Reviews on Recent Clinical Trials - Volume 10, Issue 2, 2015

Breast cancer continues to be a major health problem. Both patients and clinicians demand faster access to drugs that could result in better outcomes. In part motivated by this necessity, there has been a change in the dominant paradigm regarding how drugs become approved. Complete pathological response (pCR), understood as the absence of remanent and viable tumor after a neoadjuvant treatment, is now considered by a large proportion of the medical community as a valid surrogate. The presumption is that patients achieving pCR are less likely to develop tumor recurrence. Consequently, if a drug can improve the number of patients achieving pCR it could then obtain approval by the regulatory agencies. Pertuzumab, an anti-HER- 2 monoclonal antibody, was granted accelerated approval based on this principle. The unprecedented approval of this drug is now an example that can help us to understand the advantages but also the potential risks associated with this new approach. In this review, we will discuss the results of the two clinical trials leading to the FDA-approval of pertuzumab in the neo-adjuvant setting. We will also analyze the outcomes from long term follow up of two important neoadjuvant clinical trials, the NeoALTTO and the NOAH studies. These last ones had provided further insights regarding the magnitude, the quality as well as some limitations of the relationship between pCR and harder endpoints such as event-free or overall survival. It seems evident that the acknowledgement of pCR as a potential surrogate endpoint represents an important step in the right direction. However, it still remains controversial whether this is applicable to all subtypes of breast cancers. Additional investigations may be necessary to safely generalize this concept.

Between 20–25% of all breast cancers are diagnosed in patients younger than 50 years of age, most of whom are still premenopausal. Currently, tamoxifen is considered the standard of care for adjuvant treatment in these cases. However, in postmenopausal women, aromatase inhibitors (AIs) are a better choice. Given the superiority of AIs over tamoxifen in postmenopausal women, multiple investigators explored the potential role of AIs in premenopausal patients receiving ovarian suppression. Until very recently, available data derived from the ABCSG-12 clinical trial argued against the combination of AIs and ovarian suppression. This idea, however, may have changed with the release of the combined analysis of two clinical trials: SOFT and TEXT which evaluated the use of ovarian suppression in combination therapy. Clinicians will soon reconsider the possibility of using this strategy for premenopausal patients. Given the availability of this new data this review will analyze the consequences derived from this study, contextualize this new information within the vast available literature of anti-hormonal therapy, and discuss potential arguments in favor of and against the use of this approach.

Triple negative breast cancer (TNBC) is more prevalent in younger patients and those carrying BRCA mutations. Although the incidence of breast cancer in general has dropped during the last years, TNBC has shown a relative increase. It is recognized as a breast cancer subtype with a high risk of tumor relapse and mortality. However, patients who achieve pathological complete response (pCR) with the use of neoadjuvant treatments have better prognosis and may attain cure. The lack of effective targeted therapies makes the use of conventional chemotherapy the only alternative available to fight this disease. Since many TNBCs share at least some phenotypic characteristics with germline BRCA-mutated tumors (BRCAness) cross-linking agents, such platinum salts, are particularly useful. Recently, two randomized phase 2 clinical trials support this presumption. However, improvement in pCR rates does not come free of toxicity. Given the potential change in practice associated with the generalized use of carboplatin in the neoadjuvant setting for TNBC patients, the aim of this review is to discuss the benefits as well as the potential drawbacks linked with the use of this strategy.

Current indications for implantable cardioverter defibrillators (ICDs) in patients with channelopathies and cardiomyopathies of non-ischemic origin are mainly based on non-randomized evidence. In patients with nonischemic dilated cardiomyopathy (NIDCM), there is a tendency towards a beneficial effect on total mortality of ICD therapy in patients with significant left ventricular (LV) dysfunction. Although an important reduction in sudden cardiac death (SCD) seems to be clearly demonstrated in these patients, a net beneficial effect on total mortality is unclear mostly in cases with good functional status. Risk stratification has been changing over the last two decades in patients with hypertrophic cardiomyopathy (HCM). Its risk profile has been delineated in parallel with the beneficial effect of ICD in high risk patients. Observational results based on “appropriate” ICD interventions do support its usefulness both in primary and secondary SCD prevention in these patients. Novel risk models quantify the rate of sudden cardiac death in these patients on individual basis. Less clear risk stratification is available for cases of arrhythmogenic right ventricular cardiomyopathy (ARVC) and in other uncommon familiar cardiomyopathies. Main features of risk stratification vary among the different channelopathies (long QT syndrome -LQTS-, Brugada syndrome, etc) with great debate on the management of asymptomatic patients. For most familiar cardiomyopathies, ICD therapy is the only accepted strategy in the prevention of SCD. So far, genetic testing has a limited role in risk evaluation and management of the individual patient. This review aims to summarize these criticisms and to refine the current indications of ICD implantation in patients with cardiomyopathies and major channelopathies.

The overactive bladder syndrome and the neurogenic detrusor overactivity figure among the most impacting voiding dysfunctions with a high global prevalence and negative impacts on quality of life. Despite such urinary disorders being easily diagnosed, often based exclusively on clinical data, a large number of people complaining of urgency, frequency, nocturia and, in many cases, urinary incontinence, have their urinary condition neglected. The first line treatment with oral anticholinergics presents a high rate of dropouts over a few months of use, due absence of success or the adverse events frequently observed with this therapy. Intradetrusor botulinum toxin injection was initially used for patients with spinal cord injury and multiple sclerosis, nearly 15 years ago. Its successful results led to the injections in detrusor of botulinum toxin also in refractory idiopathic overactive bladder.

Background: It has been reported that the combination of inflammation parameters, such as albumin and C-reactive protein, in the modified Glasgow prognostic score (m-GPS) is a poor prognostic indicator in several malignancies. Here, we quantify the prognostic impact of this score and assess its value in colorectal cancer. Methods: A systematic review of electronic databases was conducted to identify publications exploring the association of m-GPS with outcome in colorectal cancer. Overall survival (OS) was the primary outcome, and cancer-specific survival (CSS), progression-free survival, and disease-free survival were secondary outcomes. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) were included in a metaanalysis. Pooled HRs were computed and weighted using generic inverse-variance and random effects modeling. All statistical tests were two-sided. Results: Nine studies, which included a total of 2,227 patients, were included in the analysis. Overall, according to multivariate analysis, m-GPS ≥1 was independently associated with an HR for OS of 1.69 (95% CI=1.4–2.04; P<0.00001), an effect observed in all stages of disease. Six studies including a total of 1,751 patients reported HR for CSS. Overall, a high m-GPS was associated with an HR for CSS of 1.84 (95% CI=1.43–2.37; P<0.00001). Conclusions: A high m-GPS is associated with poor OS in colorectal cancer. The m-GPS is a cheap and easily evaluable biomarker, and its incorporation into known prognostic scores for clinical decision making warrants further investigation in this setting.

Metastatic pancreatic cancer still represent one of the most deadly disease for which there are few therapeutic options, especially in second line and beyond setting. Nabpaclitaxel plus gemcitabine activity was demonstrated in first line setting, but there are no clear evidence suggesting its use after that. We report a retrospective data analysis of 23 patients who received nab-paclitaxel plus gemcitabine after first line treatment at our Oncology Department. We observed a significant clinical benefit (43,5%) with a median overall survival of 5 months. In addition, manageable side effects were reported. Our data, despite the small sample, seem to indicate that nab- paclitaxel plus gemcitabine is an active and well tolerated regimen even in pretreated patients.

Monoclonal antibodies (mAbs) are produced by clones of a unique parent cell which has monovalent affinity and can bind to the same epitope. The chronological breakthrough in mAbs clinical utilization was in 1975, when it becomes possible to produce mAbs to known antigens and immortalize the cell lines. However, the clinical usefulness of mAbs was hampered for many years, basically because of their immunogenicity due to the murine origin. This situation lasted until 1988 when a technique to humanize mAbs was defined. Nuclear Medicine researchers were very quick to gathered the opportunity provided by the development of mAbs. The first papers reporting the preclinical use of radiolabelled mAbs date the early 80’s soon followed by the first pivotal use in humans. However, mAbs did not gain a wide clinical use for several reasons connected to the chemistry and biochemistry of radiolabelled mAbs the emergence of clinical 18F-FDG PET. However, the “magic bullet” concept has resisted in the cultural background of Nuclear Medicine physicians for almost twenty years, and has regained importance with the development of engineered mAbs. Herein we present a selected review of preclinical and clinical studies of PET/CT with mAbs in gastrointestinal malignancies.

Diarrhea disease is one of the most important problem which leads to mortality and morbidity in under developing country. Pharmacists play an important role in providing health services to local communities for this common health issues. The purpose of our study was to assess diarrhea related attitude and knowledge of pharmacist in Iran. This study has been performed in Iranian Pharmacist Association congress in2012. This is conducted as a questionnaire base, in 100 randomly Persian pharmacists, consists of questions about demographic data of pharmacists such as age, sex, college, year of study, attitude and knowledge of pharmacists on management of acute diarrhea. Pharmacists believed that it was important to ask about the age of patients (98%), initiation (98%) and frequency (95%) of diarrhea, blood (90%) in diarrhea, other symptoms such as fever or pain (95%) as well as recent foods consumption (91%). However there was a significance differences between male and female pharmacist about their diarrhea knowledge. Among pharmacists, 75% asked about the recent travel and 63% asked about other affected family members .Most pharmacists (78) dispensed ORS for the pediatric acute diarrhea. However, some believed in recommending ORS+ antimotility drugs (9%), ORS+ antismaspolitic (11%) and ORS + antibiotics (2 %). Although iranian pharmacist were in a good attitude however the rule of periodic studies should highlighted.

Background: Topical antifungal agents along with the steroids may provide not only rapid symptomatic relief but also clearance of disease causing fungi in inflamed cutaneous mycoses (ICM). Aim: To assess the efficacy and safety of fixed dose combination (FDC) of Eberconazole nitrate 1% and Mometasone furoate 0.1% w/w cream, in subjects with ICM. Methods: This was a multi-centric, non-comparative study conducted in 155 eligible adult Indian subjects with ICM. They were treated with study medication for 21 days (D21) and followed up on day 35 (D35). Efficacy (by Investigator’s Static Global Assessment–ISGA, symptom severity scores) and safety were assessed to evaluate the therapeutic response. Results: Of 155 subjects, 129 completed the study. Lesions healed completely in 77.52% and improved markedly in 22.48% patients by D21. There was a statistically significant reduction (p< 0.001) in total symptom score (TSS) and mean severity scores of erythema, scaling and pruritus on days 7 and 21 compared to baseline. There was no treatment failure. Only 11 patients remained culture positive on D21 compared to 68 at baseline. Physicians evaluated the drug as ‘Good’ in 72% and ‘Excellent’ in 28% of subjects; adverse events were reported in 27.74% subjects and none was severe. There was a decrease in serum cortisol level in 4.52% (7/155) subjects and was considered clinically significant in three subjects. On D35, 18.55% and 24.20% subjects had greater ISGA score and TSS respectively, compared to D21. Conclusion: Tested FDC demonstrated efficacy and was well tolerated by study population. It offers an effective and safe therapeutic option for the management of ICM.