Melatonin

Property	Information
Drug Name	Melatonin
FDA Approval	No
Used for	Jet lag, insomnia, various types of cancer including Glioblastoma Multiforme (GBM)
Clinical Trial Phase	Phase-2 and Phase-3 trials
Clinical Trial Explanation	Melatonin has been part of numerous clinical trials, particularly in Italy, often in combination with chemotherapy or immunotherapy. The outcomes have shown potential benefits including increased survival rates and tumor regression: In a study with 30 GBM patients, those treated with melatonin in addition to radiation therapy showed significantly higher survival rates compared to those receiving only radiation. Larger trials involving various types of advanced metastatic cancers have reported that melatonin enhanced the efficacy of chemotherapy, leading to higher rates of tumor regression and increased survival. Despite these positive findings, the studies often involved small sample sizes or patients in terminal stages, which might influence broader clinical acceptance.Property "Has clinical trial explanation" (as page type) with input value "Melatonin has been part of numerous clinical trials, particularly in Italy, often in combination with chemotherapy or immunotherapy. The outcomes have shown potential benefits including increased survival rates and tumor regression:</br></br>* In a study with 30 GBM patients, those treated with melatonin in addition to radiation therapy showed significantly higher survival rates compared to those receiving only radiation.</br>* Larger trials involving various types of advanced metastatic cancers have reported that melatonin enhanced the efficacy of chemotherapy, leading to higher rates of tumor regression and increased survival.</br>* Despite these positive findings, the studies often involved small sample sizes or patients in terminal stages, which might influence broader clinical acceptance." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Common Side Effects	No known toxic side effects
OS without	1 out of 16 patients was alive after one year.
OS with	6 out of 14 patients were alive after one year
PFS without	Not specified
PFS with	Not specified
Usefulness Rating	4
Usefulness Explanation	* Immune System Enhancement: Augmentation of T-helper cell activity, crucial for targeting cancer cells. Inhibition of Angiogenesis: Reduction in blood vessel formation essential for tumor growth. Direct Cytotoxic Effects: Induction of apoptosis in cancer cells, including glioblastoma. Reduction of Chemotherapy Toxicity: Mitigation of chemotherapy side effects, improving tolerability and adherence to treatment schedules. Modulation of Tumor Metabolism: Affects energy production pathways in cancer cells, making them more susceptible to treatments.Property "Has Usefulness Explanation" (as page type) with input value "* Immune System Enhancement: Augmentation of T-helper cell activity, crucial for targeting cancer cells.</br>* Inhibition of Angiogenesis: Reduction in blood vessel formation essential for tumor growth.</br>* Direct Cytotoxic Effects: Induction of apoptosis in cancer cells, including glioblastoma.</br>* Reduction of Chemotherapy Toxicity: Mitigation of chemotherapy side effects, improving tolerability and adherence to treatment schedules.</br>* Modulation of Tumor Metabolism: Affects energy production pathways in cancer cells, making them more susceptible to treatments." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Toxicity Level	1
Toxicity Explanation	Melatonin is considered to have a low toxicity level, with no known toxic side effects. It is generally regarded as safe for use in the dosages typically administered for both sleep disorders and experimental cancer treatment protocols.

Notes: Melatonin is a hormone that regulates the body's diurnal rhythm and is used for the treatment of sleep disorders. In cancer treatment, it's hypothesized to boost the immune system, inhibit angiogenesis, and have direct cytotoxic effects on certain cancer cells. Clinical research, primarily in Italy, has explored its use alone or in combination with chemotherapy or immunotherapy, showing potential for increasing survival rates and reducing chemotherapy toxicity.

Patients considering melatonin for GBM should consult with their oncologist. It’s essential to discuss the potential benefits and risks, considering that the most compelling evidence supports its use alongside chemotherapy. There might also be concerns about interactions with other medications and the appropriate dosage for anti-cancer effects, typically higher than those used for sleep disorders.

GBM Study

• Trial: Randomly assigned 30 GBM patients to radiation alone or radiation with 20 mg/day of melatonin.
• Survival:
  • With Melatonin: 6 out of 14 patients were alive after one year.
  • Without Melatonin: 1 out of 16 patients was alive after one year.
• Reference: [Melatonin in the Treatment of Cancer (PDF)](https://www.acesototalhealth.com/wp-content/uploads/2020/07/Melatonin-in-the-tx-of-cancer.pdf).

Larger Trials (Advanced Metastatic Cancer)

• Trial: 250 patients with advanced metastatic cancer of various types were randomized to chemotherapy alone or chemotherapy plus 20 mg of melatonin per day.
• Tumor Regression:
  • With Melatonin: 42 out of 124 patients had tumor regression (including 6 complete regressions).
  • Without Melatonin: 19 out of 126 patients had tumor regression (with zero complete regressions).
• Survival:
  • With Melatonin: 63 out of 124 patients were alive after one year.
  • Without Melatonin: 29 out of 126 patients were alive after one year.
• Reference: [Melatonin in Cancer Management: Progress and Promise](https://aacrjournals.org/cancerres/article/79/18/4827/636539/Melatonin-in-Cancer-Management-Progress-and-Promise).

Metastatic Non-Small-Cell Lung Cancer Study

• Trial: 100 patients with metastatic non-small-cell lung cancer compared chemotherapy alone versus chemotherapy with melatonin.
• Tumor Regression:
  • With Melatonin: 17 out of 49 patients had either complete (2) or partial (15) regression.
  • Without Melatonin: 9 out of 51 patients had a partial tumor regression.
• Survival:
  • With Melatonin: 40% of patients survived for one year and 30% for two years.
  • Without Melatonin: 20% of patients survived for one year and 0% for two years.
• Reference: [Memorial Sloan Kettering Cancer Center](https://www.mskcc.org/cancer-care/integrative-medicine/herbs/melatonin) and [Melatonin Research](https://www.melatonin-research.net/index.php/MR/article/view/45).

Aggregate Study (Lung, Colorectal, and Gastric Cancer)

• Patients: 370 patients with lung cancer, colorectal cancer, and gastric cancer.
• Response Rate:
  • With Melatonin: 36% response rate (tumor regression).
  • Without Melatonin: 20% response rate.
• Survival:
  • With Melatonin: 25% two-year survival rate.
  • Without Melatonin: 13% two-year survival rate.

Ongoing Research

• Research: Mayo Clinic is investigating the use of melatonin to enhance glioblastoma treatment with temozolomide.
• Reference: [Mayo Clinic](https://www.mayo.edu/research/labs/brain-tumor-stem-cell-research/research/melatonin-enhance-cancer-treatments).

Links: https://www.mdpi.com/2073-4409/11/21/3467 https://www.mdpi.com/2073-4409/9/3/599 https://academic.oup.com/noa/article/3/Supplement_1/i13/6186371?login=false https://www.mayo.edu/research/labs/brain-tumor-stem-cell-research/research/melatonin-enhance-cancer-treatments

From Ben Williams Book: This is a naturally occurring hormone secreted by the pineal gland that regulates the body's diurnal rhythm. It is commonly used for the treatment of jet lag and for insomnia. It is readily available in any health food store and most drug stores. Its role in cancer treatment has been based on the assumption that it boosts the immune system, with the current hypothesis being that it augments the activity of T-helper cells. It recently also has been shown to inhibit angiogenesis (225). It may also have direct cytotoxic effects on some types of cancer cells, notably melanoma cells. It has no known toxic side effects.

Clinical research on the use of melatonin for cancer treatment has been done primarily in Italy, where it has been used either as a single agent after radiation treatments, or in combination with various chemotherapy or immunotherapy regimens, most frequently interleukin-2. Part of the rationale for such combinations is that it decreases the side effects of the chemotherapy, especially with respect to blood counts. One of the clinical 32

studies (226) randomly assigned 30 GBM patients either to radiation alone (n=16) or to radiation concomitant with 20 mg/day of melatonin (n=14). Melatonin was continued after completion of the radiation. Survival was significantly greater for subjects receiving the melatonin. In terms of one-year survival rates, 6/14 patients receiving melatonin were alive, while only 1/16 patients without melatonin was alive.

This GBM study involved a relatively small number of patients, so that the effects should be considered tentative until a larger study is conducted. However, comparable effects have been reported in a similar design for the use of melatonin with advanced lung cancer (227). Like the GBM study, a substantial increase in survival rate occurred for the patients receiving melatonin.

To date there have been at least a dozen phase-2 clinical trials using melatonin either alone or in combination with other agents and five phase-3 trials involving random assignment of subjects to melatonin versus some type of control group. The majority of these has been relatively small and has involved patients in the terminal stages of their disease, which is perhaps why American oncologists have largely ignored them.

However, some trials have been much larger and seem to leave little doubt that melatonin significantly increases the efficacy of chemotherapy. One of the most extensive randomized clinical trials involved 250 patients with advanced metastatic cancer of various types (228). Patients were randomly assigned to chemotherapy alone (using different chemotherapies for different types of cancer) or chemotherapy plus 20 mg of melatonin per day. Objective tumor regression occurred in 42 (including 6 complete regressions) of 124 patients receiving melatonin but in only 19/126 (with zero complete regressions) of the control patients. A comparable difference occurred for survival rate: 63/124 of those receiving melatonin were alive after one year while only 29/126 were alive of those receiving chemotherapy alone. A different trial, involving 100 patients with metastatic non small-cell lung cancer (229), compared chemotherapy alone with chemotherapy in combination with melatonin. With chemotherapy alone, 9 of 51 patients had a partial tumor regression, while 17 of 49 chemo + melatonin patients had either a complete (n=2) or partial (n=15) regression. Twenty percent of the chemo-alone patients survived for one year and zero for two years, while the corresponding numbers for chemo + melatonin were 40% and 30%. Melatonin not only increased the efficacy of chemotherapy, but also significantly reduced its toxicity.

The most extensive report included 370 patients, subdivided into three different types of cancer: lung cancer (non-small cell), colorectal cancer, and gastric cancer (230). Aggregated over all three types, the response rate (percentage of patients with tumor regression) was 36% for those treated with chemotherapy and melatonin, versus 20% for those treated with chemotherapy alone. The corresponding two-year survival rates were 25% vs. 13%. Melatonin’s benefits occurred for all three cancer types that were included. Moreover, patients receiving melatonin had fewer side effects. 33

These trials leave little doubt that the effects of melatonin are of clinical significance. Moreover, a recent study has shown that using multiple components of the pineal gland secretions instead of melatonin alone enhances clinical effectiveness still further (231). One caveat about the use of melatonin is that a recent randomized trial compared radiation treatment for metastatic brain cancer with and without melatonin and found no benefit of the melatonin (232). Given that almost all of the supporting evidence for the use of melatonin has come from its addition to chemotherapy, it is possible that it offers no benefit when added to radiation, perhaps because of its strong antioxidant properties.Property "Has original text" (as page type) with input value "This is a naturally occurring hormone secreted by the pineal gland that regulates the</br>body's diurnal rhythm. It is commonly used for the treatment of jet lag and for insomnia.</br>It is readily available in any health food store and most drug stores. Its role in cancer</br>treatment has been based on the assumption that it boosts the immune system, with the</br>current hypothesis being that it augments the activity of T-helper cells. It recently also</br>has been shown to inhibit angiogenesis (225). It may also have direct cytotoxic effects on</br>some types of cancer cells, notably melanoma cells. It has no known toxic side effects.</br></br>Clinical research on the use of melatonin for cancer treatment has been done primarily in</br>Italy, where it has been used either as a single agent after radiation treatments, or in</br>combination with various chemotherapy or immunotherapy regimens, most frequently</br>interleukin-2. Part of the rationale for such combinations is that it decreases the side</br>effects of the chemotherapy, especially with respect to blood counts. One of the clinical</br>32</br></br>studies (226) randomly assigned 30 GBM patients either to radiation alone (n=16) or to</br>radiation concomitant with 20 mg/day of melatonin (n=14). Melatonin was continued</br>after completion of the radiation. Survival was significantly greater for subjects receiving</br>the melatonin. In terms of one-year survival rates, 6/14 patients receiving melatonin were</br>alive, while only 1/16 patients without melatonin was alive.</br></br>This GBM study involved a relatively small number of patients, so that the effects</br>should be considered tentative until a larger study is conducted. However, comparable</br>effects have been reported in a similar design for the use of melatonin with advanced</br>lung cancer (227). Like the GBM study, a substantial increase in survival rate occurred</br>for the patients receiving melatonin.</br></br>To date there have been at least a dozen phase-2 clinical trials using melatonin either</br>alone or in combination with other agents and five phase-3 trials involving random</br>assignment of subjects to melatonin versus some type of control group. The majority of</br>these has been relatively small and has involved patients in the terminal stages of their</br>disease, which is perhaps why American oncologists have largely ignored them.</br></br>However, some trials have been much larger and seem to leave little doubt that melatonin</br>significantly increases the efficacy of chemotherapy. One of the most extensive</br>randomized clinical trials involved 250 patients with advanced metastatic cancer of</br>various types (228). Patients were randomly assigned to chemotherapy alone (using</br>different chemotherapies for different types of cancer) or chemotherapy plus 20 mg of</br>melatonin per day. Objective tumor regression occurred in 42 (including 6 complete</br>regressions) of 124 patients receiving melatonin but in only 19/126 (with zero complete</br>regressions) of the control patients. A comparable difference occurred for survival rate:</br>63/124 of those receiving melatonin were alive after one year while only 29/126 were</br>alive of those receiving chemotherapy alone. A different trial, involving 100 patients with</br>metastatic non small-cell lung cancer (229), compared chemotherapy alone with</br>chemotherapy in combination with melatonin. With chemotherapy alone, 9 of 51 patients</br>had a partial tumor regression, while 17 of 49 chemo + melatonin patients had either a</br>complete (n=2) or partial (n=15) regression. Twenty percent of the chemo-alone patients</br>survived for one year and zero for two years, while the corresponding numbers for chemo</br>+ melatonin were 40% and 30%. Melatonin not only increased the efficacy of</br>chemotherapy, but also significantly reduced its toxicity.</br></br>The most extensive report included 370 patients, subdivided into three different types of</br>cancer: lung cancer (non-small cell), colorectal cancer, and gastric cancer (230).</br>Aggregated over all three types, the response rate (percentage of patients with tumor</br>regression) was 36% for those treated with chemotherapy and melatonin, versus 20% for</br>those treated with chemotherapy alone. The corresponding two-year survival rates were</br>25% vs. 13%. Melatonin’s benefits occurred for all three cancer types that were included.</br>Moreover, patients receiving melatonin had fewer side effects.</br>33</br></br>These trials leave little doubt that the effects of melatonin are of clinical significance.</br>Moreover, a recent study has shown that using multiple components of the pineal gland</br>secretions instead of melatonin alone enhances clinical effectiveness still further (231).</br>One caveat about the use of melatonin is that a recent randomized trial compared</br>radiation treatment for metastatic brain cancer with and without melatonin and found no</br>benefit of the melatonin (232). Given that almost all of the supporting evidence for the</br>use of melatonin has come from its addition to chemotherapy, it is possible that it offers</br>no benefit when added to radiation, perhaps because of its strong antioxidant properties." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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