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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Dysphagia, Lung Cancer, Pain, Esophagitis

Intervention / Treatment
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* Drug: Manuka honey in liquid form
* Drug: Manuka honey in lozenge form
* Drug: Standard supportive care


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Patients being treated with combination chemotherapy (definitive or adjuvant) and radiation therapy once daily for small cell or non-small cell lung cancer (primary population for the trial) Patients can receive chemoradiotherapy while on a Radiation Therapy Oncology Group (RTOG) lung trial or while not being on a clinical trial No patients receiving chemoradiotherapy while enrolled on a single institution trial or trials coordinated by other cooperative groups No patients with metastatic disease At least 5 cm of the esophagus must be in the 60 Gy isodose volume in 1.6 to 2.0 Gy fractions PATIENT CHARACTERISTICS: Age 18 and up Able to swallow thick liquids prior to treatment Able to speak English or Spanish in order to complete required forms (verbal completion is adequate) No patients with poorly controlled diabetes No known hypersensitivity to honey PRIOR CONCURRENT THERAPY: See Disease Characteristics No patients who have received prior chemotherapy or radiation therapy No patients receiving more than once daily treatments Therapeutic use of honey other than the Manuka honey provided for this trial is not allowed while patients are on study Patients must also avoid honey-flavored medical products and/or sugary, viscous substances Amifostine is not permitted

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Supportive Care<br>Standard supportive care | Drug: Standard supportive care<br>* 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. A compound containing viscous lidocaine and magnesium aluminum oxide (Maalox®); Liquid or solid oxycodone, 5-10 mg, every 3 hours as needed.<br>|
| Experimental: Liquid Manuka Honey<br>Manuka honey in liquid form | Drug: Manuka honey in liquid form<br>* 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.<br>|
| Experimental: Lozenge Manuka Honey<br>Manuka honey in lozenge form | Drug: Manuka honey in lozenge form<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS) | 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). | Baseline and 4 weeks from the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | 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). | Baseline, weekly during treatment, and 12 weeks from the start of treatment | 
| Dysphagia Via Daily Patient Log | 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. | Weekly during treatment and 12 weeks from the start of treatment | 
| Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | 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. | Baseline, 4 and 12 weeks from the start of treatment | 
| Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4) | 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. | Up to 12 weeks from the start of treatment | 
| Percent Change in Weight From Baseline to 4 Weeks |  | Baseline and 4 weeks from the start of treatment | 
| Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks) |  | Baseline and 4 weeks from the start of treatment | 
| Percentage of Patients Using Opioids | 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. | Baseline, 4 weeks, end of radiation treatment, and 12 weeks from the start of treatment | 
| Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | 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. | Until 12 weeks from the start of treatment | 
| 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) | 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. | Baseline and 4 weeks from the start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, dysphagia, recurrent non-small cell lung cancer, stage IA non-small cell lung cancer, stage IB non-small cell lung cancer, stage IIA non-small cell lung cancer, stage IIB non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, extensive stage small cell lung cancer, limited stage small cell lung cancer, recurrent small cell lung cancer, esophagitis