Pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma

Introduction: Liposarcomas (LPS) are a heterogeneous group of adipocytic soft tissue sarcomas with limited treatment options in the advanced/metastatic setting. Pazopanib is a multi-target tyrosine kinase inhibitor (TKI) with anti-angiogenic and antitumorigenic properties. Whilst targeted agents including TKIs have been extensively studied in other solid tumors and the sarcoma subtype gastrointestinal stromal tumor (GIST), we currently lack effective treatments for the liposarcoma subtype. Several phase II and III studies of oral TKIs in soft tissue sarcomas have excluded liposarcoma because of a reported lack of activity following the EORTC 62043 study.

Areas: We review the use of pazopanib in advanced intermediate and high-grade liposarcomas where complete surgical resection is not possible.

Expert opinion: The current clinical and pharmacological data demonstrate the efficacy of pazopanib in soft tissue sarcomas, but new data suggest that anti-angiogenic agents may have limited activity in liposarcoma. Anti-angiogenic TKIs are generally well tolerated and liposarcomas vary in their response to systemic chemotherapy; hence, there is a role for further exploration of the efficacy of this treatment amongst the histological subtypes of liposarcoma. This affords further understanding of biomarkers which may be associated with response to pazopanib and other anti-angiogenic TKI treatments.     

Efficacy of trabectedin for the treatment of liposarcoma

Introduction: Trabectedin (ET-743) is a synthetic marine derived alkylating agent, extracted originally from a Caribbean Sea sponge. It is approved for the treatment of Soft Tissue sarcomas (STS) in Europe and recently by the FDA for liposarcomas and leiomyosarcomas.

Areas covered: Trabectedin has multiple mechanisms of action, including one targeting the FUS-CHOP oncogene in Myxoid/Round cell Liposarcomas. Numerous Phase I, II and III clinical trials have been conducted with Trabectedin. It has been studied as monotherapy or in combination with other chemotherapeutic agents. The recommended dose based on clinical trials is 1.5 milligrams/m² continuous infusion over 24 hours once every 3 weeks for STS with evidence of disease control in multiple clinical trials at this dose. The most common Grade 3/4 toxicities include neutropenia and transient noncumulative elevations of ALT and AST. Steroid pretreatment has shown efficacy in reducing liver and bone marrow toxicity. In phase III testing comparing trabectedin to dacarbazine, trabectedin was associated with a significantly improved progression free survival rate in patients with advanced lipo- and leiomyosarcomas.

Expert opinion: Trabectedin is an important new addition to the limited treatment options currently available for STS, especially for patients with liposarcoma that have progressed on standard chemotherapeutic regimens.     

Pharmacological therapies for Liposarcoma

Introduction: Liposarcoma (LS) is one of the most common adult soft tissue sarcomas (STS). For metastatic disease, systemic treatment options were historically represented by standard cytotoxic chemotherapy. More recently, innovative therapies have been introduced and they are currently part of the therapeutic armamentarium, positively impacting disease control and patients’ quality of life. Moreover, in the last decade, a better understanding of the molecular characteristics of each STS subtype allowed to detect new potential targets and develop novel, biology-driven compounds at different stages of testing.

Areas covered: This review is focused on LS, retracing their pharmacological management, starting with a summary of results achieved with standard chemotherapy, then moving to a deeper analysis on data obtained with new, approved therapies and finally reporting an update on ongoing clinical trials, thus providing an overview on the current scenario and outlining how it might evolve in the coming years.

Expert commentary: Important strides have been made in the knowledge and treatment of LS. Peculiar molecular features and fundamental signalling pathways represent nowadays druggable targets for novel therapies. However, predictive biomarkers still need to be identified in order to better select the target population, to possibly test combinations of drugs, with the ultimate goal of improving outcomes.     

New therapies in soft tissue sarcoma

Importance of the field: Soft tissue sarcomas are rare mesenchymal tumors accounting for <?1% of all adult neoplasia. In the last decade, locally advanced and metastatic soft tissue sarcoma have been managed only through surgery, radiotherapy and standard chemotherapy (mainly based on anthracycline and ifosfamide). Despite the efforts, overall 5-year survival rate in patients with soft tissue sarcomas of all stages remains only 50 – 60%.

Areas covered in this review: In the present article, all the main new molecules under clinical evaluation for the treatment of soft tissue sarcoma are revised by describing the mechanism of action, the biological rationale of their use in sarcoma and by reporting the available data about safety and efficacy, up to 2009.

What the reader will gain: A brief summary of the standard treatments available at the moment and a complete analysis of the state of art about the development of new target therapies in the management of soft tissue sarcoma.

Take home message: The identification of new biological therapies that target soft tissue sarcoma tumorigenesis key points seems to offer a real opportunity of improving the prognosis of this often aggressive disease. In this sense, the best management for soft tissue sarcoma patients is in a clinical trial and participation in clinical trials should be encouraged.     

Clinical efficacy of eribulin mesylate for the treatment of metastatic soft tissue sarcoma

Introduction: Metastatic soft tissue sarcoma, a devastating disease, has a median overall survival of only 12–18 months. Treatment options remain scarce. However, eribulin mesylate, a first-in-class halichondrin B-based microtubule dynamics inhibitor, has recently been approved for the management of patients with advanced liposarcoma.

Areas covered: Based on a review of the literature between 2005 and 2017, we present a summary of eribulin mesylate’s mechanism of action and the studies showing its clinical efficacy in locally advanced or metastatic sarcomas.

Expert commentary: Future development includes the definition of a biomarker signature related to patient outcome with eribulin. Further investigation via controlled clinical trials is needed to identify combination regimens that can optimize the efficacy of eribulin while providing an acceptable safety profile in sarcoma patients.     

Current and advancing systemic treatment options for soft tissue sarcomas

Introduction: Soft tissue sarcomas are a collection of rare malignancies, the treatment of which has evolved over time. Although cytotoxic chemotherapy remains the cornerstone of management of metastatic disease, many new treatments have been developed or show great promise in the treatment of soft tissue sarcoma. Research into the different underlying pathogenesis of individual subtypes has driven progress in treatment. This has allowed development of treatments targeted to specific subtypes of sarcoma.

Areas covered: We provide a review of the current field of systemic therapy in soft tissue sarcoma. This is followed by an in-depth analysis of recent developments in treatment, as well as new treatments that are aimed at specific subtypes of sarcoma, and the biological rationale behind these therapies. We also look in detail at the promising new agents currently in development.

Expert opinion: Much progression has been made in treatment of soft tissue sarcomas with multiple exciting new treatments in development. However outcomes in general remain poor. Further research into the underlying pathogenesis of soft tissue sarcomas may help deliver more effective systemic therapies. Increased collaboration between basic science, translational and clinical investigators is required at national and international levels to maximise progress.     

An evaluation of pixantrone for the treatment of non-Hodgkin’s lymphoma

ABSTRACT

Introduction: The overall prognosis for patients with relapsed or refractory aggressive non-Hodgkin’s lymphomas is poor. Only a minority of patients are able to receive autologous stem cell transplantation. Patients not transplant-eligible or patients relapsing after transplantation have an urgent need for effective treatment options. Pixantrone is the only compound approved in Europe for this situation.

Areas covered: This review describes the clinical development of pixantrone, starting with phase I trials up to phase III trials in order to define the role of pixantrone in treatment algorithms. The effectiveness of pixantrone is considered in relation to alternative therapeutic options. Furthermore, the similarities and differences between pixantrone and anthracyclines is highlighted, with a special focus on the mode of action and on cardiotoxicity.

Expert opinion: Pixantrone is a valuable treatment option in relapsed and refractory aggressive lymphomas, with documented disease responses, manageable toxicities and clear distinctions to anthracyclines. Additional studies are needed to evaluate the role of pixantrone in combination with other compounds, especially with upcoming targeted therapies, and to confirm the effectiveness of pixantrone in other lymphoma subtypes, e.g. follicular lymphomas.     

Treatment of advanced soft tissue sarcoma: efficacy and safety of trabectedin,a multitarget agent,and update on other systemic therapeutic options

Soft tissue sarcomas (STS) are rare mesenchymal cancers. Despite optimal management, nearly 50% of patients with localized disease will develop recurrence. The outcome for patients with metastatic STS is poor. There are few systemic treatment options available in this setting. Doxorubicin, with or without ifosfamide, is considered standard first line therapy. We herein review the evidence for the use of trabectedin in adult advanced soft tissue sarcoma. Some clinical trials have confirmed the activity of trabectedin as an effective and tolerable option for adult patients previously treated with doxorubicin and ifosfamide. Trabectedin was approved in the European Union and other countries based on the results of a randomized phase II trial involving patients with advanced liposarcoma and leiomyosarcoma receiving one of two different schedules of trabectedin. Recently a multicentre phase III trial randomized liposarcoma and leiomyosarcoma patients to receive either trabectedin or dacarbazine, demonstrating a significantly improved progression-free survival for patients treated with trabectedin compared to dacarbazine.     

Pharmacological treatment of pediatric Gaucher disease

ABSTRACT

Introduction: Gaucher disease (GD) is an autosomal recessive disorder resulting from the deficiency of the lysosomal enzyme glucocerebrosidase (b-glucosidase), associated with varying degrees of visceral, bone and central nervous system pathology, leading to wide phenotypic diversity. Response to therapy and clinical outcomes are very different between the three clinical subtypes – non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms; hence a definitive clinical diagnosis is essential. The availability of two therapeutic options, i.e. enzyme replacement and substrate reduction, has transformed the natural course of the disease. As pre-treatment disease severity clearly impacts results of therapy, early diagnosis and initiation of treatment especially in the pediatric population are keys to achieving an optimal outcome.

Areas covered: We reviewed the literature concerning the treatment of GD focusing on pediatric presentations, various pharmacological treatment options and recommendations for management goals. A PubMed literature search was performed for relevant publications between 1991 and September 2018.

Expert commentary: The approval of enzyme replacement therapy (ERT) for GD in the pediatric age group has significantly altered the course of the disease, especially for non-neuronopathic and chronic neuronopathic forms, as ERT does not cross the blood-brain barrier. Early diagnosis, regular follow-up and early initiation of treatment can thus prevent some irreversible complications and improve patient quality of life.     

Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach

Importance of the field: Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual.

Areas covered in this review: The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and – most recently – pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed.

What will the reader gain: This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients.

Take home message: As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a rational approach to therapy selection. These features include prior treatment status, histologic subtype, and prognostic group. Further refinement of therapy selection is required and will require further biologic information as well as comparative randomized trials.     

Emerging therapeutics in refractory renal cell carcinoma

Introduction: Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies (‘refractory’ mRCC). Recently approved agents in this space have shown great promise.

Areas covered: This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents.

Expert opinion: Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.     

Investigational targeted therapies for the treatment of testicular germ cell tumors

Introduction: Germ cell tumors (GCTs) are the most common malignancy among men aged between 15 to 45. Despite high cure rates of >90% over all GCTs, 3 to 5% of patients will still die of platinum-refractory disease. New systemic treatment options are needed to improve treatment success in this challenging setting.

Areas covered: To review targeted treatment options and preclinical developments in platinum-refractory GCTs, a comprehensive literature search of PubMed, Medline and scientific meeting abstracts on published clinical trials and reports on molecularly targeted approaches was conducted. Outcomes of platinum-refractory disease and of patients failing high-dose chemotherapy remain poor. Currently, no molecularly targeted treatment has shown clinically meaningful activity in unselected patient populations in clinical trials, but individual patients may achieve short-lived objective responses by treatment with sunitinib, brentuximab vedotin or imatinib. Targeted trials based on molecular selection of patients have not yet been performed.

Expert opinion: The limited activity of targeted agents in refractory GCT is disappointing. Assessment of druggable biomarkers and marker-stratified treatment may help individual patients, but is largely lacking. The low incidence and high curability of GCTs make the design of larger clinical trials difficult. The potential of novel agents, i.e. immune-checkpoint inhibitors, remains to be elucidated.     

Pharmacotherapy of focal epilepsy

Introduction: Epilepsy is the most common neurological condition worldwide with significant psychosocial and physical morbidity. Its management requires expertise and good pharmacological knowledge of the available options.

Areas covered: This review covers the management of focal epilepsy addressing the common questions arising through the patients’ journey, including timing of starting initial treatment, monotherapy options, add-on treatment for refractory cases and withdrawal of medication during remission.

Expert opinion: Initiating anti-epileptic drug (AED) treatment requires assessment of patient preferences and of evidence of benefit and harm. Evidence of benefit will come primarily from randomised controlled trials, although in epilepsy, most trials are undertaken to inform regulatory decision and have important limitations for informing clinical decisions. Evidence about harm may come not only from randomised trials but also from other sources. Most patients will start treatment following a second focal seizure. Carbamazepine and lamotrigine are good initial monotherapy options. Newer AEDs have proof of efficacy as monotherapy but evidence is insufficient to recommend them as first-line treatments. For refractory cases, there are an increasing number of AEDs available, but evidence of efficacy is primarily from placebo-controlled trials, and there is no robust evidence to inform a choice among treatments.     

Clinical management of mantle cell lymphoma in the elderly

ABSTRACT

Introduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients.

Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival.

Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.     

Clinical efficacy of piperacillin/tazobactam in the treatment of complicated skin and soft tissue infections

Introduction: Complicated skin and soft tissue infections (cSSTIs) are skin and soft tissue infections (SSTIs) that involve deep soft tissue. cSSTIs often require surgical intervention and/or hospitalization. cSSTIs are associated with significant mortality and morbidity, and carry a significant burden on health care systems. Piperacillin/tazobactam has been regarded as a standard treatment for cSSTIs because of its antibiotic spectrum, safety and clinical efficacy. Several antibiotics, as compared to piperacillin/tazobactam, have been evaluated in the treatment of cSSTIs.

Areas covered: This review summarizes randomized controlled trials (RCTs) evaluating the clinical efficacy of piperacillin/tazobactam for the treatment of cSSTIs.

Expert opinion: Piperacillin/tazobactam, which covers most causative organisms in cSSTIs, is the drug of choice for the treatment of cSSTIs. Other options such as ertapenem and moxifloxacin may be reasonable where multiple daily dosing or intravenous administration is inappropriate. But in general, they should be avoided as an empirical treatment because of their highly association with resistant bacteria, which are becoming a global threat. Therefore, piperacilin/tazobactam is appropriate as an empirical therapy for the treatment of SSTIs and should be de-escalated as soon as causative organisms are identified, their drug-sensitivity results are available, and clinical condition becomes stable.     

A safety evaluation of pirfenidone for the treatment of idiopathic pulmonary fibrosis

ABSTRACT

Introduction: Pirfenidone is a novel oral anti-fibrotic agent approved for the treatment of idiopathic pulmonary fibrosis (IPF). Since IPF is a chronic and progressive disease most commonly encountered in an older population, therapeutic options should be not only effective, but also free from drug interactions and as safe and tolerable as possible.

Areas covered: Comprehensive data from randomized controlled trials, meta-analyses, safety studies, and post-marketing data are available to assess the efficacy and safety of pirfenidone in the treatment of IPF. Information on efficacy, adverse events, drug tolerability and discontinuation rates both in clinical trials and real-world clinical experiences are reported.

Expert opinion: Pirfenidone has an abundance of data supporting its use in mild-to-moderate IPF. Observational evidence suggests a similar efficacy in severe IPF. In clinical trials, observational studies and real-world use, adverse events are frequent, though generally mild and well tolerated, especially with adequate patient education. Preventative strategies, along with timely and appropriate management of adverse events are critical in improving patient compliance, thereby ensuring the benefits of long-term treatment with pirfenidone.     

Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency

ABSTRACT

Introduction: Alpha-1 antitrypsin deficiency (AATD) is most often associated with chronic lung disease, early onset emphysema, and liver disease. The standard of care in lung disease due to AATD is alpha-1 antitrypsin augmentation but there are several new and emerging treatment options under investigation for both lung and liver manifestations.

Areas covered: We review therapeutic approaches to lung and liver disease in alpha-1 antitrypsin deficiency (AATD) and the agents in clinical development according to their mode of action. The focus is on products in clinical trials, but data from pre-clinical studies are described where relevant, particularly where progression to trials appears likely.

Expert opinion: Clinical trials directed at lung and liver disease separately are now taking place. Multimodality treatment may be the future, but this could be limited by treatment costs. The next 5–10 years may reveal new guidance on when to use therapeutics for slowing disease progression with personalized treatment regimes coming to the forefront.     

Monoclonal antibodies for the treatment of Ebola virus disease

Introduction: To date, the management of patients with suspected or confirmed Ebolavirus disease (EVD) depends on quarantine, symptomatic management and supportive care, as there are no approved vaccines or treatments available for human use. However, accelerated by the recent large outbreak in West Africa, significant progress has been made towards vaccine development but also towards specific treatment with convalescent plasma and monoclonal antibodies.

Areas covered: We describe recent developments in monoclonal antibody treatment for EVD, encompassing mAb114 and the MB-003, ZMAb, ZMapp? and MIL-77E cocktails.

Expert opinion: Preventive measures, are, and will remain essential to curb EVD outbreaks; even more so with vaccine development progressing. However, research for treatment options must not be neglected. Small-scale animal and individual human case studies show that monoclonal antibodies (mAbs) can be effective for EVD treatment; thus justifying exploration in clinical trials. Potential limitations are that high doses may be needed to yield clinical efficacy; epitope mutations might reduce efficacy; and constant evolution of (outbreak-specific) mAb mixtures might be required. Interim advice based on the clinical experience to date is that treatment of patients with mAbs is sensible, provided those could be made available in the necessary amounts in time.     

Telotristat ethyl: a new option for the management of carcinoid syndrome

Introduction: Many patients with neuroendocrine tumour-related carcinoid syndrome treated with somatostatin analogues (SSA) won’t achieve adequate symptom relief with the SSA alone; new treatment options are required. Telotristat ethyl is a tryptophan hydroxylase inhibitor, developed for the treatment of carcinoid syndrome.

Areas covered: This review summarises the evidence supporting the role of telotristat ethyl in the management of carcinoid syndrome. Rationale, pharmacodynamics, pharmacokinetics, metabolism, clinical experience, efficacy and toxicity profiles are covered.

Expert opinion: The efficacy of telotristat ethyl in producing a statistically-significant and clinically-meaningful reduction in daily bowel movements has been confirmed in phase III clinical trials. Two pivotal trials, TELESTAR and TELECAST, explored the role of telotristat ethyl in the management of patients with carcinoid syndrome refractory to SSAs focusing on patients with ≥4 and <4 daily bowel movements, respectively. In addition, benefit was confirmed in patient-reported outcomes. Based on activity and safe toxicity profile, telotristat ethyl is pending regulatory agencies evaluation and is likely to add to the armamentarium used to treat carcinoid syndrome. Long-term safety and efficacy data will be available from the ongoing TELEPATH study. The impact on carcinoid heart disease, mesenteric fibrosis and other long-term complications of carcinoid syndrome as well as its role earlier in patients’ pathways remain investigational.     

Adenosine signaling pathways as potential therapeutic targets in respiratory disease

Introduction: Adenosine receptors (ARs) and their differential pattern of expression modulate a series of pleiotropic activities that are known to contribute to the control of inflammation, remodeling, and tissue repair. Consequently, pharmacological manipulation of adenosine signaling pathway is of great interest and is currently exploited as a therapeutic target for a number of respiratory diseases with several molecules with agonist and antagonist activities against known ARs being developed for the treatment of different conditions of the respiratory system.

Areas covered: Herein, we will review the rational basis leading to the development of novel therapies for asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cystic fibrosis. Their most recent clinical development will be also discussed.

Expert opinion: Advances in our understanding of the pathogenetic role of adenosine in respiratory diseases may be soon translated into effective treatment options. In consideration of the complex interplay driven by the different pattern of receptor distribution and/or affinity of the four known AR subtypes in specific cell types at different stages of the disease, it is likely that combination of selective antagonist/agonists for different AR subtypes will be required to obtain reasonable clinical efficacy. Alternatively, controlling the factors involved in driving adenosine concentrations in the tissue may be also of great significance.