title: Phase II feasibility and pharmacokinetic study of concurrent administration of trastuzumab and high-dose chemotherapy in advanced HER2+ breast cancer.
abstract: OBJECTIVE
  To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer.
  
  
  METHODS
  Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as > or =4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day -5), HDC (days -5 to -2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65.
  
  
  RESULTS
  Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day -4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13-58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively.
  
  
  CONCLUSIONS
  Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.
authors.affiliation: Bone Marrow Transplant Program and Department of Biostatistics, University of Colorado Health Sciences Center, Denver, Colorado, USA. ynieto@unav.es
authors.forename: Yago
authors.initials: Y
authors.lastname: Nieto
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Scott I
authors.initials: SI
authors.lastname: Bearman
authors.forename: Peter A
authors.initials: PA
authors.lastname: McSweeney
authors.forename: Nelson
authors.initials: N
authors.lastname: Chao
authors.forename: David
authors.initials: D
authors.lastname: Rizzieri
authors.forename: Christina
authors.initials: C
authors.lastname: Gasparetto
authors.forename: Steve
authors.initials: S
authors.lastname: Matthes
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D013997:Time Factors; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002330:Carmustine; D002945:Cisplatin; D003520:Cyclophosphamide; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab