Clinical roundtable monograph: new and emerging treatments for advanced prostate cancer

Historically, the treatment of metastatic castration-resistant prostate cancer (CRPC) has been limited to chemotherapeutic regimens that did not improve patient survival. In 2004, clinical studies began to demonstrate significant improvements in patient outcomes, including overall survival, with docetaxel versus mitoxantrone chemotherapy. Since these pivotal trials, the combination of docetaxel plus prednisone has become a standard of care for patients with metastatic CRPC. However, the limited survival benefit achieved with this regimen prompted several investigations into the development of alternative therapeutic options. Recent advances have now led to an unprecedented number of new drug approvals within the past year, providing many new treatment options for patients with metastatic CRPC. Sipuleucel-T, considered a new paradigm in cancer treatment, is the first such immunotherapeutic agent approved by the US Food and Drug Administration. Other successes include abiraterone acetate, the first androgen biosynthesis inhibitor, and cabazitaxel, a novel microtubule inhibitor, both of which have demonstrated improved survival following docetaxel failure. The bone-targeting agent denosumab, also recently approved in this setting, offers these patients significant improvement in the prevention of skeletal-related events. The data supporting the approval of each of these agents are described in this monograph, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies. The experts also discuss several of the issues regarding the introduction of these novel agents into clinical practice for metastatic CRPC patients.     

Clinical roundtable monograph. Integrating recent data in managing adverse events in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related morbidity and mortality worldwide. In the United States, HCC is the main cause of death in patients with cirrhosis, and the incidence of this malignancy is on the rise. Because HCC is associated with a particularly poor prognosis, emphasis is placed on surveillance of high-risk patients. Early detection allows a greater chance of diagnosing HCC before it has spread, thus increasing the chances that the patient can be potentially cured with surgical techniques such as resection and transplantation. However, most cases of HCC are not diagnosed until at least some of the cancer has spread or multiple nodules exist. For these patients, treatment options include percutaneous and transarterial ablation, as well as systemic chemotherapy. Systemic therapy is now considered the standard of care for patients with advanced tumors. Traditional treatment was based on cytotoxic chemotherapeutic agents, such as doxorubicin. This approach was associated with minimal benefit and a high rate of toxicity. Recently, targeted agents have proven more effective and safer in this setting. The oral multikinase inhibitor sorafenib is now approved for the treatment of unresectable HCC and is currently the only approved agent for advanced HCC. In order to maximize the benefit of sorafenib and other investigational agents for patients with advanced disease, effective interventions have been designed to mitigate their associated adverse events, such as hand-foot skin reactions and hypertension.     

Metastatic castrate‐resistant prostate cancer: a discussion of the physical and psychosocial effects

Management options for metastatic castrate‐resistant prostate cancer (mCRPC) have increased in recent years resulting in more men living for longer with the disease. The implications for patients and health care services are considered through an examination of the literature in relation to the physical and psychosocial effects of mCRPC and its treatment, looking at quality of life (QoL) and service delivery implications. QoL in advanced prostate cancer has been well documented in the literature but studies involving those with mCRPC are sparse. There is a lack of evidence regarding psychological distress and effective psychological interventions for men with mCRPC. There is a need for research to understand the impact of new treatments on QoL of men and their partners, to establish effective psychological interventions for men with mCRPC and to quantify the increased demand for services with prolonged survival. The purpose of this discussion paper is to examine the physical and psychosocial effects of both disease and treatment, alongside QoL issues and consideration of the implications for service delivery.     

No man’s land: information needs and resources of men with metastatic castrate resistant prostate cancer

The majority of men treated for prostate cancer will eventually develop castrate-resistant disease (CRPC) with metastases (mCRPC). There are several options for further treatment: chemotherapy, third-line hormone therapy, radium, immunotherapy, and palliation. Current ASCO guidelines for survivors of prostate cancer recommend that an individual’s information needs at all stages of disease are assessed and that patients are provided with or referred to the appropriate sources for information and support. Earlier reviews have highlighted the dearth of such services and we wished to see if the situation had improved more recently. Unfortunately, we conclude that there is still a lack of good-quality congruent information easily accessible specifically for men with mCRPC and insufficient data regarding the risks, harms, and benefits of different management plans. More research providing a clear evidence base about treatment consequences using patient reported outcome measures is required.     

Enzalutamide After Docetaxel and Abiraterone Therapy in Metastatic Castration-Resistant Prostate Cancer

Introduction

Enzalutamide is a novel antiandrogen which is approved for the treatment of metastatic, castration-resistant prostate cancer (mCRPC) after taxane-based chemotherapy. The efficacy of enzalutamide after the sequence docetaxel and abiraterone is not proven.

Methods

Thirty-five mCRPC patients in the German compassionate use program, who received enzalutamide after progression with taxane-based chemotherapy and abiraterone were prospectively evaluated. The endpoints of the study were overall survival, radiologic progression-free survival and safety.

Results

The median treatment duration on enzalutamide was 2.8 months. The median overall survival was 7.5 months [95% confidence interval (CI) 4.7–10.3] while median progression-free survival assessed by imaging was 3.1 months (95% CI 1.4–4.8). The most common toxicities of all grades were anemia and weight loss.

Conclusion

Although the results are limited by a small patient number, the consecutive use of enzalutamide and abiraterone after taxane-based chemotherapy shows a modest clinical activity. Thus, sequence therapy alternating between chemotherapy and antihormonal drugs might be a more promising approach in mCRPC treatment.     

Advances in the treatment of epilepsy.

Significant advances have been made in the diagnosis and treatment of epilepsy over the past decade. With the advent of electroencephalographic video monitoring, physicians are now able to reliably differentiate epilepsy from other conditions that can mimic it, such as pseudoseizures. In addition, neuroimaging has changed the way treatment for difficult epilepsy is approached. As a result, the classification systems that have been in use since the early 1980s are currently being revised. A broader range of treatment options for epilepsy is now available. Many new antiepileptic drugs have become available in recent years, including felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine and zonisamide. These medications offer options for patients with epilepsy whose seizures cannot be controlled using the classic agents. Several classic antiepileptic drugs have been modified and reformulated. The ketogenic diet has resurfaced as a treatment option in certain types of epilepsy. The vagus nerve stimulator, approved in 1997, represents a completely new treatment modality for patients with seizures not controlled by medications. Epilepsy surgery is now a well-documented and effective treatment for some patients with intractable epilepsy.     

Urinary incontinence: pharmacotherapy options

The impact of incontinence is felt by millions of people worldwide, with tremendous decrement in quality of life and enormous cost reaching billions of dollars. Urinary incontinence is defined as 'involuntary leakage of urine' and is categorized into two main types: urgency urinary incontinence (UUI) and stress urinary incontinence (SUI). Behavioral modifications and pharmacologic therapies, primarily antimuscarinic agents, are the mainstay of treatment for UUI. These drugs are moderately efficacious but have troublesome side-effects, the combination resulting in poor compliance and persistence with therapy. There are several agents on the market today, each with some variation in pharmacologic properties. Whether these translate into meaningful differences in clinical efficacy and tolerability remains a matter of debate. Treatment of SUI has seen little success with pharmacologic therapy. In Europe, duloxetine is approved for treatment of SUI with marginal success rates; this drug, although available in the United States for treatment of depression, is not approved for SUI. The search for newer and better pharmacologic options and novel therapies is on-going, fueled primarily by the high prevalence of bothersome incontinence and the tremendous number of health care dollars spent on current therapy. This review addresses pharmacologic options for treatment of urinary incontinence.     

Management of ST-segment elevation myocardial infarction in EDs

Emergency department (ED) physicians are critical in the accurate diagnosis, efficient management, and treatment of patients with ST-segment elevation myocardial infarction. The initial reperfusion strategy involves the choice between mechanical reperfusion using primary percutaneous coronary intervention and pharmacologic treatment with fibrinolytics. The benefits of these approaches are time dependent, and practices vary according to institutional resources and local guidelines. Nevertheless, the need for early intervention and the use of certain therapies are well recognized. Therefore, ED physicians must be aware of all treatment options available, including the use of adjunctive therapies. Initial treatment should include beta-blockers, aspirin (or clopidogrel if aspirin is contraindicated), nitroglycerin, and analgesia, regardless of reperfusion strategy. Clopidogrel is now approved as an adjunctive therapy for patients undergoing fibrinolysis as their reperfusion therapy. Both unfractionated heparin and low-molecular-weight heparin are feasible adjunctives in patients with ST-segment elevation myocardial infarction undergoing reperfusion therapy. In addition, multiple new antithrombin agents are being investigated. The choice adjunctive treatments should be based on specific patient populations and on the initial reperfusion strategy.     

Novel Therapies in Acute Myeloid Leukemia

ObjectiveTo provide a comprehensive review of evidence-based data on the newly approved therapeutic agents in acute myeloid leukemia (AML) with regards to appropriate indications for use, efficacy, and safety.Data SourcesPublished clinical trials and observational studies.ConclusionOptimal treatment decisions for AML should be personalized based on individual patients’ performance status, disease risk as determined by mutational profile, response status, and prior therapies received. While the treatment options have expanded, several questions remain regarding appropriate patient selection, long-term efficacy and safety of these agents, and sequencing of therapies among available options.Implications for Nursing PracticeNurses need to be familiar with the peculiarities of the administration regimens of newer AML therapies, adopt formal monitoring strategies for side effects that are unique to these agents, and develop a framework to facilitate timeliness of follow-up and monitoring while on these therapies.     

The next generation of medications for kidney transplant patients

Transplant pharmacotherapy evolves as new agents are investigated and approved for use. Clinical immunosuppression has been plagued with maintaining a balance between rejection of the transplanted organ and complications of over-immunosuppression, including infection and malignancy. Clinicians must understand current immunosuppressive regimens and their associated effects when caring for transplant patients. While all transplant patients receive some form of immunosuppressive therapy, the combinations and choices increase as new drugs are developed. In the critical and acute care settings, newly transplanted patients will likely receive induction therapy. The goal of induction therapy is to increase long-term patient and allograft survival while preventing or reducing rejection episodes. Several agents are available for induction therapy, and each transplant center designs its own protocol. The foundation for maintenance therapy rests on the combining immunosuppressives to prevent rejection through a variety of pathways. An understanding of the mechanism of action and additive effects of a drug allows practitioners to optimize therapy while decreasing adverse effects. Immunosuppressive therapy offers potential for reducing detrimental patient outcomes and improving allograft survival. It is well established that repeated rejection episodes correlate with poor long-term graft survival. Challenges facing researchers and clinicians focus on improved patient outcomes and options to address financial constraints of transplantation.     

Current Developments in Intraspinal Agents for Cancer and Noncancer Pain

Since the late 1980s, intrathecal (IT) analgesic therapy has improved, and implantable IT drug delivery devices have become increasingly sophisticated. Physicians and patients now have myriad more options for agents and their combination, as well as for refining their delivery. As recently as 2007, The Polyanalgesic Consensus Conference of expert panelists updated its algorithm for drug selection in IT polyanalgesia. We review this algorithm and the emerging therapy included. This article provides an update on newly approved as well as emerging IT agents and the advances in technology for their delivery.     

Chemotherapy for lung cancer

Chemotherapy is currently a primary treatment modality for small-cell lung cancer (SCLC). Combination chemotherapy of anticancer agents improves survival and mortality rather than chemotherapy with single agent. On the other hand, the role of chemotherapy in advanced non-small cell lung cancer(NSCLC) is still controversial. Several meta-analysis demonstrated a small but significant survival benefit of cisplatin-based chemotherapy. In the limited stage SCLC and locally advanced NSCLC, a combination of chemotherapy and thoracic irradiation was found to be superior to chemotherapy alone by several randomized trials and meta-analysis. Concurrent administration of anticancer agents with thoracic irradiation may be optimal treatment. In the last few years, several new agents have demonstrated antitumor activity against lung cancer and randomized trials of these drugs are now under way.     

Evaluating new treatment options for MDS

Myelodysplastic syndromes (MDS) comprise a collection of hematologic disorders characterized by deficiencies in peripheral blood cells, particularly those of the granulocyte, erythrocyte, and megakaryocyte lineages. A number of chromosomal abnormalities are associated with the development of MDS, including mutations involving chromosomes 7q, 5q, 20q, 6q, 11q, and 13q. Until recently, supportive care or allogeneic stem cell transplantation (ASCT) were the only available treatment options for this disease. ASCT is potentially curative but poses high mortality risk in the predominantly elderly MDS population. Supportive care options traditionally included blood transfusions and antibiotics, with the goal of reducing morbidity from ineffective hematopoiesis and improving quality of life. This approach has been enhanced by treatment with various growth factors aimed at stimulating blood cell production, including erythropoietin and granulocyte colony-stimulating factor. These growth factors, along with the use of iron chelation therapy to counteract the iron overload that can develop after frequent transfusions, have recently been shown to have the potential to prolong survival in MDS patients. In addition to these advances in supportive care, three new agents have been approved for the treatment of MDS in the past 3 years. Lenalidomide, azacitidine, and decitabine all target molecular processes underlying the pathophysiology of MDS and have shown considerable activity and, more recently, potential survival benefits in various subgroups of patients. Considerable changes in the treatment of MDS are expected in coming years as these and other novel agents are tested alone and in combination with one another to further refine the treatment paradigm for MDS.     

Emerging Therapies for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic heterogeneous group of diseases that has undergone major advances in the understanding of its etiology and pathogenesis in recent years. The development of biologics had resulted in better overall management of the disease, including lower rates of surgery and better long-term clinical and patient-reported outcomes. Treatment modalities have either been newly developed or extrapolated from their approved use for a different indication. Modes of action and treatment targets have varied as well. Treatments such as vedolizumab and ustekinumab, as well as second-generation corticosteroids have been approved by the US Food and Drug Administration (FDA) for the treatment of IBD. Other agents are currently being developed at various stages of clinical trials including anti-adhesion agents such as etrolizumab and abrilumab, JAK inhibitors such as tofacitinib, and anti-trafficking molecules. Toll-like receptors and phosphatidylcholine are also new promising emerging targets that are being investigated in phase 3 clinical trials. It is projected that many therapies will become available in the coming years if supported by the results of current clinical trials. This will provide IBD patients with a wide array of options and allow physicians to choose the best therapies for each individual patient.     

Managing side effects of the novel taxane cabazitaxel in castrate-resistant prostate cancer

Cabazitaxel, a novel taxane, was approved in June 2010 by the U.S. Food and Drug Administration for treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men previously treated with docetaxel. In TROPIC (N = 755), an open-label, randomized, phase III trial, cabazitaxel (plus prednisone) was associated with improvement in median overall survival compared with mitoxantrone plus prednisone (15.1 versus 12.7 months, p < 0.0001) in patients with mCRPC who had progressed following docetaxel-based regimens. That corresponds to a 30% relative reduction in risk of death compared with the mitoxantrone regimen. In addition, significant benefit existed in median progression-free survival with cabazitaxel versus the mitoxantrone regimen (2.8 versus 1.4 months, p < 0.0001). Most common adverse events (AEs) associated with cabazitaxel were hematologic; the rates (all grade) of neutropenia, leukopenia, and anemia were greater than 90%. Diarrhea, fatigue, asthenia, and back pain were the most common grade 3 or higher nonhematologic AEs. Because expected AEs from cabazitaxel therapy can delay or even interrupt treatment, oncology nurses need to be aware of those risks and their management. This article reviews the vital role of nurses in identifying patients at high risk for AEs associated with cabazitaxel therapy and reviews strategies for prevention and management of symptoms.     

Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges

Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin‐2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B‐Raf and MEK inhibitors and allow the treatment of patients with B‐Raf mutated melanoma. Second, there are the immunotherapies, with anti‐CTLA‐4 and anti‐PD‐1 antibodies that are used for patients harboring a B‐Raf wild‐type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.     

Nelfinavir desensitization

OBJECTIVE: To report the first case of nelfinavir desensitization in an HIV patient who was intolerant to protease inhibitors. CASE SUMMARY: A 43-year-old HIV-positive white man was treated with several protease inhibitors. The patient developed rashes in response to all protease inhibitors. His viral load was controlled only in the presence of a protease inhibitor. The patient tolerated nelfinavir longer than the other agents; therefore, the decision was made to attempt to desensitize him to nelfinavir. A six-hour inpatient protocol was used, and he tolerated the procedure without event. His disease is now well managed without recurrence of the rash. DISCUSSION: The use of protease inhibitors has had a major impact on the morbidity and mortality of HIV-infected patients, Despite their benefits, this class of drugs is not without adverse effects. Allergic reactions in the form of rashes may develop, which can severely limit treatment options in HIV patients. We report the first case of rapid desensitization of nelfinavir in a patient who developed rashes to several protease inhibitors. CONCLUSIONS: Intolerance to protease inhibitors due to rash is a well-documented phenomenon. In HIV patients, this can limit treatment options severely. This case demonstrates how desensitization to nefinavir can be performed successfully.     

Bisphosphonates: expanded roles in the treatment of patients with cancer

Bisphosphonates are important inhibitors of osteoclastic bone resorption seen in patients with bone metastases associated with malignancy. Bisphosphonates are used in the treatment of patients with bone metastases and have been shown to reduce skeletal-related events and symptoms, contributing to improved patient outcomes and quality of life. These agents first were approved in the treatment of patients with osteoporosis and have been used for the past two decades in this role. Because bisphosphonates inhibit osteoclast-mediated bone resorption, the bone remodeling cycle slows down and an increase in bone mineral density occurs. These agents are useful in treatment for both hypercalcemia and pain, although they have not definitively shown improvement in survival time. Considerable interest exists in the use of bisphosphonates for prevention of bone metastases and their potential antitumor activity. These drugs are well tolerated and have minimal side effects, but they are not inexpensive. This article discusses the role of bisphosphonates in patients with cancer and future directions for further research.     

Epigenetic biomarkers in colorectal cancer diagnostics

Colorectal cancer (CRC) is a significant health burden worldwide. Despite advancements in treatment options, improvements in CRC patient survival have been limited owing to lack of early detection and limited capacity for optimal therapeutic decision-making. Biomarkers to improve CRC diagnosis, prognosis and prediction of treatment response therefore represent opportunities to improve patient outcome. In addition to genetic alterations and genomic instability, it is now clear that epigenetic alterations play dramatic roles in driving tumor onset and progression in CRC. A recent surge in investigation of epigenetic biomarkers including DNA methylation, miRNA expression and histone modifications has demonstrated that these alterations may be enticing translational biomarker candidates in CRC. In particular, methylation kits have already been incorporated into clinical practice for a handful of cancers, including CRC. This review will aim to summarize the established and emerging roles of epigenetic modifications in CRC detection, prognostication and prediction of treatment response.     

Current and emerging therapy for primary pulmonary hypertension

OBJECTIVE: To review the epidemiology, pathophysiology, clinical symptoms, and diagnostic workup of primary pulmonary hypertension (PPH) and to discuss the available data on the current and emerging therapies being used to treat this disorder. DATA SOURCES: Primary and review articles were identified with a MEDLINE search (1966-December 2001) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and all information deemed relevant was included in this review. DATA SYNTHESIS: In the absence of a definable cause, PPH is a disorder classified by a progressive increase in pulmonary vascular resistance and mean pulmonary artery pressure. A relatively rare condition, PPH has an annual incidence of 1-2 cases per million people, slightly higher in women than men. The prognosis is poor, with a mean survival time of 2.8 years after diagnosis if untreated. Vasoconstriction, vascular remodeling, and thrombosis are hallmarks of the disease process. Anticoagulation and vasodilators are the most commonly employed treatment options, showing benefits in clinical outcomes, hemodynamic parameters, and mortality. Several new vasodilators are being evaluated for the treatment of PPH. Bosentan was recently approved as the first oral agent for the treatment of PPH. Iloprost, treprostinil, and beraprost are investigational agents in Phase III studies. CONCLUSIONS: Until additional studies and experience with these agents become available, calcium-channel blockers (CCBs) remain the first option for therapy. For patients not responding to CCBs, therapeutic options will now include epoprostenol and bosentan. Since there are no comparison trials between these 2 agents, therapeutic decisions should be based on patient-specific concerns. Clinical data and experience support the use of epoprostenol; however, in patients at risk or considered unsuitable candidates, bosentan may become a preferred option. Additional studies are warranted to address the potential therapeutic benefits of combination therapy and long-term benefits of agents to treat PPH.