Genitourinary Cancer

Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A

Systematic Review and Two-Step Meta-Analysis
MING YIN,a MONIKA JOSHI,a RICHARD P. MEIJER,b,c MICHAEL GLANTZ,d SHELDON HOLDER,a HAROLD A. HARVEY,a MATTHEW KAAG,e
ELISABETH E. FRANSEN VAN DE PUTTE,b SIMON HORENBLAS,b JOSEPH J. DRABICKa
a
Department of Hematology and Oncology, Penn State Hershey Medical Center, Hershey, Pennsylvania, USA; bDepartment of Urology,The
Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; cDepartment of Urology, University
Medical Center Utrecht, Utrecht, The Netherlands; Departments of dNeurosurgery and eUrology, Penn State Hershey Medical Center,
Hershey, Pennsylvania, USA
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Chemotherapy x Bladder cancer x Neoadjuvant x Platinum x Survival

ABSTRACT
Background. Platinum-based neoadjuvant chemotherapy has (OS) benefit associated with cisplatin-based neoadjuvant
been shown to improve survival outcomes in muscle-invasive chemotherapy (hazard ratio [HR], 0.87; 95% confidence
bladder cancer patients.Weperformed a systematic review and interval [CI], 0.79–0.96). A total of 1,766 patients were included
meta-analysis to provide updated results of previous find- in 13 retrospective studies. There was no significant difference
ings. We also summarized published data to compare clinical in pathological complete response between MVAC and GC.
outcomes of methotrexate, vinblastine, doxorubicin, and cispla- However, GC was associated with a significantly reduced over-
tin (MVAC) versus gemcitabine and cisplatin/carboplatin (GC) all survival (HR, 1.26; 95% CI, 1.01–1.57). After excluding
in the neoadjuvant setting. carboplatin data, GC still seemed to be inferior to MVAC in OS
Methods. A meta-analysis of 15 randomized clinical trials was (HR, 1.31; 95% CI, 0.99–1.74), but the difference was no longer
performed to compare neoadjuvant chemotherapy plus local statistically significant.
treatment with the same local treatment alone. Because Conclusion. These results support the use of cisplatin-based
no randomized trials have investigated MVAC versus GC in combination neoadjuvant chemotherapy in muscle-invasive
the neoadjuvant setting, a meta-analysis of 13 retrospective bladder cancer. Although GC and MVAC had similar treatment
studies was performed to compare MVAC with GC. response rates, the different survival outcome observed in this
Results. A total of 3,285 patients were included in 15 ran- study requires further investigation. The Oncologist 2016;
domized clinical trials. There was a significant overall survival 21:708–715

Implications for Practice: Platinum-based neoadjuvant chemotherapy (NCT) has been shown to improve survival outcomes in
muscle-invasive bladder cancer (MIBC) patients, but the optimal neoadjuvant regimen has not been established. Methotrexate,
vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine and cisplatin/carboplatin (GC) are two of the most commonly used
chemotherapy regimens in modern oncology. In this two-step meta-analysis, an updated and more precise estimate of the survival
benefit of cisplatin-based NCT in MIBC is provided. This study also demonstrated that MVAC might have superior overall survival
compared with GC (with or without carboplatin data) in the neoadjuvant setting.The findings suggest that NCTshould be standard
care in MIBC, and MVAC could be the preferred neoadjuvant regimen.

INTRODUCTION
In the United States, bladder cancer is the fourth most common approximately half of patients with deep, muscle-invasive
cancer and the eighth leading cause of cancer-related death bladder cancer (MIBC) involving the muscularis propria ($T2)
in humans [1]. Internationally, the incidence and mortality develop metastatic disease within 2 years of diagnosis and
of bladder cancer varies substantially, with highest rates in usually succumb to their disease [3].
Europe, North America, and Egypt [2]. Muscle invasion re- Several randomized clinical trials have shown that platinum-
mains a poor prognostic factor probably because of occult based combination neoadjuvant chemotherapy (NCT) can
metastasis at the time of diagnosis. Despite radical cystectomy, improve survival outcomes, compared with locoregional
CME

Correspondence: Joseph J. Drabick, M.D., Penn State University/Hershey Cancer Institute, Division of Hematology and Oncology, 500 University
Drive, Hershey, Pennsylvania 17033, USA. Telephone: 717-531-6585; E-Mail: [email protected] Received November 2, 2015; accepted for
publication January 26, 2016; published Online First on April 6, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi.org/10.1634/
theoncologist.2015-0440

The Oncologist 2016;21:708–715 www.TheOncologist.com ©AlphaMed Press 2016

Yin, Joshi, Meijer et al. 709

treatment alone. For example, the SWOG trial, including 307 clinical trials were available. Authors were contacted to
patients, showed a 33% reduced death risk in the methotrexate, obtain any missing information. If the authors did not
vinblastine, doxorubicin, and cisplatin (MVAC) plus cystectomy respond to our repeated requests, the missing information
arm, compared with cystectomy alone [4]. The updated was excluded from related analyses. If the same study was
BA06 30894 trial, including 976 patients, showed a statisti- presented more than once, we selected the most recent
cally significant 16% reduced death risk in the arm of cisplatin, article with updated information.
methotrexate, and vinblastine (CMV) plus cystectomy and/or
radiotherapy, as well as a 6% increase in survival at 10 years [5]. Data Extraction
In contrast, most prospective studies failed to prove a survival We extracted the following information from each published
benefit probably because of insufficient power. Therefore, article: author, year of publication, country of origin, sample
quantitative analyses by combining the results of all relevant size, NCT regimens given, type of locoregional therapy, and
randomized trials were attempted [6–8].The most recent meta- follow-up period. We used odds ratios (ORs) and adjusted Cox
analysis in 2005 included 11 randomized trials and showed a 5% proportional HRs for the quantitative analysis. If adjusted HRs
absolute improvement in overall survival (OS) at 5 years (hazard were not available and the corresponding authors did not
ratio [HR], 0.86; 95% confidence interval [CI], 0.77–0.95) in the respond to our requests, the crude HRs were used. When both
arm ofcisplatin-based NCT [7]. Based on these results, platinum- adjusted and crude HR data were not available but appropriate
based combination neoadjuvant chemotherapy has been rec- summary statistics or Kaplan-Meier curves were provided, we
ommended as standard care for MIBC. calculated HRs and 95% CIs as relevant effect measures using
Notably, most of those clinical trials included in previous published methods [10].
meta-analysis were designed in the 1990s and used MVAC or
CMV as NCT regimens, although there has been an increased Statistical Analysis
interest in a gemcitabine and cisplatin/carboplatin (GC) regimen We performed a meta-analysis to estimate clinical outcomes,
recently due to its favorable toxicities. Although no randomized including NCT response rates and OS in control and study
trials are available tocompare GC with MVAC in the neoadjuvant groups. We assessed the between-study heterogeneity by
setting, a large randomized trial showed that GC was noninferior using the Cochran Q test with a significance level of p , .05.
to MVAC in metastatic settings [9]. As a result, MVAC and GC are We performed initial analyses with a fixed-effect model, and
the two most commonly used chemotherapy regimens for confirmatory analyses were performed with a random-effect
bladder cancer in modern oncology. Since 2005, results of a model if there was significant heterogeneity. We used
number of new randomized trials have been published, and inverted funnel plots and the Egger’s test to assess the
three large randomized trials (Nordic I, Nordic II, and BA06 possibility of publication bias. All p values were two-sided,
30894) presented updated results with longer follow-up time. and all analyses were performed using the Stata software
Since 2007, a growing number of studies have compared clinical (StataCorp, College Station, TX, http://www.stata.com) and
outcomes of GC versus MVAC as neoadjuvant regimens; Review Manager version 5.3 (Cochrane, Oxford, U.K.).
however, all of these studies were limited by their small sample
sizes. In light of the new evidence, we decided to perform a two- RESULTS
step systematic review and meta-analysis aiming to provide (a) For the first step of the meta-analysis (NCT plus locoregional
an updated and more precise estimate of the effect of NCT on therapy versus locoregional therapy), 19 reports met the
survival in MIBC and (b) quantitative evidence to compare GC inclusion criteria, encompassing 15 randomized trials, all of
with MVAC in the neoadjuvant setting, because no published which were cisplatin based (Table 1). Because some of the trials
meta-analysis was available. have been reported more than once, the data contained in the
last report were used for this analysis. For example, the SWOG
METHODS 8710 trial was first reported in 2001 as an abstract [11] and then
was published in 2003 [4]. In addition, the BA06 30894 trial was
Literature Search first reported in 1999 [12] and then was updated in 2011 [5].
We conducted this systematic review in accordance with the Further, the Nordic I and II trials were first reported in 1993
guidelines of the Cochrane Collaboration. We searched for (Nordic I) [13], 1996 (Nordic I) [14], and 2002 (Nordic II) [15],
relevant papers published before August 30, 2015, by using the respectively, and they were last reported in 2004 as a joint,
electronic PubMed database, Cochrane database, and Ovid updated analysis [16]. Although the study by Cortesi et al. was
database with the following terms: “neoadjuvant,” “bladder not published, it was included in previous meta-analyses [6, 7]
cancer” or “carcinoma” or “tumor” or “neoplasm.” References and therefore was included in our analysis. For the second step
of the retrieved articles were also screened for earlier original of the meta-analysis, a total of 13 reports met the inclusion
studies.The inclusion criteria were as follows: patients with (a) criteria.Notably, partof the patient informationcontained inthe
biopsy-proven MIBC who intended to receive local definitive studies by Dash et al. [17], Pal et al. [18], and Alva et al. [19] were
treatment (defined as radical cystectomy or radiotherapy) with later incorporated into a larger investigation by Galsky et al. [20],
or without NCT, (b) chemotherapy to be platinum based and whereas part of the patient information contained in the study
given systemically, and (c) no distant metastasis. In the first step by Fairey et al. [21] was later incorporated into the investigation
CME

of the meta-analysis (NCT plus locoregional therapy versus loco- by Zargar et al. [22]. We included all 13 studies in our analysis
regional therapy), only randomized clinical trials were included; because some clinical information, such as tumor downstaging,
in the second step of the meta-analysis (GC versus MVAC), only was available in only small studies, but we also repeated our
retrospective studies were included because no randomized analysis excluding studies with redundant information. As a

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 710 Neoadjuvant Chemotherapy and Bladder Cancer

Table 1. Characteristics of included randomized clinical trials

Events/no. of patients
Median
follow-up
Study Year Country NCT Control Regimen Standard arm (months)
Wallace et al. [23] 1991 U.K. 46/83 41/76 Cisplatin R/T 16
Raghavan et al. [23] 1991 Australia 25/42 26/54 Cisplatin R/T 16
Martinez-Piñerio et al. [24] 1995 Spain 43/62 38/60 Cisplatin C 78.2
Cortesi Unpublished Italy 43/82 41/71 MVEC C 37
Shipley et al. [25] 1998 U.S. 31/61 31/62 MCV R/Twith cisplatin 6 C 60
Bassi et al. [26] 1999 Italy 53/102 60/104 MVAC C NA
Sengeløva et al. [27] 2002 Denmark 70/78 60/75 Cisplatin 1 MTX C or R/T NA
Grossman et al. [4] 2003 U.S. 90/153 100/154 MVAC C 100.8
Sherifb et al. [16] 2004 Northern 145/306 173/314 Cisplatin 1 doxorubicin or R/T 1 C or C 56.4
Europe MTX
BA06 30894 [5] 2011 International 282/491 309/485 CMV C or R/T 96
Osman et al. [28] 2014 Egypt 11/30 15/30 Gemcitabine 1 cisplatin C 36
Kitamura et al. [29] 2014 Japan NA/64 NA/66 MVAC C 55
Khaled et al. [30] 2014 Egypt NA/59 NA/55 Gemcitabine 1 cisplatin C or R/T 37.4
a
DAVECA 8901 and DAVECA 8902 trials.
b
Nordic I and Nordic II trials.
Abbreviations: C, cystectomy; CMV, cisplatin, methotrexate, and vinblastine; MCV, methotrexate, cisplatin, and vinblastine; MTX, methotrexate; MVAC,
methotrexate, vinblastine, doxorubicin, and cisplatin; MVEC, methotrexate, vinblastine, epirubicin, and cisplatin; NA, not available; NCT, neoadjuvant
chemotherapy; R/T, radiotherapy.

Table 2. Characteristics of included retrospective studies

Study Year Country MVAC GC Platinum (dosage) pCR <T2 OS Treatment
2
Dash et al. [17] 2008 U.S. 54 42 Cisplatin (70 mg/m ) Y Y NA GC q3w, MVAC q4w
Weight et al. [31] 2009 U.S. 4 23 Cisplatin (NA) Y NA NA NA
Alvaa et al. [19] 2010 U.S. 12 20 Cisplatin (70 mg/m2) or NA NA Y GC q4w, MVAC q4w
carboplatin (NA)
Kaneko et al. [32] 2011 Japan 9 22 Cisplatin (70 mg/m2) Y Y NA GC q4w, MVAC q4w
Yeshchina et al. [33] 2012 U.S. 45 16 Cisplatin (NA) Y Y Y NA
Pal et al. [18] 2012 U.S. 22 24 Cisplatin (NA) Y Y Y NA
Fairey et al. [21] 2013 U.S. 58 58 Cisplatin (NA) Y Y Y GC q3w, MVAC q4w
Meijer et al. [34] 2013 Netherlands 117 45 Cisplatin or carboplatin (NA) Y Y Y GC q3w, MVAC q2w
or q4w
Lee et al. [35] 2013 U.S. 31 41 Cisplatin (NA) Y Y NA NA
Kawamura et al. [36] 2013 Japan 44 14 Cisplatin (70 mg/m2) Y Y NA GC q3w, MVAC q4w
Iwasaki et al. [37] 2013 Japan 34 34 Carboplatin (AUC 5) Y Y NA GC q3w, MVAC q4w
Zargar et al. [22] 2015 U.S., Canada, 183 602 Cisplatin (NA) Y Y Y NA
and Europe
Galsky et al. [20] 2015 U.S. 66 146 Cisplatin (NA) Y NA Y NA
a
Only cisplatin data were included because carboplatin was used in combination with paclitaxel and gemcitabine.
Abbreviations: AUC, area under the curve; GC, gemcitabine and cisplatin/carboplatin; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; NA,
not available; OS, overall survival; pCR, pathological complete response; q3w, every 3 weeks; Y, yes.

result, the final data pool consisted of 13 studies, including cisplatin-based NCT was associated with a significant OS
1,766 bladder cancer patients who received either standard benefit, compared with locoregional therapy alone (HR, 0.87;
or dose-dense MVAC or GC as NCT regimens (Table 2). The 95% CI, 0.79–0.96; p 5 .004; p 5 .83 for heterogeneity, I2 5 0%)
flowchart of study selection is shown in Figure 1. (Fig. 2). NCT with cisplatin alone did not appear to provide a
survival benefit (HR, 1.10; 95% CI, 0.84–1.44; p 5 .48; p 5 .70 for
CME

Neoadjuvant/Locoregional Versus Locoregional Alone heterogeneity, I2 5 0%), although cisplatin-based combination

Overall Survival NCT was associated with a significantly prolonged survival (HR,
Fifteen randomized trials including 3,285 patients were eligi- 0.84; 95% CI, 0.76–0.93; p , .001; p 5 .95 for heterogeneity, I2 5
ble for this analysis. Consistent with previous meta-analysis, 0%). Notably, the majority of studies included primarily

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of GC and 667 patients of MVAC. Overall, the pCR of GC was

25.7%, whereas the pCR of MVAC was 24.3%. There was no
statistically significant difference in pCR between GC and
MVAC (GC vs. MVAC: OR, 1.17; 95% CI, 0.92–1.50; p 5 .37 for
heterogeneity, I2 5 7%) (Fig. 3). For pathological downstaging
response (T , 2), 10 studies of 1,495 patients were eligible for
analysis, including 898 patients of GC and 597 patients of
MVAC. Again, there was no significant difference between
GC and MVAC (OR, 1.07; 95% CI, 0.85–1.34; p 5 .19 for
heterogeneity, I2 5 28%).
To control potentially inferior efficacy of carboplatin, we
excluded carboplatin data (study by Iwasaki et al. [37] and
carboplatin data contained in the study by Meijier et al. [34])
from our analysis. Our conclusion was not substantially
changed (data not shown). To remove redundant informa-
tion due to partial overlapping patient information between
small and later larger studies, we excluded the studies by
Dash et al. [17], Pal et al. [18], and Fairey et al. [21] from
analysis. The results were not significantly changed for pCR
(OR, 1.14; 95% CI, 0.87–1.49; p 5 .27 for heterogeneity, I2 5
19%) or pathological downstaging response (OR, 1.02; 95%
CI, 0.80–1.31; p 5 .15 for heterogeneity, I 2 5 34%). No
Figure 1. Flowchart for article selection. Only randomized trials publication bias was detected by either the funnel plot or the
were included to compare NCT plus locoregional therapy versus Egger’s test (data not shown).
locoregional therapy, whereas retrospective studies were in-
cluded to compare GC versus MVAC because no randomized trials
were available. Overall Survival
Abbreviations: GC, gemcitabine and cisplatin/carboplatin; Seven studies, including 1,414 patients, were eligible for
MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; NCT, this analysis. Compared with MVAC, GC was associated with
neoadjuvant chemotherapy. a clinically and statistically significant increase in the haz-
ard of death (HR, 1.26; 95% CI, 1.01–1.57; p 5 .94 for
urothelial cancer patients, although the study by Khaled et al.
heterogeneity, I2 5 0%) (Fig. 4). After excluding carboplatin
[30] included 50% squamous cell carcinoma patients. How-
data in the study by Meijier et al. [34] and the studies by
ever, our results were not substantially changed by including or
Pal et al. [18], Alva et al. [19], and Fairey et al. [21] due to
excluding the study by Khaled et al. (data not shown).
redundant patient information, gemcitabine plus cisplatin
In subgroup analysis, modern NCT regimens of GC or
remained inferior relative to MVAC in OS (HR, 1.31; 95%
MVAC-like (MVAC or CMV) chemotherapy were associated
CI, 0.99–1.74; p 5 .84 for heterogeneity, I2 5 0%), but the
with a survival benefit (HR, 0.82; 95% CI, 0.74–0.91; p , .001;
difference was no longer statistically significant. No publi-
p 5 .99 for heterogeneity, I2 5 0%) and an absolute increase in
cation bias was detected by either the funnel plot or the
5-year survival of 8% (45%–53%), equivalent to a number
Egger’s test (data not shown).
needed to treat of 12.5. If only patients with cystectomy were
considered, a survival benefit associated with cisplatin-based
combination NCT remained (HR, 0.81; 95% CI, 0.70–0.93; DISCUSSION
p 5 .003; p 5 .99 for heterogeneity, I2 5 0%). There was no To our knowledge, this is the largest quantitative analysis
evidence of statistical heterogeneity (I2 5 0%) between the to examine the survival benefit of NCT in MIBC and the first
trial results. No publication bias was detected by the funnel quantitative analysis to compare clinical outcomes of GC
plot or the Egger’s test in subgroup analysis (data not shown). with MVAC in the neoadjuvant setting. In this compre-
hensive two-step meta-analysis of 15 randomized clinical
In subgroup analysis, modern NCT regimens of GC or trials and 13 retrospective studies, we confirmed a
MVAC-like (MVAC or CMV) chemotherapy were associ- significant survival benefit associated with platinum-
based combination neoadjuvant chemotherapy. We fur-
ated with a survival benefit and an absolute increase in
ther provided evidence that bladder cancer patients who
5-yearsurvival of 8% (45%–53%), equivalentto a number received MVAC might have better survival outcomes,
needed to treat of 12.5. compared with those who received a GC regimen in the
neoadjuvant setting.
Platinum-based combination neoadjuvant chemotherapy
followed by definitive locoregional therapy, such as radical
GC Versus MVAC
CME

cystectomy, should be the mainstay of treatment for MIBC.

Treatment Response Although several randomized trials and a meta-analysis in
For pathological complete response (pCR), 12 studies of 1,734 2005 have demonstrated a clear improvement in OS, NCT
patients were eligible for this analysis, including 1,067 patients remains vastly underused in the oncology community [38]. One

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 712 Neoadjuvant Chemotherapy and Bladder Cancer

Figure 2. Forest plot of overall survival in comparison of cisplatin-based neoadjuvant chemotherapy plus locoregional therapy versus
locoregional therapy alone by randomized clinical trials.
Abbreviations: CI, confidence interval; IV, inverse variance; NCT, neoadjuvant chemotherapy.

Figure 3. Forest plot of pathological complete response in comparison of GC versus MVAC by retrospective studies.
Abbreviations: CI, confidence interval; GC, gemcitabine and cisplatin/carboplatin; M-H, Mantel-Haenszel method; MVAC, methotrexate,
vinblastine, doxorubicin, and cisplatin; NCT, neoadjuvant chemotherapy.

Figure 4. Forest plot of overall survival in comparison of GC versus MVAC by retrospective studies.
Abbreviations: CI, confidence interval; GC, gemcitabine and cisplatin/carboplatin; IV, inverse variance; MVAC, methotrexate, vinblastine,
doxorubicin, and cisplatin.
CME

concern for NCTmodality has been the delay in curative-intent comparable efficacy compared with conventional NCT [39,
surgery while delivering chemotherapy. Two recent studies 40]. In addition, patients who receive chemotherapy before
suggested that NCT can be safely administered in a short time surgery are more likely to receive sufficient doses with better
using a dose-dense schedule, with less toxicity and at least tolerance.

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was no significant difference in the odds of achieving a pCR or

Platinum-based combination neoadjuvant chemother- pathological downstaging with GC versus MVAC. We found a
apy followed by definitive locoregional therapy, such as significantly better OS associated with MVAC, which was not
radical cystectomy, should be the mainstay of treat- observed in previous individual studies. The average pCR or
ment for MIBC. tumor-downstaging response of a GC regimen in our patient
population was similar to MVAC and was comparable to the
response rate of a recent pooled analysis of NCT in MIBC using
In this updated meta-analysis with a larger patient a GC regimen (pCR: 25.7 vs. 25.6%; tumor downstaging:
population, we confirmed the conclusion of previous meta- 44.8% vs. 46.5%) [42] and, therefore, should not cause
analyses and provided a more precise estimate of the effect of inferior survival of a GC patient group. A repeated analysis
NCT in MIBC. Compared with the 2005 meta-analysis, we by excluding carboplatin and smaller studies to avoid
incorporated four additional randomized trials and used duplicate patients showed a marginally significant death
updated results from three large randomized trials (Nordic I, risk in the gemcitabine plus cisplatin group versus the MVAC
Nordic II, and BA06 30894), consisting of information for 427 group (HR, 1.31; 95% CI, 0.99–1.74). The inconsistency
new patients and updated information for 1,596 patients. between pCR and survival outcomes found in our study was
Our data showed that cisplatin-based combination NCT different from previous reports suggesting that pCR or
is associated with a 16% reduction in overall death risk, pathologic downstaging may be a surrogate marker for OS
compared with locoregional therapy alone. If only GC or after NCT in bladder cancer [43, 44]. We acknowledge that
MVAC-like chemotherapy regimens are considered, NCT is the observed difference could be due to a number of factors
associated with an even better survival benefit (HR, 0.82; 95% independent of the treatment, such as dose intensity and density,
CI, 0.74–0.91) and an absolute survival benefit of 8% at 5 years duration of therapy, as well as duration and quality of clinical
(a number needed to treat of 12.5). Our results confirm the follow-up data, which cannot be adjusted by data extracted
compelling argument for an increased adoption of NCT as from published literatures. Based on our communications
standard care for MIBC patients. with other principal investigators, it appeared that a large
One important question remains unanswered: What is the proportion of patients in our studies received dose-dense
best NCT regimen? Traditionally, MVAC or CMV is the regimen MVAC, whereas fewer patients received the GC regimen in a
of choice.The regimen of GC has gained favor recently because dose-dense manner. We also realized that some important
it is easy to administer and has a less toxic profile. Both cis- variables, such as patient age and performance status, which
platin and carboplatin have been used in the past, although a are associated with inherent selection bias in GC versus
randomized phase II study showed carboplatin to be inferior to MVAC decisions, were not adjusted in our analyses. We were
cisplatin in first-line treatment of metastatic transitional cell unable to perform any further investigation in this regard
carcinoma of the urothelium [41]. Although the data were because most studies did not provide sufficiently detailed
descriptive in nature without statistical comparisons and information, and an attempt at data collection for individ-
the trial was not designed with sufficient power to detect ual treatment protocols was not successful. However, the
significant differences between arms in terms of efficacy, findings could be true because objective response and OS are
cisplatin was used preferentially over carboplatin in the highly correlated but may not be entirely consistent with
neoadjuvant setting based on extrapolation of the previously each other. The discrepancy between the pCR rate and OS
mentioned data. Nevertheless, there is no level 1 evidence to in our analysis may suggest a similar near-term efficacy
support GC in the neoadjuvant setting, and two randomized between the two types of regimens as measured by response
trials published in 2014, using GC as an NCT regimen, are rate and a possible long-term benefit associated with MVAC.
underpowered to detect statistical difference. Instead, results Regardless, the differences in observed survival are hypoth-
from a randomized phase III trial in metastatic bladder cancer eses generating and are worthy of further investigation in a
have been used to justify the routine use of GC in the prospective setting.
neoadjuvant setting [9]. In that trial, GC was associated with Despite our efforts to perform an accurate and comprehen-
similar efficacy compared with standard MVAC. We believe sive analysis, several limitations of the current meta-analysis
that extrapolation of these results to the neoadjuvant setting is need to be addressed. First, our analysis was based mainly on
potentially flawed, because these cohorts are substantially data extracted directly from the published literature. We were
different with regard to performance status and, potentially, unable to perform further in-depth analysis, such as a stratified
tumor biology. In this study, we attempted to perform an analysis or Kaplan-Meier survival curve, because we did not
“unbiased” systematic review and meta-analysis with regard have access to individual patient information. Second, the
to platinum-based NCT in MIBC. included studies differed in study designs, such as patient
Since 2008, in the absence of definitive prospective data, selection, chemotherapeutic protocol, and follow-up time.
a series of retrospective studies, including two international Conclusions derived from this paper are limited because pooling
multicenter investigations, were published to compare GC retrospective studies that used markedly different approaches
versus MVAC in the neoadjuvant setting [20, 22].Those studies may result in biased analysis results. However, the patient
did not find a difference between GC and MVAC in clinical population in these different studies seemed to be relatively
CME

outcomes, but most of them showed a nonsignificant homogeneous because there was no significant heteroge-
increased death risk in the GC group.Therefore, we performed neity between studies, as reflected in our analysis.Third, in the
a meta-analysis with a relatively large sample size to increase meta-analysis of GC versus MVAC, some patients included in the
the statistical power. Consistent with previous studies, there original small studies were later incorporatedinto larger studies.

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 714 Neoadjuvant Chemotherapy and Bladder Cancer

We were unable to identify the overlapping patients owing to AUTHOR CONTRIBUTIONS

a lack of individual data. Although such patients constituted a Conception/Design: Ming Yin, Joseph J. Drabick
small proportion of the whole patient population (,10%), there Collectionand/orassemblyofdata:Ming Yin, Richard P. Meijer, Simon Horenblas,
may be some redundant information in related analysis when Joseph J. Drabick
Data analysis and interpretation: Ming Yin, Monika Joshi, Richard P. Meijer,
both the small and large studies were included. However, Simon Horenblas, Joseph J. Drabick
our final results were not changed by excluding the smaller Manuscript writing: Ming Yin, Monika Joshi, Richard P. Meijer, Michael Glantz,
Sheldon Holder, Harold A. Harvey, Matthew Kaag, Elisabeth E. Fransen van de
studies from the quantitative analysis.
Putte, Simon Horenblas, Joseph J. Drabick
Final approval of manuscript: Ming Yin, Monika Joshi, Richard P. Meijer, Michael
CONCLUSION Glantz, Sheldon Holder, Harold A. Harvey, Matthew Kaag, Elisabeth E.
Our meta-analysis demonstrated that NCT should be the Fransen van de Putte, Simon Horenblas, Joseph J. Drabick
standard of care in MIBC. In the neoadjuvant setting, GC and
MVAC had similar treatment response rates but might be
DISCLOSURES
associated with different survival outcomes. However, this Monika Joshi: Bayer (C/A); Joseph J. Drabick: Merck (C/A). The other
conclusion is subject to the limitations of retrospective meta- authors indicated no financial disclosures.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert
analysis and requires confirmation from future prospective testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/
studies with large sample sizes and better study designs. inventor/patent holder; (SAB) Scientific advisory board

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CME This article is available for continuing medical education credit at CME.TheOncologist.com.

EDITOR’S NOTE: See the related commentary,“Systemic Therapy for Invasive Bladder Cancer: The Value Proposition” by Derek
Raghavan on page 659 of this issue.

CME

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