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

Bert O'Neil, Laura Raftery, Benjamin Calvo, A. Bapsi Chakravarthy, Anastasia Ivanova, Michael Myers, Hong Jin Kim, Emily Chan, Paul Wise, Laura Caskey, Stephen Bernard, Hanna Sanoff, Richard Goldberg, Joel Tepper

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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/m2 dose level. There was no clear evidence of suppression of nuclear factor-κB 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.

Original languageEnglish
Pages (from-to)119-125
Number of pages7
JournalClinical Colorectal Cancer
Volume9
Issue number2
DOIs
StatePublished - Apr 1 2010

Keywords

  • Maximum tolerated dose
  • NF-κB
  • PS-341
  • Proteasome inhibitors

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