Melatonin for Cancer

The indolamine hormone melatonin, secreted by the pineal gland, is widely acknowledged for its effects on sleep and circadian rhythm, and is used by many people as a sleep aid and to prevent jet lag. Less widely known are its antiproliferative, oncostatic, antioxidant, and immunostimulatory effects, which could prove beneficial in cancer treatment.

Potential mechanisms of action that have been proposed include downregulation of oncogene expression, inhibition of growth factors, suppression of linoleic acid uptake by tumor cells, and antiangiogenic effects. Melatonin also modulates the cytostatic and cytotoxic effects of chemotherapeutic agents (J. Clin. Oncol. 2002;20:2575–601).

Moreover, low levels of melatonin have been measured in patients with certain types of malignancies, such as breast, prostate, and colorectal cancers.

Clinical Trials

A recent systematic review and metaanalysis identified 10 randomized clinical trials of melatonin in cancer. The trials, all of which were led by Dr. Paolo Lissoni of San Gerardo Hospital, Milan, included a total of 643 patients with solid tumors. In the largest of these trials, undertaken between January 1996 and November 1998, 250 consecutive patients with various types of advanced, metastatic tumors were randomized to receive chemotherapy alone or chemotherapy plus melatonin.

Patients with non-small cell lung cancer were treated with cisplatin plus etoposide or with gemcitabine. Those with breast cancer were treated with doxorubicin, mitoxantrone, or paclitaxel, and patients with gastrointestinal tract tumors received 5 fluorouracil (5-FU) and folinic acid. Patients with head and neck cancers were given cisplatin plus 5-FU.

Participants were randomized to receive these therapies with or without intramuscular injections of melatonin, 20 mg/day, given in the evening.

Clinical responses and toxicity were evaluated according to World Health Organization criteria. None of the 126 patients treated with chemotherapy alone achieved a complete response, while 6 of 124 (5%) of those who also received melatonin achieved a complete response. Of these six, two had non-small cell lung cancer, two had breast cancer, one had gastrointestinal tumors, and one had head and neck cancer (Eur. J. Cancer 1999;35:1688–92).

A partial response was seen in 36 (29%) of the melatonin-treated patients, and in 19 (15%) of those given chemotherapy alone.

The median time to disease progression was 9 months in the melatonin group and 4 months in the chemotherapy group. One-year survival was significantly higher in the melatonin group, at 51%, compared with 23% in the chemotherapy group.

There was no melatonin-related toxicity, and chemotherapy-related toxicities such as myelosuppression, thrombocytopenia, and cardiotoxicity were significantly less in the melatonin group.

It is thought that melatonin's protective effects against these toxicities derive primarily from its free-radical scavenging activities, although more specific mechanisms also may be at work. For example, prevention of thrombocytopenia may relate to melatonin's thrombopoietic properties, according to the authors.

In another of Dr. Lissoni's studies, 100 patients with non-small cell lung cancer were randomized to a chemotherapeutic regimen consisting of four cycles of cisplatin and etoposide, with or without 20-mg oral melatonin each day.

A complete response was seen in 2 of 49 (4%) patients in the melatonin group, but in no patients in the chemotherapy group. A partial response was seen in 15 (31%) and 9 (18%) of those in the melatonin and chemotherapy groups, respectively. The overall proportion of responders was significantly higher in the melatonin group (J. Pineal Res. 2003;35:12–5).

Stable disease was seen in 22 patients in the chemotherapy group and 26 in the melatonin group. Progressive disease was seen in 20 of the chemotherapy patients and 6 of the melatonin patients, a difference that was statistically significant.

None of the patients treated with chemotherapy alone were alive 2 years later, while three (6%) of those in the melatonin plus chemotherapy group survived for 5 years or more. The authors noted, “This percent, although it may seem low, may have a major impact on the general population, because of the very high frequency of lung cancer.”

The investigators also observed that patients treated with melatonin experienced consistently improved quality of life because of the hormone's ability to prevent cancer-related cachexia and chemotherapy-induced lymphocyte damage. They suggested that future strategies for treating advanced cancer could include a combination of chemotherapeutic and immunobiologic approaches.

Other trials included in the metaanalysis evaluated melatonin for brain metastases, brain glioblastoma, malignant melanoma, and renal cell cancer, and showed relative risk reductions ranging from 20% to 57%. The pooled relative risk was 0.66 (J. Pineal Res. 2005;39:360–6).

Studies Underway

One of the authors of the metaanalysis, Dugald Seely, N.D., of the Canadian College of Naturopathic Medicine, Toronto, noted that all the clinical trials thus far have been done by the same group of investigators in Europe, and the results need to be replicated by other investigators.

Two clinical trials are underway in the United States—one sponsored by the National Cancer Institute for patients with brain metastases, and the other by the Cancer Treatment Centers of America for patients with non-small cell lung cancer. “We're looking forward to the results of these trials,” Dr. Seely said. The fact that there seems to be no evidence of toxicity is particularly promising, he added.

This article was originally published by www.internalmedicinenews.com