Original Article
Comparative Effectiveness of Gemcitabine Plus Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, Plus Cisplatin as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer Matthew D. Galsky, MD1†; Sumanta K. Pal, MD2†; Simon Chowdhury, MRCP3; Lauren C. Harshman, MD4; Simon J. Crabb, MRCP5; Yu-Ning Wong, MD6; Evan Y. Yu, MD7; Thomas Powles, MRCP8; Erin L. Moshier, PhD9; Sylvain Ladoire, MD10; Syed A. Hussain, MD11; Neeraj Agarwal, MD12; Ulka N. Vaishampayan, MD13; Federica Recine, MD14; Dominik Berthold, MD15; Andrea Necchi, MD16; Christine Theodore, MD17; Matthew I. Milowsky, MD18; Joaquim Bellmunt, MD4; and Jonathan E. Rosenberg, MD19; for the Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators
BACKGROUND: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC. RESULTS: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P 5.77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P 5.48). CONCLUSIONS: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice. C 2015 American Cancer Society. Cancer 2015;121:2586-93. V KEYWORDS: bladder cancer, cisplatin, gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, muscle invasion, neoadjuvant.
Corresponding author: Matthew D. Galsky, MD, Mount Sinai School of Medicine, Tisch Cancer Institute, 1 Gustave L. Levy Place, New York, NY 10029; Fax: (212) 659-5599; [email protected] 1 Department of Hematology and Medical Oncology, Mount Sinai Medical Center, New York, New York; 2Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California; 3Department of Urology, Guy’s and St. Thomas’ Hospital, London, United Kingdom; 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 5Department of Medical Oncology, Southampton General Hospital, Southampton, United Kingdom; 6Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; 7Division of Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington; 8Department of Medical Oncology, Barts Cancer Institute, London, United Kingdom; 9Division of Biostatistics, Department of Preventative Medicine, Mount Sinai Medical Center, New York, New York; 10Department of Medical Oncology, Georges Franc¸ois Leclerc Center, Dijon, France; 11Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; 12Department of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; 13Department of Hematology and Oncology, Barbara Ann Karmanos Cancer Center, Detroit, Michigan; 14Department of Medical Oncology, Samuel and Barbara Sternberg Cancer Research Foundation, Rome, Italy; 15Department of Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland; 16Department of Medical Oncology, Foundation IRCCS National Cancer Institute, Milan, Italy; 17Department of Oncology, Hospital Foch, Suresnes, France; 18Division of Hematology and Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina; 19Division of Genitourinary Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
The RISC Investigators: N. Agarwal, A. Alva, A. Bamias, J. Baniel, J. Bellmunt, D. Berthold, D. W. Bowles, L. Cerbone, S. Chowdhury, S. Crabb, G. Crehange, G. Daugaard, U. De Giorgi, M. Galsky, N. M. Hahn, L. Harshman, S. Hussain, S. Ladoire, R. Mano, M. Milowsky, R. Morales-Barrera, A. Necchi, G. Niegisch, W. K. Oh, S. Pal, T. Powles, F. Recine, J. Rosenberg, G. Sonpavde, S. Sridhar, S. Srinivas, C. Sternberg, C. Theodore, U. Vaishampayan, Y. Wong, and E. Yu. †
The first 2 authors contributed equally to this work as first authors.
DOI: 10.1002/cncr.29387, Received: November 10, 2014; Revised: January 29, 2015; Accepted: February 23, 2015, Published online April 14, 2015 in Wiley Online Library (wileyonlinelibrary.com)
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Bladder Cancer Neoadjuvant Therapy/Galsky et al
INTRODUCTION Worldwide, approximately 330,000 patients are diagnosed with bladder cancer each year, and 123,000 patients will die of the disease.1 The standard management for patients with muscle-invasive bladder cancer involves radical cystectomy and pelvic lymph node dissection. Although this treatment may be curative, a large proportion of patients will develop recurrence and will ultimately die of metastatic disease.2 Several studies have explored the integration of perioperative chemotherapy in an attempt to eradicate micrometastatic disease and improve the outcomes achieved with radical cystectomy alone. Studies have been performed in both neoadjuvant and adjuvant settings.3 The results from the latter trials generally have been less compelling, largely as a result of flawed or underpowered study designs or premature study closure. However, 2 large randomized trials have demonstrated an improvement in survival with the integration of neoadjuvant cisplatin-based combination chemotherapy, leading to the adoption of this approach as a treatment standard.4,5 Despite the survival improvement established in randomized trials with the use of neoadjuvant methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) or cisplatin, methotrexate, plus vinblastine5 (CMV), concerns regarding the balance between the toxicity and efficacy of these regimens has contributed, at least in part, to the poor uptake of neoadjuvant chemotherapy.4-6 In 2000, the results from a randomized phase 3 trial were published comparing gemcitabine plus cisplatin (GC) with standard MVAC in patients with metastatic bladder cancer.7,8 GC was associated with similar efficacy compared with MVAC, albeit with less toxicity, leading to the adoption of this regimen as among the most commonly used systemic treatments for patients with metastatic disease.9 Pragmatically, yet in somewhat of a departure from the evidence-based oncology paradigm, the results from that trial also have been used to justify the routine use and integration into practice guidelines of neoadjuvant GC, despite a lack of prospective randomized data in this setting.10-12 Given the historic difficulties of completing perioperative chemotherapy trials in muscle-invasive bladder cancer, an adequately powered clinical trial to definitively address whether neoadjuvant GC is comparable to the regimens supported by Level I evidence (MVAC and CMV) may never be completed, and additional levels of evidence are needed to support or refute what has become routine practice.
tive study with a primary objective of describing the patterns of care, management, and outcome of patients with cancers of the urothelial tract (clinical T-classification 2 [cT2] disease or greater). RISC includes consecutive patient series from 28 international centers between 2005 and 2012 (some centers included patient data over this entire period, whereas others included data over a more limited number of years). Uniform data fields, comprising baseline characteristics, laboratory and pathology information, treatments, and outcomes, are collected using a password-protected, secure, web-based, electronic datacapture tool. Training on data abstraction for RISC was conducted for each participating site using a web-based tutorial and a comprehensive study training manual. Quality control consisted of a review of each data field by the coordinating center (Icahn School of Medicine, Mount Sinai Hospital, New York, NY) for missing and inconsistent data, and data queries were subsequently completed by each participating site. The study was approved by the ethics committees at each participating institution. Patient inclusion criteria for the current analysis included a diagnosis of cT2 through cT4aN0M0 urothelial cancer of the bladder. Patients with variant histologies were included provided that transitional cell carcinoma was the predominant histology. Patients were excluded if they had not received any neoadjuvant chemotherapy or if they had received treatment with regimens other than GC or MVAC. Patients may have received MVAC in either a standard or dose-dense fashion.13 Data abstracted for the current analysis included age at the time of neoadjuvant chemotherapy, neoadjuvant chemotherapy regimen, the number of cycles of neoadjuvant chemotherapy, tumor histology at the time of radical cystectomy, Eastern Cooperative Oncology Group performance status, year of diagnosis, clinical tumor classification, race, ethnicity, sex, reason for stopping neoadjuvant chemotherapy, time from last dose of chemotherapy until cystectomy, calculated creatinine clearance using the Cockroft-Gault formula, pathologic response to neoadjuvant chemotherapy, and vital status. Detailed toxicity data are not collected in RISC because of the retrospective nature of the data collection. Statistical Analysis
MATERIALS AND METHODS Study Design and Patient Population
The Retrospective International Study of Cancers of the Urothelial Tract (RISC) is a population-based, retrospecCancer
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The primary endpoint of the study was the pathologic complete response (pCR) rate to neoadjuvant MVAC versus GC. A pCR was defined uniformly in RISC as less than pathologic T1-classification (pT1) N0 disease at the time of pathologic evaluation of the cystectomy specimen. 2587
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It is noteworthy that several studies assessing neoadjuvant chemotherapy for muscle-invasive bladder cancer have used this definition.14,15 Survival between the 2 groups was analyzed as an exploratory endpoint. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their age, calculated creatinine clearance, number of cycles of chemotherapy received, pure versus mixed transitional cell carcinoma histology, Eastern Cooperative Oncology Group performance status, year of diagnosis, cT-classification, and sex. These propensity scores were then included in a new logistic regression model, which was used to estimate an adjusted odds ratio comparing the odds of attaining a pCR for patients who received MVAC versus GC. A second analysis was conducted in which multiple imputation methods were used to fill in missing data for patients who had missing values for 1 or more variables that were included in the propensity scores.16 Five data sets containing observed and imputed data were constructed. A multivariable logistic regression model was used to compute propensity scores using data from each of the 5 data sets. These propensity scores were then included in each of 5 new logistic regression models and were used to estimate an adjusted odds ratios (and standard errors) for each of the 5 imputed data sets comparing the odds of a pCR between patients who received MVAC versus GC. Finally, the estimated parameters from each data set were combined using PROC MIANALYZE in the SAS statistical software program (SAS Institute, Inc, Cary, NC) to produce an overall propensity scoreadjusted odds ratio and 95% confidence interval (CI).
RESULTS Study Population
We identified 656 patients in the database who had received neoadjuvant chemotherapy between 2005 and 2012. Of these, 370 patients did not meet the inclusion criteria, and an additional 74 patients had missing data. The final data set was comprised of 212 patients (146 in the GC cohort and 66 in the MVAC cohort). It is noteworthy that 51 of 66 patients in the MVAC cohort received the dose-dense schedule of administration. The full details of the reasons for inclusion and exclusion are provided in Figure 1. A secondary analysis included all 286 patients (202 in the GC cohort and 84 in the MVAC cohort) for whom missing patient data were imputed. The patient characteristics are detailed in Table 1. The median age of the cohort was 63 years, and the major2588
ity of patients were men. The median creatinine clearance was significantly higher in patients who had received MVAC. A greater proportion of patients in the MVAC cohort had received treatment in recent years, probably reflecting the dose-dense schedule of administration used. Data pertaining to the number of lymph nodes retrieved at the time of cystectomy were available only for a subset of patients. In that subset, patients who received MVAC had a higher number of lymph nodes removed compared with those who received CG (n 5 55 patients in each cohort; 21 lymph nodes vs 16 lymph nodes, respectively; P 5 .0017). Neoadjuvant Chemotherapy
The details of neoadjuvant chemotherapy administration are provided in Table 2. Both groups received a median of 3 cycles of neoadjuvant chemotherapy. The reasons for treatment discontinuation and the times from completion of chemotherapy to cystectomy were similar between the 2 cohorts. It is noteworthy that 111 patients received nonstandard regimens (characterized as regimens other than CG and dose-dense or standard MVAC). These regimens are summarized in Table 3. pCR Rate
In the full cohort of 212 patients, 64 (30%) achieved a pCR, including 45 of 146 patients (31%) who received GC and 19 of 66 patients (29%) who received MVAC. The pCR rate was subsequently adjusted for propensity scores, as indicated in Table 4. There was no significant difference in the odds of achieving a pCR with MVAC versus GC (odds ratio, 0.94; 95% CI, 0.48-1.83; P 5 .86). Similar results were obtained when multiple imputation methods were used to fill in missing data for patients who had missing values for 1 or more variables (imputed odds ratio, 0.95; 95% CI, 0.70-1.28; P 5 .74). Survival
In an exploratory analysis, there was no significant difference in the overall survival of patients who received neoadjuvant MVAC versus GC (Kaplan-Meier 25th percentile: 35.5 months vs 26.8 months, respectively; P 5 .17). The hazard ratio (HR) comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (HR, 0.78; 95% CI, 0.401.54; P 5 .48) (Table 5). Similar results were obtained when multiple imputation methods were used to fill in missing data for patients who had missing values for 1 or more variables (imputed HR, 0.97; 95% CI, 0.57-1.64; P 5 .90). Cancer
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Bladder Cancer Neoadjuvant Therapy/Galsky et al
Figure 1. This flow chart illustrates patient inclusion in the primary analysis. Note that patients characterized as “other” were excluded because of 1) clinical stage T1 disease (n 5 3), 2) no pathologic response data (n 5 15), or 3) a diagnosis before 2005 (n 5 9). A single asterisk indicates that the data were imputed in secondary analysis; double asterisks; 51 of 66 patients received dose-dense methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC). Chemo indicates chemotherapy; GC, gemcitabine plus cisplatin; PS, performance status; TCC, transitional cell carcinoma.
DISCUSSION Neoadjuvant GC has become a standard treatment approach in muscle-invasive urothelial cancer of the bladder and is supported by practice guidelines, despite limited prospective, single-arm data and absent prospective, randomized data in this clinical setting.10-12 The current analysis, which is among the largest data sets to date exploring treatment with neoadjuvant GC, demonstrates similar pCR rates with neoadjuvant MVAC versus GC after adjusting for propensity scores. A single published prospective study explored neoadjuvant GC in muscle-invasive bladder cancer.17 That 22-patient, single-arm, single-center study reported a pCR rate of 26%. A 31-patient, multicenter, prospective study of neoadjuvant GC administered using a dosedense schedule was recently presented in abstract form and reported a pCR rate of 32% (95% CI, 16%-48%).18 Several prior retrospective analyses have reported pCR rates and outcomes with neoadjuvant GC in muscleinvasive bladder cancer.14,15,19-22 The majority of those prior analyses have been relatively small, singleinstitutional experiences. Nonetheless, with the exception Cancer
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of a single study, the pCR rates with neoadjuvant GC reported in those prior analyses have been similar to those reported in the current study.22,23 A few of the prior analyses also have reported comparisons of the pCR rate between GC and MVAC but have done so by including the neoadjuvant chemotherapy regimen as a variable in a standard multivariate model rather than by using propensity scores and have involved relatively small cohorts.20,21,24 Propensity scores are used to estimate the effect of an intervention by accounting for the covariates that predict the receipt of a particular intervention, thereby reducing bias because of confounding variables.25 An advantage to using propensity scores, particularly for small to moderate sized data sets, is that, by using a linear combination of covariates for a single score, the treatment groups can be balanced based on a large number of covariates.26 Thus, the propensity score attempts to create conditions similar to randomization to establish a causal connection between the intervention and the outcome. Furthermore, propensity scores allow investigators to clearly define a treatment population in the presence of treatment effect heterogeneity, which cannot be achieved 2589
Original Article TABLE 1. Patient Characteristics
TABLE 2. Treatment Administration
No. of Patients (%) Characteristic
GC, N 5 146
MVAC, N 5 66
No. of Patients (%) P Treatment Variable
Age: Median [range], y Men ECOG PS 0 1 Pure TCC Clinical tumor classification T2 T3 T4 Calc CrCl: Median [range], mL/min Year of diagnosis 2005 2006 2007 2008 2009 2010 2011 2012
63 [30-80] 115 (74)
63 [40-83] 46 (77)
88 (60) 58 (40) 121 (83)
45 (68) 21 (32) 54 (82)
90 (62) 40 (27) 16 (11) 68 [27-199]
41 (62) 17 (26) 8 (12) 90 [36-255]
4 (3) 18 (12) 23 (16) 30 (21) 23 (16) 29 (20) 12 (8) 7 (5)
4 (6) 1 (2) 3 (5) 9 (14) 10 (15) 28 (42) 10 (15) 1 (2)
.36 .29 .27
.85 .95
< .002 .0007
Abbreviations: Calc CrCl, calculated creatinine clearance using the Cockroft-Gault formula; ECOG PS, Eastern Cooperative Oncology Group performance status; GC, gemcitabine plus cisplatin; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin; TCC, transitional cell carcinoma.
with conventional multivariable models, and also to check the performance of the model by assessing covariate balance across treatment groups.27 The concordance between estimates of treatment effect when using propensity scores from observational studies and estimates derived from randomized trials is of interest and has been explored in prior analyses. Although several such studies have demonstrated concordance, these examples do not prove that a propensity score approach is guaranteed to produce valid estimates of treatment effect, but they do demonstrate that it is possible to estimate treatment effects of an intervention using observational data similar to the effects that would result from a randomized trial.28,29 Two single-arm, prospective studies have recently reported promising activity with the administration of neoadjuvant, dose-dense MVAC, with pT0 rates from 26% to 38%.30,31 A retrospective analysis of 80 consecutive patients who received dose-dense MVAC also generated consistent results.32 Indeed, several of the centers involved in those studies contributed patient data to RISC, accounting for the predominance of dose-dense MVAC in our MVAC cohort. Although the majority of patients (77%) received dose-dense MVAC in our analysis, no significant difference in the pCR rate was observed between neoadjuvant GC and MVAC. 2590
No. of cycles Median [range] 4 Reason for stopping chemotherapy Completed planned treatment Disease progression Other Patient preference Toxicity Unknown Median time from chemotherapy completion to cystectomy [range], mo No cystectomy data Missing data Patient refused surgery Toxicity Disease progression
GC, N 5 146
MVAC, N 5 66
3 [1-6] 14 (10) 75 (51) 46 (32) 11 (7)
3 [1-6] 3 (5) 32 (48) 28 (42) 3 (5)
121 (84) 4 (3) 2 (1) 1 (1) 16 (11) 0 (0) 1.3 [0.2-5.4]
58 (88) 1 (1) 0 (0) 1 (2) 5 (8) 1 (2) 1.3 [0.4-4.5]
19 (13) 5 (3) 2 (1) 2 (1) 10 (7)
10 (15) 7 (11) 0 (0) 0 (0) 3 (5)
P
.10
.41
.90
Abbreviations: GC, gemcitabine plus cisplatin; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin
TABLE 3. Chemotherapy Regimens Received by Patients Who Were Excluded From the Analysis Regimen Name
No. of Patients
Cisplatin plus 5-fluorouracil Cisplatin Cisplatin, methotrexate, plus vinblastine Irinotecan plus cisplatin Docetaxel Erlotinib Gemcitabine Gemcitabine plus carboplatin Gemcitabine, carboplatin, plus paclitaxel Gemcitabine, cisplatin, plus paclitaxel Gemcitabine plus Paclitaxel Gemcitabine plus Pemetrexed Methotrexate, carboplatin, plus vinblastine Paclitaxel Paclitaxel plus carboplatin Paclitaxel plus cisplatin Total
1 7 10 2 2 2 3 66 7 1 1 1 2 2 3 1 111
There are limitations to the current analysis. This was a retrospective analysis and was subject to all of the potential biases associated with such an approach. However, propensity score analysis was used in an attempt to minimize potential bias caused by confounding variables. Still, propensity scores cannot adjust for unknown (and consequently unmeasured) confounding variables. In addition, although important covariates like functional Cancer
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Bladder Cancer Neoadjuvant Therapy/Galsky et al
TABLE 4. Pathologic Complete Response Rate for Methotrexate, Vinblastine, Doxorubicin, Plus Cisplatin Versus Gemcitabine Plus Cisplatin Adjusted for Propensity Scores No. of Patients (%) Response pCR Yes No
GC, N 5 146
MVAC, N 5 66a
Overall, N 5 212
45 (31) 101 (69)
19 (29) 47 (71)
64 (30) 148 (70)
OR [95% CI]/P
Adjusted OR [95% CI]/Pb
Imputed OR [95% CI]/Pc
0.91 [0.48-1.72]/.77
0.94 [0.48-1.83]/.86
0.95 [0.70-1.28]/.74
Abbreviations: CI, confidence interval; GC, gemcitabine plus cisplatin; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin; OR, odds ratio; pCR, pathologic complete response rate. a The pCR rate was 31% (16 of 51 patients) in the dose-dense MVAC group and 20% (3 of 15 patients) in the standard-dose MVAC group. b Propensity scores are adjusted for age, creatinine clearance, number of cycles, histology, performance status, year of diagnosis, clinical tumor classification, and sex. c A second analysis was carried out in which multiple imputation methods (Ault 201216) were used to fill in missing data for patients who had missing values for 1 or more of the variables used for propensity scores.
TABLE 5. Overall Survival of Patients Who Received Methotrexate, Vinblastine, Doxorubicin, Plus Cisplatin Versus Gemcitabine Plus Cisplatin Adjusted for Propensity Scores No. of Patients (%) Survival Alive at last follow-up Yes No
GC, N 5 146
MVAC, N 5 66
Overall, N 5 212
101 (69) 45 (31)
54 (82) 12 (18)
155 (73) 57 (27)
Log-Rank P
Adjusted HR [95% CI]/Pa
Imputed HR [95% CI]/Pb
.1740
0.78 [0.40-1.54]/.4778
0.97 [0.57-1.64]/.8979
Abbreviations: CI, confidence interval; GC, gemcitabine plus cisplatin; HR, hazard ratio; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin. a Propensity scores are adjusted for age, creatinine clearance, number of cycles, histology, performance status, year of diagnosis, clinical tumor classification, and sex. b A second analysis was carried out in which multiple imputation methods (Ault 201216) were used to fill in missing data for patients who had missing values for 1 or more of the variables used for propensity scores.
status were included, detailed data on comorbidities were not available. Furthermore, the duration of follow-up was not consistent across centers, and precise data related to relative dose intensity were not available. Although we generated a data set from a large number of international centers, only academic centers contributed data to RISC, potentially impacting the generalizability of the findings. An intermediate endpoint, the pCR rate, was used as the primary endpoint of the analysis rather than progressionfree or overall survival. Although it has not been formally established as a surrogate endpoint, the pCR rate has been correlated with overall survival in several analyses that included the specific definition of pCR rate used in the current study.4,33 The pivotal trial comparing neoadjuvant MVAC followed by surgery versus surgery alone in patients with muscle-invasive bladder cancer (Southwest Oncology Group trial SWOG 8710) demonstrated that patients who had no residual disease at the time of surgery (pT0) had a markedly improved overall survival compared with those who had >pT0 disease (HR, 2.51; 95% Cancer
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CI, 1.47-4.27; P 5 .0008).33 A correlation between the pCR rate and clinical outcomes also was demonstrated in previous analyses of neoadjuvant GC.23 Progression-free survival data were not analyzed given the lack of uniform follow-up in this retrospective cohort. Of 656 patients retrieved in the initial query, 74 patients had missing data for the variables used in the propensity score analysis. However, imputation of missing values did not have an impact on the primary results of the analysis. Although no significant difference in the pCR rate was observed between patients receiving MVAC versus GC, noninferiority of GC cannot be addressed in this retrospective analysis. However, this would be a potential endpoint if a prospective study addressing this clinical question were feasible. Finally, the current analysis relied on investigator review of pathology reports, and there was no central pathology review of cystectomy specimens. The current analysis attempts to address a major dilemma in the clinical care of patients with bladder cancer: that is, confirmation of a practice that has been adopted as 2591
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a treatment standard in the absence of Level I evidence for a setting in which an adequately powered, prospective, randomized trial is unlikely to ever be completed. A recently initiated Southwest Oncology Group trial (SWOG 1314) is randomizing patients with muscleinvasive bladder cancer to neoadjuvant GC versus dosedense MVAC.34 However, that trial is not designed to compare the 2 regimens but, rather, to determine the utility of a gene expression model-based biomarker approach in predicting pCR. Other approaches, such as observational studies or pragmatic clinical trials, could be considered. However, in the absence of such studies, the results of the current analysis provide additional evidence to support the use of GC in the neoadjuvant setting given the similar pCR rate achieved compared with MVAC. FUNDING SUPPORT
6.
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9. 10.
11.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES Dr. Galsky reports grants from Bristol-Myers Squibb, Novartis AG, and Celgene Corporation and advisory/consulting fees from BioMotiv and Merck & Company Inc; he is a cofounder of Dual Therapeutics. Dr. Crabb reports grants for research funding from AstraZeneca and advisory/speakers’ fees from Janssen Pharmaceuticals Inc, Astellas Pharma US Inc, Dendreon Corporation, and Sanofi. Dr. Wong reports a grant from Pfizer Inc for an unrelated project and institutional clinical trial support from Bayer, Astellas Pharma US Inc, Jansen Pharmaceuticals Inc, and Millennium Pharmaceuticals. Dr. Yu reports grants from ImClone (an Eli Lilly company) for a sponsored clinical trial. Dr. Powles was supported by grants from Roche, Bristol-Myers Squibb, and Astellas Pharma US Inc. Dr. Hussain reports grants from Bayer, Pierre Fabre, and Boehringer Ingelheim; advisory/consulting fees from Astellas Pharma US Inc, Bayer, and Pierre Fabre; and meeting support from Janssen Pharmaceuticals and Boehringer Ingelheim. Dr. Bellmunt reports lecture fees from Pierre Fabre; he serves without compensation on the advisory boards of Pierre Fabre, Genentech, and Merck & Company Inc, and he is an uncompensated lecturer for Merck & Company Inc.
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assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29:2171-2177. David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. J Urol. 2007;178:451-454. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000; 18:3068-3077. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602-4608. Sonpavde G, Watson D, Tourtellott M, et al. Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. Clin Genitourin Cancer. 2012;10:1-5. National Comprehensive Cancer Network (NCCN). NCCN Guidelines, version 2.2014. Bladder Cancer. Fort Washington, PA: NCCN; 2014. http://www.nccn.org/professionals/physician_gls/pdf/ bladder.pdf. Accessed October 1, 2014. Apolo AB, Kim JW, Bochner BH, et al. Examining the management of muscle-invasive bladder cancer by medical oncologists in the United States. Urol Oncol. 2014;32:637-644. Booth CM, Siemens DR, Peng Y, Tannock IF, Mackillop WJ. Delivery of perioperative chemotherapy for bladder cancer in routine clinical practice. Ann Oncol. 2014;25:1783-1788. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42:50-54. Pal SK, Ruel NH, Wilson TG, Yuh BE. Retrospective analysis of clinical outcomes with neoadjuvant cisplatin-based regimens for muscle-invasive bladder cancer. Clin Genitourin Cancer. 2012;10: 246-250. Scosyrev E, Messing EM, van Wijngaarden E, et al. Neoadjuvant gemcitabine and cisplatin chemotherapy for locally advanced urothelial cancer of the bladder. Cancer. 2012;118:72-81. Ault K. Multiple imputation for ordinal variables: a comparison of SUDAAN’s PROC IMPUTE vs PROC MI. In: Southeast SAS Users Group (SESUG), ed. SESUG 2012: Proceedings of the Southeast SAS Users Group. Durham, NC: SESUG; 2012. Paper SD-12. Herchenhorn D, Dienstmann R, Peixoto FA, et al. Phase II trial of neoadjuvant gemcitabine and cisplatin in patients with resectable bladder carcinoma. Int Braz J Urol. 2007;33:630-638; discussion 638. Plimack ER, Hoffman-Censits JH, Kutikov A, et al. Neoadjuvant dose-dense gemcitabine and cisplatin (DDGC) in patients (pts) with muscle-invasive bladder cancer (MIBC): final results of a multicenter phase II study [abstract]. J Clin Oncol. 2014;32(5S). Abstract 4513. Dash A, Pettus JA 4th, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008;113:2471-2477. Fairey AS, Daneshmand S, Quinn D, et al. Neoadjuvant chemotherapy with gemcitabine/cisplatin vs methotrexate/vinblastine/doxorubicin/cisplatin for muscle-invasive urothelial carcinoma of the bladder: a retrospective analysis from the University of Southern California. Urol Oncol. 2013;31:1737-1743. Lee FC, Harris W, Cheng HH, et al. pathologic response rates of gemcitabine/cisplatin versus methotrexate/vinblastine/Adriamycin/cisplatin neoadjuvant chemotherapy for muscle invasive urothelial bladder cancer. Adv Urol. 2013;2013:317190. Weight CJ, Garcia JA, Hansel DE, et al. Lack of pathologic downstaging with neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder: a contemporary series. Cancer. 2009; 115:792-799. Yuh BE, Ruel N, Wilson TG, Vogelzang N, Pal SK. Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer. J Urol. 2013;189: 1682-1686.
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24. Yeshchina O, Badalato GM, Wosnitzer MS, et al. Relative efficacy of perioperative gemcitabine and cisplatin versus methotrexate, vinblastine, Adriamycin, and cisplatin in the management of locally advanced urothelial carcinoma of the bladder. Urology. 2012;79:384390. 25. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41-55. 26. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46:399-424. 27. Sturmer T, Wyss R, Glynn RJ, Brookhart MA. Propensity scores for confounder adjustment when assessing the effects of medical interventions using nonexperimental study designs. J Intern Med. 2014; 275:570-580. 28. Dehejia RH, Wahba S. Causal effects in, nonexperimental studies: re-evaluating the evaluation of training programs. J Am Stat Assoc. 1999;94:1053-1062. 29. Heckman JJ, Pinto R. Econometric mediation analyses: identifying the sources of treatment effects from experimentally estimated production technologies with unmeasured and mismeasured inputs. Econ Rev. 2015;34:6-31.
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30. Choueiri TK, Jacobus S, Bellmunt J, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014;32:1889-1894. 31. Plimack ER, Hoffman-Censits JH, Viterbo R, et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014;32:1895-1901. 32. Blick C, Hall P, Pwint T, et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder. Cancer. 2012;118:3920-3927. 33. Sonpavde G, Goldman BH, Speights VO, et al. Quality of pathologic response and surgery correlate with survival for patients with completely resected bladder cancer after neoadjuvant chemotherapy. Cancer. 2009;115:4104-4109. 34. Southwest Oncology Group, National Cancer Institute. A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) With Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer. http://www.clinicaltrials.gov/ct2/show/study/NCT02177695. Accessed January 23, 2015.
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Comparative Effectiveness of Gemcitabine Plus Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, Plus Cisplatin as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer Matthew D. Galsky, MD1†; Sumanta K. Pal, MD2†; Simon Chowdhury, MRCP3; Lauren C. Harshman, MD4; Simon J. Crabb, MRCP5; Yu-Ning Wong, MD6; Evan Y. Yu, MD7; Thomas Powles, MRCP8; Erin L. Moshier, PhD9; Sylvain Ladoire, MD10; Syed A. Hussain, MD11; Neeraj Agarwal, MD12; Ulka N. Vaishampayan, MD13; Federica Recine, MD14; Dominik Berthold, MD15; Andrea Necchi, MD16; Christine Theodore, MD17; Matthew I. Milowsky, MD18; Joaquim Bellmunt, MD4; and Jonathan E. Rosenberg, MD19; for the Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators
BACKGROUND: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC. RESULTS: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P 5.77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P 5.48). CONCLUSIONS: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice. C 2015 American Cancer Society. Cancer 2015;121:2586-93. V KEYWORDS: bladder cancer, cisplatin, gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, muscle invasion, neoadjuvant.
Corresponding author: Matthew D. Galsky, MD, Mount Sinai School of Medicine, Tisch Cancer Institute, 1 Gustave L. Levy Place, New York, NY 10029; Fax: (212) 659-5599; [email protected] 1 Department of Hematology and Medical Oncology, Mount Sinai Medical Center, New York, New York; 2Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California; 3Department of Urology, Guy’s and St. Thomas’ Hospital, London, United Kingdom; 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 5Department of Medical Oncology, Southampton General Hospital, Southampton, United Kingdom; 6Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; 7Division of Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington; 8Department of Medical Oncology, Barts Cancer Institute, London, United Kingdom; 9Division of Biostatistics, Department of Preventative Medicine, Mount Sinai Medical Center, New York, New York; 10Department of Medical Oncology, Georges Franc¸ois Leclerc Center, Dijon, France; 11Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; 12Department of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; 13Department of Hematology and Oncology, Barbara Ann Karmanos Cancer Center, Detroit, Michigan; 14Department of Medical Oncology, Samuel and Barbara Sternberg Cancer Research Foundation, Rome, Italy; 15Department of Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland; 16Department of Medical Oncology, Foundation IRCCS National Cancer Institute, Milan, Italy; 17Department of Oncology, Hospital Foch, Suresnes, France; 18Division of Hematology and Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina; 19Division of Genitourinary Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
The RISC Investigators: N. Agarwal, A. Alva, A. Bamias, J. Baniel, J. Bellmunt, D. Berthold, D. W. Bowles, L. Cerbone, S. Chowdhury, S. Crabb, G. Crehange, G. Daugaard, U. De Giorgi, M. Galsky, N. M. Hahn, L. Harshman, S. Hussain, S. Ladoire, R. Mano, M. Milowsky, R. Morales-Barrera, A. Necchi, G. Niegisch, W. K. Oh, S. Pal, T. Powles, F. Recine, J. Rosenberg, G. Sonpavde, S. Sridhar, S. Srinivas, C. Sternberg, C. Theodore, U. Vaishampayan, Y. Wong, and E. Yu. †
The first 2 authors contributed equally to this work as first authors.
DOI: 10.1002/cncr.29387, Received: November 10, 2014; Revised: January 29, 2015; Accepted: February 23, 2015, Published online April 14, 2015 in Wiley Online Library (wileyonlinelibrary.com)
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INTRODUCTION Worldwide, approximately 330,000 patients are diagnosed with bladder cancer each year, and 123,000 patients will die of the disease.1 The standard management for patients with muscle-invasive bladder cancer involves radical cystectomy and pelvic lymph node dissection. Although this treatment may be curative, a large proportion of patients will develop recurrence and will ultimately die of metastatic disease.2 Several studies have explored the integration of perioperative chemotherapy in an attempt to eradicate micrometastatic disease and improve the outcomes achieved with radical cystectomy alone. Studies have been performed in both neoadjuvant and adjuvant settings.3 The results from the latter trials generally have been less compelling, largely as a result of flawed or underpowered study designs or premature study closure. However, 2 large randomized trials have demonstrated an improvement in survival with the integration of neoadjuvant cisplatin-based combination chemotherapy, leading to the adoption of this approach as a treatment standard.4,5 Despite the survival improvement established in randomized trials with the use of neoadjuvant methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) or cisplatin, methotrexate, plus vinblastine5 (CMV), concerns regarding the balance between the toxicity and efficacy of these regimens has contributed, at least in part, to the poor uptake of neoadjuvant chemotherapy.4-6 In 2000, the results from a randomized phase 3 trial were published comparing gemcitabine plus cisplatin (GC) with standard MVAC in patients with metastatic bladder cancer.7,8 GC was associated with similar efficacy compared with MVAC, albeit with less toxicity, leading to the adoption of this regimen as among the most commonly used systemic treatments for patients with metastatic disease.9 Pragmatically, yet in somewhat of a departure from the evidence-based oncology paradigm, the results from that trial also have been used to justify the routine use and integration into practice guidelines of neoadjuvant GC, despite a lack of prospective randomized data in this setting.10-12 Given the historic difficulties of completing perioperative chemotherapy trials in muscle-invasive bladder cancer, an adequately powered clinical trial to definitively address whether neoadjuvant GC is comparable to the regimens supported by Level I evidence (MVAC and CMV) may never be completed, and additional levels of evidence are needed to support or refute what has become routine practice.
tive study with a primary objective of describing the patterns of care, management, and outcome of patients with cancers of the urothelial tract (clinical T-classification 2 [cT2] disease or greater). RISC includes consecutive patient series from 28 international centers between 2005 and 2012 (some centers included patient data over this entire period, whereas others included data over a more limited number of years). Uniform data fields, comprising baseline characteristics, laboratory and pathology information, treatments, and outcomes, are collected using a password-protected, secure, web-based, electronic datacapture tool. Training on data abstraction for RISC was conducted for each participating site using a web-based tutorial and a comprehensive study training manual. Quality control consisted of a review of each data field by the coordinating center (Icahn School of Medicine, Mount Sinai Hospital, New York, NY) for missing and inconsistent data, and data queries were subsequently completed by each participating site. The study was approved by the ethics committees at each participating institution. Patient inclusion criteria for the current analysis included a diagnosis of cT2 through cT4aN0M0 urothelial cancer of the bladder. Patients with variant histologies were included provided that transitional cell carcinoma was the predominant histology. Patients were excluded if they had not received any neoadjuvant chemotherapy or if they had received treatment with regimens other than GC or MVAC. Patients may have received MVAC in either a standard or dose-dense fashion.13 Data abstracted for the current analysis included age at the time of neoadjuvant chemotherapy, neoadjuvant chemotherapy regimen, the number of cycles of neoadjuvant chemotherapy, tumor histology at the time of radical cystectomy, Eastern Cooperative Oncology Group performance status, year of diagnosis, clinical tumor classification, race, ethnicity, sex, reason for stopping neoadjuvant chemotherapy, time from last dose of chemotherapy until cystectomy, calculated creatinine clearance using the Cockroft-Gault formula, pathologic response to neoadjuvant chemotherapy, and vital status. Detailed toxicity data are not collected in RISC because of the retrospective nature of the data collection. Statistical Analysis
MATERIALS AND METHODS Study Design and Patient Population
The Retrospective International Study of Cancers of the Urothelial Tract (RISC) is a population-based, retrospecCancer
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The primary endpoint of the study was the pathologic complete response (pCR) rate to neoadjuvant MVAC versus GC. A pCR was defined uniformly in RISC as less than pathologic T1-classification (pT1) N0 disease at the time of pathologic evaluation of the cystectomy specimen. 2587
Original Article
It is noteworthy that several studies assessing neoadjuvant chemotherapy for muscle-invasive bladder cancer have used this definition.14,15 Survival between the 2 groups was analyzed as an exploratory endpoint. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their age, calculated creatinine clearance, number of cycles of chemotherapy received, pure versus mixed transitional cell carcinoma histology, Eastern Cooperative Oncology Group performance status, year of diagnosis, cT-classification, and sex. These propensity scores were then included in a new logistic regression model, which was used to estimate an adjusted odds ratio comparing the odds of attaining a pCR for patients who received MVAC versus GC. A second analysis was conducted in which multiple imputation methods were used to fill in missing data for patients who had missing values for 1 or more variables that were included in the propensity scores.16 Five data sets containing observed and imputed data were constructed. A multivariable logistic regression model was used to compute propensity scores using data from each of the 5 data sets. These propensity scores were then included in each of 5 new logistic regression models and were used to estimate an adjusted odds ratios (and standard errors) for each of the 5 imputed data sets comparing the odds of a pCR between patients who received MVAC versus GC. Finally, the estimated parameters from each data set were combined using PROC MIANALYZE in the SAS statistical software program (SAS Institute, Inc, Cary, NC) to produce an overall propensity scoreadjusted odds ratio and 95% confidence interval (CI).
RESULTS Study Population
We identified 656 patients in the database who had received neoadjuvant chemotherapy between 2005 and 2012. Of these, 370 patients did not meet the inclusion criteria, and an additional 74 patients had missing data. The final data set was comprised of 212 patients (146 in the GC cohort and 66 in the MVAC cohort). It is noteworthy that 51 of 66 patients in the MVAC cohort received the dose-dense schedule of administration. The full details of the reasons for inclusion and exclusion are provided in Figure 1. A secondary analysis included all 286 patients (202 in the GC cohort and 84 in the MVAC cohort) for whom missing patient data were imputed. The patient characteristics are detailed in Table 1. The median age of the cohort was 63 years, and the major2588
ity of patients were men. The median creatinine clearance was significantly higher in patients who had received MVAC. A greater proportion of patients in the MVAC cohort had received treatment in recent years, probably reflecting the dose-dense schedule of administration used. Data pertaining to the number of lymph nodes retrieved at the time of cystectomy were available only for a subset of patients. In that subset, patients who received MVAC had a higher number of lymph nodes removed compared with those who received CG (n 5 55 patients in each cohort; 21 lymph nodes vs 16 lymph nodes, respectively; P 5 .0017). Neoadjuvant Chemotherapy
The details of neoadjuvant chemotherapy administration are provided in Table 2. Both groups received a median of 3 cycles of neoadjuvant chemotherapy. The reasons for treatment discontinuation and the times from completion of chemotherapy to cystectomy were similar between the 2 cohorts. It is noteworthy that 111 patients received nonstandard regimens (characterized as regimens other than CG and dose-dense or standard MVAC). These regimens are summarized in Table 3. pCR Rate
In the full cohort of 212 patients, 64 (30%) achieved a pCR, including 45 of 146 patients (31%) who received GC and 19 of 66 patients (29%) who received MVAC. The pCR rate was subsequently adjusted for propensity scores, as indicated in Table 4. There was no significant difference in the odds of achieving a pCR with MVAC versus GC (odds ratio, 0.94; 95% CI, 0.48-1.83; P 5 .86). Similar results were obtained when multiple imputation methods were used to fill in missing data for patients who had missing values for 1 or more variables (imputed odds ratio, 0.95; 95% CI, 0.70-1.28; P 5 .74). Survival
In an exploratory analysis, there was no significant difference in the overall survival of patients who received neoadjuvant MVAC versus GC (Kaplan-Meier 25th percentile: 35.5 months vs 26.8 months, respectively; P 5 .17). The hazard ratio (HR) comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (HR, 0.78; 95% CI, 0.401.54; P 5 .48) (Table 5). Similar results were obtained when multiple imputation methods were used to fill in missing data for patients who had missing values for 1 or more variables (imputed HR, 0.97; 95% CI, 0.57-1.64; P 5 .90). Cancer
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Figure 1. This flow chart illustrates patient inclusion in the primary analysis. Note that patients characterized as “other” were excluded because of 1) clinical stage T1 disease (n 5 3), 2) no pathologic response data (n 5 15), or 3) a diagnosis before 2005 (n 5 9). A single asterisk indicates that the data were imputed in secondary analysis; double asterisks; 51 of 66 patients received dose-dense methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC). Chemo indicates chemotherapy; GC, gemcitabine plus cisplatin; PS, performance status; TCC, transitional cell carcinoma.
DISCUSSION Neoadjuvant GC has become a standard treatment approach in muscle-invasive urothelial cancer of the bladder and is supported by practice guidelines, despite limited prospective, single-arm data and absent prospective, randomized data in this clinical setting.10-12 The current analysis, which is among the largest data sets to date exploring treatment with neoadjuvant GC, demonstrates similar pCR rates with neoadjuvant MVAC versus GC after adjusting for propensity scores. A single published prospective study explored neoadjuvant GC in muscle-invasive bladder cancer.17 That 22-patient, single-arm, single-center study reported a pCR rate of 26%. A 31-patient, multicenter, prospective study of neoadjuvant GC administered using a dosedense schedule was recently presented in abstract form and reported a pCR rate of 32% (95% CI, 16%-48%).18 Several prior retrospective analyses have reported pCR rates and outcomes with neoadjuvant GC in muscleinvasive bladder cancer.14,15,19-22 The majority of those prior analyses have been relatively small, singleinstitutional experiences. Nonetheless, with the exception Cancer
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of a single study, the pCR rates with neoadjuvant GC reported in those prior analyses have been similar to those reported in the current study.22,23 A few of the prior analyses also have reported comparisons of the pCR rate between GC and MVAC but have done so by including the neoadjuvant chemotherapy regimen as a variable in a standard multivariate model rather than by using propensity scores and have involved relatively small cohorts.20,21,24 Propensity scores are used to estimate the effect of an intervention by accounting for the covariates that predict the receipt of a particular intervention, thereby reducing bias because of confounding variables.25 An advantage to using propensity scores, particularly for small to moderate sized data sets, is that, by using a linear combination of covariates for a single score, the treatment groups can be balanced based on a large number of covariates.26 Thus, the propensity score attempts to create conditions similar to randomization to establish a causal connection between the intervention and the outcome. Furthermore, propensity scores allow investigators to clearly define a treatment population in the presence of treatment effect heterogeneity, which cannot be achieved 2589
Original Article TABLE 1. Patient Characteristics
TABLE 2. Treatment Administration
No. of Patients (%) Characteristic
GC, N 5 146
MVAC, N 5 66
No. of Patients (%) P Treatment Variable
Age: Median [range], y Men ECOG PS 0 1 Pure TCC Clinical tumor classification T2 T3 T4 Calc CrCl: Median [range], mL/min Year of diagnosis 2005 2006 2007 2008 2009 2010 2011 2012
63 [30-80] 115 (74)
63 [40-83] 46 (77)
88 (60) 58 (40) 121 (83)
45 (68) 21 (32) 54 (82)
90 (62) 40 (27) 16 (11) 68 [27-199]
41 (62) 17 (26) 8 (12) 90 [36-255]
4 (3) 18 (12) 23 (16) 30 (21) 23 (16) 29 (20) 12 (8) 7 (5)
4 (6) 1 (2) 3 (5) 9 (14) 10 (15) 28 (42) 10 (15) 1 (2)
.36 .29 .27
.85 .95
< .002 .0007
Abbreviations: Calc CrCl, calculated creatinine clearance using the Cockroft-Gault formula; ECOG PS, Eastern Cooperative Oncology Group performance status; GC, gemcitabine plus cisplatin; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin; TCC, transitional cell carcinoma.
with conventional multivariable models, and also to check the performance of the model by assessing covariate balance across treatment groups.27 The concordance between estimates of treatment effect when using propensity scores from observational studies and estimates derived from randomized trials is of interest and has been explored in prior analyses. Although several such studies have demonstrated concordance, these examples do not prove that a propensity score approach is guaranteed to produce valid estimates of treatment effect, but they do demonstrate that it is possible to estimate treatment effects of an intervention using observational data similar to the effects that would result from a randomized trial.28,29 Two single-arm, prospective studies have recently reported promising activity with the administration of neoadjuvant, dose-dense MVAC, with pT0 rates from 26% to 38%.30,31 A retrospective analysis of 80 consecutive patients who received dose-dense MVAC also generated consistent results.32 Indeed, several of the centers involved in those studies contributed patient data to RISC, accounting for the predominance of dose-dense MVAC in our MVAC cohort. Although the majority of patients (77%) received dose-dense MVAC in our analysis, no significant difference in the pCR rate was observed between neoadjuvant GC and MVAC. 2590
No. of cycles Median [range] 4 Reason for stopping chemotherapy Completed planned treatment Disease progression Other Patient preference Toxicity Unknown Median time from chemotherapy completion to cystectomy [range], mo No cystectomy data Missing data Patient refused surgery Toxicity Disease progression
GC, N 5 146
MVAC, N 5 66
3 [1-6] 14 (10) 75 (51) 46 (32) 11 (7)
3 [1-6] 3 (5) 32 (48) 28 (42) 3 (5)
121 (84) 4 (3) 2 (1) 1 (1) 16 (11) 0 (0) 1.3 [0.2-5.4]
58 (88) 1 (1) 0 (0) 1 (2) 5 (8) 1 (2) 1.3 [0.4-4.5]
19 (13) 5 (3) 2 (1) 2 (1) 10 (7)
10 (15) 7 (11) 0 (0) 0 (0) 3 (5)
P
.10
.41
.90
Abbreviations: GC, gemcitabine plus cisplatin; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin
TABLE 3. Chemotherapy Regimens Received by Patients Who Were Excluded From the Analysis Regimen Name
No. of Patients
Cisplatin plus 5-fluorouracil Cisplatin Cisplatin, methotrexate, plus vinblastine Irinotecan plus cisplatin Docetaxel Erlotinib Gemcitabine Gemcitabine plus carboplatin Gemcitabine, carboplatin, plus paclitaxel Gemcitabine, cisplatin, plus paclitaxel Gemcitabine plus Paclitaxel Gemcitabine plus Pemetrexed Methotrexate, carboplatin, plus vinblastine Paclitaxel Paclitaxel plus carboplatin Paclitaxel plus cisplatin Total
1 7 10 2 2 2 3 66 7 1 1 1 2 2 3 1 111
There are limitations to the current analysis. This was a retrospective analysis and was subject to all of the potential biases associated with such an approach. However, propensity score analysis was used in an attempt to minimize potential bias caused by confounding variables. Still, propensity scores cannot adjust for unknown (and consequently unmeasured) confounding variables. In addition, although important covariates like functional Cancer
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TABLE 4. Pathologic Complete Response Rate for Methotrexate, Vinblastine, Doxorubicin, Plus Cisplatin Versus Gemcitabine Plus Cisplatin Adjusted for Propensity Scores No. of Patients (%) Response pCR Yes No
GC, N 5 146
MVAC, N 5 66a
Overall, N 5 212
45 (31) 101 (69)
19 (29) 47 (71)
64 (30) 148 (70)
OR [95% CI]/P
Adjusted OR [95% CI]/Pb
Imputed OR [95% CI]/Pc
0.91 [0.48-1.72]/.77
0.94 [0.48-1.83]/.86
0.95 [0.70-1.28]/.74
Abbreviations: CI, confidence interval; GC, gemcitabine plus cisplatin; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin; OR, odds ratio; pCR, pathologic complete response rate. a The pCR rate was 31% (16 of 51 patients) in the dose-dense MVAC group and 20% (3 of 15 patients) in the standard-dose MVAC group. b Propensity scores are adjusted for age, creatinine clearance, number of cycles, histology, performance status, year of diagnosis, clinical tumor classification, and sex. c A second analysis was carried out in which multiple imputation methods (Ault 201216) were used to fill in missing data for patients who had missing values for 1 or more of the variables used for propensity scores.
TABLE 5. Overall Survival of Patients Who Received Methotrexate, Vinblastine, Doxorubicin, Plus Cisplatin Versus Gemcitabine Plus Cisplatin Adjusted for Propensity Scores No. of Patients (%) Survival Alive at last follow-up Yes No
GC, N 5 146
MVAC, N 5 66
Overall, N 5 212
101 (69) 45 (31)
54 (82) 12 (18)
155 (73) 57 (27)
Log-Rank P
Adjusted HR [95% CI]/Pa
Imputed HR [95% CI]/Pb
.1740
0.78 [0.40-1.54]/.4778
0.97 [0.57-1.64]/.8979
Abbreviations: CI, confidence interval; GC, gemcitabine plus cisplatin; HR, hazard ratio; MVAC, methotrexate, vinblastine, doxorubicin, plus cisplatin. a Propensity scores are adjusted for age, creatinine clearance, number of cycles, histology, performance status, year of diagnosis, clinical tumor classification, and sex. b A second analysis was carried out in which multiple imputation methods (Ault 201216) were used to fill in missing data for patients who had missing values for 1 or more of the variables used for propensity scores.
status were included, detailed data on comorbidities were not available. Furthermore, the duration of follow-up was not consistent across centers, and precise data related to relative dose intensity were not available. Although we generated a data set from a large number of international centers, only academic centers contributed data to RISC, potentially impacting the generalizability of the findings. An intermediate endpoint, the pCR rate, was used as the primary endpoint of the analysis rather than progressionfree or overall survival. Although it has not been formally established as a surrogate endpoint, the pCR rate has been correlated with overall survival in several analyses that included the specific definition of pCR rate used in the current study.4,33 The pivotal trial comparing neoadjuvant MVAC followed by surgery versus surgery alone in patients with muscle-invasive bladder cancer (Southwest Oncology Group trial SWOG 8710) demonstrated that patients who had no residual disease at the time of surgery (pT0) had a markedly improved overall survival compared with those who had >pT0 disease (HR, 2.51; 95% Cancer
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CI, 1.47-4.27; P 5 .0008).33 A correlation between the pCR rate and clinical outcomes also was demonstrated in previous analyses of neoadjuvant GC.23 Progression-free survival data were not analyzed given the lack of uniform follow-up in this retrospective cohort. Of 656 patients retrieved in the initial query, 74 patients had missing data for the variables used in the propensity score analysis. However, imputation of missing values did not have an impact on the primary results of the analysis. Although no significant difference in the pCR rate was observed between patients receiving MVAC versus GC, noninferiority of GC cannot be addressed in this retrospective analysis. However, this would be a potential endpoint if a prospective study addressing this clinical question were feasible. Finally, the current analysis relied on investigator review of pathology reports, and there was no central pathology review of cystectomy specimens. The current analysis attempts to address a major dilemma in the clinical care of patients with bladder cancer: that is, confirmation of a practice that has been adopted as 2591
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a treatment standard in the absence of Level I evidence for a setting in which an adequately powered, prospective, randomized trial is unlikely to ever be completed. A recently initiated Southwest Oncology Group trial (SWOG 1314) is randomizing patients with muscleinvasive bladder cancer to neoadjuvant GC versus dosedense MVAC.34 However, that trial is not designed to compare the 2 regimens but, rather, to determine the utility of a gene expression model-based biomarker approach in predicting pCR. Other approaches, such as observational studies or pragmatic clinical trials, could be considered. However, in the absence of such studies, the results of the current analysis provide additional evidence to support the use of GC in the neoadjuvant setting given the similar pCR rate achieved compared with MVAC. FUNDING SUPPORT
6.
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9. 10.
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No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES Dr. Galsky reports grants from Bristol-Myers Squibb, Novartis AG, and Celgene Corporation and advisory/consulting fees from BioMotiv and Merck & Company Inc; he is a cofounder of Dual Therapeutics. Dr. Crabb reports grants for research funding from AstraZeneca and advisory/speakers’ fees from Janssen Pharmaceuticals Inc, Astellas Pharma US Inc, Dendreon Corporation, and Sanofi. Dr. Wong reports a grant from Pfizer Inc for an unrelated project and institutional clinical trial support from Bayer, Astellas Pharma US Inc, Jansen Pharmaceuticals Inc, and Millennium Pharmaceuticals. Dr. Yu reports grants from ImClone (an Eli Lilly company) for a sponsored clinical trial. Dr. Powles was supported by grants from Roche, Bristol-Myers Squibb, and Astellas Pharma US Inc. Dr. Hussain reports grants from Bayer, Pierre Fabre, and Boehringer Ingelheim; advisory/consulting fees from Astellas Pharma US Inc, Bayer, and Pierre Fabre; and meeting support from Janssen Pharmaceuticals and Boehringer Ingelheim. Dr. Bellmunt reports lecture fees from Pierre Fabre; he serves without compensation on the advisory boards of Pierre Fabre, Genentech, and Merck & Company Inc, and he is an uncompensated lecturer for Merck & Company Inc.
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