M. Wirth Department of Urology, Technical University of Dresden

M. Wirth

Department of Urology, Technical University of Dresden

Adjuvant or Salvage Radiotherapy after Radical

Prostatectomy

Adjuvant or Salvage Radiotherapy after Radical Prostatectomy:

Background

6- 3+4 4+3 8-100

20

40

60

80

100

0-4 ng/ml4.1-10 ng/ml

10.1-20 ng/ml20+ ng/ml

% PSA-relapse (0.2 ng/ml) after 10 years

Gleason-ScoreHan, 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


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 22911 (n=1005)

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


wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911 (n=1005)

EORTC trial 22911 (n=1005) clinical progression free survival


Clinical progression-free survival

EORTC trial 22911 (n=1005) biochemical progression free survival


PSA progression-free survival

EORTC trial 22911 (n=1005)

cumulative incidence of locoreg. failure


local progression-free survival

Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005)

Van der Kwast, JCO 2007



Margins

ECE

SV

Gleason

Postop. PSA





control arm



immediate postoperative radiation

EORTC trial 22911 (n=1005) cumulative incidence of late complications


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 2006

100

60

80

40

20

0

Per

cent

age



Overall survival p=0.023



Metastatic-free survival p=0.016



Metastatic-free survival, PSA < / > 0.2 p=0.03



Summary

Wiegel et al., ASCO 2005 [in press as full article: J Clin Oncol 2009]

adjuvant RT (60 Gy) no adjuvant RT

Adjuvant radiotherapy after RPE (ARO 96-02 / AUO AP 09/95 , pT3R0-1, PSA 0, n=108)

% PSA recurrence after 4 years

0

20

40

60

80

100p<0.0001, hazard ratio 0.4

81 %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 prostatectomyfor 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


PCA specific survival

PSA failure following salvage radiotherapy – CaPSURE data (retrospective study, n=194)

Macdonald et al., Urol Oncol 2008

0 20 40 60 80 100

time / months

0,0

0,2

0,4

0,6

0,8

1,0

p b

ne

d

PSA ≤ 0,5 ng/ml

PSA ≥ 0,5 ng/ml

p = 0,031 (log rank test)

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 efficacyLiterature review

Bottke and Wiegel, Urologe 2008

35-54 %

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


Taylor et al., IntJRadOncBiolPhys 2003



Adjuvant RT



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)


No biochemical failure

Adjuvant RTX for pN+ disease (retrospective study, n=250)


PCA-specific survival

p<0.0001

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=130.375 vs. 375.235)

PCA, no RT0

1.5

0.5

odds-ratio for secondary malignancy

1

2

1.89 (1.85-1.95)

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)

0 100 200 300 400 500 6000

20

40

60

80

100

weeks after RPE

recurrence-free survival [%]

log-rank-Test, p=0.0041

0 100 200 300 400 500 6000

20

40

60

80

100survival [%]

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

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

benefit flutamidepT3-4pN0

Wirth et al., 2004

no difference

benefit bicaluta-mide

T1b-T4Mc Leod et al., 2006

no data available

benefit LHRH- analog

stage CPrayer-Galetti et al., 2000

benefit benefitorchiectomy 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

6- 3+4 4+3 8-100

20

40

60

80

100

0-4 ng/ml4.1-10 ng/ml

10.1-20 ng/ml20+ ng/ml

% PSA-relapse (0.2 ng/ml) after 10 years

Gleason-ScoreHan, 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


cT3: MSKCC-Nomogramm:pT-Stage Exampel: cT3, PSA 10 ng/ml, Gleason 3+3=6


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

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)


wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911

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


wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911

EORTC trial 22911 clinical progression free survival


EORTC trial 22911 biochemical progression free survival


EORTC trial 22911 cumulative incidence of locoreg. failure


Patients who benefit from immediate postoperative RT – EORTC trial 22911


Wiegel et al., ASCO 2005

adjuvant RT (60 Gy) no adjuvant RT

Adjuvant Radiotherapy after RPE (ARO 96-02 / AUO AP 09/95 , pT3R0-1, PSA 0, n=108)

% PSA recurrence after 4 years

0

20

40

60

80

100p<0.0001, hazard ratio 0.4

81 %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



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



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

0.51-1.0 ng/ml

1.01-1.50 ng/ml1.51+ ng/ml

PSA Failure following Salvage Radiotherapy – CaPSURE data

Macdonald et al., UrolOncolSemOrigInv 2008

Adjuvant Radiotherapy or after PSA-Recurrence (n=162)



Jereczek-Fossa, IntJRadOncolBiolPhys 2008

Adjuvant RT

Salvage RT



p<0.0001

RT for PSA-Recurrence after RPE: Dosage?(n=122)

0 3 6 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<0.0001PSA 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

Authors Stages Regimen Progression Survival

Bolla et al., 1997, 2002 T1-T4N0-x LHRH analogues

advantage advantage

Pilepich et al., 1997, Lawton et al., 2001, Pilepich et al., 2003

stage C or D1 LHRH analogues

advantage advantage

Granfors et al., 1998, 2006 T1-4N0-1 orchiectomy advantage advantage in N1 subgroup

Hanks et al., 2003 T2b-T4, PSA<150 ng/ml

LHRH analogues plus

flutamide

advantage advantage in Gleason score 8-10 subgroup

D’Amico et al., 2004 Gleason score 7+, cT3-4 or

PSA>10 ng/ml

LHRH analogues

advantage advantage

Wirth et al., 2001,McLeod et al., 2006

T1b-T4N0-1M0

bicalutamide advantage advantage in locally

advanced disease

D’Amico et al., 2006 Localized or locally advanced, PSA velocity

>2ng/ml/y

Not specified advantage advantage

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 Jahre 65+ Jahre

HR: 2.6; 95% CI: 1.4-4.7; 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)

Documents

M. Wirth Department of Urology, Technical University of Dresden