Dysphagia, Lung Cancer, Pain, Esophagitis
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGManuka 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.
DRUGManuka 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.
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.
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| Percent Change in Weight 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. |
| Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks) | Baseline and 4 weeks from the start of treatment | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Supportive Care Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment. | 53 |
| Liquid Manuka Honey Manuka honey in liquid form during concurrent chemotherapy and radiation treatment. | 53 |
| Lozenge Manuka Honey Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment. | 54 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Supportive Care | Liquid Manuka Honey | Lozenge Manuka Honey | Total |
|---|---|---|---|---|
| Age, Continuous | 65 years | 66 years | 65 years | 65 years |
| Sex: Female, Male Female | 27 Participants | 24 Participants | 23 Participants | 74 Participants |
| Sex: Female, Male Male | 26 Participants | 29 Participants | 31 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 37 / 48 | 46 / 50 | 38 / 50 |
| serious Total, serious adverse events | 16 / 48 | 13 / 50 | 9 / 50 |
Outcome results
Primary
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).
Time frame: Baseline and 4 weeks from the start of treatment
Population: Randomized eligible patients with NRPS score at both baseline and 4 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Supportive Care | Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS) | 1 units on a scale |
| Liquid Manuka Honey | Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS) | 1 units on a scale |
| Lozenge Manuka Honey | Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS) | 1 units on a scale |
Comparison: 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).p-value: 0.92Wilcoxon (Mann-Whitney)
Comparison: 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).p-value: 0.93Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Until 12 weeks from the start of treatment
Population: Randomized eligible patients who started protocol treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Supportive Care | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 2 | 20.8 percentage of patients |
| Supportive Care | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 4 | 2.1 percentage of patients |
| Supportive Care | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 1 | 6.3 percentage of patients |
| Supportive Care | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 3 | 10.4 percentage of patients |
| Supportive Care | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 5 | 0.0 percentage of patients |
| Liquid Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 3 | 8.0 percentage of patients |
| Liquid Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 4 | 0.0 percentage of patients |
| Liquid Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 5 | 0.0 percentage of patients |
| Liquid Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 2 | 26.0 percentage of patients |
| Liquid Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 1 | 16.0 percentage of patients |
| Lozenge Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 5 | 0.0 percentage of patients |
| Lozenge Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 1 | 12.0 percentage of patients |
| Lozenge Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 2 | 18.0 percentage of patients |
| Lozenge Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 3 | 8.0 percentage of patients |
| Lozenge Manuka Honey | Adverse Events Associated With Manuka Honey Using CTCAE v4.0 | Grade 4 | 2.0 percentage of patients |
Secondary
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.
Time frame: Weekly during treatment and 12 weeks from the start of treatment
Population: Randomized eligible patients who received protocol treatment with at least one dysphagia score completed across all time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Supportive Care | Dysphagia Via Daily Patient Log | Baseline | 1 units on a scale |
| Supportive Care | Dysphagia Via Daily Patient Log | Week 1 | 1 units on a scale |
| Supportive Care | Dysphagia Via Daily Patient Log | Week 2 | 1 units on a scale |
| Supportive Care | Dysphagia Via Daily Patient Log | Week 3 | 1.36 units on a scale |
| Supportive Care | Dysphagia Via Daily Patient Log | Week 4 | 1.86 units on a scale |
| Supportive Care | Dysphagia Via Daily Patient Log | Week 5 | 2.5 units on a scale |
| Supportive Care | Dysphagia Via Daily Patient Log | End of RT | 2 units on a scale |
| Supportive Care | Dysphagia Via Daily Patient Log | Week 12 | 1 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | Week 2 | 1 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | End of RT | 2.86 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | Week 3 | 2 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | Week 4 | 2 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | Week 5 | 2 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | Baseline | 1 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | Week 1 | 1 units on a scale |
| Liquid Manuka Honey | Dysphagia Via Daily Patient Log | Week 12 | 1 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | Week 2 | 1.07 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | Week 1 | 1 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | Baseline | 1 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | Week 3 | 1.86 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | End of RT | 3 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | Week 5 | 2.71 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | Week 4 | 2.07 units on a scale |
| Lozenge Manuka Honey | Dysphagia Via Daily Patient Log | Week 12 | 1 units on a scale |
Comparison: 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.p-value: 0.7Mixed Models Analysis
Comparison: 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.p-value: 0.71Mixed Models Analysis
Comparison: 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.p-value: 0.0002Mixed Models Analysis
Comparison: 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.p-value: 0.0051Mixed Models Analysis
Comparison: 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.p-value: <0.0001Mixed Models Analysis
Secondary
Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks)
Time frame: Baseline and 4 weeks from the start of treatment
Population: Randomized eligible patients with serum prealbumin at baseline and 4 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Supportive Care | Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks) | -3.34 mg/dl |
| Liquid Manuka Honey | Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks) | 5.25 mg/dl |
| Lozenge Manuka Honey | Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks) | 0.17 mg/dl |
p-value: 0.2t-test, 2 sided
p-value: 0.28t-test, 2 sided
Secondary
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.
Time frame: Baseline and 4 weeks from the start of treatment
Population: Randomized eligible patients who started treatment with measure at both baseline and 4 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Supportive Care | 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) | 1 units on a scale |
| Liquid Manuka Honey | 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) | 1 units on a scale |
| Lozenge Manuka Honey | 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) | 1 units on a scale |
Comparison: 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.p-value: 0.39Wilcoxon (Mann-Whitney)
Comparison: 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.p-value: 0.69Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Up to 12 weeks from the start of treatment
Population: Randomized eligible patients who started protocol treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Supportive Care | Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4) | 12.5 percentage of participants |
| Liquid Manuka Honey | Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4) | 2.0 percentage of participants |
| Lozenge Manuka Honey | Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4) | 6.0 percentage of participants |
p-value: 0.06Fisher Exact
p-value: 0.31Fisher Exact
Secondary
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.
Time frame: Baseline, 4 weeks, end of radiation treatment, and 12 weeks from the start of treatment
Population: Randomized eligible patients with opioid use information at at least one time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Supportive Care | Percentage of Patients Using Opioids | Baseline | 13.2 percentage of participants |
| Supportive Care | Percentage of Patients Using Opioids | Week 4 | 37.0 percentage of participants |
| Supportive Care | Percentage of Patients Using Opioids | End of RT | 46.5 percentage of participants |
| Supportive Care | Percentage of Patients Using Opioids | Week 12 | 32.6 percentage of participants |
| Liquid Manuka Honey | Percentage of Patients Using Opioids | Week 12 | 17.4 percentage of participants |
| Liquid Manuka Honey | Percentage of Patients Using Opioids | Baseline | 9.4 percentage of participants |
| Liquid Manuka Honey | Percentage of Patients Using Opioids | End of RT | 36.2 percentage of participants |
| Liquid Manuka Honey | Percentage of Patients Using Opioids | Week 4 | 14.3 percentage of participants |
| Lozenge Manuka Honey | Percentage of Patients Using Opioids | Week 12 | 18.2 percentage of participants |
| Lozenge Manuka Honey | Percentage of Patients Using Opioids | Week 4 | 29.2 percentage of participants |
| Lozenge Manuka Honey | Percentage of Patients Using Opioids | End of RT | 43.2 percentage of participants |
| Lozenge Manuka Honey | Percentage of Patients Using Opioids | Baseline | 13.0 percentage of participants |
Secondary
Percent Change in Weight From Baseline to 4 Weeks
Time frame: Baseline and 4 weeks from the start of treatment
Population: Randomized eligible patients with weight at both baseline and 4 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Supportive Care | Percent Change in Weight From Baseline to 4 Weeks | -2.22 percentage of baseline value |
| Liquid Manuka Honey | Percent Change in Weight From Baseline to 4 Weeks | -0.62 percentage of baseline value |
| Lozenge Manuka Honey | Percent Change in Weight From Baseline to 4 Weeks | -2.64 percentage of baseline value |
p-value: 0.53t-test, 2 sided
p-value: 0.88t-test, 2 sided
Secondary
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.
Time frame: Baseline, 4 and 12 weeks from the start of treatment
Population: Randomized eligible patients who received protocol treatment with at least 1 EORTC score completed across all time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Supportive Care | 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 - Global health status | 66.67 units on a scale |
| Supportive Care | 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 - Pain | 16.67 units on a scale |
| Supportive Care | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 4 - Global health status | 66.67 units on a scale |
| Supportive Care | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 4 - Pain | 25.00 units on a scale |
| Supportive Care | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 12 - Global health status | 66.67 units on a scale |
| Supportive Care | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 12 - Pain | 0.00 units on a scale |
| Liquid Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 12 - Pain | 16.67 units on a scale |
| Liquid Manuka Honey | 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 - Global health status | 66.67 units on a scale |
| Liquid Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 4 - Pain | 16.67 units on a scale |
| Liquid Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 12 - Global health status | 58.33 units on a scale |
| Liquid Manuka Honey | 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 - Pain | 16.67 units on a scale |
| Liquid Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 4 - Global health status | 62.50 units on a scale |
| Lozenge Manuka Honey | 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 - Pain | 16.67 units on a scale |
| Lozenge Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 4 - Global health status | 66.67 units on a scale |
| Lozenge Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 12 - Pain | 16.67 units on a scale |
| Lozenge Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 4 - Pain | 33.33 units on a scale |
| Lozenge Manuka Honey | 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 - Global health status | 66.67 units on a scale |
| Lozenge Manuka Honey | Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks | Week 12 - Global health status | 66.67 units on a scale |
Comparison: 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.p-value: 0.086Mixed Models Analysis
Comparison: 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.p-value: 0.2Mixed Models Analysis
Comparison: 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.p-value: 0.44Mixed Models Analysis
Comparison: 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.p-value: 0.0066Mixed Models Analysis
Comparison: 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.p-value: 0.36Mixed Models Analysis
Comparison: 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.p-value: 0.94Mixed Models Analysis
Comparison: 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.p-value: 0.58Mixed Models Analysis
Comparison: 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.p-value: 0.28Mixed Models Analysis
Comparison: 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.p-value: <0.0001Mixed Models Analysis
Comparison: 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.p-value: 0.28Mixed Models Analysis
Secondary
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).
Time frame: Baseline, weekly during treatment, and 12 weeks from the start of treatment
Population: Eligible patients who started protocol treatment with at least 1 NRPS score completed across all time points
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Baseline | 0 units on a scale |
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 1 | 0 units on a scale |
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 2 | 0 units on a scale |
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 3 | 0 units on a scale |
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | 4 weeks | 1 units on a scale |
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 5 | 2.5 units on a scale |
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | End of RT | 3 units on a scale |
| Supportive Care | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 12 | 0 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 2 | 0 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | End of RT | 3 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 3 | 1 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | 4 weeks | 1 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 5 | 2 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Baseline | 0 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 1 | 0 units on a scale |
| Liquid Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 12 | 0 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 2 | 0 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 1 | 0 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Baseline | 0 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 3 | 1 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | End of RT | 4 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 5 | 3 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | 4 weeks | 2 units on a scale |
| Lozenge Manuka Honey | Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) | Week 12 | 0 units on a scale |
Comparison: 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.p-value: 0.87Mixed Models Analysis
Comparison: 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.p-value: 0.46Mixed Models Analysis
Comparison: 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.p-value: 0.0023Mixed Models Analysis
Comparison: 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.p-value: 0.0025Mixed Models Analysis
Comparison: 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.p-value: <0.0001Mixed Models Analysis