Transcript 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% 7% 1998-2000 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 1988-1997 Patients 425 EORTC 22911 1992-2001 1005 ARO 9602 1997-2004 268
Adjuvant Radiation Therapy
Eligibility
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
ARO Adjuvant Radiation Therapy
Results
Freedom Biochemical from Relapse Local Control RP RP+RT RP RP+RT Actuarial Endpoint 54 72* NS NS 5 yrs EORTC SWOG 53 44 25 74* 72* 51* 85 78 78 95* 92* 5 yrs 5 yrs 92* 10 yrs
*Statistically significant with RT All numbers are in percentages
Adjuvant Radiation Therapy
Results
Clinical Free Disease Survival Metastasis Survival Free Overall Survival RP RP+RT RP RP+RT RP RP+RT Actuarial Endpoint ARO NS EORTC 81 SWOG 70 49 NS 91* 84* 70* NS 94 82 61 NS 94 87 71* 95 93 97 92 5 yrs 5 yrs 90 91 5 yrs 66 74* 10 yrs
*Statistically significant with RT All numbers are in percentages
Radical Prostatectomy Adjuvant Androgen Suppression + Pelvic Lymph Nodes +S.V., +Margins, Extracapsular extension Study Outcome Messing Prospective Randomized RTOG 8531 – Subset Analysis Improved Survival 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 84-95% Specificity 89-100% Accuracy 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 Neuhof Ward Brooks Stephenson Maier Buskirk Pazona Pt., No.
171 211 114 1540 170 368 223 Salvage RT Dose Median (Gy) 63.0
64.0
64.0
Biochemical Response % 83 90 69 64.8
68.0
59 BCR-free% 35 48-66 33 32 44 64.8
63.0
73 30 25 Endpoint actuarial 5-yr 5-yr. 6-yr. 6-yr. 7-yr. 8-yr. 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 2 69% 53% 3 4-5 26% 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 Koppie Cadeddu Choo Macdonald Wiegal vander Kooy Syndikus Pt, No.
34 25 44 42 20 35 26 RT Dose Median (Gy) 68.4
64.0
63.0
68.4
65.0
64.0
52.0
Local control % 97 95 95 97 54 BCR-free% 39 14 11 27 68 56 Actuarial Endpoint 3 yrs 5 yrs 5 yrs 5 yrs 5 yrs 8 yrs 10 yrs
RTOG guidelines salvage RT
Positive apical margin + bCR
ECE + SVI
Dose Constraints
Rectum Bladder RTOG 0534 Cozzarrini Fonteyne Sidhom V 40 <45% V 65 <25% V 50 <63% V 55 <57% V 60 <50% V 40 <84% V 50 <68% V 60 <59% V 65 <48% V 40 <60% V 60 <40% V 40 <60% V 65 <40% Femori Comments V 50 <10% Rectum:rectosigmoid junction ischium; bladder: entire; femori: head intertrochanter Rectum: rectosigmoid junction anal verge Rectal wall: 0.6 cm superior to target volume inferiorly 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 Our results Bolla et al.
EORTC 22911 Thompson et al.
SWOG 8794 Feng et al.
Zelefsky et al.
Choo et al. Forman et al.
# pts.
308 1005 214 959 42 98 50 F/U mths.
Grade 2 Grade 3 Grade 4 61 45 127 55 24 50 16 1.3% 0% 2.5% 3.3% 4% 4% 0.4% 5% 0% 0.3% 0.3% 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