title: Postoperative radiation and concomitant bolus fluorouracil with or without additional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.
abstract: BACKGROUND
  Randomized studies have shown that postoperative chemotherapy with or without radiation therapy (RT) improved local control and survival of patients with stages II or III rectal cancer. However, the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a highly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced colorectal cancer. However, this difference in response rate did not translate into a survival benefit.
  
  
  OBJECTIVE
  To evaluate the impact on the disease-free survival (DFS) and overall survival (OS) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV.
  
  
  METHODS
  From October 1989 until February 1997, 220 patients were randomized postoperatively to receive either one cycle of chemotherapy with FU (600 mg/m2/week x 6 followed by a two-week rest) and leucovorin (LV, 500 mg/m2/week x 6 as a two-hour infusion) followed by pelvic RT with concomitant FU (400 mg/m2) as a rapid intravenous injection during the first three and last three days of RT, and three more cycles of the same chemotherapy with FU and LV (standard, group A, 111 patients) or pelvic RT with concomitant FU only (experimental, group B, 109 patients).
  
  
  RESULTS
  As of August 1998, after a median follow-up of 4.9 years, there was no significant difference in either three-year DFS (Group A, 70.3%; group B, 68.2%, P = 0.53) or OS (group A, 77%; group B, 73.3%. P = 0.75). Cox multivariate analysis revealed stage of disease, number of infiltrated nodes, tumor grade, presence of regional implants and perforation to be significant prognostic factors. The incidence of severe side effects was significantly higher in the patients in group A than in those in group B (32.4% vs. 4.6%, P < 0.0001).
  
  
  CONCLUSIONS
  The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a > or = 10% three-year survival benefit over that of concomitant RT and bolus infusion of FU, and significantly increases toxicity in patients with stages II or III rectal cancer.
authors.affiliation: Aristotle University of Thessaloniki Medical School, Greece. hecogoff@otenet.gr
authors.forename: G
authors.initials: G
authors.lastname: Fountzilas
authors.forename: A
authors.initials: A
authors.lastname: Zisiadis
authors.forename: U
authors.initials: U
authors.lastname: Dafni
authors.forename: C
authors.initials: C
authors.lastname: Konstantaras
authors.forename: G
authors.initials: G
authors.lastname: Hatzitheoharis
authors.forename: A
authors.initials: A
authors.lastname: Liaros
authors.forename: E
authors.initials: E
authors.lastname: Athanassiou
authors.forename: N
authors.initials: N
authors.lastname: Dombros
authors.forename: C
authors.initials: C
authors.lastname: Dervenis
authors.forename: G
authors.initials: G
authors.lastname: Basdanis
authors.forename: O
authors.initials: O
authors.lastname: Gamvros
authors.forename: A
authors.initials: A
authors.lastname: Souparis
authors.forename: E
authors.initials: E
authors.lastname: Briasoulis
authors.forename: E
authors.initials: E
authors.lastname: Samantas
authors.forename: A
authors.initials: A
authors.lastname: Kappas
authors.forename: P
authors.initials: P
authors.lastname: Kosmidis
authors.forename: D
authors.initials: D
authors.lastname: Skarlos
authors.forename: N
authors.initials: N
authors.lastname: Pavlidis
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D002955:Leucovorin; D005472:Fluorouracil