Prostate cancer — chemoprevention
Introduction
Epidemiological data, specifically the large differences in the incidence and mortality of prostate cancer in different parts of the world, provide strong leads for the potential effectiveness of preventive measures applied to men at risk for prostate cancer. Candidate mechanisms and studies will be reviewed.
Cancer prevention has been sub-classified as follows:
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Primary prevention: intervention to prevent the occurrence of cancer in healthy people.
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Secondary prevention: intervention in the subclinical phase, no cancer diagnosed, prevent disease in an ‘at risk’ population.
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Tertiary prevention: alter the course of minimal clinical disease.
All three types of prevention are subject to study. Primary prevention is population based and requires large trials ideally with the endpoint of cancer mortality. Secondary prevention entails screening for cancer with the goal of early detection in populations at risk. Tertiary prevention has the goal of slowing the progression of clinically diagnosed minimal disease. The typical situation in prostate cancer: a rising prostate specific antigen (PSA) after failed attempts of curative management.
The field of prevention of prostate cancer is developing very rapidly. A complete review is a challenge, which is difficult or impossible to meet. An attempt will be made to cover the most important aspects and to discuss them in relation to the epidemiological findings and the knowledge of endocrine dependence of the prostate and of prostate cancer specifically.
Obviously, investigations relating to the three different definitions of cancer prevention require different methodology. Primary prevention addresses the general population at risk for a certain disease and, in the case of prostate cancer, should consider the timing and duration of the subclinical phase of the disease. To address this issue properly investigators must determine whether they wish to address the initiation or progression phase of the disease. Strong evidence exists that prostate cancer is already initiated at ages 30–35 [1]. Progression, as witnessed by worldwide incidence data, probably starts around the age of 50 years. Due to the very long natural history of the disease long observation times are required to reach the most suitable endpoint, prostate cancer mortality, and surrogate endpoints are therefore in common use.
Secondary prevention, screening for prostate cancer, will not be covered within this presentation.
Considering the increasing number of men who experience progression after potentially curative management of prostate cancer, tertiary prevention has become a major issue. The methodology is less demanding: clinical progression or progression identified by means of PSA can be utilised as an endpoint, although with some caution. Recruitment to studies is easy because of ignorance about the best management of patients with minimal disease and rising PSA. In line with the shorter duration trials, tertiary prevention can also address issues like dosage, treatment duration, proper participant selection, effectiveness in relation to available prognostic factors and others. It is an open question whether agents and regimens shown to be effective in tertiary prevention can also be considered to qualify for primary prevention or primary prevention trials.
Section snippets
Why prevention in prostate cancer?
The incidence and mortality of prostate cancer shows strong worldwide variations [2]. Prior to the PSA era, which has induced strong increases in the incidence of prostate cancer worldwide, the highest rates of incidence and mortality were found in African-Americans. The lowest rates were identified in Japan and other Asian countries. Ten to fifteen-fold differences in mortality rates have been reported. Racial predetermination is unlikely because of the results of the so-called ‘migrant
Possible preventive mechanisms and agents
Up to now the approach of inhibiting the two known 5AR enzymes, type I and type II, which are responsible for synthesising DHT from testosterone in prostatic tissue and in peripheral tissues, has been the most studied and most effective approach. In men with benign prostatic enlargement the use of clinically available 5ARIs leads to a reduction in prostatic volume of around 30%, and serum PSA levels are reduced by 50 to 60%. The mechanism by which prostate cancer is prevented is subject to
Selected phase II studies
Uncontroversial proof of effectiveness has not been established for any of the dietary substances and mechanisms mentioned.
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Selenium and vitamin E have been the study components of one of the largest trials ever conducted, the SELECT trial [11]. This trial was discontinued on September 2, 2008 after a safety monitoring committee review. No difference between the three study arms, including a placebo arm, were found at an interim analysis; however, there were sideeffects including a higher chance
Phase III studies
The most important study in prostate cancer is the Prostate Cancer Prevention Trial (PCPT) which randomised 18,882 eligible men to receive either placebo or finasteride for a period of 7 years. At entry, men had to have a PSA level of less then 3.0 ng/ml, a negative rectal examination and no evidence of prostate cancer. Biopsies were taken as a result of yearly check-ups if PSA rose above 4 ng/ml or if rectal examination became abnormal. All participants were supposed to undergo an ‘end of
Conclusions
The scientific interest in identifying preventive mechanisms and agents that could be applied to prostate cancer has experienced an important growth in recent years. However, this has not led to more clarity with respect to the effectiveness of food products. One dietary supplement was shown to prolong PSA doubling time in a small randomised cross-over study. Experimental and clinical data available so far on food products are contradictory, which is best shown with the example of lycopene.
The
Conflict of interest statement
None declared.
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Cited by (6)
A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry
2013, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :There have been a number of studies on CaP preventive therapy, also previously defined chemoprevention, to reduce cancer incidence and mortality [1,2,3,4,5,6,7,8–11,12].
Coffee and risk of prostate cancer incidence and mortality in the Cancer of the Prostate in Sweden Study
2013, Cancer Causes and ControlSerum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study
2011, Cancer Epidemiology Biomarkers and PreventionCoffee consumption and prostate cancer risk and progression in the health professionals follow-up study
2011, Journal of the National Cancer Institute