Preliminary Analysis of RTOG 9902: Increased Toxicity Observed with the Use of Adjuvant Chemotherapy

Reviewer: Chika Madu, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 20, 2005

Presenter: H.M. Sandler
Presenter's Affiliation: University of Michigan, Ann Arbor, MI
Type of Session: Scientific

Background

The current standard of care for patients with high risk prostate cancer includes local radiotherapy in conjunction with long-term androgen ablation (LTAA). However, recurrence and metastasis following treatment continues to be problematic in this group of patients. Chemotherapy in the past has been used to salvage hormone refractory metastatic cancer with about a 50% PSA response. The goal of this study was then to evaluate the role of chemotherapy in the adjuvant setting for high risk prostate cancer patients.

Materials and Methods

397 of planned 1440 patients were accrued between 1/2000 to 10/2004
Inclusion criteria were: PSA 20-100 and GS ≥7 or clinical stage ≥T2 and GS ≥8
Patients were randomized to androgen ablation (AA) for 8 weeks, then radiotherapy and LTAA plus or minus chemotherapy
Chemotherapy consisted of 4, 21-day cycles of oral estramustine 280mg TID x 14days, oral VP-16 50mg/m2/day divided BID, and paclitaxel 135mg/m2 IV on day 2
Warfarin was given initially at 1mg/day, then increased later due to thromboembolic effects (TE)
Radiation was given to a small pelvic field (true pelvis) to 46.8Gy/26fx followed by a boost to the prostate to a total dose of 70.2Gy
Primary endpoint was overall survival

Results

Due to toxicity, this study closed accrual in 2004 after 397 patients were enrolled
68% of patients had GS ≥8, median PSA was 22.7, 33% clinical T3
199 patients received less intense anticoagulation, while 178 received more intense warfarin
There were 34 ≥ Grade 4 toxicities in the chemotherapy arm versus none in the non-chemotherapy arm. 2 of these were Grade 5 toxicities
Grade ≥4 events were blood/bone marrow, cardiovascular(TE, arrhythmia), GI, ischemia

Author's Conclusions

Toxicity likely due to estramustine led to early closure of RTOG 9902
Less toxic chemotherapy used in the adjuvant setting may show better results when used in the adjuvant setting.

Clinical/Scientific Implications

The goal of this study was to show an overall survival advantage when chemotherapy is used adjuvantly with current standard of care for high risk prostate cancer. This study closed early due to toxicity most likely related to estramustine. There were 6 TEs in the chemotherapy group and the authors are unaware of any prior history or predilection for TE in the affected patients. It is clear that the disease free survival rates and overall survival rates with standard radiation and LTAA leave more to be desired, but the toxicities associated with certain chemotherapy agents, may not be worth any presumed survival advantage, if any. The use of less toxic chemotherapy may be more useful to evaluate the role of chemotherapy in this setting. An upcoming trial will be RTOG 05-21 which will randomize high risk prostate cancer patients to radiation (72-75.6Gy) and 28 months of androgen ablation plus or minus 6 cycles of the more tolerable docetaxel and prednisone. It will be interesting to see the results of this study, especially with a more standard radiation dose.