title: Pilot trial of trastuzumab starting with or after the doxorubicin component of a doxorubicin plus paclitaxel regimen for women with HER2-positive advanced breast cancer.
abstract: OBJECTIVE
  Combining trastuzumab with doxorubicin and paclitaxel (AT) is attractive because of the activity of AT and survival improvements observed when trastuzumab is added to either agent in HER2-positive metastatic breast cancer. This pilot study evaluates the efficacy and cardiac tolerability of AT followed by paclitaxel with trastuzumab started with AT or paclitaxel alone and investigates pharmacokinetic interactions.
  
  
  METHODS
  Two cohorts of 16 patients were enrolled. Cohort 1 received three cycles of AT (60/150 mg/m2) plus trastuzumab (4 mg/kg initial dose followed by 2 mg/kg), initiated concomitantly with doxorubicin, followed by nine cycles of paclitaxel (80 mg/m2) plus trastuzumab and then trastuzumab alone. Cohort 2 was treated with the same regimen, but trastuzumab was initiated with paclitaxel after AT. Cardiac function, pharmacokinetic interactions, and efficacy were evaluated.
  
  
  RESULTS
  Median baseline left ventricular ejection fraction (LVEF) was 62% (range, 57-74%) and 66% (range, 57-77%) in cohorts 1 and 2, respectively. Most patients had an absolute decrease in LVEF. Congestive heart failure was not observed. LVEF in three patients decreased to <50% but recovered despite continued treatment. Response rates were 87.5% in both cohorts (cohort 1:2 complete response, 12 partial response; cohort 2:3 complete response, 11 partial response). No unexpected side effects were observed. Pharmacokinetics of paclitaxel and its metabolites and of doxorubicin were similar without and with trastuzumab.
  
  
  CONCLUSIONS
  Trastuzumab administered with AT followed by weekly paclitaxel alone is highly active whether trastuzumab is initiated with AT or paclitaxel. Congestive heart failure was not observed, and LVEF decreases were reversible. Further studies of this regimen are warranted.
authors.affiliation: Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bianchi
authors.forename: John
authors.initials: J
authors.lastname: Albanell
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.forename: Giordano
authors.initials: G
authors.lastname: Vitali
authors.forename: David
authors.initials: D
authors.lastname: Borquez
authors.forename: Lucia
authors.initials: L
authors.lastname: Viganò
authors.forename: Rafael
authors.initials: R
authors.lastname: Molina
authors.forename: Günter
authors.initials: G
authors.lastname: Raab
authors.forename: Alberta
authors.initials: A
authors.lastname: Locatelli
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhauwere
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002318:Cardiovascular Diseases / Q000139:chemically induced; D004317:Doxorubicin / Q000008:administration & dosage; D004452:Echocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D010865:Pilot Projects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004317:Doxorubicin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab