<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03801876</url>
  </required_header>
  <id_info>
    <org_study_id>NRG-GI006</org_study_id>
    <secondary_id>NCI-2018-03378</secondary_id>
    <secondary_id>NRG-GI006</secondary_id>
    <secondary_id>NRG-GI006</secondary_id>
    <secondary_id>U10CA180822</secondary_id>
    <secondary_id>U10CA180868</secondary_id>
    <nct_id>NCT03801876</nct_id>
  </id_info>
  <brief_title>Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer</brief_title>
  <official_title>Phase III Randomized Trial of Proton Beam Therapy (PBT) Versus Intensity Modulated Photon Radiotherapy (IMRT) for the Treatment of Esophageal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NRG Oncology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>NRG Oncology</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This trial studies how well proton beam radiation therapy compared with intensity modulated&#xD;
      photon radiotherapy works in treating patients with stage I-IVA esophageal cancer. Proton&#xD;
      beam radiation therapy uses a beam of protons (rather than x-rays) to send radiation inside&#xD;
      the body to the tumor without damaging much of the healthy tissue around it. Intensity&#xD;
      modulated photon radiotherapy uses high-energy x-rays to deliver radiation directly to the&#xD;
      tumor without damaging much of the healthy tissue around it. It is not yet known whether&#xD;
      proton beam therapy or intensity modulated photon radiotherapy will work better in treating&#xD;
      patients with esophageal cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine if overall survival (OS) is improved with proton beam radiation therapy (PBT)&#xD;
      treatment as compared to intensity modulated photon radiation therapy (IMRT) as part of&#xD;
      planned protocol treatment for patients with esophageal cancer.&#xD;
&#xD;
      II. To determine if OS with PBT is non-inferior to IMRT as part of planned protocol treatment&#xD;
      and that there will be less grade 3+ cardiopulmonary toxicity with PBT than with IMRT.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To compare the symptom burden and impact on functioning of patients between treatment&#xD;
      modalities based on Patient Reported Outcome (PRO) measures of symptoms using MD Anderson&#xD;
      Symptom Inventory (MDASI) and Patient-Reported Outcomes Measurement Information System&#xD;
      (PROMIS)-Fatigue.&#xD;
&#xD;
      II. To compare the Quality-Adjusted Life Years (QALY) using EuroQol five-dimensional&#xD;
      questionnaire (EQ5D) as a health outcome between PBT and IMRT, if the protocol primary&#xD;
      endpoint is met.&#xD;
&#xD;
      III. To assess the pathologic response rate between PBT and IMRT. IV. To assess the&#xD;
      cost-benefit economic analysis of treatment between radiation modalities.&#xD;
&#xD;
      V. To compare the length of hospitalization after protocol surgery between PBT and IMRT.&#xD;
&#xD;
      VI. To compare the incidence of grade 4 lymphopenia during chemoradiation between PBT and&#xD;
      IMRT.&#xD;
&#xD;
      VII. To compare lymphocyte nadir at first follow-up visit after completion of chemoradiation&#xD;
      between PBT &amp; IMRT.&#xD;
&#xD;
      VIII. To estimate the locoregional failure, distant metastatic free survival, and&#xD;
      progression-free survival of patients treated with PBT versus IMRT.&#xD;
&#xD;
      IX. To compare incidence of both early (&lt; 90 days from treatment start) and late (≥ 90 days&#xD;
      from treatment start) cardiovascular and pulmonary events between PBT versus IMRT.&#xD;
&#xD;
      X. To compare the Total Toxicity Burden (TTB) of IMRT versus PBT based on a composite index&#xD;
      of 9 individual cardiopulmonary toxicities.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To collect biospecimens for future analyses, for example to assess cardiac and&#xD;
      inflammatory biomarkers in association with treatment complications.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 groups.&#xD;
&#xD;
      GROUP I: Patients undergo PBT over 28 fractions 5 days a week for 5.5 weeks. Patients also&#xD;
      receive paclitaxel intravenously (IV) and carboplatin IV on days 1, 8, 15, 22, 29, and 36&#xD;
      while undergoing PBT.&#xD;
&#xD;
      GROUP II: Patients undergo IMRT over 28 fractions 5 days a week for 5.5 weeks. Patients also&#xD;
      receive paclitaxel IV and carboplatin IV on days 1, 8, 15, 22, 29, and 36 while undergoing&#xD;
      IMRT.&#xD;
&#xD;
      In both groups, within 4-8 weeks after completion of chemotherapy and radiation therapy,&#xD;
      patients may undergo an esophagectomy per physician discretion.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3-6 months for 3 years&#xD;
      and then annually thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 15, 2019</start_date>
  <completion_date type="Anticipated">December 21, 2031</completion_date>
  <primary_completion_date type="Anticipated">December 21, 2026</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival (OS)</measure>
    <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</time_frame>
    <description>Will be estimated by the Kaplan-Meier method. The distributions of OS between treatment arms will be compared using the log rank test.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of specific grade 3+ cardiopulmonary adverse events (AEs) that are definitely, probably, or possibly related to protocol treatment</measure>
    <time_frame>From baseline up to 8 years</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pathologic response rate</measure>
    <time_frame>At time of surgery</time_frame>
    <description>A Chi-square test will be used to compare the pathologic response rates between the treatment arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Grade 4 lymphopenia during chemoradiation</measure>
    <time_frame>From the start of chemoradiation to the end of chemoradiation treatment assessed up to 31 days</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lymphocyte counts</measure>
    <time_frame>From the last date of chemoradiation up to 8 weeks post chemoradiation</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Locoregional failure (LRF)</measure>
    <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</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distant metastatic-free survival (DMFS)</measure>
    <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</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <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</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality-adjusted life years (QALY)</measure>
    <time_frame>Assessed up to 8 years</time_frame>
    <description>Will be evaluated and compared using EuroQol five-dimensional questionnaire (EQ-5D) only if the primary endpoint is met.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost-benefit economic analysis of treatment</measure>
    <time_frame>Assessed up to 8 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Clinical Stage I Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage I Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage II Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage II Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage III Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage III Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IVA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage I Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage I Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IA Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IB Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IC Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage II Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage II Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIA Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIB Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage III Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage III Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IVA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage I Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage I Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage II Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage II Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage III Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage III Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IIIA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IIIB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IVA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8</condition>
  <condition>Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Thoracic Esophagus Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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 chemotherapy (Choice of 3 regimens: 1. Carboplatin/Paclitaxel, 2. FOLFOX/CAPOX or 3. Docetaxel/5-FU [with capecitabine as an acceptable substitute for 5-FU]) per institutional standards while undergoing PBT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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 chemotherapy (Choice of 3 regimens: 1. Carboplatin/Paclitaxel, 2. FOLFOX/CAPOX or 3. Docetaxel/5-FU [with capecitabine as an acceptable substitute for 5-FU]) per institutional standards while undergoing IMRT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>Blastocarb</other_name>
    <other_name>Carboplat</other_name>
    <other_name>Carboplatin Hexal</other_name>
    <other_name>Carboplatino</other_name>
    <other_name>Carbosin</other_name>
    <other_name>Carbosol</other_name>
    <other_name>Carbotec</other_name>
    <other_name>CBDCA</other_name>
    <other_name>Displata</other_name>
    <other_name>Ercar</other_name>
    <other_name>JM-8</other_name>
    <other_name>Nealorin</other_name>
    <other_name>Novoplatinum</other_name>
    <other_name>Paraplatin</other_name>
    <other_name>Paraplatin AQ</other_name>
    <other_name>Paraplatine</other_name>
    <other_name>Platinwas</other_name>
    <other_name>Ribocarbo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Esophagectomy</intervention_name>
    <description>Undergo esophagectomy</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>excision of the esophagus</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Intensity-Modulated Radiation Therapy</intervention_name>
    <description>Undergo IMRT</description>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>IMRT</other_name>
    <other_name>Intensity Modulated RT</other_name>
    <other_name>Intensity-Modulated Radiotherapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paclitaxel</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>Anzatax</other_name>
    <other_name>Asotax</other_name>
    <other_name>Bristaxol</other_name>
    <other_name>Praxel</other_name>
    <other_name>Taxol</other_name>
    <other_name>Taxol Konzentrat</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Proton Beam Radiation Therapy</intervention_name>
    <description>Undergo PBT</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>PBRT</other_name>
    <other_name>Proton Radiation Therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Questionnaire Administration</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>FOLFOX regimen</intervention_name>
    <description>Folinic acid, flurouracil and oxaliplatin</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>FOLFOX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CAPOX regimen</intervention_name>
    <description>Capecitabine combined with oxaliplatin</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>CAPE-OX</other_name>
    <other_name>OxCap</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Docetaxel</intervention_name>
    <description>Chemotherapy</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>Taxotere</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5FU</intervention_name>
    <description>Chemotherapy</description>
    <arm_group_label>Group I (PBT, Chemotherapy, Esophagectomy)</arm_group_label>
    <arm_group_label>Group II (IMRT, Chemotherapy, Esophagectomy)</arm_group_label>
    <other_name>5-FU</other_name>
    <other_name>flurouracil</other_name>
    <other_name>Tolak</other_name>
    <other_name>Fluoroplex</other_name>
    <other_name>Efudex</other_name>
    <other_name>Carac</other_name>
    <other_name>Adrucil</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  PRIOR TO STEP 1 REGISTRATION:&#xD;
&#xD;
          -  Histologically proven diagnosis of adenocarcinoma or squamous cell carcinoma of the&#xD;
             thoracic esophagus or gastroesophageal junction (Siewert I-II)&#xD;
&#xD;
          -  Stage I-IVA, excluding T4b, according to the American Joint Committee on Cancer (AJCC)&#xD;
             8th edition based on the following diagnostic workup:&#xD;
&#xD;
               -  History/physical examination&#xD;
&#xD;
               -  Whole-body fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed&#xD;
                  tomography (CT) with or without (+/-) contrast (preferred) or chest/abdominal&#xD;
                  (include pelvic if clinically indicated) CT with contrast&#xD;
&#xD;
                    -  For patients who DID NOT receive induction chemotherapy, scan must occur&#xD;
                       within 30 days prior to Step 1 registration&#xD;
&#xD;
                    -  For patients who DID receive induction chemotherapy, scan must occur:&#xD;
&#xD;
                         -  Within 30 days after final induction chemotherapy dose; OR&#xD;
&#xD;
                         -  Within 30 days prior to Step 1 registration&#xD;
&#xD;
                    -  Note: Patients who had prior endoscopic mucosal resection (EMR) with a&#xD;
                       diagnosis of AJCC stage I-IVA, excluding T4b, esophageal cancer are eligible&#xD;
&#xD;
          -  Surgical consultation to determine whether or not the patient is a candidate for&#xD;
             resection after completion of chemoradiation&#xD;
&#xD;
          -  Induction chemotherapy for the current malignancy prior to concurrent chemoradiation&#xD;
             allowed if last dose is no more than 90 days and no less than 10 days prior to Step 1&#xD;
             registration. Only FOLFOX will be allowed as the induction chemotherapy regimen.&#xD;
&#xD;
          -  Zubrod performance status 0, 1, or 2&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) (within 30 days prior to Step 1 registration)&#xD;
&#xD;
               -  For patients who DID NOT receive induction chemotherapy: ANC &gt;= 1,500 cells/mm^3&#xD;
&#xD;
               -  For patients who DID receive induction chemotherapy: ANC &gt;= 1,000 cells/mm^3&#xD;
&#xD;
          -  Platelets (within 30 days prior to Step 1 registration)&#xD;
&#xD;
               -  For patients who DID NOT receive induction chemotherapy: Platelets &gt;= 100,000/uL&#xD;
&#xD;
               -  For patients who DID receive induction chemotherapy: Platelets &gt;= 75,000/uL&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.0 g/dl (Note: The use of transfusion or other intervention to achieve&#xD;
             Hgb &gt;= 8.0 g/dl is acceptable) (within 30 days prior to Step 1 registration)&#xD;
&#xD;
          -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or Creatinine clearance &gt; 40&#xD;
             mL/min estimated by Cockcroft-Gault formula (within 30 days prior to Step 1&#xD;
             registration)&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN) (within 30 days prior to Step 1&#xD;
             registration)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =&lt; 3 x ULN (within&#xD;
             30 days prior to Step 1 registration)&#xD;
&#xD;
          -  Negative pregnancy test (serum or urine) within 14 days prior to Step 1 registration&#xD;
             for women of child bearing potential&#xD;
&#xD;
          -  The patient or a legally authorized representative must provide study-specific&#xD;
             informed consent prior to study entry&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cervical esophageal cancers arisen from 15-18 cm from the incisors&#xD;
&#xD;
          -  Patients with T4b disease according to the AJCC 8th edition&#xD;
&#xD;
          -  Definitive clinical or radiologic evidence of metastatic disease&#xD;
&#xD;
          -  Any active malignancy within 2 years of study registration that may alter the course&#xD;
             of esophageal cancer treatment&#xD;
&#xD;
          -  Prior thoracic radiotherapy that would result in overlap of radiation therapy fields&#xD;
&#xD;
          -  Severe, active co-morbidity defined as follows:&#xD;
&#xD;
               -  Active uncontrolled infection requiring IV antibiotics at the time of Step 1&#xD;
                  registration&#xD;
&#xD;
               -  Uncontrolled symptomatic congestive heart failure, unstable angina, or cardiac&#xD;
                  arrhythmia not controlled by any device or medication at the time of Step 1&#xD;
                  registration&#xD;
&#xD;
               -  Myocardial infarction within 3 months prior to Step 1 registration&#xD;
&#xD;
          -  Pregnant and/or nursing females&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV) positive with CD4 count &lt; 200 cells/microliter.&#xD;
             Note that patients who are HIV positive are eligible, provided they are under&#xD;
             treatment with highly active antiretroviral therapy (HAART) and have a CD4 count &gt;=&#xD;
             200 cells/microliter within 30 days prior to registration. Note also that HIV testing&#xD;
             is not required for eligibility for this protocol. This exclusion criterion is&#xD;
             necessary because the treatments involved in this protocol may be significantly&#xD;
             immunosuppressive&#xD;
&#xD;
          -  PRIOR TO STEP 2 REGISTRATION:&#xD;
&#xD;
          -  Unable to obtain confirmation of payment coverage (insurance or other) for either&#xD;
             possible radiation treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steven Lin</last_name>
    <role>Principal Investigator</role>
    <affiliation>NRG Oncology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic Hospital in Arizona</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>855-776-0015</phone>
    </contact>
    <investigator>
      <last_name>Christopher L. Hallemeier</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Arizona</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85259</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>855-776-0015</phone>
    </contact>
    <investigator>
      <last_name>Christopher L. Hallemeier</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Coral Gables</name>
      <address>
        <city>Coral Gables</city>
        <state>Florida</state>
        <zip>33146</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>305-243-2647</phone>
    </contact>
    <investigator>
      <last_name>Benjamin Spieler</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Deerfield Beach</name>
      <address>
        <city>Deerfield Beach</city>
        <state>Florida</state>
        <zip>33442</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>305-243-2647</phone>
    </contact>
    <investigator>
      <last_name>Benjamin Spieler</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Miami Miller School of Medicine-Sylvester Cancer Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>305-243-2647</phone>
    </contact>
    <investigator>
      <last_name>Benjamin Spieler</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Miami Cancer Institute</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33176</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>786-596-2000</phone>
    </contact>
    <investigator>
      <last_name>Michael D. Chuong</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Orlando Health Cancer Institute</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Emory Proton Therapy Center</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30308</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>404-251-2854</phone>
      <email>allyson.anderson@emory.edu</email>
    </contact>
    <investigator>
      <last_name>Mark W. McDonald</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Emory University Hospital Midtown</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30308</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>888-946-7447</phone>
    </contact>
    <investigator>
      <last_name>Mark W. McDonald</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Emory University Hospital/Winship Cancer Institute</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>404-778-1868</phone>
    </contact>
    <investigator>
      <last_name>Mark W. McDonald</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Emory Saint Joseph's Hospital</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30342</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>404-851-7115</phone>
    </contact>
    <investigator>
      <last_name>Mark W. McDonald</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Northwestern Medicine Cancer Center Kishwaukee</name>
      <address>
        <city>DeKalb</city>
        <state>Illinois</state>
        <zip>60115</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>630-352-5360</phone>
      <email>Donald.Smith3@nm.org</email>
    </contact>
    <investigator>
      <last_name>Stephen A. Mihalcik</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Northwestern Medicine Cancer Center Delnor</name>
      <address>
        <city>Geneva</city>
        <state>Illinois</state>
        <zip>60134</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>630-352-5360</phone>
      <email>Donald.Smith3@nm.org</email>
    </contact>
    <investigator>
      <last_name>Stephen A. Mihalcik</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Northwestern Medicine Cancer Center Warrenville</name>
      <address>
        <city>Warrenville</city>
        <state>Illinois</state>
        <zip>60555</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>630-352-5360</phone>
      <email>Donald.Smith3@nm.org</email>
    </contact>
    <investigator>
      <last_name>Stephen A. Mihalcik</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Maryland Proton Treatment Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>410-369-5226</phone>
      <email>info@mdproton.com</email>
    </contact>
    <investigator>
      <last_name>Jason K. Molitoris</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Maryland/Greenebaum Cancer Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-888-8823</phone>
    </contact>
    <investigator>
      <last_name>Jason K. Molitoris</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UM Upper Chesapeake Medical Center</name>
      <address>
        <city>Bel Air</city>
        <state>Maryland</state>
        <zip>21014</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>443-643-3010</phone>
    </contact>
    <investigator>
      <last_name>Jack J. Hong</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital Cancer Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>877-726-5130</phone>
    </contact>
    <investigator>
      <last_name>Florence K. Keane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>McLaren Cancer Institute-Bay City</name>
      <address>
        <city>Bay City</city>
        <state>Michigan</state>
        <zip>48706</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>313-576-9790</phone>
      <email>ctoadmin@karmanos.org</email>
    </contact>
    <investigator>
      <last_name>Christian C. Hyde</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Beaumont Hospital - Dearborn</name>
      <address>
        <city>Dearborn</city>
        <state>Michigan</state>
        <zip>48124</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>248-551-7695</phone>
    </contact>
    <investigator>
      <last_name>John M. Robertson</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Wayne State University/Karmanos Cancer Institute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>313-576-9790</phone>
      <email>ctoadmin@karmanos.org</email>
    </contact>
    <investigator>
      <last_name>Christian C. Hyde</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Weisberg Cancer Treatment Center</name>
      <address>
        <city>Farmington Hills</city>
        <state>Michigan</state>
        <zip>48334</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>313-576-9790</phone>
      <email>ctoadmin@karmanos.org</email>
    </contact>
    <investigator>
      <last_name>Christian C. Hyde</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>McLaren Cancer Institute-Flint</name>
      <address>
        <city>Flint</city>
        <state>Michigan</state>
        <zip>48532</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>313-576-9790</phone>
      <email>ctoadmin@karmanos.org</email>
    </contact>
    <investigator>
      <last_name>Christian C. Hyde</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Karmanos Cancer Institute at McLaren Greater Lansing</name>
      <address>
        <city>Lansing</city>
        <state>Michigan</state>
        <zip>48910</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>313-576-9790</phone>
      <email>ctoadmin@karmanos.org</email>
    </contact>
    <investigator>
      <last_name>Christian C. Hyde</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>McLaren Cancer Institute-Lapeer Region</name>
      <address>
        <city>Lapeer</city>
        <state>Michigan</state>
        <zip>48446</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>313-576-9790</phone>
      <email>ctoadmin@karmanos.org</email>
    </contact>
    <investigator>
      <last_name>Christian C. Hyde</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>McLaren Cancer Institute-Owosso</name>
      <address>
        <city>Owosso</city>
        <state>Michigan</state>
        <zip>48867</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>313-576-9790</phone>
      <email>ctoadmin@karmanos.org</email>
    </contact>
    <investigator>
      <last_name>Christian C. Hyde</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>William Beaumont Hospital-Royal Oak</name>
      <address>
        <city>Royal Oak</city>
        <state>Michigan</state>
        <zip>48073</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>248-551-7695</phone>
    </contact>
    <investigator>
      <last_name>John M. Robertson</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>William Beaumont Hospital - Troy</name>
      <address>
        <city>Troy</city>
        <state>Michigan</state>
        <zip>48085</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>248-551-7695</phone>
    </contact>
    <investigator>
      <last_name>John M. Robertson</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Health System in Albert Lea</name>
      <address>
        <city>Albert Lea</city>
        <state>Minnesota</state>
        <zip>56007</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Unity Hospital</name>
      <address>
        <city>Fridley</city>
        <state>Minnesota</state>
        <zip>55432</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>952-993-1517</phone>
      <email>mmcorc@healthpartners.com</email>
    </contact>
    <investigator>
      <last_name>Charles Shideman</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Health Systems-Mankato</name>
      <address>
        <city>Mankato</city>
        <state>Minnesota</state>
        <zip>56001</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Minnesota Oncology Hematology PA-Maplewood</name>
      <address>
        <city>Maplewood</city>
        <state>Minnesota</state>
        <zip>55109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>952-993-1517</phone>
      <email>mmcorc@healthpartners.com</email>
    </contact>
    <investigator>
      <last_name>Charles Shideman</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hennepin County Medical Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55415</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>952-993-1517</phone>
      <email>mmcorc@healthpartners.com</email>
    </contact>
    <investigator>
      <last_name>Charles Shideman</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Radiation Therapy-Northfield</name>
      <address>
        <city>Northfield</city>
        <state>Minnesota</state>
        <zip>55057</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>855-776-0015</phone>
    </contact>
    <investigator>
      <last_name>Christopher L. Hallemeier</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>855-776-0015</phone>
    </contact>
    <investigator>
      <last_name>Christopher L. Hallemeier</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center at West County Hospital</name>
      <address>
        <city>Creve Coeur</city>
        <state>Missouri</state>
        <zip>63141</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-600-3606</phone>
      <email>info@siteman.wustl.edu</email>
    </contact>
    <investigator>
      <last_name>Gregory R. Vlacich</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-600-3606</phone>
      <email>info@siteman.wustl.edu</email>
    </contact>
    <investigator>
      <last_name>Gregory R. Vlacich</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center-South County</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63129</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-600-3606</phone>
      <email>info@siteman.wustl.edu</email>
    </contact>
    <investigator>
      <last_name>Gregory R. Vlacich</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center at Christian Hospital</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63136</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center at Saint Peters Hospital</name>
      <address>
        <city>Saint Peters</city>
        <state>Missouri</state>
        <zip>63376</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-600-3606</phone>
      <email>info@siteman.wustl.edu</email>
    </contact>
    <investigator>
      <last_name>Gregory R. Vlacich</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Basking Ridge</name>
      <address>
        <city>Basking Ridge</city>
        <state>New Jersey</state>
        <zip>07920</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>212-639-7592</phone>
    </contact>
    <investigator>
      <last_name>Abraham J. Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Monmouth</name>
      <address>
        <city>Middletown</city>
        <state>New Jersey</state>
        <zip>07748</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>212-639-7592</phone>
    </contact>
    <investigator>
      <last_name>Abraham J. Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Bergen</name>
      <address>
        <city>Montvale</city>
        <state>New Jersey</state>
        <zip>07645</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>212-639-7592</phone>
    </contact>
    <investigator>
      <last_name>Abraham J. Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Commack</name>
      <address>
        <city>Commack</city>
        <state>New York</state>
        <zip>11725</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>212-639-7592</phone>
    </contact>
    <investigator>
      <last_name>Abraham J. Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Westchester</name>
      <address>
        <city>Harrison</city>
        <state>New York</state>
        <zip>10604</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>212-639-7592</phone>
    </contact>
    <investigator>
      <last_name>Abraham J. Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>New York Proton Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10035</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>646-968-9031</phone>
      <email>ichoi@nyproton.com</email>
    </contact>
    <investigator>
      <last_name>Jehee I. Choi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>212-639-7592</phone>
    </contact>
    <investigator>
      <last_name>Abraham J. Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Nassau</name>
      <address>
        <city>Uniondale</city>
        <state>New York</state>
        <zip>11553</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>212-639-7592</phone>
    </contact>
    <investigator>
      <last_name>Abraham J. Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UHHS-Chagrin Highlands Medical Center</name>
      <address>
        <city>Beachwood</city>
        <state>Ohio</state>
        <zip>44122</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Geauga Hospital</name>
      <address>
        <city>Chardon</city>
        <state>Ohio</state>
        <zip>44024</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Cincinnati Cancer Center-UC Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45219</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>513-584-7698</phone>
      <email>cancer@uchealth.com</email>
    </contact>
    <investigator>
      <last_name>Jordan Kharofa</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Case Western Reserve University</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mercy Cancer Center-Elyria</name>
      <address>
        <city>Elyria</city>
        <state>Ohio</state>
        <zip>44035</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>UH Seidman Cancer Center at Landerbrook Health Center</name>
      <address>
        <city>Mayfield Heights</city>
        <state>Ohio</state>
        <zip>44124</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UH Seidman Cancer Center at Lake Health Mentor Campus</name>
      <address>
        <city>Mentor</city>
        <state>Ohio</state>
        <zip>44060</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UH Seidman Cancer Center at Southwest General Hospital</name>
      <address>
        <city>Middleburg Heights</city>
        <state>Ohio</state>
        <zip>44130</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospitals Parma Medical Center</name>
      <address>
        <city>Parma</city>
        <state>Ohio</state>
        <zip>44129</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospitals Portage Medical Center</name>
      <address>
        <city>Ravenna</city>
        <state>Ohio</state>
        <zip>44266</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UH Seidman Cancer Center at Firelands Regional Medical Center</name>
      <address>
        <city>Sandusky</city>
        <state>Ohio</state>
        <zip>44870</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospitals Sharon Health Center</name>
      <address>
        <city>Wadsworth</city>
        <state>Ohio</state>
        <zip>44281</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Cincinnati Cancer Center-West Chester</name>
      <address>
        <city>West Chester</city>
        <state>Ohio</state>
        <zip>45069</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>513-584-7698</phone>
      <email>cancer@uchealth.com</email>
    </contact>
    <investigator>
      <last_name>Jordan Kharofa</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UH Seidman Cancer Center at Saint John Medical Center</name>
      <address>
        <city>Westlake</city>
        <state>Ohio</state>
        <zip>44145</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UHHS-Westlake Medical Center</name>
      <address>
        <city>Westlake</city>
        <state>Ohio</state>
        <zip>44145</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Jennifer A. Dorth</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Oklahoma Health Sciences Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>405-271-8777</phone>
      <email>ou-clinical-trials@ouhsc.edu</email>
    </contact>
    <investigator>
      <last_name>Tyler Gunter</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania/Abramson Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-474-9892</phone>
    </contact>
    <investigator>
      <last_name>John P. Plastaras</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Thompson Proton Center</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37909</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>865-531-5118</phone>
      <email>jwilso31@covhlth.com</email>
    </contact>
    <investigator>
      <last_name>Grant M. Clark</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Thompson Cancer Survival Center</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37916</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>865-331-1812</phone>
    </contact>
    <investigator>
      <last_name>Grant M. Clark</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Thompson Oncology Group-Maryville</name>
      <address>
        <city>Maryville</city>
        <state>Tennessee</state>
        <zip>37804</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>865-331-1812</phone>
    </contact>
    <investigator>
      <last_name>Grant M. Clark</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Thompson Oncology Group-Oak Ridge</name>
      <address>
        <city>Oak Ridge</city>
        <state>Tennessee</state>
        <zip>37830</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>865-331-1812</phone>
    </contact>
    <investigator>
      <last_name>Grant M. Clark</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>MD Anderson in The Woodlands</name>
      <address>
        <city>Conroe</city>
        <state>Texas</state>
        <zip>77384</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>866-632-6789</phone>
      <email>askmdanderson@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Saumil Gandhi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>877-632-6789</phone>
      <email>askmdanderson@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Saumil Gandhi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>MD Anderson West Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77079</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>877-632-6789</phone>
      <email>askmdanderson@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Saumil Gandhi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>MD Anderson League City</name>
      <address>
        <city>League City</city>
        <state>Texas</state>
        <zip>77573</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>877-632-6789</phone>
      <email>askmdanderson@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Saumil Gandhi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>MD Anderson in Sugar Land</name>
      <address>
        <city>Sugar Land</city>
        <state>Texas</state>
        <zip>77478</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>877-632-6789</phone>
      <email>askmdanderson@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Saumil Gandhi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Huntsman Cancer Institute/University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>888-424-2100</phone>
      <email>cancerinfo@hci.utah.edu</email>
    </contact>
    <investigator>
      <last_name>Shane Lloyd</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Inova Alexandria Hospital</name>
      <address>
        <city>Alexandria</city>
        <state>Virginia</state>
        <zip>22304</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>703-776-2580</phone>
      <email>Stephanie.VanBebber@inova.org</email>
    </contact>
    <investigator>
      <last_name>Avani D. Rao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Inova Schar Cancer Institute</name>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <zip>22031</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>703-720-5210</phone>
      <email>Stephanie.VanBebber@inova.org</email>
    </contact>
    <investigator>
      <last_name>Avani D. Rao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Inova Fair Oaks Hospital</name>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <zip>22033</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>703-720-5210</phone>
      <email>Stephanie.VanBebber@inova.org</email>
    </contact>
    <investigator>
      <last_name>Avani D. Rao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Inova Loudoun Hospital</name>
      <address>
        <city>Leesburg</city>
        <state>Virginia</state>
        <zip>20176</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>703-858-6000</phone>
      <email>Keary.janet@inova.org</email>
    </contact>
    <investigator>
      <last_name>Avani D. Rao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Washington Medical Center - Montlake</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98195</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-804-8824</phone>
    </contact>
    <investigator>
      <last_name>Smith Apisarnthanarax</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Health System-Eau Claire Clinic</name>
      <address>
        <city>Eau Claire</city>
        <state>Wisconsin</state>
        <zip>54701</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>855-776-0015</phone>
    </contact>
    <investigator>
      <last_name>Christopher L. Hallemeier</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 3, 2019</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>July 31, 2023</last_update_submitted>
  <last_update_submitted_qc>July 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Adenocarcinoma</mesh_term>
    <mesh_term>Esophageal Neoplasms</mesh_term>
    <mesh_term>Esophageal Squamous Cell Carcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Docetaxel</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Albumin-Bound Paclitaxel</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03801876
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
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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 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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
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
description: Will be estimated by the Kaplan-Meier method. The distributions of OS between treatment arms will be compared using the log rank test.
measure: 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
description: 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.
measure: Pathologic response rate
time frame: At time of surgery
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
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
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
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
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
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
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
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.
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group type: Experimental
description: 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 chemotherapy (Choice of 3 regimens: 1. Carboplatin/Paclitaxel, 2. FOLFOX/CAPOX or 3. Docetaxel/5-FU [with capecitabine as an acceptable substitute for 5-FU]) per institutional standards while undergoing PBT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion.
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
arm group type: Active Comparator
description: 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 chemotherapy (Choice of 3 regimens: 1. Carboplatin/Paclitaxel, 2. FOLFOX/CAPOX or 3. Docetaxel/5-FU [with capecitabine as an acceptable substitute for 5-FU]) per institutional standards while undergoing IMRT. Within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion.
intervention type: Drug
intervention name: Carboplatin
description: Given IV
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: Blastocarb
other name: Carboplat
other name: Carboplatin Hexal
other name: Carboplatino
other name: Carbosin
other name: Carbosol
other name: Carbotec
other name: CBDCA
other name: Displata
other name: Ercar
other name: JM-8
other name: Nealorin
other name: Novoplatinum
other name: Paraplatin
other name: Paraplatin AQ
other name: Paraplatine
other name: Platinwas
other name: Ribocarbo
intervention type: Procedure
intervention name: Esophagectomy
description: Undergo esophagectomy
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: excision of the esophagus
intervention type: Radiation
intervention name: Intensity-Modulated Radiation Therapy
description: Undergo IMRT
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: IMRT
other name: Intensity Modulated RT
other name: Intensity-Modulated Radiotherapy
intervention type: Drug
intervention name: Paclitaxel
description: Given IV
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: Anzatax
other name: Asotax
other name: Bristaxol
other name: Praxel
other name: Taxol
other name: Taxol Konzentrat
intervention type: Radiation
intervention name: Proton Beam Radiation Therapy
description: Undergo PBT
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
other name: PBRT
other name: Proton Radiation Therapy
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: Quality of Life Assessment
intervention type: Other
intervention name: Questionnaire Administration
description: Ancillary studies
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
intervention type: Drug
intervention name: FOLFOX regimen
description: Folinic acid, flurouracil and oxaliplatin
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: FOLFOX
intervention type: Drug
intervention name: CAPOX regimen
description: Capecitabine combined with oxaliplatin
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: CAPE-OX
other name: OxCap
intervention type: Drug
intervention name: Docetaxel
description: Chemotherapy
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: Taxotere
intervention type: Drug
intervention name: 5FU
description: Chemotherapy
arm group label: Group I (PBT, Chemotherapy, Esophagectomy)
arm group label: Group II (IMRT, Chemotherapy, Esophagectomy)
other name: 5-FU
other name: flurouracil
other name: Tolak
other name: Fluoroplex
other name: Efudex
other name: Carac
other name: Adrucil
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Steven Lin
role: Principal Investigator
affiliation: NRG Oncology
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country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Adenocarcinoma
mesh term: Esophageal Neoplasms
mesh term: Esophageal Squamous Cell Carcinoma
mesh term: Paclitaxel
mesh term: Docetaxel
mesh term: Carboplatin
mesh term: Albumin-Bound Paclitaxel
mesh term: Fluorouracil