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The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease, "Beyond the Abstract," by Florence K. Keane, MD; Ming-Hui Chen, PhD; and Anthony V. D’Amico, MD, PhD

BERKELEY, CA (UroToday.com) - Intermediate-risk prostate cancer (PC)[1] is a diverse disease with a variable risk of PC-specific mortality (PCSM) after treatment. In 2013, Zumsteg et al.[2] proposed a division of intermediate-risk PC into favorable and unfavorable groups by demonstrating that patients with unfavorable intermediate-risk PC had an increased risk of PCSM compared to favorable intermediate-risk PC following radiotherapy (RT), with or without androgen deprivation therapy (ADT). We provided further validation for this prognostic subdivision using mature data with a median follow-up of 14.3 years from a prospective randomized trial comparing RT alone with RT and 6 months of ADT.[3] We also compared the risk of PCSM in patients with unfavorable intermediate-risk PC versus patients with high-risk PC.

Our study is notable for two key findings. First, there were no PC deaths observed in favorable intermediate-risk patients, despite 50% receiving RT to 70Gy alone. It is important to note that the favorable intermediate-risk patients in our study would not have been appropriate candidates for active surveillance. They had clinically significant disease (43% had GS 3+4 and 30% had T2a lesions) and were otherwise healthy (86% had minimal or no comorbidities). These findings suggest that ADT may not be needed to improve outcomes in this population, which is particularly important given the potential toxicities associated with ADT.[4, 5]

Second, there was not a statistically significant difference in the risk of PCSM in men with unfavorable intermediate-risk PC compared to men with high-risk PC after randomizing for age, comorbidities and treatment arm. While it is possible that a difference may emerge with longer follow-up, these results suggest that some men with unfavorable intermediate-risk PC may harbor occult GS 8-10 disease and could benefit from a 3.0-Tesla multiparametric MRI and targeted biopsy to rule out GS 8-10 disease. If patients are found to have GS 8-10 disease they should receive treatment for high-risk PC with 28 to 36 months of ADT instead of the 4 to 6 months of ADT currently used in intermediate-risk PC.

The role of long-term ADT in unfavorable intermediate-risk patients who are not found to have GS 8-10 disease remains an open question. RTOG 9910,[6] a trial of predominantly intermediate-risk PC patients (84%) randomized to 8 weeks versus 28 weeks of neoadjuvant ADT prior to 8 weeks of concurrent ADT and RT, did not show a significant improvement in outcomes in patients receiving long-term ADT. However, this trial may have been limited by inclusion of a significant number of favorable intermediate-risk patients, who have excellent outcomes with monotherapy alone. Complete data on the proportion of patients with favorable intermediate-risk PC is not yet available, but enrollment of a significant number of favorable intermediate-risk patients would have decreased the power of the study to observe a difference in PCSM. RTOG 9910’s 10-year estimated PCSM of 4-5%, which is lower than the 7.8% 10 year estimated PCSM in unfavorable intermediate-risk PC in our study, suggests that some patients had favorable intermediate-risk PC. Finally, while the currently accruing RTOG 0815,[7] a phase 3 trial of intermediate-risk patients randomized to dose-escalated RT with or without 6 months of ADT, will provide information on the impact of short-term ADT with dose-escalated RT, it will not answer whether long-term ADT will improve outcomes in unfavorable intermediate-risk PC. Further study is needed to determine the optimal treatment regimen for unfavorable intermediate-risk PC, and future trials will need to account for the heterogeneous outcomes in favorable and unfavorable intermediate-risk patients.

References:

  1. Mohler, J. L.; Kantoff, P. W.; Armstrong, A. J.; Bahnson, R. R.; Cohen, M.; D'Amico, A. V.; Eastham, J. A.; Enke, C. A.; Farrington, T. A.; Higano, C. S.; Horwitz, E. M.; Kawachi, M. H.; Kuettel, M.; Lee, R. J.; Macvicar, G. R.; Malcolm, A. W.; Miller, D.; Plimack, E. R.; Pow-Sang, J. M.; Richey, S.; Roach, M.; Rohren, E.; Rosenfeld, S.; Small, E. J.; Srinivas, S.; Stein, C.; Strope, S. A.; Tward, J.; Walsh, P. C.; Shead, D. A.; Ho, M. Prostate cancer, version 1.2014. J Natl Compr Canc Netw 2013, 11, 1471–1479.
  2. Zumsteg, Z. S.; Spratt, D. E.; Pei, I.; Zhang, Z.; Yamada, Y.; Kollmeier, M.; Zelefsky, M. J. A New Risk Classification System for Therapeutic Decision Making with Intermediate-risk Prostate Cancer Patients Undergoing Dose-escalated External-beam Radiation Therapy. Eur. Urol. 2013,64,895-902.
  3. Keane, F. K.; Chen, M.-H.; Zhang, D.; Loffredo, M. J.; Kantoff, P. W.; Renshaw, A. A.; D'Amico, A. V. The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease. Cancer 2014. [Epub ahead of print]
  4. D'Amico, A. V.; Denham, J. W.; Crook, J.; Chen, M.-H.; Goldhaber, S. Z.; Lamb, D. S.; Joseph, D.; Tai, K.-H.; Malone, S.; Ludgate, C.; Steigler, A.; Kantoff, P. W. Influence of androgen deprivation therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J. Clin. Oncol. 2007, 25, 2420–2425.
  5. Keating, N. L.; O'Malley, A. J.; Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J. Clin. Oncol. 2006, 24, 4448–4456.
  6. Pisansky, T. M.; Hunt, D.; Lomella, L. G.; Amin, M. B.; Balogh, A. G.; Chinn, D. M.; Seider, M.; Duclos, M.; Rosenthal, S. A.; Sandler, H. M. Radiation Therapy Oncology Group 9910: Phase 3 Trial to Evaluate the Duration of Neoadjuvant (NEO) Total Androgen Suppression (TAS) and Radiation Therapy (RT) in Intermediate-Risk Prostate Cancer (PCa). International Journal of Radiation Oncology*Biology*Physics 2013, 87, S1.
  7. National Institutes of Health. NCT00936390. RTOG 0815: Radiation Therapy With or Without Androgen Deprivation Therapy in Treating Patients With Prostate Cancer. Available at: clinicaltrials.gov. Accessed February 25, 2014.

Written by:
Florence K. Keane, MD;1 Ming-Hui Chen, PhD;2 and Anthony V. D’Amico, MD, PhD3 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

1Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA USA
2Department of Statistics, University of Connecticut, Storrs, CT  USA
3Department of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA USA

The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease - Abstract

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