Intensity-Modulated Radiation Therapy, Cisplatin, and Bevacizumab Followed by Carboplatin and Paclitaxel in Treating Patients Who Have Undergone Surgery for Endometrial Cancer

PRIMARY OBJECTIVE:

I. To assess the treatment-related, grade 3+, non-hematologic adverse-event rate within 90 days from the start of treatment with concurrent intensity-modulated radiotherapy, cisplatin, and bevacizumab followed by carboplatin and paclitaxel in patients with high-risk endometrial cancer.

SECONDARY OBJECTIVES:

I. To evaluate treatment-related adverse events occurring within 1 year from the start of treatment.

II. To evaluate all treatment-related adverse events. III. To evaluate disease-free and overall survival. IV. To evaluate local, regional, and distant failure.

OUTLINE:

Patients undergo pelvic intensity-modulated radiotherapy (IMRT) once daily, 5 days a week, for 5 weeks. Patients may also undergo optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Patients also receive concurrent cisplatin intravenously (IV) over 1 hour on days 1 and 29 and bevacizumab IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin IV over 1 hour and paclitaxel IV over 3 hours on day 1. Treatment with carboplatin and paclitaxel repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Inclusion criteria

• Histologically confirmed endometrial cancer, including 1 of the following cellular types:

• Endometrioid endometrial adenocarcinoma
• Clear cell carcinoma
• Papillary serous adenocarcinoma
• Adenosquamous cell carcinoma
• Other adenocarcinoma variant
• No carcinosarcoma
• Meets 1 of the following criteria:

• Grade 3 carcinoma with > 50% myometrial invasion (stage IC or IIA) (all papillary serous or clear cell carcinoma will be considered grade 3)
• Grade 2 or 3 carcinoma with any cervical stromal invasion (stage IIB)
• Known extra-uterine disease confined to the pelvis (stage III or IVA)

• Patients with stage III or IVA disease must have undergone computed tomography (CT) scan or positron emission tomography (PET)/CT scan of the abdomen and pelvis within the past 56 days
• Has undergone hysterectomy (i.e., total abdominal, vaginal, robotic-assisted, radical, or laparoscopic-assisted vaginal hysterectomy) and bilateral salpingo-oophorectomy within the past 56 days
• No positive common iliac or positive para-aortic nodal disease (defined as lymph nodes ? 2 cm in any dimension on CT scan or biopsy) or positive peritoneal cytology
• No evidence of metastatic extrauterine disease, gross or residual disease (not including pelvic nodal disease), or distant metastases
• Zubrod performance status 0-1
• Absolute neutrophil count (ANC) ? 1,500/mm^3 (without growth factor support)
• Platelet count ? 100,000/mm^3
• Hemoglobin ? 10 g/dL (transfusion allowed)
• Total bilirubin ? 1.5 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2 times ULN
• Serum creatinine ? 1.5 mg/dL
• Urine protein:creatinine ratio ? 0.5 OR urine protein < 1,000 mg on 24-hour urine collection
• International normalized ratio (INR) < 1.5 (for patients treated with warfarin within the past 14 days)
• Not nursing
• No neuropathy ? Common Terminology Criteria for Adverse Events (CTCAE) grade 1
• No ototoxicity > CTCAE grade 2
• No serious, active comorbidity, including any of the following:

• Unstable angina and/or New York Heart Association (NYHA) class II-IV congestive heart failure requiring hospitalization within the past 12 months
• Transmural myocardial infarction within the past 12 months
• Acute bacterial or fungal infection requiring IV antibiotics
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control (CDC) definition (human immunodeficiency virus [HIV] testing is not required)
• Active gastrointestinal (GI) ulcers, GI bleeding, inflammatory bowel disease, or GI obstruction
• Inadequately controlled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg and/or diastolic BP > 90 mm Hg on antihypertensive medications
• Significant vascular disease, including aortic aneurysm, aortic dissection, or arteriovenous malformation within the past 12 months
• Serious cardiac arrhythmia on medication (well-controlled atrial fibrillation on medication allowed)
• Serious non-healing wound, ulcer, or bone fracture
• No history of hypertensive crisis or hypertensive encephalopathy
• No stroke/cerebrovascular event within the past 12 months
• No arterial thromboembolic events, including transient ischemic attack or clinically symptomatic peripheral artery disease within the past 12 months
• No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 6 months
• No other invasive malignancies within the past 3 years other than nonmelanomatous skin cancer
• No significant trauma within the past 28 days
• No mental status changes or bladder problems that would preclude the ability to comply with bladder-filling instructions
• No mental or psychiatric illness that would preclude giving informed consent
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• No prior allergic reaction to bevacizumab, cisplatin, carboplatin, or paclitaxel
• No concurrent erythropoietin, St. John's wort, therapeutic anticoagulants, aminoglycoside antibiotics, or amifostine
• No prior organ transplantation
• No prior external-beam radiotherapy to the pelvis resulting in overlapping of radiotherapy fields
• No prior systemic chemotherapy for uterine cancer

• Prior chemotherapy for a different cancer is allowed
• No prior therapy with anti-vascular endothelial growth factor (VEGF) compounds
• More than 28 days since prior major surgical procedure requiring open biopsy incision
• No concurrent surgery (except for vascular access device placement or procedures that do not require significant incision)
• No concurrent warfarin at doses > 1 mg/day

• Concurrent prophylactic low molecular weight heparin allowed