figure 14-5C. A basket was advanced through the instrument channel and used to remove the stone. Also shown on page 255.
CA-VII
Figure 14-6D. Following resection 6 weeks later, no viable tumor was present, and hepatic vessels containing microspheres
were identified in the background of necrosis. Also shown on page 258.
CA-VIII
Figure 14-6E. Another look at resection 6 weeks later, no viable tumor was present, and hepatic vessels containing microspheres were identified in the background of necrosis. Also shown on page 258.
CA-IX
Figure 15-2A. Endoscopic appearance of an obstructing esophageal cancer. Also shown on page 289.
CA-X
CA-XII
Figure 15-5B. The covered esophageal Z-stent. Also shown on page 294.
CA-XIII
Figure 15-6. Illustration of an esophageal Flamingo stent bridging a distal esophageal tumor. Also shown on page 294.
Figure 15-7. Covered Dua stent with distal sleeve to prevent acid
reflux into esophagus post-stent deployment. Also shown on page
295.
CA-XIV
CA-XV
Figure 15-10. Enteral
Wallstent seen extending
proximally through the
pylorus into the stomach.
Stent was placed through
pylorus into duodenum
for malignant gastric outlet obstruction. Also
shown on page 298.
Figure 18-2. Endoscopic image of nodule with HGD and ALA-enhanced fluorescence
imaging of identical nodule. (Courtesy of Norman Nishioka, MD, Boston, Mass.) Also
shown on page 372.
CA-XVI
Figure 18-4. (A) OCT image of esophageal adenocarcinoma. Scale bar 500 m. (B)
Corresponding histopathology (H&E, orig. mag x 40). (Courtesy of Brett Bouma, PhD
and Gary Tearney, MD, PhD, Boston, Mass.) Also shown on page 377.