Journal
CLINICAL COLORECTAL CANCER
Volume 9, Issue 2, Pages 119-125Publisher
CIG MEDIA GROUP, LP
DOI: 10.3816/CCC.2010.n.017
Keywords
Maximum tolerated dose; NF-kappa B; PS-341; Proteasome inhibitors
Categories
Funding
- National Cancer Institute [P50CA106991, P50CA95103, UL1 RR024975, P30 CA068485, K23CA118431]
- Amgen
- Astellas
- Bristol-Myers Squibb Company
- Genentech, Inc.
- Idera Pharmaceuticals, Inc.
- ImClone Systems Incorporated
- Merck KGaA
- Pfizer Inc.
- Plexxikon, Inc.
- Roche Pharmaceuticals
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Background: Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation. Patients and Methods: Patients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m(2)/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies. Results: Nine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m(2) dose level. There was no clear evidence of suppression of nuclear factor-kappa B target gene expression in biopsy samples. Conclusion: The MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.
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