Manuka Honey 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 liquid form (Drug): 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 lozenge form (Drug): 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.
• Standard supportive care (Drug): 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.

Primary outcomes

• Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS) [Baseline and 4 weeks from the start of treatment]: 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).

Secondary outcomes

• Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) [Baseline, weekly during treatment, and 12 weeks from the start of treatment]: 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 Via Daily Patient Log [Weekly during treatment and 12 weeks from the start of treatment]: 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".
• Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks [Baseline, 4 and 12 weeks from the start of treatment]: 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.
• Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4) [Up to 12 weeks from the start of treatment]: 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.
• 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 [Baseline, 4 weeks, end of radiation treatment, and 12 weeks from the start of treatment]: 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 Associated With Manuka Honey Using CTCAE v4.0 [Until 12 weeks from the start of treatment]: 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.
• 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) [Baseline and 4 weeks from the start of treatment]: 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.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS) (Primary), Median, units on a scale: Supportive Care 1 (0 to 4); Liquid Manuka Honey 1 (0 to 4); Lozenge Manuka Honey 1 (0 to 4) (p 0.92)
• Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) (Secondary), Median, units on a scale: Supportive Care 0 (0 to 0); Liquid Manuka Honey 0 (0 to 0); Lozenge Manuka Honey 0 (0 to 0) (p 0.87)
• Dysphagia Via Daily Patient Log (Secondary), Median, units on a scale: Supportive Care 1 (1 to 1); Liquid Manuka Honey 1 (1 to 1); Lozenge Manuka Honey 1 (1 to 1) (p 0.70)
• Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks (Secondary), Median, units on a scale: Supportive Care 66.67 (54.17 to 83.33); Liquid Manuka Honey 66.67 (50.00 to 83.33); Lozenge Manuka Honey 66.67 (50.00 to 83.33) (p 0.086)
• Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4) (Secondary), Number, percentage of participants: Supportive Care 12.5 (3.1 to 21.9); Liquid Manuka Honey 2.0 (0.0 to 5.9); Lozenge Manuka Honey 6.0 (0.0 to 12.6) (p 0.06)
• Percent Change in Weight From Baseline to 4 Weeks (Secondary), Mean, percentage of baseline value: Supportive Care -2.22 (-7.26 to 14.79); Liquid Manuka Honey -0.62 (-1.57 to 2.83); Lozenge Manuka Honey -2.64 (-4.53 to 5.64) (p 0.53)
• Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks) (Secondary), Mean, mg/dl: Supportive Care -3.34 (-9.46 to 17.98); Liquid Manuka Honey 5.25 (-6.42 to 34.70); Lozenge Manuka Honey 0.17 (-1.94 to 6.28) (p 0.20)
• Percentage of Patients Using Opioids (Secondary), Number, percentage of participants: Supportive Care 13.2; Liquid Manuka Honey 9.4; Lozenge Manuka Honey 13.0
• Adverse Events Associated With Manuka Honey Using CTCAE v4.0 (Secondary), Number, percentage of patients: Supportive Care 6.3; Liquid Manuka Honey 16.0; Lozenge Manuka Honey 12.0
• 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) (Secondary), Median, units on a scale: Supportive Care 1 (0 to 2); Liquid Manuka Honey 1 (0 to 2); Lozenge Manuka Honey 1 (0 to 2) (p 0.39)

Adverse events

Serious adverse events by term

Other adverse events by term

• Lawrence B. Berk, MD, PhD, Principal investigator, Tampa General Hospital, University of South Florida