Dr. Ribal began by highlight the European Association of Urology (EAU) Guidelines on muscle-invasive and metastatic bladder cancer which state that adjuvant radiotherapy should be offered when no neoadjuvant chemotherapy has been given and patients have pT3, pT4, or pN+ disease. She highlighted that the National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), and European Society for Medical Oncology (ESMO) guidelines provide similar guidance.
She then highlighted data from the EORTC 30994 trial, Comparison of Immediate and Delayed Adjuvant Chemotherapy in Treating Patients Who Have Undergone a Radical Cystectomy for Stage III or Stage IV Transitional Cell Carcinoma of the Bladder Urothelium (EORTC 30994), which showed a significant improvement in progression-free survival for patients with pT3-pT4 or pN+ bladder cancer who received immediate (adjuvant), versus deferred, chemotherapy with a hazard ratio of 0.54 (95% confidence interval 0.4 to 0.73) but notably without a significant improvement in overall survival (hazard ratio 0.78, 95% confidence interval 0.56 to 1.08). However, she emphasized that this trial was limited in power and there may be subgroups of patients who benefit. To this end, she highlighted observational data in a similar patient population demonstrating that 5-year overall survival was significantly higher among patients who received adjuvant chemotherapy (37%) as compared to those who underwent observation (29%; hazard ratio 0.70, 95% confidence interval 0.64 to 0.76). However, adjuvant chemotherapy use was poor (23%) in this group, raising concerns for selection biases.
She then highlighted relatively recent data from Dr. Berg and colleagues utilizing the NationalCancer database which demonstrated an overall survival benefit to the use of adjuvant chemotherapy for patients with urothelial histology but not for those with concomitant variant histology or pure variant histology. These data suggest potential subsets of patients who we should focus on the use of adjuvant therapy.
Examining rationales for the use of adjuvant, as compared to neoadjuvant approaches, Dr. Ribal highlighted the potential for perioperative morbidity on account of the receipt of neoadjuvant therapy. However, the available data to date does not support an increased risk based on this approach. In contrast, surgical complications may delay the ability (or completely preclude) the ability to provide adjuvant chemotherapy.
Synthesizing these data, she presented results of a 2013 systematic review and meta-analysis published in European Urology assessing the role of adjuvant chemotherapy. These data are limited by small sample size and between-study heterogeneity.
In addition to chemotherapy, radiotherapy has been suggested as an adjuvant modality following radical cystectomy. Dr. Ribal highlighted data from the National Cancer Data Base which examined patients who received neoadjuvant chemotherapy followed by cystectomy. Of 1646 included patients, 59 (3.6%) received adjuvant radiotherapy while the remainder were observed. This report demonstrated no survival advantage in the overall population though suggested the potential for benefit among those with positive surgical margins. However, prospective studies are needed to validate this approach.
Transitioning back to systemic therapy, Dr. Ribal highlighted emerging data on adjuvant immunotherapy, including the IMvigor 010 trial, a phase III trial of adjuvant atezolizumab versus observation in patients with high-risk muscle-invasive bladder cancer (MIBC). This trial failed to demonstrate a difference in disease-free survival with a median DFS among those receiving atezolizumab of19 months compared with 17 months among those observed.
She then highlighted data from many disease sites, including hormone receptor-positive breast cancer, high-risk kidney cancer, colon cancer, and prostate cancer in which adjuvant therapies have failed to provide a survival benefit. This is particularly true in the urologic world.
Dr. Ribal then suggested that, instead of trying new agents in the adjuvant setting, we should stop and consider what may be wrong with this approach: for example, suggesting that the use of adjuvant therapy may predispose to poorer response to chemotherapy at the time of disseminated disease. Thus, failure to improve overall survival with the use of adjuvant approaches suggests that we should perhaps withhold these therapies until more advanced disease is present given the known, and predictably common, toxicities of these agents.
Presented By: Maria J. Ribal, MD, Ph.D., Associate Professor of Urology, the University of Barcelona, Barcelona, Spain
Written By: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC) (#EMUC20 ), November 13th - 14th, 2020