A phase I-II study on a gemcitabine-cyclophosphamide-fluorouracil/folinic acid triplet combination in anthracycline- and taxane-refractory breast cancer patients

Giuseppe Frasci, Giuseppe D'aiuto, Pasquale Comella, Renato Thomas, Immacolata Capasso, Gerardo Botti, Giuseppina Rosa Cortino, Maurizio Di Bonito, Rosaria Rubulotta, Paolo Vallone, Giuseppe Comella

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Purpose: 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 ≤ 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/m2, 5-FU 425 mg/m2, LFA 100 mg/m2 and escalating doses of CTX, starting from 500 mg/m2, on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occured 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/m2 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/m2 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, occuring 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/m2 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.

Original languageEnglish
Pages (from-to)25-32
Number of pages8
Issue number1
Publication statusPublished - 2002


  • Breast cancer
  • Cyclophosphamide
  • Fluorouracil
  • Folinic acid
  • Gemcitabine
  • Triplet chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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