This cohort study assesses the comparative effectiveness of adjuvant chemotherapy vs observation for patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder pretreated with neoadjuvant chemotherapy and radial cystectomy.
Key Points
Question
What is the role of adjuvant chemotherapy for patients with adverse pathologic features after neoadjuvant chemotherapy and radical cystectomy?
Findings
In this cohort study of 788 patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder, the receipt of adjuvant chemotherapy after neoadjuvant chemotherapy and radical cystectomy was associated with an overall survival benefit.
Meaning
Adjuvant chemotherapy after neoadjuvant chemotherapy and radical cystectomy may prolong overall survival among patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder.
Abstract
Importance
Despite existing evidence of a benefit associated with cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) for chemotherapy-naive patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder (UCB), to our knowledge, no studies have addressed the effectiveness of AC in those who received neoadjuvant chemotherapy (NAC) before surgery.
Objective
To assess the comparative effectiveness of AC vs observation for patients with pT3/T4 and/or pN+ UCB previously treated with NAC and RC.
Design, Setting, and Participants
This observational cohort study used the National Cancer Data Base (January 1, 2006, through December 31, 2012) to identify individuals who received NAC and RC followed by AC or observation for pT3/T4 and/or pN+ UCB.
Main Outcomes and Measures
After multiple imputation was used to handle missing data, inverse probability of treatment weighting (IPTW)–adjusted Kaplan-Meier and Cox proportional hazards regression analyses were performed with a 6-month conditional landmark to compare overall survival (OS) among patients who received NAC and RC followed by AC vs observation. In addition, exploratory analyses were conducted to examine the heterogeneity of the treatment effect according to age (continuous), sex (female vs male), Charlson comorbidity index (≥1 vs 0), pT/N stage (pT3/T4N0 vs pTanyN+), and surgical margin status (positive vs negative) by testing interaction terms within the IPTW-adjusted Cox proportional hazards regression model.
Results
Of the 788 patients with pT3/T4 and/or pN+ UCB (mean [SD] age, 65.3 [9.4] years; 603 [76.5%] male and 185 [23.5%] female), 184 (23.4%) received NAC and RC followed by AC and 604 (76.6%) received NAC and RC followed by observation. The 6-month conditional landmark, IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for NAC and RC followed by AC (29.9 months; interquartile range, 15.1-85.4 months) vs NAC and RC followed by observation (24.2 months; interquartile range, 12.9-58.9 months) (P = .046). The 5-year IPTW-adjusted rates of OS were 36.8% for NAC and RC followed by AC vs 24.7% for NAC and RC followed by observation. In the IPTW-adjusted Cox proportional hazards regression analysis, NAC and RC followed by AC was associated with a significant OS benefit (hazard ratio, 0.78; 95% CI, 0.61-0.99; P = .046). Interaction term analyses indicated that the OS benefit of NAC and RC followed by AC decreased significantly with age (hazard ratio, 0.97; 95% CI, 0.95-0.99; P = .02), whereas no significant interaction was observed with sex (P = .82), Charlson comorbidity index (P = .51), pT/N stage (P = .95), and surgical margin status (P = .29).
Conclusions and Relevance
This study found that AC after NAC and RC may be associated with an OS benefit for patients with pT3/T4 and/or pN+ UCB. The present findings should be considered as preliminary evidence to conduct a randomized clinical trial to address this association.
Introduction
On the basis of level 1 evidence, neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) constitutes the standard of care for individuals with localized muscle-invasive urothelial carcinoma of the bladder (UCB). Despite the well-established downstaging and survival benefits associated with this approach, approximately 20% of patients harbor adverse pathologic features at surgery.
Of interest, current evidence suggests that the receipt of cisplatin-based adjuvant chemotherapy (AC) after RC for pT3/T4 and/or pN+ UCB may decrease the risk of recurrence and ultimately prolong survival. However, these studies were limited to individuals who did not receive NAC before undergoing RC; the role of AC after NAC and RC for non–organ-confined disease at definitive surgery, to our knowledge, has never been evaluated in a randomized setting. To date, a single observational study with a small sample size has addressed this topic. Although the investigators found no difference in recurrence-free and cancer-specific survival between patients who received AC vs observation after NAC and RC, others have shown a potential benefit for salvage chemotherapy in those previously treated with platinum-based regimens for metastatic UCB. As such, we hypothesized that AC after NAC and RC for pT3/T4 and/or pN+ disease may provide an overall survival benefit relative to observation.
Methods
From a population of 313 040 individuals diagnosed with bladder cancer from January 1, 2006, through December 31, 2012 (International Classification of Diseases of Oncology, Third Edition codes C67.0-C67.9), in the National Cancer Data Base (NCDB), we identified 788 patients who received NAC and RC followed by AC or observation for pT3/T4 and/or pN+ UCB (eFigure 1 in the Supplement). First, multiple imputation using chained equations was performed to handle missing data that were assumed to be missing at random for all covariates; we generated 15 imputed data sets by using a sequential regression method. In all subsequent analyses, Rubin’s rules were applied to summarize the effect estimates and variances from the 15 different analyses across multiple imputed data sets. Second, to account for selection bias, observed differences in baseline characteristics between the 2 groups were controlled for with inverse probability of treatment weighting (IPTW)–adjusted analyses. The goodness-of-fit statistic of the propensity score model, including linear or nonlinear covariates categorized with clinically relevant cutoffs, was assessed using the method described by Lemeshow and Hosmer. Covariate balance was evaluated by using the standardized differences approach and Kernel density plots. Third, to account for immortal-time bias, summary 6-month conditional landmark, IPTW-adjusted Kaplan-Meier curves were calculated to compare overall survival between patients who received NAC and RC followed by AC vs observation. We further fitted an IPTW-adjusted Cox proportional hazards regression model to compute the corresponding hazard ratios (HRs). A post hoc power analysis was performed to evaluate our ability to detect an association between treatment and overall survival. Fourth, we conducted exploratory analyses to examine heterogeneity of treatment effect according to age (continuous), sex (female vs male), Charlson comorbidity index (≥1 vs 0), pT/N stage (pT3/T4N0 vs pTanyN+), and surgical margin status (positive vs negative) by testing interaction terms within the IPTW-adjusted Cox proportional hazards regression model. A waiver was obtained before the study was conducted from the Brigham and Women's Hospital, Harvard Medical School, Institutional Review Board in accordance with institutional regulation when dealing with deidentified, previously collected data.
All statistical analyses were performed using STATA software, version 14.0 (StataCorp) (eAppendix in the Supplement). Two-sided statistical significance was defined as P < .05.
Results
Patient Characteristics
Of the 788 patients with pT3/T4 and/or pN+ UCB (mean [SD] age, 65.3 [9.4] years; 603 [76.5%] male and 185 [23.5%] female), 184 (23.4%) received NAC and RC followed by AC and 604 (76.6%) received NAC and RC followed by observation (eFigure 1 in the Supplement). Unweighted and weighted baseline characteristics of eligible patients, stratified according to the receipt of NAC and RC followed by AC vs observation, are reported in Table 1. Standardized differences of unweighted comparisons showed that both treatment groups differed significantly with respect to most clinical, socioeconomic, demographic, and tumor characteristics of interest.
Table 1. Baseline Characteristics of the Study Patients .
| Characteristic | Unweighted Study Populationa | Standardized Difference, % | Weighted Study Populationb | Standardized Difference, % | ||||
|---|---|---|---|---|---|---|---|---|
| Overall (n = 788) |
Adjuvant Chemotherapy (n = 184) |
Observation (n = 604) |
Overall | Adjuvant Chemotherapy | Observation | |||
| Age, mean (SD), y | 65.3 (9.4) | 62.7 (9.9) | 66.1 (9.1) | −34.9 | 65.4 (9.5) | 65.7 (10.0) | 65.3 (9.3) | 5.0 |
| Sex | ||||||||
| Male | 603 (76.5) | 139 (75.5) | 464 (76.8) | 3.0 | 76.4 | 75.8 | 76.6 | 1.9 |
| Female | 185 (23.5) | 45 (24.5) | 140 (23.2) | 23.6 | 24.2 | 23.4 | ||
| Race | ||||||||
| White | 727 (92.3) | 171 (92.9) | 556 (92.1) | −2.9 | 92.1 | 91.4 | 92.3 | 2.2 |
| Black | 42 (5.3) | 9 (4.9) | 33 (5.5) | 5.6 | 6.5 | 5.4 | ||
| Other | 19 (2.4) | 4 (2.2) | 15 (2.4) | 2.3 | 2.1 | 2.3 | ||
| CCI | ||||||||
| 0 | 588 (74.6) | 143 (77.7) | 445 (73.7) | −9.1 | 74.6 | 75.0 | 74.5 | −0.6 |
| 1 | 165 (20.9) | 34 (18.5) | 131 (21.7) | 20.8 | 20.3 | 21.0 | ||
| ≥2 | 35 (4.5) | 7 (3.8) | 28 (4.6) | 4.6 | 4.7 | 27.5 | ||
| Insurance type | ||||||||
| Private | 310 (39.4) | 80 (44.0) | 230 (38.0) | −15.6 | 39.8 | 41.5 | 39.3 | −5.1 |
| Medicaid or other government | 48 (6.1) | 18 (9.5) | 30 (5.0) | 6.3 | 6.4 | 6.2 | ||
| Medicare | 405 (51.4) | 78 (42.7) | 327 (54.1) | 50.9 | 49.5 | 51.4 | ||
| No insurance | 25 (3.1) | 8 (3.8) | 17 (2.9) | 3.0 | 2.6 | 3.1 | ||
| Income level | ||||||||
| High | 498 (63.2) | 114 (62.1) | 384 (63.6) | 3.0 | 63.8 | 65.4 | 63.4 | −4.1 |
| Low | 290 (36.8) | 70 (37.9) | 220 (36.4) | 36.2 | 34.6 | 36.6 | ||
| Educational level | ||||||||
| High | 501 (63.6) | 124 (67.6) | 377 (62.4) | −11.0 | 63.2 | 61.9 | 63.6 | 3.6 |
| Low | 287 (36.4) | 60 (32.4) | 227 (37.6) | 36.8 | 38.1 | 36.4 | ||
| County type | ||||||||
| Metro | 640 (81.2) | 140 (76.0) | 500 (82.8) | 15.3 | 45.4 | 48.1 | 44.6 | 0.4 |
| Urban | 129 (16.3) | 39 (21.1) | 90 (14.9) | 39.4 | 37.0 | 40.1 | ||
| Rural | 19 (2.5) | 5 (2.9) | 14 (2.3) | 15.2 | 14.9 | 15.3 | ||
| Facility type | ||||||||
| Academic | 527 (66.8) | 99 (53.8) | 428 (70.8) | 35.7 | 67.5 | 68.9 | 67.1 | −3.8 |
| Nonacademic | 261 (33.2) | 85 (46.2) | 176 (29.2) | 32.5 | 31.1 | 32.9 | ||
| Facility location | ||||||||
| East | 350 (44.4) | 70 (37.8) | 280 (46.4) | 20.3 | 81.1 | 80.8 | 81.2 | −5.4 |
| Center | 316 (40.2) | 77 (42.1) | 239 (39.6) | 16.5 | 17.1 | 16.3 | ||
| West | 122 (15.4) | 37 (20.1) | 85 (14.0) | 2.4 | 2.1 | 2.5 | ||
| Year of diagnosis | ||||||||
| 2006 | 46 (5.8) | 11 (6.0) | 35 (5.8) | 0.7 | 5.7 | 5.9 | 5.6 | −4.7 |
| 2007 | 63 (8.0) | 15 (8.1) | 48 (7.9) | 8.5 | 8.8 | 8.5 | ||
| 2008 | 105 (13.3) | 20 (10.9) | 85 (14.1) | 13.0 | 10.4 | 13.9 | ||
| 2009 | 152 (19.3) | 39 (21.2) | 113 (18.7) | 20.2 | 25.0 | 18.7 | ||
| 2010 | 137 (17.4) | 33 (17.9) | 104 (17.2) | 17.4 | 18.2 | 17.1 | ||
| 2011 | 134 (17.0) | 32 (17.4) | 102 (16.9) | 16.7 | 15.0 | 17.2 | ||
| 2012 | 151 (19.2) | 34 (18.5) | 117 (19.4) | 18.5 | 16.7 | 19.1 | ||
| Pathologic stage | ||||||||
| pT3N0 | 314 (39.5) | 50 (27.2) | 264 (43.7) | 37.3 | 40.1 | 40.8 | 39.9 | −1.5 |
| pT4N0 | 114 (15.0) | 26 (14.1) | 88 (14.6) | 14.2 | 13.7 | 14.3 | ||
| pTanyN+ | 360 (45.5) | 108 (58.7) | 252 (41.7) | 45.7 | 45.5 | 45.8 | ||
| Surgical margins | ||||||||
| Negative | 656 (83.2) | 153 (83.1) | 503 (83.3) | 0.5 | 83.1 | 82.9 | 83.2 | 0.7 |
| Positive | 132 (16.8) | 31 (16.9) | 101 (16.7) | 16.9 | 17.1 | 16.8 | ||
Abbreviation: CCI, Charlson comorbidity index.
Data are presented as number (percentage) of patients unless otherwise indicated.
Data are presented as percentage of patients unless otherwise indicated.
Determinants of Receiving NAC and RC Followed by AC vs Observation
Results of multivariable logistic regression analysis determining the receipt of NAC and RC followed by AC vs observation with adequate goodness of fit are reported in Table 2. The odds of receiving NAC and RC followed by AC vs observation remained stable over time (annual percentage change, 0.00%; 95% CI, −0.02 to 0.02%; P = .93) (eFigure 2 in the Supplement).
Table 2. Multivariable Logistic Regression Model Determining the Receipt of Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs Observation .
| Variable | OR (95% CI) | P Value |
|---|---|---|
| Age at initial diagnosis | 0.97 (0.94-0.99) | .005 |
| Sex | ||
| Male | 1 [Reference] | NA |
| Female | 1.19 (0.79-1.81) | .40 |
| Race | ||
| White | 1 [Reference] | NA |
| Black | 0.98 (0.43-2.26) | .97 |
| Other | 0.97 (0.30-3.20) | .96 |
| Charlson comorbidity index | ||
| 0 | 1 [Reference] | NA |
| 1 | 0.92 (0.58-1.45) | .72 |
| ≥2 | 1.08 (0.44-2.67) | .87 |
| Insurance type | ||
| Private | 1 [Reference] | NA |
| Medicaid/other government | 1.57 (0.78-3.19) | .21 |
| Medicare | 0.98 (0.61-1.58) | .94 |
| No insurance | 1.01 (0.39-2.64) | .99 |
| Income level | ||
| High | 1 [Reference] | NA |
| Low | 0.93 (0.57-1.51) | .78 |
| Educational level | ||
| High | 1 [Reference] | NA |
| Low | 0.72 (0.47-1.12) | .15 |
| County type | ||
| Metro | 1 [Reference] | NA |
| Urban | 1.81 (1.06-3.10) | .03 |
| Rural | 1.57 (0.48-5.11) | .45 |
| Facility type | ||
| Academic | 1 [Reference] | NA |
| Nonacademic | 2.12 (1.48-3.05) | <.001 |
| Facility location | ||
| East | 1 [Reference] | NA |
| Center | 1.20 (0.80-1.78) | .38 |
| West | 1.72 (1.04-2.85) | .04 |
| Year of diagnosis | 1.01 (0.92-1.11) | .78 |
| Pathologic stage | ||
| pT3N0 | 1 [Reference] | NA |
| pT4N0 | 1.46 (0.83-2.57) | .19 |
| pTanyN+ | 2.25 (1.51-3.35) | <.001 |
| Surgical margins | ||
| Negative | 1 [Reference] | NA |
| Positive | 0.86 (0.53-1.39) | .54 |
Abbreviations: NA, not applicable; OR, odds ratio.
Treatment Effect of NAC and RC Followed by AC vs Observation
After IPTW adjustment, all standardized differences were less than 10%, which indicated that patients who received NAC and RC followed by AC vs observation were subsequently comparable (eFigure 3 in the Supplement). Propensity score distribution between the treatment groups achieved adequate balance after IPTW adjustment (eFigure 4A and B in the Supplement).
The median follow-up in the weighted population was 45.7 months (interquartile range [IQR], 31.2-67.8 months). The 6-month conditional landmark, IPTW-adjusted Kaplan-Meier curves (Figure) showed that median overall survival was significantly longer for NAC and RC followed by AC (29.9 months; IQR, 15.1-85.4 months) vs observation (24.2 months; IQR, 12.9-58.9 months) (P = .046). The 5-year IPTW-adjusted rates of overall survival were 36.8% for NAC and RC followed by AC vs 24.7% for NAC and RC followed by observation. In IPTW-adjusted Cox proportional hazards regression analysis, NAC and RC followed by AC was associated with a significant overall survival benefit (HR, 0.78; 95% CI, 0.61-0.99; P = .046).
Figure. Six-Month Conditional Landmark Inverse Probability of Treatment Weighting–Adjusted Kaplan-Meier Analysis of Overall Survival for Patients Who Received Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs Observation for pT3/T4 and/or pN+ Urothelial Carcinoma of the Bladder.
Data are weighted proportions and not absolute numbers.
The post hoc power calculation showed that we had adequate power to detect a clinically significant HR. Specifically, with our sample size of 788 patients, we had 80% power with a 5% significance level to detect an HR of 0.78 for NAC and RC followed by AC vs observation using a log-rank test (20% alive in the observation group at the end of the study).
Interaction term analyses indicated that the overall survival benefit of NAC and RC followed by AC decreased significantly with age (HR, 0.97; 95% CI, 0.95-0.99; P = .02), whereas no significant interaction was observed with sex (P = .82), Charlson comorbidity index (P = .51), pT/N stage (P = .95), and surgical margin status (P = .29).
Discussion
Although evidence supporting the role of AC for advanced UCB treated with RC is contentious, the use of a cisplatin-based regimen is generally advocated in sufficiently healthy individuals who did not receive NAC before surgery. However, less is known about the association of AC with survival among patients with pT3/T4 and/or pN+ UCB who received NAC and RC. As such, we sought to investigate the role of this treatment strategy in a large NCDB sample that included nearly 800 individuals. Of interest, with a median follow-up of approximately 4 years, our IPTW-adjusted analysis showed a significant overall survival benefit for AC when adverse pathologic features are found after NAC and RC. Specifically, individuals who received AC were more than 20% less likely to die of any cause after NAC and RC compared with their observation counterparts; this translated into a 5-month overall survival benefit.
To our knowledge, the present study represents the first sizeable comparative effectiveness assessment of AC after NAC and RC. Indeed, the only observational report in the literature included 80 patients with pT3/T4 and/or pN+ disease after NAC and RC, 29 of whom further received AC that was not independently associated with recurrence-free or cancer-specific survival. However, that analysis had limited power to detect a significant benefit, especially after adjusting for potential confounders in multivariable models.
Limitations
Our results need to be interpreted within the limitations of the observational study design. Of note, the present analyses are subject to selection bias, which we attempted to correct by using an IPTW-adjusted approach. Nonetheless, several unmeasured confounders, including performance status or renal function, may have affected the receipt of NAC and RC followed by AC vs observation in this study. In addition, the detailed chemotherapy regimen administered at the time of NAC or AC as well as the completeness and number of chemotherapy cycles in both contexts are not recorded in the NCDB; as a result, we could not comment on the specific treatment sequence that would provide the greatest overall survival benefit. That said, from a biological perspective, it may be appropriate to sequentially deliver different combination regimens with complementary cytotoxic effects to target different cell populations in the primary tumor.
Conclusions
To summarize, we observed that AC after NAC and RC was associated with an overall survival benefit for pT3/T4 and/or pN+ UCB. The present findings should be considered as preliminary evidence to conduct a randomized clinical trial to address this association.
eFigure 1. Flowchart Describing the Selection of Patients Who Received Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs observation for pT3/T4 and/or pN+ Urothelial Carcinoma of the Bladder in the National Cancer Data Base (2006-2012)
eFigure 2. Utilization of Adjuvant Chemotherapy vs Observation in Patients With pT3/T4 and/or pN+ Urothelial Carcinoma of the Bladder Who Received Neoadjuvant Chemotherapy and Radical Cystectomy
eFigure 3. Effect of Inverse Probability of Treatment Weighting Adjustment on the Baseline Characteristics Distribution of Patients Who Received Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs Observation for pT3/T4 and/or pN+ Urothelial Carcinoma of the Bladder
eFigure 4. Kernel Density Plots Showing the Distribution of Propensity Scores in the Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs Observation Groups Before (A) and After (B) Inverse Probability of Treatment Weighting Adjustment
eAppendix. Stata Codes for the National Cancer Data Base (2006-2012) Analysis of the Comparative Effectiveness of Adjuvant Chemotherapy vs Observation in Patients With Adverse Features at Radical Cystectomy Who Previously Received Neoadjuvant Chemotherapy for Muscle-Invasive Urothelial Carcinoma of the Bladder
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Associated Data
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Supplementary Materials
eFigure 1. Flowchart Describing the Selection of Patients Who Received Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs observation for pT3/T4 and/or pN+ Urothelial Carcinoma of the Bladder in the National Cancer Data Base (2006-2012)
eFigure 2. Utilization of Adjuvant Chemotherapy vs Observation in Patients With pT3/T4 and/or pN+ Urothelial Carcinoma of the Bladder Who Received Neoadjuvant Chemotherapy and Radical Cystectomy
eFigure 3. Effect of Inverse Probability of Treatment Weighting Adjustment on the Baseline Characteristics Distribution of Patients Who Received Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs Observation for pT3/T4 and/or pN+ Urothelial Carcinoma of the Bladder
eFigure 4. Kernel Density Plots Showing the Distribution of Propensity Scores in the Neoadjuvant Chemotherapy and Radical Cystectomy Followed by Adjuvant Chemotherapy vs Observation Groups Before (A) and After (B) Inverse Probability of Treatment Weighting Adjustment
eAppendix. Stata Codes for the National Cancer Data Base (2006-2012) Analysis of the Comparative Effectiveness of Adjuvant Chemotherapy vs Observation in Patients With Adverse Features at Radical Cystectomy Who Previously Received Neoadjuvant Chemotherapy for Muscle-Invasive Urothelial Carcinoma of the Bladder