Antiangiogenesis agents in the treatment of soft tissue sarcomas

Abstract

Soft tissue sarcomas (STSs) are a heterogeneous group of malignancies that includes >50 different subtypes, each with unique clinical and pathologic qualities. In general, there is a 50% cure rate, and most cures are achieved with complete surgical resection with or without radiation therapy. The results from chemotherapeutic agents for unresectable or metastatic disease have been disappointing with minimal long-term benefit. New targeted and novel agents are needed to improve response and survival. Tumor angiogenesis has been an intense focus in cancer therapy over the past decade. Several of numerous antiangiogenesis agents have been developed, and many already have been approved for the treatment of both solid and liquid tumors. Certain STSs are highly vascular tumors that often demonstrate angiogenesis markers. The objective of this review was to evaluate these angiogenesis markers in defining the role of angiogenesis in the treatment of patients with STS. In addition, the authors conducted an indepth review of the results from using key antiangiogenesis agents in the treatment of STS. Cancer 2010;116:1177-83. V C 2010 American Cancer Society.KEYWORDS: soft tissue sarcoma, angiogenesis, vascular endothelial growth factor, microvessel density, bevacizumab.Soft tissue sarcomas (STSs) are tumors of mesenchymal origin with more than 50 different subtypes. These tumors are uncommon, and the mainstay of treatment is complete surgical resection, with or without radiation therapy, which results in a 50% cure rate. The outcome for patients with unresectable or metastatic disease, however, is unacceptably poor. Chemotherapeutic agents result in short-lived responses and generally do not improve survival. Novel and targeted agents are needed to improve the outcome of these patients.It has been demonstrated that angiogenesis plays an important role in the growth and metastasis of several solid tumors. The response rates (RRs) to single-agent angiogenesis inhibitors generally are low; however, in combination with chemotherapy, these agents have produced improvements in overall survival in several solid tumors, including colon cancer and lung cancer.1,2 Several of these agents have been approved for the treatment of cancer over the past decade. Angiogenesis markers can aid in defining the importance of angiogenesis in each tumor type, and several surrogate markers of angiogenesis have been evaluated extensively.3 In this report, we update implications of these markers for outcome and review current clinical trials with antiangiogenesis agents. Tumor VascularityMicrovessel density (MVD) is 1 of the first markers of angiogenesis that seem to correlate with outcome in some solid tumors. However, the value of MVD as a prognostic factor in STS is controversial. Comandone and colleagues correlated MVD and survival in 45 patients with extremity STS, mostly liposarcoma (LPS) and malignant fibrous histiocytoma (MFH).4 At a median follow-up of 23 months, patients who had low MVD had improved median disease-free survival (DFS) (24 m...

Ex Vivo Behaviour of Human Bone Tumor Endothelial Cells

“…In addition, cell-based assays using various TECs could be a rational approach to study ECs in tumor tissues. Finally, these findings may be of great importance in designing more tissue-specific antiangiogenic therapies for sarcoma and bone metastasis treatment or identifying novel markers to improve clinical outcomes [15,39]. …”

“…Bone sarcomas are a group of mesenchymal malignancies, highly vascularized with many different subtypes each with unique clinical pathological features [14]. To improve the outcome of unresectable, chemoresistant or metastatic patients, ongoing trials are testing antiangiogenic drugs as adjuvant therapy [15]. However, not all subtypes are expected to respond since bone tumor microenvironments are poorly understood and no data are available on the phenotypic and functional characteristics of TECs.…”

Therapeutic pipeline for soft-tissue sarcoma

“…The clinical benefit rate (CBR), defined as CR, PR or SD for more than 16 weeks (4 months), was 30% for the bone sarcoma stratum, 36% for the leiomyosarcoma stratum, 22% for the LPS stratum and 22% for the other STS stratum. These numbers are in keeping with the activity of anti-angiogenic agents in STS [22], which is a possible explanation, as mTOR targeting agent have been recognized to have anti-angiogenic activity [48]. Once again, no predictive biomarkers have yet emerged.…”

Highlights from the 1st Latin American meeting on metronomic chemotherapy and drug repositioning in oncology, 27–28 May, 2016, Rosario, Argentina

“…The potential role of angiogenesis in ES was analysed, noting that EWS-FLI1 may function as a promoter for vascular endothelial growth factor, especially in sarcomas, that are highly vascular tumours [42]. She mentioned the literature background for the use of cyclophosphamide-based MCT, and some of the weaknesses of this therapy, related to the absence of validated biomarkers and randomised phase-II trials [39].…”