title: Preoperative concomitant hyperfractionated radiotherapy and gemcitabine for locally advanced rectal cancers: a phase I-II trial.
abstract: OBJECTIVE
  The purpose of this study was to determine the maximum tolerated dose of gemcitabine when it was administered concomitantly with hyperfractionated radiotherapy before surgery in patients with locally advanced rectal cancers and to investigate the midterm efficacy of such a regimen.
  
  
  METHODS
  Thirty-seven patients with stage II-III tumors as assessed by computed tomography/echoendoscopy were enrolled. Radiotherapy consisted of 50 Gy given in two daily fractions of 1.25 Gy over 4 weeks. The starting dose of gemcitabine was 10 mg/m(2)/day (in a 30-minute i.v. perfusion) twice weekly with planned escalation steps of 5 mg/m(2)/day. Surgery was planned at 6 weeks after the end of radiotherapy. Main end-points of the study were complete pathological tumor response, the rate of clear margin resection, and actuarial locoregional control and disease-free survival. The median follow-up for all patients was 32 months (range: 10-51 months).
  
  
  RESULTS
  At the level of 45 mg/m(2), two of four patients presented with dose-limiting rectal toxicities (severe acute proctitis requiring hospitalization in the immediate postradiotherapy period). Thus, the gemcitabine biweekly dose of 40 mg/m(2) was considered to be the maximum tolerated dose. Among the 36 patients who underwent surgery, 17 (47%) had a marked pathological response, including six patients (17%) with a microscopically complete response and 11 (30%) with only microscopically residual carcinoma of less than 1 cm. All of them had clear surgical margins. At 3 years, actuarial overall survival rate was 85%, locoregional control was 94.5%, and disease-free survival was 67%.
  
  
  CONCLUSIONS
  The present study determined the recommended dose of gemcitabine to be 40 mg/m(2) when administered concurrently twice a week with 50 Gy hyperfractionated radiotherapy for the preoperative treatment of locally advanced rectal cancers. The encouraging pathological response rate and the very low locoregional recurrence rate suggest that this innovative approach merits further investigation.
authors.affiliation: Radiation Oncology Service, University Hospital of Geneva, 24 Rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. abdelkarim.allal@hcuge.ch
authors.forename: Abdelkarim S
authors.initials: AS
authors.lastname: Allal
authors.forename: Sabine
authors.initials: S
authors.lastname: Bieri
authors.forename: Pascal
authors.initials: P
authors.lastname: Gervaz
authors.forename: Claudio
authors.initials: C
authors.lastname: Soravia
authors.forename: Jacques
authors.initials: J
authors.lastname: Bernier
authors.forename: Philippe
authors.initials: P
authors.lastname: Gertsch
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Roth
mesh_terms: D000328:Adult; D000368:Aged; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011300:Preoperative Care; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D018714:Radiotherapy, Adjuvant; D020266:Radiotherapy, Conformal; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine