Clinical investigation
Brain
Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

https://doi.org/10.1016/j.ijrobp.2007.01.012 Get rights and content

Purpose: To determine if high-dose melatonin for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Class 2 patients with brain metastases improved survival over historical controls, and to determine if the time of day melatonin was given affected its toxicity or efficacy. RTOG 0119 was a phase II randomized trial for this group of patients.

Methods and Materials: RTOG RPA Class 2 patients with brain metastases were randomized to 20 mg of melatonin, given either in the morning (8–9 am) or in the evening (8–9 pm). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon. Melatonin was continued until neurologic deterioration or death. The primary endpoint was overall survival time. Neurologic deterioration, as reflected by the Mini-Mental Status Examination, was also measured.

Results: Neither of the randomized groups had survival distributions that differed significantly from the historic controls of patients treated with whole-brain radiotherapy. The median survivals of the morning and evening melatonin treatments were 3.4 and 2.8 months, while the RTOG historical control survival was 4.1 months.

Conclusions: High-dose melatonin did not show any beneficial effect in this group of patients.

Introduction

Melatonin, an indoleamine molecule (N-acetyl, 5-methoxytryptamine), plays an important role in a number of processes, including circadian-rhythm regulation, sleep disorders, seasonal reproduction, retinal physiology, immune function, intermediary metabolism (1, 2), and carcinogenesis (3). It is also a highly efficient and potent free-radical scavenger and antioxidant molecule. Physiologic blood levels of melatonin correlate with the total antioxidant capacity of the serum (4). Oral ingestion of microgram amounts of melatonin results in near-physiologic nocturnal blood levels of melatonin (5, 6). The oral bioavailability of milligram doses of oral melatonin from nutritional supplements is about 15% (7), and results in supraphysiologic melatonin levels.

Numerous studies demonstrated that physiologic and pharmacologic blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia (6, 8, 9). A preliminary study demonstrated that pretreatment of rats bearing hepatomas for 2 weeks before a single dose of radiation was administered just before lights off, and then with a nontumor-inhibiting dose of melatonin also given just before lights off, had a marked radiosensitizing effect. Pretreatment of tumor-bearing rats with morning doses of melatonin were ineffective (10).

The great majority of human trials of melatonin for cancer treatment or supportive care have come from Lissoni et al. (11, 12) at the Ospedale San Gerardo (Monza, Italy). Two of their trials form the basis of the present trial. In the first trial, Lissoni et al. randomized 50 patients who had previously undergone radiation therapy for brain metastases from solid tumors and who subsequently had intracranial progression to either supportive care or supportive care and 20 mg/day of melatonin at 8:00 pm daily until further deterioration or death (11). Neurologic stability and survival were both higher in the melatonin arm. The second trial randomized 30 patients with glioblastoma multiforme to either radiation therapy alone (60 Gy) or radiation therapy and 20 mg/day of melatonin (12). The survival of patients receiving melatonin was significantly higher at 1 year, with 6 of 14 surviving in the melatonin arm, and only 1 of 16 in the control arm (p < 0.05).

The Radiation Therapy Oncology Group (RTOG) developed BR-0119 based on the two trials by Lissoni et al. (11, 12) and on experimental cancer work showing the circadian-stage dependence of melatonin’s antitumor action and its antitumor effects. The trial was designed to compare whole-brain radiation therapy alone to radiation therapy and 20 mg/day melatonin for patients with brain metastases from solid tumors. All previous trials administered melatonin in the evening. Preclinical data suggest that the timing of melatonin administration relative to radiation therapy may be important (3). Therefore, patients were randomly assigned to receive melatonin in the morning or in the evening. Because the previous trial of melatonin given during radiation therapy for patients with glioblastoma multiforme (12) showed a marked improvement in survival, it was decided to give melatonin concurrently with radiation therapy. Preclinical studies also support concurrent administration (3). All patients received radiation therapy in the afternoon, to eliminate time of treatment as a variable. Patients in the two arms were then compared with the RTOG historical database of patients treated for brain metastases, to determine if there was any evidence of increased survival in either arm. If such evidence is seen, a phase III trial will be run to confirm it.

Section snippets

Eligibility and randomization

Eligible patients were those with recursive partitioning analysis (RPA) Class 2 brain metastases (Zubrod performance status 0–1, and any of the following: ≥65 years of age, extracranial metastases, or uncontrolled primary tumor). The patients were not on concurrent chemotherapy. Patients were randomized to morning (am) or evening (pm) 20-mg melatonin, according to a permuted block design, balanced by institution. The randomization was stratified by planned chemotherapy (yes vs. no). Patients

Results

The trial opened May 21, 2002, and closed July 1, 2003. One hundred and thirty patients were accrued from 36 different institutions. One hundred and twenty-six were available for analysis (62 assigned to am melatonin, and 64 to pm melatonin). Four patients were excluded from analysis: one because the patient received systemic therapy for small-cell carcinoma after study entry, one was not a confirmed RPA Class II at time of registration, one refused treatment with melatonin, and one received no

Discussion

The majority of randomized trials showing the clinical efficacy of melatonin among cancer patients are from the group of Lissoni et al. (11, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32). Three independent randomized trials, including this trial, have been run (33, 34). It is noteworthy that all trials from the group of Lissoni et al. (11, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) have had positive outcomes, but so far there have been no confirmatory publications

Conclusions

This trial did not confirm the hypothesis that 20 mg of melatonin improved survival in patients with solid tumors metastatic to the brain who were receiving palliative whole-brain radiotherapy. This is in contrast to a previous trial by Lissoni et al., in which 20 mg of melatonin produced a significant increase in 1-year survival among patients with brain metastases and neurologic progression after radiation therapy (11). The cause of this difference is not apparent. Further studies of the

References (37)

  • R.L. DeMuro et al.

    The absolute bioavailability of oral melatonin (0091–2700)

    J Clin Pharmacol

    (2000)
  • T. Akagi et al.

    Chronopharmacology of melatonin in mice to maximize the antitumor effect and minimize the rhythm disturbance effect

    J Pharmacol Exp Ther

    (2004)
  • H. Bartsch et al.

    Effect of melatonin on experimental tumors under different photoperiods and times of administration

    J Neural Transm

    (1981)
  • D.E. Blask et al.

    Melatonin radiosensitizes tumors and radioprotects normal tissues: Time-of-day dependency

    Am Assoc Cancer Res

    (2000)
  • P. Lissoni 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)
  • P. Lissoni et al.

    Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone

    Oncology

    (1996)
  • E. Haus

    Chronobiology of the mammalian response to ionizing radiationPotential applications in oncology

    Chronobiol Int

    (2002)
  • T.A. Rich et al.

    Chronomodulated chemotherapy and irradiation: An idea whose time has come?

    Chronobiol Int

    (2002)
  • Cited by (53)

    • Diet and supplements in cancer prevention and treatment: Clinical evidences and future perspectives

      2018, Critical Reviews in Oncology/Hematology
      Citation Excerpt :

      The pineal gland hormone melatonin (N-acetyl-5-methoxytryptamine) induces apoptosis of cancer cells in vitro and stimulates the immune system, including NK cells and Th1 lymphocytes (Srinivasan et al., 2008). Several small RCTs have tested the anticancer efficacy of oral melatonin, mostly at a daily dosage of 20 mg, alone or in combination with chemotherapy, radiotherapy or low-dose interleukin 2 in different types of advanced solid tumors (Berk et al., 2007; Brivio et al., 2010; Cerea et al., 2003; Lissoni, 2007; Lissoni et al., 1995; Lissoni et al., 1992; Lissoni et al., 1994a,1994b; Lissoni et al., 1999; Lissoni et al., 1994a, 1994b; Lissoni et al., 2008; Lissoni et al., 1996a; Lissoni et al., 2003; Lissoni et al., 1996b; Lissoni et al., 1997a; Lissoni et al., 1997b; Sookprasert et al., 2014; Yan et al., 2002). One meta-analysis of 8 RCTs found that melatonin improved both remission rates and 1 year survival rates compared with the placebo (Wang et al., 2012).

    • Role of drugs in the prevention and amelioration of radiation induced toxic effects

      2018, European Journal of Pharmacology
      Citation Excerpt :

      Various in vitro and in vivo investigations have established radioprotection with melatonin and its analogues (El-Missiry et al., 2007; Manda et al., 2008, 2007; Tan et al., 1998). Clinical investigation of melatonin has been done in a phase II Radiation Therapy Oncology Group trial (Berk et al., 2007). This study reported that concurrent administration of melatonin with radiation was well tolerated but the treatment had no significant effect on survival time or neurologic function.

    View all citing articles on Scopus

    This study was supported by National Cancer Institute grants RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115.

    Conflict of interest: none.

    View full text