High-dose chronomodulated infusion of 5-fluorouracil (5-FU) and folinic acid (FA) (FF5-16) in advanced colorectal cancer patients

Edmondo Terzoli, Carlo Garufi, Albina Rita Zappalà, Barbara Vanni, Patrizia Pugliese, Giancarlo Antonini Cappellini, Anna Maria Aschelter, Maria Perrone, Diana Giannarelli

Research output: Contribution to journalArticlepeer-review


Purpose: The best way to deliver infusional 5-fluorouracil (5-FU) and folinic acid (FA) has yet to be determined. The aim of this prospective phase II trial was to verify the tolerability, activity and efficacy of chronomodulated 5-FU-FA (FF5-16) every 3 weeks in 48 untreated patients (group A), and 28 pretreated and four non-measurable, advanced colorectal cancer (ACC) patients (group B). Methods: The sinusoidal delivery of both drugs started at 10.00 p.m. and ended at 10.00 a.m., with peak flow at 4.00 a.m. for 5 consecutive days. The initial 5-FU dose was 900 mg/m2/day with intra-patient dose increase at 1,000 and 1,100 mg/m2/day, at the second and third course, respectively; FA was injected at a fixed dose of 150 mg/m2/day (Garufi et al. 1997). Results: Neither death from toxicity nor hematological toxicities were encountered. Maximal toxicity consisted of Grade 3 oral mucositis in 41% of patients, in only 8% of 535 courses. It was possible to achieve objective responses in 31% of untreated patients, with a progression free survival (PFS) of 7 months, median survival of 14 months and a 2-year survival rate of 28%. Similar results for PFS and survival were obtained in pretreated patients as well. Univariate analysis and multivariate analysis showed that response was related to the occurrence of mucositis and diarrhea (p = 0.03 and p = 0.0007) and to performance status (PS) (p = 0.01). Quality of life, measured with the EORTC QLQ-C30 + 3 questionnaire, was unaffected by treatment and was better in patients with good PS and responsiveness. Conclusions: In this chronomodulated FF5-16 phase II study, the probability of obtaining a relevant tumor reduction was significantly correlated with a patient variable such as PS, and toxicity variables such as mucositis and diarrhea. This observation and the validation of predictive factors for QoL deserve further investigation in ACC patients.

Original languageEnglish
Pages (from-to)445-452
Number of pages8
JournalJournal of Cancer Research and Clinical Oncology
Issue number8
Publication statusPublished - Aug 2004


  • 5-fluorouracil
  • Chronotherapy
  • Colorectal carcinoma
  • Leucovorin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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