title: Is continuous 24-hour infusion of 5-fluorouracil plus high-dose folinic acid effective in patients with progressive or recurrent colorectal cancer? A phase II study.
abstract: BACKGROUND
  To evaluate the therapeutic activity of 24-hour continuously infused 5-fluorouracil (5-FU) modulated by high-dose folinic acid in patients with metastatic colorectal cancer who had recurred or progressed following mainly bolus 5-FU/folinic acid chemotherapy.
  
  
  METHODS
  Forty-two patients with a median age of 59 years (45-76) were enrolled. Karnofsky status was 90% (80-100), previous chemotherapy regimen bolus 5-FU/folinic acid (n=33, 79%) or 24-hour continuous 5-FU+/-interferon alpha2 (n=9, 21 %). Chemotherapy was given as a weekly infusion of 500 mg/m2 folinic acid over 2 h followed by a 24-hour continuous infusion of 2,600 mg/m2 5-FU for 6 consecutive weeks followed by a 2-week rest period.
  
  
  RESULTS
  No complete but 6 partial responses were observed (ORR: 14%, CI95%: 3.5-25.1%) with a median response duration of 7.3 months (range: 1.4-10.6). The median survival from the start of continuous infusion of 5-FU was 11.6 months (range: 2-27, CI95%: 9.4-13.8) and the 1-year survival rate was 46%. Disease stabilization and minor responses were achieved in another 25 patients (61%). WHO grade III/IV diarrhea occurred in 26% of patients, mucositis, nausea/vomiting and hand-foot syndrome in 5% each. Two cases of WHO grade III anemia and leukocytopenia were observed (5% each). Dose reductions had to be performed in 11 patients because of unacceptable diarrhea with subsequent stop of treatment in 2 patients. Progressive disease while receiving previous bolus 5-FU chemotherapy was associated with a lower response rate, shorter progression-free interval and overall survival compared to response and survival of patients who had achieved temporary disease stabilization during previous bolus 5-FU therapy.
  
  
  CONCLUSIONS
  Continuous infusion of 5-FU/folinic acid displays activity in pretreated and refractory colorectal cancer with acceptable toxicity. Patients who had achieved disease stabilization or objective remission with previous 5-FU bolus therapy appear to be more likely to benefit from second-line treatment. Questions remaining to be addressed include the optimal starting dose of continuously infused 5-FU and whether the dose of folinic acid can be reduced or completely eliminated with respect to toxicity and health economics.
authors.affiliation: Department of Hematology/Oncology/Immunology, Eberhard Karl University Medical Center II, Tübingen, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Hartmann
authors.forename: C H
authors.initials: CH
authors.lastname: Köhne
authors.forename: H J
authors.initials: HJ
authors.lastname: Schmoll
authors.forename: T
authors.initials: T
authors.lastname: Daikeler
authors.forename: L
authors.initials: L
authors.lastname: Kanz
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002955:Leucovorin; D005472:Fluorouracil