title: Phase I trial of high-dose mitoxantrone plus cyclophosphamide and filgrastim in patients with advanced breast carcinoma.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) of mitoxantrone that could be safely used in combination with cyclophosphamide and filgrastim in patients with advanced breast carcinoma.
  
  
  METHODS
  Twenty-seven patients with metastatic (n = 24) or locally advanced (n = 3) breast carcinoma received escalating doses of mitoxantrone (16, 20, 24, 28, or 32 mg/m2) plus cyclophosphamide at one of three dose levels: group 1, 1,200 mg/m2; group 2, 2,400 mg/m2; and group 3,600 mg/m2. All patients also received filgrastim 5 micrograms/kg administered subcutaneously beginning on day 2 and continuing until the post-nadir absolute neutrophil count (ANC) was > or = 10,000/microL. Treatment was repeated every 3 weeks if the ANC was > or = 2,000/microL and platelet count > or = 90,000/microL for a maximum of six cycles. Dose escalation occurred within each group if zero of three or one of four patients had dose-limiting toxicity during the first cycle.
  
  
  RESULTS
  The MTD of mitoxantrone was 24 mg/m2 in group 1, less than 16 mg/m2 in group 2, and 28 mg/m2 in group 3. Neutropenia was dose-limiting, and cumulative neutropenia and thrombocytopenia occurred with continued therapy. Nonhematologic toxicity consisted predominantly of nausea, vomiting, alopecia, and fatigue. Three patients (11%) had a > or = 10% decrease in the left ventricular ejection fraction (LVEF), one patient (4%) had a decrease in the LVEF below normal, and none developed clinical congestive heart failure. Of patients with stage IV breast carcinoma who had not received prior chemotherapy for advanced disease, objective responses occurred in nine of 20 (45%), and the median response duration was 5 months.
  
  
  CONCLUSIONS
  In combination with 600 mg/m2 of cyclophosphamide and filgrastim, the MTD of mitoxantrone is 28 mg/m2, a dose that is approximately twofold to 2.8-fold higher than the conventional dose used without a hematopoietic growth factor.
authors.affiliation: Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10467, USA. Sparano@Jimmy.harvard.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Sparano
authors.forename: N
authors.initials: N
authors.lastname: Robert
authors.forename: P
authors.initials: P
authors.lastname: Silverman
authors.forename: H
authors.initials: H
authors.lastname: Lazarus
authors.forename: U
authors.initials: U
authors.lastname: Malik
authors.forename: U
authors.initials: U
authors.lastname: Venkatraj
authors.forename: C
authors.initials: C
authors.lastname: Sarta
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006321:Heart / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D011994:Recombinant Proteins
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D008942:Mitoxantrone; D000069585:Filgrastim