Acupuncture-Like Transcutaneous Electrical Nerve Stimulation (ALTENS) or Pilocarpine in Treating Early Dry Mouth in Patients Undergoing Radiation Therapy for Head and Neck Cancer

Study Overview
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Brief Summary
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RATIONALE: Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) and pilocarpine may help to relieve chronic xerostomia (dry mouth). It is not yet known which remedy is more effective in treating chronic dry mouth caused by radiation therapy in patients with head and neck cancer. PURPOSE: This randomized phase II/III trial is studying ALTENS to see how well it works compared with pilocarpine in treating chronic dry mouth caused by radiation therapy in patients with head and neck cancer.

Detailed Description
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OBJECTIVES: Primary Determine the feasibility of successfully delivering acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) using the Codetron™ unit in a cooperative group setting in head and neck cancer patients with early radiotherapy-induced xerostomia. (phase II) Compare the efficacy of ALTENS treatment vs pilocarpine hydrochloride in these patients in reducing overall xerostomia burden, as measured by the University of Michigan 15-item Xerostomia-Related Quality of Life Scale (XeQOLS) at 9 months after randomization. (phase III) Secondary Evaluate the effect of ALTENS treatment on overall xerostomia burden at 6 months after study entry in these patients. (phase II) Compare the efficacy of these treatments in these patients in reducing overall xerostomia burden at 4, 6, and 15 months after randomization. (phase III) Compare the efficacy of these treatments in these patients in reducing symptom burden, as measured by the four domains of the XeQOLS (i.e., physical functioning, social functioning, personal/psychological functioning, and pain/discomfort) at 4, 6, 9, and 15 months after randomization. (phase III) Compare the efficacy of these treatments in these patients in increasing stimulated (i.e., citric acid primed) whole salivary production (WSP), as measured by sialometry, at 4, 6, 9, and 15 months after randomization. (phase III) Compare the efficacy of these treatments in these patients in increasing unstimulated (i.e., basal primed) WSP, as measured by sialometry at 4, 6, 9, and 15 months after randomization. (phase III) Compare adverse events associated with these treatments in these patients. (phase III) OUTLINE: This is a phase II followed by a phase III multicenter study. Phase II:Patients undergo placement of surface electrodes at the following acupuncture points: large intestine, spleen, stomach, and conception vessel. Patients then undergo acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) to each of these points using the Codetron™ unit for 20 minutes twice weekly for 12 weeks. No further treatment is given after 12 weeks. Phase III:Patients are stratified according to prior use of pilocarpine (no vs yes) and length of time from completion of chemotherapy and/or radiotherapy (3-6 months vs 6-12 months vs > 12 months). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral pilocarpine three times daily for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Arm II: Patients undergo ALTENS treatment using the Codetron™ unit twice weekly for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo quality of life (QOL) assessment at baseline and at 6 months after registration in phase II. In phase III patients complete assessments for basal and stimulated whole salivary production, xerostomia burden, and QOL at baseline and at 4, 6, 9, and 15 months after study entry. After completion of study therapy, patients are followed at 3 months. PROJECTED ACCRUAL: A total of 45 patients will be accrued to the phase II portion and 144 patients to the phase III portion of this study.

Official Title
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A Phase II/III Study Comparing Acupuncture-like Transcutaneous Electrical Nerve Stimulation (ALTENS) Versus Pilocarpine in Treating Early Radiation-Induced Xerostomia

Conditions
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Head and Neck Cancer, Xerostomia

Intervention / Treatment
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* Drug: Pilocarpine
* Procedure: ALTENS


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of head and neck cancer No clinical evidence of disease recurrence by ear, nose, and throat exam with a nasopharyngeal scope, if indicated, 8 weeks prior to registration Completed radiotherapy (i.e., standard or intensity-modulated radiotherapy) with or without chemotherapy ≥ 3 months and up to 2 years prior to study entry Grade 1-2 radiotherapy-induced xerostomia according to the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.3.0 and the dry mouth/salivary gland xerostomia scale Must have evidence of residual salivary function with unstimulated (basal) whole salivary production ≥ 0.1 ml/min after having refrained from eating or drinking oral fluid for 2 hours No patients with normal saliva production (i.e., no salivary gland changes or no xerostomia) No history of serious adverse events after prior treatment with and discontinuation of pilocarpine No chronic lymphocytic leukemia PATIENT CHARACTERISTICS: See Disease Characteristics Zubrod performance status of 0-2 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other invasive malignancy except non-melanomatous skin cancer or cancer from which the patient has been disease-free for at least 3 years (e.g., carcinoma in situ of the breast, oral cavity, or cervix) No concurrent contraindications to pilocarpine (e.g., uncontrolled asthma, miosis, or hypersensitivity) No severe, active co-morbidity, including any of the following: Unstable cardiac disease or requirement for a pacemaker in-situ Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Transmural myocardial infarction within the past 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to registration Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects No Sjögren syndrome PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 2 weeks since prior pilocarpine or cevimeline and no concurrent use for ophthalmic or non-ophthalmic indications No concurrent regular medications that induce xerostomia (e.g., tricyclic antidepressants, antihistamines with anticholinergic effects, or narcotics) No concurrent oral stimulating agents or salivary gland medical stimulants

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: One arm Phase II followed by a two-arm Phase III
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pilocarpine: Phase III<br> | Drug: Pilocarpine<br>* 5mg by mouth 3 times a day for 12 weeks<br>* Other names: pilocarpine hydrochloride;|
| Experimental: ALTENS: Phase III<br> | Procedure: ALTENS<br>* Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit<br>* Other names: acupuncture-like transcutaneous electrical nerve stimulation;|
| Experimental: ALTENS: Phase II<br> | Procedure: ALTENS<br>* Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit<br>* Other names: acupuncture-like transcutaneous electrical nerve stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Treatment Compliance (Number of Compliant Patients) | Patients completing at least 19 out of 24 ALTENS therapy sessions were categorized as compliant. Fleming's two-stage was used, assuming a successful target compliance rate of 80%, statistical power of 0.87, and a type I error rate of 0.13. If fewer than 9 of the first 13 patients were compliant, then treatment delivery will be deemed not feasible. If there were between 9-12 compliant patients, the second stage analysis would be required to determine feasibility of treatment delivery. If all 13 patients are compliant, treatment delivery will immediately be deemed feasible. The second stage analysis required at least 31 compliant out of 39 overall patients for the treatment delivery to be deemed feasible. | Randomization to 12 weeks | 
| Phase III: Change From Baseline in Overall Xerostomia Burden at 9 Months | Xerostomia burden is measured by the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS). The XeQOLS is a validated patient-reported 15-item assessment scale with 4 domains: physical functioning,pain/discomfort, personal/psychologic functioning, and social functioning.The score is the average of all responses of all domains and can range from 0 to 4, with higher scores indicating increased xerostomia burden. Change in xerostomia burden is calculated by subtracting the baseline score from the 9-month score such that a negative change indicates an improvement of the xerostomia burden. | Baseline (randomization) and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Pecentage of Patients With Beneficial Treatment Response | This secondary objective was to evaluate the effect of ALTENS treatment on overall radiation-induced xerostomia burden by looking at treatment response. Treatment response was determined by a reduction of at least 20% from baseline to 6 months in the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS). The XeQOLS is a validated patient-reported 15-item assessment scale with 4 domains: physical functioning,pain/discomfort, personal/psychologic functioning, and social functioning.The score is the average of all responses of all domains and can range from 0 to 4. Higher scores indicate increased xerostomia burden. This scale has high reproducibility and sensitivity. For the first and second stage analyses, 4 and 10 patients, respectively, must respond to treatment in order to proceed to the phase III component. | Pre-treatment and 6 months from registration | 
| Change From Baseline in Overall Xerostomia Burden at 4, 6, and 15 Months (Phase III) | Xerostomia burden is measured by the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS). The XeQOLS is a validated patient-reported 15-item assessment scale with 4 domains: physical functioning,pain/discomfort, personal/psychologic functioning, and social functioning.The score is the average of all responses of all domains and can range from 0 to 4, with higher scores indicating increased xerostomia burden. Change in xerostomia burden is calculated by subtracting the baseline score from the 9-month score such that a negative change indicates an improvement of the xerostomia burden. | Baseline, 4, 6, and 15 months from randomization | 
| Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) | Symptom burden is measured by the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS). The XeQOLS is a validated patient-reported 15-item assessment scale with 4 domains: physical functioning,pain/discomfort, personal/psychologic functioning, and social functioning. The domain score is the average of all responses on a given domain and can range from 0 to 4, with higher scores indicating increased symptom burden. Change in symptom burden is calculated by subtracting the baseline score from the 9-month score such that a negative change indicates an improvement of the symptom burden. | Baseline, 4, 6, 9 and 15 months from randomization | 
| Change From Baseline in Stimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) | Stimulated (citric acid primed) whole salivary production (WSP) was measured by expectoration weight, with one gram of saliva produced considered as one ml of saliva. WSP is expressed in ml/min calculated by dividing the measured weight or volume of WSP by five. Procedure: Patients refrain from eating, drinking, and smoking at least two hours prior to each measurement. Stimulation is elicited by asking patients to rinse 5 ml of 2% citric acid solution in the mouth for 15 seconds and then completely expectorating the citric acid. For each measurement, patients are asked to expectorate continuously into a pre-weighed dry plastic container over a 5-minute period without swallowing. The collected saliva with the plastic container will be weighed (total weight) immediately after each collection. The total weight minus the weight of the container is the weight or volume of whole saliva collected. | Baseline, 4, 6, 9 and 15 months from randomization | 
| Change From Baseline in Unstimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) | Basal whole salivary production (WSP) was measured by expectoration weight, with one gram of saliva produced considered as one ml of saliva. WSP is expressed in ml/min calculated by dividing the measured weight or volume of WSP by five. Procedure: Patients refrain from eating, drinking, and smoking at least two hours prior to each measurement. For each measurement, patients are asked to expectorate continuously into a pre-weighed dry plastic container over a 5-minute period without swallowing. The collected saliva with the plastic container will be weighed (total weight) immediately after each collection. The total weight minus the weight of the container is the weight or volume of whole saliva collected. | Pre-treatment to 4, 6, 9 and 15 months from randomization | 
| Quality of Life (QOL) as Measured by the University of Washington Head and Neck Questionnaire (UWHNSS) Phase III | The UWHNSS includes ten categories-pain, disfigurement, activity, recreation/entertainment, employment, eating, saliva, taste, speech, mucus/phlegm. Patient scores on the UWHNSS range from 0 to 100 with higher scores indicating declining quality of life. Change in total score was calculated by subtracting baseline from follow-up , thus a positive change score indicates a worsening while a negative change score indicates an improvement. | Baseline and 9 months from randomization. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, paranasal sinus and nasal cavity cancer, oropharyngeal cancer, salivary gland cancer, metastatic squamous neck cancer with occult primary, xerostomia, tongue cancer