Cisplatin, Capecitabine, and Radiation Therapy With or Without Cetuximab in Treating Patients With Esophageal Cancer

OBJECTIVES:

Primary

* To determine whether the addition of cetuximab to definitive chemoradiotherapy comprising cisplatin, capecitabine, and radiotherapy shows evidence of enhanced overall survival in patients with carcinoma of the esophagus.
* To determine the safety of this regimen in these patients.
* To determine the feasibility of this regimen in these patients.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive cisplatin IV over 2 hours on days 1, 22, 43, and 64 and oral capecitabine twice daily on days 1-84. Beginning in week 7 patients also undergo radiotherapy 5 days a week for 5 weeks (weeks 7-11). Treatment continues in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive cisplatin and capecitabine and undergo radiotherapy as in arm I. Patients also receive cetuximab IV over 1-2 hours on day 1 in weeks 1-12. Treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life and health economics are assessed at baseline, during treatment, and at pre-specified time points during follow-up.

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then annually for a minimum of 5 years.

• cetuximab (Biological)
• capecitabine (Drug)
• cisplatin (Drug)
• radiation therapy (Radiation)

Primary outcomes

• Treatment-failure rate at 24 weeks
• Overall survival

Secondary outcomes

• Feasibility
• Toxicity
• Quality of life
• Quality of assurance
• Health economics

Sex: All, ages: 18 Years to any

DISEASE CHARACTERISTICS:

* Histologically confirmed carcinoma of the esophagus

  * Adenocarcinoma
  * Squamous cell
  * Undifferentiated carcinoma
  * Siewert type I tumor of the gastroesophageal junction
* Localized, nonmetastatic disease (T1-4, N0-1) confirmed by endoscopic ultrasound (EUS) and spiral CT scan
* Total disease length (primary and lymph nodes) < 10 cm by EUS
* Not suitable for surgery (either for medical reasons or patient's choice)
* No metastatic disease (i.e., M1a or M1b according to UICC TNM version 6)
* No significant (> 2 cm) extension of tumor into the stomach

PATIENT CHARACTERISTICS:

* WHO performance status 0-1
* Absolute neutrophil count ≥ 1,500/mm³
* White blood cell count ≥ 2,000/mm³
* Platelet count ≥ 100,000/mm³
* Hemoglobin ≥ 10 g/dL (should be corrected to > 10 g/dL before treatment)
* Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
* ALT/AST ≤ 2.5 times ULN
* Alkaline phosphatase ≤ 3 times ULN
* Glomerular filtration rate > 40 mL/min OR > 60 mL/min estimated by Cockcroft-Gault formula
* Adequate cardiac ejection fraction ≥ 40% by MUGA or ECHO
* FEV_1 ≥ 1 L by spirometry
* Not pregnant
* Negative pregnancy test
* Fertile patients must use effective contraception
* No malignancy within the past 5 years
* No unstable angina, uncontrolled hypertension, cardiac failure, or other clinically significant cardiac disease
* No major trauma within the past 4 weeks
* No known dihydropyrimidine dehydrogenase deficiency
* No hearing impairment or sensory-motor neuropathy > grade 2

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* At least 4 weeks since prior sorivudine and analogues
* At least 4 weeks since prior major surgery
* At least 4 weeks since prior monoclonal antibody
* At least 3 months since prior radiotherapy
* No prior treatment for invasive esophageal carcinoma or gastroesophageal junction carcinoma (not including photodynamic therapy or laser therapy for high-grade dysplasia/carcinoma in situ)
* No other prior treatment for this malignancy that would compromise the ability to deliver definitive mediastinal chemoradiotherapy or compromise survival

• Tom Crosby, MD, Study chair, Velindre NHS Trust