Key PointsQuestions
What is the recommended dose of trabectedin in combination with radiotherapy at a dose of 30 Gy with fractionation of 3 Gy/d for 10 days, and does this combination offer an enhancement of activity in terms of tumor reduction that cannot be achieved with systemic therapy alone?
Findings
In this nonrandomized phase 1/2 clinical trial of 45 patients, the maximum tolerated dose of trabectedin when combined with the specified radiotherapy regimen in phase 1 was 1.5 mg/m2, which was the recommended dose used in phase 2. The overall response rate in the 25 patients with evaluable data was 72% and 60% in local and central assessments, respectively.
Meaning
The higher response rate seen with the combination therapy, in comparison with the response rate with systemic therapy alone, suggests potential for greater relief in cases where symptoms are related to tumor volume in second-line treatment of advanced soft-tissue sarcomas.
Importance
Active 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/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 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 Measures
The 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.
Results
Eighteen 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 Relevance
The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. 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.
Trial Registration
ClinicalTrials.gov Identifier: NCT02275286
First-line systemic treatment for metastatic soft-tissue sarcomas (STSs) has hardly improved over 40 years, doxorubicin being the standard approach; no significant overall survival (OS) benefit has been demonstrated with combination schemes.1-5 Nevertheless, anthracycline-based polychemotherapy regimens can be recommended if the aim is surgical resection or fast palliation, since they offer a significantly higher probability of tumor shrinkage.6
In second and further lines of treatment, the therapeutic aim is to offer disease control at the lowest possible toxicity level. All second-line drugs approved for use in STSs exhibited an overall response rate (ORR) lower than 10% in pivotal trials: 9.9%, 6.0%, and 4.0% for trabectedin,7 pazopanib,8 and eribulin,9 respectively. To date, tumor-volume response is therefore an unmet need in second-line therapies of advanced STS, with a few exceptions, such as high-dose ifosfamide in synovial sarcoma.10
Concurrent exposures to trabectedin and radiotherapy (RT) appeared to be synergistic in preclinical experiments. Trabectedin has been argued to exert radiosensitization action through interference with the DNA repair mechanisms11 or by inducing arrest in the G2/M phase of the cell cycle, which is the most sensitive to RT.12 Supported by these data and by observations in the context of clinical palliation, we designed a phase 1/2 trial of trabectedin plus low-dose external RT for patients with metastatic, nonresectable STS. We expected that trabectedin, when used in this combination, would enhance the activity of RT in the irradiated nodules, preserving the tumor control for all metastatic lesions. Two additional cohorts are being conducted in the same study to address the same concept among patients with localized myxoid liposarcoma13 and retroperitoneal sarcomas.
The TRASTS (Trabectedin and Radiotherapy in Soft-Tissue Sarcoma) study was conducted from April 13, 2015, to November 20, 2018, at 9 sarcoma referral centers: 6 in Spain (Santa Creu i Sant Pau Hospital, Barcelona; Gregorio Marañon University Hospital and University Hospital La Paz, Madrid; University Hospital Son Espases, Mallorca; University Hospital Virgen del Rocío, Sevilla; and University Hospital of the Canary Islands, Tenerife); 2 in France (Institut Bergonié, Bordeaux; Centre Léon Bérard, Lyon, France); and 1 in Italy (Candiolo Cancer Institute, Turin). The study protocol for this phase 1/2 nonrandomized clinical trial was approved by the ethics committees at all participating centers, and procedures were performed in accordance with each center’s Ethics Committee guidelines and in compliance with the Declaration of Helsinki.14 All patients signed a written informed consent form to participate in the study. The full trial protocol appears in Supplement 1. Translational and preclinical studies also were performed and are described in eMethods in Supplement 2.
A total of 45 patients older than 18 years and with a diagnosis of metastatic STS, progressing at least after 1 line of chemotherapy, were enrolled. Other relevant inclusion/exclusion criteria and the baseline assessments are described in eMethods in Supplement 2.
Patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin combined with the RT regimen constituted the per-protocol population for phase 2 of the study; those who received at least 1 cycle of trabectedin, the safety population.
Phase 1 followed the classic 3 + 3 design. Two dose levels for trabectedin escalation were planned: 1.3 mg/m2 as the starting dose (level 0), and 1.5 mg/m2 as an escalated dose (level +1). To allow a better assessment of cardiotoxic effects, the starting dose level was expanded if no predefined dose-limiting cardiotoxic effects were observed at level 0. In addition, a de-escalated dose (level –1) was foreseen at 1.1 mg/m2 if the starting dose level was associated with at least 2 dose-limiting toxic events.
The main end point of phase 2 was ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The Simon 1-sample, 2-stage optimal design15 was applied, with an ORR of 35% or greater considered to support the hypothesis that the treatment was effective, and with an ORR of 10% or less considered to support the null hypothesis. For type I and II errors of 10%, at least 2 of the first 11 patients had to have objective RECIST response to complete the required sample with 19 accrued patients. Because synchronization between chemotherapy and RT was crucial, an accrual of 5 additional patients was estimated to be necessary so as to ensure a sample of at least 19 patients for the per-protocol stage.
Trabectedin (Yondelis; Pharma Mar SA) was administered every 3 weeks in a 24-hour infusion, following manufacturer’s instructions. An RT regimen delivering a total dose of 30 Gy in 10 fractions of 3 Gy per day was selected to allow the inclusion of several lesions in the irradiation field while also including bulky lesions and fitting with normal tissue dosimetric constraints. Radiotherapy had to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2). Central review was planned for confirmation of the pathological findings, RT planning, and radiological assessment of disease response.
The main end point of phase 1 was to determine the recommended dose of trabectedin for use in combination with low-dose RT. Data on adverse events were collected by following the CTCAE (Common Terminology Criteria for Adverse Events), version 4.03.16 Secondary end points included quality of life and the post hoc determination of the predictive value of HMG (the high-mobility group gene) in blood.
The main end point for phase 2 was ORR according to RECIST, version 1.1. Progression-free survival (PFS) and OS were secondary objectives.
Statistical analysis was performed from September 12 to September 23, 2019 by using SPSS Statistics, version 20 (IBM Corporation). Time-to-event variables were measured from the start of treatment and were estimated according to the Kaplan-Meier method. Comparisons between the variables of interest were done by the log-rank test.
Variables following binomial distributions were expressed as frequencies, percentages, and/or 95% CIs. Comparisons between quantitative and qualitative variables were performed through nonparametric tests (Mann-Whitney or Kruskal-Wallis). All P values reported were 2-sided, and statistical significance was defined by P ≤ .05.
From April 2015 to November 2018, a total of 45 patients (24 [53%] male and 21 [47%] female; median age of 50 [range of 23-74] years) with progressing metastatic STS were enrolled in the study: 18 patients were enrolled in phase 1, and 27 other patients were enrolled in phase 2. Eleven of the 18 (61%) enrolled in phase 1 were male, and 14 of the 27 (52%) in phase 2 were female. The median age (range) was 42 (23-74) years for those in phase 1, and 51 (27-73) years for those in phase 2. Demographic and baseline clinical characteristics are shown in the Table.
A total of 90 three-week cycles of trabectedin were given to the 18 patients in phase 1, and 17 of the 18 completed the scheduled protocol for RT without any delay. One patient received just 1 cycle of trabectedin at the initial dose level because of early aggressive progression with a hemothorax, which occurred on day 1 of cycle 1. A total of 277 three-week cycles of trabectedin were administered in phase 2. Twenty-five of the 27 patients who received at least 1 cycle of trabectedin followed by the RT regimen (phase 2, per-protocol population) were included in the analysis. One patient (phase 2, safety population) died of septic shock during the first week and was included in the safety population; another patient, who was unable to be in a supine position (and consequently unable to receive RT) because of rapidly progressive disease, was excluded from participation in phase 2 because of an ECOG (Eastern Cooperative Oncology Group) performance status score of 2 (Figure 1). (ECOG scores range from 0, indicating no impairment, to 4, indicating complete inability to carry out any self-care, and confinement to a bed.)
The median baseline numbers of pulmonary nodules per patient enrolled in study phases 1 and 2, respectively, were 7 (range, 1-22) and 4 (range, 1-83), and the median numbers of irradiated nodules per patient were 3 (range, 1-6) and 1 (range, 1-4). For nodule counts per patient, see eTable 1 in Supplement 2.
All 18 patients had values of forced expiratory volume in the first second greater than 1.0 L, with a median value of 2.1 L (range, 1.3-3.6 L) (higher values indicate better pulmonary function), and the median percentage of the predicted normal forced expiratory volume in the first second was 76% (range, 50%-97%). Likewise, the diffusing capacity of lung for carbon monoxide was greater than 40% in all patients, with a median of 78% (range, 44%-110%).
Twelve patients were enrolled at an initial trabectedin dose level of 1.3 mg/m2 to allow better assessment of cardiotoxic effects. The expansion from 6 to 12 patients was recommended by the trial steering committee after detecting a grade 2 decrease in the left ventricular ejection fraction (LVEF) in the first 2 patients who received trabectedin at the 1.3 mg/m2 dose level (LVEF, 49% and 45%, respectively). No additional cardiotoxic effects were observed in the remaining patients at that initial dose level (n = 10) or in patients at the 1.5 mg/m2 level (n = 6). Both patients who experienced a decrease in LVEF had received a substantial cumulative dose of previous doxorubicin (>750 mg/m2). There was no difference between the LVEF values at baseline (median, 62% [range, 54%-68%]) and before cycle 3 (median, 61% [range, 45%-68%]) (P = .45).
Dose-limiting toxic effects were reported as follows: grade 4 neutropenia lasting more than 5 days was seen in 1 patient at the initial dose level, and a transient grade 4 increase in alanine aminotransferase levels was observed among the 6 patients enrolled at the escalated dose level (+1 dose level). Thus, the recommended dose of trabectedin in combination with the RT regimen was 1.5 mg/m2 for phase 2 of the study.
The toxicity profile of this combination therapy was the same as that expected for trabectedin alone (eTable 2 in Supplement 2), with the exception of 1 case of grade 3 pneumonitis coincident with disease progression.
The clinical cutoff for final data analyses was August 31, 2019. At that time, 7 of 26 patients (27%) were still receiving treatment, while 19 (73%) had discontinued trabectedin therapy: 13 (69%) because of progression, 4 (21%) because of toxic effects, 1 (5%) because of consent withdrawal, and 1 (5%) because of death associated with septic shock in the context of neutropenia.
For the 25 evaluable patients, the RECIST-based ORR was 72% (95% CI, 53%-91%) in local radiological assessment: 2 patients experienced a complete response; 16, partial response; 4, stable disease; and 3, progression. The RECIST-based ORR was 60% (95% CI, 39%-81%) in central radiological assessment: 2 patients experienced complete response; 13, partial response; 5, stable disease; and 5, progression (Figure 2). Moreover, the median of dimensional reduction in irradiated nodules was –44% (range, +16% to −100%); in 6 of 25 patients (24%), the irradiated nodules progressed at the time of RECIST progression (eTable 1 in Supplement 2).
With a median follow-up interval of 14.0 months (range, 5.0-21.0 months), the median PFS was 9.9 months (95% CI, 7.0-12.7 months) (eFigure 1 in Supplement 2), and the 12-month PFS rate was 44% (95% CI, 23%-65%). Of note, if only irradiated nodules are considered, the median PFS was not reached, while the 12-month PFS rate was 65% (95% CI, 45%-88%). The median of OS (eFigure 1 in Supplement 2) was not reached, and the 18-month OS rate was 86% (95% CI, 71%-100%). In the univariate analysis, only the metastasis-free interval and the RECIST-based response had a significant prognostic role in survival (eTable 3 in Supplement 2). Grade 3 pneumonitis was observed in 3 patients (eTable 4 in Supplement 2).
Global health status analyses and RT central review data, along with HMGs as potential prognostic biomarkers (eTable 5 in Supplement 2) and preclinical results, are described in the eResults in Supplement 2.
In this phase 1/2 trial of trabectedin and RT, the recommended dose of trabectedin was 1.5 mg/m2. In phase 2, ORR for trabectedin and RT was 72% according to RECIST, and thus, the trial met its primary end point.
Toxic effects of this combination therapy were comparable with data published for trabectedin alone,7 the only exception being pneumonitis: summing our data from phases 1 and 2, a total of 4 patients had grade 3 pneumonitis. In 3 of these 4 patients, pneumonitis proved reversible; in the fourth patient, recovery was impeded by cancer progression.
The radiation pneumonitis rate among patients undergoing stereotactic body RT (SBRT) for lung cancer has been reported as 9% to 28% and has been associated with the volume of irradiated lung and the mean lung dose.18 In a previous patient series, radiation pneumonitis of grade 2 or higher was found in 10.9% of patients treated with SBRT and 17.6% treated with conventional RT.19 Previous metastasectomy, as in 2 of our patients, might increase the risk for radiation pneumonitis.20
The findings of our study are consistent with antitumoral activity enhancement of trabectedin and low-dose RT in patients with metastatic STS. The 72% ORR represents a remarkable outcome in the treatment of advanced-stage STS. Recently, an increasing use of SBRT has been noticed in retrospective pulmonary metastatic STS series; however, radiologic assessment of disease response was seldom performed in these studies.21-27 Stragliotto et al28 reported a response rate of 41% among 88 nodules irradiated with SBRT in 28 patients with different metastatic STS locations. A trend was observed in their study between greater clinical target volume and lower mean dose for tumors showing progression, the mean (SD) dose being 194.5 (84.5) Gy (equivalent dose administered in 2-Gy fractions). Our prospective trial resulted in an ORR of 72%, whereas the RECIST-based ORR with trabectedin alone in patients with advanced STS is below 10%.7 In other words, the combination therapy tested in our study provides higher ORR and longer PFS in a context where the use of higher radiation doses such as those in SBRT has not been explored to date: that is, in an unselective context of metastatic STS (not necessarily limited to lungs or oligometastatic or small lesions, nor requiring irradiation of all lesions). Furthermore, the 12-month PFS rate of 44% and the 18-month OS rate of 86% constitute good survival in second or further lines of treatment in metastatic STS. To our knowledge, results like these have never previously been reported in this setting.
Of note, trabectedin induced G2/M accumulation in our preclinical experiments, which has been reported as a likely mechanism of radiosensitization.13,29 Nevertheless, trabectedin also increases FAS-dependent cell death,30 a mechanism that may play a role in the activity of this therapy combination, since FAS upregulation has also been reported after RT.31
This study has the inherent limitations of all phase 1 and single-arm phase 2 trials: the lack of a comparative cohort, and a low number of cases. Encouraged by these results, a randomized phase 2 trial was designed, aiming to demonstrate the potential superiority of the combination of trabectedin and low-dose RT, not only in terms of ORR but also regarding benefits of survival and quality of life among patients with symptoms related to tumor volume.
This study’s findings suggest that the combination of trabectedin plus low-dose RT may allow substantial shrinkage of target lesions in a high proportion of patients with previously treated metastatic STS, enabling more effective symptom palliation and more durable tumor control than can be achieved with systemic therapy alone.
Accepted for Publication: November 26, 2019.
Published Online: February 20, 2020. doi:10.1001/jamaoncol.2019.6584
Correction: This article was corrected on August 13, 2020, to fix the affiliations of Drs Grignani and Gatti in the Author Affiliations section.
Corresponding Author: Javier Martin-Broto, PhD, MD, TERABIS Group, IBiS (Instituto de Biomedicina de Sevilla), LAB 214, Calle Antonio Maura Montaner S/N, 41013 Sevilla, Spain (jmartin@mustbesevilla.org).
Author Contributions: Dr Martin-Broto had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Martin-Broto, Lopez-Pousa, Cruz Jurado, Gatti, Dei Tos, Romero, Gronchi, Blay.
Acquisition, analysis, or interpretation of data: Martin-Broto, Hindi, Peinado-Serrano, Alvarez, Alvarez-Gonzalez, Italiano, Sargos, Cruz Jurado, Isern-Verdum, Dolado, Rincon-Perez, Sanchez-Bustos, Gutierrez, Romagosa, Morosi, Grignani, Luna, Alastuey, Redondo, Belinchon, Martinez-Serra, Sunyach, Coindre, Dei Tos, Romero, Gronchi, Blay, Moura.
Drafting of the manuscript: Martin-Broto, Cruz Jurado, Gutierrez, Morosi, Belinchon, Blay, Moura.
Critical revision of the manuscript for important intellectual content: Martin-Broto, Hindi, Lopez-Pousa, Peinado-Serrano, Alvarez, Alvarez-Gonzalez, Italiano, Sargos, Isern-Verdum, Dolado, Rincon-Perez, Sanchez-Bustos, Gutierrez, Romagosa, Grignani, Gatti, Luna, Alastuey, Redondo, Martinez-Serra, Sunyach, Coindre, Dei Tos, Romero, Gronchi, Blay, Moura.
Statistical analysis: Martin-Broto, Sargos, Cruz Jurado, Gutierrez, Moura.
Obtained funding: Martin-Broto, Cruz Jurado, Blay.
Administrative, technical, or material support: Martin-Broto, Hindi, Lopez-Pousa, Cruz Jurado, Isern-Verdum, Sanchez-Bustos, Gutierrez, Romagosa, Grignani, Gatti, Redondo, Martinez-Serra, Sunyach, Coindre, Blay, Moura.
Supervision: Martin-Broto, Peinado-Serrano, Alvarez, Alvarez-Gonzalez, Cruz Jurado, Gutierrez, Morosi, Grignani, Gatti, Dei Tos, Gronchi.
Conflict of Interest Disclosures: Dr Martin-Broto reported receiving research grants from PharmaMar, Eisai, and Novartis outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar; honoraria for advisory board participation from Eli Lilly and Company, Bayer, and Eisai; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Bayer, Eisai, Lixte, Karyopharm, Deciphera, Blueprint, Nektar, Forma, Amgen, and Daichii-Sankyo. Dr Hindi reported receiving travel support from PharmaMar; honoraria from PharmaMar and Eli Lilly and Company; and institutional research grants from PharmaMar, Eisai, and Novartis. Dr Alvarez reported receiving honoraria from Boehringer-Ingelheim, Roche/Genentech, Bristol-Myers Squibb, Eli Eli Lilly and Company and Company, Novartis, and PharmaMar, and travel support from Roche and PharmaMar. Dr Italiano reported receiving a research grant and travel support from PharmaMar. Dr Sargos reported receiving research support and honoraria from Nanobiotix. Dr Cruz-Jurado reported receiving speaker fees, and honoraria for service as a consultant/advisor, from Glaxo, AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Eli Lilly and Company, Celgene, Astellas, Amgen, and Pfizer. Ms Sanchez-Bustos reported receiving institutional research grants from PharmaMar, Eisai, and Novartis outside the submitted work. Dr Romagosa reported receiving travel support and grants from PharmaMar outside the submitted work and grants from Grupo Español de Investigación de Sarcomas (GEIS) during the conduct of the study. Dr Grignani reported receiving research grants, travel support, and honoraria for advisory board participation from PharmaMar, Eisai, and Pfizer, and grants and honoraria for advisory board participation from Bayer and Novartis outside the submitted work. Dr Redondo reported receiving grants and honoraria for advisory board participation from PharmaMar and Roche; honoraria for advisory board participation from Eli Lilly and Company, Novartis, Amgen, AstraZeneca, and Tesaro; and grants from Eisai outside the submitted work. Dr Luna reported receiving travel support from PharmaMar and honoraria for advisory board participation from PharmaMar and Eli Lilly and Company. Dr Dei Tos reported serving on a PharmaMar advisory board and receiving a research grant and travel support from PharmaMar. Dr Romero reported receiving honoraria from Celgene and Roche. Dr Gronchi reported receiving honoraria from Novartis, Pfizer, Bayer, Eli Lilly and Company, PharmaMar, SpringWorks, and Nanobiotix outside the submitted work, and an institutional research grant from PharmaMar. Dr Blay reported receiving grants and honoraria for advisory board participation from PharmaMar during the conduct of the study; research support and honoraria for work on sarcoma with LyriCan (INCa–INSERM–DGOS project 12563), NetSarc+, EuroSarc (FP7 grant), and EuraCan (EC grant 739521); and grants and honoraria from GSK, Novartis, and Bayer. Dr Moura reported receiving institutional research grants from PharmaMar, Eisai, and Novartis outside the submitted work, and travel support from PharmaMar, Eisai, and Celgene. No other disclosures were reported.
Funding/Support: PharmaMar provided partial funding for organizational management of the clinical research, drug supply, and shipping.
Role of the Funder/Sponsor: PharmaMar had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: The authors thank the Spanish, Italian, and French national sarcoma research groups (GEIS, ISG, and FSG, respectively) for supporting the administrative activation procedures for the study. GEIS also supported data management, monitoring, drug labeling, insurance, shipping, data analyses, pharmacovigilance, translational research, and meetings. Melissa Fernandez Pinto, MSc, project manager in the GEIS data center, Madrid, Spain, and Patricio Ledesma, BEng, head of clinical operations of Sofpromed Investigación Clínica, Palma, Spain, contributed data management; these persons did not receive any compensation. Vivienne Birch, BA, verified the English-language manuscript and was compensated for her work.
2.Ryan
CW, Merimsky
O, Agulnik
M,
et al. PICASSO III: a phase III, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma.
J Clin Oncol. 2016;34(32):3898-3905. doi:
10.1200/JCO.2016.67.6684
PubMedGoogle Scholar 3.Tap
WD, Papai
Z, Van Tine
BA,
et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial.
Lancet Oncol. 2017;18(8):1089-1103. doi:
10.1016/S1470-2045(17)30381-9
PubMedGoogle Scholar 4.Martin-Broto
J, Pousa
AL, de Las Peñas
R,
et al. Randomized phase II study of trabectedin and doxorubicin compared with doxorubicin alone as first-line treatment in patients with advanced soft tissue sarcomas: a Spanish Group for Research on Sarcoma study.
J Clin Oncol. 2016;34(19):2294-2302. doi:
10.1200/JCO.2015.65.3329
PubMedGoogle Scholar 5.Demetri
GD, Le Cesne
A, Chawla
SP,
et al. First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study.
Eur J Cancer. 2012;48(4):547-563. doi:
10.1016/j.ejca.2011.12.008
PubMedGoogle Scholar 6.Judson
I, Verweij
J, Gelderblom
H,
et al; European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.
Lancet Oncol. 2014;15(4):415-423. doi:
10.1016/S1470-2045(14)70063-4
PubMedGoogle Scholar 7.Demetri
GD, von Mehren
M, Jones
RL,
et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial.
J Clin Oncol. 2016;34(8):786-793. doi:
10.1200/JCO.2015.62.4734
PubMedGoogle Scholar 8.van der Graaf
WT, Blay
JY, Chawla
SP,
et al; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.
Lancet. 2012;379(9829):1879-1886. doi:
10.1016/S0140-6736(12)60651-5
PubMedGoogle Scholar 9.Schöffski
P, Chawla
S, Maki
RG,
et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial.
Lancet. 2016;387(10028):1629-1637. doi:
10.1016/S0140-6736(15)01283-0
PubMedGoogle Scholar 12.Tavecchio
M, Natoli
C, Ubezio
P, Erba
E, D’Incalci
M. Dynamics of cell cycle phase perturbations by trabectedin (ET-743) in nucleotide excision repair (NER)–deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach.
Cell Prolif. 2007;40(6):885-904. doi:
10.1111/j.1365-2184.2007.00469.x
PubMedGoogle Scholar 13.Gronchi
A, Hindi
N, Cruz
J,
et al. 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.
EClinicalMedicine. 2019;9:35-43. doi:
10.1016/j.eclinm.2019.03.007
PubMedGoogle Scholar 20.Hayes
JT, David
EA, Qi
L, Chen
AM, Daly
ME. Risk of pneumonitis after stereotactic body radiation therapy in patients with previous anatomic lung resection.
Clin Lung Cancer. 2015;16(5):379-384. doi:
10.1016/j.cllc.2015.01.006
PubMedGoogle Scholar 21.Dhakal
S, Corbin
KS, Milano
MT,
et al. Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival.
Int J Radiat Oncol Biol Phys. 2012;82(2):940-945. doi:
10.1016/j.ijrobp.2010.11.052
PubMedGoogle Scholar 23.Baumann
BC, Nagda
SN, Kolker
JD,
et al. Efficacy and safety of stereotactic body radiation therapy for the treatment of pulmonary metastases from sarcoma: a potential alternative to resection.
J Surg Oncol. 2016;114(1):65-69. doi:
10.1002/jso.24268
PubMedGoogle Scholar 24.Frakulli
R, Salvi
F, Balestrini
D,
et al. Stereotactic radiotherapy in the treatment of lung metastases from bone and soft-tissue sarcomas.
Anticancer Res. 2015;35(10):5581-5586.
PubMedGoogle Scholar 26.Mehta
N, Selch
M, Wang
PC,
et al. Safety and efficacy of stereotactic body radiation therapy in the treatment of pulmonary metastases from high grade sarcoma.
Sarcoma. 2013;2013:360214. doi:
10.1155/2013/360214
PubMedGoogle Scholar 29.Simoens
C, Korst
AE, De Pooter
CM,
et al. In vitro interaction between ecteinascidin 743 (ET-743) and radiation, in relation to its cell cycle effects.
Br J Cancer. 2003;89(12):2305-2311. doi:
10.1038/sj.bjc.6601431
PubMedGoogle Scholar 30.Martínez-Serra
J, Maffiotte
E, Martín
J,
et al. Yondelis® (ET-743, trabectedin) sensitizes cancer cell lines to CD95-mediated cell death: new molecular insight into the mechanism of action.
Eur J Pharmacol. 2011;658(2-3):57-64. doi:
10.1016/j.ejphar.2011.02.035
PubMedGoogle Scholar 31.Garnett
CT, Palena
C, Chakraborty
M, Tsang
KY, Schlom
J, Hodge
JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes [published correction appears in
Cancer Res. 2005;65(1):374].
Cancer Res. 2004;64(21):7985-7994. doi:
10.1158/0008-5472.CAN-04-1525
PubMedGoogle Scholar