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

Cancer Categories

Gastrointestinal (GI)

Karmanos Trial ID

NRG-GI006

NCT ID

NCT03801876

Age Group

Adult

Scope

National

Phase

Phase III

Principal Investigator

Christian
Hyde, M.D., DABR
Oncology - Radiation View Profile

Objective:

Primary Objectives:

To determine if overall survival (OS) is improved with proton beam therapy (PBT) treatment as compared to intensity modulated radiation therapy (IMRT) as part of planned protocol treatment for patients with esophageal cancer.
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:

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 PROMIS-Fatigue;
To compare the Quality-Adjusted Life Years (QALY) using EQ5D as a health outcome (Kilbridge 2010) between PBT and IMRT, if the protocol primary endpoint is met;
To assess the pathologic response rate between PBT and IMRT;
To assess the cost-benefit economic analysis of treatment between radiation modalities;
To compare the length of hospitalization after protocol surgery between PBT and IMRT;
To compare the incidence of grade 4 lymphopenia during chemoradiation between PBT and IMRT;
To compare lymphocyte nadir at first follow-up visit after completion of chemoradiation between PBT & IMRT;
To estimate the locoregional failure, distant metastatic free survival, and progression-free survival of patients treated with PBT versus IMRT;
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;
To compare the Total Toxicity Burden (TTB) of IMRT versus PBT based on a composite index of 9 individual cardiopulmonary toxicities.

Exploratory Objectives:

To collect biospecimens for future analyses, for example to assess cardiac and inflammatory biomarkers in association with treatment complications.

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Eligibility

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:

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