Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK)


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Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK)
Annals of Oncology
Leyvraz  S., Bacchi  M., Cerny  T., Lissoni  A., Sessa  C., Bressoud  A., Hermann  R.
0923-7534 (Print)
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Clinical Trial
Clinical Trial, Phase I
Journal Article
Multicenter Study --- Old month value: Aug
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. PATIENTS AND 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.
Adolescent Adult Aged Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use Bone Neoplasms/*drug therapy/pathology Dose-Response Relationship, Drug Doxorubicin/administration & dosage/adverse effects Drug Administration Schedule Drug Therapy, Combination Female Genital Neoplasms, Female/*drug therapy/pathology Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage Humans Ifosfamide/administration & dosage/adverse effects Infusions, Intravenous Male Middle Aged Sarcoma/*drug therapy/pathology Soft Tissue Neoplasms/*drug therapy/pathology Survival Analysis Treatment Outcome
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28/01/2008 8:32
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25/09/2019 6:08
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