Efficacy and Safety of Exogenous Melatonin in the Adjuvant Therapy of Tumor: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 XU Weiping ¹ , WANG Weidi ¹ , XU Tingjuan ¹ , WEI Wei ² , SUN Zhigang ³ , HU Shilian ¹ , YAN Guang ¹

1. Anhui Provincial Hospital, Hefei 230001, China;2. Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China;3. The Sixth Hospital of Shijiazhuang, Shijiazhuang 050051, China;

Corresponding author：

XU Weiping, Email: xwp5606@163.com

Keywords：

Melatonin; Tumor; Adjuvant therapy; Meta-analysis; Systematic review

DOI：

10.7507/1672-2531.20110119

Video：

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Objective 　To evaluate the efficacy and safety of melatonin as an adjuvant therapy for the tumor patients receiving chemotherapy or radiotherapy.
Methods 　Such databases as MEDLINE (1980 to Jan. 2010), The Cochrane Library (Issue 4, 2009), WanFang Data (1980 to Jan. 2010), CBM (1980 to Jan. 2010), CNKI (1980 to Jan. 2010), ELSEVIER ScienceDirect (SDOS, 1980 to Jan. 2010), Nature (1980 to Jan. 2010) and ongoing clinical trials (www.clinicaltrials.gov and www.controlled-trials.com) were searched to collect randomized controlled trials (RCTs). The data were extracted and the quality of the included RCTs was assessed by two reviewers. Then meta-analyses were performed by using Stata 10.1 software.
Results 　Eight RCTs were included. The results of meta-analyses showed that melatonin significantly improved the remission rate for tumor patients (RR=1.98, 95% CI 1.52 to 2.58) and the one-year survival rate (RR=1.90, 95%CI 1.28 to 2.83), and significantly reduced the toxic effects of bone marrow suppression caused by chemotherapy or radiotherapy (RR=0.12, 95%CI 0.06 to 0.27). No reports of adverse events were associated with melatonin.
Conclusion 　The existing evidence reveals that the melatonin, as an adjuvant therapy drug for tumor, plays a certain role in improving disease remission rate, reducing the toxicity of chemotherapy and radiotherapy, and prolonging the life. It requires more high-quality RCTs for further verification because of the limitation of the included studies.

Citation： XU Weiping,WANG Weidi,XU Tingjuan,WEI Wei,SUN Zhigang,HU Shilian,YAN Guang. Efficacy and Safety of Exogenous Melatonin in the Adjuvant Therapy of Tumor: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2011, 11(6): 681-686. doi: 10.7507/1672-2531.20110119 Copy

1.	1 Blask DE. Melatonin, sleep disturbance and cancer risk. Sleep Med Rev , 2009, 13(4): 257-264.
2.	Pacchierotti C, Iapichino S, Bossini L, et al . Melatonin in psychiatric disorders: a review on the melatonin involvement in psychiatry. Front Neuroendocrinol , 2001, 22(1): 18-32.
3.	de Castro-Silva C, de Bruin VM, Cunha GM, et al . Melatonin improves sleep and reduces nitrite in the exhaled breath condensate in cystic fibrosis--a randomized, double-blind placebo-controlled study. J Pineal Res , 2010, 48(1): 65-71.
4.	Sainz RM, Reiter RJ, Tan DX, et al . Critical role of glutathione in melatonin enhancement of tumor necrosis factor and ionizing radiation-induced apoptosis in prostate cancer cells in vitro. J Pineal Res , 2008, 45(3): 258-270.
5.	Korkmaz A, Tamura H, Manchester LC, et al . Combination of melatonin and a peroxisome proliferator-activated receptor-gamma agonist induces apoptosis in a breast cancer cell line. J Pineal Res , 2009, 46(1): 115-116.
6.	Pizarro JG, Yeste-Velasco M, Esparza JL, et al . The antiproliferative activity of melatonin in B65 rat dopaminergic neuroblastoma cells is related to the downregulation of cell cycle-related genes. J Pineal Res , 2008, 45(1): 8-16.
7.	Leon-Blanco MM, Guerrero JM, Reiter RJ, et al . Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro. J Pineal Res , 2003, 35(3): 204-11.
8.	Dauchy RT, Blask DE, Dauchy EM, et al . Antineoplastic effects of melatonin on a rare malignancy of mesenchymal origin: melatonin receptor-mediated inhibition of signal transduction, linoleic acid metabolism and growth in tissue-isolated human leiomyosarcoma xenografts. J Pineal Res , 2009, 47(1): 32-42.
9.	D. Moher, A. Liberati, J. Tetzlaff, et al . Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Journal of Clinical Epidemiology , 2009, 62(10): 1006-1012.
10.	Jadad AR, Moore RA, Carroll D, et al . Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials , 1996, 17(1): 1-12.
11.	Lissoni P, Barni S, Mandalà 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.
12.	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.
13.	Lissoni P, Chilelli M, Villa S, et al . 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.
14.	晏建军, 沈锋, 王葵, 等. 褪黑素对中晚期肝癌肝动脉化疗栓塞的协同和保护作用. 第二军医大学学报, 2001, 22(9): 858-861.
15.	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.
16.	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.
17.	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.
18.	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.
19.	Cucina A, Proietti S, D'Anselmi F, et al . Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells. J Pineal Res , 2009, 46(2): 172-180.
20.	Joo SS, Yoo YM. Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. J Pineal Res , 2009, 47(1): 8-14.
21.	Watanabe M, Kobayashi Y, Takahashi N, et al . Expression of melatonin receptor (MT1) and interaction between melatonin and estrogen in endometrial cancer cell line. J Obstet Gynaecol Res , 2008, 34(4): 567-573.
22.	Martín-Renedo J, Mauriz JL, Jorquera F, et al . Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res , 2008, 45(4): 532-540.
23.	Lissoni P, Barni S, Ardizzoia A, et al . A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer , 1994, 73(3): 699-701.
24.	蒋旭琴, 韩志君, 梅晓冬. 褪黑素对免疫系统的调节作用及其应用研究进展. 细胞与分子免疫学杂志, 2007, 23(11): 1091-1093.
25.	Mills E, Wu P, Seely D, et al . Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res , 2005, 39(4): 360-366.

1. 1 Blask DE. Melatonin, sleep disturbance and cancer risk. Sleep Med Rev , 2009, 13(4): 257-264.
2. Pacchierotti C, Iapichino S, Bossini L, et al . Melatonin in psychiatric disorders: a review on the melatonin involvement in psychiatry. Front Neuroendocrinol , 2001, 22(1): 18-32.
3. de Castro-Silva C, de Bruin VM, Cunha GM, et al . Melatonin improves sleep and reduces nitrite in the exhaled breath condensate in cystic fibrosis--a randomized, double-blind placebo-controlled study. J Pineal Res , 2010, 48(1): 65-71.
4. Sainz RM, Reiter RJ, Tan DX, et al . Critical role of glutathione in melatonin enhancement of tumor necrosis factor and ionizing radiation-induced apoptosis in prostate cancer cells in vitro. J Pineal Res , 2008, 45(3): 258-270.
5. Korkmaz A, Tamura H, Manchester LC, et al . Combination of melatonin and a peroxisome proliferator-activated receptor-gamma agonist induces apoptosis in a breast cancer cell line. J Pineal Res , 2009, 46(1): 115-116.
6. Pizarro JG, Yeste-Velasco M, Esparza JL, et al . The antiproliferative activity of melatonin in B65 rat dopaminergic neuroblastoma cells is related to the downregulation of cell cycle-related genes. J Pineal Res , 2008, 45(1): 8-16.
7. Leon-Blanco MM, Guerrero JM, Reiter RJ, et al . Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro. J Pineal Res , 2003, 35(3): 204-11.
8. Dauchy RT, Blask DE, Dauchy EM, et al . Antineoplastic effects of melatonin on a rare malignancy of mesenchymal origin: melatonin receptor-mediated inhibition of signal transduction, linoleic acid metabolism and growth in tissue-isolated human leiomyosarcoma xenografts. J Pineal Res , 2009, 47(1): 32-42.
9. D. Moher, A. Liberati, J. Tetzlaff, et al . Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Journal of Clinical Epidemiology , 2009, 62(10): 1006-1012.
10. Jadad AR, Moore RA, Carroll D, et al . Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials , 1996, 17(1): 1-12.
11. Lissoni P, Barni S, Mandalà 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.
12. 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.
13. Lissoni P, Chilelli M, Villa S, et al . 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.
14. 晏建军, 沈锋, 王葵, 等. 褪黑素对中晚期肝癌肝动脉化疗栓塞的协同和保护作用. 第二军医大学学报, 2001, 22(9): 858-861.
15. 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.
16. 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.
17. 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.
18. 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.
19. Cucina A, Proietti S, D'Anselmi F, et al . Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells. J Pineal Res , 2009, 46(2): 172-180.
20. Joo SS, Yoo YM. Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. J Pineal Res , 2009, 47(1): 8-14.
21. Watanabe M, Kobayashi Y, Takahashi N, et al . Expression of melatonin receptor (MT1) and interaction between melatonin and estrogen in endometrial cancer cell line. J Obstet Gynaecol Res , 2008, 34(4): 567-573.
22. Martín-Renedo J, Mauriz JL, Jorquera F, et al . Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res , 2008, 45(4): 532-540.
23. Lissoni P, Barni S, Ardizzoia A, et al . A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer , 1994, 73(3): 699-701.
24. 蒋旭琴, 韩志君, 梅晓冬. 褪黑素对免疫系统的调节作用及其应用研究进展. 细胞与分子免疫学杂志, 2007, 23(11): 1091-1093.
25. Mills E, Wu P, Seely D, et al . Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res , 2005, 39(4): 360-366.

Chinese Journal of Evidence-Based Medicine

Efficacy and Safety of Exogenous Melatonin in the Adjuvant Therapy of Tumor: A Meta-analysis

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