Safely combining trabectedin with radiotherapy to treat myxoid liposarcoma.
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ABSTRACT:
SUBMITTER: Chen M
PROVIDER: S-EPMC6510721 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Safely combining trabectedin with radiotherapy to treat myxoid liposarcoma.
EClinicalMedicine 20190331
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Project description:ImportancePreclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring.ObjectiveTo explore the effectiveness and safety of trabectedin combined with RT.Design, setting, and participantsThis international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall.InterventionsTrabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment.Main outcomes and measuresThe primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response.ResultsA total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated.Conclusions and relevanceAlthough the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.
| S-EPMC10064283 | biostudies-literature
Project description:IntroductionMyxoid/round-cell liposarcoma (MRCL) is a specific histological subtype that accounts for 30-35% of liposarcomas and whose virulence depends on the quantity of round-cells within the tumor. MRCL is associated with specific chromosomal translocations resulting in the formation of CHOP/FUS and CHOP/EWS fusion proteins. A high sensitivity of MRCL to trabectedin was reported.Case reportWe report the case of a 63-year-old woman with a bulky and metastatic MRCL, treated with trabectedin 1.5 mg/m(2) as a first-line treatment. She experienced a long-lasting clinical benefit. The patients received 14 cycles of trabectedin and achieved a durable partial response to the metastases and a stable disease of the primary tumor, which is a very favorable safety profile. Also noteworthy is that we have observed a calcification of the primary tumor and the metastasis. The response, which lasted 30 months, led to a symptomatic improvement, associated with an excellent general condition and an absence of pain.ConclusionTo the best of our knowledge, this is the first report of a MRCL treated with trabectedin that resulted in a calcification of the primary tumor and the metastases, associated with an outstandingly long response. This case suggests that trabectedin may represent a feasible first-line therapeutic option for patients with MRCL, with meaningful clinical benefits and an acceptable safety profile.
| S-EPMC3999575 | biostudies-literature
Project description:Compared to other sarcomas, myxoid liposarcoma (MLS) is exceptionally sensitive to radiation therapy, but the underlying mechanism remains unknown. The objective was to assess the tissue-based changes in MLS during and after neoadjuvant radiotherapy in 26 patients of the DOREMY trial. Morphological assessment was performed on biopsies pre-treatment, after 8 fractions, 16 factions, and after surgical resection and included percentage of viable tumor cells, hyalinization, necrosis, and fatty maturation. Furthermore, immunohistochemistry was performed for apoptosis (cleaved caspase-3), anti-apoptosis (Bcl-2), activity of mTOR signaling (phospho-S6), hypoxia (CAIX), proliferation (Ki67), inflammation (CD45 and CD68), and microvessel density (CD34 Chalkley count). A pronounced reduction in vital tumor cells was observed early with a drop to 32.5% (median) tumor cells (IQR 10-93.8%) after 8 fractions. This decreased further to 10% (IQR 5-30%) after 16 fractions and 7.5% (IQR 5-15%) in the surgical specimen. All but one patient had an excellent response with < 50% remaining tumor cells. Inversely, treatment response was mainly observed as hyalinization and less often as fatty maturation. Additionally, a decrease of inflammatory cells was noticed especially during the first eight fractions. Microvessel density remained stable over time. Immunohistochemical markers for apoptosis, anti-apoptosis, activity of mTOR signaling, proliferation, and hypoxia did not show any marked changes within the remaining tumor cells during and after radiotherapy. As a modest dose of neoadjuvant radiotherapy induces profound tissue changes in MLS, mainly during the first 8 fractions, current findings might suggest that in a carefully selected patient population further deintensification of radiotherapy might be explored.
| S-EPMC10611607 | biostudies-literature
Project description:BackgroundMyxoid liposarcoma is a histological subtype of liposarcoma particularly sensitive to trabectedin. In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. No other effective therapies are available for trabectedin-resistant patients.MethodsThrough repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin.ResultsAt basal level, the morphology of the resistant and sensitive models did not differ, in keeping with the finding that the transcriptional profiles of the resistant and sensitive tumours were very similar. After trabectedin treatment adipogenesis was induced in the parental xenograft but not in the resistant one, as assessed by pathological and molecular analysis. A defective transcription-coupled-nucleotide excision repair in the resistant tumour due to mutation of the UVSSA gene may be implicated in the mechanism of resistance.ConclusionsThis is the first in vivo model of myxoid liposarcoma with acquired resistance to trabectedin. Although further studies are necessary to characterise the resistance mechanisms, this is a useful tool for studying new therapeutic strategies to overcome trabectedin resistance in patients.
| S-EPMC6738121 | biostudies-literature
Project description:To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes we have developed and characterized two MRCL xenografts differing for the breakpoint of the fusion gene FUS- HOP, respectively of type II and III. Transcription profiling experiments were carried out after trabectidin treatment in four separate time points (control, 24h after the first dose, 24h after the third dose, and 15 days after the third dose) for both types of xenografts in order to identify genes and pathways involved with the mechanisms of action of trabectedin in MRCL.
2013-12-10 | E-MTAB-1809 | biostudies-arrayexpress
Project description:ImportanceCurrently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity.ObjectiveTo assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity.Design, setting, and participantsThe Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020.InterventionsThe experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks.Main outcomes and measuresAs a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects.ResultsAmong the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%.Conclusions and relevanceThe findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers.Trial registrationClinicalTrials.gov Identifier: NCT02106312.
| S-EPMC7662477 | biostudies-literature
Project description:BackgroundMyxoid 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.MethodsPatients 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.FindingsFrom 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).InterpretationT 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.FundingThis study was partially supported by Pharmamar.
| S-EPMC6510725 | biostudies-literature
Project description:An amendment to this paper has been published and can be accessed via a link at the top of the paper.
| S-EPMC7109093 | biostudies-literature
Project description:PurposeLeiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti-PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma.Patients and methodsA single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression.Results33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01).ConclusionsAlthough the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.
| S-EPMC9249583 | biostudies-literature
Project description:BackgroundMyxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis.MethodsThis retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined.ResultsLung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00-7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13-0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25-0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008-0.95]) were the significant inhibitory factors of achieving NED.ConclusionsThis is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.
| S-EPMC7491192 | biostudies-literature