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Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

ABSTRACT: Background:Treatment options for soft tissue sarcoma (STS) patients aged ?65?years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial. Patients and methods:Patients were randomized 2 : 1 to trabectedin (n?=?384) or dacarbazine (n?=?193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup. Results:Among 131 (trabectedin?=?94; dacarbazine?=?37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (?6 cycles) in the trabectedin arm (43% versus 23%, respectively; P?=?0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5?months, respectively; hazard ratio (HR)=0.40; P?=?0.0002] but no statistically significant improvement in OS (15.1 versus 8.0?months, respectively; HR?=?0.72; P?=?0.18) or ORR (9% versus 3%, respectively; P?=?0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population. Conclusions:This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients. Trial registration:www.clinicaltrials.gov, NCT01343277.

SUBMITTER: Jones RL

PROVIDER: S-EPMC6454486 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

Jones R L RL Demetri G D GD Schuetze S M SM Milhem M M Elias A A Van Tine B A BA Hamm J J McCarthy S S Wang G G Parekh T T Knoblauch R R Hensley M L ML Maki R G RG Patel S S von Mehren M M

Annals of oncology : official journal of the European Society for Medical Oncology 20180901 9

<h4>Background</h4>Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safet ...[more]

PMID: 30084934

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Project description:BACKGROUND:Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. MATERIALS AND METHODS:Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m2 intravenously (later reduced to 850 mg/m2). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. RESULTS:The study included 37 patients (19 female); median age was 55 years (range 26-87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression-free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m2, only 3 of the final 12 (25%) patients required dose reduction. CONCLUSION:This phase II study met its primary endpoint with an 18-week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. IMPLICATIONS FOR PRACTICE:Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease-control rates; however, it also increases the potential for significant toxicity.

Project description:BackgroundRetroperitoneal soft tissue sarcomas (STS) include a number of histologies but are rare, with approximately 3000 cases in the USA per year. Retroperitoneal STS have a high incidence of local and distant recurrence. The purpose of this study was to review the University of Maryland Medical Center's (UMMC) treatment experience of retroperitoneal STS, where the patient population served represents a diverse socioeconomic and ethnic catchment.MethodsIRB approval was obtained. We constructed a de-identified database of patients diagnosed with retroperitoneal liposarcomas (LPS) or leiomyosarcomas (LMS) treated at UMMC between 2000 and 2013. A total of 49 patients (Pts) with retroperitoneal STS met our eligibility criteria. Kaplan-Meier plots were used to graphically portray progression-free survival (PFS) and overall survival (OS). The log-rank test was used to compare time-to-event distributions.ResultsThe median OS for all patients (Pts) was 6.3 years, and the 2-year OS rate was 81%. The median PFS for all Pts was 1.8 years, and the 2-year PFS rate was 45%. There was no difference in OS and PFS among LMS and LPS patients; the median OS for LMS was 3.8 years vs. LPS 6.4 years (p = 0.33), and the median PFS for LMS was 1.2 years vs. LPS 2.5 years (p = 0.28). There was a significant difference between histology and race (p = 0.001). LPS were primarily Caucasian 86% vs. 14% black, whereas LMS were primarily black 52% vs. 33% Caucasian. OS was influenced by functional status, gender, American Joint Committee on Cancer (AJCC) stage, grade, histology, tumor size, and extent of resection. PFS was influenced by AJCC stage, grade, and extent of resection. Neither adjuvant chemotherapy (1 Pt) nor neoadjuvant/adjuvant radiation therapy (18 Pts) influenced OS or PFS. There was a non-significant difference that Pts who could undergo resection of local recurrence had improved 2-year OS, with 100% LMS and LPS compared to 2-year OS of 71% (LMS) and 78% (LPS) not undergoing resection of local recurrence.ConclusionsThis study suggests a higher incidence of leiomyosarcoma in the African-American population. This study confirms the prognostic importance of grade, tumor size, AJCC stage, histology, and extent of resection in patient outcomes, at a large substantially diverse academic medical center. Future research into the biological features of liposarcoma and leiomyosarcoma Pts imparting these characteristics will be important to define.

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Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

Publications

Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

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