Paclitaxel, Cisplatin, and Radiation Therapy With or Without Cetuximab in Treating Patients With Locally Advanced Esophageal Cancer

A Phase III Trial Evaluating the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for Patients With Esophageal Cancer Who Are Treated Without Surgery

RATIONALE: Drugs used in chemotherapy, such as paclitaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may stop the growth of esophageal cancer by blocking blood flow to the tumor. It is not yet known whether giving paclitaxel and cisplatin together with radiation therapy is more effective with or without cetuximab in treating esophageal cancer.

PURPOSE: This randomized phase III trial is comparing how well giving paclitaxel and cisplatin together with radiation therapy works with or without cetuximab in treating patients with locally advanced esophageal cancer.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: cetuximab; Drug: cisplatin; Drug: paclitaxel; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

Primary

• To evaluate whether the addition of cetuximab to chemotherapy comprising paclitaxel, cisplatin, and radiotherapy improves overall survival compared with paclitaxel, cisplatin, and radiotherapy alone in patients with esophageal cancer treated without surgery.

Secondary

• To evaluate whether the addition of cetuximab to paclitaxel, cisplatin, and radiotherapy improves local control by increasing the clinical complete response and decreasing local recurrence in these patients.
• To evaluate adverse events in these patients.
• To evaluate endoscopic complete response rates in these patients.
• To evaluate if the addition of cetuximab to paclitaxel, cisplatin, and radiotherapy improves the Esophageal Cancer Subscale (ECS) score of the Functional Assessment of Cancer Therapy - Esophagus (FACT-E) quality of life tool.
• To evaluate the quality-adjusted survival of each treatment arm using EQ-5D if the primary endpoint supports the primary hypothesis.

OUTLINE: This is a multicenter study. Patients are stratified according to histology (adenocarcinoma vs squamous), cancer lesion size (< 5 cm vs ≥ 5 cm), and disease status of celiac nodes (present vs absent). Patients are randomized to 1 of 2 treatment arms.

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Saint John Regional Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill Cancer Centre at McGill University
• United States
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Oncology - Tucson
  • California
    • Auburn, California, United States, 95603
      • Auburn Radiation Oncology
    • Cameron Park, California, United States, 95682
      • Radiation Oncology Centers - Cameron Park
    • Carmichael, California, United States, 95608
      • Mercy Cancer Center at Mercy San Juan Medical Center
    • Chico, California, United States, 95926
      • Enloe Cancer Center at Enloe Medical Center
    • Fresno, California, United States, 93720
      • California Cancer Center - Woodward Park Office
    • Fresno, California, United States, 93720
      • Saint Agnes Cancer Center at Saint Agnes Medical Center
    • Modesto, California, United States, 95355
      • Memorial Medical Center
    • Roseville, California, United States, 95661
      • Radiation Oncology Center - Roseville
    • Sacramento, California, United States, 95815
      • Radiological Associates of Sacramento Medical Group, Incorporated
    • Sacramento, California, United States, 95819
      • Mercy General Hospital
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • Vacaville, California, United States, 95687
      • Solano Radiation Oncology Center
    • Vallejo, California, United States, 94589
      • Sutter Solano Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers - Aurora
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
  • Connecticut
    • New Britain, Connecticut, United States, 06050
      • George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus
    • Norwich, Connecticut, United States, 06360
      • William W. Backus Hospital
  • Delaware
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Jupiter, Florida, United States, 33458
      • Ella Milbank Foshay Cancer Center at Jupiter Medical Center
    • Lakeland, Florida, United States, 33805
      • Center for Cancer Care and Research at Watson Clinic, LLP
    • Miami, Florida, United States, 33176
      • Baptist-South Miami Regional Cancer Program
    • Miami Beach, Florida, United States, 33140
      • CCOP - Mount Sinai Medical Center
    • Orlando, Florida, United States, 32806
      • M.D. Anderson Cancer Center at Orlando
  • Georgia
    • Columbus, Georgia, United States, 31904
      • John B. Amos Cancer Center
    • Savannah, Georgia, United States, 31405
      • Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Cancer Research Center of Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Queen's Cancer Institute at Queen's Medical Center
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Medical Center - East
  • Idaho
    • Boise, Idaho, United States, 83706
      • Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
    • Park Ridge, Illinois, United States, 60068-1174
      • Advocate Lutheran General Cancer Care Center
    • Rockford, Illinois, United States, 61104-2315
      • Swedish-American Regional Cancer Center
    • Springfield, Illinois, United States, 62702
      • Cancer Institute at St. John's Hospital
  • Indiana
    • Anderson, Indiana, United States, 46016
      • Saint John's Cancer Center at Saint John's Medical Center
    • Bloomington, Indiana, United States, 47403
      • Bloomington Hospital Regional Cancer Institute
    • Fort Wayne, Indiana, United States, 46805
      • Parkview Regional Cancer Center at Parkview Health
    • Fort Wayne, Indiana, United States, 46804
      • Radiation Oncology Associates Southwest
    • Indianapolis, Indiana, United States, 46202
      • Methodist Cancer Center at Methodist Hospital
    • Indianapolis, Indiana, United States, 46219
      • Central Indiana Cancer Centers - East
    • Muncie, Indiana, United States, 47303-3499
      • Cancer Center at Ball Memorial Hospital
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, PC
    • Des Moines, Iowa, United States, 50309
      • John Stoddard Cancer Center at Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50314
      • Mercy Cancer Center at Mercy Medical Center - Des Moines
    • Mason City, Iowa, United States, 50401
      • Mercy Cancer Center at Mercy Medical Center - North Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • James Graham Brown Cancer Center at University of Louisville
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center - Baton Rouge
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • St. Agnes Hospital Cancer Center
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
    • Baltimore, Maryland, United States, 21204
      • Greater Baltimore Medical Center Cancer Center
  • Massachusetts
    • Fall River, Massachusetts, United States, 02721
      • Hudner Oncology Center at Saint Anne's Hospital - Fall River
  • Michigan
    • Ann Arbor, Michigan, United States, 48106-0995
      • Saint Joseph Mercy Cancer Center
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Grand Rapids, Michigan, United States, 49503
      • Lacks Cancer Center at Saint Mary's Health Care
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
    • Livonia, Michigan, United States, 48154
      • St. Mary Mercy Hospital
    • Port Huron, Michigan, United States, 48060
      • Mercy Regional Cancer Center at Mercy Hospital
    • Saginaw, Michigan, United States, 48601
      • Seton Cancer Institute at Saint Mary's - Saginaw
  • Minnesota
    • Bemidji, Minnesota, United States, 56601
      • MeritCare Bemidji
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology - Maplewood
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital Cancer Care Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Cancer Clinic
  • Missouri
    • Cape Girardeau, Missouri, United States, 63703
      • Cancer Institute of Cape Girardeau, LLC
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Cancer Center
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Cancer Center
    • Saint Louis, Missouri, United States, 63141
      • David C. Pratt Cancer Center at St. John's Mercy
  • Montana
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
    • Great Falls, Montana, United States, 59405
      • Sletten Cancer Institute at Benefis Healthcare
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Estabrook Cancer Center
    • Omaha, Nebraska, United States, 68130
      • Lakeside Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Nevada Cancer Research Foundation
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • Payson Center for Cancer Care at Concord Hospital
    • Dover, New Hampshire, United States, 03820
      • Seacoast Cancer Center at Wentworth - Douglass Hospital
    • Exeter, New Hampshire, United States, 03833
      • Center for Cancer Care at Exeter Hospital
    • Keene, New Hampshire, United States, 03431
      • Kingsbury Center for Cancer Care at Cheshire Medical Center
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
    • Manchester, New Hampshire, United States, 03103
      • Elliot Regional Cancer Center at Elliot Hospital
  • New Jersey
    • Long Branch, New Jersey, United States, 07740-6395
      • Monmouth Medical Center
    • Marlton, New Jersey, United States, 08053
      • Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
    • Sparta, New Jersey, United States, 07871
      • Frederick R. and Betty M. Smith Cancer Treatment Center
    • Toms River, New Jersey, United States, 08755
      • J. Phillip Citta Regional Cancer Center at Community Medical Center
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • New York
    • Albany, New York, United States, 12206
      • New York Oncology Hematology, PC at Albany Regional Cancer Care
    • Binghamton, New York, United States, 13905
      • Lourdes Regional Cancer Center
    • Glens Falls, New York, United States, 12801
      • Charles R. Wood Cancer Center at Glens Falls Hospital
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10025
      • St. Luke's - Roosevelt Hospital Center - St.Luke's Division
    • New York, New York, United States, 10003-3803
      • Beth Israel Medical Center - Petrie Division
    • Sleepy Hollow, New York, United States, 10591
      • Memorial Sloan-Kettering Cancer Center at Phelps Memorial Hospital Center
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals - Memorial Campus
    • Burlington, North Carolina, United States, 27216
      • Alamance Cancer Center at Alamance Regional Medical Center
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
    • Kinston, North Carolina, United States, 28501
      • Kinston Medical Specialists
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • CCOP - MeritCare Hospital
  • Ohio
    • Akron, Ohio, United States, 44307
      • McDowell Cancer Center at Akron General Medical Center
    • Akron, Ohio, United States, 44309-2090
      • Summa Center for Cancer Care at Akron City Hospital
    • Barberton, Ohio, United States, 44203
      • Barberton Citizens Hospital
    • Canton, Ohio, United States, 44710-1799
      • Aultman Cancer Center at Aultman Hospital
    • Canton, Ohio, United States, 44708
      • Mercy Cancer Center at Mercy Medical Center
    • Cleveland, Ohio, United States, 44106-5065
      • Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Cancer Care Center at MetroHealth Medical Center
    • Mentor, Ohio, United States, 44060
      • Lake/University Ireland Cancer Center
    • Middleburg Heights, Ohio, United States, 44130
      • Southwest General Health Center
    • Orange Village, Ohio, United States, 44122
      • UHHS Chagrin Highlands Medical Center
    • Ravenna, Ohio, United States, 44266
      • Robinson Radiation Oncology
    • Westlake, Ohio, United States, 44145
      • UHHS Westlake Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at St. Francis Hospital
  • Oregon
    • Clackamas, Oregon, United States, 97015
      • Clackamas Radiation Oncology Center
    • Eugene, Oregon, United States, 97401
      • Willamette Valley Cancer Center - Eugene
    • Portland, Oregon, United States, 97213-2967
      • Providence Cancer Center at Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence St. Vincent Medical Center
  • Pennsylvania
    • Beaver, Pennsylvania, United States, 15009
      • UPMC Cancer Center at Beaver Medical Center
    • Clairton, Pennsylvania, United States, 15025
      • UPMC Cancer Center at Jefferson Regional Medical Center
    • Drexel Hill, Pennsylvania, United States, 19026
      • Delaware County Regional Cancer Center at Delaware County Memorial Hospital
    • Erie, Pennsylvania, United States, 16505
      • Regional Cancer Center - Erie
    • Gettysburg, Pennsylvania, United States, 17325
      • Adams Cancer Center
    • Greensburg, Pennsylvania, United States, 15601
      • UPMC Cancer Center - Arnold Palmer Pavilion
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Cancer Center
    • Philadelphia, Pennsylvania, United States, 19114
      • Frankford Hospital Cancer Center - Torresdale Campus
    • Pittsburgh, Pennsylvania, United States, 15213-2582
      • UPMC - Shadyside
    • Pittsburgh, Pennsylvania, United States, 15215
      • UPMC Cancer Center at UPMC St. Margaret
    • Pittsburgh, Pennsylvania, United States, 15237
      • UPMC Cancer Center at UPMC Passavant
    • Reading, Pennsylvania, United States, 19612-6052
      • McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
    • Seneca, Pennsylvania, United States, 16346
      • UPMC Cancer Center at UPMC Northwest
    • York, Pennsylvania, United States, 17405
      • York Cancer Center at Apple Hill Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Comprehensive Cancer Center
    • Providence, Rhode Island, United States, 02904
      • Northmain Radiation Oncology
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Greenville, South Carolina, United States, 29615
      • CCOP - Greenville
    • Greenville, South Carolina, United States, 29605
      • Cancer Centers of the Carolinas - Faris Road
    • Seneca, South Carolina, United States, 29672
      • Cancer Centers of the Carolinas - Seneca
    • Spartanburg, South Carolina, United States, 29303
      • CCOP - Upstate Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
    • Spartanburg, South Carolina, United States, 29307
      • Cancer Centers of the Carolinas - Spartanburg
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City Regional Hospital
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sanford Cancer Center at Sanford USD Medical Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • Thompson Cancer Survival Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Harrington Cancer Center
    • Bedford, Texas, United States, 76022
      • Texas Oncology, PA at Harris Center HEB
    • Denton, Texas, United States, 76210
      • Texas Oncology, PA at Texas Cancer Center - Denton South
    • Fort Worth, Texas, United States, 76104
      • Klabzuba Cancer Center at Harris Methodist Fort Worth Hospital
    • Houston, Texas, United States, 77024
      • Memorial Hermann Hospital - Memorial City
    • Longview, Texas, United States, 75601
      • Longview Cancer Center
    • Lubbock, Texas, United States, 79410-1894
      • Joe Arrington Cancer Research and Treatment Center
    • San Antonio, Texas, United States, 78217
      • Cancer Care Centers of South Texas - Northeast
    • Sherman, Texas, United States, 75090
      • Texas Oncology, PA at Texas Cancer Center - Sherman
    • Sugar Land, Texas, United States, 77479
      • Texas Oncology, PA at Texas Oncology Cancer Center Sugar Land
    • Tyler, Texas, United States, 75702
      • Tyler Cancer Center
    • Wichita Falls, Texas, United States, 76310
      • Texas Oncology, PA - Wichita Falls
  • Utah
    • Murray, Utah, United States, 84157
      • Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
    • Saint George, Utah, United States, 84770
      • Dixie Regional Medical Center - East Campus
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute at University of Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists at UCS Cancer Center
  • Washington
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists at Vancouver Cancer Center
  • West Virginia
    • Wheeling, West Virginia, United States, 26003
      • Schiffler Cancer Center at Wheeling Hospital
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Green Bay, Wisconsin, United States, 54303
      • St. Mary's Hospital Medical Center - Green Bay
    • Marinette, Wisconsin, United States, 54143
      • Bay Area Cancer Care Center at Bay Area Medical Center
    • Milwaukee, Wisconsin, United States, 53295
      • Veterans Affairs Medical Center - Milwaukee
    • Oconomowoc, Wisconsin, United States, 53066
      • Regional Cancer Center at Oconomowoc Memorial Hospital
    • Sturgeon Bay, Wisconsin, United States, 54235-1495
      • Door County Cancer Center at Door County Memorial Hospital
    • Waukesha, Wisconsin, United States, 53188
      • Waukesha Memorial Hospital Regional Cancer Center
    • Wausau, Wisconsin, United States, 54401
      • University of Wisconcin Cancer Center at Aspirus Wausau Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pathologically (histologic or cytologic) proven diagnosis of primary squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction within 12 weeks prior to registration. Patients with involvement of the gastroesophageal junction with Siewert type I or II tumors (tumors arising from the distal esophagus and involving the esophagogastric junction or tumors starting at the esophagogastric junction and involving the cardia) are eligible.

   • 1.1 Disease must be encompassed in a radiotherapy field.
   • 1.2 Patients with celiac, perigastric, mediastinal or supraclavicular adenopathy are eligible.
   • 1.3 Patients with cervical esophageal carcinoma are eligible.

2. Stage T1N1M0; T2-4, Any N, M0; Any T, Any N, M1a, based upon the following minimum diagnostic work-up:

   • 2.1 History/physical examination within 6 weeks prior to registration
   • 2.2 Positron emission tomography (PET)/positron emission tomography-computed tomography (PET-CT) scan (strongly recommended) or chest/abdominal CT within 6 weeks prior to registration
   • 2.3 Electrocardiogram (EKG) within 6 weeks of study entry
   • 2.4 Endoscopy with biopsy or cytology by fine needle aspiration (FNA) (must be able to document histologic subtype) within 12 weeks of study entry. Patients with T3-4 proximal thoracic esophageal tumors (15-25 cm) must undergo bronchoscopy to exclude fistula. (NOTE: Any images from endoscopic procedures up to the time of progression must be kept in the patient's confidential study file.)
3. Zubrod performance status 0-2
4. Age ≥ 18 and ≤ 74 (upper limit was set at 74 in an amendment)

5. Complete blood count (CBC)/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function defined as follows:

   • 5.1 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
   • 5.2 Platelets ≥ 100,000 cells/mm3
   • 5.3 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥8.0 g/dl is acceptable.)

6. Additional laboratory studies obtained within 2 weeks prior to registration on study

   • 6.1 Creatinine ≤ 1.5 mg/dl
   • 6.2 Bilirubin ≤ 1.5 x upper limit of normal
   • 6.3 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 x upper limit of normal
   • 6.4 Serum pregnancy test for women of childbearing potential
7. Patient's total intake (oral/enteral) must be ≥ 1500 kCal/day
8. Patient must provide study-specific informed consent prior to study entry
9. Women of childbearing potential and male participants must practice adequate contraception

Exclusion Criteria:

1. Evidence of tracheoesophageal fistula, or invasion into the trachea or major bronchi. Patients with T3-4 proximal thoracic esophageal tumors (15-25 cm) must undergo bronchoscopy to exclude fistula.
2. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 2 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
3. Prior systemic chemotherapy for esophageal cancer; note that prior chemotherapy for a different cancer is allowable.
4. Prior radiation therapy that would result in overlap of planned radiation therapy fields.
5. Prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR) pathway.
6. Prior platinum-based and/or paclitaxel-based therapy.
7. Prior allergic reaction to the study drugs involved in this protocol.
8. Prior severe infusion reaction to a monoclonal antibody.

9. Severe, active comorbidity, defined as follows:

   • 9.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months
   • 9.2 Transmural myocardial infarction within the last 6 months
   • 9.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
   • 9.4 Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   • 9.5 Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immunocompromised patients.
10. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
11. Women who are nursing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chemoradiation + Cetuximab; External beam radiation therapy (RT) with concurrent weekly paclitaxel, cisplatin, and cetuximab	Drug: cetuximab; Weekly with external beam radiation therapy for a total of six doses. The initial dose of cetuximab is 400 mg/m^2 intravenously administered over 120 minutes on day 1, followed by weekly infusions of 250 mg/m^2 intravenously over 60 minutes on days 8, 15, 22, 29, and 36. The infusion rate of cetuximab must never exceed 5 mL/min.; Drug: cisplatin; Weekly with external beam radiation therapy for a total of six doses. Patients receive 25 mg/m^2 as an intravenous infusion over 30-60 minutes on days 1, 8, 15, 22, 29 and 36.; Drug: paclitaxel; Weekly with external beam radiation therapy for a total of six doses. Patients receive 50 mg/m^2 as an intravenous infusion over 1 hour on days 1, 8, 15, 22, 29 and 36.; Radiation: radiation therapy; 1.8 Gy daily for 28 days (over 5-6 weeks) for a total dose of 50.4 Gy.
Active Comparator: Chemoradiation; External beam radiation therapy with concurrent weekly paclitaxel, and cisplatin	Drug: cisplatin; Weekly with external beam radiation therapy for a total of six doses. Patients receive 25 mg/m^2 as an intravenous infusion over 30-60 minutes on days 1, 8, 15, 22, 29 and 36.; Drug: paclitaxel; Weekly with external beam radiation therapy for a total of six doses. Patients receive 50 mg/m^2 as an intravenous infusion over 1 hour on days 1, 8, 15, 22, 29 and 36.; Radiation: radiation therapy; 1.8 Gy daily for 28 days (over 5-6 weeks) for a total dose of 50.4 Gy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (24-month Rate Reported)	Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur after at least 281 deaths have been observed, unless an early stopping rule was satisfied.	From randomization to last follow-up. Analysis was planned to occur after at least 281 deaths had been observed. Maximum follow-up at time of analysis was 74.5 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local Failure (24-month Rate Reported)	Local failure (LF) was defined as residual cancer on posttreatment biopsy findings or biopsy-proven recurrent primary disease and local failure time was measured from randomization to failure or last follow-up. Nonprotocol surgery to the primary site with gross residual disease was considered a LF as of the surgery date. Patients with no viable disease or microscopic residual disease at nonprotocol surgery were censored for LF as of the surgery date. Local failure was estimated by the cumulative incidence method with death considered a competing risk.	From randomization to last follow-up. Analysis was planned to occur after at least 281 deaths had been observed. Maximum follow-up at time of analysis was 74.5 months.
Percentage of Patients With Acute Grade 4 or 5 Non-hematologic Treatment-related Adverse Events	Adverse events (AE) are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE	From start of treatment to 90 days from end of treatment
Endoscopic Complete Response Rate	All patients were to undergo a repeat endoscopy (EUS) 6-8 weeks after the completion of chemoradiation. At the time of EUS a visual inspection of the site of the original primary disease would be documented. Those patients found to be free of disease were NOT required to undergo repeat biopsy. These patients would be scored as clinical complete responses (cCR). Patients deemed to have residual disease or suspicion of residual disease would undergo a biopsy in order to pathologically confirm findings. Any patient with pathologically confirmed residual disease would be scored as a local failure. Patients who were pathologically proven to have no evidence of disease would be scored as cCRs.	From randomization to 6-8 weeks after completion of chemoradiation (11-14 weeks)
Percentage of Patients With Improvement in the Functional Assessment of Cancer Therapy - Esophagus (FACT-E) Esophageal Cancer Subscale (ECS) Subscale After Treatment	The ECS is a 17-item self-report instrument designed to measure multidimensional quality of life in patients with esophagus cancer. It is to be administered with the Functional Assessment of Cancer Therapy - General (FACT-G). There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score which ranges from 0-68. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-E including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicated better QOL. Improvement in FACT-E score is defined as an increase from baseline score of at least 5 points.	Baseline, 6-8 weeks after completion of chemoradiation , 1 year and 2 years from treatment start.
Quality-adjusted Survival (Using EQ-5D), Only if Primary Hypothesis is Supported		Baseline, 6-8 weeks after completion of chemoradiation, 1 year and 2 years from treatment start.

Collaborators and Investigators

• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); NRG Oncology
• Investigators: Study Chair: David H. Ilson, MD, PhD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Mohan Suntharalingam, MD, University of Maryland Greenebaum Cancer Center

Publications and helpful links

General Publications

• Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy AB, Anker CJ, Thakrar H, Horiba N, Dubey A, Greenberger JS, Raben A, Giguere J, Roof K, Videtic G, Pollock J, Safran H, Crane CH. Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2017 Nov 1;3(11):1520-1528. doi: 10.1001/jamaoncol.2017.1598. Erratum In: JAMA Oncol. 2017 Nov 1;3(11):1589.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): May 20, 2022

Study Registration Dates

• First Submitted: April 9, 2008
• First Submitted That Met QC Criteria: April 9, 2008
• First Posted (Estimate): April 10, 2008

Study Record Updates

• Last Update Posted (Actual): June 14, 2022
• Last Update Submitted That Met QC Criteria: May 23, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: squamous cell carcinoma of the esophagus; stage IIB esophageal cancer; stage IIIA esophageal cancer; stage IIIB esophageal cancer; stage IIIC esophageal cancer; stage IV esophageal cancer; stage IIA esophageal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Paclitaxel; Cisplatin; Cetuximab
• Other Study ID Numbers: RTOG 0436; CDR0000538085

Plan for Individual participant data (IPD)

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: NCT00655876
   Information comments: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.