Is There a Benefit From Lycopene Supplementation in Men With Prostate Cancer? A Systematic Review

F Haseen; MM Cantwell; JM O'Sullivan; LJ Murray

Disclosures

Prostate Cancer Prostatic Dis. 2009;12(4):316–324 

In This Article

Discussion

This systematic review was undertaken to evaluate existing evidence for a protective effect of lycopene/tomato-based supplementation on post-diagnostic progression of prostate cancer in order to provide evidence-based recommendations for prostate cancer patients and their clinicians. Only intervention (experimental) studies were included in the review and only eight such studies were identified, all of which were reported between 2001 and 2006. In general, the studies were very small, with supplementation for short periods, and were of poor quality, with only three studies including a control group, two of which were RCTs. Moreover, the studies involved widely different groups of prostate cancer patients and included a range of different outcome measures, some of which are of debatable clinical significance, although all studies measured changes in PSA, which is widely used in clinical practice to assess prostate cancer progression.[39,40]

Before-after studies and controlled studies without randomization do not provide robust evidence of the effectiveness of an intervention, as any effect observed may be attributable to the natural history of the disease, as well as to concomitant treatments or confounding, rather than to the intervention under investigation. Therefore, although four of the six nonrandomized studies showed declines in PSA after lycopene supplementation, which are consistent with slowing of prostate cancer progression, these findings cannot be interpreted as evidence of a beneficial effect of lycopene on disease progression. These studies do, however, provide reasonably convincing evidence that lycopene supplementation is well tolerated by prostate cancer patients.

There was no difference in PSA changes between the intervention and nonintervention arms in the very small RCT undertaken by Kucuk et al.,[36] but men in this study received lycopene for a very short period (3 weeks) before radical prostatectomy. There were more encouraging findings from the RCT of 54 Indian patients with metastatic prostate cancer treated with orchidectomy alone or with orchidectomy plus 2 years of lycopene supplementation.[37] A greater decrease in the serum PSA level was observed in the combined therapy arm, as well as a better relief of bone pain and fewer lower urinary tract symptoms. Prolongation of survival is arguably the most important outcome in trials such as these and the RCT by Ansari and Gupta[37] also showed lower mortality at 2 years in the treatment group compared with mortality in the control group. This study could, however, be criticized on a number of grounds, including a poor survival rate in the control arm, imbalance between cohorts and quality control. Methodologically, it could not achieve the quality score because of lack of information on the randomization process, on the blinding approach, as well as on description of dropouts and withdrawals. However, it remains to be seen whether lycopene supplementation provides a long-term survival advantage. Furthermore, the results of this study may not be generalizable to prostate cancer patients with less advanced disease, to those receiving different primary treatments for their disease or to patients from other countries or ethnic groups. Moreover, orchidectomy is now rarely performed in Western countries as a prostate cancer treatment and it is unclear whether the results of this study can be generalized to patients receiving medical castration therapy.

Mechanism of Action

Little is known with regard to the biology of dietary lycopene in the human body. Once absorbed, lycopene is distributed to tissues around the body, but not uniformly. Compared with other carotenoids, significantly higher concentrations of lycopene are found in the liver, in adrenal glands, testes and prostate.[41–45] There have been several proposed mechanisms by which lycopene may protect against prostate cancer development, with much of the focus being directed toward its antioxidant properties and its role in the prevention of oxidative damage to cellular protein, lipid and DNA.[46,47] Lycopene has also been demonstrated to have other possible anticancer activities particularly relating to the modulation of intercellular communication and alterations in intracellular signaling pathways,[48] including an upregulation in intercellular gap junctions,[19] an increase in cellular differentiation,[49] alterations in phosphorylation of some regulatory proteins[50] and inhibiting insulin-like growth factor type 1-induced proliferation of a number of tumor cell lines.[16] Some intervention studies included in this review suggested that lycopene supplementation may decrease the growth of prostate cancer, possibly because of increased gap-junctional intercellular communication,[36] decreased oxidative damage to DNA[32] and increased apoptotic cell death.[35] However, owing to small sample size in all studies, a definitive decision cannot be made with regard to the mechanism of action of any anticarcinogenic role that lycopene may have in relation to prostate cancer.

Dose and Method of Administration of Lycopene

The optimal dose to achieve a biologically active lycopene concentration in the human prostate is unknown. This may explain the wide variation in the dose used in the identified studies, which ranged from 4 to 120 mg per day. No side effects have been reported from eating tomato-based products or by taking lycopene supplements. Animal studies also showed the absence of any significant toxicological findings with synthetic lycopene even at very high dose levels.[51,52] Furthermore, the form in which lycopene is administered may also affect its bioavailability. Lycopene in processed foods such as tomato sauce, tomato soup, salsa, ketchup and tomato paste is more readily bioavailable than fresh tomato,[53–55] and lycopene capsules seem to have a bioavailability similar to that of processed tomato.[56,57] Two of the studies included in the review confirm that lycopene supplementation (30 mg for 3 weeks) results in increased prostatic lycopene levels: by ~50% in Kucuk et al.[36] and by almost threefold in Chen et al.[32]

The wide variety of doses used, the different methods of delivery of lycopene, the variation in the length of supplementation, the differences in patient groups, the variability in outcome measures used and the lack of information on baseline dietary habits indicate that the experimental studies included in this review do not provide clarity on the most appropriate dose, duration of treatment or method of administration of lycopene for further investigation in better conducted RCTs. However, the longest duration RCT among the studies showed a positive effect, with a low dose of lycopene (4 mg per day) administered (form was not mentioned) for 2 years.[37] Long-term supplementation may be required to affect clinically relevant markers of disease, but further research is needed to identify the most appropriate dose, duration and method of administration of lycopene.

Strengths/Limitations of the Review

This is the first systematic review that concentrates on the effect of lycopene supplementation on the progression of prostate cancer. A recent review included a mixed supplementation study and focused on RCTs only.[25] We incorporated information from studies examining only lycopene supplementation to identify more clearly its effect on prostate cancer. Moreover, we included all types of intervention studies rather than only RCTs. We searched the most relevant databases, including sources of complementary medicine studies, and included hand searches of relevant reviews, with two reviewers independently appraising the evidence from included studies. We also did not include the term 'trials' or relevant synonyms in the search strategy in case some of the reports with these designs were not appropriately classified. Moreover, unlike the review by Van Petter et al.,[25] we did not restrict the language of publication to English and we did not restrict the year of publication.

Conclusion/Implications for Practice/Future Research

The trials summarized in this systematic review do not provide sufficient evidence to recommend the use of lycopene supplements in routine clinical practice for patients diagnosed with prostate cancer, although the studies do indicate that lycopene is unlikely to be harmful to such patients. However, no study has been conducted with an adequately sound methodology. Many questions remain unanswered, including which patient group may be most likely to benefit from lycopene supplementation, and what are the most appropriate dose, duration and methods of supplementation. Large robust randomized controlled trials in broader patient groups with clinically relevant end points are required to answer these questions. A double-blinded RCT to assess the ability of lycopene to slow down the progression of prostate cancer or to increase survival is required; however, the role of other carotenoids and phytochemical compounds in tomatoes also needs to be addressed. It is already evident from animal studies that a tomato product diet has a much greater effect than isolated lycopene.[58] Therefore, research focused on the effects of lycopene should also consider the effects of other active components in tomato products.

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