A Phase I Study of Bortezomib in Combination With Standard 5-Fluorouracil and External-Beam Radiation Therapy for the Treatment of Locally Advanced or Metastatic Rectal Cancer

作者：O'Neil Bert H^*; Raftery Laura; Calvo Benjamin F; Chakravarthy A Bapsi; Ivanova Anastasia; Myers Michael O; Kim Hong Jin; Chan Emily; Wise Paul E; Caskey Laura S; Bernard Stephen A; Sanoff Hanna K; Goldberg Richard M; Tepper Joel E

来源：Clinical Colorectal Cancer, 2010, 9(2): 119-125.

DOI：10.3816/CCC.2010.n.017

• Maximum tolerated dose
• NF-kappa B
• PS-341
• Proteasome inhibitors

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.

• 出版日期2010-4