title: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.
abstract: OBJECTIVE
  Phase II trials suggested that weekly paclitaxel might be more effective and less toxic than every-3-weeks administration for metastatic breast cancer (MBC). Cancer and Leukemia Group B (CALGB) protocol 9840 was initiated to address this question. Subsequently trastuzumab was demonstrated to improve outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2)-positive patients, and was therefore incorporated. Because inhibition of HER-family signaling had potential efficacy even without HER-2 overexpression, we randomly assigned for trastuzumab in this population.
  
  
  METHODS
  Patients were randomly assigned to paclitaxel 175 mg/m(2) every 3 weeks or 80 mg/m(2) weekly. After the first 171 patients, all HER-2-positive patients received trastuzumab; HER-2 nonoverexpressors were randomly assigned for trastuzumab, in addition to paclitaxel schedule. A total of 577 patients were treated on 9840. An additional 158 patients were included in analyses, for combined sample of 735. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival, and toxicity. Primary comparisons were between weekly versus every-3-weeks paclitaxel, and trastuzumab versus no trastuzumab in HER-2 nonoverexpressors.
  
  
  RESULTS
  In the combined sample, weekly paclitaxel was superior to every-3-weeks administration: RR (42% v 29%, unadjusted odds ratio [OR] = 1.75; P = .0004), TTP (median, 9 v 5 months; adjusted HR = 1.43; P < .0001), and survival (median, 24 v 12 months; adjusted HR = 1.28; P = .0092). For HER-2 nonoverexpressors, trastuzumab did not improve efficacy. Grade 3 neuropathy was more common with weekly dosing (24% v 12%; P = .0003).
  
  
  CONCLUSIONS
  Weekly paclitaxel is more effective than every-3-weeks administration for MBC. Trastuzumab did not improve efficacy for HER-2 nonoverexpressors. Neurotoxicity is a treatment-limiting toxicity for weekly paclitaxel.
authors: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. seidmana@mskcc.org
authors: Andrew D
authors: AD
authors: Seidman
authors: Donald
authors: D
authors: Berry
authors: Constance
authors: C
authors: Cirrincione
authors: Lyndsay
authors: L
authors: Harris
authors: Hyman
authors: H
authors: Muss
authors: P Kelly
authors: PK
authors: Marcom
authors: Grandella
authors: G
authors: Gipson
authors: Harold
authors: H
authors: Burstein
authors: Diana
authors: D
authors: Lake
authors: Charles L
authors: CL
authors: Shapiro
authors: Peter
authors: P
authors: Ungaro
authors: Larry
authors: L
authors: Norton
authors: Eric
authors: E
authors: Winer
authors: Clifford
authors: C
authors: Hudis
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab