Men with intermediate-risk prostate cancer (PC)1 have 5-year prostate-specific antigen (PSA) progression-free rates that range from 30% (a high-risk outcome) to 98% (a low-risk outcome).2 Based on this variation, investigators from Memorial Sloan Kettering proposed two intermediate-risk subgroups:3
Favorable: Gleason 3 + 4 or less and percent positive biopsies (ppb) ≤50% and only one intermediate-risk factor excluding 4 + 3
Unfavorable: Gleason 4 + 3 or at least two intermediate-risk factors or ppb >50%
The clinical significance of this subdivision relates to a more judicious use of androgen deprivation therapy (ADT) for men with intermediate-risk PC. Specifically, investigators have shown that using radiation therapy without ADT in men with favorable intermediate-risk PC results in very low rates of death from PC after 10 years (<2%),4-5 which is consistent with low-risk PC where ADT is not indicated.6 Therefore, if men with favorable intermediate-risk PC are enrolled in randomized studies evaluating the impact of ADT duration on death from PC, the power of the trial to observe a difference decreases because death from PC will not be affected by differing durations of ADT in these men.4-5 So, while a significant reduction in death from PC may be associated with longer-course ADT in men with unfavorable intermediate-risk PC, the overall study may be negative due to the lack of impact of ADT duration on death from PC in men with favorable intermediate-risk PC.
Pisansky and colleagues7 present the initial results of RTOG 9910 [National Clinical Trial (NCT) 00005044], a randomized trial evaluating the impact on death from PC of adding 4 vs 9 months of ADT to 70.2 Gray EBRT. There were 1490 eligible men (median age of 71 years) with 84% having intermediate-, 15% high-, and 1% very–high risk PC. At a median follow-up of 9.3 years, 450 (30.2%) men died, 54 (12%) of PC. The hazard ratio for death from PC was 0.81 (0.48–1.39; P = .45), and cumulative incidence estimates of prostate cancer–specific mortality at 10 years were 4% and 5% in the 9- and 4-month ADT arms, respectively. The expected number of PC deaths on which the study was powered was 270, or five times the number observed.
Realizing that a possible benefit of longer ADT may exist in men with unfavorable but not favorable intermediate-risk PC supports the need for a post-randomization, hypothesis-generating analysis evaluating the impact of the duration of ADT in these subgroups. Pending that analysis, whether 4 months of ADT is sufficient or any ADT is necessary in men with unfavorable or favorable-risk intermediate-risk PC, respectively, to reduce death from PC remains unanswered. Therefore, while awaiting the post-randomization analyses of the RTOG 9910 study and other randomized studies8-9 that can address this issue, withholding ADT in men with favorable intermediate-risk PC and adding 4 or 6 months of ADT to radiation therapy in men with unfavorable intermediate-risk PC are reasonable options.
- Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 1.2014. J Natl Compr Canc Netw. 2013;11(12):1471-1479. http://www.jnccn.org/content/11/12/1471.long
- Mitchell JA, Cooperberg MR, Elkin EP, et al. Ability of 2 pretreatment risk assessment methods to predict prostate cancer recurrence after radical prostatectomy: data from CaPSURE. J Urol. 2005;173(4):1126-1131. http://www.jurology.com/article/S0022-5347%2805%2961020-8/abstract
- Zumsteg ZS, Spratt DE, Pei I, et al. A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy. Eur Urol. 2013;64(6):895-902. http://www.sciencedirect.com/science/article/pii/S0302283813002571
- Castle KO, Hoffman KE, Levy LB, et al. Is androgen deprivation therapy necessary in all intermediate-risk prostate cancer patients treated in the dose escalation era? Int J Radiat Oncol Biol Phys. 2013;85(3):693-699. http://www.redjournal.org/article/S0360-3016%2812%2900856-5/abstract
- Keane FK, Chen M-H, Zhang D, et al. The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease. Cancer. 2014;120(12):1787-1793. http://onlinelibrary.wiley.com/doi/10.1002/cncr.28609/abstract
- Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365(2):107-118. http://www.nejm.org/doi/full/10.1056/NEJMoa1012348
- Pisansky TM, Hunt D, Gomella LG, et al. Duration of androgen suppression before radiotherapy for localized prostate cancer –Radiation Therapy Oncology Group Randomized Clinical Trial 9910 [published online ahead of print December 22, 2014]. J Clin Oncol. doi: 10.1200/JCO.2014.58.0662. http://jco.ascopubs.org/content/early/2014/12/22/JCO.2014.58.0662.long
- Zapatero A, Guerrero A, Maldonado, et al. Randomized phase 3 trial of adjuvant androgen deprivation in combination with high dose conformal radiation therapy in intermediate- and high-risk prostate cancer. Int J Radiat Oncol. 2014;90(1 Suppl):S1.
- Radiation Therapy Oncology Group. Radiation therapy with or without androgen-deprivation therapy in treating patients with prostate cancer. ClinicalTrials.gov Website. Available at: https://clinicaltrials.gov/ct2/show/NCT00936390. Updated July 21, 2014. Accessed January 4, 2015.