Post-operative Radiation Therapy following Radical Prostatectomy for Prostate Cancer 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 1992-20011005

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





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





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



• 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



• 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

Documents

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