title: Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-overexpressed/amplified breast cancer is not feasible because of excessive diarrhea.
abstract: OBJECTIVE
  Dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel and trastuzumab (PT) is feasible. Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer. We conducted a pilot study of dose-dense AC followed by PT plus lapatinib (PTL) followed by trastuzumab plus lapatinib (TL).
  
  
  METHODS
  Patients with stages I to III, HER2-positive breast cancer and left ventricular ejection fraction (LVEF) of > or = 50% were enrolled. Treatment consisted of AC (60 mg/m(2) and 600 mg/m(2)) for 4 cycles every 2 weeks (with pegfilgrastim 6 mg on day 2) followed by paclitaxel (80 mg/m(2)) for 12 doses weekly plus trastuzumab and lapatinib. Trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly during paclitaxel then 6 mg/kg every 3 weeks after paclitaxel) and lapatinib (1,000 mg daily) were given for 1 year. The primary end points were feasibility defined as > or = 80% patients completing the PTL phase without a dose delay/reduction and a cardiac event rate of < or = 4%.
  
  
  RESULTS
  From March 2007 to April 2008, we enrolled 95 patients. Median age was 46 years (range, 28 to 73 years). At a median follow-up of 22 months, 92 were evaluable. Of the 92 patients, 41 patients (45%) withdrew for PTL-specific toxicities. Overall, 40 (43%) of 92 patients had lapatinib dose reductions, and 27 (29%) of 92 patients had grade 3 diarrhea. Three patients (3%) had congestive heart failure; three patients dropped out because of significant asymptomatic LVEF decline during PTL followed by TL.
  
  
  CONCLUSIONS
  Dose-dense AC followed by PTL and then followed by TL was not feasible because of a high rate of lapatinib dose reduction, mostly caused by unacceptable grade 3 diarrhea. Lapatinib (1,000 mg/d) was not feasible combined with weekly PT.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. dangc@mskcc.org
authors.forename: Chau
authors.initials: C
authors.lastname: Dang
authors.forename: Nancy
authors.initials: N
authors.lastname: Lin
authors.forename: Beverly
authors.initials: B
authors.lastname: Moy
authors.forename: Steven
authors.initials: S
authors.lastname: Come
authors.forename: Steven
authors.initials: S
authors.lastname: Sugarman
authors.forename: Patrick
authors.initials: P
authors.lastname: Morris
authors.forename: Alyson
authors.initials: A
authors.lastname: Abbruzzi
authors.forename: Carol
authors.initials: C
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Steingart
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Eric
authors.initials: E
authors.lastname: Winer
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005240:Feasibility Studies; D005260:Female; D000069585:Filgrastim; D005500:Follow-Up Studies; D005784:Gene Amplification; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D000077341:Lapatinib; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D010865:Pilot Projects; D011092:Polyethylene Glycols; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins; D015996:Survival Rate; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D000077341:Lapatinib; D017239:Paclitaxel; D011092:Polyethylene Glycols; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D000068878:Trastuzumab; C455861:pegfilgrastim