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