title: Efficacy of lenograstim on hematologic tolerance to MAID chemotherapy in patients with advanced soft tissue sarcoma and consequences on treatment dose-intensity.
abstract: OBJECTIVE
  This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy.
  
  
  METHODS
  Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner.
  
  
  RESULTS
  Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles.
  
  
  CONCLUSIONS
  Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.
authors.affiliation: Sarcoma Group, French Federation of Cancer Centers: Fondation Bergonié, Bordeaux.
authors.forename: B N
authors.initials: BN
authors.lastname: Bui
authors.forename: B
authors.initials: B
authors.lastname: Chevallier
authors.forename: C
authors.initials: C
authors.lastname: Chevreau
authors.forename: I
authors.initials: I
authors.lastname: Krakowski
authors.forename: A M
authors.initials: AM
authors.lastname: Peny
authors.forename: A
authors.initials: A
authors.lastname: Thyss
authors.forename: C
authors.initials: C
authors.lastname: Maugard-Louboutin
authors.forename: D
authors.initials: D
authors.lastname: Cupissol
authors.forename: P
authors.initials: P
authors.lastname: Fargeot
authors.forename: F
authors.initials: F
authors.lastname: Bonichon
mesh_terms: D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D003606:Dacarbazine / Q000008:administration & dosage; D004311:Double-Blind Method; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006417:Hematuria / Q000139:chemically induced; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D007902:Length of Stay; D000078224:Lenograstim; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D015080:Mesna / Q000008:administration & dosage; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control*; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D012044:Regression Analysis; D012509:Sarcoma / Q000188:drug therapy* / Q000556:secondary; D012983:Soft Tissue Neoplasms / Q000188:drug therapy*; D013280:Stomatitis / Q000209:etiology
chemical_list: D006454:Hemoglobins; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000078224:Lenograstim; D003606:Dacarbazine; D004317:Doxorubicin; D015080:Mesna; D007069:Ifosfamide