Reviews on Recent Clinical Trials - Volume 7, Issue 3, 2012

Brachytherapy nowadays has become a widely accepted treatment modality in the management of localized prostate cancer. With recent improvements in ultra-sound technology, imaging, treatment planning and post-implant dosimetry, permanent implantation has become minimally invasive, well tolerated, and safe and most importantly has progressed to a treatment modality comparable to external beam radiation therapy (EBRT) and radical prostatectomy. Multiple studies have proven the efficacy of brachytherapy analyzing also its superiority in health related quality of life; especially in potency preservation after treatment.

We reviewed the comparative trials of the Flotrac/VigileoTM versus the thermodilution method, published in the last five years. The results about the agreement between the two methods measuring cardiac output are contrasting. We also noticed that almost the whole pertinent literature include studies conducted without a correct statistical design, particularly about the sample size. For this reason we consider that results of the published studies about the agreement between pulse contour analysis for cardiac output measurement and thermodilution method may be not reliable.

Anemia is a very common complication of chronic kidney disease (CKD). Anemia confers significant risk of cardiovascular disease and contributes to decreased quality of life. Anemia in CKD patients can be multi-factorial, including but not invariably due to the underlying renal insufficiency. Identifying the type of anemia is important in this group of patients and can often be challenging. Diagnosing anemia of renal disease due to erythropoietin (EPO) deficiency is a diagnosis of exclusion. Erythropoiesis stimulating agents (ESA) are the mainstay for the treatment of anemia secondary to CKD. However, over the last four years the use of ESA in the treatment of anemia in CKD patients has undergone a severe interrogation as several trials have reported adverse outcomes with targeting higher hemoglobin (Hb) levels with these agents. Thereby, this review describes the pathophysiology of anemia in CKD patients, diagnosis and the current role of ESA's as it relates to anemia of CKD as well as safety and efficacy of ESA's.

Although clinical trials evaluating therapy with implantable cardioverter defibrillators (ICD) have had clear limitations, there are few interventions in which multiple trial settings over a long period have consistently produced a 20% to 30% reduction in total mortality in patients with left ventricular dysfunction. Substantial differences between the Guidelines on ICD implantation have resulted and the number of patients actually implanted following these recommendations remains relatively low. As well as this, different reasons have been proposed to explain why randomized trials of ICD versus control subjects implanted early after myocardial infarction do not show survival benefit. Moreover, many factors in addition to ejection fraction (EF) do influence the prognosis of patients with coronary disease. However, there are few tools to use this information to guide clinical decisions. Recent years have seen an ongoing debate on the further risk stratification of patients who will benefit most from ICD implantation and a combination of a few readily available clinical variables indicating advanced disease and comorbid conditions identifies ICD patients at high risk. In addition, the role of these devices in patients with nonischemic cardiomyopathies, in older patients and females, for prevention of sudden cardiac death (SCD), has long been debated. This review aims to summarize these criticisms and to refine the current indications of ICD implantation in patients with moderate-severe left ventricular dysfunction.

Spurred by remarkable findings in animal studies, there has been strong interest in evaluating the potential of adult stem cells to improve left ventricular function in the past decade. Driven by the need to treat the increasing number of patients with coronary artery disease, numerous studies have attempted to define a role for bone marrow cell therapy in clinical use. However, the conflicting results of these studies can be confusing. This article will review the landmark trials evaluating bone marrow cell therapy in the past decade and describe the current state of adult stem cell therapy and its future direction herein.

Till date the synthetic hepato-protective agents used in clinical practices are therapeutically non-promising and may itself lead to hepatotoxicity. Herbal medicines and their bioactives are considered to be relatively safe and have been used in the treatment of liver diseases for a long time. The 21st century has seen a paradigm shift towards therapeutic standardization of herbal drugs in hepatic disorders by evidence-based randomized controlled clinical trials to support their clinical efficacy. Even so, the specific hepato-protective clinical trial protocols for herbal medicines are not established till now. So, the efficacy of herbal medicines needs to be evaluated through rigorously designed multicentre clinical studies. In this review, we have enlightened the clinically evaluated hepatoprotective herbals and herbal formulations with respect to their status in different trial stages. Moreover, the problems and their strategic solutions during the development of clinical trial protocol for hepatoprotective herbal medicine are also addressed.

Standard chemotherapy can cure only a fraction (30-40%) of younger and very few older patients with acute myeloid leukemia (AML). While conventional allografting can extend the cure rates, its application remains limited mostly to younger patients and those in remission. Limited efficacy of current therapies and improved understanding of the disease biology provided a spur for clinical trials examining novel agents and therapeutic strategies in AML. Clinical studies with novel chemotherapeutics, antibodies, different signal transduction inhibitors, and epigenetic modulators demonstrated their clinical activity; however, it remains unclear how to successfully integrate novel agents either alone or in combination with chemotherapy into the overall therapeutic schema for AML. Further studies are needed to examine their role in relation to standard chemotherapy and their applicability to select patient populations based on recognition of unique disease and patient characteristics, including the development of predictive biomarkers of response. With increasing use of nonmyeloablative or reduced intensity conditioning and alternative graft sources such as haploidentical donors and cord blood transplants, the benefits of allografting may extend to a broader patient population, including older AML patients and those lacking a HLA-matched donor. We will review here recent clinical studies that examined novel pharmacologic and immunologic approaches to AML therapy.

Background: In the 21st century, tubal ectopic pregnancies (EPs) are diagnosed earlier in their natural history due to transvaginal ultrasound technology. More women are haemodynamically stable and therefore can be offered non-invasive outpatient management with systemic Methotrexate (MTX). However there is no evidence that MTX is necessary in all these early EPs, as many may resolve spontaneously in the absence of any treatment. To date there are no published randomized trials comparing systemic MTX with a placebo. The aim of this study is to verify if MTX is more effective than the placebo in women with tubal EP and rising/plateauing serum human chorionic gonadotrophin (hCG) levels. Methods/Design: This is a multi-centre double-blind randomized controlled trial conducted in Australia. Haemodynamically stable women with a confirmed ultrasound diagnosis of tubal EP and a rising/plateauing serum hCG &<1500 IU/L are eligible for the trial. Women with a declining serum hCG, hCG>1500 IU/L at 48hrs, viable tubal EP, severe abdominal pain, evidence of haemoperitoneum on ultrasound, diagnostic uncertainty, non-tubal ectopic pregnancy, or women with contraindications to MTX will be excluded. Systemic MTX in a single dose intramuscular regimen (50mg/m2) is compared to an identical placebo in an outpatient setting. All women will attend for a serum hCG measurement on day 4. Provided patients are haemodynamically stable, they will attend for another blood test on day 7. If a decline in serum hCG > 15% between days 4 - 7 is observed, weekly blood tests will be scheduled until undetectable hCG levels. If serum hCG levels increase or decrease < 15% between days 4 - 7, a second dose of MTX will be given and weekly blood tests will be scheduled until undetectable serum hCG. If any increase in serum hCG > 15% between days 4 - 7 or at any subsequent follow-up, women will be treated with MTX. Primary outcome measure is treatment success, defined as uneventful decline of serum hCG to an undetectable level (<5 IU/L) by the initial intervention. Secondary outcome measures are re-interventions (additional systemic MTX injections and/or surgery for haemodynamic instability/trophoblast persistence), treatment complications and length of follow-up. Discussion: This trial will clarify the actual effectiveness of MTX in haemodynamically stable women with an early tubal EPs and rising or plateauing hCG.

A randomised controlled trial (RCT) is considered the hierarchical peak of evidence-based medicine and a general demand for any result to be evaluated by RCTs has evolved. Yet, many advances in operative surgery do not result from RCTs and many controversies remain without an RCT being conducted. A randomised comparison of laparoscopic versus open liver resection has recently been called for. Using such a trial and others as examples, we examine the limitations of randomised design in skill-dependant interventions. Surgical procedures are skill-dependant, constantly developing, irreversible and traumatising. Additionally, placebo control is usually unethical and adequate blinding difficult or impossible to accomplish. Under these circumstances, surgeon and patient participation will be problematic and the resulting data will tend to have low external validity. While some of these obstacles can be modified, others will remain. Nonrandomised, prospective cohort comparison has other weaknesses, but may add complementary data with good external validity. An alternative hierarchy of evidence is warranted in this field.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies and has significant mortality. Its multi-step cumulative features strongly support early management. Cancer chemoprevention has been accepted as a promising intervention for early management, and has made enormous progresses over the past 30 years due to the large number of research studies including many randomized clinical trials. Overall, chemoprevention is an appealing approach for fighting HNSCC because it is generally safe, cost-effective, and widely available. In this review, we summarize and discuss new findings and evidences from the most recent clinical trials in chemoprevention of HNSCC. Our literature search is limited only to those trials published within the past 10 years (2001-2011). Based on our review, the most extensively studied agents/compounds for chemoprevention continue to be retinoids (e.g., 13-cRA). Additional agents considered include COX inhibitors, Vitamin A and E forms, and green tea and other natural extracts. However, we found disappointing results in the studies using retinoids, COX inhibitors and vitamin forms, while encouraging outcomes were found with most natural extracts. Further study is warranted for validation or improvement of treatment efficacy with current agents and strategies. Future research may include identification of new biomarkers/targets, improvement of bioavailability or tissue penetration, combinations of different compounds (or development of dual-action agents) to act on multiple pathways, and specific study of non-smoking related or other untraditional causes.