title: Erythropoietin and granulocyte-macrophage colony-stimulating factor allow acceleration and dose escalation of cyclophosphamide/epidoxorubicin/5-fluorouracil chemotherapy: a dose-finding study in patients with advanced breast cancer.
abstract: To verify whether the association of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) would allow both the acceleration and the dose escalation of the cyclophosphamide/epidoxorubicin/5-fluorouracil (CEF) regimen as first-line therapy in advanced breast cancer patients, we conducted a dose-finding study. Cohorts of three consecutive patients received cyclophosphamide (Ctx, dose range 800-1400 mg/m2), epidoxorubicin (Epidx, dose range 70-100 mg/m2), and 5-fluorouracil (5-Fu, 600 mg/m2, fixed dose) given as an intravenous bolus on day 1 every 14 days; GM-CSF at 5 micrograms/kg given as a subcutaneous injection from day 4 to day 11; and EPO at 150 IU/kg given as a subcutaneous injection three times a week. In no single patient was any dose escalation allowed. A total of 14 patients entered the study. At the 4th dose level (Ctx 1400 mg/m2, Epidx 100 mg/m2, 5-Fu 600 mg/m2), two patients had dose-limiting mucositis and one patient developed dose-limiting neutropenia. Therefore, the 3rd cohort received the maximum tolerated dose, i.e. Ctx at 1200 mg/m2, Epidx at 90 mg/m2, and 5-Fu at 600 mg/m2, given every 18.5 (+/-2.5) days. Toxicity was moderate and manageable in an outpatient setting. Only 1 admission at the 4th dose level was required. Throughout the 4 dose levels there was no toxicity-related death; grade IV leukopenia ranged from 24% to 75% of cycles and grade IV thrombocytopenia ranged from 6% to 8%. No grade IV anemia was recorded. Increasing the doses of Ctx and Epidx while maintaining a fixed dose of 5-Fu with the support of both EPO and GM-CSF allows safe acceleration and dose escalation of CEF chemotherapy. Further controlled studies will evaluate the activity and efficacy of this strategy.
authors.affiliation: Oncologia Medica 1, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Venturini
authors.forename: L
authors.initials: L
authors.lastname: Del Mastro
authors.forename: F
authors.initials: F
authors.lastname: Testore
authors.forename: M
authors.initials: M
authors.lastname: Danova
authors.forename: O
authors.initials: O
authors.lastname: Garrone
authors.forename: C
authors.initials: C
authors.lastname: Lanfranco
authors.forename: F
authors.initials: F
authors.lastname: Latini
authors.forename: M R
authors.initials: MR
authors.lastname: Sertoli
authors.forename: R
authors.initials: R
authors.lastname: Lionetto
authors.forename: P
authors.initials: P
authors.lastname: Queirolo
authors.forename: A
authors.initials: A
authors.lastname: Ardizzoni
authors.forename: R
authors.initials: R
authors.lastname: Rosso
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001853:Bone Marrow / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008875:Middle Aged; D010045:Outpatients; D010865:Pilot Projects; D016896:Treatment Outcome
chemical_list: D004921:Erythropoietin; D015251:Epirubicin; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D005472:Fluorouracil