Robin L. Jones
Medical Oncology Division University of Washington Fred Hutchinson Cancer Research Center Seattle WA, USA

Abstract:

Soft tissue sarcomas are rare malignancies of mesenchymal origin, which consist of more than 50 histological subtypes. For a number of years two chemotherapeutic agents have been used to treat locally advanced and metastatic disease, namely doxorubicin and ifosfamide. The introduction of imatinib as an effective therapy for metastatic gastro intestinal stromal tumours heralded the development of the concept of targeted therapy in solid tumours. Other rational therapies have shown efficacy in this histological sub type including sunitinib and nilotinib. Initial results of a randomized Phase III trial have demonstrated significantly longer recurrence-free survival in patients treated with adjuvant imatinib compared to placebo.

The systemic management of other soft tissue sarcomas is changing. There is now greater emphasis on the differential sensitivity of each subtype to chemotherapy. Taxanes are established as effective agents in angiosarcoma, gemcitabine and docetaxel for leiomyosarcoma and trabectedin for liposarcoma and leiomyosarcoma. Trabectedin appears to be particularly effective in myxoid/ round cell liposarcoma. We have performed retrospective studies demonstrating a higher response rate to anthracycline-based chemotherapy in patients with myxoid/ round cell liposarcoma compared to those with well-/ dedifferentiated liposarcoma. We have also confirmed that clear cell sarcoma and solitary fibrous tumor are not sensitive to standard anthracycline and ifosfamide chemotherapy. Navelbine has shown promise in epithelioid sarcoma.

An anti angiogenic agent, pazopanib, acting on the vascular endothelial growth factor receptor (VEGFR) has displayed activity in an European trial of soft tissue sarcoma patients (however, activity was not observed in those with liposarcoma). The results of randomized placebo controlled Phase III trail of this agent in metastatic soft tissue sarcoma are awaited. Recently presented results have shown benefit for the anti angiogenic drug (cidiranib) in alveolar soft part sarcoma, a subtype unresponsive to conventional chemotherapy. IGF1-R (insulin-like growth factor-1 receptor) inhibitors have shown promise in relapsed/ refractory Ewing’s sarcoma. Further work is required to identify which patients are most likely to benefit from agents targeting the IGF1-R.

Other developments include the use of inhibitors of mTOR (mammalian target of rapamycin) in peri vascular epithelioid cell tumour (PEComa) and ALK inhibitors in inflammatory myofibroblastic tumor. Giant cell tumours of bone are associated with overexpression of receptor activator for nuclear factor kappa B (RANK) and RANK ligand. Denusomab a monoclonal antibody to RANKL has resulted in clinical benefit in patients with inoperable giant cell tumours of bone.

In addition we are studying the potential of immunotherapy in certain subtypes such as synovial sarcoma, osteosarcoma and chondrosarcoma.

Further work is required in translocation driven sarcomas and the selection of rationally designed drugs for specific targets in individual subtypes. The nature of systemic treatment of soft tissue sarcomas is likely to change further over the coming years with the greater understating of the underlying biology of these diseases and the identification of drugs targeting specific molecular drivers of these tumours.