Dataset Information

Impact of Adjuvant Chemotherapy on Survival of Patients with Advanced Residual Disease at Radical Cystectomy following Neoadjuvant Chemotherapy: Systematic Review and Meta-Analysis.

ABSTRACT:

Background

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with pelvic lymph-node dissection is the standard treatment for cT2-4a cN0 cM0 muscle-invasive bladder cancer (MIBC). Despite the significant improvement of primary-tumor downstaging with NAC, up to 50% of patients are eventually found to have advanced residual disease (pT3-T4 and/or histopathologically confirmed nodal metastases (pN+)) at RC. Currently, there is no established standard of care in such cases. The aim of this systematic review and meta-analysis was to assess differences in survival rates between patients with pT3-T4 and/or pN+ MIBC who received NAC and surgery followed by adjuvant chemotherapy (AC), and patients without AC.

Materials and methods

A systematic search was conducted in accordance with the PRISMA statement using the Medline, Embase, and Cochrane Library databases. The last search was performed on 12 November 2020. The primary end point was overall survival (OS) and the secondary end point was disease-specific survival (DSS).

Results

We identified 2124 articles, of which 6 were selected for qualitative and quantitative analyses. Of a total of 3096 participants in the included articles, 2355 (76.1%) were in the surveillance group and 741 (23.9%) received AC. The use of AC was associated with significantly better OS (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75-0.94; p = 0.002) and DSS (HR 0.56, 95% CI 0.32-0.99; p = 0.05). Contrary to the main analysis, in the subgroup analysis including only patients with pN+, AC was not significantly associated with better OS compared to the surveillance group (HR 0.89, 95% CI 0.58-1.35; p = 0.58).

Conclusions

The administration of AC in patients with MIBC and pT3-T4 residual disease after NAC might have a positive impact on OS and DSS. However, this may not apply to N+ patients.

SUBMITTER: Krajewski W

PROVIDER: S-EPMC7915645 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Impact of Adjuvant Chemotherapy on Survival of Patients with Advanced Residual Disease at Radical Cystectomy following Neoadjuvant Chemotherapy: Systematic Review and Meta-Analysis.

Krajewski Wojciech W Nowak Łukasz Ł Moschini Marco M Poletajew Sławomir S Chorbińska Joanna J Necchi Andrea A Montorsi Francesco F Briganti Alberto A Sanchez-Salas Rafael R Shariat Shahrokh F SF Palou Juan J Babjuk Marek M Teoh Jeremy Yc JY Soria Francesco F Pradere Benjamin B Ornaghi Paola Irene PI Pawlak Aleksandra A Dembowski Janusz J Zdrojowy Romuald R

Journal of clinical medicine 20210208 4

<h4>Background</h4>Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with pelvic lymph-node dissection is the standard treatment for cT2-4a cN0 cM0 muscle-invasive bladder cancer (MIBC). Despite the significant improvement of primary-tumor downstaging with NAC, up to 50% of patients are eventually found to have advanced residual disease (pT3-T4 and/or histopathologically confirmed nodal metastases (pN+)) at RC. Currently, there is no established standard of care ...[more]

PMID: 33567656

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Project description:ImportanceDespite 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.ObjectiveTo 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 participantsThis 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 measuresAfter 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.ResultsOf 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 relevanceThis 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.

Project description:Introduction and objectiveMuscle invasive bladder cancer with extravesical extension is an aggressive disease entity that requires multimodal therapy. The benefits of adjuvant chemotherapy (AC) in patients with a positive soft-tissue surgical margin (STSM), however, are relatively unknown due to exclusion of this population in randomized controlled trials of AC. We sought to define survival benefits in this patient population through our institutional bladder cancer database.MethodsRetrospective review of all patients undergoing radical cystectomy for urothelial carcinoma of the bladder from 2004-2020 with ≥pT3b disease irrespective of neoadjuvant chemotherapy (NAC) use was conducted. Progression-free survival (PFS) and overall survival (OS) estimates were obtained using the Kaplan-Meier method with log-rank test, and the Cox-proportional hazards model was used to identify predictors of improved PFS and OS. AC was defined by any chemotherapy use within 90 days of cystectomy, regardless of STSM status.Results476 patients with pT3b disease or worse were identified. Median follow-up was 12.3 months. An amount of 21% of patients were treated with AC. An amount of 24% of patients had positive STSM. Median OS for patients with positive STSM was 8.4 months [95% CI 7-11.5] and 18.3 months [95% CI 15.6-20.8] (p < 0.001) for patients with negative STSM. In the overall cohort, positive STSM (HR 1.93, 95% CI 1.45-2.57, p < 0.001), AC use (HR 0.68, 95% CI 0.51-0.90, p = 0.007), and pN1-3 disease (HR 1.47, 95% CI 1.16-1.87, p = 0.002) were independent predictors of OS when adjusted for performance status, pT-stage, and neoadjuvant chemotherapy use. In patients with positive STSM, median survival was seven months [95% CI 5.2-8.4] without AC, compared to 16.2 months [95% CI 11.5-52.5] with AC (p = 0.0038). For patients with negative STSM, median survival was 17.4 months [95% CI 14-20.1] without AC compared to 22.3 months [95% CI 17.2-36.9] with AC (p = 0.23). In patients with positive STSM, AC use was the only factor associated with an OS benefit with a HR of 0.41 (95% CI 0.21-0.78, p = 0.007). In patients with negative STSM, pT4 and pN1-3 disease were the only factors associated with worse overall survival with a HR of 1.32 (95% CI 1.00-1.74, p = 0.050) and 1.97 (95% CI 1.49-2.60, p < 0.001), respectively.ConclusionsAdministration of adjuvant chemotherapy is of particular benefit in patients with positive STSM following radical cystectomy for gross extravesical disease. Positive STSM may be a representative of "early metastatic" or micrometastatic disease.

Project description:Importance:Locoregional failure for patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity and mortality. Adjuvant radiotherapy (RT) can decrease locoregional failure but has not been studied in the chemotherapy era. Objective:To investigate if adjuvant sequential RT plus chemotherapy can improve locoregional recurrence-free survival (LRFS) compared with adjuvant chemotherapy alone. Design, Setting, and Participants:A randomized phase 3 trial was opened to compare adjuvant RT vs sequential chemotherapy plus RT after RC for LABC, but a third arm was added later as a randomized phase 2 trial to compare chemotherapy plus RT vs adjuvant chemotherapy alone, an emerging standard. The intent-to-treat phase 2 trial reported herein enrolled patients from December 2002 to July 2008. Data were analyzed from August 3, 2015, to January 6, 2016. Routine follow-up and surveillance pelvic computed tomographic (CT) scans every 6 months during the first 2 years were performed. The setting was an academic center. Patients with bladder cancer 70 years or younger having 1 or more risk factors (≥pT3b, grade 3, or positive nodes) with negative margins after radical cystectomy plus pelvic lymph node dissection were eligible. Patients had Eastern Cooperative Oncology Group performance status of 0 to 2, no evidence of distant metastases on CT scan of the abdomen and pelvis or on chest imaging, and adequate renal, hepatic, and hematologic function. Ninety-one percent (109 of 120) had ≥ pT3 disease. Interventions:Chemotherapy plus RT included 2 cycles of gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15) and cisplatin (70 mg/m2 intravenously on day 2) before and after RT to 4500 cGy in 150 cGy twice-daily fractions over 3 weeks using 3-dimensional conformal techniques. Chemotherapy alone included 4 cycles of gemcitabine and cisplatin. Main Outcome and Measure:Locoregional recurrence-free survival. Results:The chemotherapy plus RT arm accrued 75 patients, and the chemotherapy-alone arm accrued 45 patients, with a weighted randomization to speed accrual. Fifty-three percent (64 of 120) had urothelial carcinoma, and 46.7% (56 of 120) had squamous cell carcinoma or other. The arms were balanced except for age (median, 52 vs 55 years; P = .04) and tumor size (mean, 4.9 vs 5.8 cm; P < .01), both favoring chemotherapy plus RT. Two-year outcomes and overall adjusted hazard ratios (HRs) for chemotherapy plus RT vs chemotherapy alone were 96% vs 69% (HR, 0.08; 95% CI, 0.02-0.39; P < .01) for LRFS, 68% vs 56% (HR, 0.53; 95% CI, 0.27-1.06; P = .07) for disease-free survival, and 71% vs 60% (HR, 0.61; 95% CI, 0.33-1.11; P = .11) for overall survival (OS). Five patients (7%) had RT-associated late grade 3 gastrointestinal tract adverse effects in the chemotherapy plus RT arm. Conclusions and Relevance:Adjuvant chemotherapy plus RT was reasonably well tolerated and was associated with significant improvements in LRFS and marginal improvements in disease-free survival vs chemotherapy alone in LABC. The addition of adjuvant RT should be considered for LABC. This regimen warrants further study in phase 3 trials. Trial Registration:clinicaltrials.gov Identifier: NCT01734798.

Dataset Information

Impact of Adjuvant Chemotherapy on Survival of Patients with Advanced Residual Disease at Radical Cystectomy following Neoadjuvant Chemotherapy: Systematic Review and Meta-Analysis.

Background

Materials and methods

Results

Conclusions

Publications

Impact of Adjuvant Chemotherapy on Survival of Patients with Advanced Residual Disease at Radical Cystectomy following Neoadjuvant Chemotherapy: Systematic Review and Meta-Analysis.

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