Adjuvant or Salvage Radiotherapy after Radical Prostatectomy M

Adjuvant or Salvage Radiotherapy after Radical Prostatectomy M. Wirth Department of Urology, Technical University of Dresden

Adjuvant or Salvage Radiotherapy after Radical Prostatectomy: Background

PSA-relapse after RPE in locally advanced PCa (n=2091) % PSA-relapse (0. 2 ng/ml) after 10 years 100 80 60 preop. PSA 40 20+ ng/ml 10. 1 -20 ng/ml 4. 1 -10 ng/ml 0 -4 ng/ml 20 0 6 - 3+4 4+3 8 -10 Gleason-Score Han, Partin et al. , J Urol 2003

c. T 3: MSKCC-Nomogramm: p. T Stage Exampel: c. T 3, PSA 10 ng/ml, Gleason 4+4=8 extracapsular: 82 % organconfined: 18 % Ohori, Kattan et al. , J Urol 2004

c. T 3: MSKCC-Nomogramm: p. T-Stage Exampel: c. T 3, PSA 10 ng/ml, Gleason 3+3=6 organconfined: 50 % extracapsular: 50 % Ohori, Kattan et al. , J Urol 2004

Adjuvant or Salvage Radiotherapy after Margin Positive Radical Prostatectomy • Patients with R 1 after RPE are at an increased risk of biochemical, local and distant failure [1]. • With R 1, the risk of biochemical recurrence may supersede 50 % after 10 years [2]. • The associated 10 -year local recurrence rate accounts for narrowly 30 % [2]. 1 EAU guidelines 2008; 2 Pfitzenmaier et al. , BJU Int 2008

Adjuvant Radiotherapy vs. Wait-and-see after Radical Prostatectomy

Wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911 (n=1005) randomised controlled trial n p. T 3 or positive margins, p. N 0 n age < 76 years, WHO perf. status 0 -1 n n wait-and-see (n=503) vs. irradition (60 Gy) within 16 w. after RPE (n=502) Bolla et al. , Lancet 2005

wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911 (n=1005) n n n age 65 y. (61 -69) PSA: 12. 4 ng/ml (7. 2 -20. 3) PSA: 3 weeks after RPE, before RTX 0. 2 (0. 0 -0. 3) median FU 5 y. biochemical and clinical progression free survival significantly improved after ART overall survival with trend towards improvement after ART, but not (yet? ) significant Bolla et al. , Lancet 2005

EORTC trial 22911 (n=1005) clinical progression free survival Clinical progression-free survival Bolla et al. , Lancet 2005

EORTC trial 22911 (n=1005) biochemical progression free survival PSA progression-free survival Bolla et al. , Lancet 2005

EORTC trial 22911 (n=1005) cumulative incidence of locoreg. failure local progression-free survival Bolla et al. , Lancet 2005

Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Van der Kwast, JCO 2007

Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Margins ECE SV Gleason Postop. PSA Van der Kwast, JCO 2007

Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Van der Kwast, JCO 2007

Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) control arm Van der Kwast, JCO 2007

Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) immediate postoperative radiation Van der Kwast, JCO 2007

EORTC trial 22911 (n=1005) cumulative incidence of late complications Late complications Bolla et al. , Lancet 2005

Adjuvant RTX for T 3 N 0 M 0 PCA – randomised SWOG trial 8794 (n=425) Randomised controlled trial n clinical T 1/T 2 preoperatively n p. T 3 or positive margins, N 0 M 0 n WHO perf. status 0 -2 n n Wait-and-see (n=211) vs. Irradition (60 -64 Gy, n=214) Thompson et al. , J Urol 2009

Adjuvant RT in p. T 3 PCA (randomised study SWOG 8794, n=425) 100 Percentage 80 60 40 20 0 Thompson et al. , JAMA 2006

Adjuvant RTX for T 3 N 0 M 0 PCA – randomised SWOG trial 8794 (n=425) Overall survival p=0. 023 Thompson et al. , J Urol 2009

Adjuvant RTX for T 3 N 0 M 0 PCA – randomised SWOG trial 8794 (n=425) Metastatic-free survival p=0. 016 Thompson et al. , J Urol 2009

Adjuvant RTX for T 3 N 0 M 0 PCA – randomised SWOG trial 8794 (n=425) Metastatic-free survival, PSA < / > 0. 2 p=0. 03 Thompson et al. , J Urol 2009

Adjuvant RTX for T 3 N 0 M 0 PCA – randomised SWOG trial 8794 (n=425) Summary Thompson et al. , J Urol 2009

Adjuvant radiotherapy after RPE (ARO 96 -02 / AUO AP 09/95 , p. T 3 R 0 -1, PSA 0, n=108) % PSA recurrence after 4 years 100 p<0. 0001, hazard ratio 0. 4 80 60 40 81 % 20 60 % 0 adjuvant RT (60 Gy) no adjuvant RT Wiegel et al. , ASCO 2005 [in press as full article: J Clin Oncol 2009]

RPE with and without adjuvant RT in p. T 3 -PCA Bottke and Wiegel, Urol Int 2007

Adjuvant radiotherapy following radical prostatectomy for pathologic T 3 or margin-positive prostate cancer A systematic review and meta-analysis Survival Biochemical progression Morgan et al. , Radiother Oncol 2008

Salvage Radiotherapy vs. Observation at PSA Failure after Radical Prostatectomy

PCA specific survival following salvage RTX vs observation after RPE – survival no salvage treatment (n=397) vs. salvage radiotherapy (n=160) vs. salvage radiotherapy + HT (n=78) n significant increase of PC-specific survival for both SRT (HR 0. 32, p<0. 001) and SRT+HT (HR 0. 34, p=0. 003) n improvement limited to patients with - PSA-doubling time < 6 month - SRT within 2 y. after recurrence n Trock et al. , JAMA 2009

PCA specific survival following salvage RTX vs. observation after RPE – survival PCA specific survival Trock et al. , JAMA 2009

PSA failure following salvage radiotherapy – Ca. PSURE data (retrospective study, n=194) Macdonald et al. , Urol Oncol 2008

Radiotherapy at biochemical recurrence after RPE (retrospective study, n=162) No biochemical recurrence Wiegel et al. , IJROBP 2008

Radiotherapy at biochemical recurrence after RPE (retrospective study, n=162) No biochemical recurrence Wiegel et al. , IJROBP 2008

Radiotherapy at biochemical recurrence after RPE (retrospective study, n=162) No biochemical recurrence Wiegel et al. , IJROBP 2008

Salvage RTX at PSA progression: long-term efficacy Literature review 35 -54 % Bottke and Wiegel, Urologe 2008

Arguments pro delayed radiotherapy for positive surgical margins • Questionable survival advantage for immediate adjuvant RTX • Sparing of side effects and costs in about 50 % of patients • Improved risk stratification by monitoring of PSA value and PSA kinetics • High rate of disease control with timely applied salvage therapy

Adjuvant vs. Salvage Radiotherapy after Radical Prostatectomy

Adjuvant vs. Salvage Radiotherapy Matched-control analysis (n=192) Five-year freedom from biochemical failure from end of RT Trabulsi et al. , Urology 2008

Adjuvant vs. Salvage Radiotherapy Matched-control analysis (n=192) Five-year freedom from biochemical failure from end of surgery Trabulsi et al. , Urology 2008

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Adjuvant RT Salvage RT n=410 Jereczek-Fossa, Int. JRad. Oncol 2008

Adjuvant and Salvage RTX after RPE Grade 2 or greater rectal and urinary toxicity n=410 Adjuvant RT Salvage RT Jereczek-Fossa, Int. JRad. Oncol 2008

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al. , Int. JRad. Onc. Biol. Phys 2003

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Adjuvant RT Taylor et al. , Int. JRad. Onc. Biol. Phys 2003

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Salvage RT +/adj. androgen ablation Taylor et al. , Int. JRad. Onc. Biol. Phys 2003

Adjuvant RTX for p. N+ disease?

Conclusions: This study is the first to report a significant protective role for adjuvant RT in BCR-free survival and CSS of node-positive patients. Da Pozzo et al. , Eur Urol 2009

Adjuvant RTX for p. N+ disease (retrospective study, n=250) No biochemical failure Da Pozzo et al. , Eur Urol 2009

Adjuvant RTX for p. N+ disease (retrospective study, n=250) PCA-specific survival Da Pozzo et al. , Eur Urol 2009

RT for PSA-Recurrence after RPE: Dosage? (n=122) No new PSA-recurrence p<0. 0001 0 3 6 y King et al. IJROBP 2008

RT in prostate cancer induces secondary malignancies (n=130. 375 vs. 375. 235) ! odds-ratio for secondary malignancy 2 1. 5 1. 89 (1. 85 -1. 95) 1 0. 5 0 PCA, no RT PCA, RT Chamie et al. , AUA 2008 #393

Risk stratification?

Biological heterogeneity of R 1 disease: risk of failure after 2 years, nomogram (n=2911) Failure risk: 6% 65 % ! Walz et al. , J Urol 2009

Summary • definite evidence for adjuvant RTX for margin -positive disease is still pending • patients should be informed on the significance of the presently available results from randomized trial • stratification by recurrence risk is a plausible but not yet proven concept to select patients • with “temporarily delayed” RTX at PSA relapse, early onset is needed to maintain the chance of durable remission

Adjuvant hormonal therapy?

Prospective randomised study: flutamide vs. control after RPE in p. T 3 -4 p. N 0 (n=309) recurrence-free survival [%] 100 80 80 60 60 40 40 Flutamide, n=152 20 control, n=157 20 0 log-rank-Test, p=0. 0041 0 100 200 300 400 500 600 0 log-rank-Test, p=0. 92 0 100 200 300 400 500 600 weeks after RPE Wirth et al. , Eur Urol 2004

EPC program: objective progression (prospective randomised trial, n=8116, FU 7. 4 y) Mc. Leod et al. , BJU Int 2006

EPC program: overall survival (prospective randomised trial, n=8116, FU 7. 4 y) Mc. Leod et al. , BJU Int 2006

Adjuvant hormonal therapy after RPE for p. N+-PCa (randomised trail, n=98, FU 11. 9 y) Messing et al. , Lancet Oncol 2006

Adjuvant hormonal therapy after RPE author, year stage regimen progression survival Messing et al. , 1999, 2003 p. N+ orchiectomy or LHRHanalog benefit stage C LHRHanalog benefit no data available p. T 3 -4 p. N 0 flutamide benefit no difference T 1 b-T 4 bicalutamide benefit no difference Prayer-Galetti et al. , 2000 Wirth et al. , 2004 Mc Leod et al. , 2006

BACKUP

Adjuvant or Salvage Radiotherapy after Radical Prostatectomy M. Wirth Klinik und Poliklinik für Urologie

PSA-relapse after RPE in locally advanced PCa (n=2091) % PSA-relapse (0. 2 ng/ml) after 10 years 100 80 60 preop. PSA 40 20+ ng/ml 10. 1 -20 ng/ml 4. 1 -10 ng/ml 0 -4 ng/ml 20 0 6 - 3+4 4+3 8 -10 Gleason-Score Han, Partin et al. , J Urol 2003

c. T 3: MSKCC-Nomogramm: p. T Stage Exampel: c. T 3, PSA 10 ng/ml, Gleason 4+4=8 extracapsular: 82 % organconfined: 18 % Ohori, Kattan et al. , J Urol 2004

c. T 3: MSKCC-Nomogramm: p. T-Stage Exampel: c. T 3, PSA 10 ng/ml, Gleason 3+3=6 organconfined: 50 % extracapsular: 50 % Ohori, Kattan et al. , J Urol 2004

RPE with and without adjuvant RT in p. T 3 -PCA Bottke and Wiegel, Urol Int 2007

Adjuvant RTX for T 3 N 0 M 0 PCA – SWOG 8794 Randomised controlled trial n clinical T 1/T 2 preoperatively n p. T 3 or positive margins, N 0 M 0 n WHO perf. status 0 -2 n n Wait-and-see (n=211) vs. Irradition (60 -64 Gy, n=214) Thompson et al. , JUrol 2009

Adjuvant RTX for T 3 N 0 M 0 PCA – SWOG 8794 Thompson et al. , JUrol 2009

wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911 Randomised controlled trial n p. T 3 or positive margins, p. N 0 n age < 76 years, WHO perf. status 0 -1 n n Wait-and-see (n=503) vs. Irradiation (60 Gy) within 16 w. after RPE (n=502) Bolla et al. , Lancet 2005

wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911 n n n Age 65 y. (61 -69) PSA: 12. 4 ng/ml (7. 2 -20. 3) PSA: 3 weeks after RPE, before RTX 0. 2 (0. 0 -0. 3) median FU 5 y. biochemical and clinical progression free survival significantly improved after ART overall survival with trend towards improvement after ART, but not (yet? ) significant Bolla et al. , Lancet 2005

EORTC trial 22911 clinical progression free survival Bolla et al. , Lancet 2005

EORTC trial 22911 biochemical progression free survival Bolla et al. , Lancet 2005

EORTC trial 22911 cumulative incidence of locoreg. failure Bolla et al. , Lancet 2005

Patients who benefit from immediate postoperative RT – EORTC trial 22911 Van der Kwast, JCO 2007

Adjuvant Radiotherapy after RPE (ARO 96 -02 / AUO AP 09/95 , p. T 3 R 0 -1, PSA 0, n=108) % PSA recurrence after 4 years 100 p<0. 0001, hazard ratio 0. 4 80 60 40 81 % 20 60 % 0 adjuvant RT (60 Gy) no adjuvant RT Wiegel et al. , ASCO 2005

PSA Recurrence after RPE: Salvage Radiotherapy vs. Observation

Salvage radiotherapy within 2 years of biochemical recurrence was associated with a significant increase in Ca. P–specific survival among men with a PSA doubling time <6 months, independent of pathological stage or Gleason score. JAMA 2008

PCA specific survival following salvage RTX vs observation after RPE – survival Trock et al. , JAMA 2009

PCA specific survival following salvage RTX vs observation after RPE – survival no salvage treatment (n=397) vs. salvage radiotherapy (n=160) vs. salvage radiotherapy + HT (n=78) n significant increase of PC-specific survival for both SRT (HR 0. 32, p<0. 001) and SRT+HT (HR 0. 34, p=0. 003) n improvement limited to patients with - PSA-doubling time < 6 month - SRT within 2 y. after recurrence n Trock et al. , JAMA 2009

PSA Recurrence after RPE: Salvage Radiotherapy vs. Observation: Timing?

Radiotherapy for PSA-Recurrence (n=1540) bis 0. 5 ng/ml 0. 51 -1. 0 ng/ml 1. 01 -1. 50 ng/ml 1. 51+ ng/ml Stephenson et al. , JCO 2007

PSA Failure following Salvage Radiotherapy – Ca. PSURE data Macdonald et al. , Urol. Oncol. Sem. Orig. Inv 2008

Adjuvant Radiotherapy or after PSARecurrence (n=162) Wiegel et al. , IJROBP 2009

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Adjuvant RT Salvage RT Jereczek-Fossa, Int. JRad. Oncol. Biol. Phys 2008

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al. , Int. JRad. Onc. Biol. Phys 2003

RT for PSA-Recurrence after RPE: Dosage? (n=122) No new PSA-recurrence p<0. 0001 0 3 6 Jahre King et al. IJROBP 2008

Radiotherapy for PSA-Recurrence(n=1540) Stephenson et al. , JCO 2007

Summary (I) • adjuvant and Salvage-RT after RPE both improve recurrance free survival and offer a second chance of cure • adjuvant RT should be considered in patients with positive margins

Summary (II) • Salvage-RT should be performed at a low PSA-level << 1. 0 ng/ml • postoperative RT has a limited effect on patients with p. N+ • optimal radiation dose unclear

BACKUP

Summary (I) • adjuvant and salvage-RT after RPE both improve recurrance free survival and offer a second chance of cure • adjuvant RT should be considered in patients with positive margins

Summary (II) • salvage-RT should be performed at a low PSA-level << 1. 0 ng/ml • postoperative RT has a limited effect on patients with p. N+ • optimal radiation dose unclear

Radiotherapy + HT vs. hormonal Therapy alone

Adjuvant RT in p. T 3 PCA (randomised study SWOG 8794, n=425) Thompson et al. , JAMA 2006

RT + hormonal therapy* vs. hormonal therapy* alone in locally advanced PCA (n=875) PSA recurrence (%) *flutamide 3 x 250 mg/d P<0. 0001 Widmark et al. , Lancet 2009

RT + Hormonal Therapy* vs. Hormonal Therapy* alone in lokally advanced PCA (n=875) P=0. 004 Hormonal Therapy alone Radiotherapy + Hormonal Therapy *flutamide 3 x 250 mg/d Widmark et al. , Lancet 2009

Adjuvant HT* after RT in organ confined high risk tumor *6 mo. , n=206 D‘Amico et al. , JAMA 2008

Short vs. long* adjuvant ADT after RT *3 years vs. 6 months Overall survival Bolla et al. , ASCO 2007

Adjuvant hormonal treatment after RTX for locally advanced prostate cancer Authors Stages Regimen Progression Survival T 1 -T 4 N 0 -x LHRH analogues advantage stage C or D 1 LHRH analogues advantage T 1 -4 N 0 -1 orchiectomy advantage in N 1 subgroup Hanks et al. , 2003 T 2 b-T 4, PSA<150 ng/ml LHRH analogues plus flutamide advantage in Gleason score 8 -10 subgroup D’Amico et al. , 2004 Gleason score 7+, c. T 3 -4 or PSA>10 ng/ml LHRH analogues advantage Wirth et al. , 2001, Mc. Leod et al. , 2006 T 1 b-T 4 N 0 -1 M 0 bicalutamide advantage in locally advanced disease D’Amico et al. , 2006 Localized or locally advanced, PSA velocity >2 ng/ml/y Not specified advantage Bolla et al. , 1997, 2002 Pilepich et al. , 1997, Lawton et al. , 2001, Pilepich et al. , 2003 Granfors et al. , 1998, 2006

Increased cardiovascular mortality at hormonal therapy after RPE (n=3262) HR: 2. 6; 95% CI: 1. 4 -4. 7; p =0. 002 <65 Jahre 65+ Jahre Tsai et al. , JNCI 2007

Negative consequences of androgen suppression in men with comorbidities and RT in high-risk PCA (randomised trial, n=206) D‘Amico et al. , JAMA 2008

After RPE adjuvant hormonal therapy is not necessary! After radiotherapy an adjuvant hormonal therapy is recommended(side effects!) for at least 3 years.

Summary (I) • good results after RPE • adjuvant / early RT after RPE improves recurrance free survival and offers a second chance of cure • neoadjuvant hormonal therapy after RPE not necessary

Summary (II) • adjuvant hormonal therapy after RPE is not necessary – no survival benefit • radiotherapy + hormonal therapy is recommended • best concept of hormonal therapy adjuvant to radiotherapy is unclear