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Oxaliplatin

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Folinic Acid

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Vitamin B9

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.

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.

Esophagectomy

Intensity-Modulated Radiation Therapy

Proton Beam Radiation Therapy

Quality-of-Life Assessment

Questionnaire Administration

Folinic acid, flurouracil and oxaliplatin

FOLFOX regimen

CAPOX regimen

Site Public Contact

Christopher L. Hallemeier

William Jin

Michael D. Chuong

Gregory R. Vlacich

Stephen A. Mihalcik

Jason K. Molitoris

Jack J. Hong

Florence K. Keane

Christian C. Hyde

John M. Robertson

Charles Shideman

Abraham J. Wu

Jehee I. Choi

Lauren E. Henke

Jordan Kharofa

Tyler Gunter

John P. Plastaras

Grant M. Clark

Saumil Gandhi

Shane Lloyd

Avani D. Rao

Steven Lin

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.

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.

Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer

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

Will be estimated by the Kaplan-Meier method. The distributions of OS between treatment arms will be compared using the log rank test.

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.

A Chi-square test will be used to compare the pathologic response rates between the treatment arms.

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.

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.

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.

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.

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.

Will be evaluated and compared using EuroQol five-dimensional questionnaire (EQ-5D) only if the primary endpoint is met.

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.

National Cancer Institute (NCI)

NRG Oncology

Spots Global Cancer Trial Database for capox regimen