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Original Investigation
July 6, 2017

Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal CancerThe NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial

Author Affiliations
  • 1University of Maryland Medical System, Baltimore
  • 2NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
  • 3Memorial Sloan-Kettering Cancer Center, New York City, New York
  • 4Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
  • 5Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
  • 6The Chester County Hospital, West Chester, Pennsylvania
  • 7Huntsman Cancer Hospital, University of Utah, Salt Lake City
  • 8MBCCOP, John H. Stroger Jr Hospital of Cook County, Chicago, Illinois
  • 9Food and Drug Administration, Bethesda, Maryland
  • 10Department of Oncology, USON-Texas, Bedford, Texas
  • 11Shadyside Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • 12Christiana Care Health Services Inc, CCOP, Newark, Delaware
  • 13Greenville South Carolina, CCOP, Greenville
  • 14Southeast Cancer Control Consortium Inc, CCOP, Winston Salem, North Carolina
  • 15Cleveland Clinic, Cleveland, Ohio
  • 16The Schiffler Cancer Center, Wheeling, West Virginia
  • 17Brown University Oncology Group, Providence, Rhode Island
  • 18University of Texas MD Anderson Cancer Center, Houston
JAMA Oncol. Published online July 6, 2017. doi:10.1001/jamaoncol.2017.1598
Key Points

Question  Does the addition of an epidermal growth factor receptor (EGFR) inhibitor to chemoradiation improve survival outcomes for patients with esophageal cancer?

Findings  This phase 3 randomized clinical trial compared survival for patients receiving cetuximab plus platinum, taxane, and radiation therapy to the same chemoradiation regimen alone. No significant improvement in survival was seen in patients receiving cetuximab.

Meaning  The addition of EGFR inhibition to concurrent chemoradiation therapy did not improve survival outcomes for esophageal cancer patients.


Importance  The role of epidermal growth factor receptor (EGFR) inhibition in chemoradation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain.

Objective  To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma.

Design, Setting, and Participants  A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013.

Interventions  Patients were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m2 on day 1 then 250 mg/m2 weekly).

Main Outcomes and Measures  Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided α = .025.

Results  Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47).

Conclusions and Relevance  The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer.

Trial Registration  clinicaltrials.gov Identifier: NCT00655876