Post-operative Radiation Therapy following

Post-operative Radiation Therapy following Radical Prostatectomy for Prostate Cancer Stephen Ko, M.D. Mayo Clinic Jacksonville

Prostate Cancer • One third of patients undergo radical prostatectomy as initial therapy • 25-33% of patients are at risk of treatment failure following radical prostatectomy • 60-70% will develop metastatic disease within 10 years without further treatment

Post-operative Radiation Therapy following Radical Prostatectomy • Adjuvant radiotherapy – presence of adverse factors – undetectable PSA • Salvage Radiotherapy – rising PSA • Salvage Radiotherapy – clinically apparent recurrent tumor in the prostatic fossa

Adjuvant Radiation Therapy Rationale • Residual disease in the prostatic fossa is the primary cause of treatment failure • A substantial number of cells may be present before PSA is detectable • Greatest opportunity for cure exists when the cells are fewest in number and localized

Adjuvant Radiation Therapy Declining in Utilization 12%

1998-2000

7%

2004-2005

Adjuvant Radiation Therapy Pathologic Indications • Extraprostatic extension • Seminal Vesicle invasion

• Positive Surgical Margins

Adjuvant Radiation Therapy Prospective Randomized Clinical Trials Study SWOG

No. 8794

Years Patients 1988-1997 425

EORTC

22911

1992-2001

1005

ARO

9602

1997-2004

268

Adjuvant Radiation Therapy Eligibility SWOG

Exraprostatic extension + S.V. + Margins Undetectable PSA

EORTC

ARO

Adjuvant Radiation Therapy Endpoints SWOG Biochemical Relapse Free survival

Local Relapse Metastasis Free Survival Overall Survival

EORTC

ARO

Adjuvant Radiation Therapy Results Freedom from Biochemical Relapse

Local Control

RP

RP+RT

RP

RP+RT

Actuarial Endpoint

ARO

54

72*

NS

NS

5 yrs

EORTC

53

74*

85

95*

5 yrs

SWOG

44

72*

78

92*

5 yrs

25

51*

78

92*

10 yrs

*Statistically significant with RT All numbers are in percentages

Adjuvant Radiation Therapy Results Clinical Disease Free Survival

Metastasis Free Survival

Overall Survival

RP

RP+RT

RP

RP+RT

RP

RP+RT

Actuarial Endpoint

ARO

NS

NS

NS

NS

95

97

5 yrs

EORTC

81

91*

94

94

93

92

5 yrs

SWOG

70

84*

82

87

90

91

5 yrs

49

70*

61

71*

66

74*

10 yrs

*Statistically significant with RT All numbers are in percentages

Radical Prostatectomy Adjuvant Androgen Suppression Study

Outcome

+ Pelvic Lymph Nodes

Messing Prospective Randomized

Improved Survival

+S.V., +Margins, Extracapsular extension

RTOG 8531 – Subset Analysis

Improved Survival

MRC PR 10

Accruing

EORTC 22043-33041

Accruing

Post-operative Radiation Therapy following Radical Prostatectomy • Adjuvant radiotherapy – presence of adverse factors – undetectable PSA • Salvage Radiotherapy – rising PSA • Salvage Radiotherapy – clinically apparent recurrent tumor in the prostatic fossa

Salvage Radiotherapy • PSA Serum Half-Life = 3.1 days

• PSA should be undetectable > 4 weeks after RP • Biochemical Relapse – AUA > 0.2, twice consecutively – Stephenson > 0.4, twice consecutively

Radical Prostatectomy: Biochemical Relapse Factors Associated with Metastatic Disease and Death • Persistently elevated PSA after Prostatectomy • Shorter interval from surgery to biochemical relapse • Shorter PSA doubling time • Higher Gleason Scores • Higher GPSM Scores • Non-diploid tumor DNA

Radical Prostatectomy GPSM Scoring Algorithm GPSM – Prostatectomy Gleason Score + 1 (Pre-op PSA 4-10) + 2 (Pre-op PSA 10.1-20) + 3 (Pre-op PSA >20) + 2 (+S.V. or +Nodes) + 2 (Positive Surgical Margins) GPSM score of >10: Increased biochemical relapse; Increased risk of death

GPSM Scoring Outcomes

Radical Prostatectomy: Post-op PSA kinetics (doubling time) • PSA Working Group Guidelines for PSAdt calculations • >3 PSA values which are >0.2 ng/ml and increasing within 12 months • Stable testosterone levels (not recovering from androgen suppression) • Relationship of PSAdt clinical relapse and mortality – continuum

Radical Prostatectomy: PSA doubling time • Strongly associated with clinical relapse • PSAdt 2 ng/ml

Biochemical Relapse MRI sites of Recurrence • Vesicourethral anastomosis: 44% • Retrovesicle space: 30% • Seminal vesicle region: 23%

Biochemical Relapse: Salvage Prostate Bed Radiation Therapy Results Author

Pt., No.

Salvage RT Dose Median (Gy)

Neuhof

171

63.0

83

35

5-yr

Ward

211

64.0

90

48-66

5-yr.

Brooks

114

64.0

69

33

6-yr.

Stephenson

1540

64.8

59

32

6-yr.

Maier

170

68.0

-

44

7-yr.

Buskirk

368

64.8

-

30

8-yr.

Pazona

223

63.0

73

25

10-yr.

Biochemical Response %

BCR-free%

Endpoint actuarial

Salvage Prostate Bed Radiation Therapy Prognostic Factors • • • • • • • • •

Prostatectomy Gleason Score Tumor DNA ploidy Persistently detectable post-op PSA PSA level before prostatectomy PSAdt postoperatively Surgical Margin status Seminal vesicle invasion Pelvic lymph node involvement Delay in initiation of salvage RT

Salvage Prostate Bed Radiation Therapy Prognostic Scoring Systems

• Stephenson Nomogram • Mayo Scoring System

Stephenson Nomogram

Stephenson Algorithm

Mayo Scoring System

Mayo Scoring System Points

5y BCR

0-1

69%

2

53%

3

26%

4-5

6%

Dose Response Analysis

Dose Response PSA 0.6

Salvage Radiation Therapy +/Androgen Suppression •

RTOG 9601 – Prostate fossa – RT + placebo – RT + bicalutamide

•

RTOG 0534 – Prostate fossa RT – Prostate fossa RT with androgen suppression – Prostate fossa + Node RT with androgen suppression

•

Japan Clinical Oncology Group 0401 – Prostate fossa RT – Prostate fossa RT + bicalutamide

•

Medical Research Council PR 10 – Prostate fossa RT – Prostate fossa RT + 6 months androgen suppression – Prostate fossa RT + 2 years androgen suppression

Salvage Radiation Therapy Consensus Based Guidelines • Organizations which support offering salvage RT to all men with a detectable PSA – – – –

NCCN European Association of Urology European Society of Medical Oncology Australian and New Zealand Radiation Oncology Genito-Urinary Group

Post-operative Radiation Therapy following Radical Prostatectomy • Adjuvant radiotherapy – presence of adverse factors – undetectable PSA • Salvage Radiotherapy – rising PSA • Salvage Radiotherapy – clinically apparent recurrent tumor in the prostatic fossa

Radical Prostatectomy Clinically-Apparent Local Recurrence Author

Pt, No.

RT Dose Median (Gy)

Local control %

BCR-free%

Actuarial Endpoint

Koppie

34

68.4

-

39

3 yrs

Cadeddu

25

64.0

-

14

5 yrs

Choo

44

63.0

97

11

5 yrs

Macdonald

42

68.4

95

27

5 yrs

Wiegal

20

65.0

95

68

5 yrs

vander Kooy

35

64.0

97

56

8 yrs

Syndikus

26

52.0

54

-

10 yrs

RTOG guidelines salvage RT

Positive apical margin + bCR

ECE + SVI

Dose Constraints Rectum

Bladder

Femori

Comments

RTOG 0534

V40