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
Ultima Vez Modificado: 20 de octubre del 2005

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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.


News
In other study, adjuvant chemo linked to better survival versus surgery alone in gastric cancer

May 5, 2010 - The incidence of noncardia gastric cancer has declined overall in America since the late 1970s but increased among whites aged 25 to 39, and the use of adjuvant chemotherapy with fluorouracil for gastric cancer is associated with lower mortality risk compared to surgery alone, according to two studies in the May 5 issue of the Journal of the American Medical Association.



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