Preliminary Analysis Of Rtog 9902: Increased Toxicity Observed With The Use Of Adjuvant Chemotherapy

Purpose/Objective: High risk, clinically localized prostate cancer (PCa) is generally treated with a combination of radiotherapy (RT) and long term, androgen ablation (LTAD). However, many patients (Pts) develop recurrence following therapy, ultimately with distant disease. Cytotoxic chemotherapy (CT) is beginning to have a larger clinical role in management of hormone refractory prostate cancer (HRPCa) and it was our hypothesis that adjuvant CT would improve the survival rate of high risk PCa when used in combination with RT and LTAD. Materials/Methods: Pts with PSA 20–100 and Gleason score (GS) ≥7 or clinical stage ≥T2 and GS ≥8 were randomized to androgen ablation for 8 weeks then RT and LTAD with or without four 21-day cycles of CT with oral estramustine 280 mg tid × 14 days, oral VP-16 50 mg/m2 in divided doses bid × 14 days, and paclitaxel 135 mg/m2 iv on day 2. Warfarin was originally given at 1 mg/day during CT, but, after thromboembolic (TE) toxicity was observed, the dosage was increased to keep the INR between 1.5 and 2.5. The RT consisted of 46.8 Gy to a small pelvic field (in order to minimize hematologic toxicity) followed by a boost to the prostate of 23.4 Gy for a total dose of 70.2 Gy. Results: This study opened on Jan 11, 2000 and closed on Oct 4, 2004 with a total of 397 Pts (of a planned 1440) entered. Pts had high risk features: 68% had GS 8 or greater, median PSA was 22.7 ng/mL, and 33% were cT3. 378 Pts have toxicity information available. 199 Pts were enrolled with less intense anticoagulation and 179 Pts were enrolled after the anticoagulation was intensified. After the warfarin was increased, toxicity information was carefully scrutinized and the rate of TE event was found to exceed the rate prospectively defined as the maximum allowable (2 TE events occurred among first 10 eligible and analyzable Pts). This information was reported to the DMC and patient accrual was suspended on Jul 30, 2004 and permanently closed to patient accrual on Oct 4, 2004 for patient safety. Overall, there were 34 Pts who experience at least one grade ≥4 events (2 grade 5) in the CT arm vs. 0 in the no-CT arm. Using Kaplan-Meier analysis and log rank testing, there were statistically significant increases in grade ≥3 GI, cardiovascular, and TE toxicities in the CT arm. In the CT arm, the 12 month cumulative estimate of cardiovascular toxicity was 12% and, for TE events, it was 10%. For those Pts who actually received CT, the 1-yr rate of TE toxicity was 16% with less intense anticoagulation and 8% with more intense anticoagulation. Conclusions: Increased toxicity was seen in the CT arm of RTOG 9902. Careful monitoring led to an appropriate halt in patient accrual. Despite the early stoppage due to toxicity, this trial of nearly 400 Pts is the largest prospective chemotherapy-radiotherapy study in PCa and demonstrates that the RTOG can carry out CT trials in localized prostate cancer. Estramustine is associated with TE toxicity, which led to the early stoppage of this trial. Recent studies in HRPCa seem to indicate that this agent no longer needs to be a part of chemotherapy regimens for PCa. The RTOG will follow patients enrolled in this trial for outcome and longer term toxicity analysis. A successor trial (RTOG 0521) will be activated in high risk, localized PCa utilizing docetaxel without estramustine in order for further evaluate the hypothesis that adjuvant CT can improve survival in high risk, but clinically and radiographically non-metastatic PCa.