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Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: A systematic review

  • Author Footnotes
    1 These authors contributed equally to this work.
    Dragan Ilic
    Correspondence
    Corresponding author at: Level 6, The Alfred Centre, 99 Commercial Rd, Monash University, Melbourne, VIC 3004, Australia. Tel.: +61 3 9903 0386.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Epidemiology & Preventive Medicine, School of Public Health & Preventive Medicine, Monash University, Melbourne, Australia
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Marie Misso
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Women's Public Health Research, School of Public Health & Preventive Medicine, Monash University, Victoria, Australia
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Abstract

      Background

      Prostate cancer is a leading cancer affecting men worldwide. Benign prostatic hyperplasia (BPH) is a common disease of the prostate affecting men as they age, and a risk factor for developing prostate cancer. Lycopene is a member of the carotenoid family, whose strong anti-oxidant properties have been hypothesised to assist in the prevention and treatment of BPH and prostate cancer. The aim of this systematic review was to examine the effectiveness of lycopene for the prevention and treatment of BPH and prostate cancer.

      Methods

      A search of the MEDLINE, EMBASE, AMED (Allied and Complementary Medicine) and the Cochrane Library databases was performed for published randomised controlled trials (RCTs) comparing lycopene to placebo (or other interventions) for the treatment of BPH and prostate cancer. All included studies were assessed for methodological quality using the Cochrane Collaboration's risk of bias tool.

      Results

      Eight RCTs met the inclusion criteria for this systematic review. All included studies were heterogeneous with respect to their design and implementation of lycopene. Methodological quality of three studies was assessed as posing a ‘high’ risk of bias, two a ‘low’ risk of bias and the remaining three an ‘unclear’ risk of bias. Meta-analysis of four studies identified no significant decrease in the incidence of BPH (RR (relative risk) = 0.95, 95%CI 0.63, 1.44) or prostate cancer diagnosis (RR = 0.92, 95%CI 0.66, 1.29) between men randomised to receive lycopene and the comparison group. Meta-analysis of two studies indicated a decrease in PSA levels in men diagnosed with prostate cancer, who received lycopene (MD (mean difference) = −1.58, 95%CI −2.61, −0.55).

      Conclusions

      Given the limited number of RCTs published, and the varying quality of existing studies, it is not possible to support, or refute, the use of lycopene for the prevention or treatment of BPH or prostate cancer.

      Keywords

      1. Introduction

      Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate gland [
      • Wilt T.
      • Ishani A.
      Pygeum africanum for benign prostatic hyperplasia.
      ]. This proliferative disorder affects the epithelial cells and smooth muscle within the transitional zone of the prostate gland [
      • Auffenberg G.
      • Helfan B.
      • McVary K.
      Established medical therapy for benign prostatic hyperplasia.
      ]. BPH is a common disease in elderly men, with histological evidence of BPH in approximately 50% of men aged in the 50s, increasing up to 90% in men aged 80 years and above [
      • Berry S.
      • Coffey D.
      • Walsh P.
      • Ewing L.
      The development of human benign prostatic hyperplasia with age.
      ,
      • Schwarz S.
      • Obermuller-Jevic U.
      • Hellmis E.
      • Koch W.
      • Jacobi G.
      • Biesalski H.
      Lycopene inhibits disease progression in patients with benign prostate hyperplasia.
      ]. BPH may lead to increased smooth muscle tone and resistance, as well as obstruction of the proximal urethra – leading to lower urinary tract symptoms (LUTS) [
      • McVary K.
      • Roehrborn C.
      • Avins A.
      • et al.
      Update on AUA guideline on the management of benign prostatic hyperplasia.
      ]. The obstructive symptoms of BPH impacts upon storage (increased urinary frequency, nocturia, urinary incontinence), voiding (slow and/or weak stream, terminal dribble) and post-micturition (sense of incomplete emptying) [
      • Coyne K.
      • Sexton C.
      • Thompson C.
      • et al.
      The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study.
      ].
      Pharmaceutical interventions, including the use of alpha-blockers and 5-alpha reductase inhibitors, are the primary form of managing BPH. Evidence from systematic reviews indicates improved urine flow, nocturia and quality of life, when used either in combination, or as a monotherapy [
      • Tacklind J.
      • Fink H.
      • MacDonald R.
      • Rutks I.
      • Wilt T.
      Finasteride for benign prostatic hyperplasia.
      ]. Recent studies indicate that 5-alpha reductase inhibitors may be beneficial in reducing prostate cancer incidence among men who undergo regular screening [
      • Wilt T.
      • MacDonald R.
      • Hagerty K.
      • Schellhammer P.
      • Kramer B.
      5-Alpha-reductase inhibitors for prostate cancer prevention.
      ] Adverse events of pharmaceutical interventions may include erectile dysfunction, decreased libido, dizziness and hypotension [
      • Tacklind J.
      • Fink H.
      • MacDonald R.
      • Rutks I.
      • Wilt T.
      Finasteride for benign prostatic hyperplasia.
      ]. If medical intervention is not successful, transurethral resection of the prostate (TURP) may be performed as a surgical option. The use of TURP may be successful in up to 75% of patients with BPH, however it is also associated with an increase in morbidity including blood loss, urinary incontinence, infection and sexual dysfunction [
      • Hoffman R.
      • MacDonald R.
      • Wilt T.
      Laser prostatectomy for benign prostatic obstruction.
      ].
      Prostate cancer is the second most commonly diagnosed cancer in the world, and the sixth leading cause of death in men worldwide [
      • Jemal A.
      • Bray F.
      • Center M.
      • Ferlay J.
      • Ward E.
      • Forman D.
      Global cancer statistics.
      ]. The incidence of prostate cancer varies more than 25-fold worldwide, with incidence highest in developed countries of North America, Europe and Australia, and lower incidence rates in developing countries [
      • Jemal A.
      • Bray F.
      • Center M.
      • Ferlay J.
      • Ward E.
      • Forman D.
      Global cancer statistics.
      ]. This difference in incidence patterns may accrue due to the increased levels of screening and testing for prostate cancer in these developed countries [
      • Jemal A.
      • Bray F.
      • Center M.
      • Ferlay J.
      • Ward E.
      • Forman D.
      Global cancer statistics.
      ]. Evidence from recent systematic reviews conclude that screening for prostate cancer does not significantly decrease disease-specific mortality [
      • Ilic D.
      • O’Connor D.
      • Green S.
      • Wilt T.
      Screening for prostate cancer: an updated Cochrane systematic review.
      ,
      • Ilic D.
      • O’Connor D.
      • Green S.
      • Wilt T.
      Screening for prostate cancer.
      ].
      A variety of treatment options are available to men diagnosed with prostate cancer. Surgical options include radical prostatectomy, be it by open radical prostatectomy, laparoscopic or robotic-assisted laparoscopic approach. Other interventions include external beam radiation therapy, brachytherapy, active surveillance (or watchful waiting), as well as investigational treatments such as high intensity focused ultrasound and focal therapy [
      • Heidenreich A.
      • Bellmunt J.
      • Bolla M.
      • et al.
      EAU Guidelines on prostate cancer part 1: screening, diagnosis, and treatment of clinically localised disease.
      ].
      Radical prostatectomy is currently recommended as a front-line treatment for men diagnosed with localised prostate cancer and with a life expectancy greater than 10 years [
      • Heidenreich A.
      • Bellmunt J.
      • Bolla M.
      • et al.
      EAU Guidelines on prostate cancer part 1: screening, diagnosis, and treatment of clinically localised disease.
      ]. However, each treatment option aims to reduce the risk of prostate cancer-specific mortality, whilst minimising treatment-related morbidity and maintaining a good quality of life. Common physical side effects include erectile dysfunction, urinary incontinence and infection, whilst psychosocial adverse effects may impact upon patient quality of life.
      With greater accessibility to healthcare information, consumers are more confident to seek greater involvement in their healthcare [
      • Ilic D.
      • Maloney S.
      • Green S.
      Guiding users to quality information about osteoarthritis on the Internet: a pilot study.
      ]. Many patients are turning to complementary and alternative medicines to improve general well-being, quality of life and treatment for medical ailments [
      • Beebe-Dimmer J.
      • Wood D.
      • Gruber S.
      • et al.
      Use of complementary and alternative medicine in men with family history of prostate cancer: a pilot study.
      ]. Lycopene is a red pigment member of the carotenoid family, which is predominantly found in tomatoes, strawberries and watermelon [
      • Chan J.
      • Gann P.
      • Giovannucci E.
      Role of diet in prostate cancer development and progression.
      ]. Lycopene has been established as a strong antioxidant, with these properties potentially useful in protecting DNA from oxidation and cancer-related mutations [
      • Wertz K.
      • Siler U.
      • Goralczyk R.
      Lycopene: modes of action to promote prostate health.
      ].
      Evidence from case–control and cohort studies suggests that high levels of dietary lycopene intake are associated with a lower risk of prostate cancer (including limiting tumour growth) and cell proliferation (benefiting BPH) [
      • Etminan M.
      • Takkouche B.
      • Caamano-Isorna F.
      The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies.
      ,
      • Giovannucci E.
      Tomato products, lycopene and prostate cancer: a review of the epidemiological literature.
      ]. In 2007 the World Cancer Research Fund reported that a high fruit and vegetable intake may be beneficial in reducing the risk of cancer, including lycopene for prostate cancer [
      • World Cancer Research Fund/American Institute for Cancer Research
      Food, nutrition physical activity and the prevention of cancer: a global perspective.
      ].
      The objective of this systematic review was to determine the effectiveness of lycopene supplementation in reducing the incidence of BPH, prostate cancer and prostate cancer-specific mortality. Secondary objectives of this review included assessing the impact of lycopene supplementation on PSA and lycopene levels, prostate symptoms, nocturia, urine flow and adverse events.

      2. Methods

      2.1 Study selection

      All RCTs that included men aged over 18 years of age, diagnosed either with BPH or prostate cancer were eligible for inclusion in this systematic review. No limits were placed on ethnicity or language. Studies were eligible for inclusion if the intervention included dietary interventions aimed at increasing lycopene intake; lycopene supplements and lycopene-containing products. Studies that combined lycopene in combination with other therapies for BPH or prostate cancer were also included. Comparisons were made with any study employing a placebo, or usual care without lycopene supplementation. The primary outcome of this systematic review included prostate cancer-specific mortality and size/volume of the prostate gland. Secondary outcomes included changes in PSA levels, clinical symptoms and quality of life (as identified by the International Prostate Symptom Score (IPSS) or the American Urological Association's IPSS questionnaire), levels of lycopene and adverse events.

      2.2 Data sources

      Electronic searches were conducted across MEDLINE, EMBASE, AMED (Allied and Complementary Medicine) and the Cochrane Central Register of Controlled Trials (CENTRAL) databases. No language or other limitations were imposed. The search strategy used for MEDLINE (and adopted for other databases) was:
      • 1.
        carotenoid$.mp. or Carotenoids
      • 2.
        lycopene.mp
      • 3.
        Antioxidants
      • 4.
        Lycopersicon esculentum
      • 5.
        1 or 2 or 3 or 4
      • 6.
        Prostatic Neoplasm
      • 7.
        prostate cancer.mp
      • 8.
        6 or 7
      • 9.
        Prostatic Hyperplasia
      • 10.
        benign prostatic hyperplasia.mp
      • 11.
        bph.mp
      • 12.
        9 or 10 or 11
      • 13.
        8 or 12
      • 14.
        5 and 13
      • 15.
        limit 14 to (randomized controlled trial)
      Two reviewers (DI and MM) independently screened the titles and abstracts of all articles returned from the search strategy. Full-text copies were obtained for articles on which a decision to include, or exclude, from the review was not possible based solely on the title or abstract of the article. All articles that met the selection criteria were included. Any discrepancies were resolved by discussion.

      2.3 Data collection, extraction and assessment of quality

      Data extraction was performed by two reviewers (DI and MM) independently. Data extracted included demographic information and number of participants, methodology (including descriptions of the intervention and comparison, mode of delivery and study setting), and results. Any discrepancies were resolved by discussion.
      The quality of each study was assessed using the Cochrane Collaboration's risk of bias assessment tool [
      ]. Each study was assessed for sequence generation, allocation concealment, blinding of participants and outcome assessors, outcome data, and selective-outcome reporting. Each criterion was assessed as ‘met’, ‘unmet’, or ‘unclear’. Any discrepancies were resolved by discussion.

      2.4 Data analysis

      Statistical analysis was performed according to the statistical guidelines referenced in the Cochrane Handbook for Systematic Reviews of Interventions [
      ]. Relative risk ratios (RR), with 95%confidence intervals (CI), were used to express dichotomous outcomes whilst continuous outcomes scores were expressed as mean differences (MD) with 95% confidence intervals. Heterogeneity was analysed by graphical interpretation of the forest plot and with the I2 statistic. An I2 value above 75% was considered to be an indicator of considerable heterogeneity [
      ]. The Cochrane Collaboration's software program RevMan was used to calculate effect size, 95% CIs and heterogeneity [

      Review manager (RevMan) version 5.0 for windows. Copenhagen: The Nordic Cochrane Centre.

      ].

      3. Results

      3.1 Description of studies

      A total of 43 articles were identified through the searches of the literature, of which 34 were excluded (Fig. 1). Among these excluded studies, nine were not RCTs, 18 had an intervention that did not include lycopene and six had population, or outcomes, not meeting the inclusion criteria and one was a preliminary report of a phase II RCT. Full-text examination of nine articles identified one duplicate publication. Subsequently, a total of eight studies met the inclusion criteria. Information on study methodology, participants, interventions and outcomes for included studies are detailed in Table 1.
      Figure thumbnail gr1
      Fig. 1Flowchart for selection of inclusion of RCTs (RCT: randomised controlled trial).
      Table 1Summary of included studies.
      StudyMethodsParticipantsInterventionsOutcomes
      Ansari and Gupta
      • Ansari M.
      • Gupta N.
      A comparison of lycopene and orchidectomy vs. orchidectomy alone in the management of advanced prostate cancer.
      Randomised controlled trial in India. Individuals were randomised to receive orchidectomy alone, or orchidectomy plus lycopene. Participants were followed for a minimum of 2 years (24–28 months)The inclusion criteria for the trial were patients with histologically confirmed metastatic prostate cancer. Patients treated with other methods (e.g. radiotherapy, chemotherapy, etc.) and with a life-expectancy of less than 3 months were not eligible for inclusion in the study. Numbers include:

       • Intervention group (orchidectomy plus lycopene) – 27

       • Comparison group (orchidectomy) – 27
      Participants were treated via orchidectomy, or orchidectomy plus lycopene. Lycopene commenced on the day of orchidectomy at 2 mg twice daily. Concurrent therapy was permitted and included analgesics, antibiotics and surgery in patients with severe obstructive featuresChanges in serum PSA levels were assessed at 6 months and 2 years post-intervention. Peak flow rate was assessed at 2 years post-intervention. All-cause mortality was reported at the 2 year follow-up period
      Bunker et al.
      • Bunker C.
      • McDonald A.
      • Evans R.
      • de la Rosa N.
      • Boumosleh J.
      • Patrick A.
      A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk.
      Randomised controlled trial in Tobago, Trinidad and Tobago. Individuals were randomised to receive a multivitamin alone or the 30 mg/day lycopene plus multivitamin. This study reports on participants that were followed for a 4 month period from August to December 2003The inclusion criteria for the trial were pathological evidence of High Grade Prostate Intraepithelial Neoplasia (HGPIN) or atypical foci, or more than one non-cancerous biopsy, no history of prostate cancer. Men were assigned sequential intervention study ID numbers at enrolment before randomisation. Numbers include:

       • Intervention group – 40

       • Control group – 40
      All participants underwent a 3 week course of oral ciprofloxacin, 250 mg/day, prior to randomisation, to reduce the likelihood that serum PSA decline after lycopene administration might reflect an anti-inflammatory response in men with subclinical prostatitis rather than cancer regression. Participants in the intervention received ‘Lyc-O-Mato’, which was 15 mg lycopene. The supplement was provided in two capsules (total 30 mg lycopene/day) with instructions to take one with breakfast, and one with the evening meal. A standard multivitamin with minerals was used daily in the multivitamin group (This multivitamin included vitamin A (vitamin A acetate and 40% as beta-carotene), 5000 IU, Vitamin E (dl-alpha tocopheryl acetate), 30 IU, vitamin C (as ascorbic acid), 60 mg, and selenium (as sodium selenate), 20 micrograms (μg))PSA Serum samples were taken at baseline, 1 month and 4 months post-randomisation. Patients were also assessed via the American Urological Association Benign Prostatic Hyperplasia (BPH) Scale and National Institutes of Health Chronic Prostatitis Symptom Index was assessed during these time points as well
      Grainger et al.
      • Grainger E.
      • Schwartz S.
      • Wang S.
      • et al.
      A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen.
      Randomised controlled trial conducted in Ohio, USA. This study reports on an 8-week trial in which patients received lycopene or soy protein for a 4-week period, after which both groups were instructed to consume both lycopene and soy protein. The results are limited to reporting on the 8-week treatment phase of the studyA total of 41 men with recurrent, asymptomatic prostate cancer were randomised into two groups. Participants receiving chemotherapy, radiotherapy or biological therapy at the time of the study were excluded along with men that had abnormal kidney or liver function, and a history of a malabsorptive disorder (or any other metabolic disorder requiring specific dietary requirements). Numbers include:

       • Group ‘A’ – 20

       • Group ‘B’ – 21
      Individuals underwent a ‘wash-out’ phase at 1 week post study enrolment, which consisted of abstaining from foods containing tomatoes and/or tomato products and any sources of soy protein or soy isoflavones. Participants were randomised to either group ‘A’ (consisting of tomatoes and/or tomato products to provide at least 25 mg lycopene per day), or group ‘B’ (consisting of 40 g soy protein isolate per day). After the initial 4-week period, all participants were instructed to consume both 25 mg lycopene and 40 grams of soy proteinTotal lycopene levels, at 4-weeks were reported after the 8-week treatment phase of the study
      Kucuk et al.
      • Kucuk O.
      • Sarkar F.
      • Sakr W.
      • et al.
      Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.
      Randomised controlled trial conducted in the USA. Individuals were randomised to receive either 15 mg lycopene, or no supplementation, 3 weeks prior to radical prostatectomyA total of 26 patients with clinical localised prostate cancer were randomised into groups. Patients were excluded if they had any prior therapy for prostate cancer, or if they consumed any nutritional and herbal supplements (apart from a single multivitamin tablet) once daily. Numbers include:

       • Intervention group – 15

       • Control group – 11
      Participants in the intervention group received a 4-week supply of 15 mg lycopene capsules (Lyc-O-Mato). The lycopene soft gel capsules contained 15 mg lycopene, 2.5 mg phytoene/phytofluene and minor carotenoids suspended in natural tomato matrix and encapsulated in gelatin. Participants randomised to the control group were asked to continue their regular diet and recommended to increase daily fruit and vegetable intake to five servings a dayOutcomes included biomarkers of cell growth and differentiation, grade/volume of the tumour and PSA levels
      Mohanty et al.
      • Mohanty N.
      • Saxena S.
      • Singh U.
      • Goyal N.
      • Arora R.
      Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia.
      Randomised controlled trial at the Department of Urology in New Delhi, India. Individuals were randomised to receive either 4 mg lycopene, to be consumed twice a day for a year, or nothing (for the control participants). Both groups were followed for a 2-year periodA total of 40 patients with high-grade prostatic intraepithelial neoplasia (HGPIN) were randomised into two groups. Both the intervention and control groups had equal number of participants with HGPIN, with grade II disease and HGPIN. Number include:

       • Intervention group – 20

       • Control group – 20
      Participants randomised to the intervention group received 4 mg lycopene, twice a day for 1 year continuously. Participants in the control group were not given any interventions, but advised to reduce intake of tomato and melonOutcomes assessed included changes in PSA levels, and incidence of BPH and prostate cancer
      Schwarz et al.
      • Schwarz S.
      • Obermuller-Jevic U.
      • Hellmis E.
      • Koch W.
      • Jacobi G.
      • Biesalski H.
      Lycopene inhibits disease progression in patients with benign prostate hyperplasia.
      Randomised controlled trial in Hohenheim, Stuttgart, Germany. Individuals were randomised to receive either a placebo or 15 mg/day lycopene. This study reports on participants that were followed for a 6-month period from October 2004 to July 2005Participants included men from Hohenheim. The inclusion criteria for the trial included a serum prostate-specific antigen (PSA) concentration greater than 4.0 mg/L, histologically confirmed BPH, aged between 45 and 70 years and the absence of acute illness. A total of 40 participants were initially recruited, with three participants dropping out during the course of the study. Two participants dropped out before commencing the supplement intake and one participant in the placebo group was excluded after 50 days due to an unexpected hospitalisation due to factors not related to the trial (family member's death). Numbers include:

       • Intervention group – 18

       • Control group – 19
      Lycopene supplements were provided as hard gelatin capsules containing 15 mg synthetic lycopene. A commercially available powder formulation containing 10% lycopene embedded in a matrix of gelatin and sucrose was used to fill the capsules. The placebo was a powder formulation without lycopeneThe primary endpoint was defined as inhibition of the delta increase, or decreased PSA levels in blood. Secondary endpoints were increases in the lycopene concentrations in blood and tissue (buccal mucosa cells (BMC)), reduced circulating insulin-like growth factor (IGF-1), and increases in IGF-binding protein-3 (IGF-BP-3) concentrations in blood. Additional variables measured were circulating concentrations of testosterone (free and bound), LDL cholesterol and total cholesterol, and blood glucose concentrations and routine hemograms. Additional examinations were digital rectal examination (DRE), trans-rectal ultrasonography (TRUS) of the prostate and assessment of the International Prostate Symptom Score (IPSS)
      Vaishampayan et al.
      • Vaishampayan U.
      • Hussain M.
      • Banerjee M.
      • et al.
      Lycopene and soy isoflavones in the treatment of prostate cancer.
      Phase II prospective randomised study in Detroit, Michigan, USA. Participants were randomised to receive either lycopene at a dose of 15 mg twice a day, or combination lycopene and isoflavone at a dose of 40 mg twice a day. Mean duration of therapy was 6 months in the lycopene group, and 5.5 months in the lycopene plus isoflavone groupParticipants included men with histologically proven prostate cancer. All patients had to be off any therapy for prostate cancer, except those already on hormone luteinizing hormone releasing hormone. Patients taking other supplements including soy, vitamin E, lycopene or selenium were not eligible for inclusion in the study. Participants also needed to have a life expectancy greater than 3 months. Numbers include:

       • Intervention (lycopene) – 38

       • Comparison (lycopene + isoflavone) – 33
      The intervention group received lycopene (Lyc-O-mato) at a dose of 15 mg orally twice a day. The comparison group received combination lycopene (at the same dose as the intervention group) plus isoflavone (Solgen) at a dose of 40 mg twice a day orallyOutcomes assessed included PSA levels
      van Breemen et al.
      • van Breemen R.
      • Sharifi R.
      • Viana M.
      • et al.
      Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial.
      Randomised, double-blind, placebo-controlled phase II trial in Chicago, Illinois, USA. Participants were randomised to receive either lycopene at a dose of 30 mg, or placebo in the form of 2 gel capsules. Participants were followed-up for 21 days, before a biopsy was performed. The study period was from June 2000 to June 2005Participants were African American men aged 50–83 years, who were being scheduled for prostate biopsy as a result of PSA levels greater than 4 ng/mL, an abnormal DRE and/or ultrasonography. Men who had a history of chronic disease associated with oxidative stress, inflammatory bowel disease, cancer or a hypersensitivity to tomatoes or tomato extract were excluded. Men with alcohol or substance abuse problems, along with those who were taking dietary supplements containing lycopene were also excluded. Numbers include:

       • Intervention – 69

       • Control – 62
      The intervention group received 30 mg lycopene (LycoRed). The lycopene capsule consisted of lycopene, triglycerides, plant sterols, tocopherols, phytoene, phytofluene and beta-carotene. The placebo capsule consisted of soybean oil. Both groups were instructed to take two pills a day (each intervention pill contained 15 mg lycopene for a total of 30 mg lycopene)Outcomes assessed included lycopene levels, BPH diagnosis, prostate cancer diagnosis

      3.2 Risk of bias

      Risk of bias for each study is illustrated in Fig. 2, and determined as follows:
      • Ansari and Gupta [
        • Ansari M.
        • Gupta N.
        A comparison of lycopene and orchidectomy vs. orchidectomy alone in the management of advanced prostate cancer.
        ] – ‘unclear’ risk of bias
      • Bunker et al. [
        • Bunker C.
        • McDonald A.
        • Evans R.
        • de la Rosa N.
        • Boumosleh J.
        • Patrick A.
        A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk.
        ] – ‘high’ risk of bias
      • Grainger et al. [
        • Grainger E.
        • Schwartz S.
        • Wang S.
        • et al.
        A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen.
        ] – ‘high’ risk of bias
      • Kucuk et al. [
        • Kucuk O.
        • Sarkar F.
        • Sakr W.
        • et al.
        Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.
        ] – ‘unclear’ risk of bias
      • Mohanty et al. [
        • Mohanty N.
        • Saxena S.
        • Singh U.
        • Goyal N.
        • Arora R.
        Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia.
        ] – ‘high’ risk of bias
      • Schwarz et al. [
        • Schwarz S.
        • Obermuller-Jevic U.
        • Hellmis E.
        • Koch W.
        • Jacobi G.
        • Biesalski H.
        Lycopene inhibits disease progression in patients with benign prostate hyperplasia.
        ] – ‘low’ risk of bias
      • Vaishampayan et al. [
        • Vaishampayan U.
        • Hussain M.
        • Banerjee M.
        • et al.
        Lycopene and soy isoflavones in the treatment of prostate cancer.
        ] – ‘unclear’ risk of bias
      • van Breemen et al. [
        • van Breemen R.
        • Sharifi R.
        • Viana M.
        • et al.
        Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial.
        ] – ‘low’ risk of bias
      Figure thumbnail gr2
      Fig. 2Risk of bias summary of included studies.

      3.3 Effect of interventions

      3.3.1 Prostate cancer diagnosis

      Incidence of prostate cancer diagnosis was reported in two studies (Mohanty et al. [
      • Mohanty N.
      • Saxena S.
      • Singh U.
      • Goyal N.
      • Arora R.
      Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia.
      ] and van Breemen et al. [
      • van Breemen R.
      • Sharifi R.
      • Viana M.
      • et al.
      Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial.
      ]). Although a decrease in prostate cancer diagnosis following lycopene was reported in a meta-analysis of the two studies, this decrease was not statistically significant (RR = 0.95, 95%CI 0.63, 1.44) (Fig. 3).
      Figure thumbnail gr3
      Fig. 3Meta-analysis of lycopene versus comparison – outcome: prostate cancer diagnosis.

      3.3.2 BPH diagnosis

      Incidence of BPH diagnosis was reported in two studies (Mohanty et al. [
      • Mohanty N.
      • Saxena S.
      • Singh U.
      • Goyal N.
      • Arora R.
      Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia.
      ] and van Breemen et al. [
      • van Breemen R.
      • Sharifi R.
      • Viana M.
      • et al.
      Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial.
      ]). A meta-analysis of these two studies indicated a decrease in BPH diagnosis with lycopene, however this decrease was not statistically significant (RR = 0.92, 95%CI 0.66, 1.29) (Fig. 4).
      Figure thumbnail gr4
      Fig. 4Meta-analysis of lycopene versus comparison – outcome: BPH diagnosis.

      3.3.3 PSA levels

      PSA levels were reported in two studies (Bunker et al. [
      • Bunker C.
      • McDonald A.
      • Evans R.
      • de la Rosa N.
      • Boumosleh J.
      • Patrick A.
      A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk.
      ] and Kucuk et al. [
      • Kucuk O.
      • Sarkar F.
      • Sakr W.
      • et al.
      Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.
      ]). A meta-analysis of these two studies indicated a significant decrease in PSA levels in men diagnosed with prostate cancer and treated with lycopene (MD = −1.58, 95%CI −2.61, −0.55) (Fig. 5). However, the statistical heterogeneity of this meta-analysis was high (I2 > 67%). PSA levels were also addressed by the Ansari and Gupta [
      • Ansari M.
      • Gupta N.
      A comparison of lycopene and orchidectomy vs. orchidectomy alone in the management of advanced prostate cancer.
      ] study, which compared PSA levels in men receiving lycopene plus orchidectomy to orchidectomy alone. This study identified a statistically significant decrease in PSA levels in the group receiving the lycopene (MD = −6.00, 95%CI −8.92, −3.08).
      Figure thumbnail gr5
      Fig. 5Meta-analysis of lycopene versus comparison – outcome: PSA levels.

      3.3.4 Lycopene levels

      Four studies reported lycopene levels in men diagnosed with prostate cancer (Bunker et al. [
      • Bunker C.
      • McDonald A.
      • Evans R.
      • de la Rosa N.
      • Boumosleh J.
      • Patrick A.
      A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk.
      ] and van Breemen et al. [
      • van Breemen R.
      • Sharifi R.
      • Viana M.
      • et al.
      Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial.
      ]) and BPH (Schwarz et al. [
      • Schwarz S.
      • Obermuller-Jevic U.
      • Hellmis E.
      • Koch W.
      • Jacobi G.
      • Biesalski H.
      Lycopene inhibits disease progression in patients with benign prostate hyperplasia.
      ] and van Breemen et al. [
      • van Breemen R.
      • Sharifi R.
      • Viana M.
      • et al.
      Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial.
      ]). Meta-analysis of these studies identified a statistically significant increase in lycopene levels in both men diagnosed with prostate cancer (MD = 0.12, 95%CI 0.07, 0.17) and men diagnosed with BPH (MD = 0.74, 95%CI 0.59, 0.89) that were treated with lycopene compared to those who received placebo. The study by Grainger et al. [
      • Grainger E.
      • Schwartz S.
      • Wang S.
      • et al.
      A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen.
      ] reported lycopene levels in men receiving soy versus those receiving combination soy and lycopene. This study similarly reported a statistically significant increase in lycopene levels in the lycopene only group (MD = 0.92, 95%CI 0.88, 0.96).

      3.3.5 Other outcomes

      The study by Schwarz et al. [
      • Schwarz S.
      • Obermuller-Jevic U.
      • Hellmis E.
      • Koch W.
      • Jacobi G.
      • Biesalski H.
      Lycopene inhibits disease progression in patients with benign prostate hyperplasia.
      ] reported no significant difference between participants with respect to prostate symptom score (MD = 0.20, 95%CI −2.66, 3.06). The study by Ansari and Gupta [
      • Ansari M.
      • Gupta N.
      A comparison of lycopene and orchidectomy vs. orchidectomy alone in the management of advanced prostate cancer.
      ] also identified no significant difference in peak flow rate between participants (MD = 1.20, 95%CI −0.21, 2.61).

      4. Discussion

      A total of eight RCTs, with a total of 480 participants were included in this systematic review. None of the studies reported on prostate cancer-specific mortality. All of the included studies differed with respect to their methodological design, including participants recruited, randomisation process, allocation and implementation of lycopene and assessment of outcomes. This large degree of clinical heterogeneity limits the value on the pooled estimates identified from any meta-analysis completed.
      Despite this heterogeneity, it was identified that lycopene supplementation may lead to a decrease in the incidence of BPH and prostate cancer diagnosis, although this is not a statistically significant trend. This finding concurs with a meta-analysis of 11 case–control studies, five nested case–control studies and five cohort studies, which identified a non-statistically significant 6% decrease (moderate lycopene intake) and an 11% decrease (high lycopene intake) in prostate cancer incidence [
      • Etminan M.
      • Takkouche B.
      • Caamano-Isorna F.
      The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies.
      ].
      Findings from this systematic review demonstrated a significant decrease in PSA levels in men diagnosed with prostate cancer, who had consumed lycopene. The findings also suggest an inverse relationship between lycopene and PSA levels; that as serum lycopene levels increase, serum PSA levels may decrease. These findings are supported by two previous systematic reviews, which also reached similar conclusions on this topic [
      • Haseen F.
      • Cantwell M.
      • O'Sullivan J.
      • Murray L.
      Is there a benefit from lycopene supplementation in men with prostate cancer? A systematic review.
      ,
      • Ilic D.
      • Forbes K.
      • Hassad C.
      Lycopene for the prevention of prostate cancer.
      ]. Furthermore, the increase in serum lycopene found in the groups treated with lycopene demonstrates that these supplementation methods are effective for increasing the levels of circulating lycopene required to exert its effect on BPH and prostate cancer outcomes.
      All of the studies included in this systematic review administered lycopene in the form of supplements to participants. Previous research has suggested that the any beneficial outcomes from lycopene may be a result of a range of micronutrients present in the diet (e.g. ‘Mediterranean’ diet) as a whole, rather than supplements, which promote the antioxidant effects [
      • Ahn J.
      • Gammon M.
      • Santella R.
      • et al.
      Associations between breast cancer risk and the catalase genotype, fruit and vegetable consumption and supplement use.
      ]. The ‘ideal’ daily intake of lycopene is unknown, although it has been suggested that a daily lycopene intake of 6 mg may be sufficient to promote its beneficial antioxidant properties [
      • Porrini M.
      • Riso P.
      What are typical lycopene intakes?.
      ]. The majority of studies included in this systematic review provided participants with between 15 and 30 mg of lycopene daily, without demonstrating a significant decrease in BPH or prostate cancer incidence. A decrease in PSA levels was evident in men consuming lycopene, however both studies had very limited follow-up periods (3 weeks and 5 months).
      The rate of dietary supplement consumption has steadily increased over the year. In the United States (U.S.), one in two consumers use dietary supplements, with this figure increasing to 70% of consumers aged over 70 years [
      • Bailey R.
      • Gahche J.
      • Lenito C.
      • et al.
      Dietary supplement use in the United States 2003–2006.
      ]. Given this increase in the consumption of supplements, and the lack of evidence currently available on the effectiveness of lycopene, there is a need for a high quality RCT to investigate the effectiveness of lycopene in men diagnosed with BPH and prostate cancer. Until such evidence is available, and given the limited number of studies published on this topic, and their varying quality and methodological design, there is currently not sufficient evidence to support, or refute, the use of lycopene for the prevention or treatment of BPH or prostate cancer.

      Contributors

      Dragan Ilic designed the systematic review, performed the searches, selected and appraised the trials, extracted the data, performed the analysis and interpretation of the data and drafted the manuscript.
      Marie Misso assisted with the selection and appraisal of the trials, extracted the data, assisted with the data analysis and interpretation and drafted the manuscript.

      Competing interests

      None declared.

      Funding

      No external funding was received.

      Provenance and peer review

      Commissioned and externally peer reviewed.

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