title: A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.
abstract: BACKGROUND
  Oxaliplatin (OXA) significantly enhanced the antitumour activity of 5-fluorouracil (FUra) in patients with advanced colorectal cancer and displayed radiosensitising properties in preclinical studies. This study was thus performed to test the feasibility, identify the recommended doses (RDs) and explore preliminarily the clinical activity of weekly OXA and infused FUra combined with preoperative pelvic radiotherapy.
  
  
  METHODS
  Forty-six patients with recurrent or locally advanced (cT3-4 and/or N+) adenocarcinomas of the mid-low rectum were treated with escalating doses of OXA (25, 35, 45, 60 mg/m2, weekly for 6 weeks) and FUra (200-225 mg/m2/day, 6-week infusion) concurrent to preoperative pelvic radiotherapy (50.4 Gy/28 fractions). The RDs for the phase II part of the study were immediately below the level resulting in dose-limiting toxicities in more than one third of the patients, or corresponded to the last planned dose level.
  
  
  RESULTS
  In the escalation phase, dose-limiting toxicities only occurred in one patient at the fourth level and one of six patients treated at the last planned dose level (grade III diarrhoea). OXA 60 mg/m2 and FUra 225 mg/m2/day are therefore the RDs for the regimen. Among 25 patients globally treated at these doses (phase II part), the incidence of grade III diarrhoea was 16% with no grade IV toxicity. Neurotoxicity did not exceed grade II (12%). All patients completed radiotherapy and were operated on as scheduled. Twenty-one of 25 patients had the tumour down-staged after chemoradiation with seven (28%) pathological complete responses and 12 (48%) residual tumours limited to ypT1-2N0.
  
  
  CONCLUSIONS
  Weekly OXA, at doses potentially active systemically, can be combined with full-dose, infused FUra and radiotherapy. Given the low toxicity and promising activity, this regimen is being compared to standard FUra-based pelvic chemoradiation in a randomised study.
authors.affiliation: Department of Medical Oncology, Radiotherapy and Surgery, Padova University Hospital, Padova. aschele@tin.it
authors.forename: C
authors.initials: C
authors.lastname: Aschele
authors.forename: M L
authors.initials: ML
authors.lastname: Friso
authors.forename: S
authors.initials: S
authors.lastname: Pucciarelli
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.forename: L
authors.initials: L
authors.lastname: Sartor
authors.forename: G
authors.initials: G
authors.lastname: Fabris
authors.forename: E D L
authors.initials: ED
authors.lastname: Urso
authors.forename: P
authors.initials: P
authors.lastname: Del Bianco
authors.forename: G
authors.initials: G
authors.lastname: Sotti
authors.forename: M
authors.initials: M
authors.lastname: Lise
authors.forename: S
authors.initials: S
authors.lastname: Monfardini
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011300:Preoperative Care; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil