Thrombin receptor antagonism –the potential of antiplatelet medication SCH 530348

Importance of the field: Coronary artery disease is a leading cause of morbidity and mortality worldwide. Platelet activation and subsequent thrombus formation play a central role in disease progression and development of acute coronary syndromes (ACS). Despite widespread use of single and dual antiplatelet therapies in atherothrombotic disease, ischemic complications remain common. Therefore, the need exists for new antiplatelet agents that are more effective, but with acceptable safety profiles (i.e., do not increase risk of bleeding). Antiplatelet agents available at present are effective in blocking the cyclo-oxygenase, ADP-mediated and final common (IIb/IIIa receptor) pathways for platelet activation. Recently, there has been more interest in inhibition of the proteinase-activated receptor-1 (PAR-1), which blocks thrombin-mediated platelet activation.

Areas covered in this review: This review covers the pharmacology, pharmacokinetics and development of the new PAR₁ antagonist, SCH 530348 in a review of all publications relevant to the topic over the last 10 years. Phase II clinical trials indicate that addition of this agent to current antiplatelet regimens may provide additional antithrombotic protection without an increase in bleeding. Results of the ongoing Phase III trials, examining the use of SCH 530348 in patients with ACS and for secondary prevention of ischemic events are anxiously awaited.

What the reader will gain: The review is a summary of all pharmacologic properties and current clinical data available on the PAR1 antagonist SCH 530348. The readers will be introduced to its novel mechanism of action, advantages over current antiplatelet agents and potential future applications should ongoing clinical trials confirm its efficacy in reducing platelet activity.

Take home message: SCH 530348 is a new, orally administered antiplatelet agent that blocks the protease-activated thrombin receptor on the platelet. Early clinical data indicate that it is associated with a lower risk of bleeding. However, its efficacy in improving clinical outcomes in patients with coronary disease remains to be confirmed in ongoing Phase III clinical trials.     

Emerging neuroprotective drugs for the treatment of acute ischaemic stroke

Introduction: Neuroprotection aims to restrict the ischaemic damage following stroke by preventing salvageable neurons from dying. Despite successes in experimental stroke studies, neuroprotective strategies have failed in clinical trials so far. Nevertheless, promising neuroprotective drugs are currently being investigated in clinical trials.

Areas covered: This review provides an overview of the existing treatment of acute ischaemic stroke, discusses current research goals and puts special emphasis on emerging neuroprotective drugs. The authors systematically searched the database Clinicaltrials.gov for ongoing Phase II and Phase III clinical trials of neuroprotective drugs for acute ischaemic stroke. Mechanisms of action of these candidate neuroprotectants and the results of preceding preclinical studies and clinical pilot trials are described.

Expert opinion: In order to facilitate a successful translation from bench to bedside, future experimental studies should follow rigorous quality standards. Recent concepts to overcome the translation roadblock include the implementation of multicentre preclinical Phase III studies, the use of stroke models in non-human primates and the introduction of a preclinical trial registration.     

Safinamide in the treatment of Parkinson's disease

Importance of the field: Current therapy for Parkinson's disease (PD) is primarily directed at reversing the motor symptoms that are the consequence of dopamine deficiency and includes levodopa, dopamine agonists and monoamine oxidase (MAO) B inhibitors. New drugs offering both dopaminergic and non-dopaminergic actions could offer a significant advantage.

Areas covered in this review: This review surveys the current treatment strategies for PD. Defining unmet needs and how a new compound – safinamide, which has both dopaminergic and non-dopaminergic actions – might address these.

What the reader will gain: The reader will gain an understanding of safinamide and its mechanisms of action, including reversible MAOB inhibition and reduced dopamine reuptake with antiglutamatergic effects, and how it may potentially provide improvement of PD motor symptoms with an antidyskinetic effect through its effect on glutamate release. The clinical trial profile of safinamide is reviewed. Early results are promising in terms of improved motor function and reduced ‘OFF’ time. Additional Phase III trials are now in progress for this adjunctive indication. Finally, the reader will understand the potential role for safinamide in the selection and sequencing of drugs for PD.

Take home message: safinamide combines both dopaminergic and non-dopaminergic actions that may add a new dimension to PD treatment options as an adjunct to current drugs. Its efficacy is under active evaluation in Phase III clinical trials.     

Antiplatelet therapy in acute coronary syndromes

Introduction: Coronary thrombosis is a frequent cause of death and myocardial infarction most often explained by superimposition of a platelet-rich thrombus on existing coronary artery disease. Therefore, antiplatelet drugs are essential in the treatment and secondary prevention of acute coronary syndromes (ACS) and during percutaneous coronary intervention. Several novel antiplatelet drugs are now available.

Areas covered: For several years, aspirin and clopidogrel remained the cornerstone of treatment for ACS. However, prasugrel and ticagrelor have a more consistent, faster-acting and more potent antiplatelet effect than clopidogrel, which translates into improved clinical outcomes, although at the expense of an increased bleeding risk. Importantly, some patients experience cardiovascular events despite current antiplatelet treatment, because platelet activation may occur via pathways not inhibited by these agents. Therefore, improved antiplatelet strategies are warranted.

Expert opinion: Despite undisputable benefits of current antiplatelet strategies, a considerable number of patients continue to experience adverse thrombotic events, although clinical outcomes have been improved with new oral P2Y₁₂ antagonists. New drugs have been developed, including intravenous P2Y₁₂ antagonists and oral antagonist targeting the protease-activated receptor-1 platelet activation pathway stimulated by thrombin. This review provides an overview of current and novel antiplatelet strategies and also discusses unmet needs related to antiplatelet therapy for ACS.     

Zibotentan for the treatment of castrate-resistant prostate cancer

Importance of the field: Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.

Areas covered in this review: This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ET_A receptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ET_A receptor.

What the reader will gain: Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.

Take home message: Modulating the activity of ET-1 through the ET_A receptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ET_A inhibitor, to determine the effect of this agent on overall survival in these patients.     

Dimethyl fumarate for multiple sclerosis

Importance of the field: One of the disadvantages of currently available disease-modifying drugs (DMDs) for multiple sclerosis (MS) is their parenteral administration. Moreover, efficacy is only partial. Most patients treated with first-line DMDs do not remain relapse-free. There is a need for new oral drugs that are more effective than currently available compounds. Innovative oral drugs with new mechanisms of action showed promising results in clinical trials. One of these emerging drugs is BG00012 (BG-12), a fumaric acid ester (FAE). Its active agent, dimethyl fumarate had first been included in FAE treatments for psoriasis.

Areas covered in this review: Results that highlight the potential role of BG-12 in MS treatment. We focus on findings of experimental studies and current results of clinical studies with FAE in MS.

What the reader will gain: An overview of the immunomodulatory and neuroprotective effects of FAE, their effect in animal models of MS and their short-term efficacy and safety profile in a Phase IIb clinical trial.

Take home message: BG-12 is a promising emerging treatment for relapsing–remitting MS, combining anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. However, the future role of BG-12 in treatment of MS will have to be determined after the completion of ongoing Phase III studies.     

Antiplatelet therapy in acute coronary syndromes

Introduction: Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes in the acute phase and in long-term management. Over the last few years, new antiplatelet drugs have been developed and the therapeutic landscape has rapidly evolved.

Areas covered: We review the available evidence and most recent data concerning all of the principal classes of antiplatelet agents, including aspirin, thienopyridines and glycoprotein IIb/IIIa inhibitors, as well the impact of the new drugs prasugrel and ticagrelor and the available data concerning cangrelor, elinogrel and PAR-1 inhibitors (still under development).

Expert opinion: This review considers the management of antiplatelet therapy in the light of recent advances, highlighting how to identify patients who will receive the greatest benefit from the older and newer agents, and underscoring the importance of carefully balancing the risks of ischaemia and bleeding in order to improve clinical outcomes. Finally, the paper discusses the potential role of functional and genetic tests in guiding the choice of antiplatelet therapy in a future perspective of ‘personalised medicine’.     

Inhaled drug therapy development for the treatment of migraine

Introduction: The inhalation of substances, both medicinally and recreationally, is a commonly used method of drug administration but has been underutilized in the treatment of neurologic disorders such as migraine. Three drugs have been studied as potential inhalable treatments for acute migraine: dihydroergotamine (MAP0004), prochlorperazine (Staccato prochlorperazine), and loxapine (Staccato loxapine).

Areas covered: This review discusses the available literature describing the pharmacokinetics, tolerability and efficacy of MAP0004, Staccato prochlorperazine and Staccato loxapine, including data from Phase II and Phase III clinical trials.

Expert opinion: Inhaled DHE offers rapid absorption with a pharmacokinetic profile similar to IV administration. Improved side effect profile results from more selective binding at antimigraine serotonergic receptors 5-HT_1B and 5-HT_1D. Inhaled prochlorperazine is rapidly absorbed and resulted in statistically significant migraine pain relief at 2 hours compared to placebo but is not currently being pursued by the manufacturer as a potential migraine abortive. Inhaled loxapine is also rapidly absorbed into systemic circulation but Phase IIb trials did not show statistically improved pain relief or pain freedom compared to placebo. MAP0004 will likely provide a good alternative to patients seeking rapid relief without the need for injection or other invasive routes.     

Ticagrelor for the treatment of arterial thrombosis

Importance of the field: High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y₁₂ blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y₁₂ receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y₁₂ receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor.

Areas covered in this review: We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y₁₂ receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about ‘AZD6140’ and ‘ticagrelor’ in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings.

What the reader will gain: This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y₁₂ receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers.

Take home message: Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use.     

NX-1207: a novel investigational drug for the treatment of benign prostatic hyperplasia

Importance of the field: Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) is a common affliction among older men that can have significant impact on health-related quality of life. BPH is a progressive condition that can lead to complications including acute urinary retention (AUR) and to surgical intervention. There is an ongoing need for new, safe and effective treatments for BPH. Currently available therapies have significant safety and efficacy limitations. NX-1207 is a promising first-in-class drug currently in Phase III trials for the treatment of BPH.

Areas covered in this review: This review provides an overview of BPH and currently approved medical treatments and drugs as described in the literature and treatment practice guidelines in the past 10 years, an outline of the results of the Phase II trials of NX-1207 and an expert opinion on the role NX-1207 may play in the treatment of men with clinical BPH.

What the reader will gain: This review aims to introduce readers to NX-1207, a new treatment for BPH that is administered in an office-based procedure by transrectal intraprostatic injection under ultrasound guidance. NX-1207 has selective pro-apoptotic properties, which induces focal cell loss in prostate leading to prostate volume reduction with both short- and long-term symptomatic improvement.

Take home message: In four US clinical trials to date, NX-1207 has shown evidence of symptomatic improvement substantially better than currently approved BPH medications with no significant safety issues. Larger Phase III trials are ongoing to further confirm the efficacy, safety and tolerability for this minimally invasive, anesthetic free, clinic-based treatment for BPH.     

Development of novel therapy of schizophrenia in children and adolescents

Introduction: Typical and atypical antipsychotics are efficacious treatments for early-onset schizophrenia (EOS) with very subtle differences in their efficacy. Therefore, when choosing an antipsychotic, the side-effect profile of the individual antipsychotic needs to be taken into account. There is a growing body of neurobiological and genetic evidence for early-onset patients, but these findings have not yet translated into the clinic.

Areas covered: The authors summarize the current treatment options for EOS and discuss the novel treatment options that are under evaluation. The authors focus specifically on Phase II and Phase III clinical trials.

Expert opinion: Currently, there are no truly groundbreaking pharmacological treatment options emerging in EOS. There are several newer antipsychotic agents (iloperidone, lurasidone, asenapine, blonanserin) that are currently in clinical trials. It is unclear whether therapeutic efficacy of any of these agents will be superior or even similar to the existing treatment and the main differentiating factor between individual drugs remains to be their side-effect profile. Beyond these antipsychotics, oxytocin and N-acetylcysteine are the only new pharmacological treatment options that are being evaluated in EOS. Therefore, a major change in the treatment development paradigm is necessary to identify novel and efficacious drugs.     

Abiraterone acetate for castration resistant prostate cancer

Importance of the field: Androgen deprivation therapy has been the standard of care in advanced prostate cancer for >?50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone (termed castration resistant prostate cancer, CRPC). Intratumor and extra-gonadal androgens (specifically adrenal androgens) represent a means for continued androgen receptor-mediated growth in CRPC and have thus become therapeutic targets. One novel therapeutic is abiraterone acetate (AA): an inhibitor of CYP17, an enzyme that catalyzes two key serial reactions in androgen and estrogen biosynthesis. Data from Phase I and II trials suggest that clinically important antitumor activity is seen in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. The toxicity profile has also been found to be acceptable. Two large Phase III clinical trials are currently open to accrual and will hopefully validate the impressive Phase II data.

Areas covered in the review: The chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy and safety/tolerability of AA.

What the reader will gain: Readers will understand the function of non-gonadal androgens, the importance of continued androgen deprivation in advanced prostate cancer and the role/clinical efficacy of AA.

Take home message: The recent realization that non-gonadal sources of androgens (adrenal and intracrine de novo synthesis) may be a major mediator of disease progression forms the biological rationale behind the development of abiraterone acetate and related drugs. Abiraterone acetate is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from Phase I and II trials suggest that prostate specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large Phase III clinical trials are currently open to accrual and, if proven to be efficacious, will result in widespread use of a drug specifically developed to suppress adrenal androgens.     

New directions for pharmacotherapy in the treatment of acute coronary syndrome

Introduction: Acute coronary syndromes (ACS) are one of the leading causes of death worldwide. Several landmark trials, followed by a widespread introduction of new agents, have significantly improved ACS outcomes in recent years. However, despite the use of contemporary therapy, a substantial number of ACS patients continue to suffer from cardiovascular events.

Areas covered: The aim of this review was to summarize available data on innovative drugs and pharmacological strategies that have potential to amend the current ACS therapy. We present the results of recent large clinical trials, as well as insights from ongoing phase III and phase IV studies, exploring the value of new strategies for the improvement of outcomes in ACS.

Expert opinion: More potent platelet inhibition, more profound lipid reduction and possibly anti-inflammatory action are considered to have potential to further reduce the rates of adverse cardiovascular and thrombotic events in ACS patients. ‘Hit fast, hit hard’ approach regarding novel antiplatelet and lipid-lowering therapy seems attractive, but it has to be considered that these strategies may be associated with increased adverse events rate. Introduction of cangrelor and ezetimibe, and potentially future recognition of proprotein convertase subtilisin/kexin type 9 antibodies, are likely to alter the landscape of ACS pharmacotherapy.     

Eribulin mesylate for the treatment of breast cancer

Importance of the field: Breast cancer is the most common cause of cancer-related death among women in the USA, and additional effective and well-tolerated chemotherapeutic agents are urgently needed. Eribulin mesylate (E7389), a synthetic analog of the marine macrolide halichondrin B, is a microtubule inhibitor with a unique tubulin binding site and mechanism of action.

Areas covered in this review: Based on a review of the literature between 2005 and 2010, we present a summary of eribulin and its clinical activity, specifically in metastatic breast cancer.

What the reader will gain: The mechanism of action of eribulin, preclinical data indicating antitumor activity of eribulin and data from Phase I and II clinical trials evaluating the efficacy and tolerability of eribulin are presented.

Take home message: Based on data from Phase I and II clinical trials, we conclude that eribulin seems to have efficacy in metastatic breast cancer, even among women with heavily pretreated and taxane-resistant disease. In addition, eribulin has a manageable side-effect profile, consisting mainly of neutropenia and fatigue, and most notably a low incidence of peripheral neuropathy. With these encouraging results, additional Phase II and III studies are ongoing. Eribulin seems to be a promising new agent for the treatment of metastatic breast cancer.     

Developments in antiplatelet therapy for acute coronary syndromes and considerations for long-term management

ABSTRACT

Objective: This article reviews the currently available antiplatelet therapies and emerging investigational drugs in the treatment of acutecoronary syndrome (ACS), and considerations for primary and secondary prevention in the long-term management of ACS patients undergoing percutaneous coronary intervention (PCI).

Research design and methods: Primary studies and reviews in the peer-reviewed, English-language literature were identified through searches of MEDLINE (1966–2008) using the terms ‘acute coronary syndrome’, ‘antiplatelet’, ‘aspirin’, ‘long-term management’, ‘P2Y₁₂ receptor’, and ‘thienopyridine’. Additional references were obtained by searching the reference lists of the identified articles. Articles were included if they were recently published and pertinent, patient-focused, and authors were recognized as leaders in the field. Current review is limited by literature search on single database.

Results: Platelets play a major role in atherogenesis and the formation of thrombi, the main events in the pathogenesis of ACS. Although aspirin is an effective antiplatelet agent, efficacy and safety data from a number of randomized clinical trials on atherothrombotic disease support the use of dual antiplatelet therapies such as aspirin and thienopyridines over single antiplatelet therapy for ACS and up to 1?year following ACS. Antiplatelet agents reduce, but do not eliminate, ischemic events after ACS due, in part, to variable individual response (or resistance) in antiplatelet agents, non-compliance, progression of atherosclerosis, modest inhibition of platelet aggregation (IPA) levels and other factors. Several antiplatelet agents, including novel P2Y₁₂-receptor antagonists and thrombin-receptor antagonists, are currently under investigation for ACS and primary and secondary prevention in the long-term management of patients undergoing PCI.

Conclusions: Current antiplatelet therapies have clinical benefits such as reducing immediate and long-term cardiovascular risk, but substantial residual risk remains indicating a need for new therapeutic agents. Additional large randomized trials are necessary to determine the most appropriate treatment regimens for ACS patients.     

AIT-082, a novel purine derivative with neuroregenerative properties

Introduction: The interaction between the VEGFRs and their ligands plays an important role in tumor angiogenesis. Despite a series of problems encountered during early work on blocking growth factors, current evidence injects further vigor into researching the modulation of VEGFR activity. Emerging preclinical and clinical studies suggest that attenuating receptor activity can synergistically promote antitumor action if utilized concurrently with conventional therapies.

Areas covered: This review presents an up-to-date assessment of the potential role of modulating receptor activities in various cancers. The sentinel work on the proof of principles in various animal models, and the current translational research on these small molecule inhibitors and receptor blocking antibodies, from Phase I to Phase III trials, has been systematically examined with an emphasis on agents in earlier stages of development.

Expert opinion: Many clinical trials are ongoing, but early phase trials show promising results. Recently, there has been a huge explosion of research activity either in the development of new drugs or in the understanding its biology. Many current trials lend support to the rationale behind these therapies, which can function as adjuvants to conventional treatments. It has been argued that normalization of tumor-induced vasculature can promote better drug delivery and prevent resistance to radiotherapy. However, strategies involving the inhibition of the interaction of VEGFRs with ligands and their downstream pathways are not, in general, at a stage where it will be directly useful in clinical cancer treatment. A deeper understanding of these biologic therapies will help to improve the efficacy of conventional treatments and furthermore reduce dose-dependent cytotoxic activity.     

Principle and evolving role of intraperitoneal chemotherapy in ovarian cancer

Introduction: Intraperitoneal (i.p.) chemotherapy has been extensively studied in the ovarian cancer field. Despite the fact that three large randomized trials that were conducted in the United States showed survival benefit, meta-analysis also showed survival benefit and the National Cancer Institute (NCI) released a clinical announcement recommending i.p. chemotherapy for optimally debulked advanced stage ovarian cancer in 2006, i.p. chemotherapy has not been widely accepted by the gynecologic oncology community, mainly because of its toxicities.

Areas covered: In this review, previously available evidence, new evidence published since the NCI clinical announcement and ongoing clinical trials will be discussed.

Expert opinion: Three currently ongoing randomized Phase III trials will provide extremely important information about whether a less toxic i.p. regimen using carboplatin will be beneficial for patients with advanced ovarian cancer. They are important because it may be possible to solve many of the questions or unmet needs in i.p. chemotherapy by combining these three trials.     

Safety evaluation of tirofiban

Importance of the field: Heightened platelet activity is pivotal in the thrombosis underlying acute coronary syndrome (ACS). The glycoprotein IIb/IIIa inhibitor tirofiban is a powerful platelet inhibitor with demonstrated efficacy and safety across the spectrum of ACS. Despite tirofiban's impact on the platelet compared with placebo, only an excess in minor and importantly not major bleeding has been observed. Thrombocytopenia with tirofiban seems to be extremely rare and immediately reversible on infusion discontinuation.

Areas covered in this review: The review includes the rationale for potent antiplatelet therapy in the management of ACS, particularly patients at high risk for ischemic complications. Additionally, it provides an overview of tirofiban's pharmacology and summary of the clinical efficacy and safety data of two dosing regimens.

What the reader will gain: The reader will gain a perspective on the efficacy and safety data from the key trials of tirofiban.

Take home message: Tirofiban is safe and effective in patients with ACS. The single bolus dose regimen produces potent platelet inhibition resulting in significant improvement in clinical events over placebo when initiated just prior to percutaneous coronary intervention and at first medical contact. When compared with abciximab, tirofiban demonstrates similar efficacy though significantly lower rates of thrombocytopenia.     

Emerging drugs for high-grade osteosarcoma

Importance of the field: Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. This review focuses on the most promising therapeutic markers and drugs which may potentially be considered for innovative high-grade OS treatments.

Areas covered in this review: The list of drugs and compounds reviewed has been generated by taking into account those which target markers of potential clinical interest for high-grade OS and have been included in Phase I, II or III clinical trials. The literature search covers the last 40 years, starting from the first OS chemotherapy reports of the early 1970s. Particular relevance was given to reports and reviews on new targeted therapies of possible clinical usefulness for high-grade OS.

What the reader will gain: This review gives an updated overview of novel therapeutic approaches which have been or are going to be evaluated in Phase I/II/III clinical studies for high-grade OS.

Take home message: On the basis of the information that has emerged so far, it can be predicted that in the next 5 – 10 years, new agents to be included in innovative treatment strategies for selected subgroups of high-grade OS patients may become available.