Epirubicin and ifosfamide in advanced soft tissue sarcomas.
ABSTRACT To evaluate the feasibility, toxicity and efficacy of the combination of (IFO) ifosfamide and epirubicin (EPI) given at conventional doses for monochemotherapy, we started a phase II study in advanced/metastatic soft tissue sarcoma patients.
Treatment consisted of: epirubicin 75 mg/m2 i.v. day 1; IFO 1.8 g/m2 days 1 to 5; MESNA 20% of the IFO dose at 4-hour intervals three times a day during IFO administration. Cycles were given every 3-4 weeks for at least three cycles.
The overall response rate for non-visceral sarcomas (51 pts) was 31% (95% confidence limits +/- 13%). Among the 13 visceral sarcomas no response was seen for the leiomyosarcomas of the gastrointestinal tract, whereas one complete and one partial remission were observed for the uterine sarcomas. The duration of response was 10 months (range 5-34+) for complete responses and 9 (range 4-42+) for partial responses. The median survival for responders is 18 months (range 2-60+) and for non-responders 10 months (range 1-33) (p < 0.004).
This combination proved to be feasible and tolerable. The overall response rate does not appear to be superior to those with other standard treatments, but it should be pointed out that our patient population was totally unselected.
Article: Ifosfamide-based combination chemotherapy in advanced soft-tissue sarcoma: a practice guideline.[show abstract] [hide abstract]
ABSTRACT: In adult patients with inoperable locally advanced or metastatic soft-tissue sarcoma, do combination chemotherapy regimens containing ifosfamide have an advantage in terms of response rate, time to progression, or survival, as compared with similar regimens without ifosfamide when used as first-line therapy? What are the adverse effects and effects on quality of life of ifosfamide-containing combination chemotherapy as compared with similar regimens without ifosfamide? The prognosis for patients with inoperable or meta-static soft-tissue sarcoma (sts) remains grim. Although the surgical resection of pulmonary metastases may be curative in 15%-30% of patients with isolated slow-growing metastases, most patients receive chemotherapy for palliative purposes. Ifosfamide has documented activity in patients who have received prior treatment with, or who have progressed on, doxorubicin. A number of studies have suggested a schedule and a dose-response relationship for ifosfamide in metastatic sts. Ifosfamide has also been assessed in combination with other drugs such as doxorubicin and dacarbazine (dtic); results of such studies have led some authors to suggest that polychemotherapy using "appropriate doses" of ifosfamide and doxorubicin may represent the "most effective systemic treatment" in this population. Given the limited effective therapeutic options available for patients with metastatic sts, the Sarcoma Disease Site Group (dsg) felt that a need existed to more specifically evaluate the potential benefits of ifosfamide-containing combination chemotherapy in that setting. The Sarcoma dsg developed an evidence-based series report through systematic review, evidence synthesis, and input from practitioners across Ontario. Outcomes of interest included survival, response rate, adverse events, and quality of life. A systematic review and meta-analysis served as the evidentiary base for this clinical practice guideline. The report was reviewed and approved by the Sarcoma dsg, which comprises medical oncologists, radiation oncologists, surgeons, methodologists, and patient representatives. The results of an external review by Ontario practitioners, obtained through a mailed survey, were incorporated into this report. Final approval of the evidence-based series report was obtained from the Report Approval Panel of Cancer Care Ontario's Program in Evidence-Based Care (pebc). The current practice guideline reflects a combination of the draft recommendations (based on the evidence identified in a systematic review and meta-analysis) and the external feedback from Ontario practitioners and the pebc's Report Approval Panel. In patients with metastatic sts, the addition of ifosfamide to standard first-line doxorubicin-containing regimens is not recommended over single-agent doxorubicin. However, in patients with symptomatic, locally advanced, or inoperable sts, in whom tumour response might potentially result in reduced symptomatology or render a tumour resectable, use of ifosfamide in combination with doxorubicin is reasonable. QUALIFYING STATEMENT: In combination with a doxorubicin-containing regimen, the dose of ifosfamide should not exceed 7.5 g/m(2), given as either a split bolus or a continuous infusion.Current Oncology 09/2007; 14(4):144-8. · 2.47 Impact Factor
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ABSTRACT: BACKGROUND: Soft tissue sarcomas comprise less than 1% of all solid malignancies. The presentation and behavior of these tumors differs depending on location and histological characteristics. Standard therapy consists of complete surgical resection in combination with adjuvant radiotherapy. The role of chemotherapy is not clearly defined and is largely restricted to clinical trials. Only a limited number of agents have proved to be effective in soft tissue sarcomas. The use of doxorubicin, epirubicin and ifosfamide allowed response rates of more than 20%. In addition, recent chemotherapy trials did not demonstrate any significant differences in efficacy for various histological subtypes. METHODS: The objective of this study was to gain additional information about the chemosensitivity of soft tissue sarcomas to seven 7 different chemotherapy agents as single drugs and 4 combinations. Therefore we used an established ATP based in-vitro testing system and examined 50 soft tissue sarcomas. Chemosensitivity was assessed using a luciferin-luciferase-based luminescence assay providing individual chemosensitivity indices for each agent tested. RESULTS: The sensitivity varied widely according to the histological subtypes. The tumors state of cellular dedifferentiation played a crucial role for the efficiency of the chemotherapeutic agents. The sensitivity also depended on the presentation of the sarcoma as a primary or recurrent tumor. The highest sensitivity was demonstrated for actinomycin D as a single agent, with 74% of the tumor samples exhibiting a high-grade sensitivity (20% low sensitivity, no resistance). The combination of actinomycin D and ifosfamide yielded a high sensitivity in 76% (2% resistance). Doxorubicin as a mono-therapy or in combination with ifosfamide achieved high sensitivity in 70% and 72%, respectively, and resistance in 6% of the samples. CONCLUSION: Chemosensitivity testing is feasible in soft tissue sarcomas. It can be used to create sensitivity and resistance profiles of established and new cytotoxic agents and their combinations in soft tissue sarcomas. Our data demonstrate measurable discrepancies of the drug efficiency in soft tissue sarcomas, sarcoma subtypes and tumor recurrencies. However, current therapeutic regime does not take this in consideration, yet.World Journal of Surgical Oncology 05/2005; 3(1):20. · 1.12 Impact Factor
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ABSTRACT: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Until recently, surgery has been the only effective therapy for GIST. However, even after complete resection of tumor, many patients still eventually die of disease recurrence. Conventional chemotherapy and radiation therapy have been of limited value. Within the last few years, it was discovered that most GISTs have a gain-of-function mutation in the c-kit proto-oncogene. This results in ligand-independent activation of the KIT receptor tyrosine kinase and an unopposed stimulus for cell growth. STI-571 is a small molecule that selectively inhibits the enzymatic activity of the ABL, platelet-derived growth factor receptor, and KIT tyrosine kinases and the BCR-ABL fusion protein and is a landmark development in cancer therapy. Its clinical development marks a new era of rational and targeted molecular inhibition of cancer that emanates from direct collaborations between scientists and clinicians. It provides proof of the principle that a specific molecular inhibitor can drastically and selectively alter the survival of a neoplastic cell with a particular genetic aberration. The advent of STI-571 has markedly altered the clinical approach to GIST. It has proven to be effective in metastatic GIST and is also under investigation as a neoadjuvant and adjuvant therapy.Human Pathlogy 06/2002; 33(5):466-77. · 2.88 Impact Factor