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Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03801876
Recruitment Status : Recruiting
First Posted : January 14, 2019
Last Update Posted : October 8, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Tracking Information
First Submitted Date  ICMJE January 3, 2019
First Posted Date  ICMJE January 14, 2019
Last Update Posted Date October 8, 2020
Actual Study Start Date  ICMJE March 15, 2019
Estimated Primary Completion Date February 1, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2019)
  • Overall survival (OS) [ 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 ]
    Will be estimated by the Kaplan-Meier method. The distributions of OS between treatment arms will be compared using the log rank test.
  • Incidence of specific grade 3+ cardiopulmonary adverse events (AEs) that are definitely, probably, or possibly related to protocol treatment [ Time Frame: From baseline up to 8 years ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2019)
  • Pathologic response rate [ Time Frame: At time of surgery ]
    A Chi-square test will be used to compare the pathologic response rates between the treatment arms.
  • Grade 4 lymphopenia during chemoradiation [ Time Frame: From the start of chemoradiation to the end of chemoradiation treatment assessed up to 31 days ]
    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.
  • Lymphocyte counts [ Time Frame: From the last date of chemoradiation up to 8 weeks post chemoradiation ]
    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.
  • Locoregional failure (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 ]
    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.
  • Distant metastatic-free survival (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 ]
    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.
  • Progression-free survival [ 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 ]
    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.
  • Quality-adjusted life years (QALY) [ Time Frame: Assessed up to 8 years ]
    Will be evaluated and compared using EuroQol five-dimensional questionnaire (EQ-5D) only if the primary endpoint is met.
  • Cost-benefit economic analysis of treatment [ Time Frame: Assessed up to 8 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer
Official Title  ICMJE Phase III Randomized Trial of Proton Beam Therapy (PBT) Versus Intensity Modulated Photon Radiotherapy (IMRT) for the Treatment of Esophageal Cancer
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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Procedure: Esophagectomy
    Undergo esophagectomy
    Other Name: excision of the esophagus
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Radiation: Proton Beam Radiation Therapy
    Undergo PBT
    Other Names:
    • PBRT
    • Proton Radiation Therapy
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
Study Arms  ICMJE
  • Experimental: Group I (PBT, paclitaxel, carboplatin, esophagectomy)
    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 paclitaxel (50 mg/m^2) IV and carboplatin (AUC=2 [maximum 300 mg]) IV on days 1, 8, 15, 22, 29, and 36 while undergoing PBT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion.
    Interventions:
    • Drug: Carboplatin
    • Procedure: Esophagectomy
    • Drug: Paclitaxel
    • Radiation: Proton Beam Radiation Therapy
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
  • Active Comparator: Group II (IMRT, paclitaxel, carboplatin, esophagectomy)
    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 paclitaxel (50 mg/m^2) IV and carboplatin (AUC=2 [maximum 300 mg]) IV on days 1, 8, 15, 22, 29, and 36 while undergoing IMRT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion.
    Interventions:
    • Drug: Carboplatin
    • Procedure: Esophagectomy
    • Radiation: Intensity-Modulated Radiation Therapy
    • Drug: Paclitaxel
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 9, 2019)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2032
Estimated Primary Completion Date February 1, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • 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)
  • Creatinine clearance > 50 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
    • Symptomatic congestive heart failure, unstable angina, or cardiac arrhythmia not controlled by pacer device 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03801876
Other Study ID Numbers  ICMJE NRG-GI006
NCI-2018-03378 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GI006 ( Other Identifier: NRG Oncology )
NRG-GI006 ( Other Identifier: CTEP )
U10CA180822 ( U.S. NIH Grant/Contract )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party NRG Oncology
Study Sponsor  ICMJE NRG Oncology
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Steven Lin NRG Oncology
PRS Account NRG Oncology
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP