The EORTC 62012 trial attempted to resolve controversy regarding whether Ifosfamide ( Holoxan ) had been previously tested at too low dose when used with Doxorubicin ( Adriamycin; Adriblastin ) by evaluating whether a higher dose of Ifosfamide plus Doxorubicin could improve response rate and progression free survival in patients with locally advanced or metastatic, grade 2 or 3 soft tissue sarcoma.

This phase III randomized trial enrolled patients with soft tissue sarcoma aged 60 years and less who were randomized to Doxorubicin at 75 mg/m2 or Doxorubicin at the same dose plus Ifosfamide given at 10 g/m2 over four days together with Mesna and Pegfilgrastim as first-line treatment.
Randomization was stratified by performance status ( 0 or 1 ), patient age of less than 50 years or 50 years and older, the presence or absence of liver metastases and histological grade of 2 versus 3.

Patients were treated every three weeks for a maximum of six cycles or until progression. A total of 455 patients from 38 Centers were randomized; 228 received Doxorubicin and 227 were given Doxorubicin plus Ifosfamide. At a median follow-up of 56 months, overall survival, the primary endpoint, at one year was slightly, but not significantly, improved with the combination; overall survival was 60% with Ifosfamide and Doxorubicin compared to 51% with sole Doxorubicin ( hazard ratio, HR=0.82; p = 0.061 ).

No difference between treatment arms was seen in the two year overall survival rates of 31% Ifosfamide / Doxorubicin compared with 28% Doxorubicin. Median progression-free survival was significantly increased to 7.4 months in Ifosfamide / Doxorubicin patients compared to 4.6 months with Doxorubicin ( HR=0.72; p=0.002 ).

Response rates favoured the combination treatment; complete response were seen in 4 versus 1 patients, partial response in 56 ( 24.7% ) versus 30 ( 13.2% ) and stable disease was achieved by 114 ( 50.2% ) Ifosfamide / Doxorubicin patients versus 105 ( 46.1% ) Doxorubicin patients, respectively.

Combination therapy was associated with increased adverse events; 45.9% versus 13.6% and 35.3% versus 4.6% of Ifosfamide / Doxorubicin patients compared to Doxorubicin patients, respectively, reported neutropenia and anemia.

Doxorubicin remains the gold standard first line chemotherapy of patients with metastatic soft tissue sarcoma. Significantly improved overall survival was not demonstrated by combination therapy and routine use of Ifosfamide / Doxorubicin was not supported, although response rates suggest that Ifosfamide / Doxorubicin may be justified in selected patients younger than 60 years where tumor shrinkage is critical, bearing in mind the higher toxicity rate.

Source: European Society for Medical Oncology ( ESMO ) Congress, 2012

XagenaMedicine2012