CHICAGO, IL USA (UroToday.com) - This study is an update on an EORTC intergroup phase III randomized controlled clinical trial of the effectiveness of immediate adjuvant chemotherapy, when used in patients with muscle-invasive bladder cancer, treated with radical cystectomy. The study question is of particular clinical importance as many patients with clinical T2N0 urothelial carcinoma are upstaged at the time of cystectomy, due to unexpected lymph node involvement or the presence of T3 or T4 disease on pathologic evaluation. It is of additional importance as multiple other studies aiming to answer the question of the value of adjuvant chemotherapy in this population have not been able to meet accrual goals.
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In this investigation, Dr. Cora Sternberg and the EORTC investigators sought to determine whether immediate adjuvant chemotherapy prolongs overall and progression-free survival as compared to delayed palliative chemotherapy for metastatic disease. They enrolled patients with pT3 or pT4 and/or N+ M0 transitional cell carcinoma of the bladder (no pure squamous or adenocarcinoma histology, no microscopic residual disease) within 90 days after undergoing radical cystectomy. All patients had WHO performance status 0-1 and GFR > 60 mL/min. Patients were randomized to receive 4 cycles of chemotherapy (regimen per preference of the treating physician; either gemcitabine and cisplatin (GC), methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), or high-dose MVAC), or 6 cycles of chemotherapy (same options for regimen) at the time of relapsed disease. The primary endpoint of the study was overall survival (OS), and progression-free survival (PFS) was a secondary endpoint. The results of the study were evaluated via intention-to-treat, and the investigators used Cox models stratified by primary treatment center, stage (pT1T2 versus pT3T4), and nodal status (lymph node positive (with or without adequate lymph node dissection) versus lymph node negative) to compare overall survival and progression-free survival between groups.
Like other studies attempting to evaluate adjuvant treatment for patients with high-risk urothelial cancer, this trial failed to meet accrual goals. Of 660 patients planned to meet the pre-specified statistical threshold for interpretation, only 284 (43% of planned) patients were enrolled in the study. The trial included patients from 63 sites in 13 countries, and enrollment occurred from April 2002 through August 2008. During that period, two interim analyses by the data safety monitoring board took place, and the second ordered closure of the study due to poor accrual. Despite premature closure, follow-up continued for 5 years until August 2013.
Baseline patient characteristics reflect appropriate randomization and were well-balanced between the treatment groups (immediate versus delayed chemotherapy). The median age was 61 years, and patients had similar pT stage and nodal status. In total, 70% of patients enrolled had lymph node involvement. The majority (> 84% of each group) was treated with GC chemotherapy.
Overall 62% of participants progressed or died during the study, including 51.8% in the immediate treatment group, and 72% in the deferred treatment group. Median and 5-year progression-free survival varied significantly between groups (2.9 years and 48.8% on immediate treatment and 0.9 years and 29.5% on deferred treatment). Median and 5-year overall survival was 6.8 years and 53.6% on the immediate and 4.6 years and 47.7% on the deferred treatment arm, though this difference failed to meet significance.
In terms of toxicity, there were several grade 3/ 4 adverse events in the immediate arm. These included the following:
- myelosuppression (26%),
- neutropenia (38%), and
- thrombocytopenia (28%).
This study is the largest randomized, controlled phase three study of adjuvant chemotherapy for high-risk muscle-invasive bladder cancer that has been reported. Although it did not reach pre-specified accrual goal or significance in terms of overall survival benefit, the study demonstrates a significant progression-free survival advantage with immediate rather than delayed chemotherapy. The importance of the clinical question of the utility of adjuvant chemotherapy in this population makes this study relevant and immediately useful in routine practice. Clinicians who find pT3/T4 or lymph node positive urothelial carcinoma in patients who have not received neoadjuvant chemotherapy should strongly consider referral to a medical oncologist to discuss the possibility of adjuvant chemotherapy.
Presented by Cora N. Sternberg, MD, FACP at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting - May 30 - June 3, 2014 - Chicago, Illinois USA
Hospital San Camillo-Forlanini, Rome Italy
Written by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com