Clinical Trials /

Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer

NCT03801876

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Esophageal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NRG-GI006
  • SECONDARY ID: NCI-2018-03378
  • SECONDARY ID: NRG-GI006
  • SECONDARY ID: NRG-GI006
  • SECONDARY ID: U10CA180822
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03801876

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

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboGroup I (PBT, paclitaxel, carboplatin, esophagectomy)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratGroup I (PBT, paclitaxel, carboplatin, esophagectomy)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (PBT, paclitaxel, carboplatin, esophagectomy)ExperimentalPatients 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.
  • Carboplatin
  • Paclitaxel
Group II (IMRT, paclitaxel, carboplatin, esophagectomy)Active ComparatorPatients 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.
  • Carboplatin
  • Paclitaxel

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Pathologic response rate
Time Frame:At time of surgery
Safety Issue:
Description:A Chi-square test will be used to compare the pathologic response rates between the treatment arms.
Measure:Grade 4 lymphopenia during chemoradiation
Time Frame:From the start of chemoradiation to the end of chemoradiation treatment assessed up to 31 days
Safety Issue:
Description: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.
Measure:Lymphocyte counts
Time Frame:From the last date of chemoradiation up to 8 weeks post chemoradiation
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Quality-adjusted life years (QALY)
Time Frame:Assessed up to 8 years
Safety Issue:
Description:Will be evaluated and compared using EuroQol five-dimensional questionnaire (EQ-5D) only if the primary endpoint is met.
Measure:Cost-benefit economic analysis of treatment
Time Frame:Assessed up to 8 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NRG Oncology

Last Updated

October 5, 2020