Six-month Androgen Suppression Plus Radiation Therapy vs. Radiation Therapy Alone for Patients with Clinically Localized Prostate Cancer

Authors: D'Amico, A. et al.
Affiliation: Dept. of Rad Onc, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA
Source:JAMA, August 18, 2004, Vol 292, No. 7

Background

In addition to overall survival, disease-specific survival is a very useful endpoint in cancer epidemiology. The latter can be particularly instructive in older patient groups that generally have a high incidence of comorbidities and intercurrent deaths. While overall survival can reflect the impact of all competing causes of mortality, disease-specific survival can better reflect the efficacy of a given intervention in preventing a cancer-related death. In prostate cancer , it is well recognized that the proportion of deaths attributable to this diagnosis rises with the stage, PSA level, and Gleason score. As a result, these intermediate and high-risk subsets of patients continue to be the subjects of ongoing research for better treatment outcomes, including the study discussed here.

The current standard of care in the treatment of high-grade clinically localized prostate cancer is external beam radiation therapy (EBRT) to a dose of about 70 Gray (Gy). Pollack et al . have used higher radiation doses to achieve improved biochemical-disease-free survival rates, with PSA progression serving as a surrogate for disease progression. However, a relatively higher PSA level post-treatment does not reliably predict for death from prostate cancer in most cases, ie: it is not a consistent or linear relationship. To date, the survival data from the study of dose escalation in prostate cancer are not published, and so the standard dose remains 70 Gy. In contrast, an overall survival benefit has been shown with the addition of androgen suppression therapy (AST) for 3 years duration to 70 Gy EBRT (Bolla et al ).

However, the well-described adverse effects of long-term AST prompted this study by D'Amico et al. The goal was to evaluate whether the use of AST for six months duration with EBRT provides a survival benefit over EBRT alone. In other words, does decreasing the duration of AST from 36 months to 6 months eliminate the previously documented survival benefit?

Materials and Methods

• Prospective, unblinded, randomized study of 206 patients enrolled between 1/1/95 and 4/15/01 from Harvard Outreach hospitals and medical centers
• Eligible patients had stage T1b to T2b, Nx, M0 prostate adenocarcinoma, PSA of at least 10 ng/mL, and Gleason score of 7 or higher
• Patients were required to have a negative bone scan and negative radiographic lymph node assessment within 6 months of randomization
• Low-risk patients not eligible UNLESS they had evidence of extracapsular (ECE) extension (T3a) or seminal vesicle (SV) invasion (T3b) on MRI pelvis with endorectal coil
• No prior hormone therapy use allowed
• Patients were stratified by baseline PSA level and Gleason score into 1 of 4 groups:
  • Group 1 PSA 20-40 ng/mL
  • Group 2 GS > 7
  • Group 3 PSA 10-20 ng/mL and GS of 6 or less
  • Group 4 low risk and ECE extension or SV invasion by MRI
• Arm 1 (n=104): 3-D conformal radiation therapy (CRT) to 70 Gy
• Arm 2 (n=102): 3-D conformal radiation therapy (CRT) to 70 Gy + 6 mos of AST
• 3-D CRT consisted of >/= 10 MV photon beam therapy delivered
• Simulation was performed prior to any AST and using CT-based planning
• Initial fields included prostate and seminal vesicles with 1.5 cm margins, treated to 45 Gy in 1.8 Gy daily fractions
• Conedown fields included prostate with 1.5 cm margins, treated for 22 Gy in 2 Gy daily fractions
• AST consisted of total androgen suppression with leuprolide or goserelin (LHRH-agonists) and flutamide (an anti-androgen) given for 6 months total: 2 months before, 2 months during, and 2 months after RT
• Follow-up, including PSA level measurements, occurred every 3 months for 2 years, every 6 months for additional 3 years, then annually
• Patients with PSA failure > 1.0 ng/mL and increasing by more than 0.2 ng/mL on 2 consecutive measurements were restaged
• Patients with PSA failure with PSA > 10 ng/mL were started on salvage AST, either using regimen identical to that described above, or bilateral orchiectomy
• Patients were followed until 1/15/04 or death, whichever came sooner.
• Death from prostate cancer was defined as death with increasing PSA while on AST and with metastatic disease
• Primary study endpoints were time to PSA failure and overall survival (OS).
• Secondary endpoints included prostate cancer-specific mortality (PCSM) and survival free of salvage AST (SFSA).

Results

• Median follow-up = 4.52 years
• Arm 2 had significantly:
• • higher 5-yr OS (88% vs. 78%, p=.04), lower PCSM (p=.02), higher SFSA (82% vs. 57%, p=.002)
• Median time to salvage AST after PSA failure was not significantly different between the arms (8 mos. vs. 7 mos, p=.57)
• There was significantly more grade 1-2 gynecomastia and grade 3 impotence in arm 2.

Discussion

The results of this study suggest that the addition of 6 months of AST to 70 Gy 3-D conformal radiation therapy provides an overall survival benefit in patients with clinically localized prostate cancer. The benefit appears to be of the same magnitude as that provided by 3 years of AST as used in the Bolla trial. The authors point out several important issues that still remain, including whether a larger dose than 70 Gy, or alternatively larger-sized pelvic treatment fields, might have resulted in an even bigger survival benefit. Also, is total androgen suppression always necessary, or would partial blockade suffice still provide the survival advantage?

It is important to note in evaluating this study that there is no AST-only control arm. Finally, and perhaps most importantly, this study can not make any definitive conclusions about 6 months vs. 36 months of AST without actually testing them directly in a randomized study. However, the promising results of this trial certainly have significant clinical implications and suggest the need for further study in this area.