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Radioterapia Adjuvante vs. Agresiva após Prostatectomía com Márgens Positivos

Este estudo compara os efeitos da radioterapia adjuvante e agressiva após prostatectomía em pacientes com margens positivos, ajudando a entender a progressão do câncer de próstata e fatores preditivos para recorrência e metástases.

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Radioterapia Adjuvante vs. Agresiva após Prostatectomía com Márgens Positivos

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  1. Radioterapia adjuvante vs agressiva após prostatectomía, em doentes com márgenes positivos Eduardo Solsona solsona@pulso.com

  2. Progresión PSA (40-50%) Md=6-7y Md=3y -Local recurrence: 6-9% M+ (34%) (Md FU= 8yrs) Md=??y (2nd wave) Cancer-specific mortality (17%) (within 15 yrs) Natural history of patients at high risk of biochemical recurrence RP: pT3/ pT2 m(+)/ Gleason 8-10/ PSA≥ 20ng/ml

  3. Meaning of BP after RP Local recurrence (LR)/ Distant mets (M+) or both No reliable imaging method: TRUS; MRI; PET/TAC Predictive factors for LR - margins (+) - PSA dt>12ms - Gleason7 - pN0 - Tº to PSA>2-3a (PR) Predictive factors for M+ - PSA dt<3m (3-9m) - PSAv >2ng/ml/año - Gleason8 - pN+ - Tº to PSA<2yr (PR) - VVSS + (?) Predictive factors for BP only - PSA dt>15m - Gleason6 - pN0 - Tº to PSA>3a (PR) Pound CR JAMA (05) 281:1597; D’Amico AV J.Urol. (03) 169:1320; Katz MS JCO (03) 21; Freedland SJ JAMA (05) 294: 433;

  4. Therapeutic Alternatives Methods: - Surveillance - Radiotherapy (RT)  ADT - Androgen deprivation therapy (ADT) - Systemic chemotherapy (under investigation) When to apply: - Adjuvant - Salvage . After biochemical progression . After objective progression

  5. Adjuvant RT (ART)

  6. ART: Phase III results Phase III trials: P3 or P2m (+), N0, M0 Trials Pts Md FU PSA>0.2 Gy Md age SRT EORTC 22911 968 10.8yrs 29.9% 60 65 yr 33% ARO 96-02 307 53.7ms 20%* 60 64 yr SWOG 87-94 425 12.6yrs 29.8% 60-64 65 yr 33% * Excluded by protocol Bolla M Eur.Urol (11) abstr: 218/227); Thompson IM J.Urol (09): 181: 956; Wiegel T JCO (09)27:2924

  7. ART: Biochemical progression. Phase III 72% vs 54% (HR=0.53, p=.015) 64% vs 35% (HR=0.43, p<.0001) Md FU=10.8yrs 60.6% vs 41.1% (HR=0.41.1, p<.0001) Wiegel T JCO (09)27:2924; Thompson IM J.Urol (09): 181: 956Bolla M. Lancet (05) 366:572Bolla M Eur.Urol (11) abstr: 218/227 74% vs 52.6% (HR=0.43, p<.0001)

  8. ART: Recurrence-free survival. Phase III SWOG 87-94 EORTC 22911 70.3% vs 64.8% (HR=0.81, p=.054) 13.8 vrs 9.9 yrs (HR=0.62, p<.001) Bolla M. Lancet (05) 366:572; Thompson IM J.Urol (09): 181: 956

  9. EORTC (md FU=10.8yrs) - mets-free survival: 76.5 vs 71.3, p>01 - c. incidence (10yrs) of M+ -10.1 vs 11.0 (p>0.1) ART: Metastasis-free survival. Phase III SWOG SWOG 87-94 71% vs 61%(HR=0.71; p=.016) Bolla M. Eur.Urol (11) abstr: 218/227; Thompson IM J.Urol (09): 181: 956

  10. ART: Overall survival. Phase III trials SWOG 87-94 EORTC (md FU=10.8yrs) - 76.9% vs 80.0%, p>01 74% vs 66% Md survival= 13.3 vs 15.2 yrs HR= 0.72; p=.023 Bolla M. Eur.Urol (11) abstr: 218/227; Thompson IM J.Urol (09): 181: 956

  11. ART: Local progression. Phase III trials SWOG 8794 EORTC 22911 Md FU 12.6yrs 10.6yrs PS P0-1=98.6% P0-1=99.5% 10yr M+ 71% (RT) vs 61% (WW) 76.5% (RT) vs 71.3% (WW) 10yr OS 74% (RT) vs 66% (WW) 76.9% (RT) vs 80.7% (WW) 10yr BR 64% (RT) vs 35% (WW) 60.6% (RT) vs 41.1% (WW) Bolla M. Eur.Urol (11) abstr: 218

  12. ART: Increase side effects Type RP RP+RT p EORTC 22911 GI/II GIII 10% 2.6% 20% 4.2% .0005 .076 SWOG 97-94 GI GU GU (incontinence) (-) 9.5% 2.8% 3.3% 17.8% 6.5% .02 .02 .11

  13. Salvage RT (SRT)

  14. Auhtor (yr) Pts Pre-RT md PSA Md Gy 5 yr 10 yr Pisansky (00) 166 0.9 64 46 Pazona (05) 307 0.8 64 46 35 (8yr) Katz (03) 115 0.87 70.2 Buskirk (06) 386 0.7 64.8 40 25 Ward (04) 211 0.6 64 34 Stephenson (07) 1540 1.1 65 32 (6yr) Neuhof (07) 171 1.1 60-66 35 Wiegel (09) 162 0.33 65 54 (3.5yr) Do (02) 73 45 Loeb (09) 192 0.7 63 56 (7yr) SRT: PSA-free survival % PSA-free Survival 5yr (10 yrs) PSA-free Survival  44% (38%) ART: 5yr (10 yrs) PSA-FS  72-75% (64-66%)

  15. Author (yr) Pts. Overall C-specific Mets-free Disease-free Katz (03) 115 95 83 Ward (04) 211 97 100 (83) 90 (71) Buskirk (06) 386 90 (80) 96 (86) Anscher (00) 87 92 72 Wiegel (09) 162 98 96 95 Quero (08) 59 87 96 Trock (08)* 238 81.6 88.7 72.8 Loeb (09) 192 90.7 87.5 SRT: Overall (OS), Mets-free (MFS), Cancer specific survival (CSS) % 5yr (10yr) survival 5-yr OS (93%), MFS (92%), CSS (94%) ART: 5-yr OS (86-92%), MFS (85-94%)

  16. SRT: Comparative study (case-control) 635 pts with BP after RP (Md FU=9yrs.) - salvage RT: 160 - salvage RT+ADT=78 - No treatment=397 Trock BJ JAMA (2008) 299: 2760

  17. SRT: Algoritm/Nomogram 1540pts; multicentric study Variables: Pre-RT PSA; Gleason; Margins; PSADT; ADT; pN 6yr-PSA-free survival (32% CI=0.69) Stephenson AJ JCO (07) 25:2035

  18. Doses: - ART: 60-64 Gy (EORTC, SWOG; ARO) - SRT: 64-66 Gy (Stephenson, Trock) Dose-escalation: 122 pts (King) - 60 Gy: 25% PSA-free survival - 70 Gy: 58% PSA-free survival (p<0.001) - increase 3% PSA-free survival per 1 Gy ART/SRT: Doses Technique: . Conventional (EROTC; SWOG)/ 3-D CR (ARO, Trock)/ IMR (Ost) IRM (74Gy): 104 pts SRT - PSA-free survival (3 & 5yrs)= 93% (+20% of phase III trials) Bolla M. Lancet (05) 366:572; Thompson IM J.Urol (09)181: 956;;Ost P IJROBP (10) epub; King CR IJROBP (08) 71; 23 ; Stephenson AJ JCO (07) 25:2035; Trock BJ JAMA (2008) 299: 2760

  19. Pre-RT PSA % 6yr-BPFS 0.5 48 0.5-1.0 40 1.1-1.50 28 >1.5 18 SRT: When to start? Pre-RT PSA cut off: ASTRO (<1.5)/ Neuhof (<1.5)/ Schild (<1.1)/ Stephenson (<0.5) / Wiegel (0.33) PSA>2.0ng/ml: 18% 6-yr PSA-free survival independent of Gleason and positive margins Multivariate A: . pre-RT PSA (< / ≥0.33ng/ml (HR=2.2, p<0.0005) Stephenson AJ JCO (07) 25:2035; Wiegel T IJROBP (09) 73:109; Wiegel T Eur Urol (11) Abstr: 221

  20. SRT: PSA after SRT as predictive factor Response to SRT: - PSA decrease - PSA decrease up to undetectable (≤0.2ng/ml) Progression - ASTRO: 2 consecutive PSA increase - 2 consecuitive PSA increase after nadir - PSA above nadir: 0.2/0.3/ 0.4ng/ml Multivariate A: - PSA after SRT (un vs detectable PSA) (HR=8.43, p<0.0005) . Related to PSADT Wiegel T IJROBP (09) 73:109

  21. Adjuvant (ART) vs Salvage RT (SRT)

  22. ART vs SRT: matched groups ART vs SRT alone 5-yr PSA-free surival Pts I. Criteria Md. Gy After RP After RT ART 96 P3; PSA<0.2; <1yr 60 75% 73% SRT 96 P3; PSA>0.2-<2.0;>1yr 64.8 66% 50% HR= (p) HR=1.6 (p=.049) HR=2.3 (p=.0007) ART significantly increased BPFS compared to SRT. This difference can be compensated by 46-48% of pts without progression (observation arms EORTC/ SWOG) Trabulsi EJ. Urology (2008) 72: 1298

  23. ART OB  SRT (matched) 102 159 p=0.7 p=0.09 ART vs SRT: matched groups ART vs Observation (OB)  SRT 753 (PR): matched study (Age, stage, Gleason sum, margins, RT- Gy-). (Md FU=11yrs) RP+ Pts 10 (20) yr OS* 10 (20)-yr CSS* ART OB  SRT (unmatched) 118 634 75.5 (40.0) 81.1 (44.8) p=.01 86.3 (69.3) 97.3 (89.0) p<.001 *OS (Overall Survival); CSS (Cancer-Specific Survival) Porter CR BJU Int. (08)103:597

  24. ART vs SRT: Paradigms • Higher rate Mets than local recurrence? • Predictive factors for Mets repond to RT? • - High Gleason • - PSA>0.2ng/ml after RP • 3. Who are suitable patients for ART and SRT?

  25. ART 3.5% 3.7% 8% 7% 0.5% ART vs SRT: Paradigms • Incidence of Local Recurrence and Mets: • - response to ART (EROTC /SWOG) EORTC (5yrs) SWOG (10yrs) Local R M+ Local R M+ Local R + M+ Observation 14.5% 3.5% 22% 16% 6% Predominance of local recurrence over mets

  26. ART vs SRT: Paradigms 2. Subgroup analysis: ART benefit for all subgoups included Gleason≥7, Seminal vesicle invasion (PSA-free survival) ARO 96-02 SWOG 8794 Thompson I. J.Urol. (2009): 181:956; Wiegel T JCO (2009)27:2924

  27. ART vs SRT: Paradigms 2. Subgroup analysis: only benefit for ART for positive margins (PSA-free survival) EORTC 22911 5-yr PSA-free survival (%) Margins RT Control HR (p) Negative 76.1 67.4 0.97 (.60) Positive 77.6 48.5 0.38 (<.0001) Van der Kwast TH: JCO (2007)25:4178

  28. ART vs SRT: Paradigms 3. PSA>0.2 after RP respond to ART (SWOG 87-94) Observation arm ART arm PSA failure PSA ≤0.2 PSA>0.2 ≤1.0 Observation 72% 80% ART 42% 73% Swanson GP JCO (07) 25: 2225

  29. ART PSA ≤0.2 PSA>0.2 122 68 7% 9% 4% 14% 0 1.4% ART vs SRT: Paradigms 3. PSA>0.2 after RP respond to ART Observation PSA ≤0.2 PSA>0.2 Pts 122 62 Local R 20% 26% M+ 12% 25% Local R + M+ 5% 8% PSA >0.2ng/ml after PR doen’t mean M+ and respond to ART Swanson GP JCO (07) 25: 2225

  30. 5. Poor Response to ART/SRT - Margins (-), Gleason 8-10: 18% (PSA-free survival) - Margins (-), Gleason 8-10: 58% CSS - Margins (-); LVI (+)/ VVSS(+) ART vs SRT: Paradigms 4. Response to SRT in pts at high risk Stephenson (PSA<2.0ng/ml) - Gleason 8-10, margins (+), PSADT>10ms ► 50% PSA-free S (6yrs) - PSADT<10mg, margins (+), Gleason 4-7 ► 57% PSA-free S (6yrs) - PSA≤ 0.5, Gleason ≥8, margins (+), PSADT<10 ►41% PSA-Free S (6y) Trock (early SRT & interval <2yrs) - PSADT<6ms : 82% CSS, independent of Gleason, margin - PSADT >6ms, Gleason 8-10, margin (+): 100% CSS, Stephenson AJ JCO (07) 25: 2035; Trock BJ JAMA (09) 299: 2760, Budiharto T. Rad Oncol (10) 97:474

  31. ART vs SRT: Patinets’ selection 4. Patients selection for ART/ SRT 1. ART - positive margins & ≥2 negative prognostic factors (Gleason 8-10, seminal vesicles invasion, ECE) 2. SRT - positive margins & 1 negative prognostic factors (Gleason 8-10, ECE) - negative margins & good prognostic factors (Gleason ≤7) 3. Systemic therapy - negative margins & poor prognosctic factors (Gleason ≥8 or PSADT<10ms)

  32. PR Pts 5yr-PFS 5yr-OS (Gl.8) RT+ADT 53 57% 100% (100%) RT 31 31% 87% (54%) p .0012 .008 (.05) RT+ ADT may benefit “very” high risk pts RTOG 85-31(adjuvant RT)1 Retrospective study: RP (BP)2 PR Pts 5yr-PFS RT+ADT 65 65% RT 42 42% p .002 Comparative study3: - No difference between SRT vs SRT+ADT (unfavorable group) 1Corn BW Urology (00)54:495; 2King CP IJROBP (04)59:341; 3Trock BJ JAMA (08)299: 2760

  33. Solutions RTOG 00-11: RT alone vs RT+LHRH (2yrs) vs LHRH (2yrs) RTOG 96-01:SRT (64.4 Gy) vs SRT+BCL (2yrs) RTOG 05-34 (SPPORT): Salvage bed RT (64-70Gy) vs salvage bed RT+ADT (4-6mo) vs salvage pelvic RT (45Gy)+bed RT+ADT(4-6mo) MRC PR10 (RADICALS): ART vs SRT & No ADT vs ADT (6mo) vs ADT (24mo.) GETUG 16:salvage RTLHRH (6mo)

  34. SRT.Predictive factors for PSA-free survival:margins (+), low pre-RT PSA, long PSAdt, Gleason 5-7, No SV invasion Author (yr) Margins Pre-RT PSA PSAdt SV invasion Gleason Leventis (01) HR=3.22 (.025) HR=0.3 (.020) Katz (03) HR=1.42 (.03) HR=1.34 (.13) HR=1.68 (<.01) Stephenson (04) HR=1.9 (<.001) HR=2.3 (<.001) HR=1.7 (<.001) HR=1.4 (.02) HR=2.6 (<.001) Ward (04) HR=1.41 (<.0001) HR=3.8 (.032) HR=3.22 (.008) HR=2.57 (<.001) Liaw (08) HR= 0.6 (.0044) HR=0.77 (0.1852) Wiegel (09) HR=0.41 (.0017) HR=0.47 (.003) Loeb (09) HR=1.03 (<.0001) HR=2.2 (<.0001) HR=1.7 (<.0001) Multivariate analysis (0.2 (0.2

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