Phase III Study of Mitomycin-C with Protracted Venous Infusion or Circadian-Timed Infusion of 5-Fluorouracil in Advanced Colorectal Carcinoma

• Published in: Clinical colorectal cancer Vol. 3; no. 4; pp. 235 - 242
• Main Authors: Price, Timothy J., Ross, Paul J., Hickish, Tamas, Tait, Diana, Norman, Andy R., Ford, Hugo E.R., Middleton, Gary, Sumpter, Kate, Hill, Mark, Oates, Jacqui, Cunningham, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2004
• Subjects: Adenocarcinoma - drug therapy; Antineoplastic Agents - administration & dosage; Circadian Rhythm; Colorectal Neoplasms - drug therapy; Fluorouracil - administration & dosage; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Metastatic disease; Mitomycin - administration & dosage; Oxaliplatin; Palmar—plantar erythema; Radiation therapy; Survival Analysis; Treatment Outcome; Irinotecan; Metastatic disease; Leucovorin; Oxaliplatin; Radiation therapy; Palmar—plantar erythema
• ISSN: 1533-0028; 1938-0674
• DOI: 10.3816/CCC.2004.n.004

The combination of protracted venous infusion (PVI) fluorouracil (5-FU) and mitomycin-C has previously been shown to be superior to PVI 5-FU alone in terms of response rate and failure-free survival. This study explores the effect of dose intensification by circadian timing of 5-FU in this combination on response, toxicity, and survival. Patients with advanced colorectal carcinoma were randomized to receive PVI 5-FU 300 mg/m 2 daily or circadiantimed infusion (CTI) of 5-FU, beginning at 600 mg/m 2 and subsequently reduced to 450 mg/m 2, delivered as a flat-rate infusion from 10:15 PM to 9:45 AM. Both groups received mitomycin-C at a dose of 7 mg/m 2 given every 6 weeks. From April 1996 to August 1998, 320 patients were randomized, including 263 with metastatic disease and 21 with circumferential margin involvement. The overall response rate for the PVI 5-FU group was 38%, compared with 30.3% for the CTI group ( P = 0.176). There was no statistically significant difference in terms of failure-free survival (8.0 months vs. 9.9 months; P = 0.131) or overall survival (15.8 months vs. 16.3 months; P = 0.275) between the treatment groups. There were no differences in global quality of life. Grade 3/4 diarrhea occurred significantly more frequently with CTI 5-FU (6.5% vs. 19.8%; P < 0.001); a nonsignificant trend toward increased incidences of grade 3/4 infection and palmar—plantar erythema were observed with CTI 5-FU. This study confirms the high response rate and overall survival figures for the combination of PVI 5-FU and mitomycin-C in colorectal cancer. However, dose intensification of 5-FU using a circadian-timed, flat-rate infusion did not lead to improved response or survival.