Angiosarcoma is a rare and highly aggressive sarcoma subtype and occurs throughout the body at any age [1]. The prognosis of angiosarcoma is generally poor even in localized disease with 5-year overall survival (OS) up to only 60% with a median survival of around 3–10 months for metastatic disease [1–4].

In case of localized disease, standard treatment is surgical resection, sometimes combined with preoperative and postoperative radiation. However, negative surgical margins could be often difficult to achieve especially in the head and neck or in the presence of multifocal disease. These inoperable or metastatic diseases are treated with systemic chemotherapy [5]. Doxorubicin and weekly paclitaxel (wPac) are currently regarded as a preferred option for first- or second-line therapy with a median OS of approximately 8 to 10 months [6,7]. However due to the rarity of the disease, there are only limited efficacy data for such therapies.

Meanwhile, several components involved in angiogenesis have been investigated as potential targets to treat angiosarcoma [8]. These include vascular endothelial growth factor (VEGF) and multiple VEGF receptors, which are the key regulators of angiogenesis that are overexpressed in angiosarcoma [9,10]. Bevacizumab is a recombinant human antibody against VEGF and has been tested in clinical trials both as a monotherapy and in combination with other drugs [11]. Multi-target tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib) have also been applied, but the efficacy of such treatment was inconclusive as the numbers of angiosarcoma patients involved were low [1,12].

As consensus treatment strategy for angiosarcoma is not well established, it is necessary to better understand the clinicopathological features of angiosarcoma and correlate them with the treatment response and clinical outcomes. In this retrospective study, we reviewed the patients with advanced angiosarcoma who undergone systemic chemotherapy and evaluated clinical outcomes and their prognostic significance. In addition, we tried to delineate the efficacy of systemic therapies currently available for advanced angiosarcoma.

Here we described the clinical outcomes and prognostic factors of advanced angiosarcoma patients treated with systemic chemotherapy. ECOG PS was a significant prognostic factor in our study, which is consistent with previous literature [4]. Primary hepatic angiosarcoma had been associated with poor prognosis [4], and we found that liver involvement by primary or metastatic mass was associated with poor prognosis. Although previous study involving angiosarcoma patients some of whom received radical surgery described that histologic grade is associated with prognosis [16], we did not find any association of histologic grade with prognosis in patients with advanced stages.

We observed that some of the patients responded to first-line wPac or later-line pazopanib who showed significantly prolonged survival. Although there had been no clinical trials comparing the outcome of palliative systemic chemotherapy versus best supportive care, these results indicate that there are subsets of patients who may benefit from the palliative first-line wPac and second-line pazopanib in terms of survival gain. The same has also been suggested in previous retrospective analysis [17]. We also demonstrated that patients without liver involvement might benefit from wPac compared with other regimens.

Our results on first-line wPac showed seemingly inferior efficacy compared with previous studies. A prospective phase II clinical trial on wPac produced ORR of 45.8%, PFS of 6.6 months, and OS of 19.5 months [18]. Retrospective studies on first-line wPac demonstrated ORR of 45.5%–52%, PFS of 5.6–5.7 months, and OS of 13.1–18.6 months [17,19]. However, these results could be partly due to relatively lower number of patients with poor ECOG PS and liver involvement enrolled in other studies. Indeed, we showed in our study that both of these clinical features were poor prognostic factors. Another previous phase II clinical trial on wPac for angiosarcoma patients showed ORR of 18%, PFS of 4 months and OS of 8 months, which were comparable with our results [7].

Efficacy of second- or later-line of pazopanib in our study showed inferior results compared with the previous study of phase II clinical trial of pazopanib for metastatic STS, which showed PFS of 4.6 months and OS of 12.5 months [12]. However, this result may be attributed to the higher portion of other STSs in the enrolled patients such as leiomyosarcoma and synovial sarcoma, which have generally better prognosis than angiosarcoma [1]. Anti-angiogenesis agents for angiosarcoma generally produced ORR up to 14% and PFS around 3.8–4.7 months, which are similar to our study results [1]. A retrospective study on pazopanib for advanced vascular sarcomas also exhibited comparable ORR of 20%, and PFS and OS of 3 and 9.9 months, respectively, in angiosarcoma [20]. A multicenter phase II prospective trial of pazopanib is ongoing to confirm these results (Clinical trial information: NCT01462630).

Angiosarcoma is an endothelial tumor in which all three subtypes of VEGF receptors can be overexpressed [9,10,21]. In addition, recurrent mutations in PTPRB and PLCG1 genes, which are intimately linked to angiogenesis, have also been identified in angiosarcoma [22]. Therefore, there has been great interest in targeting angiogenesis for angiosarcoma [1]. Both wPac and pazopanib have anti-angiogenesis effects. wPac exerts anti-angiogenesis effects by multiple mechanisms including inhibition of the release of VEGF and angiopoietin-1 by tumor cells [23], while pazopanib directly targets VEGFR1/2/3, platelet-derived growth factor receptor and several other key proteins responsible for angiogenesis [24]. Despite some efficacy of using anti-angiogenesis drugs in angiosarcoma patients, there seems to be more factors involved in resistance to such treatments in angiosarcoma [25].

In this study, we showed that liver involvement, either by primary mass or metastatic mass, was potentially associated with poor treatment outcome. Poor survival of hepatic angiosarcoma has been reported in association with various clinical features such as intraabdominal hemorrhage due to tumor rupture and acute liver failure [26,27]. We showed that poor survival associated with liver involvement may be partly due to poor liver function represented as pre-chemotherapy bilirubin and albumin level, which would have affected drug tolerability and patient’s performance status. However, tendency to poor PFS and ORR in patients with liver involvement implicate additional mechanisms on tumor biology. Such resistance mechanism of liver involvement by tumors has been also implicated in other cancers and other antitumor agents, such as lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors and melanoma to immune checkpoint inhibitors, which exhibited reduced CD8⁺ T cell density at the invasive tumor margin at pretreatment biopsies [28,29]. In addition, previous study showed that vessel co-option, a process whereby cancer incorporates pre-existing vessels from surrounding tissue, is a clinically relevant mechanism of resistance to anti-angiogenic therapy in liver metastases of colorectal and breast cancers [30]. Whether these mechanisms are also involved in angiosarcoma resistance would require further studies.

The limitations of this study include its retrospective nature; therefore, the results presented should be interpreted carefully. Also, as angiosarcoma can have diverse patterns of the clinical course according to involved sites, the ORR, the PFS, and the OS presented in this study would have been affected by the heterogeneity. However, due to the rarity of this disease, designing a clinical trial for advanced angiosarcoma is difficult, as observed in the previous phase II clinical trial, which enrolled 30 patients with heterogeneous primary sites [7]. In addition, most of the clinical trials involving angiosarcoma include other sarcomas, which results in even more heterogeneous study population with angiosarcoma being a small portion of the entire population. In this study, we collected data from homogeneous and relatively large number of patients in advanced setting who received palliative systemic chemotherapy. Therefore, our results provide clinicians with fair information of real-world treatment outcomes in advanced angiosarcoma patients. Secondly, whether liver function represented as more relevant scoring systems such as Child-Pugh or Model for End-Stage Liver Disease scores is correlated with clinical outcome should be further evaluated. Nevertheless, the baseline serum total bilirubin and albumin levels may provide clinical insights to physicians and researchers in deciding on treatments and designing stratifications for clinical trials. Lastly, our study implicates the liver involvement as a prognostic marker, not a predictive marker. Therefore, the presence or absence of liver involvement should not be used as a factor that could influence the decision on the initiation of chemotherapy.

In conclusion, treatment with first-line chemotherapy with wPac regimen and later-line pazopanib showed comparable efficacy to that reported in previous studies and may provide survival benefit for subset of patients, especially those without liver involvement. Clinicians would need to be aware that patients with presence of liver involvement may have poor prognosis. Further investigations with large number in multicenters or prospective design considering these results are warranted.