Short-term Endocrine Therapy Prior to and During Radiation Therapy Improves Overall Survival in Patients with T1b – T2b Adenocarcinomas of the Prostate and PSA ? 20: Initial Results of RTOG 94-08
Reviewer: Christine Hill-Kayser, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2009
Presenter: Christopher Jones
Presenter's Affiliation: Radiological Associates of Sacramento, Sacramento, CA
Type of Session: Plenary
- The potential benefits of the addition of androgen deprivation treatment to radiotherapy in definitive treatment of prostate cancer have been recognized for the past three decades.
- Multiple studies have demonstrated that patients with high- and intermediate-risk disease may achieve improved biochemical failure-free survival, disease specific survival, and overall survival with addition of androgen ablation treatment to radiation.
- Recent studies have, however, demonstrated that delivery of androgen ablation treatment contributes to worse overall health, including decreased bone health and increased risk of fracture (Shahinian, 2005), and increased risk of diabetes and coronary heart disease (Keating, 2006).
- Clinicians are thus faced with a decision-making process that requires weighing the risks and benefits of delivery of androgen deprivation treatment with regard to risk of death from prostate cancer versus risk of death from other adverse health events.
- The Radiation Therapy Oncology Group (RTOG) 94-08 trial was designed to examine the impact of adding total androgen deprivation therapy to definitive radiotherapy for a heterogenous group of prostate-cancer patients.
Materials and Methods
- This trial was designed as a randomized, phase III trial, which randomized patients to either radiotherapy alone or radiotherapy with the addition of total androgen depriviation delivered for two months prior to radiation and two months during radiation.
- The primary study end point was overall survival.
- The accrual goal was 1980 patients in order to detect a 21.6% reduction in relative risk of death with 90% power.
- Patients were stratified by PSA (<4 vs. 4-20), histologic disease grade (well vs moderately vs poorly differentiated), and nodal disease (N0 vs Nx).
- Radiation treatment consisted of 46.8 Gray (Gy) delivered to the whole pelvis using conformal radiotherapy in 1.8 Gy fractions, followed by a 19.8 Gy boost to the prostate. Patients with low-risk disease received radiation to the prostate only, with a total dose of 68.4 Gy delivered in 1.8 Gy fractions. All radiotherapy doses were prescribed to the isocenter.
- Total androgen deprivation consisted of flutamide, 250 mg three times daily, and either goserelin (3.6 mg monthly) or leuprolide (7.5 mg monthly) delivered for two months prior to radiation, and for two months during radiation.
- All patients were required to undergo repeat prostate biopsy 2 years after completion of radiotherapy.
- Between October, 1994 and April, 2001, 2028 patients were enrolled on this trial (an average of 26 patients per month). Of these, 1979 were eligible for analysis.
- Median follow-up was 9.1 years.
- Patient characteristics were well-balanced between the two arms, and a median patient age of 71 years.
- Major deviations with regard to radiotherapy occurred in 5% of cases, and occurred in 4% of cases with regard to hormonal therapy.
- Ten-year overall survival was 62% in the group receiving androgen ablation treatment, and 57% in the group not, with a hazard ratio for death in the radiotherapy alone group of 1.17 (p = 0.03).
- On multivariate analysis, negative prognostic factors were Gleason score of 7 or greater and non-white race.
- Ten-year disease specific survival was 96% in the group receiving androgen ablation, versus 93% in the radiotherapy alone group (p < 0.01), with a hazard ratio of 1.84.
- On multivariate analysis, negative prognostic factors were Gleason score of 7 or greater and T2 disease.
- Ten-year rates of death from other diseases were similar between the two groups (35% and 37%, respectively, p = 0.49).
- Biochemical failure rates, based on the Phoenix definition (PSA nadir + 2), were 26% in the group receiving androgen ablation treatment versus 41% in the radiotherapy alone group (p < 0.01), with a hazard ratio for biochemical failure of 1.74.
- On multivariate analysis, negative prognostic factors were PSA of 4-20 and Gleason score of 7 or greater.
- Rebiopsy was performed in 834 cases, 439 of patients receiving androgen ablation treatment and 404 of those receiving radiation alone. Biopsies were negative in 78% of cases in the former group, and 60% of those not (p < 0.01).
- Patient outcomes were reanalyzed according to disease-risk. Patient were examined in three groups – low risk (Gleason score of 6 or less, PSA of 10 or less, stage T2a or less), intermediate risk (Gleason score 7 and/or PSA 10-20 and/or stage T2b), and high risk (Gleason score 8-10).
- Overall survival, disease specific survival, and biochemical failure free survival were impacted most significantly by the addition of androgen ablation in the intermediate-risk group. The low-risk group did not appear to benefit significantly.
· Benefits appeared to be similar across races, with overall survival improving from 68% - 74% with the addition of androgen ablation in the Caucasian cohort, and 63% - 70% in the African-American cohort.
- The authors conclude that the addition of four months of androgen ablation therapy to radiotherapy improves overall survival in prostate cancer patients treated with the techniques described in this study.
- They conclude that secondary endpoints, including disease specific survival and biochemical free survival, were also improved, and that biopsy specimens appeared less likely to contain prostate cancer cells in patients who had received androgen ablation.
- They note that no increased risk of intercurrent disease appeared to accompany use of androgen ablation.
- They describe that the intermediate-risk group appeared to benefit most from this treatment, and that use of androgen ablation treatment is not supported in the low-risk group.
- This study represents a well-designed, interesting contribution, which confirms prior findings demonstrating that intermediate-risk prostate cancer patients likely achieve benefit from addition of androgen ablation treatment to definitive radiotherapy.
- Unfortunately, neither the techniques nor doses used to treat patients on this study are applicable to current clinical practice. As use of intensity-modulated radiotherapy (IMRT) has become more widespread, techniques for treating prostate cancer have changed, and more conformal treatment has allowed dose escalation.
- Several groups have demonstrated that higher dose delivery results in improved outcomes, but long-term data regarding dose escalation with androgen ablation treatment are not yet available. Most recently, an update of the RTOG 9509 trial which randomized patients to receive 70.2 Gy versus 79.2 Gy demonstrated increased time to PSA failure with higher dosing (ASTRO, 2009). Patients in this study did not receive androgen deprivation treatment, however.
- Androgen ablation treatment remains an important tool in consideration of treatment for prostate cancer. Because very long follow-up is required for full assessment of any technique in treatment of prostate cancer, assessment of current techniques remains difficult. This study demonstrates firm improvements in outcomes of patients receiving androgen ablation in the setting of pre-IMRT dosing, and this may be extrapolated to apply to modern practice. Perhaps most interesting is that the authors did not observe any increased risk in death from intercurrent disease with addition of androgen ablation. Overall, this study is well-designed, and addresses an important question. Unfortunately, the question of use of androgen ablation in the setting of higher radiotherapy doses remains unanswered, and further studies will be of interest. In the meantime, the data presented here is an important contribution to the literature and will likely guide modern practice.