Robinson, Steven I

Abstract Purpose: Soft-tissue sarcomas are rare malignancies with poor prognosis and limited systemic treatment options. We conducted a phase II study to assess the efficacy and safety of trabectedin and olaparib in patients with advanced disease. Patients and Methods: Patients with soft-tissue sarcoma who received ≥1 prior therapy were recruited into two cohorts. Cohort 1 included leiomyosarcoma and liposarcoma; cohort 2 included other histologies. All patients received trabectedin (1.1 mg/m2 24-hour infusion every 21 days) and olaparib (150 mg twice daily continuously). The study was conducted using a Simon minimax two-stage design with a primary endpoint of objective response (OR) rate per RECIST 1.1. Results: Twenty-nine (cohort 1, 16; cohort 2, 13) patients enrolled; one patient in cohort 2 was not evaluable. There were no confirmed ORs in cohort 1; the best response was stable disease in 12 (75%) patients and progressive disease in four (25%). Two partial responses were observed in cohort 2 (n = 12). The most common adverse events were fatigue (75%), neutropenia (75%), anemia (68%), and thrombocytopenia (68%). The median progression-free survival and overall survival for all patients were 3.5 (95% confidence interval, 3.3–8.2) and 13.2 months (95% confidence interval, 10.3–20.9), respectively. Next-generation sequencing of 17 tumors revealed multiple abnormalities, most commonly in TP53, RB1, and ATRX. Conclusions: Trabectedin plus olaparib conferred high rates of toxicity and failed to demonstrate ORs in leiomyosarcoma and liposarcoma. Preliminary evidence of clinical benefit in two patients in cohort 2 suggests potential value of either or both drugs in other sarcomas.

Perioperative radiation therapy (RT) has been associated with reduced local recurrence in patients with retroperitoneal sarcomas (RPS); however, selection criteria remain unclear. We hypothesized that perioperative RT would improve survival in patients with RPS and would be associated with pathological factors. The National Cancer Database (NCDB) from 2004 to 2012 was reviewed for patients with nonmetastatic RPS undergoing curative intent resection. Tumor size was dichotomized at 15 cm based on 8th edition American Joint Committee on Cancer (AJCC) staging. Patients with the highest comorbidity score were excluded. Unadjusted Kaplan–Meier and adjusted Cox proportional hazards modeling analyzed overall survival (OS). Multivariable logistic regression modeled margin positivity. A total of 2,264 patients were included; 727 patients (32.1%) had perioperative radiation in whom 203 (9.0%) had radiation preoperatively. Median (IQR) RPS size was 17.5 [11.0–27.0] cm. Histopathology was high grade in 1048 patients (43.7%). Multivariable analysis revealed that perioperative radiation was independently associated with decreased mortality (HR 0.72, 95% confidence intervals (CIs) 0.62–0.84,p<0.001), and preoperative RT was associated with reduced margin positivity (HR 0.72, 95% CI 0.53–0.97,p=0.032). Stratified survival analysis showed that radiation was associated with prolonged median OS for RPS that were high-grade (64.3 vs. 43.6 months,p<0.001), less than 15 cm (104.1 vs. 84.2 months,p=0.007), and leiomyosarcomatous (104.8 vs. 61.8 months,p<0.001). Perioperative radiation is independently associated with decreased mortality in patients with high-grade, less than 15 cm, and leiomyosarcomatous tumors. Preoperative radiation is independently associated with margin-negative resection. These data support the selective use of perioperative radiation in the multidisciplinary management of RPS.

Objectives. To assess the clinical features and local control (LC) outcomes in adult patients with localized Ewing Sarcoma (ES).Methods. The records of 102 ES patients with localized disease ≥18 years of age seen from 1977 to 2007 were reviewed. Factors relevant to prognosis, survival, and LC were analyzed.Results.The 5-year overall survival (OS) and event-free survival (EFS) were 60% and 52%, respectively, for the entire cohort. Treatment era (1977–1992 versus 1993–2007) remained an independent prognostic factor for OS on multivariate analysis, with improved outcomes observed in the 1993–2007 era (P=0.02). The 5-year OS and EFS for the 1993–2007 era were 73% and 60%, respectively. Ifosfamide and etoposide based chemotherapy and surgery were more routinely used in the 1993–2007 era (P<0.01). The 5-year local failure rate (LFR) was 14%, with a 5-year LFR of 18% for surgery, 33% for radiation, and 0% for combined surgery and radiation in the 1993–2007 era (P=0.17).Conclusion. Modern survival outcomes for adults with localized ES are similar to multi-institutional results in children. This improvement over time is associated with treatment intensification with chemotherapy and increased use of surgery. Aggressive LC (combined surgery and radiation) may improve outcomes in poor prognosis patients.