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

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as irinotecan 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 bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of esophageal cancer by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and monoclonal antibody therapy together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving irinotecan, cisplatin, and bevacizumab together with radiation therapy followed by surgery and bevacizumab works in treating patients with locally advanced esophageal cancer.

Detailed Description
-----------------
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.

Official Title
-----------------
Phase II Trial of Irinotecan, Cisplatin, Bevacizumab and Concurrent Radiotherapy in Locally Advanced Esophageal Adenocarcinoma

Conditions
-----------------
Esophageal Cancer

Intervention / Treatment
-----------------
* Biological: bevacizumab
* Drug: cisplatin
* Drug: irinotecan hydrochloride
* Genetic: proteomic profiling
* Other: diagnostic laboratory biomarker analysis
* Other: mass spectrometry
* Procedure: adjuvant therapy
* Procedure: neoadjuvant therapy
* Procedure: therapeutic conventional surgery
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger<br>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 | Biological: bevacizumab<br> <br> Drug: cisplatin<br> <br> Drug: irinotecan hydrochloride<br> <br> Genetic: proteomic profiling<br> <br> Other: diagnostic laboratory biomarker analysis<br> <br> Other: mass spectrometry<br> <br> Procedure: adjuvant therapy<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: therapeutic conventional surgery<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Safety and Toxicity | All toxicity will be graded according to the National Cancer Institute (NCI) Common Toxicity Criteria v3.0. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adenocarcinoma of the esophagus, recurrent esophageal cancer, stage III esophageal cancer, stage II esophageal cancer