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 <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
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
Radical Prostatectomy:
Biochemical Relapse – MRI findings
• Endorectal MR
Sensitivity
Specificity
Accuracy
84-95%
89-100%
86-94%
• Local Recurrence averaged 1.5 cm in diameter
• Patients typically had PSA levels > 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
Dose Response >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<45%
V65<25%
V40<60%
V65<40%
V50<10%
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
V40<60%
V60<40%
-
-
Rectum: rectosigmoid junction 
1.5 cm inferior of CTV
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
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
Post-op Prostate Bed Radiation
Therapy Early Adverse Effects
•
•
•
•
•
Dysuria
Urgency/Frequency
Proctalgia
Increased daily stools
Hematochezia
Post-op Prostate Bed Radiation
Therapy Early Adverse Effects
• Prognostic Factors
– Rectal dose
– Pelvic nodal RT
– Diabetes Mellitus
– Hemorrhoids
– Androgen Suppression
– Anticoagulant Use
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%
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%
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%)
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 nervesparing prostatectomy
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
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
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
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
Zelefsky et al.
42
24
Choo et al.
98
50
Forman et al.
50
16
4%
0.4%
0.3%
5%
4%
-
0%
0%
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
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