Soft-tissue sarcomas are an uncommon set of malignancies that pose a therapeutic challenge. Representing a mixture of multiple histologies, approximately 9,000 cases were newly diagnosed in the United States in 2006. We are limited in our biologic understanding of these tumors because of a paucity of preclinical models and cell lines to evaluate in the laboratory. The standard chemotherapies that have been used in the treatment of these tumors-doxorubicin, ifosfamide(Drug information on ifosfamide), and dacarbazine(Drug information on dacarbazine)-produce response rates that range from 18% to 27% when used as single agents.[1] Combination therapy, including newer regimens with gemcitabine(Drug information on gemcitabine) (Gemzar) and docetaxel(Drug information on docetaxel), have demonstrated higher response rates.[2] However, these regimens have not yet been tested in randomized trials to assess whether they lead to improved overall survival in the adjuvant or metastatic disease setting.
Therefore, we are in need of newer agents for the management of these malignancies. Ideally, such agents would have limited normal organ toxicity, target biologically relevant tumor targets for growth and survival, and, when combined with other therapies, have nonoverlapping toxicities. The following review will highlight new therapies, focusing on antiangiogenic agents, mammalian target of rapamycin (mTOR) inhibitors, and tyrosine kinase inhibitors (TKIs).
Cytotoxic Chemotherapy
Trabectedin (ET-743, Yondelis) is a novel alkylating chemotherapy agent that binds to the minor groove of DNA. It appears to produce its cytopathic effect via inhibition of specific transcription factor activation and is more effective in patients with abnormalities in nucleotide excision repair.[3] Derived from the sea squirt Ecteinascidia turbinata, this agent first showed activity in sarcomas in a phase I study employing a 24-hour continuous infusion. Several patients with sarcomas had long-term disease stabilization as well as responses. A compassionate use trial again demonstrated long-term stable disease in heavily pretreated patients receiving this agent.[4,5]
Subsequent phase II studies have shown a 4% to 8% response rate in previously treated patients as well as minor responses in an additional 6% to 8%.[6-8] Intriguingly, one of these studies showed a 26% 6-month progression-free survival rate. This agent has been shown in vitro to have synergy with other chemotherapy agents,[9-11] and phase I studies have evaluated combinations with doxorubicin(Drug information on doxorubicin), gemcitabine, cisplatin, and taxanes. Available data from these studies suggest that such combinations can be given with some activity noted in soft-tissue sarcomas.[12,13]
Antiangiogenic Therapies
Targeting vasculature in sarcomas is a reasonable therapeutic approach, given that these tumors are vascular and spread hematogenously. In addition, prognosis in patients with some high-grade tumors has been shown to be correlated with levels of circulating vascular endothelial growth factor (VEGF) and/or VEGF receptor (VEGFR) expression.[14,15] Bevacizumab(Drug information on bevacizumab) (Avastin), a humanized monoclonal antibody, has been shown to enhance progression-free and overall survival in patients with epithelial tumors when given with chemotherapy compared with chemotherapy alone in the metastatic disease setting.[16] This agent binds circulating VEGF, removing the ligand of VEGFR and thus removing the stimulus for growth of new blood vessels (see Figure 1).
D'Adamo and colleagues evaluated bevacizumab in combination with doxorubicin in patients with metastatic or unresectable soft-tissue sarcomas.[17] The combination resulted in only a 16% response rate in patients who were anthracycline-naive, 30% of whom had received one prior chemotherapeutic regimen. In addition, four patients had a grade 2 or worse decline in ejection fraction following one to four cycles of therapy, at doses of 75 to 300 mg/m2 of doxorubicin, thus limiting its utility. Other ongoing trials are evaluating the combination of bevacizumab with gemcitabine/docetaxel, and with radiation therapy for intermediate- to high-grade sarcomas. Lastly, an ongoing phase II trial is evaluating bevacizumab as a single agent in patients with angiosarcomas.
The Radiation Therapy Oncology Group is evaluating the role of thalidomide(Drug information on thalidomide) (Thalomid) with radiation (RTOG 0330), in two cohorts of patients. The first is testing radiation and thalidomide alone preoperatively for low-grade extremity and trunk sarcomas. Following resection, tumors resected with a positive margin receive further radiation as a boost with thalidomide. All patients then receive an additional 6 months of thalidomide. For patients with intermediate- to high-grade tumors, radiation therapy and thalidomide are being interdigitated between three preoperative cycles of MAID chemotherapy (mesna, doxorubicin [Adriamycin], ifosfamide, dacarbazine). Following resection, postoperative radiation is given with thalidomide to those with positive margins, and thalidomide is continued for an additional 12 months. This study incorporates circulating endothelial cells as a potential biomarker of efficacy.
