Head and Neck Cancer, Oral Mucositis
Conditions
Keywords
Head Cancer, Neck Cancer, Oral Mucositis, Oral Health, Radiation, Chemoradiation
Brief summary
The ARMOR Trial will test the efficacy of an oral care protocol to treat oral mucositis (OM) in patients receiving radiation (RT) or chemoradiation (chemoRT) for head and neck cancer. Participants will attend a screening/baseline visit, weekly intervention visits while they are undergoing RT or chemoRT, and a visit 3 months after completing RT or chemoRT. At intervention visits, samples will be collected (such as saliva, oral swabs) and participants will receive their assigned study intervention, either Oral Mucosal Deterging and Dental Prophylaxis protocol (OMDP), which includes a dental cleaning and treatment to the oral mucosa, or a Standard of Care Oral Hygiene, which includes teeth brushing and no treatment to the oral mucosa.
Detailed description
This is a prospective, single blind, two arm, randomized, controlled trial to test the efficacy of an oral care protocol to treat oral mucositis (OM) in patients receiving radiation (RT) or chemoradiation (chemoRT) for head and neck cancer. This trial will also measure salivary proinflammatory cytokines, and evaluate other clinical effects of the intervention during cancer therapy. In addition, oral mucosal swabs will be collected for the future characterization of changes in the microbiome associated with OM severity. Patients will be randomized in a 1:1 ratio to two different oral care protocols within 4 strata defined by type of RT (Proton beam therapy (Protons)) vs intensity-modulated radiation therapy (IMRT) and cancer treatment (RT versus chemoRT). Eligible subjects will be assigned to receive either the Oral Mucosal Deterging and Dental Prophylaxis protocol (OMDP) or a Standard of Care Oral Hygiene protocol (SOC-OH). Prior to randomization, all enrolled subjects will receive a baseline dental prophylaxis and fluoride varnish application prior to start of RT or chemoRT to ensure that all subjects enter the study with comparable oral health. Subjects assigned to OMDP will receive the OMDP Protocol (Oral Mucosal Deterging and Dental Prophylaxis) at weekly intervention visits. Subjects randomized to the SOC-OH will receive oral health instructions following the American Dental Association Guidelines and will have their teeth cleaned (brushed) during weekly intervention visits; no treatment to the oral mucosa will be provided to this group. At each bi-weekly study visit, study assessments will include the collection of saliva and oral mucosal swabs, an oral exam and OM assessment, and the completion of questionnaires. During the course of the study, subjects will attend one baseline visit, up to 9 intervention visits, and a follow-up visit approximately 3 months after completion of RT. Local supportive care, including normal saline rinses, topical anesthetics, mixed medication mouthwashes (e.g. Magic Mouthwash), feeding tubes, and pain management will be allowed according to each recruitment site's standard of care procedures.
Interventions
OTHERStandard of Care Oral Hygiene
Standard of care oral hygiene- weekly oral care visits with soft-bristled toothbrushing.
PROCEDUREOral mucosal deterging and dental prophylaxis
Subjects will receive a professional dental prophylaxis including periodontal surface debridement \[a light-touch, gentle form of instrumentation performed with an ultrasonic instrument to promote plaque removal, to facilitate biofilm disruption and endotoxin flushing, but yet with the preservation of the periodontal cementum\] and deterging of the oral mucosal surfaces.
Sponsors
NYU Langone Health
The Forsyth Institute
Medical University of South Carolina
National Institute of Dental and Craniofacial Research (NIDCR)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Blinded assessors will grade the oral mucositis.
Intervention model description
Prospective, single blind, two arm, randomized, controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Currently enrolling subjects receiving intensity-modulated radiation therapy (IMRT), with or without chemotherapy. Subject Inclusion Criteria To participate in this study, an individual must meet all the following criteria: 1. 18 years of age or older; 2. Able and willing to provide informed consent prior to initiation of study procedures; 3. Scheduled to undergo radiation or chemoradiation treatment for head/neck cancer; 4. Presents with at least one of nine areas of the oral or oropharyngeal mucosa (i.e., upper lip, lower lip, right cheek, left cheek, right ventral and lateral tongue, left ventral and lateral tongue, floor of the mouth, and soft palate) expected to receive at least 5000 cGy of RT. Patients with cancer located outside of the oral cavity will be included when at least 5000 cGy of RT will be administered to the oral cavity in addition to the RT targeted at the primary cancer site. 5. Presents with a minimum of 6 natural teeth. Subject
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: 1. Pregnant or lactating at the baseline/screening visit; 2. Participating in another oral health interventional research study at any point during their participation in this trial; 3. Receiving induction chemotherapy or concurrent radiation therapy with cetuximab; 4. Reports current use of antifungal or antibiotic at the time of enrollment; 5. Presents with immunocompromised status (defined as an absolute neutrophil count (ANC) of less than 1000); 6. Presents with any of the following conditions, which based on American Dental and American College of Cardiology guidelines, require antibiotic prophylaxis prior to dental treatment: 1. prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts; 2. prosthetic material used for cardiac valve repair, such as annuloplasty rings and chords; 3. a history of infective endocarditis; 4. a cardiac transplant with valve regurgitation due to a structurally abnormal valve; 5. the following congenital (present from birth) heart disease: unrepaired cyanotic congenital heart disease, including palliative shunts and conduits; or any repaired congenital heart defect with residual shunts or valvular regurgitation at the site of or adjacent to the site of a prosthetic patch or a prosthetic device; 7. Presents with cardiovascular implantable electronic devices (CIEDs) such as pacemakers, and implantable cardioverter-defibrillators; unless, a) in the opinion of the investigator, the OMDP protocol can be performed with hand scalers (and not with an ultrasonic device as per protocol) or upon consult with the treating cardiologist, it is determined that the ultrasonic device can be safely used; 8. Presents with severe periodontal disease for which treatment cannot be completed prior to the start of radiation/chemoradiation (at the discretion of the investigator); 9. Had surgery as part of cancer treatment and is not sufficiently healed to comply with study requirements prior to RT initiation; 10. In the opinion of the investigator, is unable or unlikely to comply fully with the study requirements or procedures for any reason (e.g. cognitive or physical impairment).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Oral Mucosal Severity (Grade 3 or 4) | Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0). | World Health Organization's Oral Toxicity Scale (WHO OTS): Oral mucositis severity as measured by the WHO OTS; severity is graded 0 through 4, with 4 being the worst. Grade 0 (none), Grade 1 (oral soreness, erythema), Grade 2 (ulceration, solid diet tolerated), Grade 3 (ulceration, liquid diet only), and Grade 4 (nothing by mouth). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inflammatory Markers Correlative Measures | Baseline and final intervention visit. | Salivary cytokines: Levels of Th1/Th2-type cytokines IL10, IL8, IL12p70, TNF alpha, IL4, IL1b, IL2, IL13, IL5, and IFN gamma will be assessed, in addition to levels of gp340. |
| Duration of OM Severity | Baseline and visits 1-9 interval during radiation therapy (area under the curve). | OM severity (Grade 3 or more) was measured by a blinded member of the study team using the WHO OTS (previously described) and the duration and time to onset of severe OM measured in days. |
| Salivary Hypofunction | Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0). | Saliva flow rate (mL/minute) from baseline to subsequent visits was assessed by a 5-minute stimulated saliva collection. The outcome analyzed was the change from baseline to subsequent visits in saliva. |
| Pain Scores | Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0). | The average pain of OM was measured subjectively (visual analog scale 0-10) and obtained by having subjects complete a questionnaire with questions based on an eleven-point numeric scale regarding oral pain (0 being no pain and 10 being maximum pain). |
| QOL and Function | Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0). | Quality of life and function was assessed using the validated EORTC-QLQ-C30 for head and neck cancers. This questionnaire assesses general quality of life as well as issues specific to head and neck cancer patients (e.g. difficulty swallowing, pain, dry mouth). The analysis was focused on EORTC-QLC30 Questions 31 through 48. High scores indicate better QOL. High scores for the Sypmton Scale are indicative of deterioration. |
Countries
United States
Participant flow
Recruitment details
H&N cancer patients were recruited to achieve 120 study subjects. The primary recruitment of 60 subjects was done through the UPenn Cancer Center. The sponsor/NIDCR prematurely ceased enrollment in proton therapy. Afterwards, the sponsor terminated the trial with 50% enrollment due to under-enrollment into specific diverse racial, ethnic, and sex/gender categories. As a result, the analysis are presented for all randomized subjects (30 per arm).
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Oral Hygiene Standard of Care Oral Hygiene group (SOC-OH): Subjects assigned to SOC-OH will attend weekly oral care visits where they will have their teeth brushed with a soft bristled toothbrush by the interventionist. No treatment to the oral mucosa will be provided to this group as part of the intervention. Subjects will receive oral care instructions and will be asked to follow SOC oral hygiene instructions at home.
Standard of Care Oral Hygiene: Standard of care oral hygiene- weekly oral care visits with soft-bristled toothbrushing. | 30 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) Oral Mucosal Deterging & Dental Prophylaxis (OMDP) protocol: Subjects assigned to OMDP will attend weekly intervention visits during which they will have their teeth cleaned and will receive the OMDP intervention as follows: subjects will receive a professional dental prophylaxis including periodontal surface debridement and deterging of the oral mucosal surfaces. Subjects will be asked to follow OMDP oral hygiene instructions at home.
Oral mucosal deterging and dental prophylaxis: Subjects will receive a professional dental prophylaxis including periodontal surface debridement \[a light-touch, gentle form of instrumentation performed with an ultrasonic instrument to promote plaque removal, to facilitate biofilm disruption and endotoxin flushing, but yet with the preservation of the periodontal cementum\] and deterging of the oral mucosal surfaces. | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 2 |
Baseline characteristics
| Characteristic | Standard of Care Oral Hygiene | Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 5 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 25 Participants | 44 Participants |
| Age, Continuous | 61.9 years STANDARD_DEVIATION 7.6 | 58.1 years STANDARD_DEVIATION 8.4 | 60.0 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 29 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 27 Participants | 56 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 26 Participants | 28 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 0 / 30 | 0 / 30 |
| serious Total, serious adverse events | 5 / 30 | 0 / 30 |
Outcome results
Primary
Oral Mucosal Severity (Grade 3 or 4)
World Health Organization's Oral Toxicity Scale (WHO OTS): Oral mucositis severity as measured by the WHO OTS; severity is graded 0 through 4, with 4 being the worst. Grade 0 (none), Grade 1 (oral soreness, erythema), Grade 2 (ulceration, solid diet tolerated), Grade 3 (ulceration, liquid diet only), and Grade 4 (nothing by mouth).
Time frame: Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0).
Population: 60 randomized subjects, 30 per arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care Oral Hygiene | Oral Mucosal Severity (Grade 3 or 4) | 9 Participants |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Oral Mucosal Severity (Grade 3 or 4) | 8 Participants |
p-value: 0.999Fisher Exact
Secondary
Duration of OM Severity
OM severity (Grade 3 or more) was measured by a blinded member of the study team using the WHO OTS (previously described) and the duration and time to onset of severe OM measured in days.
Time frame: Baseline and visits 1-9 interval during radiation therapy (area under the curve).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Standard of Care Oral Hygiene | Duration of OM Severity | 0.667 weeks |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Duration of OM Severity | 0.433 weeks |
p-value: 0.237395% CI: [-1.906, 1.4475]t-test, 2 sided
Secondary
Inflammatory Markers Correlative Measures
Salivary cytokines: Levels of Th1/Th2-type cytokines IL10, IL8, IL12p70, TNF alpha, IL4, IL1b, IL2, IL13, IL5, and IFN gamma will be assessed, in addition to levels of gp340.
Time frame: Baseline and final intervention visit.
Population: Inflammation markers were summarized by treatment group, visit and sample type using standard descriptive statistics. The impact of each treatment arm on the change from Baseline to Final Intervention Visit (FIV) for the above inflammation markers was examined and inferential tests such as two-sided t-test (for continuous inflammation scores change).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care Oral Hygiene | Inflammatory Markers Correlative Measures | IL1b | 30.4 pg/mL | Standard Deviation 26.5 |
| Standard of Care Oral Hygiene | Inflammatory Markers Correlative Measures | IL4 | 7.7 pg/mL | Standard Deviation 30 |
| Standard of Care Oral Hygiene | Inflammatory Markers Correlative Measures | IL2 | 37.9 pg/mL | Standard Deviation 39.2 |
| Standard of Care Oral Hygiene | Inflammatory Markers Correlative Measures | IL5 | 2.2 pg/mL | Standard Deviation 6.5 |
| Standard of Care Oral Hygiene | Inflammatory Markers Correlative Measures | IL1a | 53.9 pg/mL | Standard Deviation 84.4 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Inflammatory Markers Correlative Measures | IL5 | 0.5 pg/mL | Standard Deviation 8.5 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Inflammatory Markers Correlative Measures | IL1a | 50.6 pg/mL | Standard Deviation 152.9 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Inflammatory Markers Correlative Measures | IL1b | 13.3 pg/mL | Standard Deviation 44.9 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Inflammatory Markers Correlative Measures | IL2 | -64.3 pg/mL | Standard Deviation 249.8 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Inflammatory Markers Correlative Measures | IL4 | -12.7 pg/mL | Standard Deviation 34.9 |
Comparison: The change in the inflammatory marker from baseline to the final intervention visit was analyzed using 95% confidence intervals and presented by treatment group. The two-sided t-test was used to compare the change in inflammatory markers between the two groups.p-value: 0.6336t-test, 2 sided
Comparison: The change in the inflammatory marker from baseline to the final intervention visit was analyzed using 95% confidence intervals and presented by treatment group. The two-sided t- test was used to compare the change in inflammatory markers between the two groups.p-value: 0.351t-test, 2 sided
Comparison: The change in the inflammatory marker from baseline to the final intervention visit was analyzed using 95% confidence intervals and presented by treatment group. The two-sided t- test was used to compare the change in inflammatory markers between the two groups.p-value: 0.351t-test, 2 sided
Comparison: The change in the inflammatory marker from baseline to the final intervention visit was analyzed using 95% confidence intervals and presented by treatment group. The two-sided t- test was used to compare the change in inflammatory markers between the two groups.p-value: 0.8371t-test, 2 sided
Comparison: The change in the inflammatory marker from baseline to the final intervention visit was analyzed using 95% confidence intervals and presented by treatment group. The two-sided t- test was used to compare the change in inflammatory markers between the two groups.p-value: 0.2991t-test, 2 sided
Secondary
Pain Scores
The average pain of OM was measured subjectively (visual analog scale 0-10) and obtained by having subjects complete a questionnaire with questions based on an eleven-point numeric scale regarding oral pain (0 being no pain and 10 being maximum pain).
Time frame: Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care Oral Hygiene | Pain Scores | -7.39 0-10 score on a scale | Standard Deviation 3.51 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Pain Scores | 5.45 0-10 score on a scale | Standard Deviation 3.43 |
p-value: 0.6956Regression, Linear
Secondary
QOL and Function
Quality of life and function was assessed using the validated EORTC-QLQ-C30 for head and neck cancers. This questionnaire assesses general quality of life as well as issues specific to head and neck cancer patients (e.g. difficulty swallowing, pain, dry mouth). The analysis was focused on EORTC-QLC30 Questions 31 through 48. High scores indicate better QOL. High scores for the Sypmton Scale are indicative of deterioration.
Time frame: Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard of Care Oral Hygiene | QOL and Function | 0.323 0-100 score on a scale |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | QOL and Function | 0.135 0-100 score on a scale |
Comparison: The statistical analysis comprised an ANCOVA for a longitudinal response based on a generalized linear mixed effects repeated measures model (GLMER). The response variable is the mean change from Baseline to Visit 9 in EORTC QLQ-C30 Questions 31-48 (total).p-value: 0.115395% CI: [-0.4095, 0.0334]ANCOVA
Secondary
Salivary Hypofunction
Saliva flow rate (mL/minute) from baseline to subsequent visits was assessed by a 5-minute stimulated saliva collection. The outcome analyzed was the change from baseline to subsequent visits in saliva.
Time frame: Week 1 (Day 0/Randomization) - Week 8 (Day 56) during radiation therapy. Change from Baseline to Final Intervention Visit (FIV) is the endpoint being analyzed at this single timepoint (Day 56 relative to Day 0).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care Oral Hygiene | Salivary Hypofunction | -0.878 mL/minute | Standard Error 0.0822 |
| Oral Mucosal Deterging and Dental Prophylaxis (OMDP) | Salivary Hypofunction | -0.821 mL/minute | Standard Error 0.0822 |
p-value: 0.626395% CI: [-0.1755, 0.2893]ANCOVA