Increasing dose of continuous infusion ifosfamide and fixed dose of bolus epirubicin in soft tissue sarcomas. A study of the Italian group on rare tumors.
OBJECTIVE
To evaluate the maximum tolerated doses (MTD) of ifosfamide when given as a continuous infusion and in combination with fixed doses of bolus 4'-epidoxorubicin in advanced previously untreated adult soft tissue sarcoma patients.


METHODS
Treatment consisted of epidoxorubicin, 60 mg/m2 days one and two, and ifosfamide, 1.5 g/m2 every 12 hrs as a 72-hr infusion, at the first level. Further levels of ifosfamide were defined as increments of 12 hrs of the same infusion program. G-CSF 300 microg/die was administered from days +7 to +14. Dose-limiting toxicity (DLT) was defined as: G4 leukopenia or thrombocytopenia of > or =5 days; any G3 neuro or nephrotoxicity; G4 toxicity of any kind. Patients had to complete at least 2 consecutive cycles, and MTD was defined as the level in which 20% of patients developed a DLT; 10-15 patients were entered in each level.


RESULTS
First level: overall, 13 patients entered, 3 were not assessable for MTD, and only one developed a DLT. Second level: 18 patients entered, 3 were not assessable for MTD. Hematologic DLT was observed in 3/15 assessable patients. Therefore, the MTD was found at the ifosfamide level of 10.5 g/m2 given in 84 hrs. Eight patients of 29 assessable for response achieved an objective response: 1 complete and 7 partial. The overall response rate was 28% (95% CI: 13-47%).


CONCLUSIONS
If we accept 4-day G4 leukopenia as a reliable cutoff for safety, ifosfamide intensification cannot be substantially exploited over already available schedules with the combination of ifosfamide and anthracyclines.
Frustaci
S
S
Divisione di Oncologia Medica, Centro di Riferimento Oncologico, Aviano, Italy. sfrustaci@ets.it
Buonadonna
A
A
Romanini
A
A
Comandone
A
A
Dalla Palma
M
M
Gamucci
T
T
Verusio
C
C
Lionetto
R
R
Dani
C
C
Casali
P
P
Santoro
A
A
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007558:Italy; D007668:Kidney / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D015080:Mesna / Q000627:therapeutic use; D008875:Middle Aged; D017933:Peripheral Nervous System / Q000187:drug effects; D020011:Protective Agents / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy* / Q000556:secondary; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D020011:Protective Agents; D015251:Epirubicin; D015080:Mesna; D007069:Ifosfamide