title: Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK).
abstract: Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover.
  
  
  METHODS
  Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days.
  
  
  RESULTS
  The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years.
  
  
  CONCLUSIONS
  The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.
authors.affiliation: Serge.Leyvraz@chuv.hospvd.ch
authors.forename: S
authors.initials: S
authors.lastname: Leyvraz
authors.forename: M
authors.initials: M
authors.lastname: Bacchi
authors.forename: T
authors.initials: T
authors.lastname: Cerny
authors.forename: A
authors.initials: A
authors.lastname: Lissoni
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.forename: A
authors.initials: A
authors.lastname: Bressoud
authors.forename: R
authors.initials: R
authors.lastname: Hermann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007069:Ifosfamide