Proton Beam Therapy in the Treatment of Esophageal Cancer

Study Overview
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Brief Summary
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The investigators plan to include both operable and inoperable patients with esophagus cancer in this prospective trial. Since both proton and photon treatments are biologically equivalent, the investigators do not expect a difference in tumor control compared to intensity modulated radiation therapy (IMRT). The investigators have a prospective experience of physician-reported toxicity and patient outcome using IMRT for patients with inoperable esophagus cancer that will serve as a comparison group. For the resectable patients receiving trimodality therapy (chemoradiation followed by surgery), the investigators will carefully track toxicity and patient outcomes prospectively. The central hypothesis is that the biologic efficacy for tumor control should be similar between protons and photons, and therefore survival measures should be similar between the two groups, but that the main difference lies in the total severe toxicities experienced by the patients undergoing therapy.

Official Title
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A Phase II Study of Proton Beam Therapy in the Treatment of Esophageal Cancer

Conditions
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Esophagus Cancer, Esophageal Cancer, Cancer of the Esophagus

Intervention / Treatment
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* Radiation: Proton beam therapy
* Other: Patient-Reported Outcome Measures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented adenocarcinoma or squamous cell carcinoma of the cervical or thoracic esophagus or gastroesophageal junction or cardia of stomach. Staged by PET/CT and esophagogastroduodenoscopy (EGD) or endoscopic ultrasound (EUS) OR CT w/contrast and EGD to have stage II or III disease per AJCC 7th edition guidelines Prior endoscopic mucosal resection (EMR) with a diagnosis of stage II or III esophageal cancer (AJCC 7th edition) is eligible, irrespective of margin status. Induction chemotherapy prior to concurrent chemoradiation is allowed. Prior thoracic radiation is allowable if degree of overlap with the esophageal radiotherapy treatment is deemed to be safe by the treating radiation oncologist. At least 18 years of age. ECOG performance status < 2 Normal bone marrow and organ function as defined below: WBC > 2,500/mcL Platelets > 75,000/mcl Total bilirubin < 1.5 x institutional upper limit of normal (IULN) AST(SGOT)/ALT(SGPT) < 3.0 x IULN Creatinine < 1.5 x IULN OR Creatinine clearance > 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document. English speaker. Financial coverage for proton therapy. Exclusion Criteria: Planned treatment with radiation therapy alone without concurrent chemotherapy or chemotherapy alone. Previous or concomitant cancers within the past 3 years other than curatively treated carcinoma in situ of the cervix, basal cell carcinoma of the skin, curative treatment for transitional cell carcinoma of the bladder, and low risk prostate cancer. Except for prostate cancer (which can be observed if low risk), other cancers listed must have been treated in the past 3 years without evidence of recurrence at the time of registration. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia not controlled by pacer device, myocardial infarction within 3 months of registration, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 7 days of the start of treatment.

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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Resectable (proton beam therapy)<br>Proton beam therapy: total dose of 50 or 50.4 Gy Standard of care chemotherapy - the clinical trial doesn't dictate anything about the chemotherapy given, it is the treating physician's decision Surgery should ideally be performed no later than 8 to 10 weeks after completing chemoradiation Patient-reported outcome measures (PROs) performed at several time points | Radiation: Proton beam therapy<br>* The daily prescription dose will be 1.8 or 2 Gy RBE (Relative Biologic Equivalence) to be delivered to the periphery of the planning target volume (PTV). The Mevion S-250 Proton Radiation Beam Therapy System will be used.<br>* Other names: PBT;Other: Patient-Reported Outcome Measures<br>* -Prior to start of therapy, end of chemoradiation (day of end of treatment or up to 1 week after), 8 weeks, 4, 6, 9, and 12-months following end of chemoradiation<br>* Other names: PROs;|
| Experimental: Arm 2: Unresectable (proton beam therapy)<br>Proton beam therapy: total dose of 59.4 or 60 Gy Standard of care chemotherapy - the clinical trial doesn't dictate anything about the chemotherapy given, it is the treating physician's decision Patient-reported outcome measures (PROs) performed at several time points | Radiation: Proton beam therapy<br>* The daily prescription dose will be 1.8 or 2 Gy RBE (Relative Biologic Equivalence) to be delivered to the periphery of the planning target volume (PTV). The Mevion S-250 Proton Radiation Beam Therapy System will be used.<br>* Other names: PBT;Other: Patient-Reported Outcome Measures<br>* -Prior to start of therapy, end of chemoradiation (day of end of treatment or up to 1 week after), 8 weeks, 4, 6, 9, and 12-months following end of chemoradiation<br>* Other names: PROs;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to 6 months following end of chemoradiation in patient-reported outcomes of PBT for esophageal cancer as measured by the MDASI-Plus | The MDASI-plus is a reliable, validated tool for assessing cancer-related symptoms regardless of therapy or specific cancer diagnosis. Patients are asked to fill out a twenty-seven question inventory, ranking their symptoms on a 0 (no problems) to 10 (worst imaginable) scale before treatment, weekly during treatment, and in treatment follow-up. | 6 months following chemoradiation (estimated to be 9 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the EQ-5D | The EQ-5D is a standardized 2-part, patient-administered instrument used for direct and indirect assessment of health state utilities. The first part asks respondents to check the ONE box [next to the appropriate statement] that best describes your health TODAY for each of 5 health dimensions, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The second part of the EQ-5D is a visual analogue scale (VAS) valuing current health state. Both the 5-item index score and the VAS score are transformed into a utility score between 0 Worst health state and 1 Best health state. | 6 months following chemoradiation (estimated to be 9 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the SF-12 | The SF-12 will be measured at each of 7 interviews, and mental and physical component scores will be calculated in addition to calculating the measure's eight individual subscales (physical functioning, social functioning, role limitations due to physical problems, body pain, general health, role limitations due to emotional problems general health, vitality, and mental health). Higher scores indicate better quality of life. | 6 months following chemoradiation (estimated to be 9 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the MOS Social Support | The 19-item Medical Outcomes Study (MOS) Social Support Survey was designed for use with patients with chronic diseases and measures how often different kinds of support are available, if needed. Response choices range from none of the time (1) to all of the time (5). A mean social support score for all 19 items is computed with higher scores indicating a greater availability of social support. | 6 months following chemoradiation (estimated to be 9 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the 4-Item CES-D | The Center for Epidemiological Studies Depression Scale (CES-D) is a 20-item measure which evaluates depressive symptoms. This trial will make use of the validated 4-item screening version in order to reduce participant burden. | 6 months following chemoradiation (estimated to be 9 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the 4-Item CES-D | The Center for Epidemiological Studies Depression Scale (CES-D) is a 20-item measure which evaluates depressive symptoms. This trial will make use of the validated 4-item screening version in order to reduce participant burden. | 12 months following chemoradiation (estimated to be 15 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the MOS Social | The 19-item Medical Outcomes Study (MOS) Social Support Survey was designed for use with patients with chronic diseases and measures how often different kinds of support are available, if needed. Response choices range from none of the time (1) to all of the time (5). A mean social support score for all 19 items is computed with higher scores indicating a greater availability of social support. | 12 months following chemoradiation (estimated to be 15 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the SF-12 | The SF-12 will be measured at each of 7 interviews, and mental and physical component scores will be calculated in addition to calculating the measure's eight individual subscales (physical functioning, social functioning, role limitations due to physical problems, body pain, general health, role limitations due to emotional problems general health, vitality, and mental health). Higher scores indicate better quality of life. | 12 months following chemoradiation (estimated to be 15 months) | 
| Patient-reported outcomes of PBT for esophageal cancer as measured by the EQ-5D | The EQ-5D is a standardized 2-part, patient-administered instrument used for direct and indirect assessment of health state utilities. The first part asks respondents to check the ONE box [next to the appropriate statement] that best describes your health TODAY for each of 5 health dimensions, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The second part of the EQ-5D is a visual analogue scale (VAS) valuing current health state. Both the 5-item index score and the VAS score are transformed into a utility score between 0 Worst health state and 1 Best health state. | 12 months following chemoradiation (estimated to be 15 months) | 
| Change in baseline to 12 months following end of chemoradiation in patient-reported outcomes of PBT for esophageal cancer as measured by the MDASI-Plus | The MDASI-plus is a reliable, validated tool for assessing cancer-related symptoms regardless of therapy or specific cancer diagnosis. Patients are asked to fill out a twenty-seven question inventory, ranking their symptoms on a 0 (no problems) to 10 (worst imaginable) scale before treatment, weekly during treatment, and in treatment follow-up. | 12 months following chemoradiation (estimated to be 15 months) | 
| Physician-reported toxicity of PBT for esophageal cancer | -Grade 3 or higher specific cardiac, metabolism/nutrition, gastrointestinal, respiratory/thoracic/mediastinal, and skin/subcutaneous toxicity using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 | 6 months following chemoradiation (estimated to be 9 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) of proton beam therapy (PBT) for patients with resectable versus unresectable esophageal cancer | -PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. | 2 years following chemoradiation (estimated to be 2 years and 3 months) | 
| Overall survival (OS)of PBT for patients with resectable versus unresectable esophageal cancer |  | 2 years following chemoradiation (estimated to be 2 years and 3 months) | 
| Progression-free survival (PFS) of proton beam therapy (PBT) for patients with resectable | -PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. | 5 years following chemoradiation (estimated to be 5 years and 3 months) | 
| Overall survival (OS)of PBT for patients with resectable versus unresectable esophageal |  | 5 years following chemoradiation (estimated to be 5 years and 3 months) |