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Watchful Waiting/Active Surveillance for Prostate Cancer MA Prostate Ca Symposium May 15, 2006. Martin G. Sanda, M.D. Director, Prostate Care Center at BIDMC Associate Professor, Harvard Medical School. Active Surveillance for Early Stage Prostate Cancer.

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Watchful Waiting/Active Surveillance

for Prostate Cancer

MA Prostate Ca Symposium

May 15, 2006

Martin G. Sanda, M.D.

Director, Prostate Care Center at BIDMC

Associate Professor, Harvard Medical School


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Active Surveillance for Early Stage Prostate Cancer

  • Natural History of Untreated Prostate Cancer

  • Components of Active Surveillance

  • Clinical Trials in Active Surveillance

  • Examples of Active Surveillance Cases


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Natural History of Untreated Prostate Cancer in US Men

  • Albertsen et al JAMA 2005

  • CT Tumor registry

  • Diagnosed n 1970’s-1980’s

  • No Surgery or Radiation

  • Followed 20 years later

  • Death from prostate cancer vs death from other causes


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Natural History of Untreated Prostate Cancer in US Men:Gleason score = 6; Age 50-59 vs age 70-79


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Natural History of Untreated Prostate Cancer in US Men:Gleason score = 6 vs Gleason score =5 (Age 50-59)


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Natural History of Untreated Prostate Cancer in US Men:Gleason score = 6 vs Gleason =7 (Age 50-59)


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PCA Early detection/screening:Problem: most screen-detected PCa less aggressive (Andriole et al JNCI 2005)


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Active Surveillance for Early Stage Prostate Cancer

  • Natural History of Untreated Prostate Cancer

  • Components of Active Surveillance

  • Clinical Trials in Active Surveillance

  • Examples of Active Surveillance Cases


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Components of Active Surveillance

  • Biopsy Elements/Histopathology

  • Clinical Stage DRE findings

  • PSA

  • Imaging


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Components of Active Surveillance

Biopsy Elements/Histopathology

  • Gleason score

  • Amount of cancer on biopsy cores

    • Number of cores involved (proportion of 12)

    • Amount of cancer in the cores (in core with greatest cancer)

  • Other features

    • Perineural invasion


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Components of Active Surveillance

Clinical Staging - Rectal exam

  • Stage T1 – cancer not palpable

    • T1a/b: on TRUP

    • T1c: due to PSA

  • Stage T2 – nodularity limited to prostate

    • T2a: less than ½ of one side

    • T2b: more than ½ of one side

    • T2c: both sides

  • Stage T3 – nodularity beyond prostate (Seminal vesicles or extracapsular)


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Components of Active Surveillance: PSA

  • Single value

    • < 10 versus greater than 10

  • Change over time - velocity

    • Normal prostate: < 0.8 ng/ml/yr

    • Low risk cancer: <2.0 ng/ml/yr

    • Higher risk cancer: > 2.0 ng/ml/yr

  • Confounding factors:

    • Biopsy effect on PSA

    • Infection

    • Ejaculation

    • Hormonal treatment – herbal supplements


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Detecting Aggressive vs Indolent Prostate Cancer: a) Anti-AMACR autoantibody associated with Gleason Score (p=0.01) &b) more accurate in identifying aggressive Ca than PSA by ROC (AUC 0.65 vs 0.55)


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Imaging to Assist Active Surveillance for Prostate Cancer: Contrast-enhanced 3T MRI

56 yrs, PSA = 14.8;

DRE: Right nodularity

MRI: capsular extension

Biopsy: initial – low risk (1/6; 10% Gleason 6) f/u - right 3/6 biopsy cores have cancer (50% of bx core) Gleason = 6


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Active Surveillance for Contrast-enhanced 3T MRIEarly Stage Prostate Cancer

  • Natural History of Untreated Prostate Cancer

  • Components of Active Surveillance

  • Clinical Trials in Active Surveillance

  • Examples of Active Surveillance Cases


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A Randomized Phase II Trial of Dutasteride versus Placebo in Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Martin G. Sanda, M.D. PI

Glenn Bubley, M.D. co-PI

Jonathan Epstein, M.D. co-PI

ECOG GU Early Modalities Subcomittee (GEMS)


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Rationale

  • No currently active NCI or other national protocol for management of patients who opt against or are not suitable for aggressive intervention

  • 5-alpha reductase may prevent low risk prostate cancers with Gleason 6 or less (Thompson et al PCPT)

  • Dutasteride induces prostate cancer apoptosis in pilot clinicla studies (Andriole et al 2005)


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Hypothesis

Conservative management via periodic biopsy with standardized criteria of tumor progression will be a feasible alternative to immediate local therapy in patients with low risk prostate cancer, and a 5 alpha reductase inhibitor will alter tumor progression


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Primary Objective

  • To determine whether histopathological progression of early stage, low risk, primary prostate tumors can be delayed by oral dutasteride.

    Histopathological progression endpoint

  • Gleason score: development of any foci of (new) Gleason pattern 4.

  • Number of biopsy cores involved with cancer: progression to > 25% of cores involved with cancer (eg 3/12, 4/16)

  • Amount of cancer in any individual biopsy core: progression to > 50% of any individual core involved with cancer


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Secondary Objectives

  • To assess PSA velocity/DT and correlate to tumor progression rate

  • To compare HRQOL changes over time between treatment groups

  • To assess histological molecular biomarkers predictive of cancer progression versus non-progression within and across treatment arms

  • To collect serum for later assessment of serum biomarkers predictive of cancer progression versus non-progression within and across treatment arms

  • To compare histopathological evidence of extraprostatic extension and tumor volume among subjects who progress and proceed to radical prostatectomy

  • To compare prostate cancer-specific mortality between treatment groups

  • To assess variance over time and compare between arms alternative measures of histopathological progression (eg aggregate tumor volume, tumor dimension, etc)


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Inclusion Criteria

  • Patients must have prostate adenocarcinoma clinical stage T1 or T2, NX-N0, MX-M0

  • Patients must have biopsy within 6 months before registration that samples at least 6 cores from each side of the prostate and shows the following histopathological findings:

  • Gleason score < 7

  • Number of cores involved with cancer < 2 of 8

  • Not more than 50% of any individual biopsy core is involved with cancer

  • Patients must have serum PSA < 10 ng/ml within 6 months before registration

  • Patients must be at least 18 years of age.

  • Patients must have an ECOG performance status of 0-2.


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Exclusion Criteria

  • Diagnosis of prostate cancer made > 2 years prior to study entry

  • Received any prior treatment for prostate cancer [including prostatectomy (simple or TURP), radiation, hormonal (including LhRh agonist or antagonist, antiandrogen, or 5-alpha reductase inhibitor)]

  • Patients must not receive any other investigational anti-cancer agents during the period on study or the four weeks prior to entry

  • Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer. Patients with other malignancies are eligible if they have been continuously disease-free for > 5 years prior to the time of randomization

  • Patients must not have a serious intercurrent illness


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Study Design: Phase III Randomized Trial

  • Treatment/ARM A

    • Dutasteride (5mg) po + selenium (50ug) daily for 3 years.

  • Treatment/ARM B

    • Placebo po + selenium (50ug) daily for 3 years

      Duration of Follow-up

      For this protocol, all patients, including those who discontinue protocol therapy early, will be followed for response until progression and for survival for 10 years from the date of registration.


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Dutasteride vs Placebo for Early Stage PCa Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or Radiation

Sample Size

  • 380 patients (19- each arm)

  • Power: predict 12-month improvement in histopathological progression(20 months vs 32 months)

    Accrual

  • 10 patients per month x 39 months

  • 6 years to complete


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Active Surveillance for Patients with Early Stage, Low Risk Prostate Cancer Who Choose to Defer Surgery or RadiationEarly Stage Prostate Cancer

  • Natural History of Untreated Prostate Cancer

  • Components of Active Surveillance

  • Clinical Trials in Active Surveillance

  • Examples of Active Surveillance Cases