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Nat Rev Dis Primers. Author manuscript; available in PMC 2016 November 05.
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Published in final edited form as:

Nat Rev Dis Primers. ; 1: 15065. doi:10.1038/nrdp.2015.65.
COLORECTAL CANCER
Ernst J. Kuipers1, William M. Grady2, David Lieberman3, Thomas Seufferlein4, Joseph J.
Sung5, Petra G. Boelens6, Cornelis J. H. van de Velde6, and Toshiaki Watanabe7
1Erasmus MC University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The

Netherlands 2Clinical Research Division, Fred Hutchinson Cancer Research Center; Department
of Medicine, University of Washington School of Medicine, Seattle, WA, USA 3Division of
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Gastroenterology and Hepatology, Oregon Health and Science University, Portland, OR, USA
4Department of Internal Medicine I, University of Ulm, Ulm, Germany 5Department of Medicine
and Therapeutics, Chinese University of Hong Kong, Hong Kong, China 6Department of Surgery,
Leiden University Medical Center, Leiden, The Netherlands 7Department of Surgical Oncology
and Vascular Surgery, University of Tokyo, and the University of Tokyo Hospital, Tokyo, Japan
Abstract
Colorectal cancer had a low incidence several decades ago. However, it has become a predominant
cancer and now accounts for approximately 10% of cancer-related mortality in western countries.
The ‘rise’ of colorectal cancer in developed countries can be attributed to the increasingly ageing
population, unfavourable modern dietary habits and an increase in risk factors such as smoking,
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low physical exercise and obesity. New treatments for primary and metastatic colorectal cancer
have emerged, providing additional options for patients; these treatments include laparoscopic
surgery for primary disease, more-aggressive resection of metastatic disease (such as liver and
pulmonary metastases), radiotherapy for rectal cancer and neoadjuvant and palliative
chemotherapies. However, these new treatment options have had limited impact on cure rates and
long-term survival. For these reasons, and the recognition that colorectal cancer is long preceded
by a polypoid precursor, screening programmes have gained momentum. This Primer provides an
overview of the current state of art knowledge on the epidemiology and mechanisms of colorectal
cancer, as well as on diagnosis and treatment.
Introduction
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We live in an era with improved worldwide average living standards and increased access to
adequate healthcare that has considerably improved the diagnosis and treatment of diseases.
These measures have had an impact on average life expectancy in most regions of the world.
Correspondence to: Ernst J. Kuipers, ; Email: [email protected].

Author contributions
Introduction (E.J.K.); Epidemiology (T.W., E.J.K.); Mechanisms/pathophysiology (W.M.G.); Diagnosis, screening and prevention
(J.J.S., E.J.K., D.L.); Management (P.G.B., C.vd.V., T.S., E.J.K.); Quality of life (E.J.K.); Outlook (All authors); Overview of the
Primer (E.J.K).
Competing interests
T.S. has received honoraria for lectures or advisory boards from Roche, Merck-Serono, Amgen and Bayer. All other authors declare no
competing interests.
Kuipers et al. Page 2
However, although death rates from communicable diseases have improved globally as a
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result of these medical improvements, cancer-related mortality has increased by almost 40%
over the past 40 years. A further 60% increase is expected in the coming 15 years, with 13
million people estimated to die of cancer in 2030 1. The main causes of cancer-related
mortality have also changed, attributable to alterations in disease incidence, introduction of
screening programmes and therapeutic improvements. Colorectal cancer was rather rare in
1950, but has become a predominant cancer in Western countries, now accounting for
approximately 10% of cancer-related mortality. Reasons explaining this increased incidence
include population ageing and the preponderance of poor dietary habits, smoking, low
physical activity and obesity in western countries. The change in incidence is not only
apparent in the rates of sporadic disease, but also in some familial cancer syndromes.
Indeed, given that rates of Helicobacter pylori infection (a causative factor of gastric cancer)
have fallen dramatically, colorectal cancer is now the predominant presentation of Lynch
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syndrome (a hereditary non-polyposis type of colorectal cancer), whereas carriers of this

syndrome used to be predominantly affected by gastric cancer 2–4.
New treatments for primary and metastatic colorectal cancer have been developed and
include laparoscopic surgery for primary disease; resection of metastatic disease affecting,
for example, the liver and lungs; radiotherapy for rectal cancer and some forms of metastatic
disease; and neoadjuvant and palliative chemotherapy5–7. Despite advances in surgical and
medical therapies, cure rates and long-term survival have changed little in the past several
decades. Against this background, and given that colorectal cancer is preceded by a polypoid
precursor (Figure 1), screening programmes for early detection have gained momentum.
Indeed, screening is expected to have a major impact on colorectal cancer incidence and
mortality in the next 15 years, an effect that is unlikely to come from lifestyle interventions
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or from new therapeutics. Screening will only make these improvements with high uptake;
accordingly, major improvements in noninvasive screening (for example, faecal
immunochemical testing and faecal DNA testing) are being investigated as alternatives to the
current gold standard, but invasive, screening methodology — colonoscopy. Alongside these
advances, the quality of screening colonoscopy has undergone substantial improvement in
terms of technical changes and training, and quality assurance8,9.
In this Primer, we provide an overview of the current knowledge on epidemiology and

mechanisms underlying colorectal cancer, as well as on diagnosis and treatment, including
surgical and medical approaches.
Epidemiology
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Colorectal cancer is the second- and third-most common cancer in women and men,
respectively. In 2012, 614,000 women (9.2% of all new cancer cases) and 746,000 men
(10.0% of new cancer cases) were diagnosed with colorectal cancer worldwide10.
Combined, in both sexes, colorectal cancer is the third-most common cancer and accounts
for 9.7% of all cancers excluding non-melanoma skin cancer. More than half of the cases
occur in more-developed regions of world. The age-standardized incidence rate (ASRi) of
colorectal cancer is higher in men (20.6 per 100,000 individuals) than in women (14.3 per
100,000). The majority of patients with sporadic cancer are >50 years of age, with 75% of
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patients with rectal cancer and 80% of patients with colon cancer patients being ≥60 years of
age at the time of diagnosis.
Incidence varies geographically, with the highest incidence in Australia and New Zealand
(ASRi 44.8 and 32.2 per 100,000 men and women, respectively), whereas Western Africa
(ASRi 4.5 and 3.8 per 100,000) has the lowest incidence (Figure 2). More-developed regions
(Europe, Northern America, Australia, New Zealand and Japan; combined ASRi 29.2 per
100,000) have a higher incidence than less-developed regions (all regions of Africa, Asia
(excluding Japan), Latin America and the Caribbean, Melanesia, Micronesia and Polynesia;
ASRi 11.7 per 100,000) 10. The seven world regions can be ranked according to increasing
ASRi, from Africa (6.3 per 100,000), Asia (13.7 per 100,000), Latin America and Caribbean
(14.0 per 100,000), Micronesia/Polynesia (15.0 per 100,000), North America (26.1 per
100,000), Europe (29.5 per 100,000), to Oceania (34.8 per 100,000) 10. Within each of these
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regions, the ASRi can show marked variation. In Europe, Albania (8.4 per 100,000) and
Ukraine (23.4 per 100,000) have a lower incidence, whereas Slovakia (42.7 per 100,000),
Hungary (42.3 per 100,000) and Denmark (40.5 per 100,000) have a high incidence. Asia
has the greatest diversity with regard to the ASRi of colorectal cancer. The incidence is high
in Korea (45.0 per 100 000), Singapore (33.7 per 100,000) and Japan (32.2 per 100,000), but
much lower in Nepal (3.2 per 100,000), Bhutan (3.5 per 100,000) and India (6.1 per
100,000). These variations are associated with different socioeconomic levels11.
In 2013, 771,000 people died as a result of colorectal cancer globally12, making the disease
the fourth most common cause of cancer-related death worldwide after lung, liver and
stomach cancer12. The age-standardized mortality rate (ASRm) of colorectal cancer in
different countries reflects disease incidence, which explains why the ASRm is higher in
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men (10.0 per 100,000) than in women (6.9 per 100,000). Mortality also depends on the
stage distribution at diagnosis, which is influenced by the availability of a population-
screening programme and by the level of care in each country. The ASRm is almost two-fold
higher in more-developed regions (11.6 per 100,000) than in less-developed regions (6.6 per
100,000). The ASRm in both sexes ranged from 3.3 per 100,000 people in Western Africa to
14.9 per 100,000 people in Central and Eastern Europe; in men, this value ranged from 3.5
per 100,000 people in Western Africa to 20.3 in Central and Eastern Europe, whereas in
women, ASRm ranged from 3.0 per 100,000 people in Western Africa to 11.7 per 100,000
people in Central and Eastern Europe. That is, Western Africa showed the lowest age-
standardized mortality in the world and Central and Eastern Europe exhibited the highest
mortality in the world, in both men and women. Worldwide, mortality due to colorectal
cancer has increased with 57% between 1990 and 2013 12. Since the 1980s, in several
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countries in Europe, North America and Asia, mortality has tended to decrease. This
decrease might be attributable to the introduction of colonoscopy, which has improved
detection and treatment of early lesions.
Risk factors
Both genetic and environmental factors play an important part in the aetiology of colorectal
cancer. The majority of colorectal cancers are sporadic; approximately three-quarters of
patients have a negative family history. In most Western populations, the average lifetime
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risk for colorectal cancer is in the range of 3–5%. However, this risk almost doubles in
individuals with a first-degree family member with colorectal cancer who was diagnosed at
50–70 years of age; the risk triples if the first-degree relative was <50 years of age at
diagnosis. Risk further increases in individuals who have two or more affected family
members. For sporadic colorectal cancer, this increased risk in the presence of affected
family at least in part reflects low-penetrance genetic factors. Accordingly, positive family
history has a role in approximately 15–20% of patients with colorectal cancer.
Indeed, a specific subgroup of the patient population is formed by those affected by a

hereditary colorectal cancer syndrome, accounting for 5–10% of all patients. The most
common syndrome in this category is Lynch syndrome. This syndrome is caused by a
mutation in one of the DNA mismatch-repair genes: MLH1, MSH2, MSH6, PMS2 or
EPCAM. Impaired mismatch repair during replication gives rise to accumulation of DNA
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mutations, which occur, in particular, in microsatellite DNA fragments with repetitive

nucleotide sequence. This microsatellite instability (MSI) can be identified by means of
polymerase chain reaction (PCR) testing, which compares normal and tumour DNA of the
same patient. Patients with Lynch syndrome used to be identified by means of
clinicopathological criteria, such as the Amsterdam and Bethesda criteria4,13. However,
clinical practice is shifting towards unrestricted testing of tumour material of all patients
diagnosed before the age of 70 years by means of MSI PCR and immunohistochemistry for
lack of expression of specific mismatch-repair proteins14,15.
The second most common hereditary colorectal cancer syndrome is familial adenomatous
polyposis. This syndrome is caused by mutations in the adenomatous polyposis coli (APC)
gene, which controls activity of the Wnt signalling pathway4. Most patients with familial
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adenomatous polyposis develop very large numbers of colorectal adenomas and subsequent
colorectal cancer at a young age. Other hereditary colorectal cancer syndromes are polyposis
associated with mutations in the mutY DNA glycosylase (MUTYH) gene, Peutz Jeghers
syndrome, serrated polyposis and juvenile polyposis; the diagnosis and management of
which have been discussed elsewhere4.
Chronic colitis due to inflammatory bowel disease (IBD) is also associated with increased
risk of colorectal cancer. This risk increases with longer duration of IBD16. IBD explains
only 1% of colorectal cancers in western populations, and a range of studies suggest that the
incidence of colorectal cancer in those with IBD is decreasing because of effective anti-
inflammatory treatments and improved surveillance17,18, although this observation is not yet
unanimous19.
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A range of environmental — largely modifiable — lifestyle factors influence the risk of

developing colorectal cancer. The risk is increased by smoking, alcohol intake and increased
body weight. With each unit increase of the body mass index, the risk for colorectal cancer
increases by 2–3% 20. In close conjunction, patients with type 2 diabetes mellitus also have
an increased risk for colorectal cancer21. Moderate alcohol consumption (2–3 units per day)
has been estimated to increase risk by 20%, whereas even higher alcohol consumption is
associated with an up to 50% increased risk22. Prolonged heavy smoking has an effect of
similar magnitude23,24. Intake of red meat and processed meat increases colorectal cancer
risk by an estimated 1.16-fold per 100 g increase of daily intake25. By contrast, consumption
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of milk, whole grains, fresh fruits and vegetables, as well as intake of calcium, fibre,
multivitamins and vitamin D, decrease risk. The decrease of risk is estimated to approximate
10% per daily intake of every 10 g fiber, 300 mg calcium or 200 ml milk 25,26. Daily
physical activity for 30 minutes has a similar magnitude of effect 20,27. Low-dose aspirin has
also been associated with decreased risk of colorectal cancer28.
The prevalence of these modifiable lifestyle factors can explain, to a considerable extent, the
geographic and socioeconomic differences in colorectal cancer incidence29. Several studies
have estimated that 16–71% of colorectal cancers in Europe and the United States are
attributable to lifestyle factors30–32. Any benefit from lifestyle changes can be augmented by
regular intake of aspirin and other nonsteroidal anti-inflammatory drugs33; however, this
effect seems to depend on host genotype34,35. Statin use might have a small preventive effect
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on colorectal cancer incidence36,37, as does hormone therapy in post-menopausal women38.
The variety of environmental factors that influence colorectal carcinogenesis is likely

reflected in the heterogeneity of colorectal cancer, and has stimulated research into the so-
called field of ‘molecular pathological epidemiology’, which focuses on the correlation
between environmental and genetic factors, and between molecular tumour characteristics
and disease progression39. Further research into the correlation between colonic microbiota
and colorectal cancer will likely provide further insights (see below).
Mechanisms/pathophysiology
The environmental and genetic factors that cause colorectal cancer do so by promoting the
acquisition of hallmark behaviours of cancer (Box 1) in colon epithelial cells40,41. One way
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these hallmark cancer traits are acquired is through the progressive accumulation of genetic
and epigenetic alterations that activate oncogenes and inactivate tumour suppressor genes.
The loss of genomic and/or epigenomic stability has been observed in the majority of early
neoplastic lesions in the colon (namely, aberrant crypt foci, adenomas and serrated polyps)
and is likely a central molecular and pathophysiological event in the initiation and formation
of colorectal cancer42,43. The loss of genomic and epigenomic stability accelerates the
accumulation of mutations and epigenetic alterations in tumour suppressor genes and
oncogenes, which drive the malignant transformation of colon cells through rounds of clonal
expansion that select for those cells with the most aggressive and malignant behaviour44–46.
A prevailing paradigm is that the cell of origin of most colorectal cancers is a stem cell or
stem cell-like cell that resides in the base of the colon crypts47. In this model, mutations in
oncogenes and tumour suppressor genes in these cells lead to the formation of cancer stem
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cells, which are essential for the initiation and maintenance of a tumour.
Box 1
The hallmarks of cancer40,41

• Avoiding immune destruction: immune suppression in tumour
microenvironment by induction of local cytokines
• Evading growth suppressors: mutation and downregulation of growth-inhibiting

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factors and their receptors
• Genome instability and mutation: inactivation of DNA repair mechanisms
• Enabling replicative immortality: inhibition of mechanisms that induce

senescence and induction of telomerase activity
• Deregulating cellular energetics: aerobic glycolysis (Warburg phenomenon) and

glutaminolysis
• Tumour-promoting inflammation: induction of growth-promoting and

angiogenesis-promoting factors by secreted proteins made by local
inflammatory cells
• Inducing angiogenesis: induction of the formation of new blood vessels

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• Resisting cell death: escape from autonomous and paracrine mediators of

apoptosis and other forms of cell death (necrosis, necroptosis)
• Activating invasion and metastasis: remodelling of extracellular matrix to

promote cell motility and induction of epithelial–mesenchymal transition
In the colon, the evolution of normal epithelial cells to adenocarcinoma by and large follows
a predictable progression of histological and concurrent epigenetic and genetic changes
(Figure 3). In the ‘classic’ colorectal cancer formation model, the vast majority of cancers
arise from a polyp beginning with an aberrant crypt, which then evolves into an early
adenoma (<1 cm in size, with tubular or tubulovillous histology). The adenoma then
progresses to an advanced adenoma (>1cm in size, and/or with villous histology) before
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finally becoming a colorectal cancer. This process is driven by accumulation of mutations

and epigenetic alterations and takes 10–15 years to occur but can progress more rapidly in
certain settings (for example, in patients with Lynch syndrome)48. Notably, although the
histology of conventional tubular adenomas is fairly homogeneous, the molecular biology of
these polyps are heterogeneous, which might explain why some adenomas progress to
colorectal cancer (approximately 10% of polyps) and some do not49,50.
Until 5–10 years ago tubular and tubulovillous adenomatous polyps were thought to be the
only lesions capable of progressing to cancer. However, some colorectal cancers have been
shown to evolve from a subset of polyps called sessile serrated polyps, which account for
roughly 5–10% of all polyps. These serrated polyps arise by molecular and histological
events that are distinct from tubular adenomas51–53 and are classified into three categories:
hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas54. The
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sessile serrated polyps have the potential to transform into colorectal cancers through the
following sequence: hyperplastic polyp to sessile serrated polyp to adenocarcinoma51,55.
Furthermore, serrated polyps that arise in the right colon (which includes the cecum,
ascending colon and transverse colon) commonly show MSI and a form of epigenetic
instability characterized by excessive aberrant CpG island DNA methylation, termed the
CpG Island Methylator Phenotype (CIMP). By contrast, polyps that arise in the left colon
(which includes the descending colon, sigmoid colon and rectum) are typically
microsatellite stable but frequently carry mutations in KRAS and a subset of these polyps
have an attenuated form of the CIMP52,53,56.
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Given these molecular differences in the polyps and cancers they evolve into, a classification
system for colorectal cancer has been proposed, with four subgroups of differing molecular
features: hypermutable/microsatellite unstable (Hyp-MSI), hypermutable-microsatellite
stable (Hyp-MSS), microsatellite stable (MSS) or chromosome unstable (CIN) and CIMP
cancers43,57. The frequency of specific mutations can vary dramatically between the
molecular subclasses, suggesting each has its own set of cooperating drivers57. However, the
specific mutations and epigenetic alterations that define these molecular subgroups are still
being determined. Some mutations, such as those in APC and SMAD family member 4
(SMAD4), are common among all the molecular subgroups — suggesting a central role in
colorectal cancer in general — whereas others are restricted to one subgroup (for example,
BRAF in CIMP colorectal cancers)58.
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In colorectal cancer, substantial heterogeneity in the specific mutations is evident between

tumours, although the mutations seem to cluster in epistatically related groups (for example,
genes involved in a certain signalling pathway) 59–61. The most common alterations seen in
colorectal cancer include those in APC, catenin-beta1 (CTNNB1), KRAS, BRAF, SMAD4,
transforming-growth factor-beta receptor 2 (TGFBR2), TP53, phosphatidylinositol-4,5-
bisphosphate 3-kinase catalytic subunit-alpha (PIK3CA), AT-rich interactive domain 1A
(ARID1A), SRY (sex-determining region Y) box 9 (SOX9), family with sequence similarity
123B (FAM123B; also known as AMER1) and ERBB2, which promote tumorigenesis by
perturbing the function of key signalling pathways, including the Wnt–β-catenin, epidermal
growth factor (EGF)-mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-
kinase (PI3K) and TGF-β signalling pathways, or by affecting genes that regulate central
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behaviours of cells, such as DNA repair and proliferation62,63 (Table 1). Colorectal cancer is
frequently initiated by alterations that affect the Wnt signalling pathway, and the ensuing
neoplastic cells then progress upon deregulation of other signalling pathways, including the
RAS–RAF–MAPK, TGF-β, and the PI3K–AKT pathways 61,64.
In addition to gene mutations, epigenetic alterations commonly occur in polyps and

colorectal cancers and seem to cooperate with gene mutations to drive the polyp to cancer
progression59,65,66. DNA methylation affects CpG-rich regions (CpG islands), which are
often located in the 5′ region of genes and can result in transcriptional silencing through
effects on transcription factor binding and changes in chromatin structure67. Modifications
in DNA methylation related to the development of cancer (in general) include two
fundamental changes: hypermethylation of CpG islands in gene promoters, which can
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silence tumour suppressor genes, and hypomethylation of repetitive genetic elements, which
can lead to genomic instability or oncogene activation68. Hypermethylation, such as of the
septin 9 (SEPT9) gene promotor, is also used for screening purposes (see below).
Importantly, the frequencies of many of these molecular features vary depending on the
location of the tumour in the gut (from the ascending colon to the rectum)69,70. Some studies
support a gradual gradient in change in frequency of the molecular alterations, whereas
others suggest a more abrupt dichotomy. This has led to the traditional dichotomy of
‘proximal’ and ‘distal’ colorectal cancer versus adoption of a continuum model. Both
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models support the notion that the tumor microenvironment (the gut microbiome and
inflammatory state of adjacent tissue) modulates the way these mutations affect cancer
formation and disease progression. Thus, our current understanding of the pathogenesis of
colorectal cancer is that the disease results from the accumulation of alterations in genes that
then drive the formation of the tumour in the context of tumour-promoting factors derived
from the adjacent tissue. This paradigm formed the basis for recent recommendation to
determine the in situ immune cell infiltrate of the tumour as a prognostic marker alongside
its (standard) TNM stage71. In close conjunction with these data, recent research has focused
on the role of the gut microbiota in colorectal carcinogenesis. Indeed, studies have shown
the enriched presence of Fusobacteria72, in particular in cancers with CIMP status73, which
might be inversely related to the CD3+ T cells in colorectal cancers74. Together, these data
form a basis for further research into the role of the colon microbiota and colon
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carcinogenesis.
Diagnosis, screening and prevention

Diagnosis
A diagnosis of colorectal cancer either results from an assessment of a patient presenting
with symptoms, or as a result of screening. The disease can be associated with spectrum of
symptoms, including blood in stools, change in bowel habits and abdominal pain. Other
symptoms include fatigue, anaemia-related symptoms such as pale appearance and shortness
of breath, and weight loss. The predictive value of these symptoms for the presence of
colorectal cancer in an elderly patient is limited, but they do warrant further clinical
evaluation. With the widespread introduction of population screening for colorectal cancer,
many individuals are diagnosed at a pre-clinical stage. In symptomatic patients, colonoscopy
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is the preferred method of investigation, but other endoscopic methods are also available or
being developed (Box 2). For population screening, a range of other methods can be used for
primary assessment, followed by colonoscopy in case of a positive test.
Box 2
Endoscopic techniques for the diagnosis of colorectal cancer

High-definition white-light endoscopy
• Current standard for colonoscopy, combining high-definition video endoscopes

with high-resolution videoscreens
• Provides detailed image of the gastrointestinal mucosa

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• Advantage of routine endoscopy, disadvantage that it provides no specific

contrast for detection of neoplastic lesions
Chromoendoscopy
• The use of a dye spray during gastrointestinal endoscopy to improve

visualization
• Improves detection of neoplastic lesions
• Time-consuming to spray the complete colon

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• A new technique with dye incorporated into colon preparation is under

investigation
Magnification endoscopy
• Endoscope with zoom-lens in tip, which enables 6–150-fold enlargement of the
mucosa
• Can characterize and determine the extension of neoplastic lesions
• Not suitable for screening of the complete colon
• Can be combined with other methods
Narrow band imaging

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• Technique that can be built into white-light endoscopes
• Filters light to two bands, with a wave length of respectively 415 nm (blue) and
540 nm (green)
• Longer wavelength light is less scattered and, therefore, penetrates deeper into
the mucosa
• Blue light enhances superficial capillaries, whereas the green light displays
deeper, subepithelial vessels
• Can characterize and determine the extension of neoplastic lesions
• Does not increase neoplasia detection rates
Intelligent colour enhancement (FICE) imaging (Fujinon) and iScan imaging

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(Pentax)
• Similar techniques as narrow band imaging, but no filtering of the outgoing light
• Instead, processes the reflected light
Autofluorescence endoscopy
• Technique that can also be built into white-light endoscopes
• Based on the principle that illumination with a specific blue wavelength light
can lead to excitation of tissue, which then emits light with longer wavelength
• Wavelength of the emitted light is longer for neoplastic tissue
• Can be used to search for neoplastic lesions

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Endomicroscopy
• Technique of extreme magnification endoscopy
• Enables in vivo visualization of individual glands and cellular structures
• Can evaluate neoplastic lesions
• Not suitable for scanning larger mucosal surfaces

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Colonoscopy—Colonoscopy is the gold standard for diagnosis of colorectal cancer. It has

a high diagnostic accuracy and can assess the location of the tumour. Importantly, the
technique can enable simultaneous biopsy sampling and, hence, histological confirmation of
the diagnosis and material for molecular profiling. Colonoscopy is also the only screening
technique that provides both a diagnostic and therapeutic effect. Removal of adenomas using
endoscopic polypectomy can reduce cancer incidence and mortality9,75–78. Indeed, the
efficacy of colonoscopy for reduction of colorectal cancer incidence and mortality was well
demonstrated by the US National Polyp Study77,79. Recent 20-year follow-up data from this
study showed a reduction in colorectal cancer-related mortality of 53%77, an encouraging
result that has been echoed by a more-recent study80. The quality of colonoscopy is a
determining factor in the diagnostic yield of cancer and adenoma, which is the most certain
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way of avoiding interval cancers (that is, a tumour arising in between screening
visits)9,76,81,82.
The image-quality of colonoscopy has markedly improved over the past 20 years, from
original fibre-optic to videochip endoscopes. Videochip endoscopes were further improved
over the years, leading to higher resolution and wider angle of view. The current standard
combines high-power endoscopes with high-resolution videoscreens to yield high-definition
white light endoscopy (hWLE). Although various technologies for further image
enhancement in colonoscopy have been introduced over the past decade, none of them has
been shown to improve the diagnosis of polyps and colorectal cancer compared with white
light colonoscopy83. Only chromoendoscopy (Box 2), has proven to be superior to hWLE in
identifying adenomas84. Narrow band imaging, imaging with the Fujinon Intelligent Color
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Enhancement system (Fujinon Corporation, Saitama, Japan) and autofluorescence

endoscopy are not advantageous over hWLE in detecting adenomas or carcinomas85. The
Third Eye Retroscope® device (Avantis Medical Systems, California, United States) was
designed to address the fact that lesions behind mucosal folds in the gut are often missed.
This endoscope provides a simultaneous retrograde view of the colon that complements the
forward view of a standard colonoscope. Several pilot studies have indicated that it might be
useful, but more data are needed86–88. The invasive nature of colonoscopy poses a burden to
screenees and patients, which might affect participation in screening programmes. In recent
years, several alternative diagnostic methods have been introduced, such as capsule
endoscopy and biomarker tests.
Capsule endoscopy—Capsule endoscopy uses a wireless capsule device swallowed by

the screenee, and enables examination of almost the entire gastrointestinal tract without the
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use of conventional endoscopy89– 92. Capsule endoscopy is useful in diagnosing adenomas

and colorectal cancer. The first-generation capsule endoscopy was found to be able to detect
polyps ≥6 mm in size with a sensitivity of approximately 60% and specificity of >80%89.
Cancer detection was achieved in 74% patients with colorectal cancer89. With the
development of the second-generation capsule endoscopy for the colon (PillCam® Colon2
(Given Imaging Ltd, Yokne’am Illit, Israel), the frame speed was increased from a fixed
speed of four pictures per second to a variable 4–35 pictures per second depending on
capsule movement. The angle of view was widened from 156° to 172° on both ends of the
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capsule, providing a 344° view. A large trial in the United States and Israel assessed the
accuracy of this new capsule to diagnose colorectal neoplasia. With 884 patients included,
sensitivity was shown to be 88% and specificity 82% for detection of adenomas >6 mm in
size93.
The European Society for Gastrointestinal Endoscopy Guideline for Colon Capsule
Endoscopy recommends capsule endoscopy as a feasible and safe tool for visualization of
the colonic mucosa in patients, who have undergone no or incomplete colonoscopies92. This
recommendation was then also incorporated in the Asia-Pacific guidelines on colorectal
cancer screening94. The indications for capsule endoscopy are at this moment limited to
patients who refuse conventional colonoscopy and to those in whom a complete colonoscopy
is not possible for anatomical reasons. The presence of a stenosis is a contraindication for
capsule endoscopy as it could lead to capsule retention.
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CT colonography—CT colonography uses low-dose CT scanning to obtain an interior

view of the colon. The technique is well established as a diagnostic modality for colorectal
cancer95. In a systematic review and meta-analysis that included >11,000 people from 49
centres, CT colonography was shown to have a sensitivity of 96% for colorectal cancer
detection96. This performance is similar to that of conventional colonoscopy. A recent study
reported similar performance of CT colonography and capsule endoscopy in patients with
previous incomplete colonoscopy97. A large trial in 411 patients with obstructive cancers
showed excellent performance of CT colonography for evaluation of proximal synchronous
lesions98. An observational study based on data from England of 2,731 people with a
positive guaiac faecal occult blood test (gFOBT, see below) showed that the detection rate of
advanced neoplasia was significantly lower for subsequent CT colonography than for
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subsequent colonoscopy99. Furthermore, the detection and accuracy rates for advanced
neoplasia were better in high-volume centres. These findings underline the need for
adequate quality assurance similar to measures implemented for colonoscopy screening.
CT colonography requires full bowel preparation (clearance of the bowel), air inflation and
change in position of the patients during the examination. The discomfort to the screenee of
CT colonography is similar to colonoscopy in experienced hands, in particular because of
the need of significant bowel insufflation100, but it has the advantage of obviating the use of
sedation and can be used as part of the staging procedure in a confirmed case of colorectal
cancer. However, CT colonography has low sensitivity for small (6–9mm) and flat
lesions101. The technique is associated with high colonoscopy referral rates (up to 30%), and
high rates of extra-colonic findings in non-cancer cases, which translate to unnecessary
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investigations and increased anxiety for individuals102,103. The costs of CT colonography,

and the need for further investigation in a subset of screenees limit the usefulness of this
method for population screening in most countries.
CT colonography has been recommended as one of the options for colorectal cancer
screening in guidelines in the United State and Europe 104,105. In many countries, CT
colonography has replaced double-contrast barium enema (the conventional X-ray-based
imaging modality for the colon) examination and is increasingly being used as an alternative
to conventional colonoscopy. However, CT colonography has not readily been accepted in

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Europe because of radiation exposure, costs, burden to patients and high colonoscopy
referral rates. In the Asia–Pacific region, CT colonography is not recommended for
colorectal cancer screening unless in those for whom total colonoscopy is not possible94.
Biomarkers of colorectal cancer—Molecular detection of colorectal cancer offers a

noninvasive test that is appealing to patients and clinicians as samples of multiple patients
can be analysed in batch. The ideal molecular marker should be highly discriminating
between cancer and advanced adenomas from other lesions, be continuously released into
the bowel lumen or circulation, and disappear or reduce after the lesion is removed or
treated. Indeed, assays using proteins, RNA and DNA in the blood, stool and urine have
been developed but with varying degrees of success (Table 1). Stool tests are based on the
fact that early cancers as well as advanced premalignant lesions can bleed and shed cells into
the bowel lumen, which can be detected. Blood tests obviate the handling of stool and urine
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and can be performed alongside routine checking of blood sugar and cholesterol in the
elderly population.
The gene SEPT9 belongs to a class of GTPases, and hypermethylation of its promoter region
is associated with colorectal cancer; aberrant methylation of SEPT9 at the tissue level
discriminates colorectal neoplasia from normal mucosa. Early case–control studies from
referral centres showed that SEPT9 methylation testing yielded a moderate sensitivity of 50–
70% for colorectal cancer, with a specificity of 85–90%106. However, a more-recent larger
scale study in population with average risk of developing the disease suggested a colorectal
cancer detection rate of <50% when using SEPT9 methylation testing107. The reported
detection of advanced colonic adenoma by SEPT9 methylation status is only approximately
10%. As such, SEPT9 assays are outperformed by current quantitative faecal
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immunochemical tests (FITs).
Mutation of APC and KRAS has been tested in DNA shed by epithelial cells and isolated
from stool samples. The first-generation faecal DNA tests only gave satisfactory results with
fair sensitivity for the detection of colorectal cancer but low sensitivity for the detection of
advanced colonic adenomas108. Since then, several technological improvements have been
made, including the use of a stabilizing buffer, the addition of other more-discriminating
markers (KRAS mutations, aberrant NDRG family member 4 (NDRG4), bone
morphogenetic protein 3 (BMP3) methylation and presence of β-actin), the use of more-
sensitive analytical methods and the optimization of the determining algorithm — all of
which have improved the accuracy of the assay (see further description below)109. Other
potentially useful markers under investigation include circulating tumour mRNA, microRNA
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and circulating cytokeratins110.
Screening and prevention

Colorectal cancer is more suitable for population screening than any other malignancy
owing to a combination of factors1. Firstly, the incidence of the disease is high and outcome
for a significant proportion of affected patients is poor despite intense, burdensome and
often very costly treatments111. Colorectal cancer also has a long preclinical stage. For
instance, 7,151 Dutch citizens aged 55–75 years were newly diagnosed with colorectal
cancer in 2012 112, which corresponds to approximately 0.2% of the 3.5 million people in
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that age group. Such an incidence is in line with similar annual incidences in other Western
European countries. However, colonoscopy screening studies generally tend to find prevalent
colorectal cancer in 0.5–0.9% of the participants in the same age group54,63,64. Although an
increased willingness of symptomatic screenees might confound this difference, these data
suggest that colorectal cancer on average progresses for several years before becoming
symptomatic. Furthermore, colorectal cancer is preceded by colorectal adenoma. In
individuals with sporadic (non-hereditary) disease, the progression from adenoma to cancer
takes at least 5–10 years113. The long preclinical stage of disease offers a large window of
opportunity for screening.
Second, colorectal cancer is also suitable for screening because adenomas and early cancers
are detectable and treatable entities, which is in contrast to precursors of other highly
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common cancers of the breast, prostate and lung.
Last, both endoscopic removal of adenomas as well as treatment of early stage cancer have a
profound impact on colorectal cancer mortality. After 20-year follow-up of the US National
Polyp Study cohort, colorectal cancer-specific mortality was approximately 50% lower
among subjects who at baseline had undergone endoscopic removal of adenomas than in an
unscreened control cohort77. Furthermore, the 5-year survival rates for patients with early
stage cancer are approximately 90%, compared with 10% for patients diagnosed with
advanced-stage metastatic disease. Together, these factors form the background for various
international guidelines on colorectal cancer screening. Screening in most countries aims to
capture men and women aged 50–75 years, although different age ranges are being used in
various programmes depending on the available resources114. Adoption of lifestyle measures
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can also significantly impact colorectal cancer incidence.
Endoscopy—Given that imaging of the colon can confirm a diagnosis or exclude

colorectal neoplasia, clinicians often favour these methods for screening purposes.
Colorectal adenomas and early stage cancers can directly be visualized by endoscopy, CT
colonography or capsule endoscopy77,90,96,103. A randomized comparison between CT
colonography and colonoscopy for primary population screening showed a slightly higher
uptake of the former, counterbalanced by a slightly lower sensitivity for advanced
neoplasia103. Capsule endoscopy screening might in the near future provide an alternative
visualization method for primary screening90. Overall, colonoscopy has the highest accuracy
and is generally considered the gold standard for screening and is associated with a number
of advantages (Table 2). Recent large observational studies showed that screening
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colonoscopy reduced the risk for colorectal cancer by approximately 80%, and had a similar
effect on related mortality115,116. This preventive effect of colonoscopy strongly depends on
procedural quality, which can be measured in terms of adenoma detection rate of the
performing endoscopist76. Other measures for procedural quality include the level of bowel
preparation, caecal intubation rates, complication rates, average sedative medication dose
and patient burden scores9. In a study from the United States, adenoma detection rates per
colonoscopist ranged from 7% in the lowest quintile of detection to 50% in the highest
quintile — a difference that is associated with an almost two-fold risk in interval cancer81.
The correlation between risk of post-colonoscopy cancer and adenoma detection rates was
also reported in a study from Poland76. Training and quality assurance measures, and
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adherence to surveillance guidelines also have an impact on the rate of post-colonoscopy

cancers75,117.
Sigmoidoscopy, which images the rectum and sigmoid colon and can include the descending
colon, has been shown in several randomized prospective trials to reduce the incidence of
colorectal cancer by approximately 33%, and reduce related mortality by 38–59%1,118–120.
This effect was obtained by single sigmoidoscopy screening with further colonoscopy in
those with signs of advanced polyps — a finding that formed the basis for the current roll-
out of nationwide primary sigmoidoscopy screening in England. The wide use of
colonoscopy and sigmoidoscopy for primary screening in various countries supports the
introduction of non-physician endoscopists who can perform diagnostic endoscopy
according to international standards121. Further studies are needed to assess performance
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and cost efficacy122.
Population screening—Given the considerable rise in treatment costs, colorectal cancer

screening is in many countries a cost-saving exercise123. Screening can be done with a range
of methods, both invasive and non-invasive (Table 2). Most programmes are based on a
single primary screening test, followed by colonoscopy in those who test positive114. In
other settings, screenees are offered a choice between different screening methods, which
might increase or decrease participation rates depending on the local setting124,125.
Population screening must consider more than just test accuracy, but should take test uptake
and demand on resources into account. Accordingly, screening results must be reported in
terms of identification of subjects with advanced neoplasia per 1,000 invited and in numbers
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needed to scope. A very accurate test by definition has no impact on cancer incidence and
mortality in a population if not widely applied1,111. Similarly, limitations in endoscopy
capacity preclude the use of colonoscopy for primary screening. For these reasons, many
countries prefer a two-step approach in population screening, first using noninvasive
screening test to select a subgroup of screenees who are at high risk of cancer for subsequent
colonoscopy. Typically, faecal occult blood test is this primary screen1, either using gFOBTs
or FITs. FITs are now more widely used than gFOBTs because of easier handling, resulting
on average in approximately 10% higher uptake, higher sensitivity for advanced neoplasia
and automated analysis126,127. Indeed, quantitative FITs offer the additional advantage that
their cut-off points can be adjusted to match colonoscopy capacity128. For an optimal impact
on the population level, adequate quality assurance is needed over the full range of the
screening programme, as is organized active call–recall screening1.
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The effect of uptake on the yield of screening was shown by a randomized study comparing
primary colonoscopy and FIT screening in Spain129. The cancer detection rate was similar in
both groups, but a considerable proportion of cancers in the colonoscopy group were
actually detected by primary FIT after screenees first refused primary colonoscopy.
Similarly, in a range of screening trials in the Rotterdam area, the highest detection rate was
observed with repeated FIT screening1,130. This detection rate can be further increased with
the use of two samples per screening round, especially in the first screening round131,
although this approach is less cost-effective than screening with one sample132. gFOBT
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screening routinely makes use of a 1–2-year interval, the higher accuracy of FIT can allow
for extension of the screening interval to 3 years133.
The performance of the aforementioned multi-target faecal DNA plus FIT testing was
compared with FIT alone for detection of colorectal neoplasia134. All participants in the
study underwent each of the ‘experimental’ screening methods and a confirmatory
colonoscopy. The combined tests identified 60 of 65 patients (92%) with colorectal cancer
and 321 of 757 patients (42%) with advanced adenomas; FIT alone detected 48 patients with
colorectal cancer (74%, P = 0.002) and 180 patients with advanced adenomas (24% P
<0.001)134. These results provide evidence for the accuracy of the DNA test in
asymptomatic average-risk individuals, and led to FDA approval of the multi-target faecal
DNA test plus FIT. However, the positive predictive value of the multi-target faecal DNA
test was low (24%) for a non-invasive test, and the DNA test plus FIT yielded a 16.1%
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positivity rate versus 7.0% for FIT alone, thus necessitating 2.3-fold more colonoscopies in
the DNA test plus FIT arm. If both tests were compared at the same positivity rate, a crucial
determinant in countries with limited colonoscopy resources, the actual diagnostic yield and
positive predictive value could have been approximated. This assumption is supported by
previous studies that reported a similar number needed to screen to detect advanced
neoplasia135. Finally, study design did not include a component to examine uptake of either
test. For these reasons, further studies are needed to position the DNA test as a population
screening method.
Surveillance after resection

Patients who have adenomatous polyps or colorectal cancer continue to be at risk for new
neoplastic lesions after these have initially been removed — either because of biological or
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environmental factors, or both136. These patients could benefit from surveillance to detect
and remove new lesions. Most evidence supporting this hypothesis is based on surveillance
studies that have documented higher rates of tubular adenomas >10mm, adenomas with
villous histology, high-grade dysplasia or cancer in patients with neoplasia at the baseline
colonoscopy exam; the risk of developing subsequent tumours also depends on the size and
histology of polyps at the index exam136–138. Furthermore, there is a relationship between
the index lesion and subsequent risk of death from colorectal cancer139. Together, this body
of data provides a strong justification for surveillance, but does not prove with certainty that
surveillance will actually prevent recurrent cancer or reduce mortality.
Guidelines for surveillance in patients without hereditary syndromes vary in the United
States and Europe137,140,141. The underlying premise of all such recommendations is that the
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baseline exam must be complete (including the caecum), with adequate bowel preparation,
and that any detected lesions are removed completely. If the completeness of the resection or
quality of the exam comes into question, early re-examination is recommended. The
guidelines stratify risk based on the findings of the index examination (Box 3). The US
guidelines endorse a 10-year interval if the baseline exam is negative or if the patient only
has hyperplastic polyps in the rectum or sigmoid colon. New evidence adds further support
for this recommendation80,142. Interval faecal blood testing is generally not recommended,
owing to a lack of evidence of benefit137,140.
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Box 3
Risk-stratified guidelines for surveillance after removal of adenomatous
polyps or colorectal cancer
Colorectal cancer
• Patients with colorectal cancer should have intensive follow-up care
• If a complete colonoscopy was not possible prior to surgical resection,

colonoscopy should be offered within 3–6 months to detect synchronous lesions
• If a complete colonoscopy was performed at baseline, patients with cancer

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should have colonoscopy at 1 year; if negative, every 3–5 years thereafter
High-risk adenoma
• High-risk features include adenomas with high-grade dysplasia, villous

histology, tubular adenoma ≥10mm in size, serrated lesions ≥10mm in size,
serrated lesions with dysplasia or ≥3 adenomas
• The risk of advanced neoplasia during surveillance is 15–20%, which is roughly

2–3-fold higher than individuals with 1–2 small (<10mm) tubular adenomas and
5–6-fold higher than individuals with no polyps at baseline colonoscopy137
• The US Multi-Society Task Force on Colorectal Cancer (USMSTF) and

European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend
a 3-year interval for surveillance137,140
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• The UK guidelines define highest-risk features as ≥5 small adenomas or ≥3

adenomas where at least one is >10 mm in size and recommends annual
surveillance141 based on data indicating a high likelihood of finding additional
high-risk adenomas at 1 year226
• The UK guidelines define intermediate-risk features as 3–4 small (<10mm)

adenomas or ≥1 large (≥10mm) adenomas, irrespective of histology, and suggest
a 3-year screening interval
Low-risk adenoma
• Individuals with 1–2 tubular adenomas <10mm in size represent a low-risk

group
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• A statistically insignificant increase in risk, relative to patients with no polyps at

baseline colonoscopy, are attributed to these patients
• The UK guidelines recommend no specific follow-up141; the ESGE guidelines

recommend follow-up at 10 years140; the USMSTF guidelines recommend
surveillance at 5–10 years, with evidence supporting the 10-year interval if the
index exam preparation was adequate137
• Serrated lesions <10mm in size with no dysplasia might also represent a low-
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risk lesion, but evidence is weak; the USMSTF recommends a 5-year interval
for surveillance and the ESGE recommends a 10-year interval
Several longitudinal studies of patients after adenoma removal have provided some guidance
for the optimal intervals for surveillance examinations136,138. Surveillance intervals are
based on the findings at last colonoscopy (Box 3). If the patient has an adenoma with high-
risk features at baseline, but no polyp or an adenoma with low-risk features at surveillance,
the next exam is recommended at 5 years. If the patient has an adenoma with low-risk
features at baseline and at surveillance, the next exam interval is recommended at 5 years; if
there is no polyp at surveillance, the next exam interval is 10 years. Finally, if a high-risk
adenoma is found at surveillance, the next exam is recommended at 3 years. These
recommendations are designed to reduce the frequency of surveillance for many individuals
with low-risk lesions and are based on findings using high-quality colonoscopy. Complete
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examinations with good bowel preparation9 are required, but the role of other mitigating
factors during surveillance such as lifestyle, sex and race are unknown. Surveillance should
be discontinued when the risks of performing the bowel preparation and/or colonoscopy
could outweigh any potential benefit. These factors should also be considered in elderly
patients with comorbid conditions that might limit life expectancy, diminish any potential
benefit of polyp removal and increase risk of complications during the colonoscopy
procedure143,144.
How to conduct surveillance of patients with serrated lesions is under debate. Understanding
the natural history of these lesions requires accurate histological definition, endoscopic
detection and longitudinal follow-up145. Furthermore, inter-observer variability in
histological interpretation, wide variation in detection rates and virtually no longitudinal
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follow-up study of these patients have hindered surveillance assessment146. Nevertheless,

some evidence suggests that this pathway accounts >20% of colorectal cancers and patients
may be at risk for recurrent disease and, therefore, require surveillance after resection.
Further studies have to substantiate the risk for recurrent polyps and define optimal
surveillance schedules.
In addition to endoscopic surveillance after cancer resection, follow-up surveillance by

measuring carcinoembryonic antigen (CEA) levels in the plasma and/or CT imaging might
detect curatively treatable metastatic recurrence147. There have been concerns about the cost,
benefit and number needed to test to achieve a survival benefit. A randomized study found
that CEA testing resulted in 6.7% of patients receiving treatment with curative intent and CT
resulted in 8.0% receiving treatment, which was significantly more than a group receiving
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minimum follow-up care that involved only targeted diagnostic assessment if

symptomatic148. The actual survival benefit was probably small. The cost-effectiveness is
also uncertain, but CEA testing is likely to be more cost-effective than CT, depending on the
cost in different countries.
Management
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Although the molecular drivers of colorectal cancer have been described, where in the gut a
tumour occurs has implications for treatment. That is, colon cancer and rectal cancer are two
distinct cancers requiring different approaches, also depending on their stage. Cancer
registries from different countries show huge differences in outcomes after treatment for
colorectal cancer, although a trend for improvement is emerging149. Fortunately, increasing
attention is being paid to quality assurance in cancer care150. Indeed, unravelling the effects
of treatment on outcome is of utmost importance and, for this, population-based registries
and audits are used to critically assess practice.
Surgery
Surgery is the mainstay curative treatment for patients with non-metastasized colorectal
cancer. However, outcome is strongly related to the quality of surgery151,152, the quality of
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pre-operative staging and treatment selection. The dissection should ideally follow the
embryological anatomical planes to ensure that the tumour and its principle zone of
lymphatic spread are removed. Special attention should be given to the circumferential
surgical resection margins 152,153 (Figure 4). In more-advanced cases of rectal cancer,
neoadjuvant treatment (for example, preoperative chemotherapy for T4 colon cancer, and
(chemo)radiotherapy for locally advanced cancer) can reduce tumour load and even tumour
stage, and might be necessary to optimize the chances for a successful resection150,152,154.
Thus, a multidisciplinary approach before beginning treatment, based on adequate staging
information, is mandatory 151,153,155,156.
Preoperative assessment—When considering a patient for surgery, several factors such

as their age, fitness, the perioperative management plan, tumour staging, type of surgery
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(including resection planes and reconstruction) and quality assurance are important. In terms
of age, elderly patients with colorectal cancer have lower overall survival rates than their
younger counterparts149. Indeed, postoperative mortality rates increase in elderly in the
immediate postoperative period (first 30 days) and can double in the first 6–12 postoperative
months157–160. However, ‘elderly patients’ as a group are heterogeneous, with varying
comorbidities, degrees of fitness for surgery and risks for postoperative complications.
Accordingly, age alone should not be a reason not to operate.
Before surgery of colorectal cancer, it is important to be informed about the whole colon to
rule out synchronous cancers, which occur in some 4% of patients161. If preoperative
endoscopy was incomplete owing to tumour obstruction, visualization of the colon should
either be completed prior to surgery by CT colonography, or endoscopy should be performed
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in the 3 months following surgical resection161,162. Active search for distant metastases in
the lungs and liver by means of chest and abdominal CT is also recommended before
surgery155. CEA is preferably obtained before colorectal cancer surgery to provide a
baseline value for postoperative surveillance. Genetic counselling is advised in young
patients with a positive family history of colorectal cancer. Fast track protocols and
laparoscopy should be considered to minimize the surgical trauma. In those with obstructive
colorectal disease, abdominal CT imaging can also assess for T4 or stage IV disease. In
patients with rectal cancer, preoperative MRI imaging of the pelvis is further recommended
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for planning purposes, as well as to distinguish the tumour in relation to the mesorectal
fascia, and to assess T stage163. This information is necessary to select patients with T3c,
T3d and T4 tumours for preoperative (chemo)radiotherapy.
Colon surgery—Laparoscopic resection of colorectal cancer (Figure 5) has been shown to

be as safe as open surgery164–166. As with any surgical procedure, the team needs to be
skilled in laparoscopic colorectal surgery and adequately select patients. Contraindications
for laparoscopic approach are obesity, previous abdominal surgeries and advanced-stage
disease151,152,165. If, during the laparoscopic procedure, conversion to open surgery is
necessary, the earlier this is done the better the outcomes.
In colon surgery, anatomical planes of the mesocolon with the parietal cavity wall and
retroperitoneum should be followed to avoid damage of the ureters, duodenum, pancreas and
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spleen. Moreover the mesenteric margins are planned accurately, ensuring proficient
vascularization of the remnant bowel loops for the anastomosis. A tension-free and torsion-
free anastomosis must be created to avoid the feared complication of an anastomotic
leakage.
Some patients might require perioperative placement of a stoma, in which the faeces are
diverted into a bag on the outside of the body. Loop ileostomy or loop colostomy (Figure 6),
or permanent colostomies, are an essential part of surgery for rectal and sigmoid cancer,
either to protect the anastomosis or when the distal rectum is resected. In cases of a rectal
obstruction, a loop colostomy is placed on the right (ascending) side; a permanent stoma is
placed in cases an abdominoperineal excision (APE; that is removal of the anus, rectum and
part of the sigmoid colon along with the associated lymph nodes). Each stoma has its
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advantages and disadvantages; there is no strong argument for superiority of one over the
other167. Complications of stomas are numerous and cumbersome for the patient, and
include prolapse, retraction, dermatitis, leakage, para-stomal hernia, obstruction and
anastomotic leakage after stoma closure.
In patients presenting with (sub)total obstruction due to a left-sided (descending) tumour,

temporary pre-operative stenting can be considered to reduce perioperative morbidity and
risks of surgery, but the risk of perforation must be considered151,152,168. Colostomy versus
stent for palliation could be considered in patients presenting with obstruction and multiple
distant metastases151,152,169.
Rectal surgery—There are several surgical approaches for patients with rectal cancer,
depending on tumour stage. Each technique aims for adequate oncological treatment with
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complete tumour and local node resection to minimize locoregional and distant recurrence
and optimize disease-free and overall survival. In addition, sphincter preservation and
avoidance of a permanent stoma are important additional goals of rectal cancer treatment.
Accordingly, a careful, balanced choice of treatment is needed for each individual patient.
For early stage rectal cancer, advances in minimally invasive techniques have reduced the
number of open rectal resections and have improved functional outcome dramatically.
Transanal endoscopic microsurgery (TEM) is just such a minimally invasive technique for
local tumour excision of well-differentiated T1N0 tumors170–172. TEM is associated with
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better functional outcomes and is performed through the anus (and, therefore, does not leave
an abdominal scar or require a stoma), but has the trade-off of higher local recurrences.
Thus, TEM is not recommended for tumours that are unlikely to be completely resected, as
well as for poorly differentiated tumours given their high risk of local recurrence. The
technical complexity of TEM and the high costs of the apparatus led to the introduction of
new transanal techniques, in particular transanal minimally invasive surgery (TAMIS). This
technique makes use of a disposable multichannel port that is positioned transanally and
provides access for conventional laparoscopic equipment173.
Total mesorectal excision (TME) is the gold standard surgical technique for rectal tumours
staged T1, T2, and favorable T3 (T3 with negative nodal status (T3N0M0) and excluding
low-seated rectal cancers, and T3c and T3d disease). In patients with unfavourable rectal
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tumors, TME surgery is only recommended after neoadjuvant therapy to reduce the risk of
local recurrences. For tumour resection, the anatomical plane is the mesorectal fascia and the
circumferential resection margin is just outside of this fascia (Figure 7)174–176. The intact
mesorectum, the fatty envelope that surrounds the rectal bowel wall, includes the draining
lymph nodes. Complete resection involves removal of the bowel wall and these nodes. TME
can be performed by open approach as well as laparoscopically; both have similar rates of
locoregional recurrence, and disease-free and overall survival165. Rectal cancer surgery in
locally advanced stages is associated with more blood loss; longer operation duration; more
concomitant organ resections; and more postoperative complications such as anastomotic
leakage, pelvic floor dysfunction, incontinence and genitourinary problems. However,
robotic rectal resection may improve perioperative outcomes, such as reduction of
perioperative blood loss, and is being explored177.
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Local recurrences after rectal surgery can be minimized using short-course

radiotherapy178–180, although long-term data (12-year follow-up) showed no effect on
overall survival for this approach 181. The timing of surgery after short-course radiotherapy
is important. Surgery after a longer waiting period is associated with fewer complications
than immediate surgery after radiotherapy182. Importantly, neoadjuvant radiotherapy (that is,
before surgery) is associated with an increased risk for low anterior syndrome (a complex of
symptoms that include frequent and urgent stools, numerous bowel movements over a few
hours, stool incontinence and sexual dysfunction)183.
Neoadjuvant radiotherapy (or chemoradiotherapy) can be proposed for patients with

unfavourable T3 (upper and mid T3c, T3d and low T3b) rectal tumours: those that invade >5
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mm into the mesorectal fat and/or approach within 2 mm of the mesorectal fascia as
visualized on MRI. T4 and lymph node-positive rectal cancer need short-course fractionated
radiotherapy or chemoradiotherapy depending on the patient and tumour characteristics184.
After the primary radiotherapy or chemoradiotherapy, restaging by means of endoscopy and
MRI is recommended for these patients. TME surgery can be possible when the tumour has
been downsized sufficiently. In patients with advanced and recurrent rectal cancer, surgery
should aim for complete resection and conventional surgical planes may not be adhered
to185. In some patients, a clinical complete response can be achieved after chemoradiation
alone. This raises the question whether surgery can be omitted in these patients. In the
largest series of patients treated nonsurgically, high response rates were reported186. Other
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series had lower response rates187,188. Prospective research will be necessary for this group
of patients. Indeed, in 2015, the prospective International Watch & Wait Database for rectal
cancer was launched (http://www.iwwd.org); this initiative aims to produce assess whether
nonsurgical approaches are valuable alternatives to surgery.
Finally, a prospective multicentre randomized trial in Japan comparing TME alone versus
TME with dissection of lateral nodes was recently completed189. In this study,
approximately 10% of patients had pathological pelvic sidewall lymph nodes. Given that
preoperative radiotherapy on lateral nodes might not completely eradicate nodal metastases,
TME surgery with lateral lymph node clearance might be justified.
Quality assurance—The resected tumour specimen can be used to judge the quality of
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surgery; if the margin around the specimen is free of cancer cells in both colon and rectal
cancer, the surgery is considered high quality174,175. The removal and assessment of the
lymph nodes is another guide for determining whether the mesocolic or mesorectal resection
is adequate 153. Internationally, removal of 12 lymph nodes is viewed as the cut-off value
needed to provide adequate histopathological staging; the lymph nodes can also be used to
prognosticate patients. However, the role of procedures to remove the sentinel node (the first
lymph node or group of nodes draining the cancer) in colorectal cancer is still unclear.
Furthermore, quality assurance in colorectal cancer care has been defined for several aspects
of the care continuum: performing trials, working in multidisciplinary teams, integrated care
pathways, shared decision-making, auditing cancer care, centralization of complex
procedures and international comparison of cancer outcomes. Auditing is a powerful
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instrument to improve cancer care. Especially for rectal cancer, survival and local
recurrences have been shown to drastically improve with national auditing
initiatives150,190,191. To reduce the differences in Europe, an international, multidisciplinary,
outcome-based quality improvement project, European Registration of Cancer Care
(EURECCA), was launched in 2007 156. EURECCA aims to capture the best practices and
promote uniform structured data collection and analysis to study outcomes of all patients
with cancer. Although these analyses are used to feedback surgeons on the best techniques at
hand, volume is another issue that has been shown to improve patient outcome in colorectal
cancer management192.
Recovery after surgery—Perioperative protocols such as fast track and Enhanced

Recovery After Surgery (ERAS) have been designed to minimize surgical
complications193,194. The protocol describes the perioperative care pathway and lists
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elements of care for patients at various steps in the perioperative process. Considering these
elements are supported by evidence to improve recovery time after surgery, ERAS was first
implemented for patients undergoing colectomy195 and includes elements such as
preoperative counselling and bowel preparation, perioperative fluid management and
prevention of ileus (obstipation and intolerance to oral intake) and postoperative glucose
control and early mobilization. Indeed, for patients at high risk of postoperative ileus, enteral
nutrition should be anticipated even before surgery196.
Systemic treatments for primary disease

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The systemic treatment of patients with colorectal cancer has substantially developed over
the past two decades, with major improvements in the neoadjuvant setting for rectal cancer,
and adjuvant settings for cancer of the colon.
Neoadjuvant treatment—There is no accepted neoadjuvant treatment for colon cancer.

However, for rectal cancer, neoadjuvant radiotherapy or chemoradiotherapy are
recommended for intermediate-stage and advanced-stage cancer (for example, very low-tract
anteriorly located cT2 lesions, most T3 lesions, some T4a lesions with limited peritoneal
involvement, N+ lesions, cT3 lesions that invade the mesorectal fascia, and cT4a and cT4b
lesions with positive lateral nodes) to reduce the rate of local recurrence. The neoadjuvant
treatment can either be given as short-course radiotherapy followed by surgery or as
chemoradiotherapy with 5-fluorouracil or capecitabine (an oral fluoropyrimidine). Although
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preoperative (chemo-)radiotherapy is more effective than postoperative treatment in reducing

local recurrence, it does not improve overall survival181,197. Strategies that aimed to improve
neoadjuvant treatment by intensifying the chemoradiotherapy regimen (for example, by
combining 5-fluorouracil and oxaliplatin with radiotherapy instead of using 5-fluorouracil
with radiotherapy) did not exhibit clear survival benefit, but increased toxicity198; more
research is needed.
Adjuvant treatment—The cure rate by surgery alone for T3, T4a, T4b and N0M0 colon
cancers (Union for International Cancer Control (UICC) stage II) is high and only
approximately 5% of patients benefit from adjuvant chemotherapy. However, guidelines
endorsed by European and Japanese societies recommend considering adjuvant therapy in
high-risk cases (that is, poorly differentiated tumours; when <12 lymph nodes were resected;
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in cases with vascular, lymphatic or perineural tumour invasion; in cases with obstructive or
perforated tumours; or tumours with pT4 stage)199. By contrast, adjuvant treatment is
standard for UICC stage III tumours (any T, N1–2 (3 or more positive nodes), M0); a
combination of 5-fluorouracil (orally, as in the XELOX protocol, or intravenously as in the
FOLFOX4 protocol) plus oxaliplatin is used. Currently, no data support that the addition of
targeted therapies (such as epidermal growth factor receptor (EGFR)-specific or vascular
endothelial growth factor (VEGF)-specific monoclonal antibodies) improves the outcome
for patients in the adjuvant setting199. Data from pooled analyses suggest that patients >70
years of age might not benefit profoundly from oxaliplatin-based chemotherapy
combinations in the adjuvant setting. These patients may benefit from fluoropyrimidine
chemotherapy, similar to younger patients200. For rectal cancer, postoperative
chemoradiotherapy can be applied if no preoperative treatment was given and if certain risk
factors (including positive resection margins, perforation in the tumour area or defects in the
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mesorectum) are present; adjuvant chemotherapy typically uses fluoropyrimidines.
Metastatic disease
The survival of patients with metastatic disease has substantially improved over the past two
decades and a median overall survival of 30 months has been achieved in clinical trials. This
improvement in survival can be attributed to use of chemotherapeutics such as oxaliplatin
and irinotecan, the introduction of targeted therapies that address specific properties of the
tumour or its microenvironment and the incorporation of multidisciplinary approaches,

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including surgical resection of liver metastases.
Chemotherapy combinations—The chemotherapy backbone for first-line treatment of

metastatic disease is typically a combination of 5-fluorouracil, leucovorin and either
oxaliplatin (FOLFOX protocol) or irinotecan (FOLFIRI protocol). 5-Fluorouracil in the
FOLFOX regimen can be replaced by capecitabine, but combination of capecitabine with
irinotecan is more toxic than FOLFIRI. Doublet (two chemotherapeutic agents) and triplet
(three chemotherapeutic agents) chemotherapy regimens consisting of 5-fluorouracil,
leucovorin, oxaliplatin and irinotecan (the FOLFOXIRI protocol) have been shown to be
efficacious201. As compared with single-agent fluoropyrimidine, combination chemotherapy
achieves better tumour growth control. However, elderly and frail patients in particular
might benefit from a sequential approach with initial single-agent fluoropyrimidine
chemotherapy or combined fluoropyrimidine with VEGF-A-targeted therapy (bevacizumab;
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see below).
Targeted therapies—Alongside these combined chemotherapy regimens, targeted agents

are used for metastatic colorectal cancer treatment. In particular, these include three major
groups of drugs: monoclonal antibodies against EGFR (cetuximab and panitumumab),
monoclonal antibodies against VEGF-A (bevacizumab), and fusion proteins that target
multiple proangiogenic growth factors (for example, aflibercept) and small molecule-based
multikinase inhibitors (for example, regorafenib).
Approximately 80% of all colorectal cancers express or overexpress EGFR; overexpression

correlates with reduced survival and increased risk of metastases. The EGFR tyrosine kinase
can be blocked by monocloncal antibodies specific to the extracellular domain of the
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receptor, decoy receptors that bind and block the soluble ligand, or small molecules that
inhibit receptor dimerization or fit into the ATP binding pocket of its cytoplasmic tyrosine
kinase domain. Most clinical data in colorectal cancer are available for receptor-blocking
antibodies, such as cetuximab, which is a recombinant chimeric monoclonal IgG1 antibody,
and panitumumab, which is a human EGFR-specific antibody. These antibodies show
efficacy in chemotherapy-naive patients as well as in patients whose tumours are refractory
to chemotherapy by improving the overall response rate of the tumours. These strategies also
improve progression-free survival (PFS) and even overall survival in patients with metastatic
colorectal cancer. However, a prerequisite for the efficacy of these agents is that the tumours
do not harbour activating mutations in KRAS and NRAS 202,203.
RAS is mutated in about half of all colorectal cancers, with codons 12 and 13 being most
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commonly affected; codons 61 and 146 of KRAS and codons 12, 13 and 61 of NRAS are
affected to a lesser extent. HRAS mutations have so far not been described in colorectal
cancer. The mutations render the Ras GTPase constitutively active; active Ras induces a
plethora of tumorigenic intracellular signalling pathways. Thus, the Ras status of the tumour
must be examined before treatment with EGFR-specific antibodies.
Tumours establish a vascular network of their own once they reach a critical size204.
Accordingly, a major effector of tumour angiogenesis is the secreted glycoprotein VEGF-A,
which binds to VEGFR-1 and VEGFR-2. VEGF-A is produced by many tumour and stromal
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cells, promotes proliferation and migration of endothelial cells and increases vessel
permeability. VEGF is also a growth factor for various tumour cells. VEGF-specific
therapies are used in metastatic colorectal cancer, but the precise mechanisms of action are
not fully understood. These compounds might act by normalizing the dysregulated tumour
vasculature, which would lead to improved tumour oxygenation and delivery of
chemotherapy205. There are as yet no predictive biomarkers for anti-angiogenic agents.
Bevacizumab has demonstrated efficacy in combination with chemotherapy in the metastatic

setting; combined with 5-fluorouracil and irinotecan, bevacizumab significantly improved
median PFS and median overall survival of patients in a Phase III trial compared with
chemotherapy alone6. The addition of bevacizumab also significantly improved median PFS
in patients receiving a combination of fluoropyrimidine and oxaliplatin. Interestingly, the
combination of bevacizumab and 5-fluorouracil/oxaliplatin also yielded a significant
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improvement in tumour response, median PFS and median overall survival compared to
chemotherapy alone in patients with chemorefractory metastatic disease206. Bevacizumab is
also one of the few compounds that confer a survival benefit to patients when treatment is
continued even after disease progression207.
Aflibercept also targets angiogenesis. This drug is a recombinant fusion protein that consists
of the VEGF-binding portions from the extracellular domains of human VEGFR-1 and
VEGFR-2 fused to the Fc portion of the human IgG1 immunoglobulin. Aflibercept also
binds the placenta growth factor (PLGF) and, therefore, has a somewhat broader
antiangiogenic activity than bevcacizumab. Aflibercept has been shown to improve PFS and
overall survival when used in combination with FOLFIRI in the second-line setting of
treatment for metastatic disease208.
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Metastatic resection—For patients with colorectal cancer who have isolated liver and/or
lung metastases that are technically R0 resectable, surgery should be considered —
particularly when the metastases are limited in number and size. The 5-year overall survival
rate in this group is about 20%209,210, an impressive figure for metastatic disease. One
clinical trial has used a perioperative FOLFOX protocol in this group of patients and showed
an improvement in PFS, but no significant difference in overall survival compared with
surgery alone 201.
In the majority of patients with isolated liver and/or lung metastases, a R0 resection cannot
be primarily achieved. However, if the metastases can be downsized and combined with
adjuvant chemotherapy, the 5-year overall survival rate is similar to R0 resections 211. In this
situation, the most active chemotherapy should be employed to ‘convert’ the disease to a
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resectable state; FOLFOXIRI triplet chemotherapy regimen confers high response rate
(approximately 60%)212. In a RAS wild-type population, chemotherapy doublets plus
EGFR-specific treatment also result in high response rates. According to the data of the
FIRE3 study, EGFR-specific antibodies in combination with FOLFIRI seem to induce more
pronounced tumour shrinkage than FOLFIRI plus bevacizumab. Thus, this combination is an
option if the tumour is RAS wild-type213.
If a more-active treatment with the intent to downsize metastases for secondary resectability
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is used, it is important to ensure that the tumour is regularly re-evaluated by a

multidisciplinary team and resection of metastases is performed at the earliest time point
when an R0 resection is possible. In doing so, chemotherapy toxicity is reduced and
perioperative morbidity is minimized. The ‘disappearance’ of the metastases on CT imaging
does not necessarily indicate a complete destruction of the metastases in most patients, and
makes it difficult for the surgeon to completely resect all lesions214.
Further considerations—Patients with symptomatic or more-aggressive metastatic

disease without chance of secondary metastatic resection benefit from active first-line
treatment to achieve optimal tumour control. This can generally be achieved using doublet
chemotherapy in combination with a targeted agent such as bevacizumab. In patients with
RAS wild-type tumours, doublet chemotherapy together with an EGFR-specific antibody
treatment can also be used. For those who respond to this ‘induction’ treatment, or who have
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a stable disease after 4–6 months of the treatment, the intensity of the treatment should be
reduced to avoid excessive toxicity. This is particularly important if a FOLFOX protocol is
used to avoid the cumulative neurotoxicity of oxaliplatin. A Phase III trial showed that after
FOLFOX plus bevacizumab induction therapy, a maintenance strategy with fluoropyrimidine
chemotherapy plus bevacizumab prolonged PFS without significantly improving overall
survival compared to a complete treatment break215. Thus, active maintenance, but also
treatment discontinuation, can be considered when tumours respond or are stable during a 4–
6 months induction treatment and the tumour burden is not high.
In the palliative setting, a less-aggressive approach with monotherapy with fluoropyrimidine

chemotherapy or a combination of fluoropyrimidine chemotherapy with bevacizumab is
possible. Such a strategy requires the patient to be at low risk for rapid deterioration. Upon
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disease progression, treatment should be escalated and combination chemotherapy (together

with bevacizumab) should be used. However, recent data from the FIRE3 and CALGB trials
suggest that using a more-intensive treatment in the first-line setting can achieve a median
overall survival of about 30 months in a RAS wild-type population. Such survival rates have
so far not been reported in a sequential setting when treatment starts with just
fluoropyrimidine chemotherapy with or without bevacizumab201.
In the second-line palliative setting, upon further disease progression, chemotherapy should
be changed to a regimen not used in the first line (either FOLFOX/XELOX or FOLFIRI). A
recent study showed that bevacizumab can be given after disease progression and improves
overall survival in the second-line setting207. Apart from bevacizumab, aflibercept can be
used in the second-line setting (in combination with FOLFIRI). Cetuximab or panitumumab
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can also be used if not previously used and if the tumour is RAS wild-type. For these
compounds, efficacy beyond progression has not been demonstrated.
In cancers that are refractory to two lines of chemotherapy, EGFR-specific antibodies can be
used if the tumour is RAS wild-type and an EGFR-specific antibody has not been used
previously202. Regorafenib is an orally available multikinase inhibitor that has shown
efficacy in patients who had previously been treated with all available therapies.
Accordingly, it has become the standard in pre-treated patients216.
Quality of life
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Colorectal cancer can manifestly impair quality of life through, for example, direct
consequences of the disease, such as abdominal pain, change in bowel movements, blood
loss and anaemia, fatigue, and weight loss. Furthermore, treatment incurs a burden to quality
of life by means of surgery, chemotherapy and radiotherapy, which can be associated in the
short-term with impaired nutrient intake and physical activity217. Indeed, weight loss and
reduced physical condition is particularly relevant for elderly patients and those with co-
morbidities, and should be adequately monitored during treatment and follow-up care.
Each treatment modality can be associated with further specific adverse effects and
complications. One of the most feared surgical complications is the occurrence of leakage of
the anastomosis, at the suture-line of the intestinal loops after removal of the tumour. This
event usually requires further surgical or radiological intervention and is associated with
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significant morbidity and lengthening of hospital stay and mortality. Other more common
complications of surgery are wound dehiscence (rupture of the wound along a surgical
suture), and abdominal scar herniation. Overall, the impact on quality of life does not differ
between open and laparoscopic surgery133. A range of stoma-related complications can also
significantly impair social functioning and impair quality of life; these can sometimes be
managed conservatively, but may require surgical revision of the stoma.
Treatment for rectal cancer is frequently associated with long-term complications. These
include faecal incontinence and increased numbers of stools. These complications are well
defined in the validated low anterior resection syndrome (LARS) score218. Pelvic floor
problems are more frequent in rectal cancer patients receiving neoadjuvant (chemo)
radiotherapy219. Toxicity is higher after chemoradiotherapy in comparison to radiotherapy
alone 220. Moreover erectile dysfunction in men and dyspareunia in women are common
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after rectal cancer treatment 221,222.
With respect to chemotherapy, 5-fluorouracil is usually well tolerated, but oxaliplatin or

irinotecan more often give rise to adverse effects such as neutropenia and diarrhoea.
Targeted therapies have important adverse effects that must be considered. For the EGFR-
specific antibodies, papulopustulous rash and paronychia (infection of the nail) occur within
days of treatment, followed by skin atrophy after several weeks and alopecia that occurs
within a few months. High-grade skin toxicity can involve pain and secondary infections.
Antiangiogenic agents cause bleeding, arterial thromboembolic events, impaired wound
healing, hypertension and proteinuria6. Aflibercept increases (to some extent)
chemotherapy- induced adverse events such as diarrhoea, neutropenia and asthenia208.
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Metastatic disease can give rise to a range of additional symptoms that affect quality of life,
such as cachexia, loss of appetite, anaemia, liver failure, biliary obstruction and impaired
pulmonary function223. These symptoms relate to duration of survival to some extent223. A
range of interventions, with focus on management of pain, improvement of food intake and
maintenance of physical activity benefit individual patient groups. For example, a systematic
review of three studies reported that increased physical activity improved quality of life in
patients with colorectal cancer224. Clinicians are aware of the potential major impact of
colorectal cancer on many aspects of quality of life, and individualized options to improve
this should be given225 (Box 4).
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Box 4
Supportive palliative care for patients with colorectal cancer
Maintenance of adequate nutrient intake
Surgery and chemoradiotherapy can temporarily or for prolonged periods impair energy
intake. Nutritional counselling and dietary monitoring can improve nutritional status,
which benefits physical condition.
Pain relief
A substantial proportion of patients with advanced-stage disease require opioid treatment
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in the last months of their life. In a large UK study, approximately 20% of patients
received intense opioid combination therapy. Such pain relief requires adequate patient
monitoring, physician training and access to a dedicated pain treatment team227.
Physical condition maintenance

Various studies focusing on patients with advanced-stage colorectal as well as other
cancers reported that exercise programmes can improve the patient’s physical condition,
mobility and sleep, and reduce fatigue27,228.
Prevention of avoidable hospital admission

A considerable proportion of hospital admissions in patients with advanced-stage
colorectal cancer are potentially avoidable by adequate support at home and hospice
access. Potentially avoidable admissions seem to occur more often in elderly patients and
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those with end-stage disease.
Psychosocial support
Routine assessment at outpatient clinic visits or visits at home can help to identify
patients who need specific psychosocial support in a timely manner.
Outlook
Colorectal cancer has over the past several decades become one of the most common
cancers, and its incidence is expected to continue to increase in coming years. Despite major
advances in treatment, mortality from colorectal cancer remains high and 40–50% of
patients eventually die because of their disease. As discussed above, colorectal cancer arises
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as a result of environmental factors and genetic factors cooperating to generate colon polyps
that progress to colorectal cancer. The polyp to cancer progression sequence is primarily
driven at the cellular level by gene mutations and epigenetic alterations and is now
recognized to be a heterogeneous process. It is widely anticipated that insights into the
unique gene alterations will lead to more-precise and individualized care for people with
polyps and cancers, which will be guided by the molecular characterization of the
individual’s colon tumour.
The future of cancer surgery for colorectal disease is aimed at minimizing surgical trauma
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and preserving organ function. Population-based studies to unravel the effects of multimodal
strategies for elderly patients and those with comorbidities need to be undertaken. High-
precision imaging will lead to image-guided techniques. Each patient is unique and surgery
needs to be tailor-made, aimed at complete removal for cure. Feedback on performance is
required to keep on improving our efforts.
Chemotherapy has made substantial progress in recent years. We can now individualize the
treatment according to the type of metastases (isolated liver/lung metastases, resectable or
primarily not resectable), the RAS mutation state of the tumour and the response to a given
treatment (for maintenance strategies or therapeutic breaks). The Human Cancer Genome
Atlas and various other genomic projects have identified a number of novel potential
molecular targets and markers for colorectal cancer that might be used to guide more-
specific treatments for subgroups of patients (Figure 8).
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These developments in surgery and chemo(radio)therapy will improve and further

individualize treatment in the near future, which should prolong survival of patients. The
largest impact on incidence and mortality will, however, come from widespread organized
population screening. Screening programmes should aim for optimal uptake and smart use
of available resources. Opportunistic screening programmes must be replaced by organized
screening, together with incorporation of strict quality assurance measures. With such an
approach, the foreseen rapid rise in colorectal cancer incidence and mortality could be
reversed in the coming decade.
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Figure 1. Colorectal neoplasia at different stages

(a) A small sessile adenoma. (b) An advanced, larger sessile adenoma. (c) A large, dish-
shaped, ulcerating sigmoid carcinoma. The tumour covers most of the circumference, but
has not yet led to substantial obstruction of the lumen.
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Figure 2. The age-standardized incidence and mortality rates in men (m) and women (f) (per
100.000 people) across geographic zones10
Rates are consistently higher in men than in women, and vary considerably between regions.
Highest rates occur in Australia and New Zealand, Europe and North America.
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Figure 3. The polyp to colorectal cancer sequences

Currently, two discrete normal colon to colorectal cancer sequences have been identified.
Both sequences involve the progression of normal colon epithelial cells to aberrant crypt
foci, followed by early and advanced polyps with subsequent progression to early cancer and
then advanced cancer. The ‘classic’ or traditional pathway (top) involves the development of
tubular adenomas that can progress to adenocarcinomas. An alternate pathway (bottom)
involves serrated polyps and their progression to serrated colorectal cancer has been
described in the last 5–10 years. The genes mutated or epigenetically altered are indicated in
each sequence; some genes are shared between the two pathways whereas others are unique
(for example, BRAF mutations and CpG Island Methylator Phenotype (CIMP) only occur in
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the serrated pathway). The signalling pathways deregulated during the progression sequence
are also shown, with the width of the arrow reflecting the significance of the signalling
pathway in tumour formation.
APC, adenomatous polyposis coli; CIN, chromosomal instability; CTNNB1, catenin-β1;
FAM123B, family with sequence similarity 123B (also known as AMER1); FZD10, frizzled
class receptor 10; LRP5, low-density lipoprotein receptor-related protein 5; MAPK,
mitogen-activated protein kinase; MSI, microsatellite instability; PI3K, phosphatidylinositol
3-kinase; PI3KCA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-α;
PTEN, phosphatase and tensin homologue; SFRP, secreted frizzled-related protein;
SMAD4, SMAD family member 4; TGFβ, transforming growth factor-β; TGFBR2, TGFβ
_receptor 2.
Figure adapted from 229, Nature Publishing Group.
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Figure 4. Surgical planes for right colon surgery

The mesocolon harbours the major blood vessels and draining lymph nodes; surgical
planning involves considering the large blood vessels and the resection lines. For the caecum
and the ascending colon (before the hepatic flexure), the main vessels are the ileocolic and
right colic artery. The transverse colon begins at the hepatic flexure and ends at the splenic
flexure; important vessels to consider in this region are the middle colic artery (via the
superior mesenteric artery) arcading on the left side, with branches of the left colic artery
(inferior mesenteric artery). The descending colon ‘bends’ at the sigmoid colon (at the left
iliac crest) before continuing to the rectum. In the paracolic grooves, the parietal peritoneum
is attached to the lateral border of the visceral peritoneum that overlies the colon and forms
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the surgical planes referred to as White Line of Toldt, which gives access to the avascular
plane above Gerota’s fascia — the fascia on top of the retroperitoneum covering the kidney
and ureter — without interfering with peri-renal space or ureters.
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Figure 5. Laparoscopic surgery for colorectal cancer

(a) A sigmoidectomy can be performed using three to six trocars. The laparoscopic
exploration via the supraumbilical trocar (position 2) is a guide for the location of the other
operating trocars. (X) The tumour location. (1) A 5 mm trocar in the left hypochondrium, for
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retracting the descending colon. (2) The first trocar to be introduced is a 12 mm trocar
through the umbilical port. (3) A 12 mm trocar is used as an optical and operating port. (4)
A 5 mm trocar is used for retracting tissue. (5) Carbon dioxide insufflation:
pneumoperitoneum.
(b) The number of trocar ports for right colectomy varies from depending on the surgeon and
operative difficulties. Trocar positioning is also variable, but our standard for a tumour in the
caecum (shown in insert, position X) approach is to place (1) a 12 mm trocar in left
hypochondrium as an optical or operating port. (2) The umbilical port side can be extended
to a small laparotomy to extract the dissected colon and perform the extracorporeal
anastomosis. (3) A 5 mm trocar is placed for operating and retracting the tissue (ascending
colon or caecum). (4) A 5 mm trocar is used to retract the hepatic flexure, to expose
ileocolic and right colic vessels, and perform the division. In both images, the patient’s head
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is at the top, their feet at the bottom.

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Figure 6. Stoma surgery for colorectal cancer

A colostomy is a surgical procedure in which a stoma (from the Greek for ‘mouth’
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or ’opening’) is formed by drawing the healthy end of the large intestine (colon) through an
incision in the anterior abdominal wall and suturing it into place. (a) For stoma positioning
(sites 1–4), the subcostal line, lateral border of the rectal abdominus muscle, anterosuperior
spine of the ilium, shape of the abdomen and abdominal creases (for example, when trousers
and belt are worn, and while sitting) are considered. Ill-placed ostomies result in invalidating
leakage and dermatitis. The position of an end ileostomy or a loop ileostomy is preferable in
the right hypochondria (position 1); a loop transversostomy is preferred in the right upper
quadrant (position 2) to preserve the left side upper and lower quadrants (positions 3 and 4,
respectively) for a definitive end colostomy if necessary. (b) In end stoma formation, the
inside of the intestinal loop with the mucosa is placed at the abdominal wall. End stomas
provide only one lumen, commonly formed to stay. A well-placed ostomy is about 2–3 cm
above the skin, which ensures that the faeces are not in contact with the skin. (c) In loop
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stoma formation, two openings are sewn into the skin: efferent and afferent. The afferent (in)
limb produces the stool and the efferent (out) limb allows passage of flatus from the distal
portion of the bowel.
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Figure 7. Surgical planes for rectal surgery

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The plane between the urogenitoury structures (prostate, urethra and seminal vesicle in men,
and the vagina, uterus and ovaries in women) and the rectum is called Denonvilliers’ fascia.
The dissection plane of the total mesorectal excision is sharp around the mesorectal fascia
and surrounds the mesorectal fat, in which the draining lymph nodes and the rectum are
located. The plane is avascular, and avoids the parasympatethic and sympathetic nerves in
the pelvic lateral space, which coordinate sexual and urinary function. The superior
hypogastric plexus is formed at the level of the sacral promontory, distally dividing in the
hypogastric nerves. Together with the parasympathetic erigentes nerves, these form the
inferior hypogastric (pelvic) plexus, which should not to be clamped during surgery to avoid
damage. The pudendal nerve innervates the external sphincter, puborectalis muscle and
external genitalia, among other structures.
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Figure 8. Emerging drug targets and drug candidates in colorectal cancer

The Cancer Genome Atlas and various other genomics projects have identified several novel
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potential molecular targets and markers in colorectal cancer that might be used to guide
specific treatments for subgroups of patients. These targets include the Wnt, transforming
growth factor (TGF)-β and epidermal growth factor (EGF) receptor signaling pathways.
Experimental agents targeting these molecules are included in grey boxes. APC,
adenomatosis polyposis coli; BMP, Bone morphogenetic protein; BMPR, BMP receptor;
CK1, casein kinase 1; Dsh, Dishevelled; GSK3, glycogen synthase kinase 3; LRP, low-
density lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase;
mTOR, mammalian target of rapamycin; P (in a red circle), phosphate; PDK, 3-
phosphoinositide-dependent protein kinase; PI3K, phosphatidylinositol 3-kinase; PIP2,
phosphatidylinositol-(4,5)-bisphosphate; PIP3, phosphatidylinositol-(3,4,5)-trisphosphate;
PTEN, phosphatase and tensin homologue; SFRP, Secreted frizzled-related protein 1;
SMAD, SMAD family member; TGFβR, TGF)-β receptor.
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Table 1
Common genetic and epigenetic alterations in colorectal cancer*
Gene or biomarker Chromosome Function Molecular lesion Frequency (%) Predictive? Prognostic? Diagnostic?
Kuipers et al.
Tumour suppressors
Regulates Wnt signalling

APC 5 Inactivating mutations 40–70 No No Familial Adenomatous Polyposis
pathway
Member of SWI/SNF family,

ARID1A 1 regulates chromatin structure Inactivating mutations 15 No No NA
and gene transcription
Regulates Wnt signalling

CTNNB1 3 Activating mutations 1 No No No
pathway
Netrin receptor; regulates

apoptosis, deleted but not
DCC 18 mutated in colorectal cancer, Deletion/LOH 9 (mutations)/ 70(LOH) No Possible No
role in primary cancer still
unclear
Involved in Wnt signalling

FAM123B X Inactivating mutations [ 10 No No No
pathway
Regulates proteasome
FBXW7 4 Inactivating mutations 20 No No No
mediated protein degradation
Inactivating mutations, loss of

10(mutation)
PTEN 10 Regulates PI3K–AKT pathway protein by Possible No Cowdens syndrome‡
30 (loss of expression)
immunohistochemistry
Regulates GDNF signalling Inactivating mutations,

RET 10 7 (mutation); 60(methylation) No No No
pathway aberrant DNA methylation
Regulates TGF-β and BMP

SMAD4 18 Inactivating mutations, deletion 25 Possible Possible Juvenile Polypsis
pathways
TGFBR2 3 Regulates TGF-β pathway Inactivating mutations 20 No No No
Regulates expression of target
genes involved in cell-cycle
TP53 17 Inactivating mutations 50 Possible Possible Li Fraumeni Syndrome
progression, DNA repair and
apoptosis
Proto-oncogenes
Involved in MAPK signalling

BRAF 7 V600E activating mutation 8–28 Probable Probable Lynch syndrome
pathway
Involved in EGF–MAPK
ERBB2 17 Amplification 35 No No No
signalling pathway
GNAS 20 Regulates G-protein signalling Mutation 20 No No No

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Gene or biomarker Chromosome Function Molecular lesion Frequency (%) Predictive? Prognostic? Diagnostic?
Regulates IGF signalling Copy number gain, loss of
IGF2 11 7(mutations)/ 10(methylation) No No No
pathway imprinting
Regulates intracellular Activating mutations in codon

KRAS signalling via the MAPK 12 or 13 but rarely in codons 40 Yes Possible NA
Kuipers et al.
pathway 61, 117 and 146
Regulates proliferation and

MYC 8 Amplification 2(mutations)/ 10 (CNV- gain) No No No
differentiation
NRAS 1 Regulates the MAPK pathway Mutation in codon 12 or 13 2 Yes No No
al and kina20Mutase mutations

PIK3CA 3 Regulates PI3K–AKT pathway in kinase (exon 20) and 20 Probable Possible No
helical(exon 9) domain
Ligand for LGR family

RSPO2 and RSPO3 1 receptors, and activate Wnt Gene fusion translocation and 10 No No No
signalling
SOX9 17 Regulates apoptosis Copy number gain 9(mutations)/ <5 (CNV gain) No No No
TCF7L2 10 Regulates Wnt signalling Gene fusion and translocation 10 No No No
Other molecular alterations
Chromosome Instability (CIN) N/A NA Aneuploidy 70 Probable Probable No
CpG Island Methylator Methylation of >20% loci from

N/A NA 15 Probable Probable No
Phenotype (CIMP a selected panel of markers
Unstable microsatellite repeats

Microsatellite Instability (MSI) N/A NA 15 Probable Yes Lynch syndrome
in consensus panel
Loss of protein by
Regulate DNA mismatch immunohistochemistry;
Mismatch Repair Genes N/A 1–15 Possible Probable Lynch Syndrome
repair methylation; inactivating
mutations
Serum based assay for cancer

SEPT9 17 NA Methylation >90 No No
detection
VIM 10, 16 and 4, Stool based test for early
NA Methylation 75 No No
NDRG4, BMP3 respectively detection
Deletion of the long arm of

18qLOH 18 NA 50 Probable Probable No
chromosome 18
APC, adenomatous polyposis coli; ARID1A, AT-rich interactive domain 1A; BMP, bone morphogenetic protein; CNV, copy number variation; CTNNB1, catenin-β1; DCC, DCC netrin 1 receptor; EGF,
epidermal growth factor; FAM123B, family with sequence similarity 123B; FBXW7, F-box and WD repeat domain-containing 7, E3 ubiquitin protein ligase; GDNF, glial cell-derived neurotrophic factor;
GNAS, guanine nucleotide-binding protein, α-stimulating complex locus; IGF, insulin-like growth factor; LGR, leucine-rich repeat-containing G protein-coupled receptor; LOH, loss of heterozygosity;
MAPK, mitogen-activated protein kinase; N/A, not applicable; NDRG4, NDRG family member 4; PI3K, phosphatidylinositol 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic
subunit-α; PTEN, phosphatase and tensin homologue; RSPO, R-spondin; SEPT9, septin 9; SMAD4, SMAD family member 4; SOX9, SRY (sex-determining region Y) box 9; TCF7L2, transcription factor
7-like 2; TGFβ, transforming growth factor-β; TGFBR2, TGFβ _receptor 2; VIM, vimentin.
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*
Includes alterations in gene expression, gene deletions and amplifications, somatic mutations and aberrant promoter methylation.
‡
Germline mutation, not somatic.
Kuipers et al.
Page 50
Table 2
Key performance indicators for organized screening with different modalities

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Test Advantages Disadvantages Refs

gFOBT Cheap Limited sensitivity for advanced neoplasia 126,127,230
Low screenee burden Need for short screening intervals
Reasonable uptake No effect on colorectal cancer incidence
Qualitative, not automated
Multiple sampling
Moderate positive predictive value
FIT Cheap Limited sensitivity for advanced adenoma 127,129,130,135,231

Low screenee burden Moderate positive predictive value
Quantitative, automated Repeated screening needed (interval can likely be
Single sample longer than for gFOBT)
Sensitive for colorectal cancer Temperature-dependent performance*
Highest uptake
Effect on incidence and mortality
Sigmoidoscopy Sensitive for distal advanced neoplasia Low uptake 118,120,232,233

Long screening interval Moderately sensitive for proximal advanced
Effect on incidence and mortality neoplasia
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Expensive
Colonoscopy Sensitive and specific Low uptake 76,77,81,234,235

Long screening interval Expensive
Effect on incidence and mortality Burdensome
Associated with complications
CT colonography Sensitive and specific Low uptake 95,96,98–100,103,105,236

Long screening interval Expensive
Likely effect on incidence and mortality Need for repeated lavage in case of advanced
neoplasia
Radiation exposure
Burdensome
Multi-target faecal Sensitive and specific Uptake unknown 110,134

DNA test Expensive
Lack of prospective data
*
Less problematic with newer generation tests. FIT fecal immunochemical test; gFOBT, guaiac fecal occult blood test.
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1Erasmus MC University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The

Correspondence to: Ernst J. Kuipers, ; Email: [email protected].

syndrome (a hereditary non-polyposis type of colorectal cancer), whereas carriers of this

In this Primer, we provide an overview of the current knowledge on epidemiology and

Indeed, a specific subgroup of the patient population is formed by those affected by a

mutations, which occur, in particular, in microsatellite DNA fragments with repetitive

A range of environmental — largely modifiable — lifestyle factors influence the risk of

on colorectal cancer incidence36,37, as does hormone therapy in post-menopausal women38.

The variety of environmental factors that influence colorectal carcinogenesis is likely

The hallmarks of cancer40,41

• Evading growth suppressors: mutation and downregulation of growth-inhibiting

factors and their receptors

• Genome instability and mutation: inactivation of DNA repair mechanisms

• Enabling replicative immortality: inhibition of mechanisms that induce

• Deregulating cellular energetics: aerobic glycolysis (Warburg phenomenon) and

• Tumour-promoting inflammation: induction of growth-promoting and

• Inducing angiogenesis: induction of the formation of new blood vessels

• Resisting cell death: escape from autonomous and paracrine mediators of

• Activating invasion and metastasis: remodelling of extracellular matrix to

finally becoming a colorectal cancer. This process is driven by accumulation of mutations

In colorectal cancer, substantial heterogeneity in the specific mutations is evident between

In addition to gene mutations, epigenetic alterations commonly occur in polyps and

Diagnosis, screening and prevention

Endoscopic techniques for the diagnosis of colorectal cancer

• Current standard for colonoscopy, combining high-definition video endoscopes

• Provides detailed image of the gastrointestinal mucosa

• Advantage of routine endoscopy, disadvantage that it provides no specific

• The use of a dye spray during gastrointestinal endoscopy to improve

• Improves detection of neoplastic lesions

• Time-consuming to spray the complete colon

• A new technique with dye incorporated into colon preparation is under

• Can characterize and determine the extension of neoplastic lesions

• Not suitable for screening of the complete colon

• Can be combined with other methods

Narrow band imaging

• Technique that can be built into white-light endoscopes

• Can characterize and determine the extension of neoplastic lesions

• Does not increase neoplasia detection rates

Intelligent colour enhancement (FICE) imaging (Fujinon) and iScan imaging

• Instead, processes the reflected light

• Technique that can also be built into white-light endoscopes

• Wavelength of the emitted light is longer for neoplastic tissue

• Can be used to search for neoplastic lesions

• Technique of extreme magnification endoscopy

• Enables in vivo visualization of individual glands and cellular structures

• Can evaluate neoplastic lesions

• Not suitable for scanning larger mucosal surfaces

Colonoscopy—Colonoscopy is the gold standard for diagnosis of colorectal cancer. It has

Enhancement system (Fujinon Corporation, Saitama, Japan) and autofluorescence

Capsule endoscopy—Capsule endoscopy uses a wireless capsule device swallowed by

use of conventional endoscopy89– 92. Capsule endoscopy is useful in diagnosing adenomas

CT colonography—CT colonography uses low-dose CT scanning to obtain an interior

investigations and increased anxiety for individuals102,103. The costs of CT colonography,

to conventional colonoscopy. However, CT colonography has not readily been accepted in

Biomarkers of colorectal cancer—Molecular detection of colorectal cancer offers a

immunochemical tests (FITs).

and circulating cytokeratins110.