Lycopene Does Not Affect Prostate-Specific Antigen in Men with Non-Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Dear Editor We have read the study by Sadeghian et al. titled “Lycopene Does Not Affect Prostate-Specific Antigen in Men with Non-Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials” (1). This meta-analysis was conducted on six randomized controlled trials (2–7) and the pooled results indicated that lycopene supplementation had no significant effect on PSA level (WMD: −0.60, 95% CI: −2.01, 0.81 mg/L). However, subgroup analysis conducted on three studies (2–4) revealed a significant reduction effect of lycopene on PSA level in patients with higher levels of baseline PSA. Unfortunately, we found several problems in this systematic review that seriously affect the validity and interpretation of the study findings. First, it is important to note that two of the six included studies were conducted on the same overlapping population (2, 3) and authors did not consider this issue in their study. Most concerning, is the inclusion of these two studies in subgroup one analysis that was confined to studies conducted on patients with higher baseline levels of PSA (≥6.5 μg/L). Since these two studies account for the major weight of the included studies in subgroup 1 (18.23% vs. 19.13% for subtotal weight), the results of the subgroup may not be correct and need more evaluation. Therefore, it is worth noting that when multiple reports from the same underlying RCT are available, inclusion of the RCT only once in the meta-analysis is crucial, to avoid duplication of findings (8) Second the included studies were subgrouped based on mean value of serum PSA of participants at the beginning of the study, but not based on the inclusion criteria. This may lead to misclassification of subgroups. Since, there may have been a combination of patients with serum levels of PSA higher or lower than 6.5 μg/L, the mean value of serum PSA is not a correct estimation of the whole population. Third, to assess pairwise comparisons, data on three different doses of lycopene supplementation from the original RCT were included (6) and comparisons were done vs. one placebo group (three different dose of lycopene supplementation vs. one placebo group). In this case, the placebo group may have been considered 3 times in the overall analysis. Therefore, overestimation of the effect size may have led to misleading results, according to the Cochrane handbook (9). Fourth, in the inclusion criteria section, authors mentioned that they included studies that used other treatment in both intervention and control groups. However, in the exclusion criteria, it was reported that those studies that administered lycopene in combination with other bioactive components were excluded. This led to a controversy in the study methodology, as we realized that the study by Bunker et al (5) in which the comparison groups were “lycopene + multivitamin” and “multivitamin” were included in this meta-analysis and the study by Lane et al. (10) which had a factorial design assessing the effect of lycopene and green tea on PSA was excluded. It should be noted that in Lane’s study the effect of lycopene supplement was separable from green tea. Therefore, exclusion of Lane’s study might affect the accuracy of the overall results. In conclusion, considering the aforementioned points, the meta-analysis of Sadeghian et al has serious methodological limitations, that lead to reduced accuracy and reliability of the study findings.