title: A phase I toxicity and feasibility trial of sequential dose-dense induction chemotherapy with doxorubicin, paclitaxel, and 5-fluorouracil followed by high dose consolidation for high-risk primary breast cancer.
abstract: OBJECTIVE
  We studied sequential dose-dense doxorubicin, paclitaxel, and 5-fluorouracil (A-T-F) before high dose chemotherapy (HDC) with autologous peripheral blood stem cell support (PBSCT). Our aims were to determine the maximum tolerated dose (MTD) of 5-FU in the dose-dense regimen and to determine the impact of dose-dense chemotherapy on HDC/PBSCT.
  
  
  METHODS
  Patients with Stage IIIB or Stage II or IIIA breast cancer with > or = 4 involved ipsilateral lymph nodes were treated with nine cycles of chemotherapy at 14-day intervals. The regimen was doxorubicin at 80 mg/m2 x 3, followed by paclitaxel at 140 mg/m2 over 96 h x 3, then 5-FU at doses of 1285, 1470, or 1655 mg/m2 by continuous intravenous infusion over 72 h x 3. Patients then underwent a G-CSF-stimulated peripheral blood stem cell (PBSC) apheresis prior to receiving HDC with autologous PBSCT.
  
  
  RESULTS
  We identified 1285 mg/m2 as the MTD of 5-FU in this regimen. 5-FU-related DLTs included hand-foot syndrome, mucositis, and facial edema with somnolence. Unexpectedly, 3/19 treated patients developed congestive heart failure that prevented planned HDC. Compared to standard dose doxorubicin-containing adjuvant therapy, the dose-dense regimen also decreased CD34+ PBSC yields by about 40% (p = 0.049), requiring that 50% of patients have a supplemental bone marrow harvest. There was no difference in time to neutrophil, platelet, and red blood cell recovery after HDC.
  
  
  CONCLUSIONS
  This regimen resulted in an unacceptably high rate of cardiac toxicity and is not recommended for further testing. It may be feasible to use a different schedule of 5-FU-containing dose-dense chemotherapy, particularly for the induction therapy of high-risk primary breast cancer prior to novel targeted therapies.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD, USA. emensle@jhmi.edu
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
authors.forename: M John
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: John H
authors.initials: JH
authors.lastname: Fetting
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Armstrong
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D001772:Blood Cell Count; D001943:Breast Neoplasms / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004890:Erythema / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D012893:Sleep Wake Disorders / Q000139:chemically induced; D013997:Time Factors
chemical_list: D004317:Doxorubicin; D017239:Paclitaxel; D005472:Fluorouracil