Reviews on Recent Clinical Trials - Volume 9, Issue 1, 2014

Hepatitis C virus (HCV) infection affects about 160 million people worldwide. Currently, it is treated with pegylated interferon (PEG-IFN) plus ribavirin, associated with a protease inhibitor in case of genotype 1 infection. However, this combination is often contraindicated and associated with severe adverse events that limit its use in clinical practice. Several drugs active against HCV are in an advanced phase of clinical development. Among these, sofosbuvir appears one of the most promising candidates for use in association with both interferon and interferon-free combinations. This review focuses on the results of several sofosbuvir-based phase III trials that have very recently become available. These studies show that the co-administration of sofosbuvir, PEG-IFN and ribavirin for 12 weeks is associated with a very high rate of sustained virological responses (SVR) (about 90%) in naïve patients with genotypes 1, 4, 5 or 6. In patients infected by genotypes 2 or 3, the interferon-free combination of sofosbuvir and ribavirin administered for 12 weeks is associated with a SVR of 97% and 56% in naïve patients, and of 86% and 30% in experienced genotype 2 or 3 patients, respectively. The safety and tolerability profile is optimal and consistent with that of the other drugs administered in the combination (ribavirin and/or interferon). In conclusion, the recent phase III trials of sofosbuvir confirm the excellent results of phase II studies in terms of efficacy and safety and will probably open a new era in the fight against HCV.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Despite the improvement in overall survival (OS) due to new treatments and targeted therapies alone or in combination with chemotherapy up-to–date, little is known about cellular mechanisms, both of primary and acquired resistance of CRC to anti-Epidermal Growth Factor Receptor (EGFR) antibodies. EGFR is characterized by tyrosine kinase activity and occupies a key-role in the control of cellular transduction pathways. Its activation triggers both the RAS-RAF and PIK3CA pathways and is required to promote cell growth, differentiation, proliferation, and invasion. Cetuximab and panitumumab are both monoclonal antibodies (MoAbs) directed against the extracellular domain of EGFR, thus leading to inhibition of the downstream signaling pathways. Mutations in oncogene Kirsten-RAS (KRAS) are frequently associated with resistance to anti-EGFR therapy. However, a significant number of KRAS wild-type (WT) tumors fail to obtain disease control with anti-EGFR agents. Therefore, additional biomarkers of response/resistance to these drugs such as BRAF, NRAS, PIK3CA and PTEN have been investigated. This review will point attention on Neuroblastoma-RAS (NRAS) status in metastatic CRC (mCRC) patients (pts) selected for anti-EGFR therapy.

Chronic abdominal pain (CAP) is a prevalent disorder related to functional gastrointestinal disorders (FGIDs). In pediatric setting, CAP is a common presenting problem among children and adolescents ages 2 to 18 years with a median prevalence rate of 12%. It was proposed that CAP is the result of the altered pain sensation due to a dysfunction of the brain-gut axis after a complex interaction among biological, psychological and social factors. Children with CAP experience decrease in quality of life compared to children with identifiable organic disease such as inflammatory bowel disease. Despite treatment, 30% of children with CAP have long-lasting complaints with evidence that CAP is a risk factor for the occurrence of irritable bowel syndrome in adults. Efforts have subsequently been made to standardize the diagnostic criteria and adequate follow-up. CAP is associated with significative impairment with considerable impact on selfreported quality of life. The direct and indirect costs are not known in pediatric population and the access to investigations it’s frequent. A more appropriate use of Rome III criteria would allow for a clinical diagnosis. The focus of this article will be to report the updated criteria for the diagnosis, follow-up and treatment of this condition.

Fluid resuscitation with colloids is an established second line therapy for septic patients. Evidence of relative efficacy outcomes is tempered by considerations of the relative costs of the individual fluids. An assessment of recent large clinical trials was performed, resulting in a ranking in the efficacy of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) were derived and used to inform a decision analysis model comparing the effect of crystalloid, albumin and hydroxyethyl starch solutions in severe septic patients followed from hospital admission to 90 days in intensive care. The US payer perspective was used. Model inputs for costs and efficacy were derived from the peer-reviewed literature, assuming that that all fluid preparations are bio-equivalent within each class of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) data were synthesized using a Bayesian meta-analysis. Relative to crystalloid therapy, 0.21 life years were gained with albumin and 0.85 life years were lost with hydroxyethyl starch. One-way sensitivity analysis showed that the model’s outcomes were sensitive to the cost of RRT but not to the costs of the actual fluids or any other costs. We conclude that albumin may be the most cost-effective treatment in these patients when the total medical costs and iatrogenic morbidities involved in treating sepsis with fluids are considered. These results should assist and inform decision making in the choice of these drugs.

Background/Aim: The evaluation of radiotherapy toxicity in oncologic IBD patients. Defining the optimal patient and treatment factors that would be able to reduce the risk to organs. Materials and Methods: A review of all published radiotherapy trials was performed to identify the clinical and treatment factors of inflammatory bowel disease’s patients treated for different solid tumors. Results: Overall, acute (Grade ≥ 3) gastrointestinal complications attributable to RT ranged between 20-21% of the treated patients. A late Grade ≥ 3 gastrointestinal toxicity was developed in a range between 8-29%. Conclusion: A special attention should be given to the description of IBD location, activity status, concurrent chemotherapy, irradiation dose and technique, in order to minimize post-irradiation morbidity. It is not easy to distinguish late morbidity attributable to radiotherapy due to the IBD itself.

Bisphosphonates (BPs) are widely used for the treatment of a range of conditions involving bone, such as osteoporosis and bone metastases of cancer, and their efficacy has been confirmed. Nevertheless, a first case of bisphosphonate- related osteonecrosis of the jaw (BRONJ) as an adverse effect of BP treatment was reported in 2003, and several clinical studies since then have elaborated the risk, prevention and treatment of BRONJ or bisphosphonate-related osteomyelitis of the jaw (BROMJ). However, effective decision making on BP risk is hampered by a lack of accurate information for patients, physicians or dentists. Furthermore, the narrow definition of BRONJ used to date has precluded the wider development of clinical research on risk. In this review, we discuss current issues in BROMJ, with a focus on risk, prevention and treatment. In particular, we reconsider the definition of BRONJ from the standpoint of clinical evidence. Finally, we propose a new strategy for the treatment of BROMJ.