Eribulin Provides a Remarkable Effect in Trabectedin-Resistant Myxoid Liposarcoma

Adriamycin-based chemotherapy is commonly used for malignant soft tissue sarcoma including myxoid liposarcoma. However, in the case of unavailability or failure of the adriamycin-based regimen, trabectedin or eribulin can produce a good antitumor effect for myxoid liposarcoma. We relate the experience of a 64-year-old female with myxoid liposarcoma, who noticed a nodule on her left thigh and visited our institute. At initial presentation, the tumor was 18.7 cm in diameter, and the magnetic resonance imaging (MRI) showed a malignant lipomatous tumor with a myxoid component. We recommended that she undergo treatment; however, she refused. Three years later, the tumor had grown larger, so she finally decided to undergo treatment. A needle biopsy revealed a myxoid liposarcoma. The tumor massively involved the neurovascular structures; we thus determined that hip disarticulation was inevitable. Two years later, metastases in the right thigh, left lung, right ileum, and abdominal space were pointed out and chemotherapy was initiated. Adriamycin was unusable due to cardiac dysfunction, so trabectedin was administered; however, the tumors progressed. Eribulin was subsequently started and has been considerably effective for more than 2 years without severe adverse effects. In conclusion, we experienced a case showing the remarkable and long-lasting effect of eribulin against trabectedin-resistant myxoid liposarcoma.


Introduction
Liposarcoma is a relatively common malignant soft tissue tumor. Histological subtype classification is important because clinical features, including sensitivity to chemotherapy and radiotherapy and overall survival in each subtype, vary. Liposarcoma is categorized into well-differentiated, dedifferentiated, pleomorphic, and myxoid liposarcoma. Well-differentiated liposarcoma provides a good prognosis with a 5-year survival rate of about 100% [1]. In contrast, pleomorphic and dedifferentiated liposarcomas have a high-grade malignancy, in which 5-year overall survival rates are reported to be around 60% and 70%, respectively [2,3].
Myxoid liposarcoma is another subtype of high-grade potential, and overall survival varies depending on the presence of round-cell components [4].
As a treatment, surgical resection is the mainstay, which is similar to other types of sarcoma. Well-differentiated liposarcoma is low grade, in which chemotherapy or radiotherapy is not effective and surgery is the only option, unless it differentiates into the dedifferentiated type. Pleomorphic and dedifferentiated liposarcomas also respond poorly to chemotherapy and radiotherapy; therefore, surgical resection with a negative margin is preferred [1]. On the other hand, chemotherapy and radiotherapy provide a good response in myxoid liposarcoma [5]. As a chemotherapeutic treatment, the adriamycin-based regimen is standard for malignant soft tissue sarcoma [6]. However, cardiotoxicity or hematotoxicity is occasionally problematic [7].
Three anticancer agents for soft tissue sarcoma have recently been developed. In the 2010s, pazopanib, trabectedin, and eribulin were used for soft tissue sarcoma and the effectiveness of each was reported for a certain type of the sarcoma.
In a previous report, eribulin was found to be superior to dacarbazine in the dedifferentiated and pleomorphic types, but not in myxoid liposarcoma [8]. There is still no evidence of how effective eribulin is for myxoid liposarcoma.

Case Presentation
A 64-year-old female noticed a nodule in her left thigh and visited our institute. A plain radiograph indicated a slight calcification in the posterior middle part of her thigh (Figures 1(a) and 1(b)). Positron emission tomography  . From those images, we suspected a malignant lipomatous tumor such as dedifferentiated liposarcoma. We therefore planned to perform a biopsy; however, she refused treatment. Three years later, she revisited us since the tumor had progressively enlarged and skin breakdown had occurred (Figure 2(a)). The tumor had enlarged to 22 × 14 × 9 cm and invaded the neurovascular structures (Figures 2(b) and 2(c)). A needle biopsy revealed myxoid liposarcoma. As a limb-salvage procedure seemed impossible, we performed hip disarticulation ( Figure 2(d)). However, she refused adjuvant chemotherapy. Two years postoperation, multiple metastases appeared in the lower right leg, left chest wall, abdominal subcutis, and intraabdominal space ( Figure 3). After surgical resection of the leg tumor, she accepted chemotherapy, so we administered trabectedin as first-line chemotherapy without administrating adriamycin because of her cardiac dysfunction. Three cycles of trabectedin (dose: 1.2 mg/m 2 , 24 hours intravenously from a central venous catheter; no remarkable adverse effect including hematotoxicity was observed) were conducted, resulting in progressive disease (Figures 4(a)-4(f)). We subsequently switched the regimen to eribulin (dose: 1.4 mg/m 2 , intravenously), which evinced a partial response (Figures 4(g)-4(l)). That antitumor effect has lasted now for more than 2 years. So far, no drug resistance has been seen. Adverse effects have been minimal, and the patient has been very satisfied.

Discussion
In this case report, we reported on the long-lasting, antitumor effect of trabectedin-resistant myxoid liposarcoma, which has been reported to be highly sensitive to trabectedin 3 Case Reports in Orthopedics [9], but the mechanism underlying this resistance has not been fully understood.
Trabectedin is a natural alkaloid derived from the Caribbean tunicate, Ecteinascidia turbinata. It has multiple, complex mechanisms of action and, consequently, the potential for extensive clinical application. The first phase III trial to compare trabectedin with dacarbazine in patients having advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen showed that the median progression-free survival (PFS) is 4.2 months for trabectedin compared with 1.5 months for dacarbazine, although median overall survival (OS) is 12.4 months for trabectedin vs. 12.9 months for dacarbazine [10].
Eribulin mesylate is a synthetic derivative of halichondrin B, which is isolated from a marine sponge. Its mechanism of action is through microtubule inhibition, which is different from that of taxanes. Eribulin has been approved for the treatment of metastatic breast cancer and more recently for inoperable or metastatic liposarcoma in patients who have received prior anthracycline chemotherapy. The major side effects of eribulin are bone marrow suppression including neutropenia, leukopenia, anemia, and fatigue/weakness, which can be easily managed.
A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma or leiomyosarcoma showed a significant improvement in OS for the eribulin arm, with a manageable toxicity profile. Median OS was sig-nificantly improved: 13.5 vs. 11.5 months with eribulin vs. dacarbazine, respectively. PFS was not significantly different: 2.6 months for eribulin vs. 2.6 months for dacarbazine [11].
Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced nonadipocytic soft tissue sarcoma. Pazopanib for metastatic soft tissue sarcoma (PALETTE): a randomized, double-blind, placebocontrolled phase 3 trial showed that median PFS was 4.6 months for pazopanib compared with 1.6 months for the placebo, although the OS rate was 12.5 months with pazopanib vs. 10.7 months with the placebo [12].
Regarding the evaluation of chemotherapy, in some cases, trabectedin takes very long to be effective and there is even an apparent (paradoxical) increase in the tumor size after the initial cycles that are generally followed by a subsequent shrinkage of the neoplastic lesions. A previous paper mentioned that pseudoprogression may occur in inoperative soft tissue sarcoma in response to trabectedin [13]. They stated that a frequent (n = 6/31; 19.3%) pattern of response was tumor liquefaction. However, in our case, progressive disease was apparently observed during trabectedin while tumor shrinkage happened as soon as initiation of eribulin. Hence, tumor shrinkage was caused by eribulin, not trabectedin.
Some reports have mentioned that HMGA1 and UVSSA are involved in resistance to trabectedin [14,15]. The in vivo patient-derived xenograft model investigating acquired resistance has suggested that the genes involved in lipid processes and adipogenesis had been altered between sensitive and   5 Case Reports in Orthopedics resistant tumors [14]. Further investigation may unveil the detailed mechanism involved in trabectedin-related resistance.
The mechanism of eribulin seems to be unique in various ways. First is the effect on microtubule dynamics to pause microtubule growth and inhibit growth of the microtubules [16]. The second involves angiogenesis and vascular remodeling [17]. In clear-cell sarcoma, tumor reoxygenation caused by eribulin-induced vascular remodeling attenuates cell growth and inhibits ERK1/2 activity to upregulate microphthalmia-associated transcription factor expression and promote melanocytic differentiation [18]. Another is to inhibit epithelial-to-mesenchymal transition. A previous paper has demonstrated that eribulin treatment decreases expression of several mesenchymal marker genes and increases expression of several epithelial markers [19]. The last is a telomerase reverse transcriptase-(TERT-) related mechanism. Eribulin-sensitive cells showed a higher tendency for sphere formation, which is characterized by an enhanced cancer stem cell-(CSC-) like phenotype; those cells expressed a higher level of TERT [20]. The precise mechanism of eribulin remains to be determined.
Eribulin causes fewer complications such as hematotoxicity [21]; hence, it is comparatively safe; it can be used even in the elderly. There are no reports of adverse events in long-term use, but long-term treatment of women with metastatic breast cancer heavily pretreated with eribulin has been reported [22]. Eribulin also may provide longlasting effects in our case, although we should watch for such long-term complications as secondary tumorigenesis during follow-up.

Conclusion
We experienced a remarkable response in trabectedinresistant myxoid liposarcoma. Eribulin should be considered a promising anticancer drug in the treatment of myxoid liposarcoma.

Data Availability
No data were used to support this study.

Consent
The patient provided consent to participate and publish this case report.

Conflicts of Interest
The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article.
(j) (k) (l) Figure 4: Response to chemotherapy in metastatic myxoid liposarcoma. Computed tomography (a-c) before and (d-f) after 3 cycles of trabectedin showing progressive disease. Partial response was obtained 5 months after treatment with eribulin (g-i). The tumors were under control for another 10 months (j-l). 6 Case Reports in Orthopedics