1. Controversies in the management of PSA-only recurrent disease Stephen J. Freedland, MD Associate Professor of Urology and Pathology Durham VA Medical Center Duke Prostate Center Duke Cancer Institute Duke University School of Medicine

2. Treatment Options for PSA Failure Observation Local therapy – post-surgery ◦External beam radiation ◦Brachytherapy (rare) Local therapy – post-radiation ◦Cryotherapy? ◦Repeat radiation? ◦Surgery? Systemic ◦Hormonal therapy ◦Role of chemotherapy?

3. Role of Imaging in PSA Failure Is the failure local or systemic? Imaging ◦Pelvic CT – limited role in low PSA ◦Bone scan – usually negative if PSA <10 ng/ml ◦ProstaScint ® – low sensitive and specificity May be more helpful post radiation Typically treat empirically

4. Risk of Prostate Cancer-Specific Mortality (PCSM) following PSA Recurrence after Radical Prostatectomy (RP) 5,096 men treated with radical prostatectomy (RP) from 1982–2000 at Johns Hopkins 979 (19%) recurrences 379 with PSA doubling time (PSADT) data available 66 (17%) prostate cancer deaths Follow-up ◦10.3 y (range: 1–20 y) mean following surgery ◦6.8 y (range: 1–16 y) following PSA failure Freedland SJ et al. JAMA 2005;294(4):433-9.

5. Combined Risk Factors: 15-year of Cause-Specific Survival PSA-DT Biochemical Recurrence >3 years after RP Biochemical Recurrence ≤ 3 years after RP Gleason score <8 Gleason score ≥ 8 Gleason score <8 Gleason score ≥ 8 ≥ 15 mo94%87%81%62% 9.0 to 14.9 mo86%72%59%31% 3.0 to 8.9 mo59%30%16%1% <3.0 mo19%2%<1%

6. Natural History of Salvage XRT 1,540 men with PSA recurrence after RP all treated with salvage radiation therapy (XRT) Multicenter data 7.5 year median follow-up after RP Median pre-XRT PSA: 1.1 ng/ml Median pre-XRT PSADT: 6.9 months Stephenson AJ et al. J Clin Oncol 2007;25(15):2035-41.

7. PSA Response to Salvage XRT Originally published by the American Society of Clinical Oncology. [Stephenson AJ et al: 25(15), 2007:2035-41]

8. PSA Response to Salvage XRT PSA <0.5 ng/ml PSA 0.51 – 1.00 ng/ml PSA 1.01 – 1.50 ng/ml PSA >1.5 ng/ml Originally published by the American Society of Clinical Oncology. [Stephenson AJ et al: 25(15), 2007:2035-41]

9. Salvage XRT and PCSM 635 men treated with RP at Johns Hopkins from 1982 to 2004 who had PSA recurrence 397 no salvage XRT 160 salvage XRT alone 78 salvage XRT + androgen deprivation therapy (ADT) Median f/u 6 years after recurrence; 9 years after RP 116 (18%) prostate cancer deaths Trock BJ et al. JAMA 2008;299(23):2760-9.

10. Salvage XRT and PCSM Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. June 18;299(23):2760-9. Copyright © (2008) American Medical Association. All rights reserved.

11. Predictors of PCSM after Salvage XRT Trock BJ et al. JAMA 2008;299(23):2760-9. Variable No. deaths/ No. patients HR for PCSDp-value Years from RP to recurrence0.85.001 Year of surgery0.91<0.001 Path Gleason 8 vs. ≤72.26<0.001 PSA-DT <6 months No XRT XRT alone XRT + ADT 51/103 4/29 3/34 1.0 (Reference) 0.14 0.24 PSA-DT ≥6 months No XRT XRT alone XRT + ADT 38/294 14/131 6/44 1.0 (Reference) 0.85 0.66

12. Early vs. Delayed ADT: Retrospective Analysis 4,967 men treated with RP within CPDR from ’88 to ’02 1,352 had PSA recurrence 355 had “early” ADT 997 had delayed/no ADT 103 metastasis Median follow-up 5.2 years after RP Patients who received salvage XRT were excluded from this analysis Moul JW et al. J Urol 2004;171(3)1141-7.

13. Early vs. Delayed ADT: Retrospective Analysis Regardless of whether hormonal therapy was early or late, no difference was found overall. However, recall that the majority of this group of men were not going to progress to metastases. Moul JW et al. J Urol 2004;171(3)1141-7.

14. Early vs. Delayed ADT: Retrospective Analysis Evaluated group of high-risk men: - Gleason score ≥8 or - PSA doubling time <12 months Showed significant benefit to early hormonal therapy - Delayed progression time to metastatic disease Moul JW et al. J Urol 2004;171(3)1141-7.

15. Treating PSA Recurrence – Post Radiation No clear standard Most series are small ◦Most use cryotherapy or surgery ◦Highly selected men Long-term PSA control unclear ◦Some series report reasonable PSA control, though patients are highly selected

16. Treating PSA Recurrence – Post Radiation: Too Little Too Late? Surgery  fewer metastases than radiation ◦Zelefsky MJ et al. J Clin Oncol 2010;28(9):1508- 13. ◦“These results may be confounded by differences in the use and timing of salvage therapy” Time to secondary treatment after PSA rise: ◦Surgery: 13 months ◦Radiation: 69 months “Outcomes in high-risk cancers treated with EBRT could be further improved with the earlier administration of salvage therapy, local or systemic”

17. Clinical Trials for PSA Recurrence – Post Surgery RADICALS (next slide) TAX 3503 ◦PSADT < 9 months ◦1) ADT vs. 2) ADT + docetaxel ◦Progression free survival (includes PSA progression) RTOG 0534 ◦1) Prostate bed XRT vs. 2) prostate bed XRT + ADT (4-6 months) vs. 3) whole-pelvis + prostate bed XRT + ADT (4-6 months) ◦Primary outcome: Freedom from progression (includes PSA progression)

18. Clinical Trials for PSA Recurrence – Post Surgery: RADICALS Accrual on-going Primary outcome: Disease-specific survival ~4,000 men Results expected ~2020 Radical prostatectomy RADICALS - overall design Assess need: Is immediate Post-operative RT required? Uncertain RT timing RANDOMISATION Immediate RT Immediate RT Yes No Salvage RT policy Salvage RT policy Monitor on trialMonitor off trial Rise in PSANo rise in PSA Hormone duration RANDOMISATION On trial Off trial Treatment RT + 2yr HT Trial follow-up Outcomes measures RT + 6mo HT RT + no HT Outcomes measures Hormone duration RANDOMISATION RT + 2yr HT Trial follow-up Outcomes measures RT + 6mo HT RT + no HT Key http://www.ctu.mrc.ac.uk/plugins/StudyDisplay/protocols/RADICALS_Protocol_v2_2_December_2008.pdf

19. Clinical Trials for PSA Recurrence – Post Radiation None

20. Summary Determine risk of progression/death If high-enough risk, treat local first ◦XRT after surgery ◦Unknown after XRT If that fails, consider systemic therapy early for high- risk Low-risk can be safely watched for years On-going clinical trials will hopefully address many of these controversies