Review

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Combining surgery and

chemotherapy for invasive
bladder cancer: current and
future directions
Gilad E Amiel and Seth P Lerner†
More than 13,000 patients died from invasive bladder cancer in 2005 alone. Radical
cystectomy is the most commonly prescribed treatment for patients with muscle-invasive
bladder cancer, or for those with a nonmuscle-invasive disease that is refractory to
CONTENTS intravesical therapy. Despite advances in surgical technique and improved
Rationale for extended understanding of the role of pelvic lymphadenectomy, 5-year survival probabilities
lymph node dissection suggest that improvements in treatment are necessary. The maturation of several
Chemotherapeutic randomized clinical trials on perioperative chemotherapy, and particularly neoadjuvant
concepts for advanced chemotherapy, clearly suggest that an integrated treatment program of systemic
bladder cancer chemotherapy and definitive locoregional therapy may improve the outcome for
Neoadjuvant chemotherapy bladder cancer patients. The next frontier is the molecular characterization of this
Adjuvant chemotherapy spectrum of diseases that make up invasive bladder cancer and targeted therapeutics.
Prospective validation of molecular markers and evaluation of novel therapeutic agents,
Head-to-head neo &
adjuvant chemotherapy trial alone or in combination with established cytotoxic agents, provide hope of better
outcomes for bladder cancer patients.
Expert commentary
Five-year view Expert Rev. Anticancer Ther. 6(2), 281–291 (2006)

Key issues
Bladder cancer is the second most common accomplishes excellent and durable control of
References genitourinary malignancy. Transitional cell the primary tumor, the overall long-term
Affiliations carcinoma (TCC) is the predominant cell results are mixed, with a 5-year survival rate
type in North America, comprising over 90% of approximately 50%.
of bladder cancers. It is estimated that 63,210 Treatment failure is due to occult distant
new cases of bladder cancer were diagnosed in metastatic disease present at the time of
the USA in 2005, and 13,180 patients died definitive locoregional treatment. Patients
from the disease [1]. Most patients present with locally advanced primary tumors or pel-
with nonmuscle-invasive tumors, while vic node metastases are at the highest risk for
†
Author for correspondence
20–25% of patients have a muscle-invasive treatment failure [4–9]. The 5-year survival
Scott Department of Urology, cancer as the first manifestation of their dis- probability for patients with pT3 and 4
Baylor College of Medicine, ease [2]. Radical cystectomy is the treatment tumors ranges from 22 to 58%, while
6560 Fannin, Suite 2100, of choice for patients with muscle-invasive patients with pelvic lymph node metastases
Houston, cancers and for patients with nonmuscle- have a 5-year survival of less than 33% [3,6].
TX 77030, USA
Tel.: +1 713 798 6841
invasive cancer that has failed intravesical Stratifying patients with positive nodes
Fax: +1 713 798 5553 therapy or is considered too high risk for pro- according to pathologic stage reveals that
[email protected] gression to muscle-invasive cancer at initial patients with a primary bladder tumor lim-
diagnosis. Radical cystectomy is a safe proce- ited to the muscularis propria have a 50%
KEYWORDS:
adjuvant, bladder cancer, dure, with an estimated mortality rate of 5-year survival probability, which drops to as
chemotherapy, 0.5% to 3% [3]. Although radical cystectomy low as 18% for patients with advanced non-
lymphadenectomy, neoadjuvant,
p53 , radical cystectomy with bilateral pelvic lymphadenectomy organ-confined tumors and node metastasis.

www.future-drugs.com 10.1586/14737140.6.2.281 © 2006 Future Drugs Ltd ISSN 1473-7140 281

Amiel & Lerner

Rationale for extended lymph node dissection integrated multidisciplinary treatment approach utilizing neo-
A bilateral pelvic and iliac lymphadenectomy, including primary adjuvant chemotherapy (i.e., treatment before surgery), or
and secondary lymph node drainage of the bladder, provides adjuvant chemotherapy (i.e., treatment after surgery) may be
accurate staging and regional disease control. The total number beneficial to some patients. The integration and timing of sur-
of nodes removed and identified by the pathologist impacts sur- gery and chemotherapy is challenging, and has been a source of
vival in both node-negative and -positive patients. The number debate for many years due to the limited curative effect of cur-
of positive nodes impacts survival in node-positive patients, and rent chemotherapeutic regimens for invasive bladder cancer,
the so-called lymph node density is a variable that takes into and their considerable side effects.
account both the number of positive nodes and the total
number of nodes removed [10–12]. Chemotherapeutic concepts for advanced bladder cancer
The authors previously demonstrated that a significant number There is sufficient evidence in the literature to justify the state-
of patients have lymph node metastasis outside the typical bor- ment that bladder cancer is a chemotherapy-sensitive neoplasm.
ders of a lymph node dissection that includes only the external The most widely used and investigated multiagent chemothera-
and internal iliac and obturator nodes [13]. Therefore, an extended peutic regimens are based on cisplatin. In the late 1980s, Memo-
and precise lymph node dissection may improve sensitivity for rial Sloan-Kettering Cancer Center, NY, USA developed a com-
detecting node metastasis and staging the extent of the disease. In bination therapy based on methotrexate, vinblastine,
order to completely remove all the potential sites of primary and doxorubicin and cisplatin (MVAC). Since early trials of MVAC
secondary lymph node drainage originating from the bladder, a demonstrated tumor response rates of up to 70–80% [15], rand-
dissection should include bilateral common iliac, presacral, bilat- omized trials were initiated to compare MVAC with single-
eral internal and external iliac, and obturator lymph nodes. Some agent cisplatin, or with other combination therapies, such as
recommend initiating the dissection just inferior to the inferior cyclophosphamide, doxorubicin and cisplatin (CISCA) [16,17].
mesenteric artery. In addition to allowing for more accurate stag- MVAC proved superior in these trials, and therefore emerged as
ing of the disease, this may also provide a therapeutic benefit. The the standard chemotherapy regimen for patients who have meta-
number of nodes identified reflects the extent of the dissection, static bladder cancer. MVAC is associated with significant toxic-
the presentation of the nodes to the pathologist as an en bloc spec- ity, including mucositis, myelosuppression, renal dysfunction
imen or in packets and the diligence of the pathologist in identi- and peripheral neuropathy [15–17]. Some of these toxicities can
fying separate nodes. This may also be affected by prior pelvic be ameliorated with the prophylactic use of granulocyte colony-
irradiation or chemotherapy and advanced age. A minimum stimulating factor (GCSF) [18]. The European Organization for
extension of the node dissection or an ideal minimum number of the Research and Treatment of Cancer (EORTC) compared
nodes can only be determined in a randomized trial, but it has high-dose intensity MVAC, which employs the same doses of
been suggested that a minimum of 15–20 lymph nodes should be the MVAC drugs, but cycled more frequently in conjunction
obtained to assure staging accuracy [14]. with GCSF, with standard MVAC [19]. The high-dose intensity
One of the largest published outcomes of a series of patients MVAC regimen resulted in improved tolerability while
undergoing radical cystectomy and extended lymph node dissec- demonstrating similar survival rates.
tion came from the group at the University of Southern Califor- Other agents, such as gemcitabine and the taxanes, have
nia, CA, USA, in 2001 [6]. They summarized over 20 years of emerged in recent years. An international Phase III trial com-
experiences with 1054 patients undergoing the procedure. They prising 405 patients, compared a combination of gemcitabine
reported that for organ-confined muscle-invasive lymph node- and cisplatin (GC) with MVAC in advanced urothelial cancer
negative disease, the 5- and 10-year survival rates were 89 and [20]. Overall survival of patients treated with GC was similar to
78%, respectively, for pT2 tumors, and 87 and 76%, respectively, that of patients treated with MVAC. However, grade 3 and 4
for pT3a tumors. Higher stages of extravesical lymph node-nega- mucositis, granulocytopenia, fever and sepsis were significantly
tive disease had significantly worse 5- and 10-year survival rates: increased in the MVAC group. Grade 3 and 4 anemia and
62 and 61%, respectively, for pT3b tumors, and 50 and 45%, thrombocytopenia were significantly increased in the GC
respectively, for pT4 tumors. However, the 5- and 10-year sur- group. Therefore, GC has been suggested as a comparable alter-
vival rates for all patients with lymph node-positive disease were native to MVAC in metastatic bladder cancer. It is also impor-
35 and 34%, respectively. It is important to note, however, that tant to note that best chances for long-term survival after a
approximately 30% of the patients had either adjuvant or neo- combination chemotherapy treatment in metastatic bladder is
adjuvant chemotherapy. A look at subsets suggests the possibility in patients who present with preserved performance status and
that the addition of chemotherapy may have occurred with with nodal only (nonvisceral) disease [21,22].
higher frequency in those with high-stage tumors. Therefore,
these reported results may not actually reflect surgery alone. Neoadjuvant chemotherapy
Due to the high mortality rate in advanced disease, with or Advantages & disadvantages of neoadjuvant chemotherapy
without pelvic node metastases, there is clearly a large group of Neoadjuvant chemotherapy can be given prior to cystectomy in
patients that suffer from undetected micrometastasis during order to reduce tumor volume. This may result in down-staging
diagnosis that radical surgery alone cannot cure. Therefore, an of the primary tumor, treatment of micrometastatic disease or

282 Expert Rev. Anticancer Ther. 6(2), (2006)

 Surgery and chemotherapy for invasive bladder cancer

even allow for cystectomy in patients initially presenting with cystectomy alone was significantly better, with 5-year survival
unresectable disease, such as a tumor that is fixed to the pelvic rates of 85 and 82%, respectively. Initial stage (T2 vs T3 or
sidewall. Patients with clinically positive nodes (preferably biopsy T4a) and patient age (patients were divided to <65 years vs
proven), or nodes above the common iliac bifurcation, are prob- ≥65) had no significant effect on survival. The authors also
ably best treated with neoadjuvant chemotherapy followed by note that administration of neoadjuvant MVAC did not pre-
radical cystectomy and extended node dissection, as cure is vent patients from undergoing surgery, and an increase in
unlikely with surgery alone. In addition, patients may tolerate surgery-related complications was not observed.
chemotherapy better before undergoing surgery than adjuvant Another interesting approach involves the assessment of com-
therapy given after surgery. This may allow for higher doses of bining neoadjuvant chemotherapy and radiation therapy (RT)
drug to be delivered in the neoadjuvant setting, and it provides before cystectomy. Malmstrom and colleagues reported results of
the opportunity to evaluate the objective response of the tumor, a randomized neoadjuvant trial comparing neoadjuvant adria-
and/or clinically positive nodes, to the chemotherapy. mycin, cisplatin and preoperative RT prior to cystectomy with
The potential disadvantage of neoadjuvant chemotherapy is a preoperative RT and cystectomy alone. When the T3–T4 group
delay in cystectomy for the duration of treatment and beyond. of patients were evaluated, a 15% survival difference in favor of
This may be potentially harmful for those patients who do not the neoadjuvant chemoradiation group was observed [25]. In a
respond to chemotherapy or those who suffer from significant subsequent trial of 317 patients randomized to neoadjuvant
complications that require postponing the operation further. methotrexate and cisplatin followed by cystectomy, versus cystec-
tomy alone (without RT), the authors could not find a survival
Randomized trials of neoadjuvant chemotherapy advantage in favor of any of the groups. Another important study
The most recent and comprehensive systemic review and meta- is the combined analysis of the Nordic trials, published initially as
analysis of randomized, controlled trials on the efficacy of neo- an abstract in 2003 by Sharif and colleagues [26]. They assessed
adjuvant chemotherapy for bladder cancer patients has been the effectiveness of neoadjuvant cisplatin-based combination
conducted by Winquist and colleagues from the Genitourinary chemotherapy in two consecutive trials. Overall survival was ana-
Cancer Disease Site Group, Cancer Care Ontario Program in lyzed in several subgroups defined by preoperative T-stage, gen-
Evidence-Based Care Practice Guidelines Initiative [23]. This der and age. A full article was later published [27]. Overall, 620
group identified 16 trials with a total of 3315 patients. After patients with clinically T1G3, T2–T4aNXM0 urothelial bladder
eliminating trials that suffered from missing data or inconsist- cancer and WHO performance of 2 or less were included, with a
encies, the authors ultimately examined 11 trials with a total of median follow-up of 4.7 years. The combined study results dem-
2605 patients. The pooled hazard ratio from all 11 trials com- onstrated a hazard ratio of 0.80 (95% CI: 0.64–0.99) with an
bined was 0.90 (95% confidence interval [CI]: 0.82–0.99; overall survival advantage in the neoadjuvant treatment arm. Sur-
p = 0.02). This matched with the 10% decrease in risk of death vival was estimated at 56% at 5 years in the treated group versus
or a demonstrated absolute survival advantage of 5.0% (95% 48% in the control group, resulting in an 8% absolute risk reduc-
CI: 0.0.5–9.0) from 50 to 55% in this group of patients. The tion after neoadjuvant chemotherapy. When the two trials were
eight trials that used cisplatin-based combination chemother- combined into a cohort of 620 patients, the neoadjuvant chemo-
apy demonstrated a pooled hazard ratio of 0.87 (95% therapy group was found to be superior, with longer survival
CI: 0.78–0.96; p = 0.006) and an absolute survival advantage probabilities. The combined study results demonstrated a hazard
of 6.5% (95% CI: 2–11%) from 50 to 56.5%. However, the ratio of 0.80 (95% CI: 0.64–0.99) for overall survival, favoring
three single-agent cisplatin trials, with a total of 337 patients, the group receiving neoadjuvant chemotherapy. 5-year survival
did not demonstrate any survival benefit. It is also important to for the study group was 56, versus 48% in the control group,
note that a 1.1% mortality rate was observed among all patients translating into an 8% absolute risk reduction after neoadjuvant
receiving neoadjuvant chemotherapy. chemotherapy (i.e., a 20% reduction in the estimated risk
The Intergroup trial reported by Grossman and colleagues of death).
(INT-0080) examined 317 patients with T2–T4a bladder can- In 2003, a systemic review and meta-analysis was published
cer [24]. These patients were randomized to three cycles of neo- by the Advanced Bladder Cancer (ABC) Meta-analysis Collabo-
adjuvant MVAC followed by cystectomy versus cystectomy ration [28]. The authors assessed data from 2688 individual
alone. Median survival of patients in the cystectomy-alone arm patients and ten randomized trials. They demonstrated that
was 46 months, versus 77 months in the neoadjuvant chemo- platinum-based combination chemotherapy showed a signifi-
therapy plus cystectomy arm (p = 0.06 by two-sided stratified cant benefit to overall survival (combined hazard ratio
log-rank test). It is interesting to note that a status of no resid- [HR]: 0.87; [95% CI: 0.78–0·98; p = 0.016]; a 13% reduction
ual disease at cystectomy (T0) had a significant impact on sur- in risk of death; a 5% absolute benefit at 5 years; an overall sur-
vival, independent of treatment arm. Of the patients from the vival increase from 45 to 50%). This effect was observed with all
neoadjuvant chemotherapy group, 38% had no residual can- types of local treatment and subgroups of patients. The HR for
cer, while only 15% in the cystectomy-alone arm had pT0 dis- all trials, including those using single-agent cisplatin, favored,
ease (p < 0.001). This is important, since the survival benefit although modestly (p = 0·084), neoadjuvant chemotherapy
of the pT0 patients treated with neoadjuvant chemotherapy or (HR = 0.91, 95% CI: 0.83–1.01). There was a significant

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difference in the effect between platinum-based combination for consideration of perioperative chemotherapy integrated into
chemotherapy and single-agent platinum treatment in this definitive local therapy. The decision-making process for the
group of trials (p = 0.044). Furthermore, there was no evidence patient and the oncologist is complex, since many factors
to support the use of platinum as a single agent in the neoadju- should be taken into account. In counseling the patient post-
vant setting. Problems that the authors highlighted were that cystectomy, one must inform the patient of all the benefits and
few of the trials in this meta-analysis measured toxicity or qual- risk factors of all treatment options:
ity of life methodologically. Therefore, no combined • The patient’s estimated risk of relapse without treatment
meta-analysis of these issues could be made. (i.e., the estimated natural history of the patient’s disease)
This is a landmark meta-analysis for several reasons. The • The reasoning behind initiating adjuvant chemotherapy
investigators obtained primary data from each individual study (i.e., the efforts to eradicate any residual cancerous cells that
instead of depending on published summary information. They may still reside in the body)
also identified and included data from unpublished studies. A • Discuss published studies, suggesting that there is only a rela-
sensitivity analysis was performed, demonstrating that the over- tively modest effect of chemotherapy in improving disease-
all results were not disproportionately influenced by results free and overall survival with high-risk urothelial cancer. An
from any individual study. Finally, the meta-analysis results were estimate of 5–15% absolute improvement in 5-year
consistent with randomized trials in metastatic TCC, where cis- survival would be a fair statement
platin-combination therapy provides a survival advantage over
• Information regarding the risk of toxicity and anticipated
single-agent therapy [22].
side effects of each of the regimens offered, while weighed
One might conclude that treatment with neoadjuvant cispla-
against the potential benefit
tin-based chemotherapy has some effect on improving overall sur-
vival in muscle-invasive bladder cancer, although the size of the • The patient should be advised on how age, performance sta-
effect is somewhat modest. In the oncologic literature, mainly tus and comorbid conditions, especially renal and cardiac
from Europe, there is evidence that may also support the option function, may predict one’s ability to withstand and complete
of neoadjuvant chemotherapy for bladder preservation. However, the treatment, with an ultimately successful outcome
this concept has not been widely embraced in the urologic com- • It is suggested that in order to allow maximum effect, therapy
munity in North America. Another option is combining systemic should begin 6–12 weeks after surgery
chemotherapy with RT in an attempt to preserve the bladder. The genitourinary oncology group from the University of
Neoadjuvant chemotherapy is thought to sensitize the tumor to Southern California, CA, USA, in a recently published review
radiation, while concurrently treating the occult metastases [29,30]. of adjuvant chemotherapy after radical cystectomy, mentions
The results of randomized trials of neoadjuvant chemotherapy that in their busy practice, 90% of high-risk patients elect adju-
before radical cystectomy are summarized in TABLE 1. vant therapy. A total of 65% of these patients prefer the combi-
nation of GC rather than MVAC. Most patients who do receive
Adjuvant chemotherapy MVAC are less than 65 years old, with excellent performance
The major advantage of adjuvant chemotherapy in the post- status and normal renal function [31]. Their regimen consists of
operative context is the ability to very accurately define the dis- 12 weeks of therapy: three cycles of 28-day MVAC or four
ease stage by pathology, and eliminate the risk of clinical under- cycles of GC given over a 21-day period.
or over-staging. This approach may reduce exposure of patients When recommending a specific regimen, one must take into
to toxicity associated with chemotherapy, when there is no account renal function, cardiac output and the neutropenic and
pathologic evidence of locally advanced or metastatic disease. thrombocytopenic effects of cytotoxic chemotherapy. MVAC
Therefore, a major challenge is to identify those patients who cannot usually be offered to patients with creatinine above
would most benefit from perioperative chemotherapy, and to 2 mg/dl or creatinine clearance of less than 50 ml/kg/min. This
avoid unnecessary toxicities for those who will not benefit from is due to the reduced renal clearance of methotrexate and cispla-
it. Another advantage of adjuvant treatment lies in the tin toxicity. Some patients in this situation may be offered GC.
improvements in understanding the molecular biology of blad- Patients with reduced cardiac output, as measured by left ven-
der cancer and its therapeutic implications. As will be discussed tricular ejection fraction of less than 45% on echocardiography,
later in this review, selection of patients for chemotherapy or those with New York Heart Association (NYHA) grade 2
based on molecular markers, as tested in cystectomy specimens, symptomatic heart failure, should not receive doxorubicin and
is being evaluated in prospective clinical trials. therefore cannot receive MVAC. Hydration is required for cispl-
atin, which may also be a significant management challenge,
Considerations & risk factors before starting requiring close monitoring of these patients.
adjuvant treatment Although most patients experience a transient and asympto-
Pathologic staging at time of surgery is the best predictor for matic episode of neutropenia and thrombocytopenia during
the risk of relapse or death from disease. An emerging standard chemotherapy, some patients may develop fever, chills, rigors
of care for patients with pT3, pT4 or node-positive disease is a and lethargy. Gram-negative bacilli, such as Pseudomonas and
multidisciplinary approach with medical oncology consultation Klebsiella spp., should always be suspected, and early treatment

284 Expert Rev. Anticancer Ther. 6(2), (2006)

 Surgery and chemotherapy for invasive bladder cancer

Table 1. Results of randomized trials of neoadjuvant chemotherapy and radical cystectomy.

Study Series Regimen Patients Median time Median 3- or Survival Ref.
(n) to progression survival 5- year benefit
(months) (months) survival
Wallace Australia/UK Cisplatin + RT 255 - 24 39% (3-year) No [54]
vs
RT - 22 39% (3-year)
Martinez- CUETO Cisplatin 60 30.3 37.5 50% No [55]
Pineiro vs
Observation after 62 13.1 35 50%
cystectomy
Coppin Canada/ Cis + RT or Cis + RT 51 - - 47% (3-year) No [56]
NCI + cystectomy
vs
RT or RT + cystectomy 48 - - 33% (3-year)
Malstrom Nordic I Cisplatin + RT 151 23 - 59% Yes [25]
vs
RT 160 14 - 51% For
T3–T4
Sherif Nordic II Cisplatin + MTX 317 - - 53% No [57]
vs
Observation after - - 46%
cystectomy
Abol-Eneim Egypt Carboplatin 94 - - 59.1% Yes [60]
+ MTX
vs
Observation after 100 - - 41.6%
cystectomy
Bassi GUONE MVAC 102 - - 55% No [59]
vs
Observation after 104 - - 54%
cystectomy
International EORTC/MRC CMV + RT or CMV + 491 32 44 50% (3-year) No [58]
collaboration cystectomy vs
RT or cystectomy 485 25 37.5 55.5% (3-year)
Sengelov DAVECA 8901 Cis + MTX 17 - 83 64% No [61]
vs

Observation after 16 - 46 46%

cystectomy
Grossman SWOG MVAC 153 - 77 57% Yes [24]
vs
Observation after 154 - 46 43%
cystectomy
Cis: Cisplatin; CMV: Cisplatin, methotrexate and vinblastine; CUETO: Club Urologico Espanol de Treatamiento Oncologico; DAVECA: Danish Vesical Cancer Group;
EORTC: European Organization for Research on the Treatment of Cancer; GUONE: Gruppo Oncologico del Nord est; MTX: Methotrexate; MVAC: Methotrexate, vinblastine,
doxorubicin, cisplatin; RT: Radiotherapy; SWOG: Southwest Oncology Group.

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is mandatory, since urosepsis may be fatal. Patients with pro- treatment in an adjuvant setting. However, after 49 patients
longed perioperative antibiotic therapy or with diabetes should were randomized, an interim analysis demonstrated a striking
be checked for fungal septicemia. Nose bleeding, gastrointestinal advantage in the 3-year disease-free survival of the adjuvant
bleeding or easy bruising should raise the suspicion of thrombo- chemotherapy group, as compared with the control
cytopenia. When a patient is symptomatic, or has a platelet (63 vs 13%; p = 0.0015). This caused the early termination of
count of less that 20,000 µl, a platelet transfusion should be the study on the basis of ethical grounds. A significant survival
strongly considered. A foley catheter should be placed during benefit was also found in patients with node-positive disease,
treatment with methotrexate in order to reduce reabsorption of and a survival benefit in the entire randomized population was
the drug and high serum levels, which may increase toxicity. suggested in a later publication [38].
This is also important during hydration for cisplatin administra- In 1996, Freiha and colleagues published a small study of
tion in order to prevent overdistension of a neobladder or 50 patients with pT3–pT4 or node-positive disease, who were
continent cutaneous diversion and pouch rupture. randomized to radical cystectomy followed by adjuvant chemo-
therapy comprising four cycles of cisplatin, methotrexate, and
Randomized trials of adjuvant chemotherapy vinblastine or to radical cystectomy alone [35]. The study group
While reviewing the literature, one cannot deny the paucity of demonstrated a significantly improved disease-free survival
randomized clinical trials of adjuvant chemotherapy for (median: 37 vs 12 months; p = 0.01). This study was also ter-
patients undergoing radical cystectomy. Logothetis and col- minated prematurely due to poor accrual and the striking dif-
leagues were the first to report, in 1988, the possible benefit of ferences between the two groups at the first interim analysis.
CISA combination chemotherapy for patients after undergoing However, overall survival benefit could not be demonstrated, as
radical cystectomy for invasive bladder cancer [32]. This retro- many patients in the no treatment arm had received chemo-
spective and nonrandomized comparison suggested that high- therapy at time of progression. This study raises the question of
risk patients (pT3, pT4 or node-positive) receiving adjuvant whether surgical outcome would be the same if chemotherapy
chemotherapy had a significantly improved 5-year disease-free were administered preoperatively, or at the time of progression.
survival compared with those who did not (76 vs 37%; In 1989, Bono and colleagues, and in 1994 Studer and col-
p = 0.0001). leagues, published two small randomized trials, which failed to
Only five completed randomized studies comparing adjuvant show a survival benefit from adjuvant chemotherapy [36,37]. A
chemotherapy with observation have been published in the last major caveat of these two articles was the fact that they
15 years [43–47]. In 1991, Skinner and colleagues reported on included many patients with organ-confined disease (N0).
91 patients with pT3–4 or node-positive M0 TCC of the blad- Therefore, a much larger number of patients was required to
der that were randomly assigned to four cycles of cisplatin, doxo- detect statistically significant survival benefits of the adjuvant
rubicin and cyclophosphamide (CAP) or observation after radi- chemotherapy arm. Another criticism made was that the
cal cystectomy. The authors reported a significant improvement chemotherapy protocol consisted of cisplatin only.
for the group receiving adjuvant chemotherapy in 3-year disease- All the above-mentioned studies had methodological prob-
free survival (70 vs 46%; p = 0.006) and in median survival lems relating to sample size, treatment regimen, extent of pel-
(4.4 vs 2.2 years; p = 0.001). Only 91 of a total of 498 eligible vic lymph node dissection and timing of adjuvant chemother-
patients were enrolled in the study, and the chemotherapeutic apy. To address the paucity of adjuvant chemotherapy trials for
regimen administered in the study was not uniform. However, bladder cancer, a few large multicenter trials have been initi-
this was the first randomized trial that suggested a role of adju- ated in recent years. The EORTC is recruiting 1300 patients
vant chemotherapy for invasive bladder cancer after radical cys- with extravesical (pT3–T4) or node-positive TCC to be ran-
tectomy. In 2001 this group updated their results [6]. The domly assigned either to immediate postoperative chemother-
authors reported a continued improvement in time-to-recur- apy or to chemotherapy at time of relapse [39]. The participat-
rence and survival in the group that received chemotherapy. ing institutions are allowed to choose their desired
However, a statistically significant improvement in overall sur- chemotherapeutic regimen between MVAC, high-dose MVAC
vival was not achieved. Analyzing the outcomes of 255 patients or GC; results are pending.
(27%) that received adjuvant or neoadjuvant chemotherapy, the The Cancer and Leukemia Group B and the Eastern Cooper-
authors found that only patients with lymph node-positive dis- ative Oncology Group initiated a study comparing two adju-
ease had a significant improvement in recurrence-free and overall vant chemotherapy regimens after radical cystectomy, namely a
survival, following adjuvant chemotherapy. standard treatment arm as the control group and a more aggres-
In 1992, Stockle and colleagues from Mainz, Germany, sive treatment approach as the study group. This was based on
reported a study designed to enroll 100 patients with TCC the hypothesis that a chemotherapy program of rapidly cycling
pT3b, pT4a and/or node-positive disease, and randomly assign sequential regimens is supposedly more effective than a stand-
the patients to observation or three cycles of MVAC or meth- ard schedule. This stemmed from the reluctance of many
otrexate, vinblastine, cisplatin and epirubicin (MVEC), after oncologists and patients to participate in a study that might
radical cystectomy [42]. This study is unique since it is the only result in being assigned to an arm with no treatment at all. The
randomized trial that assessed standard MVAC (or MVEC) estimated sample size was 800 patients with pT3–pT4 or node

286 Expert Rev. Anticancer Ther. 6(2), (2006)

 Surgery and chemotherapy for invasive bladder cancer

positive TCC randomly assigned to either a sequenced doublet and number of nodes in the surgical specimen may influence
therapy consisting of doxorubicin and gemcitabine followed by survival after radical cystectomy, and provided additional prog-
paclitaxel and cisplatin, or to a conventional doublet therapy nostic value independent of pathologic stage and treatment
consisting of GC. As mentioned previously, GC has been arm [43]. While no prospective, randomized, controlled trial
proven to provide similar survival rates with less toxicity when exists to demonstrate the benefit of an extended lymph node
compared with MVAC in patients with measurable metastatic dissection, it is important to consider surgical factors and estab-
disease. Another adjuvant chemotherapy study, based on p53 lish prospective surgical guidelines in future trial design. For
status in the bladder pathology specimen, is also currently example, the authors did this with the original design of the
recruiting patients, and will be discussed later in this review. p53 targeted therapy trial, requiring a bilateral pelvic lym-
This study was closed, however, due to poor accrual. phadenectomy and a minimum of 15 lymph nodes in the surgi-
The latest paper published on adjuvant chemotherapy came cal specimen. Patients who do not meet this minimum criteria
from a group in Germany. Lehmann and colleagues published a may be enrolled only with a negative postoperative computed
randomized, multicenter, Phase III clinical trial (AUO-AB tomography scan of the abdomen and pelvis.
05/95) that compared cisplatin plus methotrexate (CM) with
MVEC in 327 patients with locally advanced bladder Correlation between molecular markers, tumor aggressiveness
cancer [40]. The authors reported 5-year progression-free, & response to chemotherapy
tumor-specific and overall survival rates (point estimates ± Genetic alterations that result in the activation of oncogenes,
standard error) for CM versus MVEC. These were 46.3 loss of distinct chromosomal regions and inactivation of tumor
(±4.6%) vs 48.8% (±4.5%), 52.0 (±4.6%) vs 52.3% (±4.8%) suppressor genes have been shown to affect tumor formation
and 46.1 (±4.3%) vs 45.1% (±4.6%), respectively. Interestingly, and progression. Molecular markers may be assessed as a means
WHO grade 3 and 4 leukopenia occurred in 22.2% of patients to predict survival as well as response to chemotherapy. The
treated with MVEC but only in 7.0% of patients treated with most widely studied predictive markers in bladder cancer are the
CM (p < 0.0001). The authors concluded that with regard to cell cycle regulatory genes p53, pRb and p21. One of the first
patients with locally advanced bladder cancer after radical cys- series of studies on molecular markers in bladder cancer initially
tectomy, progression-free survival after treatment with CM is correlated altered p53 expression by immunohistochemistry in
not inferior to that with MVEC. The results of randomized tri- patients with organ confined cancers with a significantly higher
als of adjuvant chemotherapy after radical cystectomy are sum- chance of recurrence compared with patients with wild-type p53
marized in TABLE 2. It is important to note that new, alternative, [44]. Thereafter, they demonstrated that patients with tumors
forms of adjuvant therapy using biologically active antitumor expressing alterations in both p53 and pRb had significantly
agents, such as HER2-inhibitors, bortezomib or erbstatin higher rates of recurrence and decreased survival compared with
inhibition, are also under investigation. patients without alterations in pRb and p53 [45,46]. Herr and col-
leagues assessed the relationship between durability of complete
Head-to-head neo- & adjuvant chemotherapy trials clinical response to chemotherapy with MVAC, and alteration
The question of whether there is an advantage of preoperative in p53 gene expression [47]. The authors found that stage T2
neoadjuvant chemotherapy over adjuvant chemotherapy in patients without detectable p53 (the wild-type state), who
patients undergoing radical cystectomy was assessed by Millikan obtained a complete response to neoadjuvant chemotherapy,
and colleagues [41]. This group randomized 140 patients with had a much better chance of preserving their bladders up to
muscle-invasive bladder cancer to two groups. The first received 10 years after chemotherapy.
two cycles of neoadjuvant MVAC followed by cystectomy and The authors have assessed the independent association
pelvic lymph node dissection, followed by three additional between alterations in p53, p21, pRB and p16, with disease pro-
cycles of adjuvant MVAC. The other group underwent cystec- gression and disease-specific survival in a group of 80 patients
tomy and pelvic lymph node dissection, followed by five cycles with a median follow-up of 101 months [48]. All patients under-
of adjuvant MVAC. At a median follow-up of nearly 6 years, went radical cystectomy and bilateral pelvic lymph node dissec-
58% of patients were alive and disease free. No statistically sig- tion. The number of altered markers was associated with an
nificant survival benefit was observed between the two groups. increased risk of bladder cancer progression and mortality, inde-
Other chemotherapy-sensitive cancers, such as breast cancer, pendent of pathologic tumor stage and lymph node metastasis.
have also failed to prove a survival benefit difference between p53 was shown to be the strongest predictive molecular marker
neoadjuvant or adjuvant chemotherapy [42]. in the study, followed by p21, stressing their important role in
bladder cancer progression. Chatterjee and colleagues from Uni-
Surgical factors versity of Southern California assessed the predictive value of
A potential shortcoming of the multicenter perioperative (neo- altered expression patterns of p53, p21 and pRb on progression
adjuvant and/or adjuvant) chemotherapy trials is the inherent of bladder cancer. Radical cystectomy specimens from 164
variability of the surgical technique for radical cystectomy and patients with a median follow-up of 8.6 years were assessed [49].
the extent of the node dissection. Herr and colleagues analyzed After stratifying the patients by stage, the authors found that the
data from the SWOG 8710 and suggested that margin status number of altered p53, p21 and pRb protein products

www.future-drugs.com 287
Amiel & Lerner

Table 2. Results of randomized trials of adjuvant chemotherapy and radical cystectomy.

Study Group Regimen Patients Progression Survival Survival Ref.
(n) benefit
Median (years) Years 5–3 (%) Median (years) 5-year (%)
Skinner USC CISCA 44 6.58 51 4.25 39 No [33]

Observation 47 1.92 34 2.41 44

Stockle Mainz MVA (E) C 26 Not 63 (3) NA NA Not [34]
reached evaluated
Observation 23 16 0 (3) NA NA
Stockle Mainz MVA (E) C 26 Not 64 (3) 38 54 Yes [38]
reached
Observation 23 16 14 (3) 17 14
Studer SAKK Cisplatin 37 NA NA Not reached 57 [36]

Observation 40 NA NA Not reached 54

Freiha Stanford CMV 25 37 50 Not reached 55 No [35]

Observation 25 12 22 Not reached 35

AUO MVEC 325 49.7 44.5 51.8 45.1 No
Cisplatin + 43.4 46 47.1 46.1
MTX
AUO: Arbeitsgemeinschaft Urologische Onkologie; CISCA: cisplatin, doxorubicin and cyclophosphamide; CMV: Cisplatin, methotrexate and vinblastine; MTX: Methotrexate;
MVA(E)C: Methotrexate, vinblastin, doxorubicin and cisplatin; MVEC: Methotrexate, vinblastine, epirubicin and cisplatin NA: Not applicable; SAKK: Swiss Group for Clinical
Cancer Research.

correlated significantly with both time to progression and overall p53 alterations will be randomly assigned to three cycles of
survival, causing those patients to be at high risk of recurrence adjuvant MVAC or observation without further treatment after
and death. These two studies suggest that alterations measured radical cystectomy. This is the first molecularly-based targeted
by immunohistochemistry may provide additional prognostic therapy in bladder cancer.
information beyond pathologic features of the tumors. Elevated endostatin and matrix metalloproteinase-9 levels have
Hussain and colleagues studied Bcl-2, a protein fundamental recently been found to be associated with higher stage and grade
to preventing apoptosis, and found that overexpression of Bcl-2 of primary transitional cell carcinoma of the bladder [51]. Vascu-
in patients receiving chemotherapy and radiation was an inde- lar endothelial growth factor (VEGF) has also been shown to
pendent indicator of poor survival in muscle-invasive bladder have an effect on survival. Many authors have shown that tumor
cancer [50]. hypoxia exerts its own influence on malignant progression by
A multicenter, international, randomized trial based on the inducing angiogenetic factors and new blood vessels inside and
status of p53 in the pathological specimen has been recently around the tumor. High microvessel density and VEGF expres-
initiated. This is based on the previously discussed data, that sion in bladder carcinoma specimens usually suggest a poor
patients with organ-confined bladder cancer and a wild-type prognosis and/or aggressive tumor behavior [52,53]
p53 have an overall good prognosis, with an estimated 5-year
disease-free survival of 90%. In addition, patients with bladder Expert commentary
cancer with p53 alterations are believed to be more sensitive to The data from randomized clinical trials of perioperative
DNA damaging agents. In a retrospective review of the USC chemotherapy, delivered either as neoadjuvant or adjuvant,
adjuvant therapy trial, p53-positive patients (altered expression) provide a strong case for the integration of perioperative chem-
treated with adjuvant chemotherapy had a threefold reduction otherapy with radical cystectomy and bilateral lymph node dis-
in relative rise of progression [45]. These patients are observed section for patients with locally advanced bladder transitional
without additional therapy. The other arm consists of patients cell carcinoma. Discussion with the patient regarding neoadju-
with organ-confined bladder cancer with altered p53 expres- vant and adjuvant chemotherapy, the role of bladder salvage
sion. These patients are reported to possess a 40% 5-year dis- and consideration of maximizing surgical control of locore-
ease free survival and are therefore predicted to benefit from gional disease are paramount to an adequate informed consent.
chemotherapy [51]. Patients with organ-confined disease, with A series of large, randomized, controlled trials are underway,

288 Expert Rev. Anticancer Ther. 6(2), (2006)

 Surgery and chemotherapy for invasive bladder cancer

and the recruitment of patients to clinical trials is crucial for addressing chemotherapy regimens, bladder salvage and tim-
adequate accrual and for expedited completion of these antici- ing of chemotherapy require the support of the urologic
pated studies. Molecular profiling of tumors is now becoming oncology community in order to define standards of treat-
an integral part of clinical trials and, with more substantial ment. The role of cell-cycle regulatory genes and other bio-
data, may improve our ability to tailor specific treatments for logic markers will be defined in prospective trials and will
an individual’s cancer and improve our ability to predict generate a new frontier of targeted therapeutics, which offer
outcome of a given treatment. the hope of precise individualized prognosis and tailoring of
treatment. The debate over neoadjuvant versus adjuvant
Five-year view chemotherapy will not be resolved.
Perioperative chemotherapy, whether adjuvant or neo-
adjuvant, is now considered by many to be the standard of Acknowledgements
care for patients with locally advanced invasive bladder can- Gilad E Amiel was supported by Lynn and Deane Monical Fel-
cer. Surgical factors are suggested to contribute significantly lowship in Urology Oncology and Minimally Invasive Surgery,
to the outcome, and the optimal strategy needs to be defined Scott Department of Urology, Baylor College of Medicine,
in prospective clinical trials. Current ongoing clinical trials Houston, TX, USA

Key issues

• It is estimated that 63,210 new cases of bladder cancer will be diagnosed in the USA in 2005, and 13,180 patients will die from
the disease.
• Radical cystectomy is the most common treatment for patients with invasive bladder cancer, or those with a noninvasive disease
that is refractory to intravesical therapy. Extended lymph node dissection has been suggested to provide accurate staging and
optimum surgical control of the disease, which must be validated in prospective trials.
• The current literature concerning perioperative chemotherapy, delivered either as neoadjuvant or adjuvant, provides a strong case
for the use of systemic multiagent chemotherapy in patients with poor-risk bladder cancer who are to undergo radical cystectomy
and lymph node dissection.
• Head-to-head neoadjuvant versus adjuvant studies are scarce, and based on the current literature, it is impossible to say whether
one is superior to the other.
• Molecular profiling and gene discovery provide new insight into pathways of bladder carcinogenesis and progression. Prospective
validation of molecular markers and their relevant targets and evaluation of novel therapeutic agents alone or in combination with
established cytotoxic agents provides hope of better outcomes for bladder cancer patients.

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