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 chemotherapy consisting of carboplatin/paclitaxel, or fluorouracil/leucovorin calcium/oxaliplatin (FOLFOX)/capecitabine-oxaliplatin (CAPOX), or docetaxel/fluorouracil (5-FU, with capecitabine an acceptable substitute for 5-FU), as determined by the patient and their treating physician while undergoing PBT. GROUP II: Patients undergo IMRT over 28 fractions 5 days a week for 5.5 weeks. Patients also receive chemotherapy consisting of carboplatin/paclitaxel, or FOLFOX/CAPOX, or docetaxel/5-FU (with capecitabine an acceptable substitute for 5-FU) as determined by the patient and their treating physician while undergoing IMRT. In both groups, within 4-8 weeks after completion of chemotherapy and radiation therapy, patients should undergo an esophagectomy if it's determined that the patient can tolerate an esophagectomy and whether the tumor is surgically resectable. Additionally, patients undergo blood sample collection, and positron emission tomography (PET)/computed tomography (CT) or CT throughout the study. After completion of study treatment, patients are followed up every 3-6 months for 3 years and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
300
Undergo blood sample collection
Oral
Given IV
Undergo CT or PET/CT
IV
Undergo esophagectomy
IV
Undergo IMRT
Oral
IV
Given IV
Undergo PET/CT
Undergo PBT
Ancillary studies
Ancillary studies
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
ACTIVE_NOT_RECRUITINGMayo Clinic in Arizona
Scottsdale, Arizona, United States
ACTIVE_NOT_RECRUITINGUniversity of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, United States
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.
Time frame: 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.
Time frame: From baseline up to 8 years
Change in patient reported outcomes (PROs) of symptom and function
Will be assessed using the MD Anderson Symptom Inventory (MDASI) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue tools. The primary analysis cohorts for PRO endpoints will be intent-to-treat, with sensitivity analyses done limited to patients that started protocol treatment. General linear models with maximum likelihood estimation will be used to assess MDASI symptom severity and functioning trends across time as the primary PRO endpoints. Mean change (follow-up time point - baseline score) in fatigue 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. Additionally, a general linear model with maximum likelihood estimation will be used to assess fatigue trends across time.
Time frame: Baseline up to 12 months after end of chemoradiation
Pathologic response rate
A Chi-square test will be used to compare the pathologic response rates between the treatment arms.
Time frame: At time of surgery
Length of hospitalization
Will be defined as number of days in the hospital post protocol-defined surgery. Mean hospitalization days 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.
Time frame: From baseline up to 8 years
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.
Time frame: From baseline up to 8 years
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.
Time frame: From baseline up to 8 years
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Assessed up to 8 years
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UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Doral
Doral, Florida, United States
RECRUITINGUniversity of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
RECRUITINGMiami Cancer Institute
Miami, Florida, United States
RECRUITINGUM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, United States
RECRUITINGOrlando Health Cancer Institute
Orlando, Florida, United States
ACTIVE_NOT_RECRUITING...and 85 more locations