title: Phase I study of 5-fluorouracil and leucovorin by continuous infusion chronotherapy and pelvic radiotherapy in patients with locally advanced or recurrent rectal cancer.
abstract: OBJECTIVE
  To determine the maximal tolerated dose of chronomodulated 5-fluorouracil (5-FU) and leucovorin (LV) given concurrently with radiotherapy in patients with rectal cancer.
  
  
  METHODS
  Forty-five patients with T3, T4 or recurrent rectal cancer received concurrent radiotherapy to a minimal dose of 4500 cGy. Chemotherapy was administered by a programmable pump in chronomodulated fashion, with 62.5% of the total dose given within 7 hours around 9:30 pm. The starting doses were LV at 5 mg/m2/d and 5-FU at 150 mg/m2/d. LV was escalated in 5-mg/m2 increments to 20 mg/m2/d; 5-FU was then escalated in 25 mg/m2 increments to the maximal tolerated dose.
  
  
  RESULTS
  Diarrhea and stomatitis were dose limiting, with Grade 3 or worse toxicity occurring in 16% and 5% of patients, respectively. Thirty-seven patients (84%) received their scheduled dose of radiotherapy (range, 4500-6000 cGy). Thirty-two patients had clinical T3 disease; all were treated with definitive surgery; 23 (71%) underwent sphincter-sparing surgery with complete resection in 28 (87%). Ten patients (31%) had no evidence of tumor in the pathologic specimen.
  
  
  CONCLUSIONS
  Preoperative chemoradiotherapy in rectal cancer using chronomodulated 5-FU and LV is feasible. The recommended Phase II dose is 5-FU 200 mg/m2 and LV 20 mg/m2 daily for 5 weeks.
authors.affiliation: Department of Medical Oncology, Kingston Regional Cancer Center, Kingston, ON, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Parulekar
authors.forename: Robert W
authors.initials: RW
authors.lastname: de Marsh
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wong
authors.forename: William
authors.initials: W
authors.lastname: Mendenhall
authors.forename: Phillip
authors.initials: P
authors.lastname: Davey
authors.forename: Robert
authors.initials: R
authors.lastname: Zlotecki
authors.forename: Scott
authors.initials: S
authors.lastname: Berry
authors.forename: W Robert
authors.initials: WR
authors.lastname: Rout
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D019454:Chronotherapy; D003131:Combined Modality Therapy; D003967:Diarrhea / Q000209:etiology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010349:Patient Compliance; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D013280:Stomatitis / Q000209:etiology
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil