Irinotecan, Cisplatin, Bevacizumab, Radiation Therapy, and Surgery in Treating Patients With Locally Advanced Esophageal Cancer

OBJECTIVES:

Primary

• Evaluate the toxicity and safety of bevacizumab when given together with cisplatin, irinotecan hydrochloride, and radiotherapy followed by surgery and adjuvant bevacizumab in patients with locally advanced esophageal adenocarcinoma.

Secondary

• Observe the rate of pathologic complete response in patients treated with this regimen.
• Observe overall survival, disease-free survival, and patterns of failure in these patients.
• Clarify toxicity and tolerability of this regimen.
• Evaluate pre-treatment levels of vascular endothelial growth factor in patient serum as a corollary of response to this regimen.
• Correlate serum proteomics data with complete pathologic response.

OUTLINE: This is a nonrandomized, open-label study.

• Induction therapy: Patients receive cisplatin IV over 30 minutes and irinotecan hydrochloride IV over 30 minutes on days 1, 8, 22, and 29. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 22.
• Combination therapy and radiotherapy: Patients receive cisplatin and irinotecan hydrochloride as in induction chemotherapy on days 43, 50, 64, and 71. Patients also receive bevacizumab IV over 30-90 minutes on days 43 and 64. Patients undergo external beam radiotherapy 5 days a week for 6 weeks beginning on day 43.
• Surgery: Patients undergo surgery 6-8 weeks after finishing combination therapy and radiotherapy.
• Maintenance therapy: Approximately 6 weeks after surgery, patients receive bevacizumab IV over 30-90 minutes every 3 weeks for 6 months.

Blood samples are obtained at baseline, after finishing chemoradiotherapy, and prior to maintenance therapy and are examined by the matrix-assisted laser-desorption ionization time of flight (MALDI-TOF) mass spectometry for proteomic profiling.

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction

• T1, N1, M0 or T2-4, any N, M0 esophageal carcinoma that is surgically resectable
• Disease must be clinically limited to the esophagus or gastroesophageal junction

• If tumor extends below the gastroesophageal junction into the proximal stomach, 50% of the tumor must involve the distal esophagus or gastroesophageal junction
• No carcinoma in situ (Tis) or tumors determined to be T1, N0 after endoscopy, endoscopic ultrasound, or CT scan
• No gastric cancers with minor involvement of the gastroesophageal junction or distal esophagus
• No metastatic disease, including any of the following:

• M1a celiac or supraclavicular disease
• Positive malignant cytology of the pleura, pericardium, or peritoneum
• Radiographic evidence of distant organ involvement, including lung, liver, bone, or brain
• No involvement of nonregional lymph nodes including supraclavicular or celiac lymph node metastases that cannot be contained within a radiation field
• No biopsy-proven tumor invasion of the tracheobronchial tree or presence of tracheoesophageal fistula
• No recurrent laryngeal nerve or phrenic nerve paralysis
• No CNS or brain metastases

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9.0 g/dL
• INR ≤ 1.5 (except for patients requiring full-dose warfarin while on bevacizumab)
• Creatinine ≤ 1.5 mg/dL
• Bilirubin ≤ 1.5 mg/dL
• AST and ALT < 2.5 times normal
• Urine protein ≤ 1+ by urinalysis OR < 1 g of protein by 24-hour urine collection
• Calcium < 12 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other prior malignancy (except for basal cell or squamous cell carcinoma of the skin, in situ cervical carcinoma, or superficial transitional cell bladder carcinoma) diagnosed and/or treated within the past 3 years
• No known Gilbert's disease
• No clinically significant hearing loss
• No known hypersensitivity to bevacizumab or other study drugs
• No severe comorbid conditions, including any of the following:

• Severe uncontrolled diabetes
• Prior stroke or cerebrovascular disease
• Uncontrolled infection
• Nonmalignant illness that precludes study treatment
• No history of serious systemic disease, including any of the following:

• Myocardial infarction within the past 6 months
• Uncontrolled hypertension (i.e., blood pressure > 160/110 mm Hg on medication)
• Unstable angina
• New York Heart Association class II-IV congestive heart failure
• Unstable symptomatic arrhythmia requiring medication

• Chronic atrial arrhythmia (i.e., atrial fibrillation or paroxysmal supraventricular tachycardia) allowed
• Peripheral vascular disease ≥ grade 2
• No significant traumatic injury within the past 28 days
• No evidence of bleeding diathesis or coagulopathy
• No other concurrent medical or psychiatric condition or disease that would preclude study participation

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy
• Recovered from prior oncologic or other major surgery
• No major surgery or open biopsy within the past 28 days
• No fine-needle aspiration or core biopsies within the past 7 days
• At least 1 week since prior and no concurrent participation in another experimental drug study (unless Genentech sponsored)
• No other concurrent major surgery
• No other concurrent chemotherapy
• No concurrent sargramostim (GM-CSF)
• No concurrent phenytoin, carbamazepine, barbiturates, rifampin, phenobarbital, Hypericum perforatum (St. John's wort), or other antiepileptic medication