Initial Report of RTOG 9601: A Phase III Trial in Prostate Cancer: Anti-androgen Therapy (AAT) with Bicalutamide during and after Radiation Therapy (RT) Improves Freedom from Progression and Reduces the Incidence of Metastatic Disease in Patients followin

Reviewer: Samuel Swisher-McClure, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2010

Authors: W.U. Shipley, D. Hunt, H. Lukka, P. Major, N.M. Heney, D. Grignon, M. Patel, J. Bahary, C. Lawton, H. Sandler.
Affiliations: Massachusetts General Hospital. Boston MA.
RTOG Statistical Center. Philadelphia, PA.
Mcmaster University Juravinski Cancer Center. Hamilton, ON
Indiana University. Indianapolis, IN.
University of Montreal. Montreal, QC.
Medical College of Wisconsin. Milwaukee, WI.
Cedars-Sinai Cancer Center. Los Angeles, CA.


Radical Prostatectomy is an effective treatment for localized prostate cancer and is associated with an improvement in overall survival compared to watchful waiting (Bill-Axelson, NEJM 2005).

  • However, when surgical pathology reveals evidence of extracapsular extension or positive surgical margins, the risk of recurrence increases significantly and additional treatment is warranted.
  • The results of the SWOG 8794 randomized trial demonstrated an OS benefit (47% vs. 37% at 15 years) associated with the addition of Adjuvant RT (60-64 Gy) for patients with pT3 disease or positive surgical margins (Thompson et al. Journal of Urology, 2009).
  • Several randomized trials have demonstrated that there is an overall survival benefit associated with the addition of AAT to RT for locally advanced prostate cancer or localized prostate cancer with unfavorable disease risk features (Bolla et al. Lancet, 2002; Pilepich et al. Int J Radiat Oncol Biol Phys, 2001; D'Amico et al. NEJM, 2004).
  • Retrospective Data has suggested that the addition of AAT to salvage RT after RP is associated with improvements in biochemical progression free survival (King et al. Int J Radiat Oncol Biol Phys, 2004).
  • The purpose of this trial was to test in a randomized fashion if long term AAT when combined with RT provides clinical benefit for patients with high risk disease features after RP.


  • This study was designed as a Phase III double-blinded, placebo-controlled trial to compare post-operative RT alone vs. RT plus long-term AAT for patients with high risk pathologic features after prostatectomy.
  • Study Eligibility Criteria:
    • Men having undergone an RP for non-metastatic prostate cancer
    • Patients with pT3N0 disease, or pT2N0 with positive surgical margins.
    • Either persistently elevated post-operative PSA or rising PSA after RP (0.2 ng/ml- 4.0 ng/ml)
  • Eligible Patients were then randomized to one or two treatments:
    • RT alone (64.8 Gy in 36 fractions of 1.8 Gy) + Placebo
    • RT plus AAT (24 months of bicalutamide, 150mg QD) during and after RT.
  • Prior to Randomization patients were stratified by the following factors:
    • Surgical Margins (Positive or Negative)
    • Nadir PSA Level (? 0.5 ng/ml or < 0.5 ng/ml)
    • PSA level at the time of Study Enrollment (? 0.5 ng/ml or < 0.5 ng/ml)
    • Receipt of Neoadjuvant AAT prior to RP (Yes or No)
  • The primary study end-point was overall survival.
  • Additional study endpoints included Freedom From PSA Progression (FFP) and reported treatment related toxicities.


  • Between March 1998 and March 2003, 771 eligible patients were randomized to RT plus AAT (387) or RT alone (383).
  • Characteristics of the Study population:
    • Median Age was 65 years
    • 252 patients (33%) were pT2N0
    • 518 patients (67%) were pT3N0
    • 672 patients (87%) had a PSA nadir after RP of < 0.5 ng/mL.
    • 655 patients (85%) had an entry PSA value of <1.6 ng/ml
    • 115 patients (15%) had an entry PSA of 1.6-3.9 ng/ml.
  • Pretreatment characteristics were balanced between the two study arms.
  • Median follow-up in surviving patients was 7.1 years.
  • The median interval between RP and the presence of a detectable PSA was 1.2 years.
  • The median interval between RP and study enrollment was 2.1 years.
  • The actuarial overall survival at 7 years was:
    • 91% for patients receiving RT plus AAT.
    • 86% for patient receiving RT alone.
  • With the current follow-up available, there were too few events (deaths) within the study group to allow for a statistical comparison between the two arms with respect to overall survival.
  • PSA progression was defined as a PSA > 0.4 ng/mL in patients whose protocol treatment resulted in an undetectable PSA or, if not, when the PSA rose 0.3 ng/mL above the entry PSA.
  • Freedom From PSA Progression (FFP) estimated at 7 years was 57% for RT plus AAT and 40% for RT alone (p < 0.0001)
  • On subgroup analysis by Gleason Sum, all patients appeared to have a FFP benefit with the addition of AAT.
    • Among 226 patients with GS < 7, FFP at 7 years was 63% and 50% (p < 0.02) favoring the AAT arm.
    • For 411 patients with GS 7, these were 55% and 39% (p < 0.0006).
    • Finally among, 134 patients with GS 8-10, 7 year FFP rates were 56% and 26% (p < 0.0008) again favoring treatment with AAT.
  • The cumulative incidence of metastatic PC at 7 years was less in the RT and AAT arm, 7.4% (25 patients), vs. 12.6% (46 patients) in the RT and placebo arm (p < 0.04).
  • Late Grade III and Grade IV toxicity were similar in the bicalutamide and placebo arms.
  • The reported rates of combined Grade 3 and Grade 4 toxicities for RT and AAT and RT alone were:
    • Bladder toxicity 5.9% vs. 5.0%.
    • Gastrointestinal toxicity 2.3% vs. 1.4%.
    • Cardiac events were rare and there was no significant difference between the two study arms (2.8% vs. 1.8%).
    • Gynecomastia (mostly all Grades I and II) differed significantly between the two treatment arms (89% vs. 15%).
    • Among patients receiving Bicalutamide, Grade 3 Hepatotoxicity occurred in 3 of 387 patients (0.8%).
  • Multivariate analysis found that entry level PSA < 0.5, the presence of positive surgical margins, and Gleason Sum < 7 were all independently associated with improved FFP at 7 years irrespective of treatment received.

Author's Conclusions

  • The addition of 24 months of peripheral androgen blockade (AAT) during and after RT significantly improved FFP and reduced the incidence of metastatic PC without adding significantly to radiation toxicity.
  • The significance of benefit in overall survival, as well analysis of risk-stratified subsets, must await longer follow-up.
  • Potential limitations of the study include the radiation treatment techniques and dose used at the time of study accrual which may have potentially been improved with dose escalation and the use of IMRT.

Clinical Implications

  • This trial was a well designed and well conducted randomized trial that examines the use of AAT in addition to salvage RT for patients with high-risk pathologic features and rising PSA after RP.
  • With approximately 7 years of follow-up data currently available, the authors report a significant benefit in FFP and the reduction of distant metastases associated with the addition of long-term AAT to RT for these patients.
  • Additional follow-up will be required in order to determine if this benefit in reducing distant metastases translates into an overall survival for these patients.
  • Limitations of the study include:
    • The RT treatment techniques and dose used at the time of study accrual (60-64 Gy) were less than doses more often used with modern treatment techniques. However, there is no prospective evidence that dose escalation in the setting of salvage RT after RP provides significant benefit.
    • All patients enrolled in this study had detectable PSA at the time of treatment and were therefore by definition treated with Salvage therapy. Patients enrolled in the SWOG 8794 trial which demonstrated an overall survival benefit associated with RT for patients with pT3 disease or positive margins were treated with adjuvant RT. Therefore, adjuvant RT is typically recommended for patients with high risk pathologic features after RP. It is unclear if the addition of AAT to adjuvant RT would provide the same observed benefit as was observed in patients undergoing salvage RT.
    • The optimal duration of AAT when combined with RT remains controversial and it is possible that a shorter course (6 months) of AAT would also provide benefit in this setting.

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