title: Increasing 4'-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a pilot study.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) of 4'-epidoxorubicin (EPI) in combination with full dose of ifosfamide (IFO) when granulocyte-macrophage colony-stimulating factor (GM-CSF) was used, to estimate its clinical efficacy, and to evaluate the mobilization of hematopoietic progenitors.
  
  
  METHODS
  Previously untreated advanced patients were treated with fixed doses of IFO at 1.8 g/m2/d for 5 days and escalating doses of EPI. The starting dose level of EPI was 50 mg/m2 bolus on days 1 and 2; subsequent levels were 60 mg/m2 and 70 mg/ m2 given on days 1 and 2. GM-CSF (5 micrograms/kg/d) was administered from days +6 to +19. Clinical evaluation of response was performed after three consecutive cycles. Mobilization of hematopoietic progenitors was evaluated as day 14 CFU-GM after the first cycle only.
  
  
  RESULTS
  Overall, six, 18, and 13 assessable patients were entered onto each EPI dose level, respectively. The first and the second EPI level were considered feasible. Conversely, at the third level, only six of 13 patients [46%] tolerated full EPI doses at the scheduled time. Therefore, the dose-intensity of the three levels was 100%, 99.7%, and 86.1%, respectively. Overall, 20 of 37 patients (54%) obtained an objective response. The response rates for the three EPI dose levels were significantly different [17%, 33%, and 100%, respectively; test for trend, P < .001]. Considering only lung metastases, the overall response rate was 72% (20%, 66%, and 100% for the three EPI levels, respectively). The most relevant mobilization effect was obtained at the third EPI level, when both GM-CSF and IL-3 were used as in vitro-stimulating factors.
  
  
  CONCLUSIONS
  The third EPI level (70 mg/m2 on days 1 and 2) is the MTD of this program, since it was administered, without dose reduction or treatment delay, for three consecutive cycles in less than half of the patients. Nevertheless, this level proved to be interesting with regard to response rate (13 of 13 objective responses) and in mobilization of the hematopoietic progenitors.
authors.affiliation: Division of Medical Oncology, Centro di Riferimento Oncologico, Aviano, Italy. oncomed@ets.it
authors.forename: S
authors.initials: S
authors.lastname: Frustaci
authors.forename: A
authors.initials: A
authors.lastname: Buonadonna
authors.forename: E
authors.initials: E
authors.lastname: Galligioni
authors.forename: D
authors.initials: D
authors.lastname: Favaro
authors.forename: A
authors.initials: A
authors.lastname: De Paoli
authors.forename: G
authors.initials: G
authors.lastname: Lo Re
authors.forename: R
authors.initials: R
authors.lastname: Sorio
authors.forename: S
authors.initials: S
authors.lastname: Tumolo
authors.forename: S
authors.initials: S
authors.lastname: Monfardini
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D012509:Sarcoma / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007069:Ifosfamide