title: A Pilot Study of Dose-Dense Paclitaxel With Trastuzumab and Lapatinib for Node-negative HER2-Overexpressed Breast Cancer.
abstract: BACKGROUND
  Dual anti-HER2 therapy is effective for HER2-amplified breast cancer. Weekly paclitaxel, trastuzumab, and full-dose lapatinib (PTL) is not feasible because of grade 3 diarrhea. We conducted a phase II feasibility study of dose-dense (DD; every other week) PTL (ClinicalTrials.gov identifier, NCT01827163).
  
  
  METHODS
  Eligible patients had HER2-positive breast cancer, tumor size ≤ 3 cm, and negative nodes. Treatment included paclitaxel (175 mg/m(2) × 4, every 2 weeks with pegfilgrastim), trastuzumab (4 mg/kg load and then 2 mg/kg weekly), and lapatinib (1000 mg daily). After paclitaxel × 4, trastuzumab (6 mg/kg every 3 weeks) plus lapatinib were continued for 1 year. The primary endpoint was feasibility, defined as (1) > 80% of patients completing PTL without a dose delay or reduction, (2) grade 3 diarrhea rate < 20%, and (3) cardiac event rate < 4%.
  
  
  RESULTS
  From May 2013 to November 2013, we enrolled 20 of 55 planned patients. The median age was 49 years (range, 34-74 years). One patient had immediate paclitaxel hypersensitivity and was deemed inevaluable. Only 13 of 19 evaluable patients (68%) completed PTL without a dose delay or reduction or unacceptable toxicities. Only 3 of 19 (16%) had grade 3 diarrhea. Rash was frequent, with all grades in 18 of 19 (95%) and grade 3 in 2 of 19 (11%). The study was stopped early because of excess toxicity.
  
  
  CONCLUSIONS
  The discontinuation rate during DD PTL was high, owing, in part, to an unexpectedly high incidence of rash. The trial was halted, because the initial discontinuation rate from overall toxicity made it unlikely that full accrual would demonstrate feasibility.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: iyengarn@mskcc.org.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Iyengar
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Monica N
authors.initials: MN
authors.lastname: Fornier
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Sugarman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Maria
authors.initials: M
authors.lastname: Theodoulou
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Troso-Sandoval
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Gabriella M
authors.initials: GM
authors.lastname: D'Andrea
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Drullinsky
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Devika
authors.initials: D
authors.lastname: Gajria
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Shari B
authors.initials: SB
authors.lastname: Goldfarb
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Comen
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Diana E
authors.initials: DE
authors.lastname: Lake
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Traina
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Mario E
authors.initials: ME
authors.lastname: Lacouture
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Melanie F
authors.initials: MF
authors.lastname: Chen
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Chau T
authors.initials: CT
authors.lastname: Dang
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D000077341:Lapatinib; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D010865:Pilot Projects; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D000077341:Lapatinib; D017239:Paclitaxel; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: ALTTO; Dose schedule; Dose-dense chemotherapy; Drug toxicity; Taxane