Combination Chemotherapy and Cetuximab in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer

1. Metastatic disease of the esophagus or gastroesophageal junction 1. Histologic, cytologic or radiologic documentation of metastatic squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction. Radiologic, endoscopic, histologic or cytologic evidence of locally recurrent or locally residual (post-resection) disease is also permitted. 2. For the purposes of this study, undifferentiated adenocarcinomas and adenosquamous tumors will be considered as adenocarcinomas. In addition, tumors involving the gastroesophageal junction will be defined by the Siewert classification. 3. Patients with gastroesophageal junction tumors who are eligible: * AEG Type I: Adenocarcinoma of the distal esophagus which usually arises from an area with specialized intestinal metaplasia of the esophagus (eg, Barrett's esophagus, and may infiltrate the esophagogastric junction from above). * AEG Type II: True carcinoma of the cardia arising from the cardiac epithelium or short segments with intestinal metaplasia at the esophagogastric junction. 4. Patients with gastroesophageal junction tumors who are NOT eligible: * AEG Type III: Subcardial gastric carcinoma which infiltrates the esophagogastric junction and distal esophagus from below. 2. Patients must have at least one paraffin block available (or at least 15 unstained slides for analysis of tumor EGFR status. 1. Patients with a history of esophageal and GE junction carcinoma treated by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease OR the primary cancer was stage I. 2. Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic esophageal or GE junction carcinoma if there is substantial clinical ambiguity regarding the nature or source of apparent metastases. 3. Patients with Measurable Disease - Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan. 4. Prior Treatment: 1. No prior chemotherapy or radiotherapy. No prior therapy which specifically and directly targets the EGF(R) pathway. 2. No prior allergic reaction to chimerized or murine monoclonal antibody therapy or documented presence of human anti-mouse antibodies (HAMA). 3. Patients must have completed any major surgery ≥ 4 weeks or any minor surgery ≥ 2 weeks before registration. Patients must have fully recovered from the procedure. Insertion of a vascular access device is not considered major or minor surgery. 4. No concurrent use of investigational agents is allowed while participating in this study. 5. Patient Characteristics: 1. ECOG Performance Status of 0-2 2. ≥ 18 years of age 3. Patients must be documented to have a stable weight (or less than one pound weight loss) for at least one week prior to registration. 4. Non-pregnant and not breast-feeding. The effects of cetuximab, cisplatin, epirubicin, fluorouracil, leucovorin, irinotecan, and oxaliplatin on a developing human fetus are not well-known. Because the risk of toxicity in nursing infants secondary to cetuximab, cisplatin, epirubicin, fluorouracil, irinotecan, and oxaliplatin treatment of the mother is unknown but may be harmful, breastfeeding must be discontinued. 6. No myocardial infarction \< 6 months prior to registration or New York Heart Association classification III or IV. 7. No ≥ grade 2 diarrhea within 7 days prior to registration. 8. Patients may not concurrently have any of the following conditions: 1. Known central nervous system metastases or carcinomatous meningitis 2. Interstitial pneumonia or symptomatic interstitial fibrosis of the lung 3. Seizure disorder or active neurological disease requiring anti-epileptic medication 4. ≥ grade 2 peripheral neuropathy 9. No evidence of Gilbert's Syndrome - Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38, the active metabolite of irinotecan. Evidence of Gilbert's Syndrome would include documentation of elevation of indirect bilirubin at any time in the patient's medical history. 10. Required Initial Laboratory Data: 1. Granulocytes ≥ 1500/µl 2. Platelet count ≥ 100,000/µl 3. Creatinine ≤ 1.5 mg/dL 4. AST (SGOT) ≤ 5.0 x Upper limits of normal 5. Total bilirubin ≤ 1.5 mg/dL 6. Albumin ≥ 2.5 grams/dL