Trabectedin and RAdiotherapy in Soft Tissue Sarcoma (TRASTS): Results of a Phase I Study in Myxoid Liposarcoma from Spanish (GEIS), Italian (ISG), French (FSG) Sarcoma Groups

Alessandro Gronchi, Nadia Hindi, Josefina Cruz, Jean-Yves Blay, Antonio Lopez-Pousa, Antoine Italiano, Rosa Alvarez, Antonio Gutierrez, Inmaculada Rincón, Claudia Sangalli, Jose Luis Pérez Aguiar, Jesús Romero, Carlo Morosi, Marie Pierre Sunyach, Roberta Sanfilippo, Cleofe Romagosa, Dominique Ranchere-Vince, Angelo P Dei Tos, Paolo G Casali, Javier Martin-Broto, Alessandro Gronchi, Nadia Hindi, Josefina Cruz, Jean-Yves Blay, Antonio Lopez-Pousa, Antoine Italiano, Rosa Alvarez, Antonio Gutierrez, Inmaculada Rincón, Claudia Sangalli, Jose Luis Pérez Aguiar, Jesús Romero, Carlo Morosi, Marie Pierre Sunyach, Roberta Sanfilippo, Cleofe Romagosa, Dominique Ranchere-Vince, Angelo P Dei Tos, Paolo G Casali, Javier Martin-Broto

Abstract

Background: Myxoid liposarcoma (ML) exhibits a special sensitivity to trabectedin (T) and radiation therapy (RT). Preclinical data suggest a synergistic effect. We aimed to study safety, feasibility and activity of the administration of pre-operative concurrent T and RT in patients affected by localized resectable ML.

Methods: Patients received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8 Gy/fraction). Dose Levels for T were: - 1 (1.1 mg/m2), 0 (1.3 mg/m2) and 1 (1.5 mg/m2). Primary endpoint was safety; antitumor activity was assessed by RECIST and Choi criteria. This study is registered at ClinicalTrials.gov, number NCT02275286. The phase 1 part of the study is complete and phase 2 is ongoing.

Findings: From February 2015 to May 2016, 14 patients (M/F 7/7), median age 36 years (range 24-70) and median tumor size 12.5 cm (range 7-17 cm), were enrolled. One dose limiting toxicity (G3 transaminitis) occurred at Level 0 and one (sepsis due to catheter infection) at Level 1. All patients completed RT. Five patients achieved PR (36%), 8 SD (57%), 1 distant PD (7%) by RECIST, while 12 achieved PR (86%), 1 SD (7%) and 1 distant PD (7%) by Choi criteria. Twelve patients underwent surgery. Median viable residual tumor was 5% (0-60).

Interpretation: T in combination with RT showed a favorable safety profile and antitumor activity in localized ML. T dose of 1.5 mg/m2 is the recommended dose for the phase 2 study, which is ongoing.

Funding: This study was partially supported by Pharmamar.

Keywords: Chemotherapy; Myxoid Liposarcoma; Neoadjuvant; Prognosis; Radiotherapy; Sarcoma; Survival; Trabectedin.

Figures

Fig. 1
Fig. 1
Outline of the trial design.
Fig. 2
Fig. 2
Waterfall plot of radiological responses after treatment by Choi criteria, including both tumor size and density information. *Patient with progressive disease due to new distant lesions while achieving CHOI partial response on primary tumor.
Fig. 3
Fig. 3
Panel a and d are examples of non-treated low grade and high grade myxoid liposarcoma respectively. Panels b, c, e and f are examples of different patterns of pathological response observed after the combination of trabectedin and radiotherapy: mature adipocytic differentiation (panel b), necrosis (panel c), sclero-hyalinosis (panel e) and areas of fibrosis with inflammatory infiltrate, vascular reactive proliferation and haemosideraphages (panel f). All changes can coexist in the same case.
Fig. 4
Fig. 4
Relapse-free survival of the 12 operated patients (panel A); disease-free survival (panel B) and overall survival (panel C) of the 14 included patients.

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Source: PubMed

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