Post-operative Radiation Therapy following Radical Prostatectomy for Prostate Cancer

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Post-operative Radiation Therapy following
Radical Prostatectomy for Prostate Cancer

• Stephen Ko, M.D.
• Mayo Clinic Jacksonville

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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

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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

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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

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Adjuvant Radiation Therapy Declining in
Utilization

• 12 1998-2000
• 7 2004-2005

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Adjuvant Radiation Therapy Pathologic Indications

• Extraprostatic extension
• Seminal Vesicle invasion
• Positive Surgical Margins

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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

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Adjuvant Radiation TherapyEligibility
SWOG EORTC ARO
Exraprostatic extension
S.V.
Margins
Undetectable PSA
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Adjuvant Radiation Therapy Endpoints
SWOG EORTC ARO
Biochemical Relapse Free survival
Local Relapse
Metastasis Free Survival
Overall Survival
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Adjuvant Radiation Therapy Results
Freedom Biochemical from Relapse Local Control
RP RPRT RP RPRT 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
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Adjuvant Radiation Therapy Results
Clinical Free Disease Survival Metastasis Survival Free Overall Survival
RP RPRT RP RPRT RP RPRT 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
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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
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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

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Salvage Radiotherapy

• PSA Serum Half-Life 3.1 days
• PSA should be undetectable gt 4 weeks after RP
• Biochemical Relapse
• AUA gt 0.2, twice consecutively
• Stephenson gt 0.4, twice consecutively

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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

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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 gt20)
• 2 (S.V. or Nodes)
• 2 (Positive Surgical Margins)
• GPSM score of gt10 Increased biochemical relapse
  Increased risk of death

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GPSM Scoring Outcomes
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Radical ProstatectomyPost-op PSA kinetics
(doubling time)

• PSA Working Group Guidelines for PSAdt
  calculations
• gt3 PSA values which are gt0.2 ng/ml and increasing
  within 12 months
• Stable testosterone levels (not recovering from
  androgen suppression)
• Relationship of PSAdt clinical relapse and
  mortality continuum

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Radical ProstatectomyPSA doubling time

• Strongly associated with clinical relapse
• PSAdt lt3 months Short life expectancy
• PSAdt lt12 months 50-75 of patients with
  clinical relapse within 10 years
• PSAdt lt15 months 90 deaths due to prostate
  cancer
• PSAdt gt15 months 33 deaths due to prostate
  cancer

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Radical ProstatectomyBiochemical Relapse

• Abnormal CT is rare with
• PSA lt 5-10 ng/ml
• PSAdt gt 6-10 months
• Abnormal bone scan is rare with
• PSA lt 10 ng/ml

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Radical ProstatectomyBiochemical 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 gt 2 ng/ml

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Biochemical RelapseMRI sites of Recurrence

• Vesicourethral anastomosis 44
• Retrovesicle space 30
• Seminal vesicle region 23

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Biochemical RelapseSalvage 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 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.
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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

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Salvage Prostate Bed Radiation Therapy Prognostic
Scoring Systems

• Stephenson Nomogram
• Mayo Scoring System

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Stephenson Nomogram
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Stephenson Algorithm
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Mayo Scoring System
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Mayo Scoring System
Points 5y BCR 0-1 69 2 53 3 26 4-5
6
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Dose Response Analysis
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Dose Response PSA lt0.6
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Dose Response gt0.6
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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

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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

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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

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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
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RTOG guidelines salvage RT
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Positive apical margin bCR
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ECE SVI
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Dose Constraints
Rectum Bladder Femori Comments
RTOG 0534 V40lt45 V65lt25 V40lt60 V65lt40 V50lt10 Rectumrectosigmoid junction ? ischium bladder entire femori head ? intertrochanter
Cozzarrini V50lt63 V55lt57 V60lt50 - - Rectum rectosigmoid junction ? anal verge
Fonteyne V40lt84 V50lt68 V60lt59 V65lt48 - - Rectal wall 0.6 cm superior to target volume ? inferiorly
Sidhom V40lt60 V60lt40 - - Rectum rectosigmoid junction ? 1.5 cm inferior of CTV
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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

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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

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Post-op Prostate Bed Radiation Therapy Early
Adverse Effects

• Dysuria
• Urgency/Frequency
• Proctalgia
• Increased daily stools
• Hematochezia

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Post-op Prostate Bed Radiation Therapy Early
Adverse Effects

• Prognostic Factors
• Rectal dose
• Pelvic nodal RT
• Diabetes Mellitus
• Hemorrhoids
• Androgen Suppression
• Anticoagulant Use

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Post-op Prostate Bed Radiation Therapy Late
Adverse Effects

• Late grade gt2 adverse events is lt20 at 5 years
• Prevalence is considerably less as many adverse
  events are not chronic
• Severe events are lt1

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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 gt2 GI events is lt5
• Severe GI events are uncommon lt1

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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 gt2 late effects is
  approximately 10
• Bladder Neck Contracture
• Urethral stricture 5
• Dysuria
• Transient hemturia (5)

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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

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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

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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

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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

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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 2.5 2.5
Thompson et al. SWOG 8794 214 127 3.3 3.3 3.3
Feng et al. 959 55 4 0.4 0.3
Zelefsky et al. 42 24 5 5 5
Choo et al. 98 50 4 4 0
Forman et al. 50 16 - 0 0
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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