Download Role of Systemic Chemotherapy in Urothelial Urinary Bladder Cancer

Neoadjuvant chemotherapy is
underutilized in muscle-invasive
bladder cancer.
Michele R. Sassi. Evening, Istanbul, Turkey. Photograph.
Role of Systemic Chemotherapy in
Urothelial Urinary Bladder Cancer
Shilpa Gupta, MD, and Amit Mahipal, MD
Background: Radical cystectomy is the standard of care for patients with localized muscle-invasive bladder
cancer; however, 50% of patients still relapse in distant sites following surgery. A systemic approach is needed
to improve outcomes in bladder cancer in the metastatic and perioperative settings.
Methods: We reviewed the literature for use of systemic chemotherapy in bladder cancer and its role in metastatic,
neoadjuvant, and adjuvant settings, including patients with comorbidities and renal dysfunction. Current
controversies on the role of chemotherapy in neoadjuvant and adjuvant settings as well as the role of novel
agents are discussed.
Results: First-line cisplatin-based polychemotherapy improves survival in the metastatic setting and is the
standard of care. Approved regimens for subsequent-line therapy do not exist. Chemotherapy has a modest
benefit in the neoadjuvant setting, but evidence is insufficient to justify its role in the adjuvant setting despite
a possible benefit. Carboplatin cannot be substituted for cisplatin in fit patients, and the addition of taxane
to a standard regimen cannot be recommended.
Conclusions: Systemic chemotherapy plays a central role in the management of invasive bladder cancer in
the metastatic and neoadjuvant settings, but its role in the adjuvant setting remains undefined. Neoadjuvant
chemotherapy is underutilized and should be routinely used. Pathological downstaging strongly correlates
with improved outcomes and may serve as a surrogate end point for survival. An urgent need exists for the
development of novel therapeutic agents to improve outcomes.
From the Department of Genitourinary Oncology (SG) and the
Clinical Research Unit (AM) at the H. Lee Moffitt Cancer Center &
Research Institute, Tampa, Florida.
Submitted May 7, 2012; accepted October 5, 2012.
Address correspondence to Shilpa Gupta, MD, Department of Genitourinary Oncology, Moffitt Cancer Center, 12902 Magnolia
Drive, Tampa, FL 33612. E-mail: [email protected]
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
200 Cancer Control
Introduction
Bladder cancer is the fourth most common cancer in
men in the United States, and approximately 72,570
new cases and 15,210 deaths will occur in men and
women in 2013 due to this disease.1
Although the majority of patients with bladder
cancer present with noninvasive bladder cancer, 20%
to 40% patients present with more advanced disease or
progress following treatment for superficial disease.2
The gold standard of treatment for clinically localized
invasive bladder cancer is radical cystectomy and, depending on the extent of primary tumor, nodal status,
July 2013, Vol. 20, No. 3
and extent of surgery, around 50% patients still relapse
after surgery, most commonly in distant sites.3-5
Combination systemic chemotherapy is widely
used for locally advanced and metastatic bladder cancer. Its use in neoadjuvant fashion improves survival
in patients with muscle-invasive bladder cancer,6 and
benefit may also exist in adjuvant chemotherapy following cystectomy in patients at high risk for relapse.
It is imperative to develop optimal, less toxic chemotherapy regimens by incorporating novel targeted
agents to improve outcomes in bladder cancer.
Chemotherapy for Metastatic Bladder Cancer
Typically, bladder cancer recurs in the pelvic lymph
nodes and distant sites. Despite the fact that bladder
cancer is chemosensitive, the prognosis of patients
with metastatic disease remains poor, with a median
survival of 14 months and a 5-year survival rate of
15%.7 Single-agent use of various chemotherapeutic
agents such as methotrexate, vinblastine, doxorubicin,
and cisplatin (MVAC) was first shown to be effective
for bladder cancer in 1987, but the use of these single
agents has been limited by low, short-lived response
rates, with few complete responses and the median
survival between 4 to 6 months.8,9 The need to improve
outcomes in metastatic bladder cancer has led to the
development of combination chemotherapy regimens.
First-line Chemotherapy
Cisplatin-containing combination chemotherapy has
been widely used for more than 20 years.10 Results
of a combination of MVAC were first reported in 1985
and showed that, although the overall response rate
was 70%, the median survival was 13 months and 24%
patients achieved long-term disease-free survival.11 A
phase III intergroup study compared the efficacy of
single-agent cisplatin with MVAC in 269 patients with
metastatic or locally advanced urothelial cancer.12,13
The response rate (39% vs 12%) and OS (12.5 vs 8.2
months) were significantly higher in patients receiving MVAC; however, this regimen was associated
with increased toxicity, including mucositis, neutropenia, infections, gastrointestinal complications, and
a toxic death rate of 3% to 4%. A small fraction of
patients received full-dose MVAC without dose modifications. While long-term follow-up results of this
trial confirmed the original findings that MVAC was
superior to cisplatin alone, durable progression-free
survival was rare and seen in less than 4% of patients. MVAC was also demonstrated to be superior
to a combination chemotherapy regimen of cisplatin, cyclophosphamide, and doxorubicin (CISCA) in
a randomized trial of 110 patients.14 The median
OS in patients treated with MVAC was 48.3 weeks
compared with 36.1 weeks in patients treated with
CISCA. In an attempt to improve efficacy of the MVAC
July 2013, Vol. 20, No. 3
regimen, a phase III randomized trial was undertaken
by Sternberg et al15 that assigned 263 patients to highdose-intensity MVAC (HD-MVAC; 2-week cycle) with
granulocyte colony-stimulating factor (G-CSF) and
standard MVAC (4-week cycle). HD-MVAC was associated with higher complete response rates (21%
vs 9%) and longer progression-free survival (9.1 vs
8.2 months), but no significant difference was found
in OS rates between the two groups (P = .122). Although the incidences of grades 3 to 4 neutropenia
and mucositis were significantly lower with HD-MVAC,
they were still associated with a toxic death rate of
3%. In the 7-year updated analysis, a borderline significant survival benefit was seen with HD-MVAC.16
The 5-year survival rate was 21.8% in the HD-MVAC
arm compared with 13.5% in the MVAC arm (hazard
ratio [HR] = 0.76; 95% confidence interval [CI], 0.58–
0.99; P = .042). MVAC with G-CSF was also found to
be superior to combination docetaxel/cisplatin (DC)
therapy with G-CSF, and it was also associated with
a lower toxicity rate than reported for MVAC without
G-CSF.17 The substantial toxicity of the MVAC regimen is especially concerning for the elderly who may
have multiple pre-existing comorbidities, a patient
population that comprises a significant proportion
of patients with bladder cancer. Therefore, a need
exists to develop newer combination chemotherapy
regimens with better toxicity profiles and equivalent
or better efficacy than the MVAC regimen. Based on
the promising clinical activity of combination gemcitabine/cisplatin (GC),18-20 a phase III randomized
trial of 405 patients was conducted to compare GC
with MVAC.7,21 The response rates (49% vs 46%), time
to progression (median: 7.4 vs 7.4 months), and OS
rates (median OS 13.8 vs 14.8 months; P = .75) were
similar in both arms. Notably, this trial was not designed as an equivalence trial but rather to detect a
33% difference in the survival rates between the two
arms. The updated analysis confirmed the expected
equivalence of these two regimens with an HR of 1.09
(95% CI, 0.88–1.34; P = .66).7 More importantly, GC
was better tolerated than MVAC, with 63% of cycles
administered with no dose modifications compared
with 37% dose modifications in the MVAC arm. Patients on the GC arm experienced less grade 3 or 4
neutropenia (71% vs 82%), neutropenic fever (2% vs
14%), and neutropenic sepsis (1% vs 12%), and grade
3 or 4 mucositis was significantly less common on the
GC arm (1% vs 22%), as was the toxic death rate (1%
vs 3%). The equivalent efficacy and better tolerability
profile of the GC regimen has led to its adoption as
the preferred, standard first-line treatment for patients
with locally advanced or metastatic bladder cancer in
the United States. Data from studies of randomized
trials of chemotherapy for metastatic bladder cancer
are presented in Table 1.7,12,14,15,17,19,21,22
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Table 1. — Selected Randomized Trials of Chemotherapy for Metastatic Bladder Cancer
Study
No. of
Patients
Experimental
Arm
Control
Arm
Relative Risk
(%)
Median Survival
(mos)
P
Value
Intergroup12
269
MVAC
Cis
39 vs 12
12.5 vs 8.2
.0001
14
Logothetis
110
MVAC
CISCA
65 vs 46
11.1 vs 8.3
.0003
MRC19
214
CMV
MV
46 vs 19
7 vs 4.5
.0065
263
HD-MVAC
MVAC
72 vs 58
14.9 vs 15.1
.0417
von der Maase
405
GC
MVAC
49 vs 46
14.0 vs 15.2
.66
Bamias17
220
DC
MVAC
37 vs 54
9.3 vs 14.2
.026
Dreicer22
85
CaP
MVAC
28 vs 36
13.8 vs 15.4
.65
Sternberg15
7,21
CaP = carboplatin and paclitaxel, Cis = cisplatin, CISCA = cisplatin, cyclophosphamide, and doxorubicin, CMV = cisplatin, methotrexate, and vinblastine,
DC = docetaxel and cisplatin, HD-MVAC = high-dose-intensity MVAC, MV = methotrexate and vinblastine, MVAC = methotrexate, vinblastine, doxorubicin,
and cisplatin.
Various studies have tested a three-drug combination using platinum and taxanes with varying response
rates to determine if the addition of a third cytotoxic
agent with a different mechanism of action but without an overlapping toxicity with GC would further
improve the efficacy of GC.21,23,24 The combination of
paclitaxel, gemcitabine, and cisplatin (PGC) showed an
overall response rate of 77.6%, with a 27.6% complete
response rate and a median survival of 15.6 months.23
Based on these encouraging results, Bellmunt et al24
compared these two regimens in a phase III study of
607 patients. The overall response rate was higher
among patients treated with PGC than those treated
with GC (55.5% vs 43.6%; P = .0031). Although the
median OS was 3.1 months longer in the PGC arm
(15.8 vs 12.7 months), it was not statistically significant
(HR = 0.85; 95% CI, 0.72–1.02; P = .075). Moreover,
patients in the PGC arm experienced more instances
of grade 3 and 4 neutropenia. Based on the results
of this randomized phase III trial that addressed the
efficacy of three cytotoxic drugs compared with only
two drugs, currently no role exists for the addition of
a third agent to the GC combination.
Carboplatin has been substituted for cisplatin for
many other cancers to provide an equivalent efficacy
rate and better tolerability. However, its substitution
as first-line chemotherapy in place of cisplatin for
patients with bladder cancer who are otherwise eligible or “fit” to receive cisplatin is not well studied.
Although some phase II studies reveal that carboplatin
is inferior to cisplatin,25-27 there exists one phase III
trial that compared MVAC to carboplatin/paclitaxel
and showed a trend toward worse survival in the
carboplatin arm, although this result was not significant.22 However, the study was closed early and no
definite conclusions can be drawn. The criteria for
defining patients as unfit for cisplatin, as proposed by
a consensus working group, include a performance
202 Cancer Control
status of 2 or higher, a creatinine clearance of less
than 60 mL/minute, hearing loss of 25 dB at two
contiguous frequencies, grade 2 or higher peripheral
neuropathy, or New York Heart Association Class III
or higher heart failure.28 The use of carboplatin in
place of cisplatin is not recommended as first-line
chemotherapy for patients with normal renal function;
by contrast, it should be considered in patients with
decreased creatinine clearance or any of the abovementioned criteria.
Second-line Chemotherapy
No standard second-line chemotherapy exists for patients with bladder cancer who progress on the standard first-line platinum-based treatment with MVAC or
GC. For selected patients who progress on first-line
cisplatin-based chemotherapy and are still eligible
for cisplatin treatment, rechallenge with cisplatincontaining chemotherapy is feasible, depending on
their initial response. Han et al29 studied the efficacy
of MVAC in patients who failed GC in a small phase
II study of 30 patients. The overall response rate was
30%, with a 6.7% complete response rate, and 7 out
of 16 patients who previously responded to GC had
a response to MVAC, while 2 out of 14 who had not
responded to GC showed a response to MVAC.
Various single agents, including paclitaxel,
docetaxel, gemcitabine, ifosfamide, oxaliplatin, and
vinflunine, have been studied in this setting with modest response rates of less than 20%.30-36 Of these,
the largest single-agent trial with 370 patients utilized vinflunine, a novel vinca alkaloid that showed
a response rate of 9% and a small but significant OS
benefit over best supportive care (6.9 vs 4.6 months;
P = .04). It had a tolerable safety profile and became
the first approved second-line chemotherapy agent
in Europe for metastatic bladder cancer, but it is not
yet available in the United States.27
July 2013, Vol. 20, No. 3
Pemetrexed, a multitargeted antifolate, is also an
active agent in the second-line setting. The Hoosier
Oncology Group37 study demonstrated a response
rate of 28% and a median survival of 9.6 months with
single-agent pemetrexed in previously treated patients
with urothelial cancer. Albumin-bound paclitaxel is
another agent that has shown promising activity in a
phase II study in 48 patients progressing on platinumbased chemotherapy. Among 47 evaluable patients,
partial responses were seen in 15 patients (32%) and
stable disease in 10 (21%), with an overall disease
control rate of 53%.38 Eribulin has demonstrated
response rates of 40% as a single agent in bladder
cancer, including in patients who had received neoadjuvant chemotherapy.39 Moreover, it is not renally
excreted and is being studied in patients with renal
dysfunction (NCT00365157).
Various combination chemotherapy regimens have
also been studied in this setting with reasonable response rates. Although no preferred regimen exists,
most studies have combined gemcitabine with another
agent. A gemcitabine/paclitaxel doublet has been extensively studied in many phase II trials, with response
rates in the range of 30% to 60%.40-45 Notably, different dosing schedules were used in these studies. Although no consensus exists on the preferred schedule,
a small study by Fechner et al43 comparing biweekly and 3-weekly dosing reported that the 3-weekly
schedule was associated with higher response rates.
A phase III trial of around 100 patients compared
short-term use (6 cycles) vs prolonged use (until progression) of gemcitabine and paclitaxel given 3 times
weekly.46 Prolonged treatment did not improve outcomes and was associated with significant toxicity,
including 2 toxic deaths. However, the short-term use
of this regimen was associated with a high response
rate of 40%, making it a promising second-line treatment option for patients with metastatic disease.
Neoadjuvant Chemotherapy
Approximately 50% of patients with invasive bladder
cancer develop distant metastases following radical
cystectomy alone.3,4,47 Neoadjuvant chemotherapy for
bladder cancer offers several potential advantages.
It may be better tolerated as opposed to the postcystectomy setting in which a delay may be possible
due to complications from surgery. Micrometastatic
disease, if present, is treated earlier. Downstaging of
the tumor may also result in making the tumor more
amenable to resection with negative margins and,
in very selected cases, bladder preservation may be
feasible, depending on response to chemotherapy,
although this therapy requires testing in a randomized
trial.48,49 Lastly, neoadjuvant chemotherapy allows the
assessment of response upfront and the determination
about whether the tumor is responsive to a particular
July 2013, Vol. 20, No. 3
chemotherapy. Conversely, many believe that neoadjuvant chemotherapy might potentially delay the
definitive treatment of bladder cancer. The tumor
may progress while on treatment if it is resistant to
chemotherapy. Discrepancies between clinical and
pathological stages have been observed in 30% of
cases, making it difficult to assess tumor response following chemotherapy. This is because patients who
are clinically staged and cured with surgery alone may
receive overtreatment.48,50 The role of neoadjuvant
chemotherapy for bladder cancer has been tested in
randomized clinical trials, but most of these studies
were underpowered to detect a difference in survival
outcomes. Moreover, the quality of surgery is a confounding factor in many studies. Initial studies were
conducted using the single agent cisplatin, which did
not render any clinical benefit; however, recent trials
have included combination cisplatin-based regimens
demonstrating either no survival benefit or a trend
toward a marginal survival benefit, with the exception
of the European Organization for the Treatment and
Cure of Cancer (EORTC)/Medical Research Council
(MRC) trial (Table 2).51-63 The EORTC/MRC trial is the
largest randomized trial of neoadjuvant chemotherapy
in bladder cancer evaluating the role of 3 cycles of
neoadjuvant cisplatin, methotrexate, and vinblastine
(CMV) chemotherapy prior to local radical treatment
consisting of radiation therapy or cystectomy.54 The
trial recruited 976 patients, of which 491 patients were
assigned to chemotherapy arm and 80% of those completed 3 cycles of chemotherapy. The chemotherapyrelated mortality rate was 1%. At the time of first
analysis (with a median follow-up of 4 years), a trend
was seen toward survival benefit, with an HR of 0.85
(95% CI, 0.71–1.02; P = .075), which translated into
a statistically nonsignificant absolute benefit of 5.5%
in the 3-year survival rate favoring patients in the
chemotherapy group. The updated results published
in 2011 demonstrated a 16% reduction in the risk of
death after neoadjuvant chemotherapy (HR = 0.84;
95% CI, 0.72–0.99; P = .037).55 The estimated 10-year
survival was 36% in the chemotherapy group and 30%
in the control arm. These results suggest that a small
survival benefit of approximately 6% was maintained
over time. The role of neoadjuvant CMV was evaluated in a randomized trial conducted by the Radiation
Therapy Oncology Group (RTOG 89-03).63 The study
population consisted of 126 patients with stage T2–
T4aNxM0 bladder cancer. Patients were randomized
to receive or not receive 2 cycles of CMV followed by
concurrent cisplatin and pelvic irradiation. Cystectomy was recommended for patients who achieved
less than a clinical complete response. The trial was
closed early due to an unexpected high rate of severe neutropenia and sepsis, with 3 toxic deaths from
neutropenic sepsis during induction chemotherapy,
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Table 2. — Selected Randomized Trials of Neoadjuvant Chemotherapy in Bladder Cancer
Study
No. of
Patients
Stage
Experimental
Arm
Control
Arm
Survival Rate
WMURG/ABCSG51
255
T2–T4NxM0
Cis + RT
RT
No difference
99
T2–T4bN0–3M0
Cis + RT/S
RT/RT + S
3-yr OS: 47% vs 33% (P = .34)
122
T2–T4aNx–N2M0
Cis + S
S
6.5-yr OS: 35.5% vs 37.3% (P = .95)
976
T2G3–T4aNxM0
CMV + S/RT
S/RT
10-yr OS: 36% vs 30% (P = .037)
206
T2–T4N0M0
MVAC + S
S
5-yr OS: 55% vs 54% (P = NS)
171
T2–T4N0M0
MVEC + S
S
Median OS: NR vs 5.5 yrs (P = NS)
325
T1G3–T4aNxM0
CA + RT + S
RT + S
5-yr OS: 59% vs 51% (P = .1)
Coppin52
CUETO53
54,55
EORTC/MRC
56
GUONE
57
GISTV
58
Nordic I
59
317
T2–T4aNxM0
CM + S
S
5-yr OS: 53% vs 46% (P = .24)
60
33
T2–T4bNx–3M0
CM + S
S
5-yr OS: 64% vs 46% (P = .76)
60
Daveca 89-02
120
T2–T4bNx–3M0
CM+ RT
RT
5-yr OS: 19% vs 24% (P = .98)
SWOG61
317
T2–T4aN0M0
MVAC + S
S
5-yr OS: 57% vs 43% (P = .06)
Abol-Enein62
196
T2NxM0
CaMV + S
S
5-yr DFS: 62% vs 42% (P = .013)
RTOG 89-0363
126
T2–T4aNxM0
CMV + RT/Cis + S
(if < CR)
RT/Cis + S
(if < CR)
5-yr OS: 48% vs 49% (P = NS)
Nordic II
Daveca 89-01
CaMV = carboplatin, methotrexate, and vinblastine, CA = cisplatin and doxorubicin, Cis = cisplatin, CM = cisplatin/methotrexate, CMV = cisplatin,
methotrexate, and vinblastine, CR = complete response, DFS = disease-free survival, MVAC = methotrexate, vinblastine, doxorubicin, and cisplatin,
MVEC = methotrexate, vinblastine, epirubicin, and cisplatin, NR = no response, NS = not significant, OS = overall survival, RT = radiation therapy,
S = surgery.
and no survival difference was observed between the
two groups.
An intergroup trial initiated by SWOG61 recruited
317 patients from 1987 to 1998 and evaluated the
benefit of neoadjuvant chemotherapy combination of
MVAC in patients with cT2–T4aN0M0 bladder cancer.
The planned radical cystectomy was performed in 82%
of the patients randomized to the chemotherapy arm.
The mean time to surgery was 115 days following randomization. The 5-year OS rates were 57% and 43% in
the neoadjuvant chemotherapy and cystectomy-only
groups, respectively, but these results did not reach
statistical significance (P = .06). In the MVAC group,
38% of patients had no residual disease at the time
of cystectomy compared with 15% of patients in the
cystectomy group (P < .001). At 5 years, more than
80% of patients who achieved pT0 at the time of surgery were alive compared with approximately 40% of
patients with residual disease at cystectomy, suggesting the pathological downstaging was associated with
improved outcomes. A cooperative group in Italy56
also conducted a trial of 206 patients exploring the
role of neoadjuvant MVAC prior to cystectomy and
demonstrated no significant difference in survival.
The 3-year survival rate was 62% for patients receiving
preoperative MVAC and 68% for patients undergoing
cystectomy alone.
The Nordic cystectomy I trial58 involving 325
patients evaluated neoadjuvant doxorubicin and cis204 Cancer Control
platin prior to radiation therapy and cystectomy vs
radiation therapy and cystectomy only. The Nordic
cystectomy II trial59 randomized 317 patients to preoperative methotrexate and cisplatin vs cystectomy
alone. Both of these trials demonstrated a trend toward survival benefit with chemotherapy that was not
statistically significant. The combined analysis of the
two trials demonstrated a 20% reduction in the risk of
death, with an HR of 0.80 (95% CI, 0.64–0.99) and an
absolute risk reduction of 8% at 5 years, with survival
rates of 56% in the neoadjuvant chemotherapy group
vs 48% in the control group.64
Because most of these trials demonstrated inconclusive results and were of modest size, several metaanalyses have been conducted to reliably assess the
value of neoadjuvant chemotherapy in bladder cancer.
The Advanced Bladder Cancer Meta-analysis Collaboration65 reported a meta-analysis in 2003 that included
2,688 individual patient data from 10 randomized trials. The data from the SWOG trial were not available
for this analysis. The pooled analysis from the nine
trials with available survival data demonstrated no
statistically significant difference in OS, with an HR
of 0.91 (95% CI, 0.83–1.01). However, when the trials
incorporating single-agent cisplatin were excluded,
the HR was 0.87 (95% CI, 0.78–0.97; P = .016), and
a statistically significant absolute benefit of 5% at
5 years was seen, with survival improvement from
45% to 50%. The same group updated the results to
July 2013, Vol. 20, No. 3
incorporate 3,005 patients from 11 randomized trials,
finding that neoadjuvant combination platinum-based
chemotherapy was associated with a significant survival benefit (HR = 0.86; 95% CI, 0.77–0.95; P = .003),
which was equivalent to a 5% absolute improvement
in survival at 5 years.66
A similar meta-analysis was performed by the
Cancer Care Ontario in Canada and included 2,605
patients from 11 trials.67 The pooled HR for survival
was 0.90 (95% CI, 0.82–0.99; P = .02). When eight
trials using cisplatin-based combination chemotherapy were included, the pooled HR was 0.87 (95%
CI, 0.78–0.96; P = .006), which was consistent with
an absolute OS benefit of 6.5% (95% CI, 2–11) from
50% to 56.5%.
The results of the above trials and meta-analyses
suggest that neoadjuvant chemotherapy is well tolerated and associated with a survival benefit of 5% to
6% in patients and pathological complete response
rates of 30% to 40%, which, in turn, help predict more
accurate survival outcomes. By contrast, even with
a high rate of complete pathological response with
neoadjuvant chemotherapy, the survival benefit is not
dramatic when compared with patients who undergo
surgery alone and have no evidence of disease, possibly suggesting that micrometastatic disease is an
early event in invasive bladder cancer and chemotherapy might not effectively eradicate it. Regardless, given the benefit associated with neoadjuvant
chemotherapy, it should be considered as the standard
of care for patients with invasive bladder cancer. In
clinical practice, neoadjuvant chemotherapy is sometimes utilized for patients with node-positive disease,
limited metastatic disease, or both. Although it may
be appropriate to offer neoadjuvant chemotherapy
as preoperative or palliative chemotherapy prior to
surgery in selected patients who are young and have
an excellent performance status, it should be noted
that the neoadjuvant clinical trials did not include
patients with N+ and/or M+ disease. Patients with N+
and/or M+ disease must be counseled to avoid unrealistic expectations with neoadjuvant chemotherapy
because they are at high risk of having persistent
disease at the time of cystectomy and may then also
require adjuvant chemotherapy.
Pathological Downstaging
Pathological tumor stage following radical cystectomy
strongly predicts patient outcomes and may serve as
a potential surrogate marker for OS rates.68,69 Rates
of pathological downstaging to pT0 at cystectomy
without neoadjuvant therapy range from 6% to 15%
and up to 38% with neoadjuvant chemotherapy.47,61,68
Tollefson et al68 reviewed the long-term outcomes
in 1,177 patients with muscle-invasive urothelial carcinoma at a single institution who underwent radiJuly 2013, Vol. 20, No. 3
cal cystectomy without neoadjuvant therapy. They
observed that pathological tumor stage strongly correlated with disease recurrence and cancer-specific
mortality. The 10-year cancer-specific survival rates
were 84.1%, 77.4%, 71.1%, and 58.5% for patients with
pT0, pTis, pT1, and pT2 tumors, respectively. Patients
with residual muscle-invasive disease had higher rates
of bladder cancer-specific and overall mortality compared with those with residual nonmuscle invasive
disease (< pT2). Even among patients with residual
nonmuscle invasive disease, those with pTis and pT1
tumors had higher rates of disease progression compared with those with pTa and pT0 disease.
The landmark intergroup trial that compared
neoadjuvant chemotherapy with MVAC followed by
cystectomy to cystectomy alone showed that, in both
groups, improved survival rate was associated with
pT0 disease at cystectomy.61 The 5-year survival rates
were 85% for the group that received neoadjuvant
chemotherapy and 82% for the control group. Neoadjuvant chemotherapy significantly increased the rates
of pathological downstaging of tumor to pT0 (38%
vs 15%; P < .001), thus indicating that that survival
benefit of neoadjuvant chemotherapy was strongly
related to pathological downstaging of tumor to pT0.
In the post-hoc analysis of the combined Nordic
Cystectomy Trials I and II to evaluate the effect of
neoadjuvant chemotherapy on tumor downstaging
and OS rate, a survival benefit was seen with chemotherapy-induced downstaging.69 The rate of complete
downstaging (CD; pT0N0) was almost double in the
neoadjuvant chemotherapy arm compared with the
control arm (22.7% vs 12.5%; P = .006). The rates of
noninvasive downstaging (pT0/pTis/pTaN0) were also
significantly increased with neoadjuvant chemotherapy. At 5 years, an absolute risk reduction of 31.1% was
seen in OS rates for the neoadjuvant chemotherapyinduced CD group compared with the control group
(P = .001) and an absolute risk reduction of 17.9%
for the neoadjuvant chemotherapy-induced noninvasive downstaging group. These results further confirm that neoadjuvant chemotherapy increases tumor
downstaging rates, which, in turn, are associated with
a survival benefit. Pathological downstaging may
represent a new outcome and point of prognosis for
clinical trials in bladder cancer utilizing neoadjuvant
chemotherapy. Moreover, this end point may help
identify patients who are resistant to standard chemotherapy and who may benefit from a patient-tailored
approach using novel targeted therapies based on the
molecular characteristics of their tumors.
Adjuvant Chemotherapy
The rationale of adjuvant chemotherapy in bladder
cancer is to delay recurrence and prolong survival
in patients with nonorgan-confined disease (pT3–
Cancer Control 205
T4, N0 or N+) as this group has a high likelihood
of recurrence with cystectomy alone. The 5-year
recurrence-free survival rate is in the range of 30%
for node-positive disease and 50% for pT3 to T4 disease.47,70 Adjuvant chemotherapy allows immediate
local treatment, avoiding delay in treatment for patients with chemotherapy-resistant tumors, and it may
also help avoid overtreatment based on inaccurate
clinical staging. However, in the postoperative setting, many patients may not receive chemotherapy
due to complications. A few randomized trials address its utility; however, available trials are limited
due to small numbers. In a comparative nonrandomized trial first reported by Logothetis et al,71 71
patients with high risk for relapse (nodal metastases,
extravesicular involvement, lymphatic/vascular invasion, or pelvic visceral invasion) received adjuvant
CISCA chemotherapy following cystectomy, while 62
patients with similar high risk for relapse did not. At
a mean follow-up of 118 weeks, a significant survival
advantage was seen in this group of patients receiving
adjuvant chemotherapy compared with those who had
unfavorable pathological findings and did not receive
adjuvant chemotherapy (70% vs 37%; P = .00012).
However, no benefit was seen in patients with favorable pathological findings who underwent adjuvant
chemotherapy following cystectomy.
In a Swiss study by Studer et al72 involving 77 patients, adjuvant use of single-agent cisplatin failed to
show a survival benefit compared with radical cystectomy alone. The first prospective randomized phase
III trial that showed a survival benefit with adjuvant
chemotherapy was reported by Skinner et al,73 in
which 91 patients with invasive T3 to T4 or N+ disease
were assigned to adjuvant chemotherapy with a cisplatin-containing combination regimen or observation
alone. Time to progression was significantly delayed
in the chemotherapy group, with 70% of the patients
being free of disease at 3 years compared with 46%
in the observation group. The median survival for
patients in the chemotherapy group was 4.3 years
compared with 2.4 years in the observation group (P =
.0062), and the extent of lymph node involvement was
found to be the most important prognostic variable.
However, one of the shortcomings of this trial was that
25% of patients assigned to the chemotherapy group
did not receive any chemotherapy. Furthermore, the
regimen used was not consistent. In a German trial
by Stockle et al,74 49 patients with pT3b, pT4a, and/
or pelvic lymph node involvement were randomized
to receive 3 adjuvant cycles of MVAC or epirubicin
(MVEC) following radical cystectomy or no adjuvant
chemotherapy. Of the 26 patients randomized to the
chemotherapy group, 18 received treatment, and, of
those, 3 had tumor progression compared with 18 of
the 23 patients in the control group. The study was
stopped early due to these results. Additional patients
were then recommended routine adjuvant chemotherapy and updated results were reported.75 Of the
collective total of 83 patients, 38 had received adjuvant
chemotherapy and 45 did not. A marked prognostic
advantage was seen in favor of patients undergoing
adjuvant chemotherapy; the 5-year progression-free
survival rate was 59% after the recommendation to
Table 3. — Selected Randomized Trials of Adjuvant Chemotherapy in Bladder Cancer
Study
No. of
Patients
Experimental
Arm
Control
Arm
Survival
Studer72
77
Cis
Surgery
No benefit
Skinner73
91
Cis-containing
combination
chemotherapy
Surgery
Benefit, DFS (4.3 vs 2.4 yrs)
No OS benefit
Stockle74,76
49
MVAC/MVEC
Surgery
Benefit, tumor-specific survival (71.8 vs 20.4 mos),
PFS (66.9 vs 11.6 mos)
No chemotherapy at time of relapse
Cognetti80
193
GC
Surgery
No benefit
Closed early
SOGUG81
142
PGC
Surgery
Benefit OS (60% vs 31%)
Bono79
83
CM
Surgery
No benefit
Freiha78
50
CMV
Surgery
Benefit, TTP (37 vs 12 mos)
Closed early
No OS benefit
Cis = cisplatin, CM = cisplatin/methotrexate, CMV = cisplatin, methotrexate, and vinblastine, DFS = disease-free survival, GC = gemcitabine/cisplatin,
MVAC = methotrexate, vinblastine, doxorubicin, and cisplatin, MVEC = MVAC or epirubicin, OS = overall survival, PFS = progression-free survival,
PGC = paclitaxel, gemcitabine, and cisplatin, TTP = time to progression
206 Cancer Control
July 2013, Vol. 20, No. 3
receive chemotherapy compared with 13% after a
recommendation of cystectomy alone. Long-term
survival data in the initial 49 patients were reported by this group, with a median follow-up of 160
months.76 The median progression-free survival was
66.9 months with adjuvant chemotherapy compared
with 11.6 months with observation alone (P = .002)
and tumor-specific survival was 71.8 compared with
20.4 months (P = .007) favoring adjuvant treatment.
Notably, patients randomized to observation after cystectomy were not given chemotherapy at the time of
relapse. However, in another contemporary German
series, adjuvant MVEC did not improve survival when
compared with cystectomy alone.77 In another trial,
55 patients with pT3b, T4, or N+ disease were randomized to observation or adjuvant chemotherapy with
CMV.78 Adjuvant chemotherapy was associated with
a longer time to progression but no improvement was
seen in OS rates. Adjuvant cisplatin/methotrexate
also failed to demonstrate a survival advantage.79 The
results from these trials were inconclusive because
the studies were small and underpowered or were
closed early due to poor accrual or interim analyses.
Several large randomized trials focusing on adjuvant chemotherapy in bladder cancer have been
reported (Table 3),72-74,76,78-81 but many closed prematurely due to poor accrual as well. An Italian multicenter trial, reported in abstract form, randomized
193 patients with pT2 grade 3, pT3-4 N0-2 urothelial
carcinoma to adjuvant GC vs chemotherapy at relapse and failed to show a significant difference in
survival.80 However, it accrued only 32% of the target
sample size and was closed early. The Spanish Oncology Genitourinary Group 99/01 study81 planned
to randomize patients with T3/T4 or N+ urothelial
carcinoma to paclitaxel, gemcitabine, and cisplatin
(PGC) vs observation. This trial was terminated due
to poor accrual as only 142 patients were enrolled
instead of the planned target of 340. The results were
reported in abstract form. With a median follow-up
of 51 months, improvement in the 5-year OS rate was
seen with chemotherapy (60% vs 31%; P < .0009). The
EORTC conducted a phase III trial (NCT00028756)
comparing immediate vs deferred chemotherapy with
MVAC, HD-MVAC with growth factor support, or GC
after radical cystectomy in patients with pT3–4 or N+
urothelial carcinoma. However, the trial was closed
after 7 years due to poor accrual, and no results are
available. The Cancer and Leukemia Group B also
attempted to compare sequential chemotherapy with
gemcitabine and doxorubicin followed by paclitaxel
and cisplatin vs GC alone as adjuvant therapy following cystectomy, but the trial was closed due to poor
accrual (NCT00014534).
Based on the available evidence, no definite recommendations can be made regarding the role of
July 2013, Vol. 20, No. 3
adjuvant chemotherapy for patients with locally advanced bladder cancer following cystectomy, even
though the meta-analysis of the available randomized controlled trials suggests a 25% relative reduction
in the risk of death with adjuvant chemotherapy.82
However, the power of the meta-analysis is limited
and does not provide enough evidence to make any
recommendations. Currently, no role of adjuvant
chemotherapy exists in patients not considered at
high risk for relapse (tumors pT2 or less, no nodal
involvement or lymphovascular invasion), but adjuvant chemotherapy may be considered for patients
at high risk for relapse, especially if no neoadjuvant
chemotherapy was given.
Overexpression of p53 has been suggested to be
a prognostic marker for recurrence in bladder cancer,83 but sufficient evidence to support this suggestion is lacking.84 In a cooperative group trial, patients
with T1/T2N0M0 urothelial bladder cancer who underwent cystectomy were tested for p53 expression.85
Those with p53-positive tumors were randomized to
adjuvant MVAC chemotherapy vs observation, while
those with p53-negative tumors were observed. Neither the prognostic value of p53 nor the benefit of
MVAC chemotherapy in patients with p53-positive
tumors was confirmed, and the trial was terminated
after an interim futility analysis. However, more studies are needed to test its predictive value in higherrisk patients rather than those in the adjuvant setting
for early-stage disease alone (T1/T2N0). Moreover,
testing might be more appropriate in a neoadjuvant
setting using pathological complete response as an
end point to help select patients who would benefit
from further therapy.
Novel Agents in Bladder Cancer
Cytotoxic chemotherapy remains at the core of systemic therapy options for bladder cancer, and no biological or immunotherapeutic agents are currently
approved. An urgent, unmet need exists to develop
and utilize novel therapies to improve outcomes in
bladder cancer.
Targeted Therapeutic Agents
Many novel targeted therapies have been studied in
bladder cancer with promising activity in early-phase
trials. HER2/neu is variably expressed in primary
tumors and metastases of urothelial bladder cancer,86
and it offers a rational target for drug discovery. In a
phase II study, trastuzumab, a monoclonal antibody
against HER2/neu receptor, was combined with a PGC
regimen in HER2/neu-positive advanced urothelial
carcinoma.87 The overall response rate was 70% and
the median survival was 14.1 months, but more than
90% of patients had grades 3 to 4 myelosuppression,
with 2 (5%) therapy-related deaths and more than
Cancer Control 207
20% patients with grades 1 to 3 cardiotoxicity. Epidermal growth factor receptor is overexpressed in
more than 50% of bladder cancers and may be a
prognostic marker.88 However, the tyrosine kinase
inhibitor (TKI) gefitinib was not effective as a single
agent and did not add to the efficacy of GC.89,90 Targeting the vascular endothelial growth factor (VEGF)
axis is an appealing pathway in bladder cancer, and
many trials using bevacizumab in bladder cancer are
underway. Sunitinib, a VEGF TKI, was studied in
previously treated patients with urothelial cancer and,
although responses were seen in 4 of 77 patients,
tumor regression or stable disease was seen in 43%
of patients.91 Ongoing trials are evaluating its role
alone or in combination in the first-line metastatic setting as well as the neoadjuvant and adjuvant settings.
Pazopanib, another VEGF TKI, is also being evaluated
in patients with metastatic urothelial cancer who are
progressing on first-line chemotherapy. Fibroblast
growth factor receptor 3 (FGFR-3) also plays a role
in the oncogenesis of bladder cancer and represents
a therapeutic target.92 Dovitinib is an oral inhibitor
of VEGFR and FGFR and is being evaluated in combination with GC or carboplatin in bladder cancer
(NCT01496534).
Immunotherapeutic Agents
Bacille Calmette-Guérin immunotherapy has been the
standard of care for high-grade noninvasive urothelial
carcinoma for a number of decades and there may
be a potential role of immunotherapeutic agents for
advanced bladder cancer.93 Many different immunotherapeutic strategies, including tumor-derived peptide vaccines, autologous T-cell vaccines, and viral
vectors carrying gene encoding for tumor antigens,
have been explored in early-phase studies in bladder cancer with variable results.94-100 ALT-801 (Altor
Bioscience Corp, Miramar, FL), a human interleukin-2,
single-chain, T-cell receptor fusion protein, is a targeted immunotherapeutic and is being studied in advanced bladder cancer in combination with GC, and
early responses have already been observed.94 Active
immunotherapy can potentially induce antitumor responses and is relatively well tolerated. However,
larger phase II and III studies are needed to determine the clinical efficacy of various immunotherapy
approaches, including testing them in combination
with cytotoxic chemotherapy.
Conclusions
Bladder cancer is a chemosensitive disease, and systemic chemotherapy plays a role in its management.
Cisplatin-based combination chemotherapy prolongs
survival in the metastatic setting, and methotrexate,
vinblastine, doxorubicin, and cisplatin or combination gemcitabine/cisplatin is the current standard of
208 Cancer Control
care. However, long-term survival in patients with
metastatic disease is rare, and treatment is still palliative in nature. Combination chemotherapy that is not
platinum based is recommended for patients who are
ineligible for cisplatin therapy. Although carboplatin
should not be substituted for cisplatin in fit patients,
it may be considered in those who are ineligible for
cisplatin. No approved second-line chemotherapy for
metastatic bladder cancer exists, and response rates
with available agents are variable.
The role of neoadjuvant cisplatin-based combination chemotherapy has been extensively evaluated
and is associated with a modest but significant survival benefit. However, this is more pronounced in patients with high-risk disease, and a strong need exists
to utilize this therapy. Studies with molecular markers and novel agents are needed to further improve
outcomes in this setting and offer tailored therapy to
patients based on risk stratification according to tumor type. The achievement of pathological complete
response (pT0) with neoadjuvant chemotherapy has
strong prognostic significance and may represent an
alternate clinical end point for clinical trials. Although
robust data are lacking for the use of chemotherapy
in the adjuvant setting after cystectomy, it may be
considered in patients who are at high risk for relapse. Unlike other solid tumors, targeted therapy is
not well established in bladder cancer, and a critical
need exists to develop novel agents that complement
or are an alternative to conventional chemotherapies.
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