Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta‐analysis

Abstract:  Most observational studies show an association between melatonin and cancer in humans. We conducted a systematic review of randomized controlled trials (RCTs) of melatonin in solid tumor cancer patients and its effect on survival at 1 yr. With the aid of an information specialist, we searched 10 electronic databases from inception to October 2004. We included trials using melatonin as either sole treatment or as adjunct treatment. Prespecified criteria guided our assessment of trial quality. We conducted a meta‐analysis using a random effects model. We included 10 RCTs published between 1992 and 2003 and included 643 patients. All trials included solid tumor cancers. All trials were conducted at the same hospital network, and were unblinded. Melatonin reduced the risk of death at 1 yr (relative risk: 0.66, 95% confidence interval: 0.59–0.73, I2 = 0%, heterogeneity P ≤ 0.56). Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported. The substantial reduction in risk of death, low adverse events reported and low costs related to this intervention suggest great potential for melatonin in treating cancer. Confirming the efficacy and safety of melatonin in cancer treatment will require completion of blinded, independently conducted RCTs.

[1]  R. Reiter,et al.  Mechanisms of cancer inhibition by melatonin , 2004, Journal of pineal research.

[2]  Vijayalaxmi,et al.  Melatonin as a radioprotective agent: a review. , 2004, International journal of radiation oncology, biology, physics.

[3]  B. Djulbegovic,et al.  Bad reporting does not mean bad methods for randomised trials: observational study of randomised controlled trials performed by the Radiation Therapy Oncology Group , 2004, BMJ : British Medical Journal.

[4]  P. Lissoni,et al.  Five years survival in metastatic non‐small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial , 2003, Journal of pineal research.

[5]  Francine Laden,et al.  Night-shift work and risk of colorectal cancer in the nurses' health study. , 2003, Journal of the National Cancer Institute.

[6]  M. Vaghi,et al.  Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. , 2003, Anticancer research.

[7]  A. Ardizzoia,et al.  Reduction of cisplatin-induced anemia by the pineal indole 5-methoxytryptamine in metastatic lung cancer patients. , 2003, Neuro endocrinology letters.

[8]  C. Gentile,et al.  The chemistry of melatonin's interaction with reactive species , 2003, Journal of pineal research.

[9]  S. Thompson,et al.  Quantifying heterogeneity in a meta‐analysis , 2002, Statistics in medicine.

[10]  Vijayalaxmi,et al.  Melatonin: from basic research to cancer treatment clinics. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  P. Lissoni.  Is there a role for melatonin in supportive care? , 2002, Supportive Care in Cancer.

[12]  D. Blask,et al.  Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. , 2002, Current topics in medicinal chemistry.

[13]  R. Stevens,et al.  Night shift work, light at night, and risk of breast cancer. , 2001, Journal of the National Cancer Institute.

[14]  A. Morera,et al.  Seguridad en el uso de la melatonina , 2001 .

[15]  Douglas G Altman,et al.  Systematic reviews of evaluations of prognostic variables , 2001, BMJ : British Medical Journal.

[16]  M. de la Varga,et al.  [Safety in melatonin use]. , 2001, Actas espanolas de psiquiatria.

[17]  G. Maestroni,et al.  Anti-angiogenic activity of melatonin in advanced cancer patients. , 2001, Neuro endocrinology letters.

[18]  M. Mandalà,et al.  Abrogation of the Negative Influence of Opioids on IL–2 Immunotherapy of Renal Cell Cancer by Melatonin , 2000, European Urology.

[19]  S. Barni,et al.  Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. , 1999, European journal of cancer.

[20]  D. Blask,et al.  Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. , 1999, Cancer research.

[21]  H. Bartsch,et al.  Melatonin in cancer patients and in tumor-bearing animals. , 1999, Advances in experimental medicine and biology.

[22]  John Calvin Reed,et al.  A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells. , 1998, British Journal of Cancer.

[23]  P. Ghezzi,et al.  Mechanism of the inhibitory effect of melatonin on tumor necrosis factor production in vivo and in vitro. , 1998, European journal of pharmacology.

[24]  B. Guardiola‐Lemaître.  Toxicology of Melatonin , 1997, Journal of biological rhythms.

[25]  W. Richardson,et al.  Selecting and Appraising Studies for a Systematic Review , 1997, Annals of Internal Medicine.

[26]  P. Lissoni,et al.  Melatonin as a new possible anti-inflammatory agent. , 1997, Journal of biological regulators and homeostatic agents.

[27]  S. Barni,et al.  A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first‐line treatment of advanced non‐small cell lung cancer patients in a poor clinical state , 1997, Journal of pineal research.

[28]  A. Brzezinski.  Melatonin in humans. , 1997, The New England journal of medicine.

[29]  S. Barni,et al.  Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma , 1996, Journal of pineal research.

[30]  S. Barni,et al.  A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. , 1996, British Journal of Cancer.

[31]  S. Barni,et al.  Is there a role for melatonin in the treatment of neoplastic cachexia? , 1996, European journal of cancer.

[32]  S. Barni,et al.  Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. , 1996, Oncology.

[33]  S. Barni,et al.  A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast-cancer patients. , 1995, Oncology reports.

[34]  C H Schmid,et al.  Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care. , 1995, Journal of clinical epidemiology.

[35]  S. Barni,et al.  A Randomized Study of Immunotherapy with Low-Dose Subcutaneous Interleukin-2 plus Melatonin Vs Chemotherapy with Cisplatin and Etoposide as First-Line Therapy for Advanced Non-Small Cell Lung Cancer , 1994, Tumori.

[36]  S. Barni,et al.  A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms , 1994, Cancer.

[37]  S. Barni,et al.  A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. , 1994, British Journal of Cancer.

[38]  K. Bichler,et al.  Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients: evidence for reduced pineal activity and relevance of urinary determinations. , 1992, Clinica chimica acta; international journal of clinical chemistry.

[39]  S. Barni,et al.  Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin. , 1992, Oncology.