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

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.

Study Overview

• Status: Completed
• Conditions: Pain; Esophagitis; Lung Cancer; Dysphagia
• Intervention / Treatment: Drug: Standard supportive care; Drug: Manuka honey in liquid form; Drug: Manuka honey in lozenge form

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 163
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Providence Cancer Center at Providence Hospital
  • California
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Stanford, California, United States, 94305-5824
      • Stanford Cancer Center
  • Delaware
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute - Jacksonville
    • Miami Beach, Florida, United States, 33140
      • CCOP - Mount Sinai Medical Center
    • Palatka, Florida, United States, 32177
      • Florida Cancer Center - Palatka
  • Georgia
    • Fayetteville, Georgia, United States, 30214
      • Piedmont Fayette Hospital
    • Savannah, Georgia, United States, 31405
      • Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Queen's Cancer Institute at Queen's Medical Center
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Medical Center - East
  • Illinois
    • Peoria, Illinois, United States, 61615-7827
      • OSF St. Francis Medical Center
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46805
      • Parkview Regional Cancer Center at Parkview Health
    • Muncie, Indiana, United States, 47303-3499
      • Cancer Center at Ball Memorial Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
  • Massachusetts
    • Hyannis, Massachusetts, United States, 02601
      • Cape Cod Hospital
  • Minnesota
    • Saint Cloud, Minnesota, United States, 56303
      • CentraCare Clinic - River Campus
  • Mississippi
    • Pascagoula, Mississippi, United States, 39581
      • Regional Cancer Center at Singing River Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
    • Saint Louis, Missouri, United States, 63141
      • David C. Pratt Cancer Center at St. John's Mercy
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • Payson Center for Cancer Care at Concord Hospital
    • Dover, New Hampshire, United States, 03820
      • Seacoast Cancer Center at Wentworth - Douglass Hospital
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
    • Manchester, New Hampshire, United States, 03103
      • Elliot Regional Cancer Center at Elliot Hospital
  • New Jersey
    • Long Branch, New Jersey, United States, 07740-6395
      • Monmouth Medical Center
    • Marlton, New Jersey, United States, 08053
      • Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
  • New York
    • East Syracuse, New York, United States, 13057
      • CCOP - Hematology-Oncology Associates of Central New York
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Rochester, New York, United States, 14620
      • Highland Hospital of Rochester
  • North Carolina
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
    • Hendersonville, North Carolina, United States, 28791
      • Pardee Memorial Hospital
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth Moore Regional Community Hospital Comprehensive Cancer Center
    • Raleigh, North Carolina, United States, 27607
      • Rex Cancer Center at Rex Hospital
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • North Dakota
    • Minot, North Dakota, United States, 58701
      • Trinity Cancercare Center
  • Ohio
    • Canton, Ohio, United States, 44708
      • Mercy Cancer Center at Mercy Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106-5065
      • Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Cancer Center at Fairview Hospital
    • Independence, Ohio, United States, 44131
      • Cleveland Clinic Cancer Center
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Cancer Center at Hillcrest Hospital
    • Parma, Ohio, United States, 44129
      • Parma Community General Hospital
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Rosenfeld Cancer Center at Abington Memorial Hospital
    • Bryn Mawr, Pennsylvania, United States, 19010
      • Bryn Mawr Hospital
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Cancer Institute at Geisinger Health
    • Dunmore, Pennsylvania, United States, 18512
      • Northeast Radiation Oncology Center
    • Gettysburg, Pennsylvania, United States, 17325
      • Adams Cancer Center
    • Hanover, Pennsylvania, United States, 17331
      • Cherry Tree Cancer Center
    • Paoli, Pennsylvania, United States, 19301-1792
      • Cancer Center of Paoli Memorial Hospital
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Cancer Center at Lankenau Hospital
    • York, Pennsylvania, United States, 17405
      • York Cancer Center at Apple Hill Medical Center
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
  • Texas
    • Galveston, Texas, United States, 77555-0361
      • University of Texas Medical Branch
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center at San Antonio
  • Washington
    • Bellingham, Washington, United States, 98225
      • St. Joseph Cancer Center
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Green Bay, Wisconsin, United States, 54303
      • St. Mary's Hospital Medical Center - Green Bay

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Supportive Care; Standard supportive care	Drug: Standard supportive care; 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.
Experimental: Liquid Manuka Honey; Manuka honey in liquid form	Drug: Manuka honey in liquid form; 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.
Experimental: Lozenge Manuka Honey; Manuka honey in lozenge form	Drug: Manuka honey in lozenge 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); NRG Oncology
• Investigators: Principal Investigator: Lawrence B. Berk, MD, PhD, Tampa General Hospital, University of South Florida

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: December 16, 2010
• First Submitted That Met QC Criteria: December 16, 2010
• First Posted (Estimate): December 17, 2010

Study Record Updates

• Last Update Posted (Actual): August 31, 2017
• Last Update Submitted That Met QC Criteria: August 29, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: recurrent non-small cell lung cancer; extensive stage small cell lung cancer; recurrent small cell lung cancer; stage IIIA non-small cell lung cancer; stage IIIB non-small cell lung cancer; pain; limited stage small cell lung cancer; stage IA non-small cell lung cancer; stage IB non-small cell lung cancer; dysphagia; stage IIA non-small cell lung cancer; stage IIB non-small cell lung cancer; esophagitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Gastrointestinal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Gastroenteritis; Pharyngeal Diseases; Otorhinolaryngologic Diseases; Esophageal Diseases; Lung Neoplasms; Deglutition Disorders; Esophagitis
• Other Study ID Numbers: RTOG 1012; RTOG-1012; CDR0000690182; NCI-2011-02620 (Registry Identifier: CTRP (Clinical Trial Reporting Program))