title: Randomized, multicenter, phase IIb study of preoperative chemoradiotherapy in T3 mid-distal rectal cancer: raltitrexed + oxaliplatin + radiotherapy versus cisplatin + 5-fluorouracil + radiotherapy.
abstract: OBJECTIVE
  To prospectively compare the rates of pathologic response, acute toxicity, and sphincter preservation with two different schedules of preoperative chemoradiotherapy in patients with cT3 mid-distal rectal cancer.
  
  
  METHODS
  Patients with cT3 and/or N+ resectable rectal carcinoma were randomized to receive one of the two following chemoradiotherapy regimens: cisplatin, 5-fluorouracil, and radiotherapy (PLAFUR) or raltitrexed, oxaliplatin, and radiotherapy (TOMOX-RT). For PLAFUR, cisplatin (60 mg/m(2)) was given on Days 1 and 29, with a prolonged infusion of 5-fluorouracil (1,000 mg/m(2)) on Days 1-4 and 29-32, plus concurrent radiotherapy (50.4 Gy in 1.8-Gy fractions daily). For TOMOX-RT, raltitrexed (3 mg/m(2)) and oxaliplatin (130 mg/m(2)) was given on Days 1, 19, and 38 with the same radiotherapy regimen as used for PLAFUR. Surgery was performed 6-8 weeks after completion of chemoradiotherapy. All pathologic specimens were reviewed by a designated expert pathologist. The primary endpoint of this study was pathologic tumor downstaging (defined as tumor regression grade 1-2). Secondary endpoints included the incidence of ypT0, clinical tumor downstaging, sphincter-saving surgery, and acute treatment-related toxicity.
  
  
  RESULTS
  Between 2002 and 2005, 164 patients were accrued in 10 Italian centers, 83 patients in the PLAFUR arm and 81 in the TOMOX-RT arm. Overall, tumor regression grade 1-2 was observed in 76 patients (46.4%) and ypT0 in 49 (29.9%). The tumor regression grade 1-2 rate was 41.0% vs. 51.9% (p = 0.162) and the ypT0 rate was 24.1% vs. 35.8% (p = 0.102) for the PLAFUR vs. TOMOX-RT arm, respectively. The overall rate of tumor regression grade 1 and ypN+ was 4.6%. The occurrence of ypT downstaging was significantly greater in the TOMOX-RT arm (p = 0.035). Grade 3-4 acute toxicity occurred in 19 patients (11.6%): 7.1% in the PLAFUR arm vs. 16.4% in the TOMOX-RT arm. Sphincter-saving surgery was performed in 143 patients (87.2%) overall: 87.9% in the PLAFUR arm and 86.4% in the TOMOX-RT arm.
  
  
  CONCLUSIONS
  Compared with the PLAFUR regimen, TOMOX-RT achieved a greater incidence of downstaging but was associated with a correspondingly greater rate of acute Grade 3+ toxicity. With longer follow-up, the local control and survival rates might offer additional guidance as to the choice of regimen.
authors.affiliation: Department of Radiation Therapy, Università Cattolica Sacro Cuore, Rome, Italy. vvalentini@rm.unicatt.it
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Valentini
authors.forename: Claudio
authors.initials: C
authors.lastname: Coco
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Minsky
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Gambacorta
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cosimelli
authors.forename: Rita
authors.initials: R
authors.lastname: Bellavita
authors.forename: Alessio G
authors.initials: AG
authors.lastname: Morganti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Torre
authors.forename: Lucio
authors.initials: L
authors.lastname: Trodella
authors.forename: Domenico
authors.initials: D
authors.lastname: Genovesi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Portaluri
authors.forename: Riccardo
authors.initials: R
authors.lastname: Maurizi-Enrici
authors.forename: Fernando
authors.initials: F
authors.lastname: Barbera
authors.forename: Ernesto
authors.initials: E
authors.lastname: Maranzano
authors.forename: Marco
authors.initials: M
authors.lastname: Lupattelli
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D009944:Organoplatinum Compounds; D011799:Quinazolines; D013876:Thiophenes; D000077150:Oxaliplatin; C068874:raltitrexed; D002945:Cisplatin; D005472:Fluorouracil