Incidence, Patterns, and Outcomes with Adjuvant Chemotherapy for Residual Disease After Neoadjuvant Chemotherapy in Muscle-invasive Urinary Tract Cancers

Abstract

Background: Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence.

Objective: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC.

Design, setting, and participants: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN⁺).

Outcome measurements and statistical analysis: Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses.

Results and limitations: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: <1-108mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10mo, p=0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p=0.01). The subgroup analyses of ypT4b/ypN⁺ patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9mo; hazard ratio 0.43; 95% confidence interval: 0.21-0.89). No difference in OS was found. Limitations include the retrospective design.

Conclusions: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials.

Patient summary: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system.

Keywords: Adjuvant chemotherapy; Muscle-invasive bladder cancer; Muscle-invasive urinary tract cancer; Neoadjuvant chemotherapy; Residual disease; Risk of relapse; Time to recurrence.

Fig. 1 –

Most frequently administered chemotherapeutic regimens in the neoadjuvant setting with the corresponding adjuvant therapy. Each line represents one patient’s pathway. Carbo = carboplatin; ddMVAC = dose-dense methotrexate-vinblastine-adriamycin-cisplatin; GC = gemcitabine-cisplatin; MVAC = methotrexate-vinblastine-adriamycin-cisplatin.

Fig. 2 –

Time to relapse (TTR) in patients with adverse residual disease (ypT3-4 and/or ypN+) despite neoadjuvant chemotherapy based on adjuvant chemotherapy use. (A) Patients with ypT3-4 and/or ypN+ residual disease. (B) Patients with ypT4b and/or ypN+ residual disease. Kaplan-Meier curves represent crude survival estimates. AC = adjuvant chemotherapy; NAC = neoadjuvant chemotherapy; Obs = observation. ^a Multivariable analyses were adjusted for pathological stage (stage III and stage IV disease), type of NAC (cisplatin based, carboplatin based, and other regimens), and age.

Fig. 3 –

Overall survival (OS) by use of adjuvant chemotherapy. Kaplan-Meier curves represent crude survival estimates. AC = adjuvant chemotherapy; NAC = neoadjuvant chemotherapy; Obs = observation. ^a Multivariable analyses were adjusted for pathological stage (stage III and stage IV disease), type of NAC (cisplatin-based and carboplatin-based and other regimens), and age.