Head and Neck Cancer, Mucositis Oral, Radiation Toxicity, Tongue Cancer
Conditions
Keywords
Recurrent squamous, basal cell carcinoma of the pharynx,larynx,lip, Oropharynx, paranasal sinus and nasal cavity, Stage I-IV lymphoepithelioma of the nasopharynx, Stage I-IV lymphoepithelioma of the oropharynx, Recurrent esthesioneuroblastoma of paranasal sinus, nasal cavity, Recurrent inverted papilloma of the paranasal sinus, nasal cavity, Recurrent midline granuloma of the paranasal sinus, nasal cavity, Untreated, current, metastatic squamous neck cancer, Recurrent verrucous carcinoma of the larynx, Recurrent lymphoepithelioma of the oropharynx, Stage I verrucous carcinoma of the larynx, Recurrent verrucous carcinoma of the oral cavity, Stage I verrucous carcinoma of the oral cavity, Stage II verrucous carcinoma of the larynx, Stage II verrucous carcinoma of the oral cavity, Stage III verrucous carcinoma of the larynx, Stage III verrucous carcinoma of the oral cavity, Stage IV verrucous carcinoma of the larynx, Stage IV verrucous carcinoma of the oral cavity, Recurrent adenoid cystic carcinoma of the oral cavity, Stage I adenoid cystic carcinoma of the oral cavity, Stage II adenoid cystic carcinoma of the oral cavity, Stage III adenoid cystic carcinoma of the oral cavity, Stage IV adenoid cystic carcinoma of the oral cavity, Recurrent mucoepidermoid carcinoma of the oral cavity, Stage I mucoepidermoid carcinoma of the oral cavity, Stage II mucoepidermoid carcinoma of the oral cavity, Stage III mucoepidermoid carcinoma of the oral cavity, Stage IV mucoepidermoid carcinoma of the oral cavity, Recurrent squamous cell carcinoma of the lip and oral cavity, Stage I squamous cell carcinoma of the lip and oral cavity, Stage II squamous cell carcinoma of the lip and oral cavity, Stage III squamous cell carcinoma of the lip and oral cavity, Stage IV squamous cell carcinoma of the lip and oral cavity
Brief summary
GM-CSF may protect normal cells from the side effects, such as mucositis, of radiation therapy and may help damaged tissue heal faster after radiation therapy. This randomized clinical trial is studying how well GM-CSF works in preventing and treating mucositis in patients who are undergoing radiation therapy for head and neck cancer.
Detailed description
OBJECTIVES: Primary * Compare the incidence of radiotherapy (RT)-induced oral mucositis of any grade, using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria (RTOG ARMSC)-Mucous Membrane, in patients treated with 1 of 2 mouthwashes (sargramostim \[GM-CSF\] or salt and soda). (prevention portion of the study) * Compare the effectiveness of the 2 mouthwashes in treating oral mucositis as defined by the incidence of RTOG ARMSC-Mucous Membrane grade 3 and 4 mucositis in patients in 1 of 3 groups (salt and soda, continuing GM-CSF, or new GM-CSF). (treatment portion of the study) Secondary * Compare the effectiveness of the 2 mouthwashes in preventing RT-induced oral mucositis by the following direct indices: * Cumulative RT dose prior to onset of oral mucositis (prevention portion only) * Severity of RT-induced oral mucositis at onset and during treatment (using Oral Mucositis Assessment Scale (OMAS)) * Severity of oral mucositis-related pain at onset and during treatment (using OMAS) * Incidence of oral mucositis-related infection at onset and during treatment (using OMAS) * Severity of oral mucositis-related problems with ingestion of food and fluids at onset and during treatment (using OMAS) * Time to healing of RT-induced oral mucositis. * Evaluate patients using the following indirect indices of oral mucositis morbidity during the prevention and treatment portions of the study. * Tolerance to RT regimen * Functional status * Quality of life. OUTLINE: This is a multicenter, randomized, controlled, double-blinded study. Patients are stratified according to radiotherapy dose schedule (standard vs hyperfractionation vs intensity modulation) and concurrent chemotherapy (yes vs no). * Prevention (no mucositis): Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral sargramostim (GM-CSF) mouthwash, holding it in their mouths and swallowing it in intervals over 1 hour once daily. * Arm II: Patients receive oral salt and soda mouthwash, holding it and swallowing it in intervals over 1 hour once daily. Treatment in both arms continues during 6-7 weeks of radiotherapy and/or the onset of mucositis. Patients also perform PRO-SELF: Mouth Aware (PSMA) twice daily. * Treatment (onset of mucositis): Patients who are currently using GM-CSF mouthwash continue use as in prevention. Patients who are currently using salt and soda mouthwash are randomized to 1 of 2 treatment arms. * Arm III: Patients receive GM-CSF mouthwash as in arm I. * Arm IV: Patients receive salt and soda mouthwash as in arm II. In both arms, treatment continues until the mucositis heals. Patients perform PSMA four times daily during and for 3 months after radiotherapy. Quality of life is assessed at baseline and periodically after radiotherapy. After completion of study treatment, patients are followed every once a month for 3 months.
Interventions
BIOLOGICALsargramostim
OTHERoral salt and soda mouthwash
Patients receive oral salt and soda mouthwash, holding it and swallowing it in intervals over 1 hour once daily.
Sponsors
Marilyn Dodd
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histopathologically confirmed diagnosis of head and neck cancer * Scheduled to undergo continuous course of conventional or hyperfractionated radiotherapy or intensity-modulated radiotherapy (IMRT) with or without concurrent chemotherapy * Planning to receive a total radiation dose ≥ 5,500 centigray (cGy), administered in a single daily fraction of 180-220 cGy (5 days a week) or twice daily fractions of 110-150 cGy * Normal baseline oral examinations (no pre-existing lesion) * Karnofsky performance status 60-100% * Mentally capable of participating in research protocol * Expected survival \> 4.5 months * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Creatinine ≤ 2.0 mg/dL * Bilirubin ≤ 2.0 mg/dL * Aspartate aminotransferase (AST) \< 5 times upper limit of normal * HIV negative
Exclusion criteria
* No unresolved adverse event from previous therapy * No prior radiotherapy to the head and neck * No prior or concurrent brachytherapy * No prior participation in this study * No T1 or T2 glottic tumors * No other serious concurrent medical illness * No history of insulin-dependent diabetes mellitus * No prior hypersensitivity reaction to yeast material * No recent history of oral ulceration, herpes simplex, oral candidiasis, severe gingivitis, active or chronic mucositis, or xerostomia * No current New York Heart Association class II-IV congestive heart failure * Not pregnant or nursing * No chemotherapy, radiotherapy, or other investigational drugs within the past 4 weeks * No major surgery within the past 2 weeks * No systemic sargramostim (GM-CSF) within the past 7 days * No systemic filgrastim (G-CSF) within the past 24 hours * No systemic long-acting pegfilgrastim within the past 14 days * No antibiotics, antifungals, or antivirals for oral conditions at baseline * No other concurrent chemotherapy agent * No concurrent enrollment on other head and neck studies * No other concurrent investigational drugs * No concurrent administration of any of the following: * Magic or miracle mouthwash containing a palliative mixture of topical anesthetics/analgesics, coating agents, and other medications without an approved indication for topical oral use except liquid antacid formulations (e.g., Maalox® or Mylanta® or their generic equivalents) * Other concurrent over-the-counter or prescription mouthwashes beyond the systematic oral care protocol provided by the study or any other drugs or agents to aid in oral hygiene (e.g., chlorhexidine, gluconate, pilocarpine, amifostine, sucralfate tablets or slurry, or benzydamine) * Use of corticosteroids for chronic conditions OR within the past 7 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Number of Participants With Grade 1 or 2 Oral Mucositis (GM-CSF and SS Groups Only) | From baseline to onset of mucositis, approximately 16 days | The number of participants with recorded grade 1 (mild; Irritation, may experience slight pain, not requiring analgesic) or grade 2 (moderate; Patchy mucositis that may produce inflammatory serosanguinitis discharge; may experience moderate pain requiring analgesia) oral mucositis using the Radiation Therapy Oncology Group (RTOG) Acute Radiation Morbidity Scoring Criteria Oral Mucosa Assessment Scale at baseline and during radiotherapy will be recorded. The RTOG grading is reliant on a clinician's ability to judge the anatomical changes associated with oral mucositis (size and characteristics of ulceration), with symptoms ranging from Grade 0 (no symptoms) to Grade 4 (Ulceration, hemorrhage, or necrosis). A comparison of incidence in the GM-CSF Group (GG) and Arm II: Salt & Soda Group (SS) will be reported. |
| Comparison of the Mean Number of Days for Mucositis to Heal Across by Group | From onset of mucositis to healing of mucositis, approximately 80 days | The mean number of days for mucositis to heal will be used to evaluate the effectiveness of the two mouthwashes in treating oral mucositis as defined by the incidence of Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of the Combined Mean Score on the Overall Quality of Life Questionnaires by Group | Up to 3 months | Quality of life at baseline, during radiotherapy, and once a month for 3 months after radiotherapy. The items on the quality of life questionnaire developed for the study range in scores from 0-10 with higher scores indicating a better quality of life. Scores at all time points were combined to compute one mean score for overall quality of life during the study. |
| Comparison of Combined Mean Score on the Karnofsky Performance Status Scale (KPS) by Group | Up to 3 months | Functional status of participants was measured by administering the KPS which contains items asking about performing daily activities. The scores are grouped in 10s ranging from 100 (Normal, no complaints) to 0 (Dead), with higher scores indicating better functional status. The KPS was administered at baseline, during radiotherapy, and once a month for 3 months after radiation therapy. Scores at all time points were combined to compute one mean to determine overall performance status during the course of the study. |
| Comparison of Combined Mean Score on the Pain Questionnaire by Group | Up to 3 months | Severity and quality of pain was measured using a pain questionnaire developed for this study with total scores ranging from 0 (no pain) to 10 (most intense pain) with higher scores indicating a greater level of pain. The questionnaire was administered at baseline, during radiotherapy, and once a month for 3 months after radiotherapy. Scores at all time points were combined to compute one mean to determine overall pain intensity score during the course of the study |
Countries
United States
Participant flow
Recruitment details
Adult (\> 18 years of age) with confirmed histopathological diagnosis of head and neck carcinoma were recruited at the University of California, San Francisco Radiation Oncology Clinic, the Helen Diller Comprehensive Cancer Center, Saint Francis Medical Center in San Francisco, and Temple University Radiation Oncology Clinic in Philadelphia from May 2005 to Dec 2009.
Pre-assignment details
Of 532 potential subjects that were screened, 374 were excluded as they did not meet the inclusion criteria, 45 refused to participate and 22 were no-shows (declined radiation therapy), thereby reducing our original target sample population to 91.
Participants by arm
| Arm | Count |
|---|---|
| Arm I: GM-CSF Group (GG) Arm I: Patients receive oral sargramostim (GM-CSF) mouthwash, holding it in their mouths and swallowing it in intervals over 1 hour once daily. Treatment continues during 6-7 weeks of radiotherapy and until the mucositis heals. | 31 |
| Arm II: Salt & Soda Group (SS) Arm II: Patients receive oral salt and soda mouthwash, holding it and swallowing it in intervals over 1 hour once daily. Treatment continues during 6-7 weeks of radiotherapy and until the mucositis heals. | 29 |
| Arm III: Salt & Soda Switched to GM-CSF (SG) Arm II patients are split, with Arm III being switched to GM-CSF when they develop mucositis. | 31 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Blood clot after chemotherapy | 0 | 0 | 1 |
| Overall Study | Change Treatment Regimen (ineligible) | 1 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Hypersensitive Reaction (to Salt & Soda) | 0 | 1 | 0 |
| Overall Study | Ischemic stroke after chemotherapy | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Low radiation dose in oral cavity | 0 | 1 | 0 |
| Overall Study | No Show | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Possible Tracheostomy leakage | 0 | 1 | 0 |
| Overall Study | Refuse Radiation Treatment | 1 | 0 | 0 |
| Overall Study | Went back to his home country | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 | 8 |
Baseline characteristics
| Characteristic | Arm I: GM-CSF Group (GG) | Arm II: Salt & Soda Group (SS) | Arm III: Salt & Soda Switched to GM-CSF (SG) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 3 Participants | 5 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 26 Participants | 26 Participants | 77 Participants |
| Age, Continuous | 53.55 years STANDARD_DEVIATION 13.73 | 54.69 years STANDARD_DEVIATION 12.22 | 56.26 years STANDARD_DEVIATION 11.29 | 54.48 years STANDARD_DEVIATION 12.43 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 28 Participants | 27 Participants | 85 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 6 Participants | 5 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 18 Participants | 16 Participants | 22 Participants | 56 Participants |
| Sex: Female, Male Female | 11 Participants | 2 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Male | 20 Participants | 27 Participants | 20 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 29 | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 18 / 29 | 26 / 28 | 27 / 28 |
| serious Total, serious adverse events | 1 / 29 | 2 / 28 | 2 / 28 |
Outcome results
Primary
Comparison of Number of Participants With Grade 1 or 2 Oral Mucositis (GM-CSF and SS Groups Only)
The number of participants with recorded grade 1 (mild; Irritation, may experience slight pain, not requiring analgesic) or grade 2 (moderate; Patchy mucositis that may produce inflammatory serosanguinitis discharge; may experience moderate pain requiring analgesia) oral mucositis using the Radiation Therapy Oncology Group (RTOG) Acute Radiation Morbidity Scoring Criteria Oral Mucosa Assessment Scale at baseline and during radiotherapy will be recorded. The RTOG grading is reliant on a clinician's ability to judge the anatomical changes associated with oral mucositis (size and characteristics of ulceration), with symptoms ranging from Grade 0 (no symptoms) to Grade 4 (Ulceration, hemorrhage, or necrosis). A comparison of incidence in the GM-CSF Group (GG) and Arm II: Salt & Soda Group (SS) will be reported.
Time frame: From baseline to onset of mucositis, approximately 16 days
Population: Intent to treat population consisted of randomized subjects who completed baseline questionnaire and had at least one dose of mouthwash
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: GM-CSF Group (GG) | Comparison of Number of Participants With Grade 1 or 2 Oral Mucositis (GM-CSF and SS Groups Only) | 28 participants |
| Arm II: Salt & Soda Group (SS) | Comparison of Number of Participants With Grade 1 or 2 Oral Mucositis (GM-CSF and SS Groups Only) | 46 participants |
Comparison: Fisher's exact two tailed testp-value: 0.09Fisher Exact
Primary
Comparison of the Mean Number of Days for Mucositis to Heal Across by Group
The mean number of days for mucositis to heal will be used to evaluate the effectiveness of the two mouthwashes in treating oral mucositis as defined by the incidence of Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring.
Time frame: From onset of mucositis to healing of mucositis, approximately 80 days
Population: Intent to treat population consisted of randomized subjects who completed baseline questionnaire and had at least one dose of mouthwash
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I: GM-CSF Group (GG) | Comparison of the Mean Number of Days for Mucositis to Heal Across by Group | 81.5 days | Standard Deviation 63.43 |
| Arm II: Salt & Soda Group (SS) | Comparison of the Mean Number of Days for Mucositis to Heal Across by Group | 79.4 days | Standard Deviation 31.24 |
| Arm III: Salt & Soda Switched to GM-CSF (SG) | Comparison of the Mean Number of Days for Mucositis to Heal Across by Group | 77.4 days | Standard Deviation 37.4 |
Comparison: Kaplan-Meier estimate of the survival curves used information from subjects who develop mucositis to the healing of the mucositis in three groups, Group GG, SS, and SG. In order to compare the three curves that were created, the Mantel-Haenszel log-rank statistic was usedp-value: 0.92Mantel Haenszel
Secondary
Comparison of Combined Mean Score on the Karnofsky Performance Status Scale (KPS) by Group
Functional status of participants was measured by administering the KPS which contains items asking about performing daily activities. The scores are grouped in 10s ranging from 100 (Normal, no complaints) to 0 (Dead), with higher scores indicating better functional status. The KPS was administered at baseline, during radiotherapy, and once a month for 3 months after radiation therapy. Scores at all time points were combined to compute one mean to determine overall performance status during the course of the study.
Time frame: Up to 3 months
Population: Of the intent to treat population, subjects who did not fill out the baseline Karnofsky functional scales were not included in our analysis. They withdrew from the study after signing the consent forms for personal reasons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I: GM-CSF Group (GG) | Comparison of Combined Mean Score on the Karnofsky Performance Status Scale (KPS) by Group | 84.52 score on a scale | Standard Deviation 12.61 |
| Arm II: Salt & Soda Group (SS) | Comparison of Combined Mean Score on the Karnofsky Performance Status Scale (KPS) by Group | 82.93 score on a scale | Standard Deviation 10.92 |
| Arm III: Salt & Soda Switched to GM-CSF (SG) | Comparison of Combined Mean Score on the Karnofsky Performance Status Scale (KPS) by Group | 83.49 score on a scale | Standard Deviation 12.49 |
p-value: 0.78Mixed Models Analysis
Secondary
Comparison of Combined Mean Score on the Pain Questionnaire by Group
Severity and quality of pain was measured using a pain questionnaire developed for this study with total scores ranging from 0 (no pain) to 10 (most intense pain) with higher scores indicating a greater level of pain. The questionnaire was administered at baseline, during radiotherapy, and once a month for 3 months after radiotherapy. Scores at all time points were combined to compute one mean to determine overall pain intensity score during the course of the study
Time frame: Up to 3 months
Population: Of the intent to treat population, subjects who did not fill out the baseline pain questionnaires were not included in our analysis. They withdrew from the study after signing the consent forms for personal reasons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I: GM-CSF Group (GG) | Comparison of Combined Mean Score on the Pain Questionnaire by Group | 2.15 score on a scale | Standard Deviation 2.4 |
| Arm II: Salt & Soda Group (SS) | Comparison of Combined Mean Score on the Pain Questionnaire by Group | 1.72 score on a scale | Standard Deviation 2.26 |
| Arm III: Salt & Soda Switched to GM-CSF (SG) | Comparison of Combined Mean Score on the Pain Questionnaire by Group | 2.15 score on a scale | Standard Deviation 2.65 |
p-value: 0.22Mixed Models Analysis
Secondary
Comparison of the Combined Mean Score on the Overall Quality of Life Questionnaires by Group
Quality of life at baseline, during radiotherapy, and once a month for 3 months after radiotherapy. The items on the quality of life questionnaire developed for the study range in scores from 0-10 with higher scores indicating a better quality of life. Scores at all time points were combined to compute one mean score for overall quality of life during the study.
Time frame: Up to 3 months
Population: Of the intent to treat population, subjects who did not fill out the baseline quality of life questionnaires were not included in our analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I: GM-CSF Group (GG) | Comparison of the Combined Mean Score on the Overall Quality of Life Questionnaires by Group | 6.91 score on a scale | Standard Deviation 1.59 |
| Arm II: Salt & Soda Group (SS) | Comparison of the Combined Mean Score on the Overall Quality of Life Questionnaires by Group | 6.80 score on a scale | Standard Deviation 1.46 |
| Arm III: Salt & Soda Switched to GM-CSF (SG) | Comparison of the Combined Mean Score on the Overall Quality of Life Questionnaires by Group | 6.77 score on a scale | Standard Deviation 1.53 |
Comparison: Multilevel regression was used.p-value: 0.28Mixed Models Analysis