Clinical trial NCT03801876: Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer
Official title: Phase III Randomized Trial of Proton Beam Therapy (PBT) Versus Intensity Modulated Photon Radiotherapy (IMRT) for the Treatment of Esophageal Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: 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
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
Postneoadjuvant Therapy Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8
Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
Thoracic Esophagus Squamous Cell Carcinoma
Lead sponsor: NRG Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2019-01-14
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival (OS)
timeFrame: 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
measure: Incidence of specific grade 3+ cardiopulmonary adverse events (AEs) that are definitely, probably, or possibly related to protocol treatment
timeFrame: From baseline up to 8 years
Secondary outcomes:
measure: Pathologic response rate
timeFrame: At time of surgery
measure: Grade 4 lymphopenia during chemoradiation
timeFrame: From the start of chemoradiation to the end of chemoradiation treatment assessed up to 31 days
measure: Lymphocyte counts
timeFrame: From the last date of chemoradiation up to 8 weeks post chemoradiation
measure: Locoregional failure (LRF)
timeFrame: 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
measure: Distant metastatic-free survival (DMFS)
timeFrame: 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
measure: Progression-free survival
timeFrame: 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
measure: Quality-adjusted life years (QALY)
timeFrame: Assessed up to 8 years
measure: Cost-benefit economic analysis of treatment
timeFrame: Assessed up to 8 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital in Arizona
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Coral Gables
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Coral Gables
state: Florida
city: Deerfield Beach
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Orlando
country: United States
facility: Orlando Health Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Emory Proton Therapy Center
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Alton
country: United States
facility: Alton Memorial Hospital
state: Illinois
city: DeKalb
country: United States
facility: Northwestern Medicine Cancer Center Kishwaukee
state: Illinois
city: Geneva
country: United States
facility: Northwestern Medicine Cancer Center Delnor
state: Illinois
city: Shiloh
country: United States
facility: Memorial Hospital East
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center Warrenville
state: Illinois
city: Baltimore
country: United States
facility: Maryland Proton Treatment Center
state: Maryland
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Bel Air
country: United States
facility: UM Upper Chesapeake Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Bay City
country: United States
facility: McLaren Cancer Institute-Bay City
state: Michigan
city: Dearborn
country: United States
facility: Corewell Health Dearborn Hospital
state: Michigan
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Farmington Hills
country: United States
facility: Weisberg Cancer Treatment Center
state: Michigan
city: Flint
country: United States
facility: McLaren Cancer Institute-Flint
state: Michigan
city: Lansing
country: United States
facility: Karmanos Cancer Institute at McLaren Greater Lansing
state: Michigan
city: Lapeer
country: United States
facility: McLaren Cancer Institute-Lapeer Region
state: Michigan
city: Owosso
country: United States
facility: McLaren Cancer Institute-Owosso
state: Michigan
city: Royal Oak
country: United States
facility: Corewell Health William Beaumont University Hospital
state: Michigan
city: Troy
country: United States
facility: Corewell Health Beaumont Troy Hospital
state: Michigan
city: Albert Lea
country: United States
facility: Mayo Clinic Health System in Albert Lea
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Fridley
country: United States
facility: Unity Hospital
state: Minnesota
city: Mankato
country: United States
facility: Mayo Clinic Health Systems-Mankato
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology PA-Maplewood
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Northfield
country: United States
facility: Mayo Clinic Radiation Therapy-Northfield
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: New York
country: United States
facility: New York Proton Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
city: Avon
country: United States
facility: UH Seidman Cancer Center at UH Avon Health Center
state: Ohio
city: Beachwood
country: United States
facility: UHHS-Chagrin Highlands Medical Center
state: Ohio
city: Chardon
country: United States
facility: Geauga Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center-UC Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Elyria
country: United States
facility: Mercy Cancer Center-Elyria
state: Ohio
city: Mayfield Heights
country: United States
facility: UH Seidman Cancer Center at Landerbrook Health Center
state: Ohio
city: Mentor
country: United States
facility: UH Seidman Cancer Center at Lake Health Mentor Campus
state: Ohio
city: Middleburg Heights
country: United States
facility: UH Seidman Cancer Center at Southwest General Hospital
state: Ohio
city: Parma
country: United States
facility: University Hospitals Parma Medical Center
state: Ohio
city: Ravenna
country: United States
facility: University Hospitals Portage Medical Center
state: Ohio
city: Sandusky
country: United States
facility: UH Seidman Cancer Center at Firelands Regional Medical Center
state: Ohio
city: Wadsworth
country: United States
facility: University Hospitals Sharon Health Center
state: Ohio
city: West Chester
country: United States
facility: University of Cincinnati Cancer Center-West Chester
state: Ohio
city: Westlake
country: United States
facility: UH Seidman Cancer Center at Saint John Medical Center
state: Ohio
city: Westlake
country: United States
facility: UHHS-Westlake Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: Knoxville
country: United States
facility: Thompson Proton Center
state: Tennessee
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center
state: Tennessee
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center - West
state: Tennessee
city: Maryville
country: United States
facility: Thompson Oncology Group-Maryville
state: Tennessee
city: Oak Ridge
country: United States
facility: Thompson Oncology Group-Oak Ridge
state: Tennessee
city: Conroe
country: United States
facility: MD Anderson in The Woodlands
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson West Houston
state: Texas
city: League City
country: United States
facility: MD Anderson League City
state: Texas
city: Sugar Land
country: United States
facility: MD Anderson in Sugar Land
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Alexandria
country: United States
facility: Inova Alexandria Hospital
state: Virginia
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Fairfax
country: United States
facility: Inova Fair Oaks Hospital
state: Virginia
city: Leesburg
country: United States
facility: Inova Loudoun Hospital
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center - Montlake
state: Washington
city: Eau Claire
country: United States
facility: Mayo Clinic Health System-Eau Claire Clinic
state: Wisconsin
Study officials:
affiliation: NRG Oncology
name: Steven Lin
role: PRINCIPAL_INVESTIGATOR
References: