Melatonin Supplementation for Cancer-Related Fatigue in Patients With Early Stage Breast Cancer Receiving Radiotherapy: A Double-Blind Placebo-Controlled Trial.

BACKGROUND: Fatigue is common in patients undergoing radiotherapy (RT) and can significantly impact quality of life. Melatonin, a safe inexpensive natural supplement, may improve symptoms and attenuate the side effects of RT. The purpose of this randomized double-blind placebo-controlled phase III trial was to assess the effects of melatonin for preventing fatigue and other symptoms in patients with breast cancer undergoing RT. METHODS: Female early stage or Ductal carcinoma in situ patients with breast cancer ≥18 years of age with Eastern Cooperative Oncology Group (ECOG) performance status <3, hemoglobin ≥9 g/dL, planned for outpatient RT treatment with curative intent, were randomized 1:1 to melatonin 20 mg or placebo, orally, starting the night before RT initiation until 2 weeks post-RT. Randomization was stratified according to treatment duration (<3 weeks, ≥3 weeks) and prior chemotherapy. The primary endpoint was the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue scale), and secondary endpoints were FACIT-F subscales, Edmonton Symptom Assessment Scale (ESAS), and Patient-Reported Outcomes Measurement Information System (PROMIS) scores obtained at baseline, and 2 and 8 weeks post-RT. A 2-sided ANOVA F-test at a 4.5% significance level for the primary endpoint was used. Secondary analyses were reported using an F-test at a 5% significance level. The goal was to recruit approximately 140 patients with interim analysis planned mid-recruitment. RESULTS: Eighty-five patients were screened for eligibility; 79 patients were randomized: 40 to melatonin and 39 to placebo; 78 patients were treated and included in the interim analysis at the mid-recruitment point. Baseline patient characteristics of age, race, and ECOG performance status were similar in both arms. The treatment effect was studied using a longitudinal mixed effects model with the effect of treatment over time (treatment × time) as the primary outcome parameter. The treatment × time for FACIT-Fatigue did not demonstrate statistical significance (P-value .83) in the melatonin group compared to placebo. In addition, secondary analyses of FACIT physical, social, emotional, and functional well-being scores did not demonstrate statistical significance (P-values of .35, .06, .62, and .71, respectively). Total PROMIS scores, collected as secondary outcome reported by patients, did not demonstrate statistically significant change over time either (P-value is .34). The other secondary scale, ESAS, was analyzed for each individual item and found to be nonsignificant, anxiety (P = .56), well-being (.82), drowsiness (.83), lack of appetite (.35), nausea (.79), pain (.50), shortness of breath (.77), sleep (.45), and tiredness (.56). Depression was the only item demonstrating statistical significance with a decrease of 0.01 unit in the placebo group, a change not considered clinically significant. Melatonin was well-tolerated with no grade 3 or 4 adverse events reported. The most common side effects were headache, somnolence, and abdominal pain. No patients died while participating in this study. Two patients died within a year of study completion from breast cancer recurrence. Sixteen patients withdrew prior to study completion for various reasons including adverse events, hospitalizations unrelated to study drug, RT discontinuation, and COVID-19 precautions. CONCLUSIONS: In this double-blind placebo-controlled phase III trial, melatonin did not prevent or significantly improve fatigue and other symptoms in patients with early stage breast cancer undergoing RT. The analysis, showing little evidence of an effect, at mid-recruitment, assured early termination of the trial.

Assessment of formaldehyde exposures under contemporary embalming conditions in U.S. funeral homes.

The funeral service profession has used formaldehyde-containing embalming solutions for the preparation of decedents since the early 1900s. The available literature regarding funeral director exposure to formaldehyde largely consists of data collected prior to 2000, with most studies reporting task-length exposure concentrations rather than full-shift time-weighted average concentrations. As formaldehyde undergoes review in the U.S. Environmental Protection Agency Toxic Substances Control Act (TSCA) risk evaluation process, accurately characterizing long-term exposure potential in this profession is critical. This study presents passive badge sampling and air change rate measurement results conducted at 13 funeral home locations across the United States. Full-shift (approximately 8-hr) samples were collected on one embalmer per day in each funeral home and on one occupational non-user (ONU), e.g., a receptionist. Additionally, task-length samples were collected during each embalming that occurred during the shift, were one to occur. Full-shift concentrations ranged from 0.007 to 1.1 ppm and 0.007 to 0.042 ppm for embalmers and ONUs, respectively. Task-length formaldehyde concentrations ranged from 0.058 to 1.4 ppm, with the average embalming taking 72.8 min to complete. Air change rates in the preparation rooms ranged from 2.8 to 28.3 air changes per hour; however, no correlation between task-length formaldehyde concentrations and air change rate was observed. Following empirical data collection, a Monte Carlo analysis of estimated annual 8-hr time-weighted average (TWA) exposure was conducted to determine the potential exposure distribution for embalmers employed at private funeral homes. Inputs to the simulation were derived from responses to a National Funeral Directors Association survey and from empirical measurements collected during the study. With respect to the reconstructed 8-hr TWAs, the median 8-hr TWA was 0.037 ppm, with 93.6% of the predicted concentrations below 0.1 ppm. This study provides a robust characterization of contemporary formaldehyde exposures in the funeral service profession. Further, it provides a strategy for interpreting the results along with surveyed responses regarding embalming frequency to better inform risks associated with formaldehyde exposure in this profession.

Human health risk assessment of arsenic, cadmium, lead, and mercury ingestion from baby foods.

Recently, the U.S. House of Representatives reported on the presence of heavy metals in raw ingredients used in baby foods and in finished baby food products themselves. In light of these concerns, this study aimed to evaluate potential risks associated with the presence of heavy metals in baby food products. We analyzed 36 baby food samples representing four ingredient categories (fruit; leguminous vegetable; root vegetable; or grain) for arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb). We assessed the potential lifetime cancer and non-cancer health risks posed to infants and toddlers following daily consumption of these chemicals in each food type, based on established daily food-specific ingestion rates. Daily doses were compared against selected reference values and oral slope factors to determine non-cancer hazard indices (HIs) and lifetime cancer risks. Hazard indices indicated a potential for non-cancer risk (e.g., HIs > 1.0) under only a few exposure scenarios, including for As and Pb under selected product type and age/concentration assumptions. Increases in lifetime cancer risks for all analytes across the ingredient categories evaluated ranged from 3.75 × 10-5 to 5.54 × 10-5; cancer risks were primarily driven by As from grain products. Though a limited set of exposure scenarios indicated a potential for health risk, the exposure assumptions in this assessment were conservative, and the heavy metal concentrations we found in baby foods are similar to those observed in similar whole foods. Based on these findings and the limited scenarios under which risks were identified, this study indicates that an infant's typical intake of baby food is unlikely to pose health risks from heavy metals above accepted tolerable risk levels under most exposure scenarios.

A randomized trial of the effectiveness of topical "ABH Gel" (Ativan(®), Benadryl(®), Haldol(®)) vs. placebo in cancer patients with nausea.

CONTEXT: The topical gel known as "ABH gel," comprising lorazepam (Ativan(®)), diphenhydramine (Benadryl(®)), and haloperidol (Haldol(®)), is frequently used to treat nausea because of its perceived efficacy, relatively low cost, and ease of use in the home setting. There are limited scientific data on this medication, however. Recent pilot studies showed no absorption of the active ingredients of the gel, prompting further prospective studies into the cause of the perceived efficacy in the clinical setting. OBJECTIVES: To determine any difference in the effectiveness of ABH gel compared with placebo in cancer patients with nausea. METHODS: A randomized, double-blind, placebo-controlled, crossover, noninferiority clinical trial was developed to test the hypothesis that there is no difference in the effectiveness of ABH gel compared with placebo in cancer patients with nausea. The primary outcome was the difference in nausea score (on a 0-10 scale) at baseline and at 60 minutes in each treatment group. The difference in the ABH gel-treated group compared with placebo was evaluated for noninferiority. Secondary outcomes included the number of vomiting episodes and side effects over time. RESULTS: The mean change in nausea score from baseline to 60 minutes after treatment in the ABH gel group was 1.7 ± 2.05 and 0.9 ± 2.45 for the placebo group (P = 0.42). The placebo group was found to be noninferior to the ABH gel group in reducing the nausea score. ABH gel also did not decrease vomiting events better than placebo (P = 0.34). Only one patient reported any side effects from the treatments in either arm of the study. CONCLUSION: ABH gel in its current formulation should not be used in cancer patients experiencing nausea.

A randomized, placebo controlled trial of oral zinc for chemotherapy-related taste and smell disorders.

Abnormalities in taste and smell are commonly reported in patients receiving chemotherapy and may hinder appetite, dietary intake, nutritional well-being, and quality of life. Oral zinc has been used to treat taste and smell abnormalities in several altered physiologic states, including renal failure, liver disease, head trauma, and pregnancy, with varying results. The authors conducted a double-blinded, placebo-controlled randomized clinic trial over 3 months. Eligible patients were those taking chemotherapy that had alterations in taste and/or smell. The measurement of the primary end point, improvement in altered taste and smell, was made using a 0-100 scale (100 describing no loss or distortion in taste and smell, and 0 describing the worst distortion or loss of taste and smell). Twenty-nine subjects were enrolled in each treatment group, of whom 31 were white, 26 African American, and 1 Native American. Forty-one patients were female. A wide range of cancer types was represented, with breast the most common (21 patients). The zinc dose was 220 mg orally twice daily (equivalent of 50 mg elemental zinc twice daily). There was no statistically significant improvement in loss or distortion of taste or smell with the addition of zinc. There was a trend toward improvement over time in all groups, except in the zinc group where there was a nonsignificant worsening in loss of smell over time. Zinc at standard doses did not provide significant benefit to taste or smell in patients receiving chemotherapy.

ABH gel is not absorbed from the skin of normal volunteers.

BACKGROUND: Lorazepam (Ativan(®)), diphenhydramine (Benadryl(®)), haloperidol (Haldol(®)) (ABH) topical gel is currently widely used for nausea in hospice because of perceived efficacy and low cost and has been suggested for cancer chemotherapy. However, there are no studies of absorption, a prerequisite for effectiveness. We completed this study to establish whether ABH gel drugs are absorbed, as a prerequisite to effectiveness. INTERVENTION: Ten healthy volunteers, aged 25 to 58 years (mean 37 years), two African Americans and eight Caucasian Americans, applied the standard 1.0 mL dose (2mg of lorazepam, 25mg of diphenhydramine, and 2mg of haloperidol in a pluronic lecithin organogel), rubbed on the volar surface of the wrists by the subject. MEASURES: Blood samples were obtained at 0, 30, 60, 90, 120, 180, and 240 minutes. Plasma concentrations were analyzed by liquid chromatography-tandem mass spectrometry using deuterated internal standards for each drug. OUTCOMES: No lorazepam or haloperidol was detected in any sample from any of the 10 volunteers down to a level of 0.05 ng/mL. Diphenhydramine was found in multiple plasma samples at concentrations >0.05 ng/mL in three patients, with the highest concentration of 0.30 ng/mL in one person at 240 minutes. Overall, five of 10 patients exhibited detectable diphenhydramine in one or more samples, supporting limited absorption. No subject noted any side effects. CONCLUSIONS/LESSONS LEARNED: As commonly used, none of the lorazepam, haloperidol, or diphenhydramine in ABH gel is absorbed in sufficient quantities to be effective in the treatment of nausea and vomiting. Diphenhydramine is erratically absorbed at subtherapeutic levels. The efficacy of ABH gel should be confirmed in randomized trials before its use is recommended.

A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients.

BACKGROUND: We tested if magnesium would diminish bothersome hot flashes in breast cancer patients. METHODS: Breast cancer patients with at least 14 hot flashes a week received magnesium oxide 400 mg for 4 weeks, escalating to 800 mg if needed. Hot flash score (frequency × severity) at baseline was compared to the end of treatment. RESULTS: Of 29 who enrolled, 25 women completed treatment. The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 (standard error (SE), 13.7) to 27.7 (SE, 5.7), a 41.4% reduction, p = 0.02, two-sided paired t test. Hot flash score was reduced from 109.8 (SE, 40.9) to 47.8 (SE, 13.8), a 50.4% reduction, p = 0.04. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial. CONCLUSIONS: Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal. A randomized placebo-controlled trial is planned.

Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare®) for chemotherapy-induced peripheral neuropathy.

CONTEXT: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and persistent consequence of numerous classes of antineoplastic agents, affecting up to 30%-40% of patients. To date, there is no effective prevention or therapy. An evolving hypothesis for reducing CIPN pain involves direct nerve stimulation to reduce the pain impulse. OBJECTIVES: To evaluate the impact on CIPN associated with the MC5-A Calmare® therapy device. METHODS: The MC5-A Calmare® therapy device is designed to generate a patient-specific cutaneous electrostimulation to reduce the abnormal pain intensity. Sixteen patients from one center received one-hour interventions daily over 10 working days. RESULTS: Of 18 patients, 16 were evaluable. The mean age of the patients was 58.6 years-four men and 14 women-and the duration of CIPN was three months to eight years. The most common drugs were taxanes, platinums, and bortezomib (Velcade, Millenium Pharmaceuticals, Cambridge MA). At the end of the study (Day 10), a 20% reduction in numeric pain scores was achieved in 15 of 16 patients. The pain score fell 59% from 5.81±1.11 before treatment to 2.38±1.82 at the end of 10 days (P<0.0001 by paired t-test). A daily treatment benefit was seen with a strong statistically significant difference between the pre- and post-daily pain scores (P<0.001). Four patients had their CIPN reduced to zero. A repeated-measures analysis using the scores from all 10 days confirmed these results. No toxicity was seen. Some responses have been durable without maintenance. CONCLUSION: Patient-specific cutaneous electrostimulation with the MC5-A Calmare® device appears to dramatically reduce pain in refractory CIPN patients with no toxicity. Further studies are underway to define the benefit, mechanisms of action, and optimal schedule.