Editing Prostate Cancer: Prevention

[[Category:Prostate Cancer]]

== 5-alpha reductase inhibitors (5-ARIs) ==
* '''<span style="color:#ff0000">Randomized trials (PCPT and REDUCE, see below ) evaluating 5-ARIs for prostate cancer prevention have found that their use results in (2)</span>'''
*# '''<span style="color:#ff0000">≈5% reduced risk of cancer</span>'''
*# '''<span style="color:#ff0000">Slight increased risk of high grade cancer</span>''' 
*#* '''<span style="color:#ff0000">Increased "risk" of high grade cancer is thought to be due to the higher probability of targeting a focus of high grade disease in a 5-ARI-induced smaller size gland</span>'''
*'''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.

=== <span style="color:#ff00ff">Prostate Cancer Prevention Trial (PCPT) (NEJM 2003)</span> ===
*'''<span style="color:#ff0000">Objective: determine whether a 5-ARI could reduce the risk of prostate cancer</span>'''
* '''<span style="color:#ff0000">Population: 18,882 men aged ≥ 55 years with normal DRE and PSA ≤ 3.0ng/ml</span>'''
* '''<span style="color:#ff0000">Randomized to finasteride</span>''' (5mg) '''<span style="color:#ff0000">vs. placebo daily</span>''' 
** '''<span style="color:#ff0000">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</span>'''
* '''<span style="color:#ff0000">Primary end point: prevalence of prostate cancer during the 7 years of the study</span>'''
* '''<span style="color:#ff0000">Results:</span>''' 
** 9060 (48%) evaluable for primary end point
** '''<span style="color:#ff0000">Significantly reduced risk of incident prostate cancer with finasteride</span>''' 
***'''<span style="color:#ff0000">Absolute risk reduction: 6%</span>''' (18.4% finasteride vs. 24.4% placebo)
** '''<span style="color:#ff0000">Significant increase biopsy Gleason score 7-10 cancers in finasteride group</span>'''
***'''<span style="color:#ff0000">Absolute risk increase: 15%</span> 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''' [https://pubmed.ncbi.nlm.nih.gov/30673548/ Goodman, Phyllis J., et al.] "Long-term effects of finasteride on prostate cancer mortality." New England Journal of Medicine 380.4 (2019): 393-394.
* [https://www.nejm.org/doi/full/10.1056/NEJMoa030660 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.

=== <span style="color:#ff00ff">REDUCE (NEJM 2010)</span> ===
* '''<span style="color:#ff0000">Objective: determine whether a 5-ARI could reduce the risk of prostate cancer</span>'''
* '''<span style="color:#ff0000">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</span>''' 
* '''<span style="color:#ff0000">Randomized to dutasteride vs. placebo daily</span>'''
* '''<span style="color:#ff0000">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)</span>'''
* '''<span style="color:#ff0000">Results:</span>''' 
**6.726 (82.6%) underwent at least one biopsy
** <span style="color:#ff0000">'''Significantly reduced risk of incident prostate cancer with dutasteride''' </span>
***'''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[https://www.nejm.org/doi/full/10.1056/NEJMoa0908127#]'''
* [https://www.nejm.org/doi/full/10.1056/NEJMoa0908127 Andriole, Gerald L., et al.] "Effect of dutasteride on the risk of prostate cancer." New England Journal of Medicine 362.13 (2010): 1192-1202.
== Vitami E ==

=== <span style="color:#ff00ff">Selenium and Vitamin E Cancer Prevention Trial (SELECT) (JAMA 2009)</span> ===
* 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'''
* [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682779 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.

== ‎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

== Others ==
*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

== Questions ==

# Describe the PCPT trial 
# List benefits of 5ARIs 
# List side effects of 5ARIs 

== Answers ==

# 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

== Next Chapter: [[Prostate Cancer: Pathology and TNM Staging|Pathology and TNM Staging]] ==

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