Patients with muscle invasive bladder cancer have at best 50% overall survival depending upon their pathological stage and lymph node status. However, despite the progress made with the use of cisplatin-based combination chemotherapy in metastatic disease, chemotherapy is seldom used for infiltrating bladder cancer in the pre and post-cystectomy settings.
Clinical trials have been fraught with difficulties. There is currently more evidence available from randomised clinical trials in favor of upfront, neoadjuvant chemotherapy. In the adjuvant post-operative setting, many clinical trials have been closed early due to poor accrual. Due to the methodological issues in many of the studies in the peri-operative setting, the only conclusions that can be drawn are from meta-analyses combining the results of randomised trials.
Neo-adjuvant chemotherapy trials in bladder cancer
Results of a recently published EORTC-MRC neoadjuvant randomized clinical trial will be highlighted. Prior meta-analysis of Phase III randomised trials with cisplatin-based combination chemotherapy has suggested a 5% benefit for cisplatin-based chemotherapy in the neo-adjuvant setting.
Nonetheless, most patients are not offered chemotherapy prior to surgery. When presented with the all too common upstaging and/or more definitive evidence of risk of relapse in the surgical pathology report, many clinicians and patients have preferred post-operative treatment despite deficiencies in evidence to support this approach.
Adjuvant chemotherapy trials
A meta-analysis demonstrated a benefit with adjuvant cisplatin combination chemotherapy. The analysis is somewhat difficult to interpret, as there were only 491 patients from six randomised controlled trials. The overall hazard ratio for survival of 0.75 (95%CI 0.60-0.96, p=0.019) suggested a 25% relative reduction in the risk of death for chemotherapy compared to control.
Since this analysis, four additional phase III studies have been closed: the Spanish Oncology Genitourinary Group SOGUG 99/01 trial, a CALGB trial, an Italian Multicenter study and EORTC trial 30994. These trials have all suffered from poor accrual, but may contribute when examined prospectively together in the future.
Most recently, a large cohort analysis assessing the effect of adjuvant chemotherapy from several large centers suggested the greatest impact of adjuvant chemotherapy is seen in patients with extravesical extension or N+ disease.
The body of evidence supports the use of perioperative chemotherapy; however, the best evidence is currently in favor of neoadjuvant rather than adjuvant therapy. Several studies have suggested a 5-15% absolute advantage for chemotherapy in the post-operative setting.
Given the small incremental benefit to adjuvant chemotherapy, the demonstration of a survival advantage may require a trial with more patients unless patients accrued can be stratified for risk benefit by clinical or pathological parameters, and/or biomarkers predictive of relapse risk and/or chemotherapy benefit.
The optimal timing and intensity of chemotherapy in the adjuvant setting remains to be determined. Accrual to trials of adjuvant therapy in urothelial cancer represents a major challenge. A formal meta-analysis including the recent adjuvant trials will be of great interest.
Saturday, 25 February
10.00-14.00: Joint Meeting of the European Organisation for Research and Treatment of Cancer Genito-Urinary Group (EORTC-GU Group), the EAU Section of Urological Research (ESUR), the EAU Section of Oncological Urology (ESOU) and the EAU Section of Uropathology (ESUP)
Current issues in prostate, renal and bladder cancer