Core Evidence最新文献

Introduction: Stage III melanoma, also referred to as regional metastatic melanoma, has five-year survival rates ranging between 40% and 78%. In order to reduce the likelihood of recurrence in this high-risk population, patients undergo resection of primary tumors and all involved nodal basins. Systemic therapy is being pursued in an effort to improve outcome data, but the best strategy has yet to be defined. Interferon alpha-2b remains to date the most promising approach available. Toxicities and intensive intravenous administration, unfortunately, are major concerns. An alternative is the use of interferon in its pegylated subcutaneous form. The aim of this research was to review the evidence for the use of pegylated interferon alpha-2b in Stage III malignant melanoma.

Evidence review: ECOG 1684 was the pivotal trial that first demonstrated a statistically significant benefit in relapse-free and overall survival for adjuvant interferon alpha-2b in high-risk melanoma. Other larger studies, such as ECOG 1690, confirmed a relapse-free survival benefit but did not achieve statistical significance for overall survival. The first study of the pegylated form of interferon alpha-2b in Stage III melanoma, EORTC 18991, is reviewed here. This trial showed a statistically significant improvement in relapse-free survival but not overall survival. Encouraging data of potential equivalent efficacy, easier administration, and fewer Grade 3 and 4 adverse reactions compared with high-dose intravenous interferon raises the question of its potential role in Stage III melanoma in the adjuvant setting.

Introduction: The selective neurokinin-1 receptor antagonist aprepitant is effective in the treatment of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with both moderately and highly emetogenic chemotherapy. Fosaprepitant has been developed as an intravenous prodrug of aprepitant.

Aims: To update the evidence underlying the use of fosaprepitant to prevent CINV.

Evidence review: Aprepitant in combination with a serotonin antagonist and a corticosteroid controls acute and delayed symptoms of CINV in patients receiving moderately to highly emetogenic chemotherapy. Bioequivalence of fosaprepitant with aprepitant has recently been demonstrated, which has led to its inclusion in clinical guidelines for treatment of acute CINV with highly, and some regimens of moderately, emetogenic chemotherapy. Early studies of the clinical efficacy of fosaprepitant have shown improvement over treatment with ondansetron. Both aprepitant and fosaprepitant are well tolerated with most adverse events observed of mild or moderate intensity. Conflicting economic evidence has shown that whilst aprepitant provides an increased quality of life in patients treated for CINV, there are differing views over its absolute cost in relation to standard therapy. The incremental cost-effectiveness ratio of aprepitant, however, appears to lie within acceptable bounds.

Place in therapy: Fosaprepitant and aprepitant are recommended in guidelines for preventing CINV due to moderately and highly emetogenic chemotherapy. Fosaprepitant is bioequivalent to aprepitant, and could offer potential benefits for patients who may be unable to tolerate oral administration of antiemetics during an episode of nausea or vomiting.

Introduction: Dronedarone, a benzofuran derivative with a structure similar to amiodarone, has been developed as a potential therapy for patients with atrial fibrillation.

Aim: To review the published evidence regarding the efficacy and safety of dronedarone use in patients with atrial fibrillation.

Evidence review: Available evidence suggests that dronedarone 400 mg orally twice daily can lengthen the time to and decrease the overall recurrence of atrial fibrillation compared with placebo. Dronedarone may reduce risk of mortality and cardiovascular hospitalization. Patients with atrial fibrillation receiving dronedarone had improved ventricular rate control compared with patients receiving placebo. Dronedarone is associated with few serious adverse events except, notably, in patients with decompensated heart failure.

Place in therapy: Dronedarone may have a role in rate and rhythm control for patients with atrial fibrillation. Dronedarone can reduce unique, but potentially serious, end points in patients with atrial fibrillation. Despite this, the exact role of dronedarone in the management of patients with atrial fibrillation continues to emerge. It remains uncertain if dronedarone should be considered a primary treatment strategy for atrial fibrillation. Dronedarone should not be administered to patients with decompensated heart failure.

Conclusion: Dronedarone is a unique drug that may serve a key role to treat patients with atrial fibrillation.

Introduction: Psoriasis is a chronic inflammatory skin disease affecting approximately 2% to 3% of the population worldwide. Discoveries over the past 3 to 5 years have significantly altered our view of psoriasis as primarily a T-cell mediated condition. The most recent research has demonstrated the essential role of specific cytokines in the development of this complex disease, including TNF-alpha, interleukin-23 (IL-23), and potentially, IL-22. These are all part of a newly defined autoimmune pathway directed by specialized T cells called Th17 helper T cells. Ustekinumab is a fully human monoclonal antibody that targets IL-12 and IL-23, thus targeting both Th1 and Th17 arms of immunity. It has a promising efficacy and safety profile that not only represents a valuable treatment alternative, but also a continuation in our constantly evolving understanding of this disorder.

Aims: To review the emerging evidence supporting the use of ustekinumab in the management of moderate to severe plaque psoriasis.

Evidence review: There is clear evidence that ustekinumab is effective in the treatment of moderate to severe psoriasis. Phase III trials (PHOENIX 1 and 2) demonstrated a statistically significant difference between Psoriasis Area and Severity Index (PASI) 75 responses achieved by patients receiving ustekinumab, given as a 45 mg or 90 mg subcutaneous injection every 12 weeks, than their placebo counterparts. Treatment with this novel agent resulted in a rapid onset of action, with over 60% of treated patients attaining Physician's Global Assessment (PGA) scores of "cleared" or "minimal" by week 12. Quality of life assessments paralleled clinical improvements.

Clinical potential: Ustekinumab is an effective and efficient therapeutic option for patients with moderate to severe psoriasis. Although further studies are required to establish ustekinumab's place in the therapy of psoriasis, with its convenient dosing schedule and rapid onset of action, this drug could provide a great addition to the current therapeutic armamentarium available for psoriatic patients.

Introduction: Parkinson's disease (PD) is a common neurodegenerative disease. In the 1960s, it was shown that the degeneration of dopamine producing neurons in the substantia nigra (SN) caused the motor features of PD. Dopamine replacement with levodopa, a dopamine precursor, resulted in remarkable benefit. Yet, the intermittent administration of levodopa is a major cause of motor complications, such as "wearing-off" of levodopa's benefit and involuntary movements, known as dyskinesia. Therefore, agents that prolong levodopa's half-life were employed, such as carbidopa, an aromatic amino acid decarboxylase (AADC) inhibitor, and entacapone, a catechol-O-methyltransferase (COMT) inhibitor. The combination product carbidopa/levodopa/entacapone (CLE) was approved in 2003 for the treatment of PD patients.

Aims: To assess the evidence for the place of CLE in the treatment of PD.

Evidence review: CLE has a good efficacy, safety and tolerability profile, similar to that of entacapone taken separately with carbidopa/levodopa (CL). Compared to CL alone, it prolongs levodopa's benefit, and improves the quality of life but not the motor performance in PD patients with nondebilitating "wearing-off" or dyskinesia. However, it increases the dyskinesia rate in early PD patients, and has adverse events in advanced patients with significant motor complications. There is insufficient evidence regarding cost-effectiveness.

Place in therapy: CLE is an attractive alternative for patients with nondisabling "wearing-off" or dyskinesia taking CL with or without entacapone. It cannot be recommended for early PD patients, as it can induce more dyskinesia than CL alone, or in any patients who seem to have more adverse events.

Introduction: Multiple myeloma (MM) is a relatively common and incurable hematological malignancy. Currently, there is no single standard therapy, with choice of treatment dependent on individual patient factors. Lenalidomide is an immunomodulatory drug with potent antitumor, antiangiogenic, immunomodulatory, and proapoptotic activity in MM.

Aims: To evaluate the evidence for the use of lenalidomide in its current indication in relapsed or refractory MM, and additionally its investigational use for the treatment of newly diagnosed MM.

Evidence review: In patients with relapsed and refractory MM, adding lenalidomide to high-dose dexamethasone significantly improves response rates and time-to-progression, relative to high-dose dexamethasone alone. This translates into a significant extension of overall survival (with a median extension of 9.1 months in a pivotal phase III study). Outcome is independent of patient age, number of previous therapies, type of previous therapy (including thalidomide or autologous stem cell transplantation), renal impairment, and beta(2)-microglobulin level. Evidence suggests that combining lenalidomide with low-dose dexamethasone improves outcomes in patients with newly diagnosed disease and is superior to lenalidomide combined with high-dose dexamethasone. Myelosuppression is the predominant toxicity observed, although some studies have shown high incidences of venous thromboembolism in the absence of prophylactic antithrombotic anticoagulation therapy. There is currently only limited evidence regarding the health economics of lenalidomide. ROLE IN THERAPY: The encouraging results obtained with lenalidomide alone and in combination with dexamethasone in patients with relapsed or refractory MM have led to its adoption as a recommended therapy in patients who have received at least one prior treatment. Emerging evidence supports the ongoing investigation of lenalidomide in combination with low-dose dexamethasone, and in other combinations including bortezomib, for use both in relapsed, refractory, and newly diagnosed MM.

Introduction: Depressive disorders are among the main causes of disability due to disease. In spite of recent progress in the pharmacotherapy of depression, there is still a high nonresponse rate of approximately 30% to the first antidepressant treatment. Furthermore, the latency of several weeks until sufficient clinical improvement and the risk of side effects remain unresolved problems. Therefore, there is still further need for the development of new antidepressants. In the last years a variety of melatonin receptor agonists have been synthesized and evaluated for the treatment of sleep disorders. Animal studies suggested that agomelatine (S-20098), a synthetic melatonergic MT(1) and MT(2) receptor agonist with serotonin receptor antagonistic properties, may have additional activating properties and may represent a new approach in the treatment of depression.

Aims: Clinical trials that have demonstrated efficacy and safety of agomelatine for the treatment of depression are reviewed.

Evidence review: In clinical trials, including phase III studies, superior efficacy compared to placebo and good efficacy compared to standard antidepressants was shown for agomelatine for the acute treatment of major depression. In all studies published so far agomelatine was safe and the overall tolerability profile was superior to selective serotonin reuptake inhibitors or selective serotonin and norepinephrine reuptake inhibitors.

Place in therapy: Agomelatine may represent a novel perspective in the treatment of acute depression. The improvement of sleep disturbances, the tolerability in terms of sexual side effects, and the lack of withdrawal symptoms after abrupt discontinuation of treatment may represent important clinical benefits compared to established antidepressants.

Introduction: Malignant gliomas are a heterogeneous group of primary central nervous system neoplasms that represent less than 2% of all cancers yet carry a significant burden to society. They are frequently associated with considerable and progressive neurological disability and are ultimately intractable to all forms of treatment. Temozolomide (TMZ) is a new second generation DNA alkylating agent that has become part of malignant astrocytoma management paradigms because of its proven efficacy, ease of administration, and favorable toxicity profile.

Aims: To review the role of TMZ in the management of malignant astrocytomas (World Health Organization grades III and IV) including newly diagnosed (n) and recurrent (r) anaplastic astrocytomas (AA) and glioblastomas.

Evidence review: A series of pivotal clinical trials have established a role for TMZ in the treatment of malignant astrocytomas. A large phase II trial examining the role of TMZ in rAA showed a response rate of 35%, and a 6-month progression-free survival of 46%. This led to the accelerated approval of TMZ by the FDA and the EU for the treatment of rAA. Evidence for a role of TMZ in nAA is currently limited but research is ongoing in this area. The role of TMZ in the management of glioblastoma at the time of recurrence (rGBM) is less impressive but evidence for its activity was demonstrated in two large phase II trials that led to the approval of TMZ for this indication in Europe and Canada but not in the US. A recent large prospective randomized phase III trial showed that the addition of TMZ during and after radiation therapy (RT) in newly diagnosed (nGBM) patients prolonged median overall survival by 2.5 months; perhaps more importantly, the 2-year survival rate for patients receiving TMZ and RT was 26% compared with 10% for those receiving RT alone. Concurrent TMZ with RT followed by adjuvant TMZ has become the standard of care for nGBM patients. Based on the evidence presented in this trial, TMZ received approval from the FDA and the EU for patients with nGBM in 2005.

Place in therapy: THERE IS EVIDENCE TO SUPPORT THE USE OF TMZ FOR THE FOLLOWING DISEASES IN THE ORDER OF MOST TO LEAST CONVINCING: nGBM, rAA, rGBM, and nAA. This order may quickly change as more trials are being designed and implemented, particularly with novel TMZ dosing schedules.

Introduction: Hypertension is an important risk factor for cardiovascular disease and its management requires improvement. New treatment strategies are needed.

Aims: This review analyses one of these strategies, which is the development of effective and safe combination therapy. Indeed, at least two antihypertensive agents are often needed to achieve blood pressure control. Exforge((R)) (Novartis) is a new drug combination of the calcium channel blocker, amlodipine, and the angiotensin II receptor blocker, valsartan.

Evidence review: The amlodipine/valsartan combination is an association of two well-known antihypertensive products with specific targets in cardiovascular protection, namely calcium channel blockade and antagonism of the renin-angiotensin-aldosterone system. This kind of association, with neutral metabolic properties and significant antihypertensive efficacy, could be a useful new antihypertensive product. Currently available data have shown that this new combination is well-tolerated and effective even in severe hypertension.

Clinical value: Clinical trials are ongoing for further assessment of the efficacy, compliance, and safety of this combination and its congeners. No data exist to prove that the amlodipine/valsartan combination is better than other antihypertensive strategies for cardiovascular or renal protection, but some trials with other combination therapies show such potential advantage.

Purpose: Oral mucositis is a significant toxicity of cytotoxic chemo- and radiation-therapy used to treat cancer. Palifermin is the first pharmaceutical/biological agent approved for the intervention of oral mucositis. The major objective of this review is to evaluate the evidence supporting the use of palifermin.

Methods: A literature search was performed using an appropriate keyword search in MEDLINE and PubMed databases.

Results: Of 100 full papers and 4 abstracts identified, 12 papers and 3 abstracts were appropriate for analysis. Level 2 evidence supporting palifermin use in patients with hematologic malignancies being treated with autologous hematopoietic stem cell transplantation (HSCT) is clear. Level 2 evidence also exists for the use of palifermin in the prevention of oral mucositis in patients with solid tumors (colorectal cancer, head and neck cancer), but is incomplete. Level >/= 3 data support the use of palifermin in allogeneic HSCT recipients and cycled chemotherapy. A single health economic study concluded that palifermin is essentially cost neutral in the autologous HSCT population.

Conclusion: Data supporting the use of palifermin in autologous HSCT recipients with hematologic malignancies is clear. Some data exist demonstrating its efficacy in other oncologic indications. Additional studies are needed to broaden the potential applications of palifermin and to ascertain its economic, but not symptomatic, effectiveness.