Fluorouracil, Cisplatin, Cetuximab, and Radiation Therapy in Treating Patients With Esophageal Cancer That Can Be Removed by Surgery

Neoadjuvant Treatment for Operable Esophageal Cancer With 5-fluorouracil, Cisplatin, and Cetuximab and Concurrent Radiotherapy: Phase I/II Study

RATIONALE: Drugs used in chemotherapy, such as fluorouracil and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving fluorouracil and cisplatin together with cetuximab and radiation therapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of fluorouracil and cisplatin when given together with cetuximab and radiation therapy in treating patients with esophageal cancer that can be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: cisplatin; Procedure: conventional surgery; Biological: cetuximab

Detailed Description

OBJECTIVES:

Primary

• To determine the maximum tolerated dose of fluorouracil and cisplatin when administered with cetuximab concurrently with esophageal radiotherapy. (Phase I)
• To determine the complete histological response rate (after surgical resection). (Phase II)

Secondary

• To determine progression-free survival and overall survival. (Phase II)
• To determine the rate of resection with negative margins (R0). (Phase II)
• To determine the overall tolerance to neoadjuvant therapy. (Phase II)
• To determine the postoperative morbidity and mortality. (Phase II)

OUTLINE: This is a multicenter study. This is a dose-escalation study of cisplatin and fluorouracil.

Patients receive cetuximab IV over 2 hours on day -7, then IV over 1 hour on days 1, 8, 15, 22, and 29. Patients also receive cisplatin IV over 1 hour on day 1 or 2 and fluorouracil IV continuously on days 1-4, 8-11, 15-18, 22-25, and 29-32. Patients undergo radiotherapy 5 days a week for 5 weeks, beginning on day 1 of chemotherapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery within 6-8 weeks after completion of chemoradiotherapy.

After completion of study therapy, patients are followed at 1 month, every 4 months for 2 years, and then every 6 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Besancon, France, 25030
    • Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
  • Bordeaux, France, 33075
    • Hopital Saint Andre
  • Brest, France, 29200
    • C.H.U. de Brest
  • Clermont-Ferrand, France, 63058
    • CHR Clermont Ferrand, Hotel Dieu
  • Dijon, France, 21034
    • Hopital Du Bocage
  • Dijon, France, 21079
    • Federation Francophone de Cancerologie Digestive
  • Lille, France, 59037
    • Centre Hospital Universitaire Hop Huriez
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Marseille, France, 13385
    • CHU de la Timone
  • Montpellier, France, 34298
    • Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud
  • Toulouse, France, 31059
    • Centre Hospitalier Regional de Purpan
  • Vandoeuvre-les-Nancy, France, 54511
    • Centre Alexis Vautrin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

Inclusion criteria:

• Histologically confirmed epidermoid or glandular carcinoma of the thoracic esophagus

  • Invasive disease
  • Only Siewert type I gastroesophageal carcinoma allowed

• Resectable disease

  • T1N+, T2N0, T2N+, T3N0, or T3N+ (stage II or III)
  • No visceral metastases or mediastinal extensions compromising resectability

Exclusion criteria:

• Inoperable disease
• Invasion of the tracheo-bronchial tree
• Recurring esophageal paralysis
• Esopho-tracheal fistula
• Cervical esophageal carcinoma (< 19 cm above the dental arches)
• Multifocal esophageal carcinoma
• Superficial esophageal carcinoma (T1N0)
• Esophageal carcinoma in the lymph nodes that cannot be included in the radiotherapy field or cannot be completely surgically resected
• Proven metastatic disease

PATIENT CHARACTERISTICS:

Inclusion criteria:

• WHO performance status 0-1
• Weight loss < 15%
• Absolute neutrophil count ≥ 1,500/mm3
• Platelet count ≥ 100,000/mm3
• Creatinine ≤ 1.25 times upper limit of normal
• PTT ≥ 80%
• Albumin ≥ 35 g/L
• FEV1 > 1 L
• Not pregnant or nursing
• Fertile patients of must use effective contraception

Exclusion criteria:

• Known liver cirrhosis
• Renal insufficiency
• Respiratory insufficiency (i.e., severe dyspnea at rest or oxygen dependence)
• Progressive coronary insufficiency
• Myocardial infarction in the past 6 months
• Legally incapacitated
• Impossible to receive study therapy due to geographical, social, or psychological reasons
• Noncompliant within constraints of the study
• Hematologic malignancy or other cancer except carcinoma in situ of the uterine cervix, treated nonmelanoma skin cancer, or intramucous disease treated within the past 3 years

PRIOR CONCURRENT THERAPY:

Exclusion criteria:

• Prior anticancer chemotherapy or radiotherapy
• Treatment with endoprosthesis
• Surgery (esophagectomy) planned without thoracotomy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant chemoradiotherapy; Weekly cetuximab (400 mg/m2 one week before start of radiotherapy RT and 250 mg/m2 during radiotherapyRT), and 5 FU (500 mg/m2 per day D1-D4) combined with cisplatin CDDP (40 mg/m2 D1) on week 1 and 5	Drug: fluorouracil; Drug: cisplatin; Procedure: conventional surgery; Biological: cetuximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete histologic response	After Surgery
Tolerance to neoadjuvant therapy	From Inclusion

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free and overall survival	From inclusion
Mortality	From Inclusion

Collaborators and Investigators

• Sponsor: Federation Francophone de Cancerologie Digestive

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: October 13, 2007
• First Submitted That Met QC Criteria: October 13, 2007
• First Posted (Estimate): October 16, 2007

Study Record Updates

• Last Update Posted (Estimate): May 30, 2016
• Last Update Submitted That Met QC Criteria: May 27, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: squamous cell carcinoma of the esophagus; adenocarcinoma of the esophagus; stage IIIA esophageal cancer; stage IIIB esophageal cancer; stage IIIC esophageal cancer; stage IV 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Fluorouracil; Cetuximab
• Other Study ID Numbers: CDR0000564075; FFCD-0505; EU-20756; EUDRACT-2006-004770-27; MERCK-FFCD-0505