Translocation-related Sarcomas Research Articles

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

AimThis randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS). MethodsPatients were randomly assigned (1:1) to receive trabectedin 1.5mg/m2 24-h intravenous (i.v.) infusion every 3weeks (q3wk) (Arm A), or doxorubicin 75mg/m2 i.v. q3wk, or doxorubicin 60mg/m2 i.v. plus ifosfamide (range, 6–9g/m2) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point. ResultsOne hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p=0.9573; hazard ratio=0.86, p=0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm. ConclusionNeither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.

13 years of trabectedin, 5 years of Yondelis®: what have we learnt?

Trabectedin (Yondelis® [PharmaMar S.A., Madrid, Spain]) is one of the most promising agents tested in the last two decades in patients with anthracycline/ifosfamide-resistant sarcomas and is the first agent highlighting the notion of prolonged tumor control in advanced soft tissue sarcoma. Indeed, the unusual pattern of tumor response to trabectedin has raised queries about the appropriateness of conventional radiological evaluation of efficacy according to Response Evaluation Criteria in Solid Tumors and has prompted the search for new end points for Phase II studies. The safety profile of trabectedin is unique and much more favorable than that of doxorubicin and ifosfamide especially as regards neutropenia and alopecia. Its efficacy in translocation-related sarcomas suggests a targeted approach to tumor control in these sarcoma subtypes. With numerous Phase II and III studies of trabectedin underway, it appears certain that the current standard-of-care paradigm in advanced soft tissue sarcoma is set for change.

A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas

AimsApproximately 20% of soft tissue sarcomas (STS) have subtype-specific chromosomal translocations; these generate chimeric oncoproteins which can act as abnormal transcription factors. Since trabectedin can bind to DNA and displace transcription factors, antitumour activity was explored in translocation-related sarcoma (TRS) subtypes. MethodsThe current retrospective pooled analysis includes data from 81 patients with TRS treated in 8 phase II trials. ResultsTRS subtypes were: synovial sarcoma (SS, n=45), myxoid-round cell liposarcoma (MRC-L-sarcoma, n=27), alveolar soft part sarcoma (ASPS, n=4), endometrial stromal sarcoma (ESS, n=3) and clear cell sarcoma (CCS, n=2). All but one patient had received prior chemotherapy (median of 2 lines). Patients received a median of 4 trabectedin cycles (range, 1–48; median dose intensity=0.40mg/m2/week). Partial responses according to Response Evaluation Criteria in Solid Tumours (RECIST) occurred in 8 patients (ORR=10%; 95% CI, 4–19%): four in MRC-L-sarcoma; three in SS and one in ESS. Tumour control rate (ORR plus stable disease) was 59% (95% CI, 48–70%). Median PFS was 4.1months (6-month PFS rate=40%). Median overall survival was 17.4months (survival rate at 12months=60%). Trabectedin had a manageable safety profile. ConclusionTrabectedin demonstrates encouraging disease control in TRS. Since these promising results were generally noted in patients following chemotherapy, a phase III randomised trial in first-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy in patients with TRS.

Efficacy of Trabectedin in Patients with Advanced or Metastatic Alveolar Soft-Part Sarcoma

Background: Alveolar soft-part sarcoma (ASPS) is a rare sarcoma often occurring in young patients that is characterized by the unbalanced translocation der(17)t(X;17) (p11;q25). Although itusuallyshowsan indolent clinical course, the prognosis is usually poor in advanced disease. Since standard chemotherapy regimens used in soft-tissue sarcomas lack efficacy in ASPS, new therapeutic options are needed. We investigated the efficacy of trabectedin, which has demonstrated activity in a variety of cancer types including some of the most prevalent translocation-related sarcomas. Patients and Methods: 7 patients with metastatic or advanced ASPS treated with trabectedin in the Sarcoma Center Berlin-Brandenburg and the University Hospital of Greifswald were analyzed for median progression-free survival (mPFS), overall survival (OS), and therapy-related toxicity. Results: In 6 patients with documented disease progression, disease stabilization was reached with trabectedin; only 1 patient experienced progressive disease. The mPFS and OS were 7 months and 21 months, respectively, since the start of trabectedin treatment. Overall, no severe Common Toxicity Criteria (CTC) grade 3 or 4 toxicity was observed. Conclusions: The poor prognosis of patients with ASPS has so far been due to the unavailability of effective systemic treatments. Trabectedin can be considered the only currently registered drug with clinical activity in this disease.

Trabectedin therapy for sarcomas

The therapeutic armamentarium of adult soft-tissue sarcomas (STS) has widened in recent years. This was also due to increased consideration of their variegated histology. Trabectedin is a new chemotherapeutic agent, which significantly strengthens the armamentarium along this direction. Trabectedin has proven efficacy in STS, mainly in leiomyosarcomas, liposarcomas, and other translocation-related sarcomas. Among further subgroups, its activity in uterine leiomyosarcomas is noteworthy. Moreover, it exerts special antitumor activity in myxoid liposarcomas, with distinct patterns of tumor response. Also, its mechanism of action is distinct in myxoid liposarcoma, apparently overcoming lipogenic cell differentiation block due to the tumor chromosomal translocation. Apart from histology, DNA repair mechanisms have been investigated as a predictive factor, with retrospective evidence in support. Combination of trabectedin with doxorubicin has limitations due to additive toxicity. Trabectedin is well tolerated as a single agent. Occasional major myelosuppression is possible but proper patient selection (with a focus on liver tests) and possibly steroid premedication are of help. Trabectedin is a new marine-derived drug with a definite role in the 'histology-driven' medical therapy of STS. There is room for further investigation, to fully elucidate its efficacy in all STS and optimize tolerability.

9401 Translocation-related sarcomas (TRS): a retrospective analysis of activity with trabectedin

9401 Translocation-related sarcomas (TRS): a retrospective analysis of activity with trabectedin