title: A phase I-II study on a gemcitabine-cyclophosphamide-fluorouracil/folinic acid triplet combination in anthracycline- and taxane-refractory breast cancer patients.
abstract: OBJECTIVE
  To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes.
  
  
  METHODS
  Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned.
  
  
  RESULTS
  Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61).
  
  
  CONCLUSIONS
  The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.
authors.affiliation: Division of Medical Oncology A, National Tumor Institute of Naples, Naples, Italy. gifrasci@sirio-concology.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Frasci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Aiuto
authors.forename: Pasquale
authors.initials: P
authors.lastname: Comella
authors.forename: Renato
authors.initials: R
authors.lastname: Thomas
authors.forename: Immacolata
authors.initials: I
authors.lastname: Capasso
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.forename: Giuseppina Rosa
authors.initials: GR
authors.lastname: Cortino
authors.forename: Maurizio
authors.initials: M
authors.lastname: Di Bonito
authors.forename: Rosaria
authors.initials: R
authors.lastname: Rubulotta
authors.forename: Paolo
authors.initials: P
authors.lastname: Vallone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Comella
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000494:pharmacology; D015996:Survival Rate; D043823:Taxoids; D000093542:Gemcitabine
chemical_list: D018943:Anthracyclines; D001952:Bridged-Ring Compounds; D043823:Taxoids; D003841:Deoxycytidine; C080625:taxane; D003520:Cyclophosphamide; D017239:Paclitaxel; D002955:Leucovorin; D005472:Fluorouracil; D000093542:Gemcitabine