Watchful WaitingActive Surveillance

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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 1970s-1980s
• 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/screeningProblem 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
• lt 10 versus greater than 10
• Change over time - velocity
• Normal prostate lt 0.8 ng/ml/yr
• Low risk cancer lt2.0 ng/ml/yr
• Higher risk cancer gt 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 (p0.01) 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 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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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

• 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

• 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

• 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 gt 25 of cores involved with
  cancer (eg 3/12, 4/16)
• Amount of cancer in any individual biopsy core
  progression to gt 50 of any individual core
  involved with cancer

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Dutasteride vs Placebo for Early Stage PCa

• 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

• 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 lt 7
• Number of cores involved with cancer lt 2 of 8
• Not more than 50 of any individual biopsy core
  is involved with cancer
• Patients must have serum PSA lt 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

• Exclusion Criteria
• Diagnosis of prostate cancer made gt 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 gt 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

• 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

• 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 Early Stage Prostate
Cancer

• Natural History of Untreated Prostate Cancer
• Components of Active Surveillance
• Clinical Trials in Active Surveillance
• Examples of Active Surveillance Cases