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Natural Medicine Journal

February 7, 2014

Benefits of Melatonin in Solid Tumors When Used Concurrently With Chemotherapy

Melatonin offers a relatively safe option to support patients undergoing active treatment
In 8 randomized controlled trials, a control group receiving standard chemo/radiotherapy was compared to an intervention group receiving the same treatment with the addition of melatonin to find out if melatonin affects tumor remission, overall survival, and mitigation of treatment side effects.

Reference

Wang YM, Jin BZ, Ai F, et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-1220.
 

Design

A meta-analysis of 8 randomized controlled trials (RCTs). The incorporated studies were neither blinded nor placebo-controlled. All studies compared a control group receiving standard chemo/radiotherapy to an intervention group receiving the same treatment with the addition of melatonin. The standard treatment was chemotherapy in 6 of the trials, radiotherapy in 1 trial, and transarterial chemoembolization (TACE) in the remaining trial.
 

Participants

A combined total of 761 subjects from 8 different RCTs that studied various solid tumors.1-8 Seven of the studies were conducted in Italy, and 1 was conducted in China. Six of the Italian studies were led by the same researcher, P. Lissoni. Studies were performed between 1996 and 2007.
 
 TABLE 1: Number of Total Subjects by Cancer type and Treatment Regimen
 
Cancer TypeTreatment + MltTreatment Alone
Lung  
Cisplatin + Etoposide171180
Gemzar1412
Breast  
Mitoxantrone2728
Doxorubicin2119
Paclitaxel76
GI  
5FU + Folinic acid2630
Irinotecan1416
Head/Neck  
5FU + Cisplatin1314
HCC  
TACE5050
Glioblastoma  
Radiation Therapy1416
 
Note: The total number of subjects displayed does not equal 761 because 1 of the trials used a melatonin metabolite (5-MTT) arm in addition to melatonin, accounting for the 33 missing subjects.2
 

Study Medication and Dosage

Melatonin (20 mg orally) once daily at night, in combination with standard treatment.
 

Outcome Measures

Tumor remission, overall survival, and mitigation of treatment side effects.
 

Key Findings

 
Table 2: Meta-analysis Results
 
Outcome# Studies
incl of 8		Melatonin
Result		Group 
Total n		Control
Result		Group 
Total n		RRP value
Overall remission rate832.6%37416.5%3871.95<0.00001
1-yr survival552.2%29128.4%2991.900.001
Thrombocytopenia5a2.2%27919.7%2890.13<0.00001
Neurotoxicity5a2.5%27915.2%2890.19<0.0001
Fatigue5a17.2%27949.1%2890.37<0.00001
 
All 5 studies conducted by same lead investigator, P. Lissoni and used chemotherapy as standard treatment; did not include radiation therapy or TACE.
 

Practice Implications

The short answer: Recommend 20 mg of melatonin, nightly, to your patients diagnosed with solid tumors to reduce side effects of chemotherapy and to improve survival/remission rates.
 
Melatonin, 20 mg nightly, offers a relatively safe option to support patients diagnosed with solid tumors, undergoing active treatment. This meta-analysis reviewed the safety and efficacy of melatonin in the setting of solid tumors only and should not be extrapolated to hematological cancers. Though the majority of available data (including small human samples, animal, and in vitro studies) assessing the safety and efficacy of melatonin in the setting of hematological cancers is positive, a few studies (1 animal and 2 in vitro) suggest the need for caution. A full discussion of this topic lies outside the scope of this article.
 
According to this review, melatonin was shown to be effective at increasing remission rate and offering a statistically significant improvement in 1-year survival rates among the study participants. Melatonin, 20 mg dosed nightly, also reduced the rates of chemotherapy-induced thrombocytopenia, neurotoxicity, and fatigue. As summarized in Table 2, more than half the pooled study subjects were patients with non-small cell lung cancer (NSCLC) who received the chemotherapy regimen cisplatin + etoposide (Cis/Eto).
 
The remaining subjects were divided across the other sites of solid tumors, including breast, GI, and head and neck. The inclusion of a small, isolated, radiotherapy study offers little strength to support the use of melatonin in this setting. The claim made by the authors in the title, “The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy…” overstates the weight of the radiotherapy evidence. The strongest evidence shown by this meta-analysis lies in the concurrent use of melatonin with Cis/Eto in patients diagnosed with NSCLC.
 
An oddity of this meta-analysis, and likely any meta-analysis done on the use of melatonin in the oncology setting, is the repetition of a single primary investigator across multiple studies.
 
 
An oddity of this meta-analysis, and likely any meta-analysis done on the use of melatonin in the oncology setting, is the repetition of a single primary investigator across multiple studies. To what extent this impacts the reproducibility, or generalizability, of the results is unknown. The results of a PubMed search on Paolo Lissoni reveal that he is involved in the authorship of 127 articles about melatonin. Conducting a meta-analysis without multiple studies by Lissoni would be very difficult. For example, a comparative meta-analysis by Seely, et al,9used broader inclusion criteria and included 21 trials, 18 of which involved Lissoni.
 
This meta-analysis only included RCTs; however, none of these trials was blinded or placebo-controlled. The lack of placebo control and blinding weakens the evidence presented. It may be argued that “placebo effect” may account, at least in part, for the benefits seen across the included trials. According to the American Cancer Society, 1 in 3 subjects taking a placebo may experience clinical benefit.10 That being stated, few conventional chemotherapy/radiotherapy trials are placebo controlled, and many are unblinded.11,12,13 Typically oncology trials compare 1 treatment regimen against a standard protocol to determine if the new therapy improves specific outcomes (eg, quality of life, progression free survival). FDA approval may be achieved with modest benefits in certain cancer settings (eg, metastatic disease), in part due to the paucity of available therapies for these patients.
 

Natural therapies should be assessed with a similar set of criteria in the oncology setting; for the same reasons, patients have few options. Because of its relatively low cost, excellent patient tolerability, and mild toxicity profile, melatonin should be considered in any integrative oncology plan for solid tumors. The results of Seely’s meta-analysis further support this conclusion and offer potentially broader applications. Additionally, melatonin plays an important role in the setting of breast cancer development and prognosis. Tina Kaczor’s article, “An Overview of Melatonin and Breast Cancer,” published by this journal in February 2010, provides an excellent synopsis of the information.14 

For more research involving integrative oncology, click here.

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References

  1.  Cerea G, Vaghi M, Ardizzoia A, 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. Anticancer Res. 2003;23(2C):1951-1954.
  2.  Lissoni P. Biochemotherapy with immunomodulating pineal hormones other than melatonin: 5-methoxytryptamine as a new oncostatic pineal agent. Pathol Biol (Paris). 2007;55(3-4):198-200.
  3.  Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer. 1999;35(12):1688-1692.
  4.  Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: A randomized trial. J Pineal Res. 2003;35(1):12-15.
  5.  Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 1996;53(1):43-46.
  6.  Lissoni P, Paolorossi F, Ardizzoia A, 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. J Pineal Res. 1997;23(1):15-19.
  7.  Lissoni P, Tancini G, Barni S, et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer. 1997;5(2):126-129.
  8.  Yan JJ, Shen F, Wang K, Wu MC. Patients with advanced primary hepatocellular carcinoma treated by melatonin and transcatheter arterial chemoembolization: A prospective study. Hepatobiliary Pancreat Dis Int. 2002;1(2):183-186.
  9.  Seely D, Wu P, Fritz H, et al. Melatonin as adjuvant cancer care with and without chemotherapy: A systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2011.
  10.  American Cancer Society. Placebo effect what is the placebo effect?. http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/placebo-effect. Updated 2010. Accessed 7/4, 2012.
  11.  Allegra CJ, Yothers G, O'Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29(1):11-16.
  12.  Venderbosch S, Doornebal J, Teerenstra S, Lemmens W, Punt CJ, Koopman M. Outcome of first line systemic treatment in elderly compared to younger patients with metastatic colorectal cancer: A retrospective analysis of the CAIRO and CAIRO2 studies of the Dutch Colorectal Cancer Group (DCCG). Acta Oncol. 2012 Jul 16. [Epub ahead of print]
  13.  Dahl O, Fluge Ø, Carlsen E, et al. Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol incolon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group. Acta Oncol. 2009;48(3):368-376.
  14.  Kaczor T. An overview of melatonin and breast cancer. Nat Med Journal. 2010;2(2). Available at http://naturalmedicinejournal.com/article_content.asp?article=108

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