1. Combined Modality Treatment of Locally Advanced Prostate Cancer: Radiation Therapy (RT) with Concurrent Androgen Deprivation Therapy (ADT) Howard Sandler

2. What is the issue with RT? Local control Can’t ask more from surgery or RT If local failure after RT is low, then what would surgery add? Morbidity is also an issue

3. Multiple Clinical Trials Examining RT+ADT

4. Chronology 1.RT alone 2.RT + short-term androgen deprivation (STAD) 3.RT + long-term androgen deprivation (LTAD) 4.RT + LTAD v. RT + STAD? 5.LTAD alone v. RT + LTAD? 6.Toxicity concerns

5. RT Alone Even early trials suggest lack of efficacy of low dose RT monotherapy for locally advanced prostate cancer

6. RT + STAD vs. RT Concerns about potential detrimental tumor-protective effects of AD during RT. RTOG 8610 - 10 yr BF rates:65% vs. 80% - 10 yr OS rates:43% vs. 34% (p =.12) - 10 yr CV events:12% vs. 9% (p =.32) Roach M et al. J Clin Oncol 2008;26(4):585-91. BF = biochemical failure; CV = fatal cardiovascular events; OS = overall survival

7. RT + LTAD vs. RT LTAD and micrometastases? EORTC 22863 (PI: Bolla) - 3 yrs vs. no AD 5 yr OS:78% vs. 62% 5 yr BFS:76% vs. 45% 82 of 109 patients had testosterone “renormalize” Bolla M et al. Lancet 2002;360(9327):103-6. BFS = biochemical disease-free survival

8. RT + LTAD vs. RT + STAD How much AD is needed? - Driven by toxicity issues RTOG 92-02 - No 10 yr OS advantage with LTAD - All other endpoints positive - Subset of patients with Gleason score (Gl) of 8-10 had 10 yr OS benefit: 45% vs. 32% Horwitz EM et al. J Clin Oncol 2008;26(15):2497-504.

9. RT + LTAD vs. RT + STAD EORTC 22961 noninferiority design 970 randomized between 1997-2002 (randomization after 6 mos of AD) 77% T3-T4, 8% cN+ or pN+, median PSA 18, 18% Gl 8-10 (22% Gl 2-5) 5 yr mortality: 15% vs. 19% (p = 0.65 for noninferiority) 5 yr CV events: 3% v 4% Bolla M et al. N Engl J Med 2009;360(24):2516-27.

10. LTAD vs. LTAD + RT? Two randomized trials testing whether local treatment adds to AD (small neg trial 1980-1985 MRC PR02) SPCG-7 (PI-Widmark) 875 pts, 78% T3, 18% WHO III, median PSA 16, most pN0 10 yr PSM24% vs. 12% 10 yr Mortality39% vs. 30% Widmark A et al. Lancet 2009;373(9660):301-8. PSM = prostate cancer-specific mortality

11. LTAD + RT vs. LTAD? Canadian Trial NCIC CTG PR.3 1205 randomized - 88% T3-T4, 18% Gl 8-10, 25% PSA > 50 7 yr OS:74% vs. 66% #CV events:24 vs. 24 Warde PR et al. Proc ASCO 2010;Abstract CRA4504.

12. Brachytherapy? HDR may offer local intensification. Does this mitigate need for AD? No randomized studies Merrick, et al. looked at 204 “high risk” PCa pts treated with brachy plus EBRT. 119 had AD, either STAD or LTAD Median PSA = 10, median Gl = 8 Better bPFS with AD (80% without AD vs. 95% for AD ≤6 mos vs. 90% for AD >6 mos, p = 0.03) bPFS = biochemical progression-free survival Merrick GS et al. Int J Radiat Oncol Biol Phys 2007;68(1):34-40.

13. Summary RT and AD both important for locally advanced prostate cancer LTAD better than STAD for locally advanced disease Randomized trials have not identified a significant increase in CV events Will higher RT doses mitigate a need for AD? How will newer AD therapies be integrated?