Prostate Cancer (PCa) is considered as in ideal target for chemoprevention, mainly because of its long natural history, its high incidence and the possibility to identify men with pre-neoplastic lesions such as Atypical Small Acinar Cell Proliferation (ASAP) and High Grad Prostatic Intraepithelial Neoplasia (HGPIN) (1). However, although many epidemiological and in vitro studies identified potential PCa chemopreventive agents, none of these findings have been confirmed in large scale randomized controlled trials (RCTs) (1, 2).
When conceiving our double-blind RCT (3) in 2008 we selected green tea catechins, selenium and lycopenes, the three substances at the time yielding the strongest evidence of ‘’PCa protective properties’’ and we used the highest non-toxic doses reported in the literature (4), hoping to enhance the chemopreventive feature of each active principle by obtaining a synergic effect. One group of patients received the three compounds daily in a single capsule whilst the other group received placebo. We chose patients with HG PIN and ASAP as the target of our study due to their high-risk of developing PCa and their consequent need of undergoing re-biopsy, thus an accurate follow-up.
Unfortunately, when recently unblinding the results (end of Phase II), evidence was not in favour of a protective effect against PCa; besides, it even suggested the supplement could promote PCa onset.
To elucidate these findings we performed analysis of miRNA expression on pre- and post-RCT biopsy tissues on two subgroups of men taking the placebo and the supplement respectively. Surprisingly, clinical findings were strengthened by molecular analysis showing downregulation of oncosuppressors and upregulation of oncogenes in those taking the supplement. These miRNA expression patterns were absent in the placebo group.
Whilst the low number of patients is an intrinsic limitation of a Phase I-II study, we believe the use of three substances together, initially conceived to enhance the preventive power of the supplementation, can now be seen as the main hindrance in interpreting our results. Recent evidence from the Selenium and Vitamin E Cancer Prevention Trial (5) highlighted a possible negative effect of selenium. Taken together with our results this could suggest selenium had a major role in promoting carcinogenesis compared to green tea catechins and lycopenes. However, it is not possible to clearly distinguish which and how many of the assessed compounds had role in ‘’promoting’’ PCa.
Nowadays, 50% of all new cancer patients use supplements (6). Similarly 51 to 39% of newly onset PCa report the use of complementary alternative medicine, selenium and lycopene being amongst the most common substances (7).
Further studies are needed to confirm our findings and possibly to identify which of the investigated substances promotes PCa. However, the use of supplements containing selenium, green tea catechins and/or lycopenes might have a dramatically negative impact considering their worldwide spread. We believe their use should not be recommended in men at risk of PCa until contrary evidence is available.
References:
1. Van Poppel H, Tombal B. Chemoprevention of prostate cancer with nutrients and supplements. Cancer management and research. 2011;3:91-100.
2. Joniau S, Goeman L, Roskams T, Lerut E, Oyen R, Van Poppel H. Effect of nutritional supplement challenge in patients with isolated high-grade prostatic intraepithelial neoplasia. Urology. 2007;69(6):1102-6.
3. Gontero P, Marra G, Soria F, et al. A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"? The Prostate. 2015.
4. World Cancer Research Fund / American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: AICR, 2007
5. Kristal AR, Darke AK, Morris JS, et al. Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. Journal of the National Cancer Institute. 2014;106(3):djt456.
6. Velicer CM, Ulrich CM. Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(4):665-73.
7. Boon H, Westlake K, Stewart M, et al. Use of complementary/alternative medicine by men diagnosed with prostate cancer: prevalence and characteristics. Urology. 2003;62(5):849-53.
Written by:
Giancarlo Marra, MD, Marco Oderda, MD, Paolo Gontero, MD
Department of Urology
San Giovanni Battista Hospital
Città della Salute e della Scienza
Turin, Italy.