Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Leyvraz, Serge; Bacchi, M.; Cerny, T; Lissoni, Alessandra; Sessa, Cristiana; Bressoud, Albéric; Hermann, Róbert

doi:10.1023/a:1008464504583

Cited by 41 publications

(25 citation statements)

References 22 publications

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“…In a previous phase I trial, we identified the maximum tolerated dose levels for combined administration of ifosfamide and doxorubicin (Leyvraz et al, 1998). The phase II trial herein presented was required to confirm the increased response rate suggested in that previous trial.…”

Section: Discussionmentioning

confidence: 90%

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

Leyvraz

Herrmann

Guillou³

et al. 2006

Br J Cancer

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Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age o60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m À2 (continuous infusion for 5 days), doxorubicin 30 mg m À2 day À1 Â 3 (total dose 90 mg m À2 ), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1 -6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33 -63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade X3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

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Section: Discussionmentioning

confidence: 90%

“…In a previous study, we defined the maximum tolerated dose of doxorubicin combined with ifosfamide, administered every 3 weeks and supported by haematopoietic growth factors (Leyvraz et al, 1998). The maximum tolerated dose of doxorubicin was 60 mg m À2 with ifosfamide at 12 g m À2 and could be increased to 90 mg m À2 with ifosfamide at 10 g m À2 .…”

mentioning

confidence: 99%

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

Leyvraz

Herrmann

Guillou³

et al. 2006

Br J Cancer

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“…Two commonly used chemotherapeutic agents, doxorubicin and ifosfamide, have response rates ranging from 17 to 33% as single-agent therapy [83][84][85][86] and 55 to 66% when used in combination [87][88][89]. However, few of the trials have combined both drugs at effective doses.…”

Section: Chemotherapymentioning

confidence: 99%

Diagnosis and management of pleomorphic sarcomas (so‐called “MFH”) in adults

Nascimento

Raut

2008

Journal of Surgical Oncology

107

101

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The existence of "malignant fibrous histiocytoma" ("MFH") as a distinct entity is controversial. Previously accepted as the most common sarcoma affecting adults, it is now known to comprise a heterogeneous group of tumors without a specific known line of differentiation. Reclassification of many tumors in this group afforded better prognostication, but traditional treatments still apply. Pleomorphic soft tissue tumors for which a line of differentiation is debatable are presently categorized as undifferentiated pleomorphic sarcoma.

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“…The main toxicity was myelosuppression, and despite the use of G-CSF, febrile neutropenia was encountered in 31% of all cycles [67]. Leyvraz et al [68] published a study of doxorubicin (90 mg/m 2 ) plus ifosfamide (10 g/m 2 ) in combination with G-CSF, which resulted in a response rate of 55%. Of note, this combination induced severe bone marrow toxicity, given World Health Organization grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles.…”

Section: Ifosfamide In Combination Therapymentioning

confidence: 99%

The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced Soft Tissue Sarcomas

et al. 2007

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After completing this course, the reader will be able to:1. Describe the current role of ifosfamide in the treatment of soft tissue sarcomas in adult patients.2. Discuss factors that may affect ifosfamide metabolism and its therapeutic index.3. Explain the advantages of ifosfamide over doxorubicin in the context of new treatment combinations.4. Discuss strategies to improve survival outcome in patients with soft tissue sarcoma.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThe treatment outcome of patients with locally advanced and metastatic soft tissue sarcomas is poor. Doxorubicin is regarded as standard treatment, but its use is featured by the occurrence of cardiotoxicity. This hinders the administration of this drug at high doses or in combination with, in theory, attractive newly developed targeted drugs, such as vascular endothelial growth factor (VEGF) pathway inhibitors. The combination of doxorubicin and VEGF pathway inhibitors has been shown to yield an unacceptable high rate of cardiomyopathy. Ifosfamide is the only drug that consistently shows response rates comparable to those of doxorubicin. The lack of cardiotoxicity renders this drug a much more attractive alternative than doxorubicin to be explored at high doses or as part of new drug combinations. This review addresses the clinical pharmacology, metabolism, and present role of ifosfamide in the treatment of locally advanced and/or metastatic soft tissue sarcomas, excluding gastrointestinal stromal tumors, the Ewing-like sarcomas, and other small blue round cell tumors. Furthermore, this review focuses on the anticipated growing role of ifosfamide in the development of new treatment strategies. The Oncologist 2007;

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Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Cited by 41 publications

References 22 publications

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

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

Diagnosis and management of pleomorphic sarcomas (so‐called “MFH”) in adults

The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced Soft Tissue Sarcomas

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