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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 No. Years Patients
SWOG 8794 1988-1997 425
EORTC 22911 1992-20011005
ARO 9602 1997-2004 268
Adjuvant Radiation TherapyEligibility
SWOG EORTC ARO
Exraprostatic extension
+ S.V.
+ Margins
Undetectable PSA
Adjuvant Radiation Therapy Endpoints
SWOG EORTC ARO
Biochemical Relapse Free
survival
Local Relapse
Metastasis Free Survival
Overall Survival
Adjuvant Radiation Therapy Results
Freedom Biochemical
from
RelapseLocal Control
RP RP+RT RP RP+RTActuarial 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
Free
Disease
SurvivalMetastasis
SurvivalFree
Overall Survival
RP RP+RT RP RP+RT RP RP+RTActuarial 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 RelapseFactors 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
Sensitivity Specificity Accuracy
• Endorectal MR 84-95% 89-100% 86-94%
• Local Recurrence averaged 1.5 cm in diameter
• Patients typically had PSA levels > 2 ng/ml
Biochemical RelapseMRI 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)
Biochemical Response % BCR-free%
Endpointactuarial
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.
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%
253%
326%
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 TherapyConsensus 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 0534V40<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
SidhomV40<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 nerve-sparing 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 4% 0.4% 0.3%
Zelefsky et al. 42 24 5%
Choo et al. 98 50 4% 0%
Forman et al. 50 16 - 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