Bevacizumab, Cisplatin, Radiation Therapy, and Fluorouracil in Treating Patients With Stage IIB, Stage III, Stage IVA, or Stage IVB Nasopharyngeal Cancer

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of bevacizumab and chemoradiotherapy comprising cisplatin and radiotherapy followed by adjuvant therapy comprising cisplatin, fluorouracil, and bevacizumab in patients with stage IIB-IVB nasopharyngeal cancer.

SECONDARY OBJECTIVES:

I. Determine the 1- and 2-year rates of locoregional progression-free in patients treated with this regimen.

II. Determine the 1- and 2-year rates of distant metastases-free in patients treated with this regimen.

III. Determine the 1- and 2-year rates of progression-free and overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter study.

BEVACIZUMAB AND CHEMORADIOTHERAPY: Patients receive bevacizumab IV over 30-90 minutes and cisplatin IV over 20-30 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Beginning in week 1, patients also undergo three-dimensional conformal radiotherapy or intensity-modulated radiotherapy once daily 5 days a week for a total of 33 fractions.

ADJUVANT THERAPY: Beginning in week 10, patients receive fluorouracil IV continuously over 96 hours on days 1-4, cisplatin IV over 20-30 minutes on day 1 OR days 1 and 2, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Inclusion criteria

• Histologically confirmed cancer of the nasopharynx based on biopsy of a primary lesion and/or lymph nodes

• Histologic WHO types I-IIb/III
• Stage IIB-IVB disease

• No T1-2, N1 disease in which node positivity is based on the presence of retropharyngeal lymph nodes
• No distant metastases
• Zubrod performance status 0-1
• WBC ? 4,000/mm?
• Hemoglobin ? 9.0 g/dL
• Platelet count ? 100,000/mm?
• Absolute neutrophil count ? 1,500/mm?
• INR ? 1.5
• aPTT ? 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ? 1.5 times ULN
• ALT and AST ? 1.5 times ULN
• Bilirubin ? 1.5 times ULN
• Creatinine ? 1.5 mg/dL OR creatinine clearance ? 55 mL/min
• Urine protein:creatinine (UPC) ratio < 1.0

• If UPC > 0.5, 24-hour urine protein must be < 1,000 mg
• Hearing loss primarily sensorineural in nature and requiring a hearing aid or intervention that interferes in a clinically significant way with activities of daily living allowed
• Conductive hearing loss from tumor-related otitis media is allowed
• No severe, active comorbidity, including any of the following:

• Ongoing bleeding diathesis, hemorrhagic disorder, or coagulopathy within the past 6 months
• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• Esophageal varices, nonhealing wound, nonhealing ulcer, or bone fracture within the past 6 months
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 30 days
• Unstable angina and/or congestive heart failure or peripheral vascular disease requiring hospitalization within the past 12 months
• Major medical or psychiatric illness that, in the opinion of the study investigator, would preclude study compliance
• Active, untreated infection and/or acute bacterial or fungal infection requiring intravenous antibiotics
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• History of significant weight loss (> 15% from baseline)
• History of arterial thromboembolic events
• Acquired immune deficiency syndrome
• Transmural myocardial infarction
• Cerebrovascular accident
• Transient ischemic attack
• Any other cardiac condition that, in the opinion of the investigator, would preclude study compliance
• No gross hemoptysis or hematemesis, defined as bright red blood of ? 1 teaspoon per coughing episode, within the last 4 weeks (incidental blood mixed with phlegm allowed)
• No other invasive malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the breast, oral cavity, or cervix
• Nutritional and physical condition considered suitable for study treatment
• No significant traumatic injury within the past 4 weeks
• No history of allergic reaction to the study drugs
• No baseline blood pressure > 150/100 mm Hg
• No peripheral neuropathy ? grade 2
• Not pregnant or nursing
• Negative serum pregnancy test
• Fertile patients must use effective contraception during and for ? 6 months after completion of study treatment
• At least 10 days since prior and no concurrent dipyridamole, ticlopidine, clopidogrel bisulfate, cilostazol, warfarin, heparin, daily treatment with acetylsalicylic acid (> 325 mg/day), or nonsteroidal anti-inflammatory medications known to inhibit platelet function
• No prior head and neck surgery of the primary tumor or lymph nodes except for incisional or excisional biopsies

• More than 15 days since prior biopsies
• More than 1 week since prior fine-needle aspirations or placement of percutaneous gastrostomy tube
• More than 4 weeks since prior major surgical procedures
• No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• No prior bevacizumab or other vascular endothelial growth factor-targeting agents
• No prior systemic chemotherapy for the study cancer

• Prior chemotherapy for a different cancer allowed
• No concurrent hematologic growth factors (e.g. filgrastim [G-CSF], darbepoetin alfa, epoetin alfa) during study chemoradiotherapy
• No concurrent prophylactic growth factors for neutropenia during study adjuvant therapy
• No concurrent prophylactic amifostine or pilocarpine
• No other concurrent experimental therapeutic cancer treatments