Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer

Study Overview
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Brief Summary
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This trial studies how well proton beam radiation therapy compared with intensity modulated photon radiotherapy works in treating patients with stage I-IVA esophageal cancer. Proton beam radiation therapy uses a beam of protons (rather than x-rays) to send radiation inside the body to the tumor without damaging much of the healthy tissue around it. Intensity modulated photon radiotherapy uses high-energy x-rays to deliver radiation directly to the tumor without damaging much of the healthy tissue around it. It is not yet known whether proton beam therapy or intensity modulated photon radiotherapy will work better in treating patients with esophageal cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if overall survival (OS) is improved with proton beam radiation therapy (PBT) treatment as compared to intensity modulated photon radiation therapy (IMRT) as part of planned protocol treatment for patients with esophageal cancer. II. To determine if OS with PBT is non-inferior to IMRT as part of planned protocol treatment and that there will be less grade 3+ cardiopulmonary toxicity with PBT than with IMRT. SECONDARY OBJECTIVES: I. To compare the symptom burden and impact on functioning of patients between treatment modalities based on Patient Reported Outcome (PRO) measures of symptoms using MD Anderson Symptom Inventory (MDASI) and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue. II. To compare the Quality-Adjusted Life Years (QALY) using EuroQol five-dimensional questionnaire (EQ5D) as a health outcome between PBT and IMRT, if the protocol primary endpoint is met. III. To assess the pathologic response rate between PBT and IMRT. IV. To assess the cost-benefit economic analysis of treatment between radiation modalities. V. To compare the length of hospitalization after protocol surgery between PBT and IMRT. VI. To compare the incidence of grade 4 lymphopenia during chemoradiation between PBT and IMRT. VII. To compare lymphocyte nadir at first follow-up visit after completion of chemoradiation between PBT & IMRT. VIII. To estimate the locoregional failure, distant metastatic free survival, and progression-free survival of patients treated with PBT versus IMRT. IX. To compare incidence of both early (< 90 days from treatment start) and late (≥ 90 days from treatment start) cardiovascular and pulmonary events between PBT versus IMRT. X. To compare the Total Toxicity Burden (TTB) of IMRT versus PBT based on a composite index of 9 individual cardiopulmonary toxicities. EXPLORATORY OBJECTIVES: I. To collect biospecimens for future analyses, for example to assess cardiac and inflammatory biomarkers in association with treatment complications. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients undergo PBT over 28 fractions 5 days a week for 5.5 weeks. Patients also receive paclitaxel intravenously (IV) and carboplatin IV on days 1, 8, 15, 22, 29, and 36 while undergoing PBT. GROUP II: Patients undergo IMRT over 28 fractions 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV and carboplatin IV on days 1, 8, 15, 22, 29, and 36 while undergoing IMRT. In both groups, within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion. After completion of study treatment, patients are followed up every 3-6 months for 3 years and then annually thereafter.

Official Title
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Phase III Randomized Trial of Proton Beam Therapy (PBT) Versus Intensity Modulated Photon Radiotherapy (IMRT) for the Treatment of Esophageal Cancer

Conditions
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Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IVA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage I Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage I Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage II Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage II Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage III Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage III Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IVA Esophageal Adenocarcinoma AJCC v8, Clinical Stage I Esophageal Adenocarcinoma AJCC v8, Clinical Stage I Esophageal Squamous Cell Carcinoma AJCC v8, Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage II Esophageal Adenocarcinoma AJCC v8, Clinical Stage II Esophageal Squamous Cell Carcinoma AJCC v8, Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Squamous Cell Carcinoma AJCC v8, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IVA Esophageal Adenocarcinoma AJCC v8, Clinical Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8, Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage I Esophageal Adenocarcinoma AJCC v8, Pathologic Stage I Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IA Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IB Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IC Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage II Esophageal Adenocarcinoma AJCC v8, Pathologic Stage II Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIA Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIB Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage III Esophageal Adenocarcinoma AJCC v8, Pathologic Stage III Esophageal Squamous Cell Carcinoma AJCC v8, Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8, Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8, Thoracic Esophagus Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Carboplatin
* Procedure: Esophagectomy
* Radiation: Intensity-Modulated Radiation Therapy
* Drug: Paclitaxel
* Radiation: Proton Beam Radiation Therapy
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: FOLFOX regimen
* Drug: CAPOX regimen
* Drug: Docetaxel
* Drug: 5FU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRIOR TO STEP 1 REGISTRATION: Histologically proven diagnosis of adenocarcinoma or squamous cell carcinoma of the thoracic esophagus or gastroesophageal junction (Siewert I-II) Stage I-IVA, excluding T4b, according to the American Joint Committee on Cancer (AJCC) 8th edition based on the following diagnostic workup: History/physical examination Whole-body fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) with or without (+/-) contrast (preferred) or chest/abdominal (include pelvic if clinically indicated) CT with contrast For patients who DID NOT receive induction chemotherapy, scan must occur within 30 days prior to Step 1 registration For patients who DID receive induction chemotherapy, scan must occur: Within 30 days after final induction chemotherapy dose; OR Within 30 days prior to Step 1 registration Note: Patients who had prior endoscopic mucosal resection (EMR) with a diagnosis of AJCC stage I-IVA, excluding T4b, esophageal cancer are eligible Surgical consultation to determine whether or not the patient is a candidate for resection after completion of chemoradiation Induction chemotherapy for the current malignancy prior to concurrent chemoradiation allowed if last dose is no more than 90 days and no less than 10 days prior to Step 1 registration. Only FOLFOX will be allowed as the induction chemotherapy regimen. Zubrod performance status 0, 1, or 2 Absolute neutrophil count (ANC) (within 30 days prior to Step 1 registration) For patients who DID NOT receive induction chemotherapy: ANC >= 1,500 cells/mm^3 For patients who DID receive induction chemotherapy: ANC >= 1,000 cells/mm^3 Platelets (within 30 days prior to Step 1 registration) For patients who DID NOT receive induction chemotherapy: Platelets >= 100,000/uL For patients who DID receive induction chemotherapy: Platelets >= 75,000/uL Hemoglobin >= 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb >= 8.0 g/dl is acceptable) (within 30 days prior to Step 1 registration) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or Creatinine clearance > 40 mL/min estimated by Cockcroft-Gault formula (within 30 days prior to Step 1 registration) Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 30 days prior to Step 1 registration) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 30 days prior to Step 1 registration) Negative pregnancy test (serum or urine) within 14 days prior to Step 1 registration for women of child bearing potential The patient or a legally authorized representative must provide study-specific informed consent prior to study entry Exclusion Criteria: Cervical esophageal cancers arisen from 15-18 cm from the incisors Patients with T4b disease according to the AJCC 8th edition Definitive clinical or radiologic evidence of metastatic disease Any active malignancy within 2 years of study registration that may alter the course of esophageal cancer treatment Prior thoracic radiotherapy that would result in overlap of radiation therapy fields Severe, active co-morbidity defined as follows: Active uncontrolled infection requiring IV antibiotics at the time of Step 1 registration Uncontrolled symptomatic congestive heart failure, unstable angina, or cardiac arrhythmia not controlled by any device or medication at the time of Step 1 registration Myocardial infarction within 3 months prior to Step 1 registration Pregnant and/or nursing females Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive PRIOR TO STEP 2 REGISTRATION: Unable to obtain confirmation of payment coverage (insurance or other) for either possible radiation 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (PBT, Chemotherapy, Esophagectomy)<br>Patients undergo PBT over 28 fractions 5 days a week for 5.5 weeks to a total dose of 50.4 Gy. Patients also receive chemotherapy (Choice of 3 regimens: 1. Carboplatin/Paclitaxel, 2. FOLFOX/CAPOX or 3. Docetaxel/5-FU [with capecitabine as an acceptable substitute for 5-FU]) per institutional standards while undergoing PBT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Esophagectomy<br>* Undergo esophagectomy<br>* Other names: excision of the esophagus;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Radiation: Proton Beam Radiation Therapy<br>* Undergo PBT<br>* Other names: Proton Radiation Therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: FOLFOX regimen<br>* Folinic acid, flurouracil and oxaliplatin<br>* Other names: FOLFOX;Drug: CAPOX regimen<br>* Capecitabine combined with oxaliplatin<br>* Other names: OxCap;Drug: Docetaxel<br>* Chemotherapy<br>* Other names: Taxotere;Drug: 5FU<br>* Chemotherapy<br>* Other names: Adrucil;|
| Active Comparator: Group II (IMRT, Chemotherapy, Esophagectomy)<br>Patients undergo IMRT over 28 fractions 5 days a week for 5.5 weeks to a total dose of 50.4 Gy. Patients also receive chemotherapy (Choice of 3 regimens: 1. Carboplatin/Paclitaxel, 2. FOLFOX/CAPOX or 3. Docetaxel/5-FU [with capecitabine as an acceptable substitute for 5-FU]) per institutional standards while undergoing IMRT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Esophagectomy<br>* Undergo esophagectomy<br>* Other names: excision of the esophagus;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: FOLFOX regimen<br>* Folinic acid, flurouracil and oxaliplatin<br>* Other names: FOLFOX;Drug: CAPOX regimen<br>* Capecitabine combined with oxaliplatin<br>* Other names: OxCap;Drug: Docetaxel<br>* Chemotherapy<br>* Other names: Taxotere;Drug: 5FU<br>* Chemotherapy<br>* Other names: Adrucil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be estimated by the Kaplan-Meier method. The distributions of OS between treatment arms will be compared using the log rank test. | From the date of randomization to the date of death due to any cause or date of last follow-up for patients without an OS event reported. This analysis occurs after 173 deaths; estimated to occur 4 years after accrual completion | 
| Incidence of specific grade 3+ cardiopulmonary adverse events (AEs) that are definitely, probably, or possibly related to protocol treatment | Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Difference in proportion of defined cardiopulmonary AEs will be analyzed with a chi-squared test. | From baseline up to 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic response rate | A Chi-square test will be used to compare the pathologic response rates between the treatment arms. | At time of surgery | 
| Grade 4 lymphopenia during chemoradiation | Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. The proportion of patients experiencing grade 4 lymphopenia during chemoradiation will be compared between treatment arms using a chi-squared test. | From the start of chemoradiation to the end of chemoradiation treatment assessed up to 31 days | 
| Lymphocyte counts | Mean lymphocyte counts at first post chemoradiation follow-up will be compared between treatment arms using a t-test. If the data do not satisfy the normality assumption, a Wilcoxin test may be used instead. | From the last date of chemoradiation up to 8 weeks post chemoradiation | 
| Locoregional failure (LRF) | Will be defined as local/regional recurrence or progression. Will be estimated by the cumulative incidence method, with death as a competing risk. The distribution of LRF estimates between the two arms will be compared using Gray?s test. The Fine-Gray regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with LRF. | From the date of randomization to the date of first LRF or date of last follow-up for patients without an LRF event reported, assessed up to 8 years | 
| Distant metastatic-free survival (DMFS) | Will be defined as appearance of distant metastasis or death due to any cause. Will be estimated by the Kaplan-Meier method and estimates between the two treatment arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with DMFS. | From the date of randomization to the date of first DMFS failure or last follow-up for patients without a reported DMFS event, assessed up to 8 years | 
| Progression-free survival | Will be defined as appearance of local/regional/distant failure or death due to any cause. Will be estimated by the Kaplan-Meier method and estimates between the two treatment arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with PFS. | From the date of randomization to the date of first PFS failure or last follow-up for patients without a reported PFS event, assessed up to 8 years | 
| Quality-adjusted life years (QALY) | Will be evaluated and compared using EuroQol five-dimensional questionnaire (EQ-5D) only if the primary endpoint is met. | Assessed up to 8 years | 
| Cost-benefit economic analysis of treatment | Will be calculated by the visual analog scale (VAS) and index scores form the EQ-5D-5L only be done if primary endpoint is met. Will be compared between treatment arms using a t-test with a 2-sided significance level of 0.05. If there are significant differences, then a cost analysis will be conducted. | Assessed up to 8 years |