• Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.

      Nielsen, O S; Judson, I; Van Hoesel, Q; Le Cesne, A; Keizer, H J; Blay, Jean-Yves; Van Oosterom, A; Radford, John A; Svancárová, L; Krzemienlecki, K; et al. (2000-01)
      In this phase II study the effect of high-dose ifosfamide (HDI) given as a 3-day continuous infusion at a dose of 12 g/m2 repeated every 4 weeks with adequate mesna protection and hydration was evaluated in patients with advanced soft tissue sarcomas. A total of 124 patients entered the trial of which 10 were ineligible. HDI was given both as first-line and second-line chemotherapy. Median age was 46 years (19-66 years). Median World Health Organization (WHO) performance status was 1 (0-1). Fifty two per cent of the patients were males. The predominant histology was leiomyosarcoma (33%). A maximum of six cycles was given. At the time of analysis 55 patients have died. The partial response (PR) rate was 16%. The median time to progression was 15 weeks. 8 of the 18 responding patients (44%) had synovial sarcomas, whereas only 5% of the patients having leiomyosarcomas responded. The grade 3 + 4 haematological toxicity encountered was neutrophils in 78% and platelets in 12%. The major grade 3 + 4 non-haematological toxicities encountered were febrile neutropenia in 39%, infection in 20%, and acute renal failure in 4%. In conclusion, it is possible to administer HDI on a multicentre basis, but the toxicity is substantial. HDI given as a continuous infusion at this dose cannot be recommended as the standard treatment of advanced soft tissue sarcomas, even in selected patients.
    • Randomised phase II trial of pegylated liposomal doxorubicin (DOXILR/CAELYXR) versus doxorubicin in the treatment of advanced or metastatic sift tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group

      Judson, Ian R; Radford, John A; Harris, Maggie A; Blay, Jean-Yves; Van Hoesel, Q; Le Cesne, A; Van Oosterom, A; Clemons, Mark; Kamby, C; Hermans, C; et al. (2001-05)
    • 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.

      Le Cesne, A; Judson, I; Crowther, Derek; Rodenhuis, S; Keizer, H J; Van Hoesel, Q; Blay, Jean-Yves; Frisch, J; Van Glabbeke, Martine M; Hermans, C; et al. (2000-07)
      PURPOSE: This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS). PATIENTS AND METHODS: Between 1992 and 1995, 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m(2) on day 1) and ifosfamide (5 g/m(2) on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m(2) on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 microgram/m(2) on days 3 to 16); all courses were repeated every 3 weeks. RESULTS: The median age of the 294 eligible patients was 50 years. They received a median of five chemotherapy cycles. The median dose and relative doxorubicin dose-intensity achieved were 245 mg and 97% in arm A and 360 mg and 99% in arm B, respectively. Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P =.65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P =.03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P =.98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B. CONCLUSION: 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.