Reviews on Recent Clinical Trials - Volume 6, Issue 1, 2011

Breast conservation surgery followed by whole breast irradiation has been established as a standard of care for the treatment of early stage breast cancer and is associated with excellent local control and overall survival. As most inbreast recurrences occur in the area surrounding the primary breast cancer, it has been hypothesized that selected breast cancer patients may be adequately treated with accelerated partial breast irradiation (APBI), obviating the need for whole breast irradiation. Advantages of APBI include a shorter treatment schedule that may result in perceived patient convenience and more women opting for breast conservation therapy. These possible benefits of APBI must be balanced with the potential risk of recurrence within untreated breast tissue and the possible long term toxicity associated with larger doses per fraction and accelerated course of irradiation. Although, the preliminary results with APBI are encouraging, appropriate patient selection and optimal dosimetric guidelines remain to be clearly defined.

Introduction and Aim: Prostate cancer (Pc) is a major public health problem, affecting 679,000 men and causing 221,000 deaths every year. Over the past decade, there has been a marked decline in Pc mortality corresponding to the introduction of prostate specific antigen (PSA) test as a screening tool (1986). Despite this clear result, the screening recommendations of various organizations differ. Recently, a large number of studies have highlighted the benefits and risks of PSA based screening. The aim of this article is to review the current screening guidelines and summarise the benefits and harms of PSA testing, analysing two large long awaited randomized multicenter clinical trials of PSA screening reported this year. Methods for the Review: We reviewed the recent literature using PUBMED research, using as words for research: Prostate- Specific Antigen, mass screening, Prostatic neoplasm mortality, follow-up studies, overdiagnosis and overtreatment. In particular, we analysed two clinical trials reported on “ The New England Journal of Medicine” this year: the European Randomized Study of Screening for Prostate Cancer (ERSPC) by Scroeder et al. and the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial by Andriole et al. Results and Conclusions: The goal of a screening is to detect a cancer at an early stage, when it is still curable. In Pc case there are different treatments with curative intent, that are associated with significant morbidity. Some man have an aggressive form for which screening might be helpful but many have a slow growing cancer that would never progress and their detection could cause anxiety and bring unnecessary medical treatment. With this review we tried to understand where we should stop the management: Overdiagnosis or Overtreatment?

The Clinical Pathway (in its complete definition Diagnostic, Clinical and Therapeutic Pathway - Percorso Diagnostico Terapeutico Assistenziale - PDTA), originally started to deal with the newly diagnosed hypertensive patient, developed also recommendations for the first-line drugs in case of specific indications/contraindications and organ damages. It has been developed by a working group of specialists in cardiology, nephrology, internal medicine (faculty included) designated by their hospitals (both public and private accredited), including all the main city hospitals, by general practitioners designated by the Medical Unions SNAMI, FIMMG, SMI and SiMI and by public health doctors belonging to the Local Health Unit of Milan, who have coordinated the proceedings and have guaranteed that possible conflicts of interest of single participants could not interfere with the PDTA, anyway approved by all in July 2009. The PDTA deals with the measuring and self- home-monitoring of blood pressure (BP) and the diagnosis of hypertension; it revises, sometimes “dries up” and rationalizes the recommendations for diagnostic tests and specialist evaluations; it develops prevention and non-pharmacological treatments, proposing also tools for patients and for prescribing correct nutrition and physical activity and a structured program for BP monitoring; but the main feature is the innovations brought in the proposed drug treatment in comparison with the current clinical practice.

The mammalian target of rapamycin (mTOR) is a central component within a complex intracellular signaling network that regulates various processes including cell growth, proliferation, metabolism, and angiogenesis. A hyperactive PI3k/Akt/mTOR signaling pathway is found in many human cancers and alterations in this pathway are associated with the development and progression of cancer. Drugs that target and inhibit mTOR activity are therefore expected to provide therapeutic value in a number of cancer types. Several classes of mTOR-targeted therapeutics are currently being evaluated in cancer clinical trials, including the rapamycins, dual PI3K-mTOR inhibitors, and ATP-competitive mTORC1/2 inhibitors. This review summarizes important findings from recently completed trials of mTOR inhibitors and also discusses preliminary data from ongoing trials.

Psoriasis is a common skin condition seen in pediatrics. Treatment modalities used to treat psoriasis in children are different from those prevailing in the adult population and require adequate testing in pediatric subjects. This article reviews the published evidence on the different treatment modalities for pediatric psoriasis over the past 5 years.

Platinum-based chemotherapy, with or without the antiangiogenetic drug bevacizumab, is the standard first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib has been recently approved as treatment of patients with EGFR mutated tumors (including first-line). Three agents are approved for treating non-selected patients who progress after one prior regimen: docetaxel, pemetrexed, and the EGFR-TKI erlotinib. Gefitinib can be used as second-line treatment in patients with EGFR mutated tumors. Although these agents have yelded similar outcomes in terms of antitumor activity and efficacy in unselected NSCLC patients, they have different toxicity profiles, and recently some strong factors that can help in the choice among them have been detected. In particular, the hystotype, the EGFR gene mutational status, the response to previous first-line chemotherapy and the correlation of the safety profile of the agents with Performance Status and comorbidities of the patients, are the most important factors that drive the choice of the second-line treatment. Obviously, the drugs administered in the first-line treatment strongly influence the choice of the second-line treatment because some of the currently available drugs can be used in both settings. Thus, more than in the past, first and second-line treatment of advanced NSCLC are linked, and the choice of second-line treatment is part of a strategy decided when beginning the firstline treatment.

This review will address the current understanding of the relationship between hyperprolactinemia and antipsychotic drugs. Hyperprolactinemia is a frequent but often neglected side effect of typical, but also of many atypical antipsychotics. Release of PRL from lactotrope cells is influenced by several factors, such as stress, physical and sexual activity and food assumption. PRL secretion is regulated by hypothalamic-pituitary portal system and its homeostasis is the result of a complex balance between stimulating and inhibitory factors, both endogeneous and esogeneous. The main physiological control mechanism of secretion is played by the inhibitory action of dopamine. Conversely, among stimulation factors, serotonin is probably the main modulator of PRL release. An high number of drugs may cause PRL increase too, such as drugs that reduce dopaminergic functions at SNC level, or drugs with an antagonistic action towards dopaminergic receptors and those increasing serotonergic neurotransmission. Hyperprolactinemia is one of the most frequent endocrine pathologies of the hypothalamic-pituitary axis. Antipsychotics (AP) are the most common cause of druginduced hyperprolactinemia. Not all AP have the same impact on inducing hyperprolactinemia. In this review we will focus on the subdivision of AP in ‘PRL-raising’ (stimulators) and ‘PRL-sparing’ (sparers) and on their differences in inducing hyperprolactinemia. Finally we evaluated different complications in patients with antipsychotics induced hyperprolactinemia that may cause not only short-term side effects but also important systemic long-term effects. At the end of the review we finally report the possible options of treatment considering however that at present there are no ideal therapies or evaluations, and decisions have to be made on a case by case basis.

While most newly-diagnosed prostate cancers are well-differentiated tumors that have high probability of cure, there is a subset of patients that present with aggressive malignancies that have significant potential for recurrence and metastasis. Single-modality treatment approaches have demonstrated relatively high failure rates, and multimodality therapy (radiation therapy and hormonal ablation therapy) has become standard of care for these patients. These treatments are not without toxicity, and a significant percentage of patients will become refractory to hormonal therapy. Historically, radiation therapy of prostate cancer was associated with significant genitourinary and gastrointestinal morbidity. With advances in radiation therapy techniques and delivery, the potential for safe dose-escalation has emerged. Further, there is an opportunity for chemotherapeutic agents to play an important syngergistic role in radiosensitizing the tumor cells at the primary site while also addressing micrometastatic disease. Concurrent chemoradiation therapy has become standard treatment for many types of locally advanced tumors, including lung, cervical, esophageal, rectal, and anal malignancies. We present a review of clinical trials examining the role of chemoradiation therapy in high-risk prostate cancer.

ACE inhibitors have proven to be effective blood pressure lowering agents with an excellent tolerability profile. The family of these drugs is still expanding, necessitating the definition of selection criteria in order to choose the “right drug”. In this article the ACE inhibitors available in the United Kingdom (UK) are scored by means of the SOJA method. The System of Objectified Judgement Analysis (SOJA) method is a model for rational drug selection. The relevant selection criteria for a certain group of drugs are defined and judged by a panel of experts and each selection criterion is given a relative weight. The more important that a selection criterion is considered, the higher the relative weight that is given to that criterion. The ideal properties for each selection criterion are determined and each drug is scored as a percentage of the score of the ideal drug for all selection criteria. The following selection criteria were used (relative weight): number of formulations (20), number of indications (20), variation in bioavailability (40), interactions (40), trough/peak ratio diastolic blood pressure lowering effect (20), efficacy (250), side-effects (150), dosage frequency (100), documentation (100) and effect on clinical endpoints (260). Ramipril showed the highest score, followed by perindopril, lisinopril and enalapril. The well documented effects on clinically relevant end points, such as cardiovascular morbidity and mortality contributed to the high score for ramipril.