title: 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.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.forename: Laura
authors.initials: L
authors.lastname: Raftery
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Calvo
authors.forename: A Bapsi
authors.initials: AB
authors.lastname: Chakravarthy
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.forename: Michael O
authors.initials: MO
authors.lastname: Myers
authors.forename: Hong Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wise
authors.forename: Laura S
authors.initials: LS
authors.lastname: Caskey
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bernard
authors.forename: Hanna K
authors.initials: HK
authors.lastname: Sanoff
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Joel E
authors.initials: JE
authors.lastname: Tepper
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib; D005472:Fluorouracil