title: Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer.
abstract: BACKGROUND
  To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer.
  
  
  METHODS
  Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6-9 weeks following the completion of chemoradiation.
  
  
  RESULTS
  Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3-4 toxicity occurred in 46.9% of patients. Grade 3-4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1-87.6%).
  
  
  CONCLUSIONS
  Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.
authors.affiliation: Departments of Medicine.
authors.forename: L S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: D P
authors.initials: DP
authors.lastname: Ryan
authors.forename: J
authors.initials: J
authors.lastname: Szymonifka
authors.forename: D R
authors.initials: DR
authors.lastname: Borger
authors.forename: A X
authors.initials: AX
authors.lastname: Zhu
authors.forename: J W
authors.initials: JW
authors.lastname: Clark
authors.forename: E L
authors.initials: EL
authors.lastname: Kwak
authors.forename: H J
authors.initials: HJ
authors.lastname: Mamon
authors.forename: J N
authors.initials: JN
authors.lastname: Allen
authors.forename: E
authors.initials: E
authors.lastname: Vasudev
authors.forename: P C
authors.initials: PC
authors.lastname: Shellito
authors.forename: J C
authors.initials: JC
authors.lastname: Cusack
authors.forename: D L
authors.initials: DL
authors.lastname: Berger
authors.forename: T S
authors.initials: TS
authors.lastname: Hong
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D011799:Quinazolines / Q000008:administration & dosage; D012004:Rectal Neoplasms / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; D005472:Fluorouracil
keywords: bevacizumab; erlotinib; radiation; rectal cancer