Randomized Phase III Study Comparing Conventional-Dose Doxorubicin Plus Ifosfamide Versus High-Dose Doxorubicin Plus Ifosfamide Plus Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor in Advanced Soft Tissue Sarcomas: A Trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group

Abstract

The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS.

Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

“…Although this observed response rate did not reach the requirement being considered promising as defined by the statistical design, it is in the range of similar response rates (40 -66%) for high-dose combination of ifosfamide and doxorubicin that have been obtained in other phase-II studies (Frustaci et al, 1997;Patel et al, 1998;Reichardt et al, 1998). The most recent trials have yielded less impressive response rates (25 -23%) but were designed such that only one agent was administered at high dose levels (Le Cesne et al, 2000;Worden et al, 2005). Indeed, the efficacy of ifosfamide alone at standard dose (5 g m À2 ) was shown to be minimal (10%) in a randomised trial (van Oosterom et al, 2002).…”

“…Lower-dose combinations led to severe neutropenia in 87 -90% and severe infection in 17% of patients (Le Cesne et al, 2000;Worden et al, 2005). One of these studies involved two toxic deaths out of 40 patients, severe thrombopenia in 50 -62% and severe anaemia in approximately 50% of patients (Worden et al, 2005).…”

“…Even standard dose levels (ifosfamide 6 g m À2 and doxorubicin 60 mg m À2 and G-CSF) led to severe neutropenia in 49%, anaemia in 23%, and thrombopenia in 15% of patients (Worden et al, 2005). In a large-scale EORTC trial, dose levels of ifosfamide 5 g m À2 and doxorubicin 50 mg m À2 but without G-CSF led also to severe neutropenia in 86%, and thrombopenia in 8% of patients (Le Cesne et al, 2000).…”

Soft tissue sarcoma presenting with metastatic disease

“…The demonstration of a benefit in other larger randomized trials in improving progression-free survival suggests that the use of chemotherapy for this reason still may be valid. 14 It remains unclear which chemotherapy regimen is superior: One large randomized trial suggested that the addition of ifosfamide added little benefit over single-agent doxorubicin in increasing progression-free survival. 15 It is possible that there may be other benefits to chemotherapy that were not documented in this study, such as palliation of symptoms or shrinkage of the tumor, that may facilitate less extensive surgical resection.…”

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

“…Schemes with anthracyclines and ifosfamide at adequate doses are those most widely used as first line treatments, especially where a greater shrinkage of lesions may lead to an improvement in long-term results (1, 2). Yet the most optimistic expectancy of the above combination with respect to response rate is less than 30%, and as regards progression-free survival, it is less than 8 months, according to phase III trials in advanced disease (3). These results have barely been improved upon in the last 2 decades, in spite of some evidence of dose-response relationship for both drugs (4).…”