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.