title: Dose-escalation of filgrastim does not improve efficacy: clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel.
abstract: OBJECTIVE
  To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10 mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5 mcg/kg/day) in this setting.
  
  
  METHODS
  Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000 mg/m(2)/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175 mg/m(2) by 3h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected.
  
  
  RESULTS
  One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence).
  
  
  CONCLUSIONS
  The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007-2198, USA. liumc@georgetown.edu
authors.forename: Minetta C
authors.initials: MC
authors.lastname: Liu
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Robert
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: I Craig
authors.initials: IC
authors.lastname: Henderson
authors.forename: Alan
authors.initials: A
authors.lastname: Lyss
authors.forename: Judith
authors.initials: J
authors.lastname: Hopkins
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kaufman
authors.forename: P Kelly
authors.initials: PK
authors.lastname: Marcom
authors.forename: Jerry
authors.initials: J
authors.lastname: Younger
authors.forename: Nancy
authors.initials: N
authors.lastname: Lin
authors.forename: Katherine
authors.initials: K
authors.lastname: Tkaczuk
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D000069585:Filgrastim; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage*; D010865:Pilot Projects; D011994:Recombinant Proteins
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D000069585:Filgrastim