Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas

Abstract

IMPORTANCEActive therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival.OBJECTIVE To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas.DESIGN, SETTING, AND PARTICIPANTS Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m 2 as the starting dose, 1.5 mg/m 2 as dose level +1, and 1.1 mg/m 2 as dose level -1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population.INTERVENTIONS Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2). MAIN OUTCOMES AND MEASURESThe dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas. RESULTSEighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment. CONCLUSIONS AND RELEVANCEThe findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m 2 . The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas.

Trabectedin Plus Radiotherapy for Advanced Soft-Tissue Sarcoma: Experience in Forty Patients Treated at a Sarcoma Reference Center

“…Here, we report on a retrospective series of 40 patients with advanced soft-tissue sarcoma treated, in real-life, with the combination of trabectedin plus radiotherapy in a sarcoma reference center. The results in this series are in line with the previous published study considering the median PFS [ 15 ], and clearly exceed those expected for trabectedin alone, or other approved second line drugs for sarcoma [ 6 , 7 , 8 ]. It is important to highlight that these results were obtained with trabectedin and external beam conventional RT in a population with bulky (median size of the irradiated lesion exceeded 5 cm), pretreated, and symptomatic disease.…”

“…A potential explanation of the lower response rate observed in the present series with respect to the clinical trial is the lower adherence to the concomitant schedule of therapy. In the previous clinical trial [ 15 ], all patients started RT immediately after the complexion of the first cycle of trabectedin. In this real-life series, a third of the patients started RT more than 24 h after trabectedin, and this delay in the initiation of RT could have impacted on the activity of the combination.…”

“…The combination showed a manageable toxicity profile and resulted in a highly effective scheme in metastatic STS patients, with 60% of patients achieving RECIST 1.1 responses, according to a central radiological review among the 25 evaluable patients. The median progression-free survival (PFS) in this study exceeded nine months and, interestingly, the 6-month PFS rate was 75%, all of which are remarkable data for second-line therapy in advanced STS [ 15 ]. Here, we present our experience in real-life patients with advanced sarcoma treated at our center with the same combination of trabectedin plus radiotherapy.…”

Effectiveness of combined low-dose radiotherapy and pazopanib for controlling the local manifestations of taxane-resistant recurrent angiosarcoma of the head

“…Few studies have reported the effects of these drugs for controlling recurrent and bleeding local lesions such as those observed in our patient. Martin-Broto et al 9 reported the safety and efficacy of combined low-dose radiotherapy and trabectedin for patients with metastatic soft tissue sarcomas. In their study, combined radiotherapy at a dose of 30 Gy and trabectedin was effective for patients with metastatic soft-tissue sarcomas.…”

(Not-so) Unexpected Tumor Response to Palliative Pelvic Radiotherapy in Mismatch Repair-Deficient Advanced Prostate Cancer

“…Our experience, however, suggests that investigation of MSI-status in these patients may be worthwhile in patient-speci c treatment choice with minimal toxicity, either as monomodality treatment (for example in the case of RT with moderate doses to large volumes encompassing all macroscopic disease) or -even more likely to result in local and systemic response -as a combination of RT and IT [23], which may result in a dramatic bene t for these patients. The concept of applying moderate RT doses to macroscopic disease in combination with newer sensitizing systemic agents is currently investigated in various settings, with rst promising results, for example for the combination of palliative dose RT and Trabectidin in patients with metastatic soft tissue sarcoma, having been reported recently [24].…”