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

Clin Colorectal Cancer. 2010 Apr;9(2):119-25. doi: 10.3816/CCC.2010.n.017.


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/m2/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-kappaB 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma / radiotherapy
  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Boronic Acids / adverse effects
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Disease Progression
  • Drug Therapy, Combination
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Pyrazines / adverse effects
  • Pyrazines / therapeutic use*
  • Rectal Neoplasms / drug therapy*
  • Rectal Neoplasms / mortality
  • Rectal Neoplasms / pathology
  • Rectal Neoplasms / radiotherapy


  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Boronic Acids
  • NF-kappa B
  • Pyrazines
  • Bortezomib
  • Fluorouracil