title: Infusional 5-fluorouracil and ZD1839 (Gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II Trial (1839IL/0092).
abstract: OBJECTIVE
  To report the final data of a Phase I and II study (1839IL/0092) on the combination of an anti-epidermal growth factor receptor drug (gefitinib), infusional 5-fluorouracil, and preoperative radiotherapy in locally advanced, resectable rectal cancer.
  
  
  METHODS
  Patients received 45 Gy in the posterior pelvis plus a boost of 5.4 Gy on the tumor and corresponding mesorectum. Infusional 5-fluorouracil (5-FU) and gefitinib (250 and 500 mg/day) were delivered during all radiotherapy course. An IORT boost of 10 Gy was allowed. The main endpoints of the study were to establish dose-limiting toxicity (DLT) and to evaluate the rate of pathologic response according to the tumor regression grade (TRG) Mandard score.
  
  
  RESULTS
  A total of 41 patients were enrolled. The DLT was not reached in the 6 patients enrolled in the dose-escalation part of the study. Of the 33 patients in the Phase II, TRG 1 was recorded in 10 patients (30.3%) and TRG 2 in 7 patients (21.2 %); overall 17 of 33 patients (51.5%) had a favorable endpoint. Overall, Grade 3+ toxicity was recorded in 16 patients (41%); these included Grade 3+ gastrointestinal toxicity in 8 patients (20.5%), Grade 3+ skin toxicity in 6 (15.3%), and Grade 3+ genitourinary toxicity in 4 (10.2%). A dose reduction of gefitinib was necessary in 24 patients (61.5%).
  
  
  CONCLUSIONS
  Gefitinib can be associated with 5-FU-based preoperative chemoradiation at the dose of 500 mg without any life-threatening toxicity and with a high pCR (30.3%). The relevant rate of Grade 3 gastrointestinal toxicity suggests that 250 mg would be more tolerable dose in a neaoadjuvant approach with radiotherapy and infusional 5-FU.
authors.affiliation: Department of Radiation, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Valentini
authors.forename: Antonino
authors.initials: A
authors.lastname: De Paoli
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Gambacorta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantini
authors.forename: Carlo
authors.initials: C
authors.lastname: Ratto
authors.forename: Fabio Maria
authors.initials: FM
authors.lastname: Vecchio
authors.forename: Brunella
authors.initials: B
authors.lastname: Barbaro
authors.forename: Roberto
authors.initials: R
authors.lastname: Innocente
authors.forename: Carlo
authors.initials: C
authors.lastname: Rossi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Boz
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Barba
authors.forename: Alessandro
authors.initials: A
authors.lastname: Frattegiani
authors.forename: Marco
authors.initials: M
authors.lastname: Lupattelli
authors.forename: Giovan Battista
authors.initials: GB
authors.lastname: Doglietto
mesh_terms: D001003:Anal Canal / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D003131:Combined Modality Therapy; D003967:Diarrhea / Q000139:chemically induced; D004361:Drug Tolerance; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000473:pathology; D000077156:Gefitinib; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity*; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery*; D012449:Safety
chemical_list: D011799:Quinazolines; D000077156:Gefitinib; D005472:Fluorouracil