Intensity-Modulated Proton Beam Therapy or Intensity-Modulated Photon Therapy in Treating Patients With Stage III-IVB Oropharyngeal Cancer

Study Overview
=================
Brief Summary
-----------------
This randomized phase II/III trial studies the side effects and how well intensity-modulated proton beam therapy works and compares it to intensity-modulated photon therapy in treating patients with stage III-IVB oropharyngeal cancer. Radiation therapy uses high-energy x-rays, protons, and other types of radiation to kill tumor cells and shrink tumors. It is not yet known whether intensity-modulated proton beam therapy is more effective than intensity-modulated photon therapy in treating oropharyngeal cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To compare the rates and severity of late grade 3-5 toxicity between intensity-modulated photon therapy (IMRT) and intensity-modulated proton therapy (IMPT) following the treatment of oropharyngeal tumors. (Phase II) II. To compare the rate of 3-year progression-free survival (PFS) between concurrent chemo-radiation strategies with IMRT and IMPT following the treatment of oropharyngeal tumors. (Phase III) SECONDARY OBJECTIVES: I. Disease-related outcomes (2-year progression-free survival, patterns of failure, 2-year overall survival, 2-year [yr] distant metastasis free survival, and second primary cancers). (Phase III) II. Patient Reported Outcome (PRO) measures of symptoms using MD Anderson Symptom Inventory (MDASI), MD Anderson Dysphagia Inventory (MDADI), Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), Xerostomia and Health Questionnaire (European Quality of Life 5-Dimension three level scale [EQ-5D-3L]), work status (Work Productivity and Activity Impairment: Specific Health Problem [WPAI: SHP]). (Phase III) III. Physician reported toxicity using Common Terminology Criteria for Adverse Events (CTCAE)-4.0. (Phase III) IV. Quality-Adjusted-Life-Years (QALY) comparison between IMPT and IMRT. (Phase III) V. Cost-benefit economic analysis of treatment. (Phase III) VI. To determine whether specific molecular profiles are associated with overall or progression-free survival. (Phase III) VII. To investigate associations between changes in serum biomarkers or human papillomavirus (HPV)-specific cellular immune responses measured at baseline and three months with overall or progression-free survival. (Phase III) VIII. To bank peripheral blood at time of enrollment, weeks 2, 4, and 6 during treatment and during follow up visits for 2 years to explore the ability of circulating markers to predict outcome. (Phase III) IX. To bank head and neck tissues to explore the ability of tissue-based markers to predict outcome. (Phase III) X. To bank peripheral blood and tissues for future interrogations. (Phase III) XI. Acute side effects of radiation therapy will be assessed. (Phase III) EXPLORATORY OBJECTIVE: I. To assess potential differences between patients on study and patients who were considered eligible for randomized, were randomized to a treatment arm, but were denied insurance coverage for the treatment arm she/he was randomized to; or may have dropped out of the study for other reasons after being randomized. These patients will compromise Group 3: consisting of patients randomized to Protons but not treated and Group 4: consisting of patients randomized to IMRT but not treated at the designated institution. Furthermore, these patients will only be followed for recurrence and survival.(Phase III) OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients undergo IMRT once daily (QD) five days a week for approximately 6.5 weeks. ARM II: Patients undergo IMPT QD five days a week for approximately 6.5 weeks. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 5 years.

Official Title
-----------------
Phase II/III Randomized Trial of Intensity-Modulated Proton Beam Therapy (IMPT) Versus Intensity-Modulated Photon Therapy (IMRT) for the Treatment of Oropharyngeal Cancer of the Head and Neck

Conditions
-----------------
Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7

Intervention / Treatment
-----------------
* Radiation: Intensity-Modulated Radiation Therapy
* Radiation: Intensity-Modulated Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Radiation: Photon Beam Radiation Therapy
* Radiation: Proton Beam Radiation Therapy
* Other: Quality-of-Life Assessment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically documented squamous cell carcinoma of the oropharynx (American Joint Committee on Cancer [AJCC] version [v]7 stage III-IV A,B) Tumor tissue (primary or cervical metastasis) available for human papilloma virus (HPV) and/or p16 (in situ hybridization [ISH], immunohistochemistry [IHC] or genotyping testing); if you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing Eastern Cooperative Oncology Group (ECOG) performance status = 0, 1, or 2 Negative pregnancy test for women of child bearing potential Concurrent chemotherapy Bilateral neck radiation Exclusion Criteria: Previous radiation treatment for head and neck mucosal primary cancers within the past 5 years (i.e. oropharynx, nasopharynx, hypopharynx, larynx, and oral cavity) Pregnant or breast-feeding females Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or hematologic disease but not limited to: Symptomatic congestive heart failure, unstable angina, or cardiac dysrhythmia not controlled by pacer device Myocardial infarction within 3 months of registration Distant metastases (stage IV C, any T, any N and M1) Previous surgical resection or neck dissection for oropharyngeal cancer, administered with therapeutic intent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (IMRT)<br>Patients undergo IMRT QD five days a week for approximately 6.5 weeks. | Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Photon Beam Radiation Therapy<br>* Undergo IMRT<br>* Other names: Radiation, Photon Beam;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm II (IMPT)<br>Patients undergo IMPT QD five days a week for approximately 6.5 weeks. | Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMPT<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Proton Beam Radiation Therapy<br>* Undergo IMPT<br>* Other names: Radiation, Proton Beam;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of late onset grade 3+ toxicity anytime (Phase II) | Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The methods described by Gooley will be used to estimate the cumulative incidence of late onset grade 3+ toxicity by 2 years for each treatment arm with death as a competing risk. The methods of Fine and Gray will be used to model the cumulative incidence of late onset grade 3+ toxicity by 2 years as a function of treatment arm and other potential prognostic factors (e.g., human papillomavirus (HPV)/p16 status, use of induction chemotherapy) considering death as a competing risk. Hazard ratios for the prognostic factors from this model with 95% confidence intervals will be estimated. | Up to 2 years | 
| Cumulative incidence of acute grade 3+ toxicity (Phase II) | Will be graded according to the NCI CTCAE version 4.0. The methods described by Gooley will be used to estimate the cumulative incidence of late onset grade 3+ toxicity by 2 years for each treatment arm with death as a competing risk. The methods of Fine and Gray will be used to model the cumulative incidence of late onset grade 3+ toxicity by 2 years as a function of treatment arm and other potential prognostic factors (e.g., HPV/p16 status, use of induction chemotherapy) considering death as a competing risk. Hazard ratios for the prognostic factors from this model with 95% confidence intervals will be estimated. | Up to 2 years | 
| Overall survival (OS) (Phase II) | Stratified by treatment arm and estimated using the product limit estimator of Kaplan and Meier. Cox proportional hazards regression will be used to model OS as a function of potential prognostic factors. Hazard ratios for the prognostic factors from this model will be estimated with 95% confidence intervals. | Up to 5 years | 
| Overall survival (Phase III) | Will be summarized at critical time points using the method of Kaplan-Meier. Kaplan-Meier plots will be used to visualize the time-to-event information by treatment arm, and the trial will be monitored based on results from log-rank tests used to compare treatment arms. Furthermore, Cox proportional hazards regression will be used to assess the time-to-event outcomes while adjusting for covariates of interest. | Up to 5 years | 
| Progression-free survival (Phase III) | Will be summarized at critical time points using the method of Kaplan-Meier. Kaplan-Meier plots will be used to visualize the time-to-event information by treatment arm, and the trial will be monitored based on results from log-rank tests used to compare treatment arms. Furthermore, Cox proportional hazards regression will be used to assess the time-to-event outcomes while adjusting for covariates of interest. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life (QoL) (Phase II and III) | QoL assessments will be summarized using the mean score and standard deviation for each time point of interest. Mean response trajectories will be plotted over the time horizon for each QoL instrument administered to patients in order to explore differences between treatment arms along with other patient characteristics of interest. Other analyses such as area under the curve and linear mixed models will be used to make statistical comparisons between treatment arms while adjusting for covariates of interest. | Up to 5 years |