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Patients swallow 10 cc (approximately 2 level teaspoons) of liquid Manuka honey 4 times per day while awake over an approximately 12 hour period (e.g. 8 a.m., Noon, 4 p.m., and 8 p.m.) 7 days/week during concurrent chemotherapy and radiation treatment.

Manuka honey in liquid form

Patients place 2 lozenges (the equivalent of 10 cc of liquid Manuka honey), one at a time, in the mouth, allowing each lozenge to dissolve on the tongue/in the mouth, swallowing the honey as it dissolves. Patients do this 4 times per day while awake over an approximately 12 hour period (e.g. 8 a.m., Noon, 4 p.m., and 8 p.m.) 7 days/week during concurrent chemotherapy and radiation treatment.

Manuka honey in lozenge form

Patients receive standard supporting care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment. The following regimen is recommended, but the local standard of care is permitted.

1. A compound containing viscous lidocaine and magnesium aluminum oxide (Maalox®);
2. Liquid or solid oxycodone, 5-10 mg, every 3 hours as needed.

Standard supportive care

Lawrence B. Berk, MD, PhD

RATIONALE: Manuka honey may prevent or reduce esophagitis-related pain caused by chemotherapy and radiation therapy. It is not yet known whether Manuka honey is more effective than standard care in preventing pain.

PURPOSE: This randomized phase II clinical trial is studying Manuka honey to see how well it works in preventing esophagitis-related pain in patients receiving chemotherapy and radiation therapy for lung cancer.

OBJECTIVES:

Primary

* Evaluate the relative efficacy of 4 times a day consumption of liquid or lozenge Manuka honey to delay or prevent radiation esophagitis-related pain (during combined chemotherapy and radiation therapy for lung cancer) as compared to standard supportive treatment, as measured at week 4 by Numerical Rating Pain Scale (NRPS) for pain upon swallowing.

Secondary

* Evaluate the trend of severity of radiation esophagitis-related pain during combined chemotherapy and radiation therapy for lung cancer using weekly measurements of the NRPS.
* Evaluate the adverse events associated with Manuka honey, as measured by CTCAE, v. 4.
* Evaluate the severity of radiation esophagitis (grade 3-4, CTCAE, v. 4).
* Assess weight loss (percent weight change from baseline to 4 weeks).
* Assess quality of life (QOL) and pain, as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-30) global QOL score and pain symptom subscale.
* Assess patient-reported dysphagia via a daily patient log.
* Assess nutritional status, as measured by the mean change in serum prealbumin levels from baseline to 4 weeks.
* Assess opioid use by collecting the patient's narcotic use in the previous 24-hour period at each weekly evaluation.
* Evaluate patient-reported adverse events associated with Manuka honey using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

OUTLINE: This is a multicenter study. Patients are stratified according to the percentage of esophagus in the radiation field (V60 \< 30% vs V60 ≥ 30%). Patients are randomized to 1 of 3 treatment arms.

* Arm I: Patients receive standard supportive care for esophagitis-related pain as needed during chemoradiotherapy.
* Arm II: Patients swallow liquid Manuka honey slowly over 3-5 minutes. Patients must refrain from eating and drinking for 1 hour after administration. Treatment continues 4 times per day during chemoradiotherapy.
* Arm III: Patients place Manuka honey lozenges in their mouth one at a time and swallow the honey as it dissolves (no chewing or swallowing it whole). Patients must refrain from eating and drinking for 1 hour after administration. Treatment continues 4 times per day during chemoradiotherapy.

Patients complete quality of life, pain swallowing diary, and pain assessments (Numerical Rating Pain Scale, EORTC QLQ-30 and Pain Subscale, and PRO-CTCAE) periodically during study treatment.

Patients are followed up at 12 weeks from the start of study treatment.

Manuka Honey in Preventing Esophagitis-Related Pain in Patients Receiving Chemotherapy and Radiation Therapy For Lung Cancer

Phase II Randomized Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy Induced Esophagitis-Related Pain During the Treatment of Lung Cancer

Esophagitis-related pain was measured using patient-reported pain on swallowing as assessed by the Numerical Rating Pain Scale (NRPS), an 11-point scale (0-10) in which 0 indicates no pain and 10 indicates the worst pain imaginable. Generally, scores of 1-4 indicate mild pain, scores of 5-6 indicate moderate pain, and scores of 7-10 indicate severe pain. Change was calculated by subtracting the baseline value from the 4-week value. The experimental arms (honey) were compared to the standard arm (supportive care).

Esophagitis-related pain was measured using patient-reported pain on swallowing as assessed by the Numerical Rating Pain Scale (NRPS), an 11-point scale (0-10) in which 0 indicates no pain and 10 indicates the worst pain imaginable. Generally, scores of 1-4 indicate mild pain, scores of 5-6 indicate moderate pain, and scores of 7-10 indicate severe pain. Change was calculated by subtracting the baseline value from values at the later time points. The experimental arms (honey) were compared to the standard arm (supportive care).

Dysphagia, as reported by the patient, was measured by the patient swallowing diary. Swallowing score has increasing severity 1-5, where 1 = "none" and 5 = "cannot swallow liquids".

The pain symptom subscale (2 items) evaluated pain and the global score (30 items) evaluated quality of life. Each ranges from 0-100 with lower scores indicating lesser burden and improved symptoms or quality of life.

Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. For esophagitis specifically, Grade 3 criteria includes severely altered eating/swallowing, tube feeding, total parenteral nutrition (TPN) or hospitalization indicated. Grade 4 criteria include life-threatening consequences, urgent operative intervention indicated.

The percentage of patients using opioid analgesics is reported. Use of opioid analgesics was assessed for a 24-hour period before completing the assessment. Patients with at least one reported administration of opioid analgesic were considered to have received opioid analgesics.

Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

Change from baseline to four weeks in patient-reported difficulty in swallowing via the PRO-CTCAE. PRO-CTCAE is an item bank consisting of individual items to assess adverse symptom events from the patient perspective. There are 78 symptoms included in the survey but the primary item of interest assesses difficulty swallowing. For each AE in the PRO-CTCAE, between 1 and 3 items are included to assess the frequency, severity, and/or interference with activities related to that AE. Frequency questions have responses ranging from never, which is scored as a 0, to almost constantly, which is scored as a 4. Severity questions have responses ranging from none, which is scored as a 0, to very severe, which is scored as a 4. Interference questions have responses ranging from not at all, which is scored as a 0, to very much, which is scored as a 4. Difficulty in swallowing only has a severity question.

National Cancer Institute (NCI)

NRG Oncology

Radiation Therapy Oncology Group

Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.

Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.

Supportive Care

Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.

Liquid Manuka Honey

Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.

Lozenge Manuka Honey

Total

Age, Continuous

Sex: Female, Male

Wendy Seiferheld, M.S.

Null hypothesis: Manuka honey in liquid form is/not effective at reducing esophagitis-related pain, measured by mean change score from 0 to 4 weeks. A 2-sample t-test for difference of means with alpha 0.05 after adjusting for multiple comparisons (1-sided with overall alpha 0.1 before the Bonferroni adjustment) and 80% statistical power for each hypothesis test requires 45 patients per arm to detect \>= 15% relative reduction (absolute difference of mean change score of 3.1; effect size=0.53).

Null hypothesis: Manuka honey in lozenge form is/not effective at reducing esophagitis-related pain, measured by mean change score from 0 to 4 weeks. A 2-sample t-test for difference of means with alpha 0.05 after adjusting for multiple comparisons (1-sided with overall alpha 0.1 before the Bonferroni adjustment) and 80% statistical power for each hypothesis test requires 45 patients per arm to detect \>= 15% relative reduction (absolute difference of mean change score of 3.1; effect size=0.53).

Randomized eligible patients with NRPS score at both baseline and 4 weeks.

Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS)

A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Liquid Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.

A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.

A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.

Baseline

Week 1

Week 2

Week 3

4 weeks

Week 5

End of RT

Week 12

Eligible patients who started protocol treatment with at least 1 NRPS score completed across all time points

Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS)

A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. Treatment (Liquid Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.

A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.

A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.

Week 4

Randomized eligible patients who received protocol treatment with at least one dysphagia score completed across all time points.

Dysphagia Via Daily Patient Log

A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Liquid Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Liquid Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.

A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60\>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.

Baseline - Global health status

Baseline - Pain

Week 4 - Global health status

Week 4 - Pain

Week 12 - Global health status

Week 12 - Pain

Randomized eligible patients who received protocol treatment with at least 1 EORTC score completed across all time points.

Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks

Randomized eligible patients who started protocol treatment

Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4)

Randomized eligible patients with weight at both baseline and 4 weeks.

Percent Change in Weight From Baseline to 4 Weeks

Randomized eligible patients with serum prealbumin at baseline and 4 weeks.

Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks)

Randomized eligible patients with opioid use information at at least one time point.

Percentage of Patients Using Opioids

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Randomized eligible patients who started protocol treatment.

Adverse Events Associated With Manuka Honey Using CTCAE v4.0

Each experimental arm was compared to the control arm (i.e. 2 comparisons) using two-sample t-tests. Forty-five patients with data in each arm, provides 80% power to detect an effect size (in standard deviation units) of 0.60 and 90% power to detect an effect size of 0.69 using a two-sided T-test with a Bonferroni adjusted significance level of 0.05 for each comparison (overall alpha 0.10). Due to the lack of prior data on the PRO-CTCAE, moderate effect sizes were used.

Randomized eligible patients who started treatment with measure at both baseline and 4 weeks.

Patient Reported Difficulty in Swallowing Associated With Manuka Honey Using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Spots Global Cancer Trial Database for manuka honey in lozenge form