Prostate Cancer: Prevention

Chemoprevention

• 5-alpha reductase inhibitors (5-ARIs)
  • Randomized trials (PCPT and REDUCE, see below ) evaluating 5-ARIs for prostate cancer prevention have found that their use results in (2)
    1. ≈5% reduced risk of cancer
    2. Slight increased risk of high grade cancer
       • Increased "risk" of high grade cancer is thought to be due to the higher probability of targetting a focus of high grade disease in a 5-ARI-induced smaller size gland

• PCPT (2003)
  • Objective: determine whether a 5-ARI could reduce the risk of prostate cancer
  • Population: 18,882 men aged ≥ 55 years with normal DRE and PSA ≤ 3.0ng/ml
  • Randomized to finasteride (5mg) vs. placebo daily
    • Biopsy was recommended at the end of the study (7 years) for all participants, or “for cause” in men who had a PSA ≥ 4 ng/ml (adjusted for the effect of finasteride) or an abnormal DRE
  • Primary end point: prevalence of prostate cancer during the 7 years of the study
  • Results:
    • 9060 (48%) evaluable for primary end point
    • Significantly reduced risk of incident prostate cancer with finasteride Absolute risk reduction: 6% (18.4% finasteride vs. 24.4% placebo)
    • Significant increase biopsy Gleason score 7-10 cancers in finasteride group Absolute risk increase: 15% among those undergoing biopsy (37% finasteride vs. 22% placebo)
    • Apparent increase in high-grade cancers with the use of 5-ARIs does not influence cancer-specific survival [Goodman, Phyllis J., et al. "Long-term effects of finasteride on prostate cancer mortality." New England Journal of Medicine 380.4 (2019): 393-394.]
  • Thompson, Ian M., et al. "The influence of finasteride on the development of prostate cancer." New England journal of medicine 349.3 (2003): 215-224.

• REDUCE (2010)
  • Objective: determine whether a 5-ARI could reduce the risk of prostate cancer
  • Population: 8,231 men aged 50-75 with a negative prior biopsy within 6 months of enrollment baseline PSA 2.5-10, prostate volume ≤80cc
  • Randomized to dutasteride vs. placebo daily
  • Primary end point: prevalence of cancer on study-mandated 10-core prostate biopsies performed at 2 and 4 years after randomization (different from PCPT where biopsy was not mandated)
  • Results: 6.726 (82.6%) underwent at least one biopsy
  • Significantly reduced risk of incident prostate cancer with dutasteride Absolute risk reduction: 5% (19.9% dutasteride vs. 25.1% placebo)
  • No difference in Gleason 7-10 cancers throughout the study, however, increased risk of Gleason 8-10 cancers during years 3 and 4 in dutasteride arm§
  • Andriole, Gerald L., et al. "Effect of dutasteride on the risk of prostate cancer." New England Journal of Medicine 362.13 (2010): 1192-1202.
• FDA concluded that 5-ARIs did not have a favourable risk-benefit profile for the chemoprevention of prostate cancer
  • FDA assessment: for every 150-200 men treated with a 5-ARI, 1 additional man would be diagnosed with high-grade prostate cancer to avert 3-4 low-grade cancers.

• SELECT (2009) (Selenium and Vitamin E Cancer Prevention Trial)
  • Objective: determine whether selenium, vitamin E, or combination thereof could reduce risk of prostate cancer
  • Population: 35,533 men with normal DRE, PSA ≤ 4 ng/ml and normal blood pressure
  • Randomized to 4 treatment arms: Selenium + placebo
  • Vitamin E + placebo
  • Selenium + vitamin E
  • Placebo + placebo
  • Primary end point: biopsy-confirmed prostate cancer Indications for biopsy not dictated by protocol
  • Results: Study planned for 12 years. Independent data and safety monitoring committee recommended discontinuation of the study because data convincingly demonstrated no effect
  • Follow-up study showed that dietary supplementation with Vitamin E increased risk of prostate cancer
  • Lippman, Scott M., et al."Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT)." Jama 301.1 (2009): 39-51.

• RCT in men with HGPIN found that daily selenium, vitamin E, and soy vs. placebo did not reduce the risk of prostate cancer
• RCT in 60 men with HGPIN found that green tea catechin reduced the risk of prostate cancer RCT in 1,467 men with HGPIN found daily toremifene did not reduce the risk of prostate cancer at 3 years
• Lycopene
  • A red-orange carotenoid found primarily in tomatoes and tomato-derived products including tomato sauce, tomato paste, and ketchup, and other red fruits and vegetables.
  • In an in vivo model in which male rats were treated with N-methyl-N-nitrosourea and testosterone to induce prostate cancer, a protective effect was observed for both calorie restriction and tomato powder but not pure lycopene. This observation suggests that tomato products contain compounds in addition to lycopene that modify prostate carcinogenesis and that reduced caloric consumption and a diet rich in tomato-based foods may be more beneficial than taking oral lycopene supplements in reducing the risk of prostate cancer.
  • Meta-analysis of 3 RCTs found no association of lycopene on prostate cancer risk

Questions

1. Describe the PCPT trial
2. List benefits of 5ARIs
3. List side effects of 5ARIs

Answers

1. Describe the PCPT trial

• Objective: determine whether a 5-ARI could reduce the risk of prostate cancer
• Design: Randomized 18,882 men aged ≥ 55 years with normal DRE and PSA ≤ 3.0ng/ml to finasteride 5mg or placebo daily for 7 years. Biopsy was recommended at the end of the study (7 years) for all participants, or “for cause” in men who had a PSA ≥ 4 ng/ml (adjusted for the effect of finasteride) or an abnormal DRE
• Primary end point: prevalence of prostate cancer during the 7 years of the study
• Results:
• Absolute risk reduction by finasteride: 6%
• Significant increase biopsy Gleason score 7-10 cancers in finasteride group

Additional references

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 107