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Cardiac Tumours
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
PD-L1 is a key immune checkpoint protein that plays a significant role in sarcomagenesis. Upregulation of PD-L1 is associated with increased tumour aggressiveness. PD-L1+ sarcomas can be targeted with single-agent immunotherapy such as pembrolizumab. MDM2 is a proto-oncogene, which is one of the most frequently mutated genes in cardiac intimal sarcomas. Upregulation of MDM2 results in loss of p53-dependent activities, such as apoptosis and cell-cycle arrest. There are no established guidelines for chemotherapy targeting MDM2. Newer agents such as olaratumab, a monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-α, combined with doxorubicin has limited data to show drug efficacy against soft-tissue sarcomas. Pazopanib, which has been used in metastatic non-adipocytic soft-tissue sarcomas, is a multi-kinase inhibitor that targets the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem-cell factor receptor. Intimal sarcomas can have PDGF and VEGF expression. A case with a moderate to strong expression of PDGFR-α and -β presented a long-term stable disease when treated with pazopanib while a case with weak expression of PDGFR-α and -β did not respond. The level of PDGFR expression in the tumour tissue may therefore be predictive of pazopanib efficacy.28
Skin and soft tissue
Published in Tor Wo Chiu, Stone’s Plastic Surgery Facts, 2018
Post-operative chemotherapy for high-grade tumours and chemosensitive tumours; possible role in palliation. There are many different regimes, including combinations that may be preferred in rapidly progressive disease, but at the cost of increased toxicity. The most commonly used agents include the following: Doxorubicin – cardiotoxicity may be reduced by continuous infusion or liposomal formulations.The use of Olaratumab with doxorubicin in adult STS is being appraised by NICE; evidence suggests that it can increase survival by 11.8 months. It is a recommended option if they have not had any previous chemotherapy, if they cannot have curative surgery or if their disease does not respond to radiotherapy.Ifosfamide – prodrug activated by liver metabolism, urothelial toxicity.Paclitaxel – good response rate in angiosarcoma.Gemcitabine, methotrexate, cisplatin, mitomycin C.Anthracycline – dermatofibrosarcoma.Trabectedin is also being appraised by NICE for use in patients who have failed treatment with anthracyclines and ifosamide.
Uterine Malignancies
Published in Malte Renz, Elisabeth J. Diver, Whitfield B. Growdon, Oliver Dorigo, Synopsis of Key Gynecologic Oncology Trials, 2019
Malte Renz, Elisabeth J. Diver, Whitfield B. Growdon, Oliver Dorigo
Study: Olaratumab and Doxorubicin in Soft-Tissue SarcomaCitation: Tap, Jones et al. Lancet (2016)Highlight: Olaratumab + doxorubicinDesign: Phase Ib and randomized phase II trial of doxorubicin 75 mg/m2 on day 1 q 3 weeks ± olaratumab 15 mg/kg on day 1 and 8 q 3 weeks × 8 C in patients with metastatic/unresectable soft-tissue sarcomaBackground: Olaratumab: Monoclonal anti-platelet-derived growth factor receptor alpha antibody (anti-PDGF-Rα)Results: In phase II, 66 patients randomized to olaratumab + doxorubicin and 67 to doxorubicin alone 24 patients vs. 27 patients with leiomyosarcoma (doxo + olara vs. doxo)Median PFS: 6.6 vs. 4.1 months, HR: 0.67 (CI 0.44–1.02), p = 0.0615Median OS: 26.5 vs. 14.7 months, HR: 0.463 (CI 0.3–0.71), p = 0.0003AEs Neutropenia: 59% vs. 39%; ≥Grade 3 febrile neutropenia 59% vs. 53%Mucositis: 53% vs. 35%Nausea: 73% vs. 52%Conclusion: → Doxorubicin + olaratumab in advanced soft-tissue sarcoma resulted in 11.8 months improvement of OS
Comparison of first line chemotherapy regimens for advanced soft tissue sarcoma: a network meta-analysis
Published in Journal of Chemotherapy, 2021
Qingling Hua, Guojie Xu, Lei Zhao, Tao Zhang
Meanwhile, several novel targeted drugs have been studied in other trials. Olaratumab, a platelet-derived growth factor receptor (PDGFR) monoclonal antibody have been evaluated in a phase 1 b and 2 trial performed by Tap et al.54. The patients (nearly half of them had been previously treated) received olaratumab plus doxorubicin achieved a highly significant improvement of 11.8 months in median OS compared with patients in doxorubicin group. However, the OS benefit of olaratumab failed to be confirmed in another informative phase III trial (ANNOUNCE) comparing olaratumab plus doxorubicin and placebo plus doxorubicin for advanced STS patients68. Other brand-new drugs such as ombrabulin, ridaforolimus, regorafenib and pazopanib have better PFS, which have been demonstrated in mounting trials including previously treated advanced STS44,45,52,55. Their potential for first line chemotherapy were evident, therefore trials focussing on first line chemotherapy should be conducted in the future.
Pharmacotherapy for liposarcoma: current state of the art and emerging systemic treatments
Published in Expert Opinion on Pharmacotherapy, 2019
Lorena P. Suarez-Kelly, Giacomo G. Baldi, Alessandro Gronchi
For unresectable and/or metastatic liposarcoma, standard first-line treatment consist of anthracycline-based chemotherapy regimens, similar to others STS histotypes [60]. A post-hoc subgroup analysis assessing the predictive and prognostic factors associated with STS response to chemotherapy of the EORTC 62012 phase III randomized trial, which compared doxorubicin alone versus doxorubicin and ifosfamide as first-line treatment of advanced or metastatic STS, showed that patients with liposarcoma had a better tumor response to chemotherapy compared to other histological subgroups [61]. In a phase Ib–II clinical trial olaratumab, a platelet derived growth factor receptor-alpha monoclonal antibody, demonstrated improved overall survival (OS) when used in combination with doxorubicin compared to doxorubicin alone in patients with advanced/unresectable STS [62]. This study lead to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approval of the use olaratumab with doxorubicin for treatment of advanced STS in 2016. This approval was conditional on the results of a phase III randomized trial in the same patient population. However, this phase III study has now been completed and disappointing final results demonstrate no OS benefits [63]. Of note, this trial included 23 patients with advanced liposarcoma, but efficacy data of this specific histological cohort are currently unavailable. The official report of this trial is expected to be available later this year.
The place of trabectedin in the treatment of soft tissue sarcoma: an umbrella review of the level one evidence
Published in Expert Opinion on Orphan Drugs, 2019
Pavlina Andreeva-Gateva, Shenol Chakar
Olaratumab is a platelet-derived growth factor receptor α (PDGFR-α) antibody [42]. Olaratumab is the first new drug from which a change in the strategy of advanced or metastatic STS, not yet treated with anthracyclines, has been suggested [43]. This drug was granted authorization in 2015 by EMA and in 2016 by the FDA for use in combination with doxorubicin in STS not yet treated with anthracyclines. Olaratumab combination therapy with anthracycline is a promising first-line therapy as it extends the lives of patients [44]. Adverse effects of the combination olaratumab and doxorubicin are considered to be less than those with ifosfamide-doxorubicin, although there is no direct comparison available. Olaratumab was added as a treatment option for soft tissue and visceral sarcomas in the European Society for Medical Oncology (ESMO) Consensus in the 2017 [45] and the combination of doxorubicin plus olaratumab seemed an option for the first line if tumor shrinkage is not critical. Early results from an ongoing phase-3 ANNOUNCE trial comparing doxorubicin plus olaratumab versus doxorubicin plus placebo, however, shows that olaratumab is not more effective at prolonging the lives of people compared with doxorubicin alone (a standard care treatment). As a result, the EMA has advised that no new people should start treatment with olaratumab and NHS England have confirmed that the Cancer Drugs Fund will not fund any new people, while full results from the study are awaited [46]. The study is expected to conclude in February 2019 [47].