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

2. 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

3. 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

4. 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

5. Adjuvant Radiation Therapy Declining in Utilization
12% 7%

6. Adjuvant Radiation Therapy Pathologic Indications
Extraprostatic extension
Seminal Vesicle invasion
Positive Surgical Margins

7. Adjuvant Radiation Therapy Prospective Randomized Clinical Trials
Study No. Years Patients
SWOG
EORTC
ARO

8. Adjuvant Radiation Therapy Eligibility
SWOG
EORTC
ARO
Exraprostatic extension
+ S.V.
+ Margins
Undetectable PSA

9. Adjuvant Radiation Therapy Endpoints
SWOG
EORTC
ARO
Biochemical Relapse Free survival
Local Relapse
Metastasis Free Survival
Overall Survival

10. Adjuvant Radiation Therapy Results
Freedom Biochemical
from
Relapse
Local
Control RP
RP+RT
Actuarial Endpoint
ARO 54
72* NS
5 yrs
EORTC 53
74* 85
95*
SWOG 44 78
92* 25
51*
10 yrs
*Statistically significant with RT
All numbers are in percentages

11. Adjuvant Radiation Therapy Results
Clinical
Free
Disease
Survival
Metastasis Survival
Overall RP
RP+RT
Actuarial Endpoint
ARO NS 95 97
5 yrs
EORTC 81
91* 94 93 92
SWOG 70
84* 82 87 90 91 49
70* 61
71* 66
74*
10 yrs
*Statistically significant with RT
All numbers are in percentages

12. Radical Prostatectomy Adjuvant Androgen Suppression
Study
Outcome
+ Pelvic Lymph Nodes
Messing Prospective Randomized
Improved Survival
+S.V., +Margins,
Extracapsular extension
RTOG 8531 – Subset Analysis
MRC PR 10
Accruing
EORTC

13. 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

14. 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

15. 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

16. Radical Prostatectomy GPSM Scoring Algorithm
GPSM – Prostatectomy Gleason Score
+ 1 (Pre-op PSA 4-10)
+ 2 (Pre-op PSA )
+ 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

17. GPSM Scoring Outcomes

18. 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

19. Radical Prostatectomy: PSA doubling time
Strongly associated with clinical relapse
PSAdt <3 months: Short life expectancy
PSAdt <12 months: 50-75% of patients with clinical relapse within 10 years
PSAdt <15 months: 90% deaths due to prostate cancer
PSAdt >15 months: 33% deaths due to prostate cancer

20. Radical Prostatectomy: Biochemical Relapse
Abnormal CT is rare with:
PSA < 5-10 ng/ml
PSAdt > 6-10 months
Abnormal bone scan is rare with:
PSA < 10 ng/ml

21. Radical Prostatectomy: Biochemical Relapse – MRI findings
Sensitivity Specificity Accuracy
Endorectal MR % % %
Local Recurrence averaged 1.5 cm in diameter
Patients typically had PSA levels > 2 ng/ml

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

23. Biochemical Relapse: Salvage Prostate Bed Radiation Therapy Results
Author
Pt., No.
Salvage RT Dose Median (Gy)
Biochemical Response %
BCR-free%
Endpoint
actuarial
Neuhof
171
63.0 83 35
5-yr
Ward
211
64.0 90
48-66
5-yr.
Brooks
114 69 33
6-yr.
Stephenson
1540
64.8 59 32
Maier
170
68.0 - 44
7-yr.
Buskirk
368 30
8-yr.
Pazona
223 73 25
10-yr.

24. 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

25. Salvage Prostate Bed Radiation Therapy Prognostic Scoring Systems
Stephenson Nomogram
Mayo Scoring System

26. Stephenson Nomogram

27. Stephenson Algorithm

28. Mayo Scoring System

29. Mayo Scoring System
Points y BCR %
2 53%
3 26% %

30. Dose Response Analysis

31. Dose Response PSA <0.6

32. Dose Response >0.6

33. 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 + bicalutamide
Medical Research Council PR 10
Prostate fossa RT + 6 months androgen suppression
Prostate fossa RT + 2 years androgen suppression

34. 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

35. 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

36. 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
Macdonald 42 95 27
Wiegal 20
65.0 68
vander Kooy 35 56
8 yrs
Syndikus 26
52.0 54
10 yrs

37. RTOG guidelines salvage RT

38. Positive apical margin + bCR

39. ECE + SVI

40. Dose Constraints Rectum Bladder Femori Comments RTOG 0534 V40<45%
Rectum:rectosigmoid junction  ischium; bladder: entire; femori: head  intertrochanter
Cozzarrini
V50<63%
V55<57%
V60<50% -
Rectum: rectosigmoid junction  anal verge
Fonteyne
V40<84%
V50<68%
V60<59%
V65<48%
Rectal wall: 0.6 cm superior to target volume  inferiorly
Sidhom
V60<40%
Rectum: rectosigmoid junction  1.5 cm inferior of CTV

41. Post-op Prostate Bed Radiation Therapy Adverse Effects
Early: During RT or within 90 days of RT completion
Late: Effects which occur or persist after 90 days of RT completion

42. Post-op Prostate Bed Radiation Therapy Adverse Effects
Prognostic Factors
Antecedent Surgery
RT Treatment Planning
RT Treatment Techniques
RT Dose Volumetric Perimeters
Imaging and localization methods

43. Post-op Prostate Bed Radiation Therapy Early Adverse Effects
Dysuria
Urgency/Frequency
Proctalgia
Increased daily stools
Hematochezia

44. Post-op Prostate Bed Radiation Therapy Early Adverse Effects
Prognostic Factors
Rectal dose
Pelvic nodal RT
Diabetes Mellitus
Hemorrhoids
Androgen Suppression
Anticoagulant Use

45. Post-op Prostate Bed Radiation Therapy Late Adverse Effects
Late grade >2 adverse events is <20% at 5 years
Prevalence is considerably less as many adverse events are not chronic
Severe events are <1%

46. Post-op Prostate Bed Radiation Therapy Late Adverse GI Effects
Increased or urgent stools/tenesmus
Proctalgia
Hematochezia
Mucous discharge
Rectal stricture
Fecal incontinence (0.2%)
Five-year incidence of >2 GI events is <5%
Severe GI events are uncommon <1%

47. Post-op Prostate Bed Radiation Therapy Late Adverse GU Effects
Difficult to accurately attribute late GU effects causality because both surgery and RT contribute
Incidence of grade >2 late effects is approximately 10%
Bladder Neck Contracture
Urethral stricture 5%
Dysuria
Transient hemturia (5%)

48. Post-op Prostate Bed Radiation Therapy Late Adverse GU Effects
Urinary incontinence is comparable to surgery alone
If urinary incontinence occurs, it is typically of mild, stress-induced nature
RT does not appear to diminish erectile dysfunction in men who undergo nerve-sparing prostatectomy

49. Post-op Prostate Bed Radiation Therapy –Late Side Effects
Mayo Clinic Jacksonville
Retrospectively reviewed 308 patients who received salvage radiation therapy for a detectable PSA after prostatectomy
Aim: Evaluate the nature and severity of late GI and GU toxicity associated with salvage radiation therapy

50. Post-op Prostate Bed Radiation Therapy –Late Side Effects
Mayo Clinic Jacksonville
GU toxicity
Grade 2: 7.7%
Grade 3-4: 1%
Included 3 patients with cystitis
14 of 18 patients who developed urethral strictures required dilatation
3.4% of patients had worsening urinary control

51. Post-op Prostate Bed Radiation Therapy –Late Side Effects
Mayo Clinic Jacksonville
GI toxicity
Grade 2: 1.3%
Grade 3-4: 0.3%
Included one patient that required a diverting colostomy

52. Comparison of Late GI Toxicity
Pro/Retrospective Adjuvant/Salvage Trials
# pts.
F/U mths.
Grade 2
Grade 3
Grade 4
Our results
308 61
1.3% 0%
0.3%
Bolla et al.
EORTC 22911
1005 45
2.5%
Thompson et al.
SWOG 8794
214
127
3.3%
Feng et al.
959 55 4%
0.4%
Zelefsky et al. 42 24 5%
Choo et al. 98 50
Forman et al. 16 -

53. Post-op Prostate Bed Patient Reported Quality of Life
Pinkawa et al. (Modern salvage RT technology)
Reduced urinary frequency and bother only at end of RT
Reduced bowel function and bother was reported through 2 months, but not thereafter