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E-TRAB was a non-interventional, prospective trial investigating the feasibility and predictive value of geriatric assessments (GA) in older STS patients treated with trabectedin as first-line therapy. Primary endpoints were overall survival (OS), quality of life and individual clinical benefit assessed by the patient-reported outcome measures QLQ-C30 and PRO-CTCAE. Further, several GA tools were applied and correlated with clinical outcomes and treatment-related toxicities. The final analyses included 69 patients from 12 German-speaking sites. The median age of patients was 78 years (range: 55 to 88). Baseline data on PROs and GA identified a diverse population of older patients with respect to their global health status, although a large proportion of them suffered from limitations, required geriatric help and had a high risk of morbidity. The Cancer and Age Research Group (CARG) score classified 38%, 29% and 23% of the patients with low, intermediate and high risks for therapy-related side effects, respectively. Median OS was 11.2 months [95%CI: 5.6; 19.4]. The study confirmed that trabectedin as first-line treatment in older patients with STS has an acceptable and manageable safety profile. Potential prognostic factors for clinical outcome and therapy-related toxicity were identified among the GA tools. Long Timed Up and Go (TUG) showed a significant correlation to OS and early death, whereas a high CARG score (>9) was associated with an increase in unplanned hospitalizations and the incidence of toxicities grade ≥ 3.
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BACKGROUND/AIM: Soft tissue sarcomas are rare and heterogenous malignancies with high recurrence rates following resection and a poor prognosis in advanced stages. Eribulin is used in metastatic soft tissue sarcoma patients, who have failed first line chemotherapy and has been approved for patients with pretreated advanced liposarcoma (LPS) in the United States and Europe following the publication of data of a phase III trial. In addition, no data are available for eribulin as postoperative treatment after potentially curative surgery. We, thus, retrospectively evaluated efficacy and tolerability of adjuvant eribulin in patients with LPS not suitable for intensive chemotherapy in the routine clinical setting. PATIENTS AND METHODS: In this retrospective single center analysis, efficacy and safety of eribulin were retrospectively evaluated in five high risk LPS patients. RESULTS: Eribulin as treatment was administered to five patients with LPS following surgical resection. Median progression-free survival and overall survival were 12.3 months and 44.3 months, respectively. Toxicity was generally manageable, and grade 3+4 events were rare. CONCLUSION: Postoperative eribulin may be feasible in selected high risk LPS patients, who are not candidates for intensive chemotherapy regimens. Further prospective trials, however, are needed.
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Liposarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Estudios Retrospectivos , Lipopolisacáridos , Liposarcoma/tratamiento farmacológico , Liposarcoma/cirugía , Liposarcoma/patología , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológicoRESUMEN
BACKGROUND: Owing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence. METHODS: During the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma. We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022. RESULTS: Sixty-two European sarcoma experts participated in the survey. Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus. CONCLUSIONS: In this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Predicción , Sarcoma/terapia , Sarcoma/tratamiento farmacológico , Consenso , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/terapia , Encuestas y CuestionariosAsunto(s)
Antineoplásicos Inmunológicos , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
INTRODUCTION: Soft tissue sarcomas are rare and heterogenous malignancies with a poor prognosis in advanced disease stages. Eribulin is used in metastatic liposarcoma (LPS) patients, who have failed first-line chemotherapy and has been approved for use in patients with LPS in the USA and Europe due to its efficacy in this histological subtype in a phase 3 trial. We have evaluated efficacy and tolerability of eribulin in LPS and leiomyosarcoma (LMS) patients in the routine clinical setting at our department. METHODS: In this retrospective single-center analysis, efficacy and safety of eribulin were retrospectively evaluated in advanced LPS and LMS patients at the Division of Oncology, Medical University of Vienna. RESULTS: A total of 32 adult patients treated with eribulin were identified and included in this analysis. Overall response rate was 9.4% for all patients, with one patient with LPS and two patients with LMS showing a partial response. Disease control rate (partial response plus stable disease) for all patients was 50% (LPS: 47.1%; LMS 53.3%). No statistically significant difference in median progression-free survival and overall survival was detected between patients with LPS and LMS (p = 0.807 and p = 0.519, respectively). Patients with LMS (n = 2) had received fewer previous therapy lines than patients with LPS (n = 14) (≤ previous treatment lines, p < 0.001). Toxicity was generally manageable, and grade 3 + 4 events were rare. CONCLUSION: The activity and tolerability of eribulin in LPS as in well in LMS patients in the routine clinical setting is comparable to outcomes reported in published phase 3 trials.
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Leiomiosarcoma , Liposarcoma , Adulto , Humanos , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/patología , Estudios Retrospectivos , Lipopolisacáridos/uso terapéutico , Liposarcoma/tratamiento farmacológico , Liposarcoma/patologíaRESUMEN
We aimed to evaluate the efficacy and toxicity of paclitaxel combined with pazopanib in advanced angiosarcoma (AS). The primary end point was progression-free survival (PFS) rate at six months (PFSR6). Planned accrual was 44 patients in order to detect a PFSR6 of >55%, with an interim futility analysis of the first 14 patients. The study did not meet its predetermined interim target of 6/14 patients progression-free at 6 months. At the time of this finding, 26 patients had been enrolled between July 2014 and April 2016, resulting in an overrunning of 12 patients. After a median follow-up of 9.5 (IQR 7.7-15.4) months, PFSR6 amounted to 46%. Two patients had a complete and seven patients a partial response. Patients with superficial AS had a significantly higher PFSR6 (61% vs. 13%, p = 0.0247) and PFS (11.3 vs. 2.7 months, p < 0.0001) compared to patients with visceral AS. The median overall survival in the entire cohort was 21.6 months. A total of 10 drug-related serious adverse effects were reported in 5 patients, including a fatal hepatic failure. Although our study did not meet its primary endpoint, the median PFS of 11.6 months in patients with superficial AS appears to be promising. Taking recent reports into consideration, future studies should evaluate the safety and efficacy of VEGFR and immune checkpoint inhibitors with or without paclitaxel in a randomized, multiarm setting.
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BACKGROUND: Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma. PATIENTS AND METHODS: We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data. RESULTS: 35 patients (median age of 50 (23-81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)-receptor interaction. CONCLUSIONS: Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.
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Neoplasias Óseas/tratamiento farmacológico , Metilación de ADN , Epigenoma , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Austria , Neoplasias Óseas/genética , Neoplasias Óseas/inmunología , Neoplasias Óseas/mortalidad , Islas de CpG , Epigenómica , Femenino , Alemania , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Osteosarcoma/genética , Osteosarcoma/inmunología , Osteosarcoma/mortalidad , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Estudios Retrospectivos , Sarcoma/genética , Sarcoma/inmunología , Sarcoma/mortalidad , Transducción de Señal , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/inmunología , Neoplasias de los Tejidos Blandos/mortalidad , Factores de Tiempo , Microambiente Tumoral , Adulto JovenRESUMEN
BACKGROUND/AIM: Ewing sarcoma (ES) and osteosarcomas (OSA) are the most common bone tumor types in adolescents and young adults (AYA). Therapy management of these tumors consists of preoperative chemotherapy, operation, and postoperative chemotherapy. The aim of this study was to evaluate the efficacy and tolerability of EURAMOS-A and EURO E.W.I.N.G. protocols. PATIENTS AND METHODS: We retrospectively evaluated 31 patients between 18 and 39 years of age with ES and OSA treated at the Department of Medicine I, Clinical Division of Oncology. Patients with ES were treated according the EURO E.W.I.N.G protocol, whereas patients with OSA according to the EURAMOS-1 protocol. RESULTS: Most frequent tumor sites for ES were thorax and pelvis, each 33%. Eight patients had initially localized disease (67%). A median of 3 cycles of full dose chemotherapy could be administered. Nine patients had a dose reduction (75%). Most common reason for dose reduction was prolonged aplasia (67%). Overall response rate (ORR) was 33%. For OSA patients, the most frequent tumor site was the lower extremity (58%). Sixteen patients (84%) had initially localized disease. A median of only 9 cycles of EURAMOS-1 in full dose could be administered. Most common reason for dose reduction was elevated methotrexate level (53%) and ORR was 90%. CONCLUSION: The two studied protocols were well-tolerated in the AYA patients included in this study. Dose reductions instead of dose delays should be considered when side effects occur.
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Neoplasias Óseas , Osteosarcoma , Sarcoma , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Humanos , Osteosarcoma/tratamiento farmacológico , Estudios Retrospectivos , Sarcoma/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND: Olaratumab is a humanized monoclonal antiplatelet-derived growth factor receptor alpha antibody that has been approved in combination with doxorubicin for the treatment of patients with metastatic soft tissue sarcoma (STS). The purpose of this retrospective study was to assess the clinical efficacy in STS patients treated with olaratumab in a real-world setting in Austria. METHODS: Retrospectively collected longitudinal data from patients treated between November 2016 and September 2018â¯at 9 Austrian centers were obtained from the respective medical charts. All patients who received at least one dose of olaratumab were eligible. Parameters of most interest were response rates, progression-free survival (PFS) and overall survival (OS). RESULTS: Altogether 55 patients were included in the analysis. The median age was 58 years. In total, 65.5% (nâ¯= 36), 21.8% (nâ¯= 12) and 12.7% (nâ¯= 7) received olaratumab as first, second or ≥third line treatment, respectively. Olaratumab was administered either in combination with doxorubicin (81.8%, nâ¯= 45) or liposomal doxorubicin (16.4%, nâ¯= 9); one patient received olaratumab as upfront monotherapy. The median PFS and OS were 2.6 and 11.4 months, respectively. The objective response rate was 11.4% and the disease control rate was 40.9%. CONCLUSION: In this real-world analysis the outcome was less pronounced compared to the results of both the phase Ib/II approval trial and the confirmatory phase III trial. The latter failed to show an improvement in OS and PFS for the doxorubicin/olaratumab combination. As such, olaratumab should not be used anymore in patients with STS.
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Protocolos de Quimioterapia Combinada Antineoplásica , Sarcoma , Anticuerpos Monoclonales , Austria , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoma/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors. To gain further insights into the staining profile with the pan-TRK assay, we analyzed a large number of soft tissue sarcomas and correlated our findings with molecular testing. Additionally, we expand the spectrum of NTRK-fusion tumors by reporting a mesenchymal lesion in the lung as well as a mesenchymal skin lesion in the spectrum of benign fibrous histiocytoma with NTRK-fusion. We retrospectively reviewed soft tissue sarcomas diagnosed at the Diagnostic and Research Institute of Pathology, Medical University of Graz, between 1999 and 2019, and cases from the consultation files of one of the authors (BLA). In total, 494 cases were analyzed immunohistochemically with pan-TRK antibody (clone EPR17341, RTU, Roche/Ventana) and positive cases (defined as any cytoplasmic/nuclear staining in more than 1% of tumor cells) underwent next-generation sequencing (NGS). Immunohistochemical staining was observed in 16 (3.2%) cases. Eleven cases with focal weak and moderate cytoplasmic/membranous or focal moderate to strong nuclear staining did not harbor an NTRK-fusion (three synovial sarcomas, three leiomyosarcomas, two extraskeletal myxoid chondrosarcomas, and one each: dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxofibrosarcoma). Four cases showed strong diffuse nuclear and/or cytoplasmatic staining, and one case showed diffuse, but weak cytoplasmic staining. All these cases demonstrated an NTRK-fusion (LMNA-NTRK1, IRF2BP2-NTRK1, TMB3-NTRK1, ETV6-NTRK3, RBPMS-NTRK3). Pan-TRK assay (clone EPR17341, RTU, Roche, Ventana) immunohistochemistry serves as a reliable diagnostic marker that can also be expressed in non-NTRK-rearranged mesenchymal neoplasms. It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin.
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Proteínas de Fusión Oncogénica/análisis , Receptor trkA/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Adolescente , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Femenino , Reordenamiento Génico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
AIM: This study assessed whether cetuximab 500 mg/m2 administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m2 followed by 250 mg/m2 once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events. RESULTS: OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715-0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804-1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031-1.617]) and the rates of lung/liver metastases resection (1.419 [1.043-1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858-1.382). CONCLUSIONS: The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas ras/genética , Anciano , Cetuximab/administración & dosificación , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Esquema de Medicación , Estudios de Equivalencia como Asunto , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Tasa de SupervivenciaRESUMEN
: Regorafenib significantly prolonged progression-free survival (PFS) in pretreated patients with advanced non-adipocytic sarcoma (HR = 0.46; p < 0.001) in a placebo-controlled, randomized, phase-II trial (NCT01900743). Thus, here, we assessed the prevalence of 57 biomarkers and their prognostic and predictive values for PFS and overall survival (OS). We analyzed 134/182 patients included in this trial, treated with regorafenib (n = 71, 53%) or placebo (n = 63, 47%). Mutational analyses were performed via full coding sequence analysis for 10 genes, and mutation hotspot panel for 50 genes (four genes in common). H19 was studied with RNA in-situ hybridization. The prognostic and predictive biomarkers' values were studied only for biomarkers found positive/mutated in at least 10 patients. Overall, 25 out of 57 studied biomarkers, including five out of seven genes involved in angiogenesis, were found mutated/positive in at least one patient, of which 23 biomarkers had low prevalence (fewer than eight out of 134 patients), contrasting with H19 (n = 24, 18%), and TP53 (n = 35, 26%). However, in multivariable models of PFS and OS, including treatment effects and interactions, no significant prognostic or predictive values of the tested biomarkers were observed. Though several promising biomarkers were found to be positive/mutated, none of them were identified as viable predictive and prognostic biomarkers.
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BACKGROUND: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology. METHODS: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system. RESULTS: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported. CONCLUSIONS: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.
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Neoplasias , Pacientes Ambulatorios , Instituciones de Atención Ambulatoria , Femenino , Humanos , Masculino , Oncología Médica , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/terapia , Estudios RetrospectivosRESUMEN
BACKGROUND: Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. PATIENTS AND METHODS: This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours-based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). RESULTS: From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4-not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15-0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23-1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). CONCLUSION: The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Anemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dolor en el Pecho/inducido químicamente , Estudios Cruzados , Diarrea/inducido químicamente , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Indazoles , Estimación de Kaplan-Meier , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Resultado del TratamientoRESUMEN
Round cell sarcomas are a heterogeneous group of mesenchymal neoplasms with overlapping morphology and immunohistochemical profile. Ewing sarcoma is the most well-known tumour in this group characterised by EWSR1/FUS rearrangements with members of the ETS family of transcription factors. Undifferentiated round cell sarcomas lacking these rearrangements, known as 'Ewing-like' sarcomas, usually show atypical clinical presentation and focal CD99 positivity. This group of tumours can be subdivided into: capicua transcriptional repressor (CIC)-rearranged sarcomas, Bcl6 corepressor (BCOR)-rearranged sarcomas, sarcomas with EWSR1 fusion to non-ETS family members and unclassified round cell sarcomas. We describe seven new cases of CIC-DUX4 rearranged sarcomas with their clinicopathological features, two of which presented in unusual locations (skin and lymph node). Patient age ranged between 23 and 54 years, three of whom were female. In five cases, aggressive behaviour was observed with rapid disease progression and lethal outcome within 15 months. One patient achieved a complete response after chemotherapy. The last patient whose tumour was located purely in the dermis demonstrated no residual tumour in the re-resection specimen, was not given any further treatment and showed no sign of disease after 24 months. Immunohistochemically, tumour cells in all cases showed focal membranous CD99 positivity, while WT1 N-/C-terminus were positive in all 5/5 cases (nuclear and/or cytoplasmic). NGS analysis revealed a CIC-DUX4 fusion in all cases. This study expands the spectrum of anatomical locations of CIC-DUX4 rearranged sarcomas, highlighting the inclusion of this rare entity in the differential diagnosis of undifferentiated tumours in various anatomical locations outside of soft tissues.
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Proteínas de Fusión Oncogénica/genética , Sarcoma/genética , Sarcoma/patología , Adulto , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Adulto JovenRESUMEN
OBJECTIVES: Osteosarcoma of the jaw (OSAJ) is fundamentally different in clinical practice from its peripheral counterparts. Studies are difficult to conduct due to low incidence rates. The primary aim of this study was to provide for the first time a comprehensive retrospective analysis of the treatment concepts and outcome data of OSAJ patients treated at the University Hospital Vienna and to compare these with two recently published studies on OSAJ. The clinical study was accompanied by a biomarker study investigating the prognostic relevance of melanoma-associated antigen-A (MAGE-A) in OSAJ specimens. METHOD: Eighteen patients were included, and their outcomes were compared to published data. Immunohistochemistry was performed with mouse monoclonal antibodies against MAGE-A. Survival rates were estimated by the Kaplan-Meyer method. The log-rank test was used to analyze potential prognostic parameters. Fisher's exact test was performed to define the significant differences between the survival rates of the current study and the DOESAK registry. RESULTS: Disease-specific survival was 93.8% after five and 56.3% after ten years. The development of metastases (p=0.033) or relapse (p=0.037) was associated with worsened outcomes in our group as well as in the comparative group. Despite the different treatment concepts of the study groups, survival rates were comparable. MAGE-A failed to show prognostic relevance for OSAJ patients. CONCLUSIONS: Uncertainties about the optimal treatment strategies of OSAJ patients will currently remain. Thus, prospective studies of OSAJ are needed but are only feasible in a multicenter study setting, conducted over a prolonged time period.
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Neoplasias Óseas/terapia , Osteosarcoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/análisis , Antígenos de Neoplasias/análisis , Austria/epidemiología , Biomarcadores/análisis , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
OBJECTIVES: Osteosarcoma of the jaw (OSAJ) is fundamentally different in clinical practice from its peripheral counterparts. Studies are difficult to conduct due to low incidence rates. The primary aim of this study was to provide for the first time a comprehensive retrospective analysis of the treatment concepts and outcome data of OSAJ patients treated at the University Hospital Vienna and to compare these with two recently published studies on OSAJ. The clinical study was accompanied by a biomarker study investigating the prognostic relevance of melanoma-associated antigen-A (MAGE-A) in OSAJ specimens. METHOD: Eighteen patients were included, and their outcomes were compared to published data. Immunohistochemistry was performed with mouse monoclonal antibodies against MAGE-A. Survival rates were estimated by the Kaplan-Meyer method. The log-rank test was used to analyze potential prognostic parameters. Fisher's exact test was performed to define the significant differences between the survival rates of the current study and the DOESAK registry. RESULTS: Disease-specific survival was 93.8% after five and 56.3% after ten years. The development of metastases (p=0.033) or relapse (p=0.037) was associated with worsened outcomes in our group as well as in the comparative group. Despite the different treatment concepts of the study groups, survival rates were comparable. MAGE-A failed to show prognostic relevance for OSAJ patients. CONCLUSIONS: Uncertainties about the optimal treatment strategies of OSAJ patients will currently remain. Thus, prospective studies of OSAJ are needed but are only feasible in a multicenter study setting, conducted over a prolonged time period.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/terapia , Osteosarcoma/terapia , Pronóstico , Austria/epidemiología , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Inmunohistoquímica , Biomarcadores/análisis , Osteosarcoma/mortalidad , Osteosarcoma/patología , Tasa de Supervivencia , Estudios Retrospectivos , Anticuerpos Monoclonales/análisis , Antígenos de Neoplasias/análisisRESUMEN
INTRODUCTION: The placebo-controlled phase-2 REGOSARC trial demonstrated the efficacy of regorafenib in patients with leiomyosarcoma, synovial sarcoma and other non-adipocytic sarcoma but not in liposarcoma. Patients initially allocated to placebo were allowed to receive regorafenib after progression. We report here an updated analysis of the trial including evaluation of regorafenib activity after cross-over. METHODS: From June 2013 to December 2014, 139 patients were enrolled in the non-adipocytic sarcoma cohorts. Median follow-up is now 32.4 months. Benefit of regorafenib versus placebo in terms of progression-free survival (PFS) and overall survival (OS) from randomisation was estimated by hazard ratio (HR) in Cox models. In the placebo arm, intra-patient benefit of regorafenib after cross-over was evaluated by the growth modulation index (GMI) (GMI was here, for each patient, PFS after cross-over regorafenib divided by PFS with placebo). Furthermore, the activity of delayed (after cross-over) versus early (at study entry) regorafenib was evaluated by comparing PFS after cross-over to regorafenib to PFS after randomisation in the regorafenib arm. RESULTS: PFS benefit of regorafenib as compared to placebo was confirmed with longer follow-up (HR = 0.50; 95% CI: 0.35-0.71; p < .0001). OS was not statistically significant different (HR = 0.78; 0.54-1.12; p = .18). This finding may partially be explained by the fact that 55/68 patients who progressed on placebo (81%) received cross-over Regorafenib after progression: 59% of them had a GMI ≥ 1.3 (95% CI, 45-71%). Delayed start of regorafenib was associated with a statistically non-significant shorter PFS as compared to early treatment (HR = 1.21; 0.84-1.73; p = .30) without impact on OS. CONCLUSIONS: Observed PFS confirms that regorafenib warrants further clinical investigation in refractory non-adipocytic sarcomas.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Placebos , Supervivencia sin Progresión , Sarcoma/mortalidad , Adulto JovenAsunto(s)
Neurofibromatosis 1 , Neurofibrosarcoma , Adulto , Humanos , Neoplasias de la Vaina del Nervio , NeurofibromaRESUMEN
Dedifferentiated chondrosarcoma is a rare primary bone malignancy with a very poor prognosis. The aim of the study was to identify pretreatment serum markers as prognostic factors for the overall survival (OS) of patients with dedifferentiated chondrosarcoma. We retrospectively reviewed 33 patients with histologically confirmed dedifferentiated chondrosarcoma treated at our department from 1977 to 2015. Kaplan-Meier estimation, uni- and multivariable Cox proportional hazard model were performed to evaluate the association between serum markers such as the C-reactive protein and OS. In univariable analysis, CRP was strongly associated with OS (HR 1.35; 95%CI 1.13-1.61; p = 0.001). This association prevailed after adjustment for AJCC tumor stage (HR 1.31; 95%CI 1.02-1.57; p = 0.031) in multivariable analysis. In conclusion, our data gave evidence that baseline CRP is an independent predictor for OS in patients with dedifferentiated chondrosarcoma. CRP could be exploited for the clinical prediction of this disease in the future. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:2797-2801, 2018.