Melatonin Beyond Sleep,Part II: Focus on Oncology

Abstract

In Part I of this review, melatonin's effects in general medicine were discussed, along with a discussion of safety. Part II of this review focuses on the uses of melatonin in oncology. This includes a discussion of the uses of melatonin in breast cancer patients, including those receiving surgery, radiation, chemotherapy, and endocrine therapy. The uses of melatonin alongside additional conventional therapies for people with other types of cancer are also discussed. Studies utilizing melatonin for people with metastatic disease are also reviewed. Lastly, a brief discussion of melatonin alongside immunotherapy is included.

Introduction

The pleiotropic molecule and methoxy indole compound melatonin is not only a chronobiotic regulator, but also functions as an antioxidant and immune regulator. Its unique properties in enhancing immunity stem from both receptor-dependent and receptor-independent effects. As mentioned in Part I of this review, these include binding of nuclear and membrane receptors, binding to intracellular proteins, and scavenging free radicals or non-radical toxic species in a receptor-independent fashion.^1,2 In Part II of this review, the uses of melatonin as an oncostatic agent and in oncology are discussed.

In vivo and in vitro data indicate a wide variety of oncostatic effects for melatonin. These effects range from the inhibition of cellular proliferation, to induction of apoptosis, to a reduction in tumor growth. Melatonin has anti-metastatic effects via its ability to modulate epithelial-mesenchymal transition, regulate the cell-matrix environment, participate in extracellular matrix remodeling by matrix metalloproteinases, and inhibit angiogenesis.³ Melatonin reduces the expression and production of inflammatory mediators, reducing both acute and chronic inflammation. It inhibits the translocation of nuclear factor-kappa B, thereby influencing numerous downstream molecular events which may be key drivers of the inflammatory response.⁴

Additionally, melatonin has also been shown to reduce the side effects seen with chemotherapy and radiation, as well as reduce drug resistance. Melatonin may also enhance the therapeutic efficacy of standard cancer treatment.³ Melatonin has been clinically studied in numerous trials in people with cancer, and assessed for its effects alongside the various modalities of standard treatment (including surgery, chemotherapy, radiation, and immunotherapy).

Note that for several of the studies referenced below, melatonin is described by the author(s) as given “daily.” This is assumed to mean it was given at bedtime, even when the particular time was not specified. The precise time when melatonin was administered has been listed for each trial that specifically provided this information.

Breast Cancer

Perhaps nowhere are melatonin's multitude of effects in oncology better demonstrated than in breast cancer. Melatonin has been shown to have positive effects across the spectrum of breast cancer treatment, including alongside surgery, radiation, chemotherapy, endocrine therapy, and in the metastatic setting. Melatonin has been proposed to reduce estrogen-dependent breast tumor development through two key mechanisms. The first is a reduction of circulating estrogens via downregulation of the hypothalamic-pituitary reproductive axis (i.e., a neuroendocrine mechanism). The second is a direct cellular effect: melatonin may behave as a selective estrogen receptor modulator by interfering with the activation of the estrogen receptor.⁵

Melatonin has also been proposed to function as a natural aromatase inhibitor. Melatonin may decrease the expression of aromatase promoters II and I.3 by downregulating cyclooxygenase enzymes, leading to a reduction in prostaglandin E2 and intracellular cyclic adenosine monophosphate.⁶ Premenopausal and postmenopausal women with early stage breast cancer have been shown to have lower levels of melatonin compared to controls (generally assessed by measuring 6-Sulfatoxymelatonin, or 6-SMT, the main urinary metabolite of melatonin, and a reliable surrogate for blood melatonin concentration).⁷

In a three-month trial, Hansen et al. assessed the effects of melatonin in women with breast cancer (ages 30–75) undergoing surgical resection. Participants had no previous sleep disorder, no use of hypnotics, and no previous depression. Women were randomized in double-blind fashion to either melatonin 6 mg (N = 28) or a placebo (N = 26) starting 1 week preoperatively and continuing for 12 weeks postoperatively. Eleven subjects withdrew from the trial (10 in the placebo group and 1 in the melatonin group). The risk of developing symptoms of depression was significantly lower in women receiving melatonin than in those receiving placebo (3 out of 27 [11%] vs. 9 out of 20 [45%]). The number needed to treat was 3.0 (95% confidence internal [CI] 1.7–11.0). There was no difference in side effects for the two groups (P = 0.78).⁸

The same authors also published their findings on secondary outcomes for this group of patients. Women that received melatonin in the perioperative period experienced significantly increased sleep efficiency (P = 0.016) after surgery compared to those receiving placebo. The melatonin group also experienced reduced nighttime waking in the postoperative period compared to the placebo group (P = 0.035).⁹ Additional analysis of this group by the authors found that the total sleep period was also significantly longer for women receiving melatonin compared to placebo, with the mean difference being 37.0 minutes per night (P = 0.03, 95% CI 3.6–69.7).¹⁰

Melatonin has also been studied for its effects alongside adjuvant chemotherapy and radiation in women with early stage breast cancer. Women with stages I–III breast cancer were randomized to receive either melatonin or placebo (N = 37 in each group) starting one week prior and continuing through one month after completion of adjuvant chemotherapy and radiation. Melatonin was dosed at 18 mg one hour before bedtime daily. At the completion of the trial, women who received melatonin scored significantly lower on the Brief Fatigue Inventory than did women who received placebo (P < 0.001). Incidence of severe fatigue was also significantly lower in the melatonin group compared to the placebo group (42.1% vs. 83.3%, P < 0.001).¹¹

A brief trial also indicated that women receiving adjuvant chemotherapy for breast cancer may experience cognitive benefits from melatonin supplementation. Thirty-six women were randomized to either melatonin (20 mg nightly) or placebo for 10 days, starting 3 days prior to their first chemotherapy treatment. Women receiving melatonin experienced improved executive function scores (assessed by the Trail Making Test), improved episodic memory and recognition (assessed by the Rey Auditory-Verbal Learning Test), and improved verbal fluency (assessed by Controlled Oral Word Association Test). The authors concluded that melatonin may have a neuroprotective effect during adjuvant breast cancer chemotherapy.¹²

Topical melatonin has been demonstrated to prevent dermatitis in patients with early stage breast cancer receiving radiation. Women with stage 0 to II breast cancer were randomized to either a melatonin group (emulsion in a cream base) or a placebo group (same emulsion-based cream without melatonin). Subjects were instructed to apply the respective cream to the treated breast twice daily, and not less than two hours prior to radiotherapy treatment. Melatonin cream was used by 26 patients, and placebo by 21 patients. After treatment, radiation dermatitis (grade 1 or 2) occurred significantly less in the melatonin group compared to the placebo group (59% of subjects using melatonin, 90% of subjects using placebo, P = 0.038). In subgroup analysis, older women seemed to benefit most: women ages 50 or older who received melatonin experienced less radiation dermatitis (100% of patients in the placebo group had radiation dermatitis, while 56% of patients in the melatonin group did).¹³

After completion of treatment for breast cancer, many patients are left with continued side effects, which can include insomnia. In a four-month trial in women (N = 95 with stage 0 to III disease) who had completed all breast cancer treatment, including hormone therapy, melatonin dosed at 3 mg daily for four months was beneficial for this concern. At baseline (during the month prior to study enrollment), 52% of participants reported poor sleep. Subjects were randomly assigned 1:1 to receive either melatonin 3 mg, or a placebo. Subjects who received melatonin experienced significantly greater improvements in subjective sleep quality, as assessed by the Pittsburgh Sleep Quality Index (PSQI). This included domains on sleep quality, daytime dysfunction, and the total PSQI score. The mean change in PSQI score was −0.1 for placebo group patients, and −1.9 for patients receiving melatonin (P < 0.001).¹⁴

In the metastatic setting, melatonin also appears to have some specific advantages for breast cancer patients receiving hormonal therapy. In subjects (N = 32) receiving either trastuzumab or endocrine therapy (including either tamoxifen or aromatase inhibitor), and melatonin dosed at 5 mg nightly for two months, there were significant improvements in sleep quality, fragmentation, and quantity (assessed by basic-motionlogger actigraph), as well as in subjective sleep, fatigue severity, global quality of life, and social and cognitive function scales (assessed using the EORTC QLQ-C30 v3.0 questionnaire). Additionally, morning clock gene expression was improved following melatonin supplementation (assessed by examining expression of clock genes hPer2 and hBmal1 in peripheral blood mononuclear cells), without any effect on diurnal cortisol rhythm.¹⁵

Among patients with metastatic breast cancer who had previously progressed on tamoxifen alone (N = 14), the addition of melatonin also appeared to convert some patients to responders. Participants received melatonin 20 mg nightly, starting seven days prior to tamoxifen, which was then added at 20 mg daily. Combined treatment was given until disease progression. Eight of 14 patients achieved stable disease (57%). A partial response (PR) was also achieved in 4 of 14 participants (28.5%). The median duration of response was eight months, with a range for response of three to nine months. Additionally, mean levels of insulin-like growth factor 1 (IGF-1) decreased significantly from baseline (P < 0.01), and the decline in IGF-1 was significantly greater for responders than in those with either progression or stable disease (P < 0.05).¹⁶

Melatonin with Conventional Therapies

Aside from breast cancer, melatonin supplementation has also been shown to have several benefits for people receiving a variety of conventional therapies for other types of cancer.

In people with head and neck cancer, melatonin is a beneficial complement to radiation or combined modality treatment (chemoradiation).

In Elsabagh et al.'s randomized controlled trial (RCT), patients undergoing radiation for head and neck cancer (N = 40) who received melatonin 20 mg daily alongside treatment had improved antioxidant status and reduced side effects. While 92.5% of all participants developed oral mucositis, control group patients were more likely to have severe symptoms than melatonin group patients (30% compared to 5% had grade 3 or 4 mucositis). Mean pain scores were significantly lower among melatonin group subjects than among placebo subjects (P < 0.001, assessed by Numeric Rating Scale). Additionally, total antioxidant capacity (TAC) was significantly decreased in the control group during treatment, with controls experiencing a 16.61% reduction in TAC, while the melatonin group experienced a 1.71% reduction.¹⁷

In Onseng et al.'s RCT, people with head and neck cancer (N = 39) receiving seven weeks concurrent chemoradiation (external beam radiation therapy five days per week to a cumulative dose of ≥50 Gray, with cisplatin either weekly for six cycles, or every three weeks for three cycles) also saw benefits with melatonin supplementation. Those randomized to the active intervention dosed melatonin as both a 10 mL gargle (20 mg per 10 mL) and an oral melatonin capsule, also 20 mg. Placebo pills and gargle were matched for color and taste. Subjects were instructed to utilize the gargle 15 minutes prior to each radiotherapy treatment, and to take the oral capsule nightly.

Patients receiving melatonin had a non-significant lower incidence of grade 3 oral mucositis and grade 2 xerostomia compared to controls (42% vs. 55%, and 20% vs. 21%). For people receiving melatonin, there was a significant delay in onset of grade 3 mucositis, with a median of 16 additional patient visits prior to onset of this side effect (P = 0.0318). Morphine use for pain was also reduced in the melatonin group compared to controls (P = 0.0342).¹⁸

For people with glioblastoma multiforme (GBM) receiving radiation, melatonin has also been shown to produce positive effects. Thirty participants with GBM were randomized to receive either radiation alone (total cumulative dose 60 Gray), or radiation plus melatonin at a dose of 20 mg daily. Melatonin was then continued after radiation until time of disease progression. One year survival was higher in people receiving the combination of melatonin and radiation, than radiation alone (6 of 14 people in the combination group, and 1/16 in the radiation-only group, P < 0.02). The survival curve for people receiving the combination was also significantly higher than it was for people receiving radiation only (P < 0.05). Importantly, melatonin was also well tolerated, and had no observed interactions with anticonvulsant medications. In addition, melatonin was also associated with a reduction in grade 4 alopecia, and a reduced incidence of infections related to radiation or corticosteroid use (P < 0.025).¹⁹

Among people receiving transcatheter arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC), melatonin supplementation is hepatoprotective and appears to enhance the efficacy of treatment. In Yan et al.'s study, people with advanced, non-resectable HCC were assigned to receive either TACE alone, or TACE with melatonin (dosed nightly at 20 mg starting seven days prior to TACE treatment). In the TACE only group, 0.5, 1, and 2 year survival were 82%, 54%, and 26%, respectively. In the melatonin combination group, these survival rates were 100%, 68%, and 40%, respectively. Levels of soluble interleukin-2 receptor (a marker of disease severity in people with chronic hepatic diseases) also decreased significantly in the combination group compared to the TACE-alone group (P < 0.01).²⁰

In patients with node-relapsed melanoma, adjuvant melatonin was also found to promote a survival benefit. This study was conducted in 30 people who were surgically treated for a regional lymph node recurrence of melanoma. Subjects were unable to receive standard adjuvant therapy (interferon at the time of this trial in the 1990s) due to poor performance status, age, or comorbidities. Melatonin was dosed at 20 mg taken nightly until disease progression. Controls received supportive care only. After a median follow up period of 31 months, disease free survival (DFS) in people receiving melatonin compared to controls was significantly better (with relapse occurring in 11 of 16 controls and 4 of 14 melatonin group patients, P < 0.05). One year DFS was also significantly higher with melatonin (P < 0.05). The DFS curve was significantly longer in people taking melatonin as well (P < 0.05).²¹

Melatonin in Metastatic Disease

In patients with metastatic solid tumors, melatonin has been shown to reduce vascular endothelial growth factor (VEGF), an important marker of angiogenesis, as a salvage therapy in some individuals. In 20 people with metastatic disease for whom no other treatment was available, melatonin was supplemented at 20 mg nightly for ≥2 months. Two subjects had a minor response, 6 achieved stable disease, and 12 patients experienced progression on melatonin. There was a significant decline in VEGF concentrations among non-progressing patients, while patients with progression showed no significant change in VEGF.²²

Two additional studies have demonstrated clinical response with use of melatonin as salvage therapy in people with metastatic disease. In a 1991 clinical trial by Lissoni et al., melatonin was given intramuscularly (I.M.) at 20 mg daily at 15:00 during an initial two month induction phase to 54 people with metastatic cancer (largely lung or colorectal cancer). The authors chose afternoon dosing based on previous animal data indicating this resulted in improved bioavailability. Following this, participants who were responding or who had an improvement in performance status took melatonin orally at 10 mg as a maintenance dose. One person experienced a PR, 2 experienced a minor response, and 21 achieved stable disease with this treatment. The remaining 30 participants progressed during the induction phase of the trial. An improved performance status was seen in 18 of the 54 participants, or 33%. Melatonin was also well tolerated, with no hematologic or organ-related toxicities.²³

In Neri et al.'s 1998 clinical trial, 31 people with metastatic solid tumors, who had no response to chemotherapy or radiation, took melatonin orally at a dose of 10 mg daily for three months. Progressive disease was seen in 19 of the 31 subjects (61%), while stable disease was seen in 12 subjects (39%). For people who responded to melatonin, this response was associated with a significant decrease in circulating levels of interleukin-6. Again, melatonin was well tolerated in these critically ill individuals.²⁴

In patients with advanced lung cancer, melatonin has been shown in a few trials to extend survival alongside chemotherapy treatment. In a randomized, double-blind, three arm study, 84 people with advanced stage lung cancer were assigned to one of three arms. The first took a placebo at 8 am, and placebo at 8 pm daily (placebo group). The second took 20 mg melatonin at 8 am, and placebo at 8 pm daily (AM melatonin group). The third took placebo at 8 am and melatonin 20 mg at 8 pm daily (PM melatonin group). All subjects were concurrently treated with standard cisplatin and etoposide chemotherapy. In a multivariate analysis, the PM melatonin group experienced a significant survival difference compared to the placebo group (P = 0.031). There was no significant difference for use of AM melatonin. In subgroup analysis, one group that saw greater benefits with PM melatonin was patients with a starting global PSQI score <7 (in other words, people with normal quality sleep at the start of the trial). Among these individuals (PSQI <7 at commencement of trial), the placebo group had a median survival time of 10.4 months, while the PM melatonin group had a median survival time of 17.6 months.²⁵

In a longer clinical trial with a five-year duration, 100 people with metastatic lung cancer were randomized to receive either chemotherapy alone, or chemotherapy plus melatonin 20 mg daily taken in the evening. A complete response (CR) was seen in 2 of 49 (4%) people treated with the combination of melatonin and chemotherapy, and in 0 patients in the control group. PR was seen in 15 of 49 (31%) people treated with melatonin, compared to 9 of 51 (18%) people treated with chemotherapy only. Progressive disease was seen in 6 of 49 people treated with melatonin, compared to 20 of 51 people in the control group (P < 0.01). Melatonin also rendered chemotherapy treatment more tolerable. The melatonin group had a reduced incidence of neuropathy, thrombocytopenia, weight loss >10%, and asthenia (P < 0.01, P < 0.01, P < 0.001, and P < 0.005, respectively). The survival curve was significantly longer for participants receiving melatonin than for controls (P < 0.001), and at five years, 3 of 49 people in the melatonin group were still alive. In contrast, at the two year mark, no patients who received chemotherapy alone were still alive in this trial.²⁶

Two meta-analyses have confirmed a reduction in side effects of chemotherapy, and an improved response to treatment, in people who take melatonin. In Seely et al.'s meta-analysis of 21 clinical trials of melatonin plus chemotherapy, improvements in CR, PR, and stable disease were seen with melatonin (response rates [RRs] of 2.33 [95% CI = 1.29–4.20], 1.90 [1.43–2.51], and 1.51 [1.08–2.12], respectively). Melatonin supplementation also significantly reduced incidence of leukopenia, nausea/vomiting, hypotension, asthenia, and thrombocytopenia. The most commonly used dose in included trials was 20 mg nightly.²⁷

In Wang et al.'s meta-analysis of 8 RCTs utilizing melatonin 20 mg nightly in combination with chemotherapy, people with advanced stage solid tumors had improved CR and PR with melatonin compared to without ((16.5 vs. 32.6%; RR = 1.95, 95% CI 1.49–2.54; P < 0.00001). The one year survival rate was also improved with melatonin supplementation (28.4 vs. 52.2%; RR = 1.90; 95% CI 1.28–2.83; P = 0.001). Melatonin improved tolerability of chemotherapy as well, resulting in significantly lower incidence of neurotoxicity, thrombocytopenia, and fatigue (P < 0.0001, P < 0.00001, and P < 0.00001, respectively).²⁸

Melatonin and Immunotherapy

Immunotherapy with checkpoint inhibitors has drastically altered the oncology treatment landscape over the past few years. These medications have been approved for use in ever larger numbers of cancer patients, with an estimated 1.54% of patients eligible for checkpoint inhibitor treatment in 2011 growing to 43.63% of patients eligible in 2018²⁹ (a figure which has most likely changed again in the intervening years). Notably, the trials of melatonin discussed in the preceding sections above were all performed in people receiving other forms of conventional therapy (i.e., chemotherapy and radiation). Because immunotherapy agents are relatively new in oncology practice, very little data is available on how melatonin may work alongside newer immunotherapy drugs. The author is aware of a single clinical trial using melatonin in people on checkpoint inhibitors.

This 2020 study compared clinical results for people receiving nivolumab (a human monoclonal antibody and inhibitor of the immune checkpoint programmed cell death protein-1) plus high dose melatonin (100 mg/day) (N = 14), to the results seen in a historical control group of patients treated with nivolumab alone (N = 50). Results were as follows:

CR was seen in 1 of 14 people in the melatonin group, compared to 1 of 50 in the nivolumab only group (7% compared to 2%).

PR was seen in 4 of 14 people in the melatonin group, compared to 8 of 50 in the nivolumab only group (29% compared to 16%).

Stable disease was seen in 7 of 14 people in the melatonin group, compared to 19 of 50 in the nivolumab only group (50% compared to 38%).

Pooling results for each of the categories above, the percent of disease control was higher for people taking melatonin plus nivolumab, than for those taking nivolumab only (86% vs. 54%, P < 0.05).

Progressive disease was seen in a significantly lower number of people taking melatonin than those taking nivolumab only (14% vs. 46%, P < 0.05).

The authors also compared the lymphocyte monocyte ratio (LMR, demonstrated as a prognosticator for people with multiple tumor types) for the two groups. People who received melatonin plus nivolumab had a significantly higher LMR than did those receiving nivolumab only (P < 0.05). The authors did not include any information regarding adverse events in this publication.³⁰

While this preliminary data from a small group of patients taking large amounts of supplemental melatonin is encouraging, larger trials in this area are eagerly awaited by both clinicians and their patients. The omission of data related to adverse events in the study mentioned above makes it difficult to draw any conclusions about the safety of combining high dose melatonin with checkpoint inhibitors. There are many areas where melatonin and checkpoint inhibitor drugs may have overlapping mechanisms (e.g., modulation of T helper 17 cell activity and/or cytokine production). This raises the question of whether or not an increase in adverse events may be seen with such a combination. With checkpoint inhibitor therapies being utilized in growing numbers of patients, clinicians have a strong need for safety data on the use of melatonin alongside these drugs, and for a greater understanding on how this supplement may impact treatment itself.

Conclusions

In Part I of this review, melatonin's clinical applications in general medicine were touched upon. Part II of this review has discussed the uses of melatonin in oncology. Melatonin has been shown to benefit cancer patients receiving a range of treatments, including surgery, chemotherapy, and radiation. Melatonin has also been shown to benefit women with breast cancer who are undergoing surgery, radiation, or chemotherapy, as well as endocrine therapy. A growing number of cancer patients with a variety of tumor types are receiving immunotherapy with checkpoint inhibitors, and clinical trials of melatonin supplementation alongside these drugs are urgently needed.▪

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