Chemoprevention of Prostate Cancer

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Chemoprevention of Prostate Cancer

• Amanda Cashen, M.D.
• Oncology Grand Rounds
• September 5, 2003

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Cancer chemoprevention Definition

• The use of agents to inhibit, delay, or reverse
  carcinogenesis

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From Clin Cancer Res, 2002 8314
Principles of Chemoprevention Multistep
Carcinogenesis
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Principles of Chemoprevention Field
Carcinogenesis

• Patients at risk for epithelial cancer have a
  wide area of carcinogenic tissue change
• Gross premalignant lesions (leukoplakia, polyps)
• Metaplasia, dysplasia
• Molecular changes (gene loss/amplification)
• Multifocal, distinct premalignant lesions can
  progress over a field of tissue
• Chemoprevention can affect the whole field

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Chemoprevention Trials

• Populations
• Primary? healthy, high-risk people
• Secondary? patients with premalignant lesions
• Tertiary? patients with prior cancer

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Chemoprevention Trials

• Phase I Trials
• Short-term dose escalation trials
• To determine the maximum dose that has minimal
  toxicity
• Phase II Trials
• To assess drug activity using surrogate endpoints
  (premalignant lesions or biomarkers)
• Can lead to FDA approval (celecoxib for FAP)
• May not identify important adverse effects
• Cant provide comprehensive risk-benefit
  information

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Chemoprevention Trials

• Phase III Trials
• Gold standard of chemopreventative activity
• Large, long-term, randomized study
• Primary endpoint is invasive cancer
• Can address important secondary endpoints and
  validate surrogate endpoints
• Need to select agents with strong mechanistic or
  experimental basis for inhibition of
  carcinogenesis
• Recruitment and compliance can be difficult

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Chemoprevention Trials v. Chemotherapy Trials
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Pitfalls in chemoprevention

• May reduce standard screening
• Same agent may inhibit and promote carcinogensis
  in different organs (tamoxifen)
• Serious adverse effects of chemopreventative
  agents
• Potentially complex risk-benefit profiles
• Endpoint of invasive cancer is not a proven
  surrogate for survival

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Proposed chemopreventive agents
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Rationale for using finasteride for the
chemoprevention of prostate cancer

• Finasteride inhibits 5a-reductase, lowering
  androgen levels
• Growth and maintenance of the prostate gland are
  dependent on androgens
• Administration of testosterone induces prostate
  tumors in laboratory animals
• Prostate cancer regresses with anti-androgen
  therapy
• Butfinasteride is not effective therapy for
  prostate cancer

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Prostate Cancer Prevention TrialNEJM 2003
349215

• Primary objective
• To determine whether treatment with finasteride
  for 7 years can reduce the prevalence of prostate
  cancer

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Prostate Cancer Prevention TrialMethods

• Eligible participants
• Men gt 55 years old
• Normal DRE, PSA lt 3 mg/ml
• Adequate compliance during placebo run-in period
• Exclusion
• Severe BPH

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Prostate Cancer Prevention TrialMethods

• Treatment
• Finasteride 5 mg qd or placebo x 7 years
• Evaluation
• Annual DRE and PSA (adjusted for finasteride
  use)? prostate biopsy for abnormal DRE or
  reported PSA gt 4.0 ng/ml
• All men were offered an end-of-study biopsy (to
  be performed 7 years /- 90 days from
  randomization)

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Prostate Cancer Prevention TrialStatistics

• Statistical assumptions
• Prevalence of prostate cancer during 7 year study
  will be 6 in placebo group
• 25 reduction in prevalence in finasteride group
  is clinically significant
• 60 of men will either have diagnosis of prostate
  cancer or undergo end-of-study biopsy
• Rate of nonadherence will be 14 and drop-in
  rate will be 5
• Analysis
• Intention-to-treat analysis includes men with
  diagnosis of prostate cancer or end-of-study
  biopsy

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Prostate Cancer Prevention TrialResults

• 18,882 men randomized
• Study was terminated 15 months early
• 86.3 completed the study

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Prostate Cancer Prevention TrialResults

• Prostate cancer detected in 18.4 of finasteride
  group v. 24.4 of placebo group? relative risk
  reduction of 24.8
• No difference in survival (5 deaths from prostate
  cancer in each group)
• More high grade tumors (Gleason 7-10) in
  finasteride group (37.0 of tumors) v. placebo
  group (22.2 of tumors)

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Cumulative incidence of prostate cancer diagnosed
in a biopsy performed for cause or after an
interim procedure
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Grade of prostate cancers detected

• Prevalence of high grade tumors 6.4 in
  finasteride group v 5.1 in placebo group
  (Plt0.001)
• Relative risk of a high-grade tumor with
  finasteride treatment v placebo 1.27 1.07-1.50

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Prostate Cancer Prevention TrialResults

• Adherence
• Rate of nonadherence (percentage of days of
  treatment missed) 14.7 in finasteride group,
  10.8 in placebo group
• Drop-in rate in placebo group 6.5 (by
  measurement of dihydrotestosterone level)
• 36.8 in finasteride group and 28.9 in placebo
  group temporarily discontinued treatment during
  the study

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Prostate Cancer Prevention Trial

• Conclusions
• Finasteride use for 7 years decreased the
  prevalence of prostate cancer by 24.8
• BUT the prevalence of high grade prostate cancer
  was higher in the finasteride-treated group (6.4
  v. 5.1)
• Prostate cancer may have been overdiagnosed in
  the study

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Prostate Cancer Prevention TrialChallenges

• Why was the rate of prostate cancer detection so
  high?
• Lifetime risk of prostate cancer diagnosis is
  16.7
• Prostate cancer is found at autopsy in 30-40 of
  men older than 50
• Were the prostate cancers found clinically
  significant?
• The cancers found in this study were mostly low
  or intermediate grade and 98 were T1 or T2

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Prostate Cancer Prevention TrialChallenges

• Why were there more high grade tumors in the
  finasteride group?
• Increased sampling with needle biopsy
• Reduction of intraprostatic androgen levels may
  give competitive advantage to high grade tumors
• Reduction of PSA level by finasteride may have
  delayed diagnosis

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Chemoprevention Future Directions

• Identifying and validating biomarkers and other
  secondary endpoints
• Allows design of more efficient and cheaper
  chemoprevention trials
• Combination chemoprevention (for example, a
  promoter of differentiation with an
  anti-proliferative agent)
• Preventative pharmacogenomicstargeting
  chemoprevention to those at genetic risk

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Progression of Oral Cancer
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Rationale for using retinoids for the
chemoprevention of head and neck cancer

• Retinoids are required for the normal growth and
  differentiation in epithelial cells
• Retinoids can suppress or reverse epithelial
  carcinogenesis in animal models
• Retinoic acid receptor-beta is suppressed in head
  and neck pre-malignant lesions, and its
  expression is upregulated by 13-cis retinoic acid
  (correlates with clinical response)

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Rationale for using retinoids for the
chemoprevention of head and neck cancer

• Retinoids can reverse oral premalignant lesions
• 3 months of isotretinoin (13-cis-retinoic acid) 2
  mg/kg/d v placebo in 44 pts? RR 67 v 10 NEJM
  19863151501 BUT high toxicity and rapid
  recurrence after stopping therapy
• 3 months of isotretinoin 1.5 mg/kg/d? RR 55? 9
  month maintenance with low-dose isotretinoin 0.5
  mg/kg/d v B-carotene? progression in 8 v 55
  NEJM 199332815 low dose RA was better
  tolerated

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Prevention of second primary tumors with
isotretinoin in SCCHN NEJM 1990323795

• Eligible participants
• S/p definitive local therapy (surgery and/or XRT)
  of Stage I-IV (M0) SCC of oral cavity,
  oropharynx, hypopharynx, or larynx
• Exclusion
• Metastatic disease
• Other cancer
• Treatment
• Isotretinoin 50-100 mg/m2/d v placebo for 12
  months
• Primary endpoint
• Occurrence of tumor progression (local
  recurrence, metastaces) or a second primary tumor

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Prevention of second primary tumors with
isotretinoin in SCCHN NEJM 1990323795

• Results (median follow-up 32 months)
• No difference in tumor progression or survival
• Rate of second primary tumors lower in retinoid
  group 2/49 (4) v 12/51 (24)
• 93 of the second primaries were in head and
  neck, esophagus, or lung
• Substantial toxicity in retinoid group
• Skin dryness, cheilitis, hypertriglyceridemia,
  conjunctivitis

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Prevention of second primary tumors with
isotretinoin in SCCHN NEJM 1990323795

• Results (median follow-up 55 months)
• 3 patients (7) in isotretinoin group and 13
  (33) in placebo group developed second primaries
  in head and neck, esophagus, or lung

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Phase III NCI trial of isotretinoin
chemoprevention in head and neck cancer

• Randomized 1190 patients to low dose isotretinoin
  (30 mg/d) or placebo for 3 years after local
  therapy for Stage I-II SCCHN
• Objective To reduce head and neck second
  primary tumors
• 2003 ASCO abstract reported tolerable toxicities
  and good long-term adherence to therapy
• Results pending

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Rationale for using tamoxifen for the
chemoprevention of breast cancer

• Efficacious for treatment of advanced breast
  cancer
• Efficacious as adjuvant therapy in early stage
  breast cancer
• Lower rate of contralateral breast cancer in
  women treated with tamoxifen
• Well-tolerated and generally safe
• Evidence in experimental systems that tamoxifen
  inhibits the initiation and growth of breast
  tumors

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Tamoxifen for Prevention of Breast Cancer NSABP
Breast Cancer Prevention Trial J of NCI
1998901371

• Primary objective
• To determine whether tamoxifen administered for 5
  years prevents invasive breast cancer in women at
  increased risk
• Eligible patients
• Women older than 60 years
• Women age 35-59 with 5-year predicted breast
  cancer risk gt 1.66 or with history of LCIS
• Treatment
• Tamoxifen 20 mg qd or placebo for 5 years

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Tamoxifen for Prevention of Breast Cancer NSABP
Breast Cancer Prevention Trial J of NCI
1998901371

• Results
• 13,175 participants with median follow-up of 54.6
  months
• 49 reduction in overall risk of invasive and
  noninvasive breast cancers with tamoxifen
  treatment
• No survival difference between the groups
• No difference in rates of ER-negative tumors

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Tamoxifen for Prevention of Breast Cancer NSABP
Breast Cancer Prevention Trial J of NCI
1998901371
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Tamoxifen for Prevention of Breast Cancer NSABP
Breast Cancer Prevention Trial J of NCI
1998901371

• Adverse events in tamoxifen group
• 2.53x greater risk of invasive endometrial cancer
  (93 were stage I)
• Trend towards more strokes
• More PEs and DVTs
• Hot flashes and vaginal discharge
• Tamoxifen use was associated with a 19 reduction
  in the incidence of fractures (not sig.)

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Tamoxifen for Prevention of Breast Cancer NSABP
Breast Cancer Prevention Trial J of NCI
1998901371

• Conclusion
• Women whose breast cancer risk is sufficiently
  high to offset the potential detrimental effects
  of tamoxifen would be candidates for the drug.

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FDA Appoval of Tamoxifen for Breast Cancer
Chemoprevention

• Primary prevention? healthy, high-risk women
• Secondary prevention? DCIS
• Tertiary prevention? early stage breast cancer