Bortezomib, Fluorouracil, and External-Beam Radiation Therapy in Treating Patients With Stage II, Stage III, or Stage IV Rectal Cancer

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of bortezomib when administered in combination with fluorouracil and external beam radiotherapy as preoperative or palliative treatment in patients with stage II-IV rectal adenocarcinoma.
• Determine the dose-limiting toxicities of this regimen in these patients.

Secondary

• Determine the dose-effect relationship of bortezomib on NF-kappa B activation induced by chemoradiotherapy.
• Determine downstream events induced by NF-kappa B activation.
• Determine downstream events related to activation of p53 in response to treatment with chemoradiotherapy and bortezomib.
• Determine the rate of complete pathologic remission in patients who undergo surgical resection of their primary tumor.
• Determine the gene expression pattern of tumors by cDNA microarray analysis before and during treatment with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib.

Patients receive bortezomib IV on days 1, 4, 8, 11, 22, 25, 29, and 32 and fluorouracil IV continuously on days 2-38. Patients also undergo external beam radiotherapy 5 days a week for 5½ weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients undergo tissue biopsy at baseline and on days 1 and 2. Samples are collected and evaluated by tissue microarray analysis for NF-kappa B pathway activation; cDNA analysis, RNase protection assay, and immunohistochemistry for analysis of downstream events induced by NF-kappa B activation; and modified TdT-mediated dUTP nick-end label for analysis of apoptosis by DNA fragmentation. NF-kappa B subunits are quantified by enzyme-linked immunosorbent assay. Serum samples are collected at baseline and stored for future studies.

After completion of study treatment, patients are followed every 3 months for up to 2 years.

DISEASE CHARACTERISTICS:

• Biopsy confirmed diagnosis of adenocarcinoma of the rectum meeting 1 of the following clinical staging criteria:

• T3-T4, N0, M0 (stage II disease)

• T4 disease defined as tumor fixed on examination or involving adjacent pelvic structures, such as the sidewall, bladder, uterus, prostate, or small bowel by ultrasound or CT scan
• Any T, N1-2, M0 (stage III disease)
• Any T, any N, M1 (stage IV disease)
• Recurrent disease (any prior stage)
• Candidate for local palliative therapy or curative resection of metastatic disease
• Previously treated CNS disease allowed provided it is stable for > 3 months

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy > 3 months
• Adequate nutrition
• WBC ≥ 4,000/mm³
• ANC > 2,000/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min
• Bilirubin ≤ 1.5 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No serious medical or psychiatric illness that would limit study compliance or limit survival to < 2 years
• No history of refractory congestive heart failure or cardiomyopathy
• No active coronary artery disease, myocardial infarction within the past 3 months, or cerebrovascular accident within the past 3 months
• No peripheral neuropathy ≥ grade 2
• No hypersensitivity to bortezomib, boron, or mannitol

PRIOR CONCURRENT THERAPY:

• More than 1 week since prior major surgery
• More than 28 days since prior investigational agents
• Prior chemotherapy allowed
• No prior pelvic radiotherapy (for treatment of any pelvic malignancy)
• No concurrent herbal medication (excluding vitamin and mineral supplements)
• No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)