title: A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer.
abstract: BACKGROUND
  Gemcitabine is active in patients with otherwise resistant or refractory ovarian cancer. As the drug is well tolerated, studies using gemcitabine combined with other antineoplastic agents are needed. The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with gemcitabine, with and without support of G-CSF.
  
  
  METHODS
  Patients with platinum-resistant or refractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800 mg/m2 day 1 and 8; 200 mg/m2 escalation per level) and epirubicin (E) (starting dose 60 mg/m2 day 1; 15 mg/m2 escalation per level) were given every 21 days for four to six cycles. G-CSF (filgrastim 5 microg/kg/die) was given in case of grade 4 neutropenia (levels without support) or from day 9 up to leukocyte count > 10.000/mm3 after nadir (levels with support). Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. MTD was determined first without and then with G-CSF.
  
  
  RESULTS
  Four levels were studied (G 800 + E 60; G 1000 + E 60; G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and three patients enrolled, respectively. DLT (grade 4 febrile neutropenia) was observed in two patients at level 3. Thus, G1000 + E 60 mg/m2 was the MTD without G-CSF. The addition of prophylactic G-CSF did not allow a further increase of the dose and grade 4 thrombocytopenia was the DLT at level 4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in four patients. Among the 13 patients with measurable or evaluable disease, 3 partial responses were observed for an overall response rate of 23.1%.
  
  
  CONCLUSIONS
  The combination of gemcitabine 1000 mg/m2 (day 1, 8) and epirubicin at 60 mg/m2 (day 1) is a feasible therapy. Grade 4 neutropenia is frequent and G-CSF support is often required. With prophylactic support of G-CSF, the DLT is thrombocytopenia.
authors.affiliation: Divisione di Oncologia Medica B, Istituto Nazionale Tumori, Napoli, Italy. pignata@sirio-oncology.it
authors.forename: S
authors.initials: S
authors.lastname: Pignata
authors.forename: E
authors.initials: E
authors.lastname: Varriale
authors.forename: G
authors.initials: G
authors.lastname: Casella
authors.forename: F
authors.initials: F
authors.lastname: Iodice
authors.forename: G
authors.initials: G
authors.lastname: De Placido
authors.forename: F
authors.initials: F
authors.lastname: Perrone
authors.forename: F
authors.initials: F
authors.lastname: Tramontana
authors.forename: P
authors.initials: P
authors.lastname: Ricchi
authors.forename: R
authors.initials: R
authors.lastname: De Vivo
authors.forename: R
authors.initials: R
authors.lastname: Costanzo
authors.forename: A
authors.initials: A
authors.lastname: Vernaglia
authors.forename: S
authors.initials: S
authors.lastname: Tramontana
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D000093542:Gemcitabine