Stephen Ko, M.D. Mayo Clinic Jacksonville 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 1992-2001 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

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

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

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 22043-33041

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 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 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) 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.

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 + bicalutamide Medical Research Council PR 10 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 Macdonald 42 95 27 Wiegal 20 65.0 68 vander Kooy 35 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% 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

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% Zelefsky et al. 42 24 5% Choo et al. 98 50 Forman et al. 16 -

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