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

Adjuvant or Salvage Radiotherapy after Radical Prostatectomy: Background

ng/ml ng/ml ng/ml 20+ ng/ml % PSA-relapse (0.2 ng/ml) after 10 years Gleason-Score Han, Partin et al., J Urol 2003 PSA-relapse after RPE in locally advanced PCa (n=2091) preop. PSA

organconfined: 18 % extracapsular: 82 % cT3: MSKCC-Nomogramm: pT Stage Exampel: cT3, PSA 10 ng/ml, Gleason 4+4=8 Ohori, Kattan et al., J Urol 2004

cT3: MSKCC-Nomogramm:pT-Stage Exampel: cT3, PSA 10 ng/ml, Gleason 3+3=6 Ohori, Kattan et al., J Urol 2004 organconfined: 50 % extracapsular: 50 %

Adjuvant or Salvage Radiotherapy after Margin Positive Radical Prostatectomy Patients with R1 after RPE are at an increased risk of biochemical, local and distant failure [1]. With R1, 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

randomised controlled trial pT3 or positive margins, pN0 age < 76 years, WHO perf. status 0-1 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 (n=1005)

age 65 y. (61-69) PSA: 12.4 ng/ml ( ) PSA: 3 weeks after RPE, before RTX 0.2 ( ) 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 wait-and-see vs. immediate postoperative radiotherapy - EORTC trial (n=1005)

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

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

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

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

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

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

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

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

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

Randomised controlled trial clinical T1/T2 preoperatively pT3 or positive margins, N0 M0 WHO perf. status 0-2 Wait-and-see (n=211) vs. Irradition (60-64 Gy, n=214) Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425)

Adjuvant RT in pT3 PCA (randomised study SWOG 8794, n=425) Thompson et al., JAMA Percentage

Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425) Overall survival p=0.023

Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425) Metastatic-free survival p=0.016

Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 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 T3N0M0 PCA – randomised SWOG trial 8794 (n=425) Summary

Wiegel et al., ASCO 2005 [in press as full article: J Clin Oncol 2009] adjuvant RT (60 Gy) no adjuvant RT A djuvant radiotherapy after RPE (ARO / AUO AP 09/95, pT3R0-1, PSA 0, n=108) % PSA recurrence after 4 years p<0.0001, hazard ratio % 60 %

Bottke and Wiegel, Urol Int 2007 RPE with and without adjuvant RT in pT3-PCA

Morgan et al., Radiother Oncol 2008 Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer A systematic review and meta-analysis Survival Biochemical progression

Salvage Radiotherapy vs. Observation at PSA Failure after Radical Prostatectomy

no salvage treatment (n=397) vs. salvage radiotherapy (n=160) vs. salvage radiotherapy + HT (n=78) significant increase of PC-specific survival for both SRT (HR 0.32, p<0.001) and SRT+HT (HR 0.34, p=0.003) improvement limited to patients with - PSA-doubling time < 6 month - SRT within 2 y. after recurrence Trock et al., JAMA 2009 PCA specific survival following salvage RTX vs observation after RPE – survival

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

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

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

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

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

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

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) Trabulsi et al., Urology 2008 Five-year freedom from biochemical failure from end of RT

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

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Jereczek-Fossa, IntJRadOncol 2008 Adjuvant RT Salvage RT n=410

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

Adjuvant and Salvage RTX after RPE Grade 2 or greater rectal and urinary toxicity Jereczek-Fossa, IntJRadOncol 2008 n=410

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003 Adjuvant RT

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003 Salvage RT +/- adj. androgen ablation

Adjuvant RTX for pN+ disease?

Da Pozzo et al., Eur Urol 2009 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.

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

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

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

Chamie et al., AUA 2008 #393 RT in prostate cancer induces secondary malignancies (n= vs ) PCA, no RT odds-ratio for secondary malignancy ( ) PCA, RT !

Risk stratification?

6 % 65 % ! Biological heterogeneity of R1 disease: risk of failure after 2 years, nomogram (n=2911) Walz et al., J Urol 2009 Failure risk:

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 Summary

Adjuvant hormonal therapy?

Prospective randomised study: flutamide vs. control after RPE in pT3-4 pN0 (n=309) weeks after RPE recurrence-free survival [%] log-rank-Test, p= survival [%] log-rank-Test, p=0.92 Flutamide, n=152 control, n=157 Wirth et al., Eur Urol 2004

EPC program: objective progression (prospective randomised trial, n=8116, FU 7.4 y) McLeod et al., BJU Int 2006

EPC program: overall survival (prospective randomised trial, n=8116, FU 7.4 y)

Adjuvant hormonal therapy after RPE for pN+-PCa (randomised trail, n=98, FU 11.9 y) Messing et al., Lancet Oncol 2006

no difference benefitflutamidepT3- 4pN0 Wirth et al., 2004 no difference benefitbicaluta- mide T1b-T4Mc Leod et al., 2006 no data available benefitLHRH- analog stage CPrayer-Galetti et al., 2000 benefit orchiectomy or LHRH- analog pN+Messing et al., 1999, 2003 survivalprogressionregimenstageauthor, year Adjuvant hormonal therapy after RPE

BACKUP

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

ng/ml ng/ml ng/ml 20+ ng/ml % PSA-relapse (0.2 ng/ml) after 10 years Gleason-Score Han, Partin et al., J Urol 2003 PSA-relapse after RPE in locally advanced PCa (n=2091) preop. PSA

organconfined: 18 % extracapsular: 82 % cT3: MSKCC-Nomogramm: pT Stage Exampel: cT3, PSA 10 ng/ml, Gleason 4+4=8 Ohori, Kattan et al., J Urol 2004

cT3: MSKCC-Nomogramm:pT-Stage Exampel: cT3, PSA 10 ng/ml, Gleason 3+3=6 Ohori, Kattan et al., J Urol 2004 organconfined: 50 % extracapsular: 50 %

Bottke and Wiegel, Urol Int 2007 RPE with and without adjuvant RT in pT3-PCA

Randomised controlled trial clinical T1/T2 preoperatively pT3 or positive margins, N0 M0 WHO perf. status 0-2 Wait-and-see (n=211) vs. Irradition (60-64 Gy, n=214) Thompson et al., JUrol 2009 Adjuvant RTX for T3N0M0 PCA – SWOG 8794

Thompson et al., JUrol 2009 Adjuvant RTX for T3N0M0 PCA – SWOG 8794

Adjuvant RT in pT3 PCA (randomised study, n=425) Thompson et al., JAMA Percentage

Thompson et al., JAMA 2006 Adjuvant RT in pT3 PCA (randomised study, n=425)

Randomised controlled trial pT3 or positive margins, pN0 age < 76 years, WHO perf. status 0-1 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

Age 65 y. (61-69) PSA: 12.4 ng/ml ( ) PSA: 3 weeks after RPE, before RTX 0.2 ( ) 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 wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911

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

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

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

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

EORTC trial cumulative incidence of late complications Bolla et al., Lancet 2005

Wiegel et al., ASCO 2005 adjuvant RT (60 Gy) no adjuvant RT A djuvant Radiotherapy after RPE (ARO / AUO AP 09/95, pT3R0-1, PSA 0, n=108) % PSA recurrence after 4 years p<0.0001, hazard ratio % 60 %

PSA Recurrence after RPE: Salvage Radiotherapy vs. Observation

Salvage radiotherapy within 2 years of biochemical recurrence was associated with a significant increase in CaP– 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

no salvage treatment (n=397) vs. salvage radiotherapy (n=160) vs. salvage radiotherapy + HT (n=78) significant increase of PC-specific survival for both SRT (HR 0.32, p<0.001) and SRT+HT (HR 0.34, p=0.003) improvement limited to patients with - PSA-doubling time < 6 month - SRT within 2 y. after recurrence Trock et al., JAMA 2009 PCA specific survival following salvage RTX vs observation after RPE – survival

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

Radiotherapy for PSA-Recurrence (n=1540) Stephenson et al., JCO 2007 bis 0.5 ng/ml ng/ml ng/ml ng/ml

PSA Failure following Salvage Radiotherapy – CaPSURE data Macdonald et al., UrolOncolSemOrigInv 2008

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

Radiotherapy at Biochemical Recurrence after RPE (n=162) Wiegel et al., IJROBOP 2008

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Jereczek-Fossa, IntJRadOncolBiolPhys 2008 Adjuvant RT Salvage RT

Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003

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

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

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 (I)

Salvage-RT should be performed at a low PSA-level << 1.0 ng/ml postoperative RT has a limited effect on patients with pN+ optimal radiation dose unclear Summary (II)

BACKUP

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 (I)

salvage-RT should be performed at a low PSA-level << 1.0 ng/ml postoperative RT has a limited effect on patients with pN+ optimal radiation dose unclear Summary (II)

Radiotherapy + HT vs. hormonal Therapy alone

Thompson et al., JAMA 2006 Adjuvant RT in pT3 PCA (randomised study SWOG 8794, n=425)

RT + hormonal therapy* vs. hormonal therapy* alone in locally advanced PCA (n=875) *flutamide 3x250 mg/d Widmark et al., Lancet 2009 P< PSA recurrence (%)

RT + Hormonal Therapy* vs. Hormonal Therapy* alone in lokally advanced PCA (n=875) P=0.004 Hormonal Therapy alone Radiotherapy + Hormonal Therapy *flutamide 3x250 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 Bolla et al., ASCO 2007 Overall survival

AuthorsStagesRegimenProgressionSurvival Bolla et al., 1997, 2002T1-T4N0-xLHRH analogues advantage Pilepich et al., 1997, Lawton et al., 2001, Pilepich et al., 2003 stage C or D1LHRH analogues advantage Granfors et al., 1998, 2006T1-4N0-1orchiectomyadvantageadvantage in N1 subgroup Hanks et al., 2003T2b-T4, PSA<150 ng/ml LHRH analogues plus flutamide advantageadvantage in Gleason score 8-10 subgroup D’Amico et al., 2004Gleason score 7+, cT3-4 or PSA>10 ng/ml LHRH analogues advantage Wirth et al., 2001, McLeod et al., 2006 T1b-T4 N0-1M0 bicalutamideadvantageadvantage in locally advanced disease D’Amico et al., 2006 Localized or locally advanced, PSA velocity >2ng/ml/y Not specifiedadvantage Adjuvant hormonal treatment after RTX for locally advanced prostate cancer

Increased cardiovascular mortality at hormonal therapy after RPE (n=3262) Tsai et al., JNCI 2007 <65 Jahre65+ Jahre HR: 2.6; 95% CI: ; p =0.002

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

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

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 (I)

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 Summary (II)