title: Multiple cycles of high-dose doxorubicin and cyclophosphamide with G-CSF mobilized peripheral blood progenitor cell support in patients with metastatic breast cancer.
abstract: BACKGROUND
  In a previous study we applied doxorubicin and cyclophosphamide in a dose-intensive regimen with GM-CSF to patients with metastatic breast cancer (MBC). That treatment failed to prolong the remission duration compared to conventional-dose chemotherapy. In the present study we escalated the dosages of the same agents to: 1) determine the maximum tolerated dosages (MTD) when given for three cycles with G-CSF mobilised peripheral blood progenitor cell (PBPC) reinfusion and 2) evaluate the antitumour effect of this regimen.
  
  
  METHODS
  For mobilisation of PBPC, G-CSF 15 microg/kg/day was given subcutaneously (s.c.), and in subsequent cohorts leucapheresis was started on days 3, 4 or 6. The intention was to treat MBC patients with three cycles of doxorubicin and cyclophosphamide at a starting dose of doxorubicin 90 mg/m2 and cyclophosphamide 1000 mg/m2. Dosages were then escalated in subsequent cohorts of at least three patients. In case of dose-limiting mucositis, only the dose of cyclophosphamide was escalated in the next cohort.
  
  
  RESULTS
  Twenty-one patients entered this protocol, of which 18 patients received high-dose chemotherapy. The mobilisation of PBPC using G-CSF only was sufficient for three cycles of high-dose chemotherapy in 10 of 21 (47%) patients. Mucositis precluded dose escalation of doxorubicin beyond 110 mg/m2. The MTD in this combination was 110 mg/m2 for doxorubicin, and 4 g/m2 for cyclophosphamide, with haemorrhagic cystitis being the dose-limiting toxicity. The overall response rate was 78% (95% confidence interval (95% CI): 57%-97%), with 22% (95% CI: 3%-41%) complete responses.
  
  
  CONCLUSIONS
  The MTD of this three cycle high-dose regimen was doxorubicin 110 mg/m2 and cyclophosphamide 4 g/m2 with mucositis and cystitis being dose-limiting toxicities. Although the primary aim was not the evaluation of antitumour effect, this high-dose regimen does not appear to provide an improvement of treatment results in comparison with our previous study with the same drugs at moderately high-dosages without stem cell support.
authors.affiliation: Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Honkoop
authors.forename: E
authors.initials: E
authors.lastname: van der Wall
authors.forename: N
authors.initials: N
authors.lastname: Feller
authors.forename: G J
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: W J
authors.initials: WJ
authors.lastname: van der Vijgh
authors.forename: E
authors.initials: E
authors.lastname: Boven
authors.forename: C J
authors.initials: CJ
authors.lastname: van Groeningen
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
authors.forename: K
authors.initials: K
authors.lastname: Hoekman
authors.forename: J B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: J
authors.initials: J
authors.lastname: Wagstaff
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000628:therapy*; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000139:chemically induced; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008875:Middle Aged
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D003520:Cyclophosphamide