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A case of heavily pretreated metastatic cardiac angiosarcoma treated successfully using eribulin

Inagaki, Chiakia,c; Shimoi, Tatsunoria; Okuma, Hitomia; Kitano, Akikoa; Shimomura, Akihikoa; Noguchi, Emia; Kodaira, Makotoa; Yunokawa, Mayua; Yonemori, Kana; Shimizu, Chikakoa; Yoshida, Akihikob; Fujiwara, Yasuhiroa; Tamura, Kenjia

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doi: 10.1097/CAD.0000000000000558
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An angiosarcoma of the heart is an extremely rare disease with a poor prognosis. The standard therapy in the metastatic setting is chemotherapy. Paclitaxel and doxorubicin are considered to be first-line agents and are administered sequentially 1,2. The benefit of chemotherapy beyond the second line is obscure.

Eribulin mesylate (eribulin) has been approved for the treatment of any kinds of soft tissue sarcomas in Japan as of February 2016. To date, the efficacy of eribulin for angiosarcoma has not been evaluated sufficiently because of the small number of patients with angiosarcoma included in previous trials 3.

Here, we report a patient with heavily pretreated metastatic cardiac angiosarcoma who showed a good response to eribulin treatment.

Case description

The patient was a previously healthy 34-year-old Japanese woman who was admitted to a local hospital because of shortness of breath. Echocardiography indicated a right atrial mass that caused tricuspid valve stenosis. She immediately underwent incomplete resection of the right atrium for the management of her symptom and was subsequently diagnosed with right atrial angiosarcoma on the basis of the pathological findings (Fig. 1). One month later, she was referred to our hospital for further treatment. Her Eastern Cooperative Oncology Group performance status score was 0 and the findings of her physical examination and laboratory testing were unremarkable. She had normal cardiac function during echocardiography and her ejection fraction was 83%.

Fig. 1
Fig. 1:
Histopathological images. High-grade spindled cells with anastomosing irregular vessels were observed in hematoxylin and eosin-stained sections (×400, a). Tumor cells were positive for immunohistochemical staining with CD31 (b) and ERG (c). The diagnosis of angiosarcoma was made on the basis of these pathological findings. CD, cluster of differentiation; ERG, ETS-related gene.

Chemotherapy was initiated for the residual disease using six cycles of paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 28-day cycle), and she was followed up accordingly (Table 1). Three months later, she was found to have a metastatic lesion in the anterior mediastinum; therefore, doxorubicin (75 mg/m2 every 3 weeks) was subsequently administered for five cycles. Four months after the end of the previous round of chemotherapy, a hepatic metastasis was found. Hence, pazopanib (800 mg/day orally, once daily) was administered for ~9 months, followed by 10 cycles of gemcitabine (1200 mg/m2 weekly for 2 weeks every 3 weeks), two cycles of dacarbazine (800 mg/m2 every 3 weeks), and three cycles of trabectedin (1.2 mg/m2 every 3 weeks); these agents were continued until disease progression. At the time when she experienced progressive disease with trabectedin, ~46 months after the initial surgery, though she remained in good health (Eastern Cooperative Oncology Group performance status score of 0), with normal cardiac function in echocardiography. Therefore, she underwent another line of chemotherapy using eribulin (1.4 mg/m2 on days 1 and 8 in a 3-week cycle).

Table 1
Table 1:
The patient’s clinical course

Because of grade 4 neutropenia in cycle 1, she did not receive day 8 eribulin and the dose was reduced to 1.1 mg/m2 on cycle 2. She redeveloped grade 4 neutropenia in cycle 2; therefore, she skipped day 8 eribulin again and the dose was adjusted to 0.7 mg/m2 on cycle 3. Afterwards, she was able to continue treatment as scheduled. She achieved a good partial response after three cycles of treatment, which continued for ~4 months (Fig. 2). However, progression was detected after eight cycles of eribulin and the patient received two cycles of vinorelbine (25 mg/m2 weekly for 2 weeks every 3 weeks), which elicited a poor response. Thereafter, her performance status had deteriorated and she was admitted to a palliative care unit at the time of writing this article.

Fig. 2
Fig. 2:
Radiographic response of the hepatic metastasis. Contrast-enhanced computed tomography before the start of eribulin treatment showed a heterogeneously enhanced mass in the posterior liver segment (a). After three cycles of eribulin treatment, contrast-enhanced computed tomography showed a partial tumor response (b). Further tumor response was observed after five cycles of eribulin treatment (c), although disease progression was detected after eight cycles (d).


Primary heart tumors are extremely rare, with an autopsy series reporting an incidence of only 0.01–0.03%, and ~25% of the cases are malignant 4. Cardiac angiosarcoma is the most common histology for malignant primary heart tumors, which typically arise from the right atrioventricular groove 5,6. It also has an aggressive nature, and a retrospective case series reported that the median survival time was 19.5 months for localized disease and 6 months for metastatic disease 7. Patients commonly present with symptoms of right-sided heart failure, such as dyspnea, cough, hemoptysis, and orthopnea, with no robust prognostic factors 4. For localized tumors, complete surgical resection is ideal to improve survival. Early recurrence after complete removal is frequently observed; therefore, adjuvant chemotherapy and/or radiotherapy is sometimes recommended. However, its impact on patient survival remains unclear 6. The recent literature described the safety and efficacy of neoadjuvant chemotherapy to increase the rates of complete resection and survival 8.

For metastatic and locally advanced unresectable disease, chemotherapy is the standard treatment. Paclitaxel and doxorubicin are considered active agents and are used sequentially in this setting, although there is no consensus on the treatment order 1,2. Chemotherapy beyond the second line of treatment for angiosarcoma is not well established and its benefit is also unclear. One retrospective study reported that gemcitabine provides favorable efficacy and acceptable toxicity 9, whereas a phase II trial showed that ifosfamide is a potentially effective treatment for soft tissue sarcomas including angiosarcoma 10. On the basis of the preclinical data, the angiogenesis signaling pathway is considered a key pathogenic pathway for angiosarcoma, and some studies evaluated the molecular therapies that target angiogenesis. For example, subgroup analysis of phase II–III trials showed that pazopanib was active among patients with angiosarcoma 11 and sorafenib provided a slight benefit for patients with angiosarcoma in one phase II trial 12. Another phase II trial yielded promising results for bevacizumab monotherapy, although the combination of bevacizumab with paclitaxel does not show benefits over paclitaxel alone 13,14.

Eribulin is a nontaxane microtubule inhibitor with high levels of activity in some solid tumors, including breast cancer 15. Furthermore, eribulin provided a significant improvement in the overall survival, compared with dacarbazine, in a phase III trial that evaluated patients with liposarcoma and leiomyosarcoma who had previously received at least two systemic treatments 16. On the basis of these results, eribulin was approved, in early 2016, by many European countries and the USA for treating patients with unresectable or metastatic liposarcoma who had previously been treated using an anthracycline-containing regimen. In Japan, eribulin was approved for the treatment of soft tissue sarcoma, irrespective of the histological subtype, in February 2016. After the approval, and because of the limited treatment options for sarcoma, our center has regularly used eribulin to treat patients with all histological subtypes of sarcoma who have failed the standard therapy. Insufficient data exist on the efficacy of eribulin against angiosarcoma, given the limited number of angiosarcoma cases in the previous trial 3. However, Wada et al.17 have recently reported a case of scalp angiosarcoma that was well controlled with eribulin treatment.

In the present case, the patient with heavily pretreated metastatic cardiac angiosarcoma experienced a good response to eribulin treatment. To the best of our knowledge, this is the first reported case of cardiac angiosarcoma that responded well to eribulin. The patient had a relatively long survival, compared with other cases of metastatic angiosarcoma, and completed nine lines of treatment with manageable toxicity.

In preclinical models, eribulin provided antimitotic activity in soft tissue sarcoma with several histopathological subtypes. At the same time, in-vitro testing indicated that eribulin can cause tumor vasculature remodeling, thereby enhancing tumor blood perfusion and inducing tumor cell differentiation 18. Thus, although no studies have evaluated the antitumor mechanism of eribulin in angiosarcoma, we speculate that our patient’s response might be related to the mitotic and vascular remodeling activities of eribulin. Paclitaxel is a common treatment for angiosarcoma and shows both antiangiogenic and antimicrotubule activities in vitro19.

There are few reports on markers for predicting the response of sarcoma to eribulin treatment. However, in breast cancer, eribulin-induced liver dysfunction and tumor-infiltrating lymphocytes may predict the response to eribulin treatment 20,21. Unfortunately, our patient’s tumor-infiltrating lymphocytes and liver damage throughout her clinical course were not examined and detected, respectively.

Our patient had a remarkable treatment sequence and survival outcome, which we believe was related to the prolonged response to multiple chemotherapeutic agents. For example, a breast cancer study showed that progression-free survival during the previous treatment line was a prognostic factor for each subsequent line of chemotherapy 22. We also believe that she might have several beneficial characteristics, including her relatively young age at the diagnosis, good performance status, symptom relief after surgery, and well-preserved organ function. Although the Asian Sarcoma Consortium has recently reported that only 10% of Asian advanced/metastatic angiosarcoma cases undergo more than three lines of chemotherapy 23, additional lines of treatment should still be considered for patients who are in good health and who can tolerate the side effects. Nevertheless, additional evidence is necessary to confirm the benefits of treatment beyond the first and second lines of chemotherapy.


This case report presented a patient with heavily pretreated cardiac angiosarcoma, who responded well to eribulin treatment, and suggested that eribulin may be an effective treatment for angiosarcoma. Further studies are needed to investigate the effects of eribulin in angiosarcoma cases and to establish markers that can predict eribulin sensitivity.


The authors would like to thank Asuka Kawachi and Tadaaki Nishikawa for useful discussion.

Conflicts of interest

There are no conflicts of interest.


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cardiac angiosarcoma; chemotherapy; eribulin; metastatic angiosarcoma; sarcoma

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