Lycopene has a chemopreventive effect against prostate cancer but its role in prostate cancer progression is unknown; many patients increase their intake of lycopene, although there are no evidence-based guidelines to suggest an effect. Our objective was to conduct a systematic review of literature to evaluate the association between lycopene intake and prostate cancer progression. MEDLINE, EMBASE CINAHL Plus, Web of Science, AMED and CENTRAL databases were systematically searched using terms for lycopene and prostate cancer progression to identify studies published before January 2009. Eight intervention studies were identified (five with no control group; one with an unmatched control group; and two randomized controlled trials (RCTs)). An inverse association was observed between lycopene intake and PSA levels in six studies. The rates of progression measured by bone scan in one RCT were lower in the intervention group. Lycopene resulted in lowering cancer-related symptoms (pain, urinary tract symptoms), and severe toxicity or intolerance was not evident. However, the evidence available to date is insufficient to draw a firm conclusion with respect to lycopene supplementation in prostate cancer patients and larger RCTs are required in broader patient groups.
Approximately one-third of men with prostate cancer take some form of dietary supplementation after diagnosis.1, 2, 3 Factors associated with a higher utilization of supplements among prostate cancer patients include higher income, being better educated and following a healthy lifestyle, having more advanced or progressive disease, a lower quality of life, presence of comorbid conditions and a lower satisfaction with treatment and health status.3, 4, 5, 6 Patients often take supplements without a full awareness of the scientific evidence related to cancer prevention or prognosis, and the majority of patients use supplements without informing their doctors.3, 7 Furthermore, as these supplements are not conventional therapies, many health professionals are unfamiliar with their effects and may feel unqualified to provide advice to their patients with regard to their use. Undisclosed use of dietary supplements may interfere with conventional cancer treatment and cause potentially dangerous side effects (that is, toxicity, increased risk of cancer) as reported with excessive use of calcium,8 selenium,9 β-carotene8 and zinc.10 To date, there is little scientific evidence to support a role of nutritional supplementation in the prevention or reduction of prostate cancer progression.
Lycopene, a carotenoid found in high quantities in tomatoes and tomato-rich products, has been explored in relation to the prevention and treatment of various kinds of cancers.11 High lycopene intake or high plasma lycopene concentrations have been associated with a lower risk of prostate cancer.8, 12, 13 However, the majority of epidemiological research has focused on tomato or tomato products as a source of lycopene, whereas very little research has targeted other carotenoids or phytochemicals found in tomatoes. Although lycopene seems to be the bioactive compound of major importance, there is also the possibility of a synergistic action with other compounds in tomato, especially glycoalkaloids (tomatine), phenolic compounds (quercetin, kaempferol, naringenin and chlorogenic acid), salicylates and carotenoids, other than lycopene (phytoene and phytofluene), which cannot be excluded. Lycopene is a potent antioxidant and possible mechanisms by which lycopene may prevent cancer may include (i) inhibition of growth and induction of differentiation in prostate cancer cells;14, 15, 16, 17 (ii) upregulation of tumor suppressor proteins and increased gap-junctional intercellular communication;18, 19 and (iii) prevention of oxidative DNA damage.20, 21
Although lycopene intake before diagnosis has been linked to reduced prostate cancer risk, there are limited data on the impact of post-diagnostic diet or supplementation and progression of prostate cancer. Nutrients that apparently protect against cancer development may continue to have an anticarcinogenic effect after diagnosis and slow disease progression.22, 23 A study examined post-diagnostic diet and risk of prostate cancer progression in prostate cancer patients from the Health Professionals Follow-up Study and showed that a higher post-diagnostic consumption of tomato sauce was associated with a substantial decrease in the risk of cancer progression: an increase of one serving of tomato sauce per day was associated with an approximately 50% lower risk of progression (measured by rising PSA levels, or metastasis to lymph nodes, bones or other organs).24 However, recommendations regarding the use of lycopene supplementation in prostate cancer patients require evidence from experimental studies, rather than from observational studies, and ideally from a systematic review/meta-analysis of the evidence from experimental studies. Recently, a review has been conducted to identify the effect of diet and dietary supplementation on prostate cancer progression, recurrence and survival,25 in which lycopene supplementation was discussed along with other nutritional supplements and prostate cancer. Results from randomized controlled trials (RCTs) showed no benefit in terms of PSA or PSA doubling time with lycopene supplementation alone or with lycopene combined with other agents including soy isoflavones. However, another important aspect of nutritional supplementation was not considered in this review, that is, intervention-related side effects, or toxicity as a result of supplementation. We therefore conducted a systematic review of all available experimental evidence relating to lycopene supplementation and prostate cancer progression to provide evidence-based recommendations for patients with prostate cancer.
OVID MEDLINE, including MEDLINE, EMBASE, CINAHL Plus, Web of Science, AMED (Allied and Complementary Medicine Database) and CENTRAL (The Cochrane Library) databases, was systematically searched for relevant studies published till January 2009. Search terms included prostate cancer (prostate cancer patient$, prostate cancer survivor$, prostate cancer$ or prostatic neoplasms$, prostate carcinoma, prostatic cancer$, ‘cancer of the prostate’,‘cancer of prostate’), lycopene (lycopene, lycopersicon esculentum, tomato$) and progression (prostate-specific antigen/ or psa, ‘prostate specific antigen’, prognosis, ‘side effect’, ‘aggressive’, ‘stage’, ‘grade’, ‘gleason score’, ‘treatment outcome’, ‘clinical response’, complication$, ‘urinary incontinence’, pain or ‘bone pain’, ‘bone metastases’, osteoporosis, an?emia or anemia, ‘weight gain’ ‘body composition’, body mass index/ or ‘body mass’, obesity/ or ‘fat mass’, tumo?r). The three categories were combined in an attempt to cover as many variations as possible for (i) prostate cancer, (ii) lycopene and (iii) progression. The search was limited to studies in humans. Bibliographies of published reviews on lycopene supplementation were also screened for potentially relevant studies.
Inclusion and exclusion criteria
Intervention studies (RCTs, nonrandomized controlled trials or before-after studies) involving lycopene supplementation in any form (for example, tablet/capsule, whole tomato, tomato sauce or tomato juice) in prostate cancer patients, regardless of their disease duration, stage and treatment modalities, were included. Studies examining mixed supplementation with lycopene and other nutrient/supplements were excluded.
The primary outcome of interest was disease progression of prostate cancer measured by changes in the PSA level. Secondary outcome measures were side effects/toxicity, complications associated with prostate cancer and its treatment (pain, urinary tract symptoms) and survival.
Study selection and data extraction
The titles and abstracts of papers identified in the initial search were reviewed and classified as potentially relevant by three independent reviewers (FH, LJM and MMC). In cases in which there was doubt with regard to the relevance of a paper, a full-text copy was examined. Full-text copies of potentially relevant copies were reviewed against the inclusion criteria by two authors (FH and MMC), and data were independently extracted from included studies by these authors. Extracted data included study setting, study design, study population (age, cancer stage, treatment received and duration), sample size, supplementation method used, doses and frequency of administration of supplement, duration of intervention and follow-up, outcome measures used, statistical approaches used and the results.
Methodological quality assessment
The quality of the included articles was assessed using the Jadad scoring method. This validated scale allows the assessment of the methodological quality of the RCT trial by quantifying the study's randomization, blinding methods and description of patient dropouts/withdrawals. This tool scores quality from 0 to 5 and studies scoring <3 points are considered to be low in quality.26
Application of the search strategy yielded 133 reports in MEDLINE, 85 in EMBASE, 135 in Web of Science, 22 in CINAHL Plus, 2 in AMED and 15 in CENTRAL. Removal of duplicates resulted in 269 potentially eligible studies. A flowchart shows the exclusion factors and numbers of articles for each factor (Figure 1). Of the 269 references screened, 11 met the inclusion criteria, but two RCTs27, 28 and one before-after study29 were excluded as they were repeat publications.
In all, eight intervention studies were identified and evaluated. Five had no control (before-after design)30, 31, 32, 33, 34 and one had an unmatched control group;35 it was unclear how the control group was selected. The remaining two studies were RCTs, but one36 was very small and included 35 patients with data available for analysis from only 26 patients. The other study,37 an RCT of lycopene supplementation for 2 years in addition to orchidectomy, was also small (54 patients), and neither RCT achieved a Jadad score of 3 or higher. Table 1 summarizes the type and duration of intervention and the outcome measures in these studies. Studies tested lycopene with variations in dose (4–120 mg per day), duration (3 weeks to 2 years) and composition (tablet, capsule, tomato sauce, tomato paste/juice), as well as with diverse patient populations (for example, with localized or metastatic disease, hormone refractory, recurrence). Meta-analysis was not possible as the studies were highly heterogeneous.
Change in PSA levels
All studies reported on the change in serum PSA level as a measure of disease progression, although PSA changes were reported in different ways, for example, normalization of PSA (to <4 ng ml−1), proportion of patients with a 50% reduction in PSA, differences in mean PSA levels between intervention and control arms, percentage change in PSA after treatment, and so on (Table 2). Three before-after studies reported a significant reduction in PSA after intervention,30, 31, 32 whereas two did not see any change in PSA.33, 34 In the study by Kim et al.,35 32 prostate cancer patients awaiting prostatectomy and treated with lycopene supplementation (tomato sauce 30 mg per day) for 3 weeks were compared with 34 controls also undergoing prostatectomy for prostate cancer. Mean PSA decreased after treatment from 10.9 to 8.7 ng ml−1 (P<0.001) and was lower in the treatment group than in the control group (13.8 ng ml−1). There was no significant difference in the percentage change in mean PSA between the intervention and nonintervention arms in the RCT undertaken by Kucuk et al.36 in which men received lycopene supplementation (30 mg per day) by capsule for a short period (3 weeks) before radical prostatectomy. In the larger RCT involving men with metastatic prostate cancer treated by orchidectomy,37 lycopene supplementation (4 mg per day for 2 years) was associated with a lower mean PSA after treatment (3.0 ng ml−1 in the intervention and 9.0 ng ml−1 in the nonintervention arms, P<0.001). Furthermore, 11 (40%) patients in the orchidectomy arm and 21 (78%) in the orchidectomy and lycopene group had a complete PSA response (reduced to <4 ng ml−1), P<0.05.
Lycopene was shown to be potentially effective in ameliorating cancer-related symptoms (pain, urinary tract symptoms) in one RCT37 and in one before-after study.30 In the before-after design trial by Ansari and Gupta,30 bone pain significantly improved after administration of 10 mg per day lycopene for 3 months. Moreover, 62% of patients managed to cut down their dose of analgesics. Analgesic use for body pain was also less evident in the supplemented group as opposed to the control group in RCT as well (15 vs 25%).37
A significant improvement in urinary peak flow rate was observed in the lycopene-supplemented group compared with the control arm in the RCT. After intervention, the urinary peak flow rate was 12.2 ml s−1 in the lycopene group compared with 11.0 ml s−1 in the control group (P<0.04), although they were comparable at baseline. Moreover, a subjective improvement in voiding symptoms (frequency, urgency and dysuria) was reported more in the supplemented group (80 vs 50%).37 Before supplementation, 90% patients had associated lower urinary tract symptoms (LUTSs) and after supplementation, LUTS improved along with urinary flow rate in 61% of patients in the before-after study.30
Evidence of progression from bone scans
In their RCT, Ansari and Gupta37 examined disease progression using bone scans. A significantly higher proportion of patients had a complete response (normal bone scan) in the intervention group compared with control group at the end of the trial (25 vs 15%, P<0.02). Moreover, progressive disease (development of any new ‘hot spot’ on bone scans) was significantly less common in the intervention group (P<0.02). Bone pain and use of analgesics showed a direct relationship with bone scan response, and patients with a complete response required no analgesic. A 25% reduction in overall metastatic lesions was also reported in the before-after study.30
Effect on survival
Survival is, of course, one of the most important measures of prostate cancer progression. Three studies reported survival rates,30, 33, 37 although none provided power calculations to show that they had sufficient power to detect a difference in these rates. Longer overall survival was observed in the supplemented group than in the control group in the trial by Ansari and Gupta;37 after a mean follow-up period of 25.5 months, 19 patients (35%) died, 12 (22%) in the control group and 7 (13%) in the supplemented group (P<0.001). Follow-up in this study was brief, hence no information was provided on long-term survival.
Side effects were examined in the four before-after studies30, 31, 33, 34 and in the two RCTs.36, 37 None of the studies reported severe toxicity or intolerance related to lycopene supplementation according to National Cancer Institute Common Toxicity Criteria.38 One patient from the study undertaken by Clark et al.34 discontinued lycopene because of grade 2 diarrhea (4–6 stools per day or nocturnal stools), and side effects, plausibly due to lycopene supplementation, were observed in the study by Jatoi et al.33 and included diarrhea, nausea, abdominal distension, flatulence, vomiting, anorexia and dyspepsia, although all were mild/moderate (grade 1 or 2, National Cancer Institute Common Toxicity Criteria).38 As these studies did not include a control group, these effects cannot be definitely ascribed to lycopene use. In the RCTs, no adverse effects or reactions were reported during and after supplementation in the intervention arm.
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 Gupta37 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, 42, 43, 44, 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 proteins50 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 DNA32 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, 54, 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.
Conflict of interest
The authors declare no conflict of interest.
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The authors acknowledge Ms Alex McIlroy for her assistance in developing the electronic search strategy used in the systematic review and Ms Helen Mulholland for her support in selecting the relevant articles.
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Haseen, F., Cantwell, M., O'Sullivan, J. et al. Is there a benefit from lycopene supplementation in men with prostate cancer? A systematic review. Prostate Cancer Prostatic Dis 12, 325–332 (2009). https://doi.org/10.1038/pcan.2009.38
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