Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis

Figures & data

Table 1 Characteristics of the included studies

Articles	Types of tumor	Case number (T/C)	Age range	Interventions	Dosage	CR (T vs C)	CR + PR (T vs C)	Survival rate	Adverse effect: T vs C	Conclusions
Sookprasert et al (2014)^Citation28	Advanced NSCLC	104/47	18–70	MLT + chemotherapy vs placebo + chemotherapy	10 or 20 mg/day orally at night	–	–	1 year: 18/104 vs 6/47	Fatigue: 89/100 vs 39/45 Anorexia: 82/100 vs 31/45 Neuropathy: 62/99 vs 31/46 Anemia: 48/102 vs 26/46 Nausea: 41/101 vs 18/45 Liver dysfunction: 21/101 vs 13/46 Mucositis: 24/100 vs 10/45 Low glomerular filtration rate: 12/102 vs 7/46 Febrile neutropenia: 7/98 vs 3/42 Thrombocytopenia: 4/100 vs 2/46	MLT in combination with chemotherapy did not affect survival and adverse events of advanced patients with NSCLC
Lissoni et al (2008)^Citation35	Metastatic solid tumor (NSCLC or gastrointestinal tract tumors)	285/286	45–78	MLT + supportive care vs supportive care	20 mg/day orally in the evening	0/285 vs 0/286	10/285 vs 0/286	2 years: 6/285 vs 0/286	–	The MLT alone was able to induce a significant increase of disease stabilization and survival time with respect to supportive care alone
Lissoni (2007)^Citation36	Metastatic NSCLC	35/33	49–73	MLT + chemotherapy vs chemotherapy alone	20 mg/day orally during the dark period of the day	1/33 vs 0/35	13/33 vs 6/35	–	Thrombocytopenia: 1/33 vs 7/35 Neurotoxicity: 2/33 vs 8/25 Asthenia: 4/33 vs 14/35	The overall response rate achieved in patients concomitantly treated with MLT was significantly higher with respect to that obtained in patients treated with chemotherapy alone. Moreover, MLT significantly reduced some chemotherapy-related toxicities, thrombocytopenia, and neurotoxicity
Lissoni (2007)^Citation37	Metastatic solid tumor (NSCLC or gastrointestinal tract tumors)	187/183	–	MLT + chemotherapy vs chemotherapy alone	20 mg/day orally in the evening	12/187 vs 5/183	68/187 vs 37/183	2 years: 47/187 vs 24/183	Thrombocytopenia: 8/187 vs 41/183 Neurotoxicity: 10/187 vs 22/183 Asthenia: 51/187 vs 96/183 Neoplastic cachexia: 9/187 vs 36/183	The response rate was greater in patients concomitantly treated with MLT than in the group of chemotherapy alone for the overall chemotherapies The percentage of 2-year survival achieved in patients concomitantly treated with MLT was higher than that in those treated with chemotherapy alone Chemotherapy was better tolerated in patients concomitantly treated with MLT
Lissoni et al (2003)^Citation38	Metastatic NSCLC	49/51	38–81	MLT + chemotherapy vs chemotherapy alone	20 mg/day orally in the evening	2/49 vs 0/51	17/49 vs 9/51	1 year: 20/49 vs 10/51 5 years: 3/49 vs 0/51	Neurotoxicity: 2/49 vs 9/51 Thrombocytopenia: 1/49 vs 7/51 Weight loss greater than 10%: 3/49 vs 21/51 Asthenia: 4/49 vs 18/51 Alopecia: 14/51 vs 11/49 Anemia: 6/51 vs 4/49	Both the overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with MLT This study confirms, in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of MLT
Cerea et al (2003)^Citation39	Metastatic colorectal cancer	14/16	37–82	MLT + irinotecan vs irinotecan alone	20 mg/day orally in the evening	–	5/14 vs 2/16	–	Diarrhea: 4/14 vs 6/16	The efficacy of weekly low-dose irinotecan (CPT-11) in pretreated metastatic colorectal cancer patients may be enhanced by a concomitant daily administration of the pineal hormone MLT
Lissoni (2002)^Citation40	Advanced solid tumor (including lung, gastrointestinal, breast, and prostate cancers)	722/718	36–86	MLT + supportive care vs supportive care	Orally at 20 mg/day during the evening	–	17/722 vs 0/718	–	Cachexia: 37/722 vs 189/718 Asthenia: 126/722 vs 292/718 Anorexia: 149/722 vs 226/718 Depressive symptoms: 96/722 vs 164/718 Anemia: 186/722 vs 218/718 Thrombocytopenia: 21/722 vs 78/718 Lymphocytopenia: 204/722 vs 489/718	The percentage of patients with disease stabilization and the percentage of 1-year survival were significantly higher in patients concomitantly treated with MLT than in those treated with supportive care alone
Lissoni (2002)^Citation40	Advanced solid tumor (including lung, gastrointestinal, breast, and prostate cancers)	98/102	36–75	MLT + chemotherapy vs chemotherapy alone	Orally at 20 mg/day during the evening	3/98 vs 0/102	32/98 vs 20/102	–	Asthenia: 25/98 vs 46/102 Alopecia: 62/98 vs 72/102 Vomiting: 46/98 vs 56/102 Stomatitis: 15/98 vs 36/102 Diarrhea: 19/98 vs 24/102 Neurotoxicity: 8/98 vs 26/102 Nephrotoxicity: 0/98 vs 6/102 Cardiotoxicity: 2/98 vs 9/102 Leukopenia: 14/98 vs 18/102 Anemia: 12/98 vs 14/102 Thrombocytopenia: 2/98 vs 17/102	The objective tumor response rate was significantly higher in patients treated with chemotherapy plus MLT than in those treated with chemotherapy alone. Moreover, MLT induced a significant decline in the frequency of chemotherapy-induced asthenia, thrombocytopenia, stomatitis, cardiotoxicity, and neurotoxicity
Yan et al (2001)^Citation41	Advanced liver cancer	70/70	29–78	MLT + TACE vs TACE alone	Orally at 20 mg/day during the evening	0/70 vs 0/70	16/70 vs 9/70	1 year: 48/70 vs 38/70	–	Compared with the control group, the MLT group significantly increased the tumor response and survival rate
Lissoni et al (2000)^Citation42	Metastatic renal cell cancer	14/16	28–63	MLT + morphine + IL-2 vs MLT + morphine	20 mg/day during the evening	0/14 vs 0/16	4/14 vs 1/16	3 years: 3/14 vs 0/16	–	The percentage of partial responses achieved in patients treated with morphine alone was significantly lower than that observed in patients concomitantly treated with MLT. Moreover, the percentage of 3-year survival was significantly higher in patients concomitantly treated with MLT
Lissoni et al (1999)^Citation43	Metastatic solid tumor (including lung, gastrointestinal, breast, and head and neck cancers)	124/126	39–81	MLT + chemotherapy vs chemotherapy alone	Orally at 20 mg/day during the evening	6/124 vs 0/126	42/124 vs 19/126	1 year: 63/124 vs 29/126	Myelosuppression: 25/124 vs 54/126 Neurotoxicity: 3/124 vs 17/126 Nephrotoxicity: 0/124 vs 4/126 Cardiotoxicity: 2/124 vs 12/126 Stomatitis: 12/124 vs 38/126 Alopecia: 63/124 vs 74/126 Vomiting: 61/124 vs 72/124 Diarrhea: 16/124 vs 24/126 Asthaenia: 33/124 vs 79/126	MLT may enhance the efficacy of chemotherapy and reduce its toxicity, at least in advanced cancer patients of poor clinical status
Lissoni et al (1997)^Citation44	Metastatic solid tumors (including lung, gastrointestinal, and breast cancer)	39/41	38–76	MLT + chemotherapy vs chemotherapy alone	Orally at 20 mg/day during the evening	1/39 vs 0/41	12/39 vs 9/41	–	Myelotoxicity: 0/39 vs 8/41 Stomatitis: 2/39 vs 9/41 Neuropathy grade 1–2: 0/39 vs 5/41 Cardiac complications: 0/39 vs 3/41 Nephrotoxicity: 0/39 vs 1/41 Hepatotoxicity: 1/39 vs 3/41 Skin reactions: 3/39 vs 3/41 Alopecia grade 1–3: 7/39 vs 9/41 Diarrhea grade 1–2: 3/39 vs 5/41 Vomiting: 11/39 vs 14/41 Asthenia: 4/39 vs 19/41	Concomitant administration of the pineal hormone MLT during chemotherapy may prevent some chemotherapy-induced side effects, particularly myelosuppression and neuropathy Evaluation of the impact of MLT on chemotherapy efficacy will be the aim of future clinical investigations
Lissoni et al (1997)^Citation45	Advanced NSCLC	34/36	39–80	MLT + chemotherapy vs chemotherapy alone	Orally at 20 mg/day during the evening	1/34 vs 0/36	11/34 vs 6/36	1 year: 15/34 vs 6/36	Myelosuppression: 4/34 vs 13/36 Vomiting: 7/34 vs 10/36 Alopecia grade 1–3: 6/34 vs 9/36 Diarrhea grade 1–3: 1/34 vs 2/34 Neuropathy: 0/34 vs 5/36 Nephropathy: 0/34 vs 3/36 Asthenia: 3/34 vs 12/36 Weight loss >10%: 0/34 vs 16/36	The concomitant administration of MLT may improve the efficacy of chemotherapy, mainly in terms of survival time, and reduce chemotherapeutic toxicity in advanced NSCLC, at least in patients in poor clinical condition
Yan et al (1997)^Citation46	Advanced liver cancer	31/29	38–72	MLT + supportive care vs supportive care	Orally at 20 mg/day during the evening	0/31 vs 0/29	8/31 vs 1/29	1 year: 10/31 vs 0/29	–	MLT may represent a new palliative therapy, capable of inducing tumor regression, prolonging the survival time and improving the life quality of patients with unresectable primary liver cancer
Lissoni et al (1996)^Citation47	Brain glioblastoma	14/16	37–76	MLT + radiotherapy vs radiotherapy alone	Orally at 20 mg/day during the evening	–	6/11 vs 4/12	1 year: 6/14 vs 1/16	–	A radio neuroendocrine approach with radiotherapy plus MLT may prolong the survival time and improve the quality of life of patients affected by glioblastoma
Lissoni et al (1996)^Citation48	Malignant melanoma	14/16	38–81	MLT + supportive care vs supportive care	Orally at 20 mg/day during the evening	–	–	1 year: 10/14 vs 11/16	–	An adjuvant endocrine therapy with MLT may be effective in preventing disease progression in node relapsed melanoma patients
Lissoni et al (1995)^Citation49	Metastatic breast cancer	19/21	–	MLT + tamoxifen vs tamoxifen	Orally at 20 mg/day during the evening	0/19 vs 0/21	7/19 vs 2/21	1 year: 12/19 vs 5/21	No MLT-related toxicity was observed	The pineal hormone MLT may make tamoxifen effective also in ER-negative metastatic breast cancer patients
Lissoni et al (1994)^Citation50	Advanced solid tumor (including lung, gastrointestinal, and breast cancers)	41/39	36–74	MLT + IL-2 vs MLT + IL-2	Orally at 20 mg/day during the evening	3/41 vs 0/39	11/41 vs 1/39	1 year: 19/41 vs 6/39	Fever: 4/41 vs 6/39 Vomiting: 1/41 vs 2/39 Anorexia: 2/41 vs 4/39 Asthenia: 1/41 vs 3/39 Arthralgia: 0/41 vs 1/39 Depressive symptoms: 1/41 vs 3/39 Transaminase increase: 4/41 vs 7/39 Anemia: 1/41 vs 2/39 Thrombocytopenia: 0/41 vs 3/39	The concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy
Lissoni et al (1994)^Citation51	Cancer with brain metastasis (including melanoma, lung, breast, and colon cancers)	24/26	38–72	MLT + supportive care vs supportive care	Orally at 20 mg/day during the evening	–	–	1 year: 9/24 vs 3/26	Steroid-related infective complications: 3/24 vs 14/26	The pineal hormone MLT may be able to improve the survival time and the quality of life in patients with brain metastases due to solid tumors
Lissoni et al (1992)^Citation34	Metastatic NSCLC	31/32	39–78	MLT + supportive care vs supportive care	Orally at 10 mg/day during the evening	–	–	1 year: 8/31 vs 2/32	–	MLT may be successfully administered to prolong the survival time in metastatic NSCLC patients who progressed under a first-line chemotherapy with cisplatin, for whom no other effective therapy is available up to now

Abbreviations: CR, complete remission; MLT, melatonin; NSCLC, non-small-cell lung cancer; PR, partial remission; TACE, transcatheter artery chemoembolization; T, treatment group; C, control group; ER, estrogen receptor; IL-2, interleukin 2.

Figure 1 The flow chart of the literature screening process.

Figure 2 Meta-analysis of the tumor remission rate of cancer treated with MLT.

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 3 Meta-analysis of the overall survival rate of cancer treated with MLT.

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 4 Meta-analysis of the overall survival rate of lung cancer treated with MLT.

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 5 Meta-analysis of the overall survival rate of multiple solid cancers treated with MLT.

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 6 Meta-analysis of the neurotoxicity rate of cancer treated with MLT during chemotherapy.

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 7 Meta-analysis of the neurotoxicity rate of cancer treated with MLT during chemotherapy after sensitivity analysis (removing the study of Sookprasert 2014).

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 8 Meta-analysis of the thrombocytopenia rate of cancer treated with MLT during chemotherapy.

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 9 Meta-analysis of the asthenia rate of cancer treated with MLT during chemotherapy.

Abbreviations: MLT, melatonin; M–H, Mantel–Haenszel.

Figure 10 Funnel plot: Harbord test: t=2.2794, df =14, P-value =0.03883.

Abbreviation: RR, relative risk.

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