Metastatic extraskeletal Ewing's sarcoma treated with trabectedin: A case report

Abstract

The Ewing's sarcoma family of tumors (ESFT) comprises a number of rare malignant tumors. Standard first-line treatment for patients with these tumors includes chemotherapy with a five-drug regimen of vincristine, doxorubicin (Adriamycin®) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). In cases of inadequate response, there are a number of second-line regimens available. However, further treatment options are required for those patients with disease unresponsive to standard treatment. Trabectedin is a novel treatment option for patients with ESFT. The present study reports the case of a Caucasian 69-year-old female patient who presented with a soft tissue mass on the chest wall that had developed 7 months earlier. A computed tomography scan revealed a 9×8×7-cm mass on the anterior chest wall above the pectoral muscle. Histopathological evaluations and molecular analysis indicated that it was consistent with a metastatic extraskeletal Ewing's sarcoma. The patient was treated with an alternating VAC/IE regimen; however, an inadequate response was observed. The patient received second-line treatment with a gemcitabine and dacarbazine combination regimen, but the disease progressed. Subsequently, treatment with trabectedin (1.5 mg/m2 as a 24-h continuous infusion every 3 weeks) was initiated. Trabectedin treatment resulted in long-lasting (18 months) progression-free survival. It is vital that novel drugs continue to being developed for patients with ESFT following progression subsequent to standard chemotherapy. The current report presents a case of a patient with metastatic, pre-treated Ewing's sarcoma achieving disease stabilization with trabectedin. Based on these results and the observed tolerability profile, trabectedin represents an alternative treatment for patients with ESFT. Further studies are required in order to determine the efficacy of trabectedin as monotherapy or in combination with other drugs. It is also important to identify which tumor subtypes, specific translocations and patient profiles will benefit the most from treatment with trabectedin.

Myelolytic Treatments Enhance Oncolytic Herpes Virotherapy in Models of Ewing Sarcoma by Modulating the Immune Microenvironment

“…Our findings also strongly support the combination therapy of oncolytic herpes simplex virus and trabectedin to improve Ewing sarcoma treatment. Trabectedin is a DNA intercalation chemotherapeutic that is particularly attractive for Ewing sarcoma because it disrupts EWS/FLI1 transcription; in some models, such activity results in single-agent activity, 28 , 29 , 30 , 31 although we did not observe any efficacy of trabectedin alone in A673 or TC71 despite administering doses previously shown to reduce EWS/FLI1 expression. In addition to inhibiting EWS/FLI-mediated tumor progression, trabectedin also depletes TRAILR2 + tumor leukocytes, such as macrophages and MDSCs.…”

“…Trabectedin is a chemotherapeutic that has been previously shown to deplete tumor macrophages. 27 While trabectedin is currently FDA approved for liposarcoma, there is a growing body of preclinical research demonstrating therapeutic efficacy in Ewing sarcoma, 28 , 29 , 30 , 31 thought to be due to the interruption of the transcriptional activation by EWS-FLI1. For these reasons we sought to test the combination of trabectedin and oncolytic virus therapy against Ewing sarcoma.…”

Role of immunotherapy in Ewing sarcoma

“…The regimens used were liposomal clodronate and trabectedin with the goal of reducing tumor macrophages, given that the M2-macrophages have been found to suppress the host antitumor and antiviral immune response. [122][123][124][125] Trabectedin is a DNA intercalating agent that disrupts EWS/FLI1 transcription, and in some models, it resulted in single-agent antineoplastic activity, [126][127][128][129] and in addition to inhibiting EWS/ Open access FLI-mediated tumor progression, trabectedin has been found to deplete TRAILR2 + tumor leukocytes (includingmacrophages and MDSCs). [130][131][132] However, Denton et al 121 did not observe any efficacy of trabectedin alone in A673 or TC71, ES cell lines, despite administering doses that had previously shown to decrease EWS/FLI1 expression.…”

Trabectedin Enhances Oncolytic Virotherapy by Reducing Barriers to Virus Spread and Cytotoxic Immunity in Preclinical Pediatric Bone Sarcoma

“…Preclinical and clinical data demonstrated Ewing sarcoma vulnerability to fusion oncogene (EWS-FLI or other FET/ETS fusion) targeting by trabectedin. 26,[28][29][30][31]46 These studies and others underscored the clinical relevance of trabectedin against Ewing sarcoma, despite initial challenges to achieve clinical outcomes at lower serum concentrations. 28,47 Indeed, a recent multicenter phase I study of trabectedin as a one-hour infusion in combination with irinotecan in recurrent Ewing sarcoma displayed clinical benefit and safety in pediatric patients, providing rationale for an ongoing phase II study.…”