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How to manage rising PSA levels following radical prostatectomy: the role of radiotherapy

How to manage rising PSA levels following radical prostatectomy: the role of radiotherapy. Dr ssa Gomellini Sara Radioterapia IRE. Postoperative Radiotherapy. The most common therapeutic procedure to eradicate the disease in localized prostate cancer. Radical Prostatectomy.

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How to manage rising PSA levels following radical prostatectomy: the role of radiotherapy

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  1. How to manage rising PSA levels following radical prostatectomy: the role of radiotherapy Dr ssa Gomellini Sara Radioterapia IRE

  2. Postoperative Radiotherapy The most common therapeutic procedure to eradicate the disease in localized prostate cancer Radical Prostatectomy LOW RISK: (T1c- T2a, Gleason score ≤ 6, PSA < 10 ng/ml) Radical Prostatectomy Exclusive Radiotherapy =

  3. Rising PSA after RP of a nonorgan confined cancer approximately 15–40% DIAGNOSTIC WORKUP AFTER RP FAILURE PRIMARY TREATMENT OPTIONS NCCN Guidelines Version 3.2012: The median time to the development of metastatic disease is 8 years!!!

  4. Postoperative Radiotherapy Rising PSA levels …..which cut-off level???? Should become undetectable within 6 weeks of radical prostatectomy (RP), as the prostate tissue has been removed, and the half-life of PSA is around 3 days The PSA level The American Urological Association (AUA) biochemical recurrence following radical prostatectomy initial serum PSA of ≥ 0.2 ng/mL, with a second confirmatory level of > 0.2 ng/mL Stamey TA, et al N Engl J Med 317:909-916,1987 Cookson MS, et al J Urol 177: 540-545, 2007

  5. > 0.2 ng/mL VS > 0.4 ng/mL Postoperative Radiotherapy Rising PSA levels …..which cut-off level???? it could potentially lead to earlier initiation of salvage radiotherapy, at lower disease burden and decreased likelihood for distant disease • have similar specificity • the lower PSA cut-off is more sensitive Stephenson AJ, Shariat SF, Zelefsky MJ JAMA 291:1325–1332,2004 Stephenson AJ, Scardino PT, Kattan MW JCO 25:2035–2041,2007

  6. Postoperative Radiotherapy • cGS ≥ 7 • clinical stage ≥ cT2 • iPSA > 10 Preoperative factors STRONGLY PREDICTIVE FOR RELAPSE Kupelian 1997 Connolly 2006 Porter 2006 Risk factors for progression after RP • pGS ≥ 7 • ECE, SV + • SM +, N + • Histopathological • factors STRONGLY RELEATED TO THE PROBABILITY OF: - BIOCHEMICAL RELAPSE - LOCAL RELAPSE Blute 1997 Van der Kwast 2007 Bolla2007

  7. Postoperative Radiotherapy • Slow rising PSA (b-Relapse>1 year • after resection) • PSA doubling time >12 months • PSA VELOCITY • (increase within 12 months <0.75 ng/Ml) • GS ≤7 at RP • SM + • Negative LN Predictive factors for LOCAL RELAPSE Pisansky TM, J Urol;163:845-850,2000 Stephenson A.J., et al JCO 25,(15): 2035-2041,2007

  8. Postoperative Radiotherapy • Short PSA doubling time (<5 mhts) • GS 8-10 at RP • SV + • Positive LN • PSA pre RT> 2 ng/ml Predictive factors for DISTANT RELAPSE Ward JF, Urol, 172:2244–2248,2004 Stephenson AJ, Curr Treat Opt Onc 5:357-365,2004 Pazona JF, J Urol 174:1282–1286,2005

  9. Postoperative Radiotherapy • Within 6 months of surgery • Undetectable post RP PSA (< 0,2 ng/ML ) • With one or more risk factors for locale relapse Adjuvant RT • More than 6 months after surgery • With one or more risk factors for locale relapse • Undetectable post RP PSA (< 0,2 ng/ML) Early Salvage RT • More than 6 months after surgery • Detectable post RP PSA (> 0,2 ng/ML) Late Salvage RT

  10. Postoperative Radiotherapy SWOG 8794** EORTC 22911 ** ARO 96-02/AUO AP 09/95 Adjuvant Radiotherapy Randomised Trials • Relationship between relapse and risk factors • Adjuvant radiotherapy: increases b-PFS, LC, MFS and OS • Low toxicities and good tolerance • LIMITS: 2/3: - used 2D RT (higher toxicities vs 3DCRT) • - ** included pts with PSA >0,2 ng/ml • nowadays considered biochemical relapse

  11. Adjuvant Radiotherapy - 425 pts (214 RT vs 211 Observation) Randomised Trial - Median age: 64,9 yr - Median F.U. 10.6 yr - Primary ENDPOINT: MFS - pT2N0M0R1or pT3N0M0 (R0-1) SWOG 8794 ** RT arm: 60-64 Gy to prostatic fossa Thompson IM et all JAMA, 296: 2329-2335, 2006 Swanson G.P. et al., JCO, 25: 2225-2229, 2007

  12. Adjuvant Radiotherapy SWOG 8794 RT did not negatively impact erectile dysfunction!! Thompson IM et all JAMA, 296: 2329-2335, 2006 Swanson G.P. et al., JCO, 25: 2225-2229, 2007

  13. Metastasis % N° pts Metastasis Free Surv HR 54% 114 12.9 aa 12.9 aa OBSERVATION 0.71* p = 0.016 43% 93 14.7 aa 14.7 aa Adjuvant RT N° pts Death % OS HR 52% 110 13.3 aa OBSERVATION p = 0.023 0.72** 88 15.2 aa 41% Adjuvant RT Adjuvant Radiotherapy SWOG 8794 Median FU 12.5 yrs 12.7 yrs Median FU 12.5yrs 12.7yrs Thompson I.M. et al. J Urol (181):956-962,2009

  14. Adjuvant Radiotherapy - 1005 pts (502 RT vs 503 Observation) Randomised Trial - Median age: 65 yr - Median F.U. 5 yr - Primary ENDPOINT: b-PFS - pT2N0M0R1or pT3a/bN0M0 (R0-1) EORTC 22911 ** RT arm: 60 Gy to prostatic fossa BOLLA et all, Cancer Radiotherapie (11):363-369,2007

  15. HR 0.34 HR 0.32 HR 0.87 HR1.11 HR 0.45 HR 0.55 neg neg HR0.29 HR 0.38 HR 0.67 HR 0.69 HR 0.72 HR 0.49 pos pos HR 0.43 - 0.60 – 0.52 Adjuvant Radiotherapy Histological revision on 566/1005 pts (272 RT vs 280 observ) pT2-3 and/or ECE and/or SM + and/or SV + Multivariate analysis: Impact of RT on bPFS as φ of risk factors EORTC 22911 GS Postop PSA SM ECE SV ≤6 7 >7 ≤0.2 >0.2 HR 0.40 - 0.52 – 0.54 HR 0.52 - 0.64 Undetectable Postoperative PSA (≤ 0.2 ng/ml) Margin Status: Most important predictive factors of b-RFS Van der Kwast T.H. et al., JCO (25): 4178-4186,2007

  16. Adjuvant Radiotherapy Histological revision on 566/1005 pts (272 RT vs 280 observ) pT2-3 and/or ECE and/or SM + and/or SV + Multivariate analysis: Impact of RT on bPFS as φ of risk factors EORTC 22911 • POSTOP PSA • GS • SV + Differences between two arms were not statistically significant POSITIVE TREND in total group but not in PSA ≤ 0.2 soubgroup • ECE If neg: no differences in b-PFS If pos: 5 yrs b-PFS: 77,6% vs 48,5% • SM • 5 yrs b-RFS in RT arm 64% SM- vs 76,5% SM+ • Adjuvant RT Avoid 291/1000 b-relapse in SM+ 88/1000 b-relapse in SM- Van der Kwast T.H. et al.,JCO (25): 4178-4186,2007

  17. Adjuvant Radiotherapy ARO 96-02/AUO AP 09/95 - 385 pts (193 RT+AD vs 192 Observ) Randomised Trial - Median F.U. 5 yr - Primary ENDPOINT: PFS - pT3/4N0M0 (R0-1) ** RT arm: 60 Gy to prostatic fossa Wiegel T. et al.,JCO,27:2924-2930,2009

  18. Adjuvant Radiotherapy ARO 96-02AUO AP 09/95 268 pts (114 RT AD vs 154 observ.) exclusion of pts with postop rising PSA If not dosable PSA: > b-RFS • GS • iPSA > 10 ng/ml • pT<3b • SM+ Outcome Predictive factors at univariate analysis: Indipendent Predictive factors at multivariate analysis irrespective of GS: • iPSA > 10 ng/ml • pT<3b • SM+ Wiegel T. et al.,JCO,27:2924-2930,2009

  19. Adjuvant Radiotherapy Retrospective Monoinstitutional Trial • 334 pts • pT3a / pT4 N0M0 (R0-1) • MULTIVARIATE ANALYSIS :RT≥ 70.2GyINDIPENDENT FACTOR RELEATED TO • b-RFS (p = 0.04) and DFS (p = 0.004) Cozzarini C. et al., IJROBP, 2009

  20. Adjuvant or Salvage Radiotherapy ?? About 50% pts wiht pathological risk features for relapse Are still b-NED at 5 years CAN WE DELAY RT TO NOT OVERTREAT PATIENTS ????

  21. ART vs SRT ONGOINGRANDOMISED TRIALS - Estimated 718 pts - ART vs SRT +6 months HT - Primary ENDPOINT: 5 years event-free survival (including biochemical progression) GETUG-17 trial NCT00667069 RADICALS RAVES NCT00860652 More than 4000 pts with: - adverse path. feat - undet postop PSA Primary ENDPOINT: 10 yrs PCSS ART vs SRT + 0, 6, 24 months of HT ART vs SRT (64Gy) without hormonal treatment. Estimated 470 pts Primary ENDPOINT: biochemical failure

  22. Salvage Radiotherapy The Swiss Group for Clinical Cancer Research (SAKK 09/10 NCT01272050) ESCALATING RT DOSE - Age ≤75 years - pT2-3 N0 R0-1 Randomised Trial- PSA ≥0.1 ng/mL ≤2 ng/mL - Estimated to enroll 350 pts - Primary ENDPOINT:FFBP (> 4ng/ml) - SRT 64 Gy vs 70 Gy without HT

  23. Salvage Radiotherapy

  24. Salvage Radiotherapy Retrospective series Biochemical response approximately 60-75% of pts > 50% pT3 > 70% (pT3 and SM+) Biochemical relapse 10 years long-term response only about 20–25% in all of these pts 5 yrs bNED 38-64% Swindle P, J Urol;174:903–907,2005 Chun FK, World J Urol;24:273–280,2006 Pinto F Urol Int 76:202–208,2006 Neuhof D IJROBP 67:1411–1417,2007

  25. Salvage Radiotherapy Retrospective Trial • 1540 pts with b-Relapse • Primary ENDPOINT: PD** after SRT • Median RT dose: 64,8 Gy • Median FU: 53 months 4-year PFS estimates after SRT alone were still improved in patients with high-risk features such as - PSA ≥ 2 ng/mL before salvage RT - Gleason Score of 8-10 - PSA doubling time ≤ 10 months Stephenson AJ, et al JCO 25:2035-2041,2007

  26. Salvage Radiotherapy • 635 pts with b-Relapse/ Local Relapse • no SRT (397) vs SRT (160) vs 78 (SRT +OT) • Primary ENDPOINT: PCSS • Median dose: 66,4 Gy • Median FU: 6 years Retrospective Trial • The addiction of hormonal therapy to SRT did not improve PCSS • The increase PCSS was most marked in men with: • - PSA doubling time < 6 months • - Gleason Score of 8 -10 Trock BJ, et al JAMA 299:2760-2769,2008

  27. Salvage Radiotherapy Retrospective Trial • 162 Pts between 1997 and 2004 with b-Relapse/Local R • no OT • Median dose: 66,4 Gy • Median FU: 41.5 months • - iPSA pre RP (≤ 12 ng/mL vs. >12 ng/mL) • Pre-RT PSA (≤ 0,33 ng/ml vs > 0,33 ng/ml) • PSA DOUBLING TIME (≤ 5m vs > 5 m) • Undetectable PSA after SRT • - Undetectabe vs Dosable PSA after RP • - GS (≤ 6 vs. ≥ 7) • - pT (≤pT2c vs. ≥pT3a) • - Seminal Vescicles status (positive vs negative) • - SM +/- • - Time to b-Relapse (≤ 5.0 vs. >5.0 months) • - Age (≤ 66 vs. > 66 years) ON Impact of risk factors on long term BIOCHEMICAL RESPONCE Wiegel T. et al., IJROBP 73 (4):1009–1016,2009 Wiegel T. et al., IJROBP, 2009

  28. Salvage Radiotherapy PREDICTOR FACTORS of b-PROGRESSION after Salvage RT UNIVARIATE ANALYSIS • 5 yrs b-Ned: 54% • Undetectable PSA post SRT: 60% Wiegel T. et al., IJROBP 73(4):1009–1016,2009

  29. Salvage Radiotherapy MULTIVARIATE ANALYSIS PREDICTIVE FACTORS of undosable PSA (~ 0) after Salvage RT with logistic regression PREDICTIVE FACTORS of b-Relapse after Salvage RT with both logistic regression and Cox regression Undosable PSA (≤ 0.1) after SRT:most significant independent predictorfactor ofb-PFS Best patients selection for Salvage RT low preRT PSA, SM+, low pT Wiegel T. et al., IJROBP 73(4):1009–1016,2009

  30. Salvage Radiotherapy PREDICTIVE NOMOGRAMS • PSA level < 2.0 ng/mL at time of SRT • Gleason score ≤ of 7 • - PSA doubling time > 10 months • - SM + • - AD therapy before or during SRT • - N - Predicting prognostic features to improve biochemical Control after SRT Hormonal Therapy NO impact on OS!! Stephenson AJ, et al JClin Oncol 25:2035-2041, 2007 Trock BJ, et al JAMA 299:2760-2769,2008 Moreira DM, et al BJU Int 104:1452-1456, 2009

  31. Salvage Radiotherapy • 441 pts with b-Relapse stratified for risk classes • SRT (441) • Median duration of HT: 11 months • concurrent ADT: 28% pts • Median dose: 68 Gy • Primary ENDPOINT: Progression-free survival PFS • Median FU: 3 years Retrospective Trial Soto D. E.et al., IJROBP 82, (3):1227–1232, 2012

  32. Salvage Radiotherapy MULTIVARIATE ANALYSIS INDIPENDENT PREDICTORS of PFS If stratified by risk group the benefits of cADT (hazard ratio, 0.65; p=0.046) were significant only in high-risk Soto D. E.et al., IJROBP 82, (3):1227–1232,2012

  33. Postoperative RT +/- HT ONGOINGRANDOMISED TRIALS RTOG 96-01 (SRT+/- Bicalutamide 150 x 2 yrs vs PLACEBO) RTOG 05-34 (Short course AD+WPRT vs p.BED RT+/- AD) SSPORT RADICALS (PORT vs PORT+6 mthsOT vsPORT+ 12mths OT)

  34. ART vs SRT CONCLUSIONS: • LEVEL 1 EVIDENCE: • In patients with pathologically advanced prostate cancer can lengthen: • biochemical disease-free • metastasis-free • overall survival • 2) Achieve a 5 years b-Control of more than 20% higher than SRT • 3) Overtreatment and unnecessarily exposing an increased number of pts to the side effects of RT • 3) Higher ≥ G2 GU ART • ONLY RETROSPECTIVE SERIES: Improved b-Control with SRT • As soon as possible (PSA levels at least 0,5 ng/ml) if long-life expectancy • 3) IF - GS ≤ 7, PSA < 2 ng/ml, SM+, SV-, PSA DT>10 mths: best pg • - measurable local recurrence worse outcome after salvage RT SRT

  35. ART vs SRT CONCLUSIONS: WE NEED THE RESULTS OF ON GOING RANDOMISED TRIALS Thanks for your attention!

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