Reviews on Recent Clinical Trials - Volume 3, Issue 2, 2008

End stage kidney disease (ESKD) is associated with a 10- to 20-fold increased risk of cardiovascular mortality compared with age- and sex-matched controls without CKD. In spite of this marked increase in risk, the vast majority of cardiovascular intervention clinical trials to date have specifically excluded subjects with CKD. The aim of this paper is to critically review the recently published clinical trial evidence that cardiac outcomes in CKD patients are modified by cardiovascular risk factor interventions, including erythropoiesis stimulating agent therapy (US Normal Hematocrit, CHOIR and CREATE trials), statins (PPP, 4D and ALERT), fibrates (VAHIT), folic acid (ASFAST, US folic acid trial, HOST), anti-oxidative stress therapy (SPACE, HOPE and ATIC), N-acetylcysteine, sevelamer (D-COR), cinacalcet (Cunningham meta-analysis), carvedilol, angiotensin converting enzyme inhibitor (FOSIDIAL), telmisartan, aspirin (HOT study re-analysis) and multidisciplinary multiple cardiovascular risk factor intervention clinics (LANDMARK). Although none of these studies could be considered conclusive, the negative trials to date should raise significant concerns about the heavy reliance of current clinical practice guidelines on extrapolation of findings from cardiovascular intervention trials in the general population. It may be that cardiovascular disease in dialysis populations is less amenable to intervention, either because of the advanced stage of CKD or because the pathogenesis of cardiovascular disease in CKD patients is different to that in the general population. Further large, wellconducted, multi-centre randomised controlled trials in this area are urgently required.

Widespread reliance on animal models during preclinical research and toxicity testing assumes their reasonable predictivity for human outcomes. However, of 20 published systematic reviews examining human clinical utility, located during a comprehensive literature search, animal models demonstrated significant potential to contribute toward the development of clinical interventions in only two cases, one of which was contentious. Included were experiments expected by ethics committees to lead to medical advances, highlycited experiments published in major journals, and chimpanzee experiments—the species most generally predictive of human outcomes. Seven additional reviews failed to demonstrate utility in reliably predicting human toxicological outcomes such as carcinogenicity and teratogenicity. Results in animal models were frequently equivocal, or inconsistent with human outcomes. Consequently, animal data may not generally be considered useful for these purposes. Regulatory acceptance of non-animal models is normally conditional on formal scientific validation. In contrast, animal models are simply assumed to be predictive of human outcomes. These results demonstrate the invalidity of such assumptions. The poor human clinical and toxicological utility of animal models, combined with their generally substantial animal welfare and economic costs, necessitate considerably greater rigor within animal studies, and justify a ban on the use of animal models lacking scientific data clearly establishing their human predictivity or utility.

Objectives: To address the rationale for anti-angiogenic targeted therapies in advanced RCC. Methods: We reviewed the international recent literature, using Pubmed search. Results: RCC is genetically linked to factors regulating angiogenesis, in particular vascular endothelial growth factor (VEGF). Sunitinib is a multitarget receptor tyrosine-kinase (TK) inhibitor, acting on VEGF receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR). Sorafenib is an oral multikinase inhibitor (VEGFR and PDGFR) showing also inhibitors effect on the Raf system. Phase I trials showed no life threatening toxicities relates to these agents. Phase II and phase III trials showed that these antiangiogenic agents are effective in the treatment of advanced RCC, mainly in cytokine refractory metastatic RCC. Survival benefits exist in particular when advanced RCC patients undergo cytoreductive nephrectomies before the initiation of the systemic therapy. To better use this kind of targeted therapy in advanced RCC, different points must be developed: the identification of clinical characteristic of RCC able to predict outcomes and responses to therapy; differences among different compounds; advantages of combination or sequential therapies. Conlusions: Targeted therapy with Sunitinib and Sorafenib has been approved to FDA and is revolutioning how we clinically approach advanced RCC.

In recent years, the success of human oocyte cryopreservation has improved dramatically. Currently, there are a couple hundred babies born worldwide with the use of cryopreserved oocytes. The oocyte survival after freezing/thawing process is in the range of 70-95%, comparable to embryo cryopreservation, depending on techniques used. With the change of cryopreservation media to cholinebase, the outcome of oocyte cryopreservation has shown to improve. Moreover, new freezing technique, vitrification, has been developed resulting in better survival outcome without the need of sophisticated equipment. Fertilization rate of cryopreserved oocytes with ICSI is approximately 70-90%, comparable to that of fresh oocytes. However, the pregnancy rate varies from 10-40%. The main reason of varying outcome is the difference in technique of cryopreservation. Clinically, oocyte cryopreservation can be applied to preserve fertility of female cancer survivors, to delay childbearing and to quarantine oocytes in oocyte donor program. Oocyte cryopreservation can also be performed as an alternative to embryo cryopreservation due to ethical consideration.

Despite improvements in survival after the introduction of chemo-radiotherapy (CRT) in the treatment of patients with cervical cancer, loco-regional control of this disease continues to be a major problem. The present article reviews current and emerging therapeutic strategies combining CRT with novel molecular agents that specifically target the abnormal tumor microenvironment, with the aim of improving local control and survival in patients with locally advanced cervix cancer. The evidence supporting the biological rational to combine novel non-cytotoxic agents with CRT is strong, and drugs targeting different molecular pathways are currently under clinical development (EGFR inhibitors, COX-2 inhibitors, hypoxia targeted agents, etc). Early pre-clinical and clinical strategies also favor the use of vascular-targeted agents with the aim to normalize the abnormal tumor vasculature, increase tumor oxygenation, and reduce interstitial fluid pressure (IFP). The integration of these novel targeted therapies with CRT in clinical trials is discussed, as well as new and promising biomarkers to test drug activity.

Patients with carcinoma of the exocrine pancreas have especially poor prognosis with a five-year survival rate of <1% and a median survival of 4-6 months. Pancreatic carcinoma is a systemic disease, insensitive to radiotherapy and mostly to chemotherapy. Accordingly, new treatment modalities are worth being investigated. One of the promising approaches is immunotherapy. Several phase I/II trials that have been published show interesting results, whereupon antibody-based strategies seem to fail and unspecific stimulation or vaccination with peptides look encouraging. Furthermore, phase II trials dealing with combination therapies are highly promising. One of them, a combination of chemoradiotherapy plus interferon-alpha is currently tested in a randomized phase III trial. As most of the trials had enrolled only limited numbers of patients and most of the trials were not conducted and/or reported according to the new standards it is difficult to draw final conclusions from the discussed trials. Immuno-monitoring was performed only in 40% of the discussed publications. In all cases immune responses were observed and correlation with the clinical outcome is discussed. Immunotherapy of pancreatic adenocarcinoma and especially combination therapies including immunotherapy is an up-and-coming approach and needs to be investigated in well conducted phase III randomized controlled trials accompanied by appropriate immunomonitoring.

Objectives- The aim of our study was to test the effect of a more viscous compound than existent hyaluronic acid formulation in helping to restore a defective glycosaminoglycan layer, and therefore in improving Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS) symptoms when administered intravesically in IC/PBS patients. Methods- A total of 23 female patients completed the study. Patients received endovesical administration of hyaluronic acid and chondroitin sulfate in normal saline, 40 ml, weekly for 12 weeks and then bi-weekly for 6 months, if there was initial response. Results- After 12 weeks treatment both Interstitial Cystitis Symptom and Problem Index (ICSI/ICPI), pelvic pain and Urgency/Frequency Symptom Scale (PUF) showed a mean significant improvement, which was maintained thereafter. The average number of voidings and mean voiding volumes revealed significant improvement after the 12 weeks' treatment period, with a significant reduction and increase, respectively. Mean voiding volume increased from 143 ml to 191, which apparently was not reflected in a corresponding reduction of number of daily voids (from 15,5 to 14). VAS values decreased from 5,4 to 3,6 (pain) and from 6,0 to 3,5 (urgency) after the treatment cycle, showing a significant improvement. Conclusions- In our preliminary experience, the administration of intravesical hyaluronic acid plus chondroitine sulphate appears to be a safe and efficacious method of treatment in IC/PBS.

Allogeneic haemopoietic stem cell transplantation (HSCT) is a potentially curative option for a wide range of haematological diseases. Graft versus Host Disease (GVHD) is an inflammatory disorder in the recipient, which accounts for significant morbidity and mortality after allogeneic HSCT and directly limits the success of this procedure. Current treatment options for GVHD include intense immunosuppression, which in turn has associated side effects, an increased risk of infective complications, and a potential for increased relapse of haematological malignancy. A major benefit of allogeneic HSCT arises from reduced relapse rate of the underlying disease, which is believed to be due to the graft versus tumour or graft versus leukaemia (GVL) effect where donor immune cells recognize recipient tumour antigens. It is well established that GVL is linked to the occurrence of GVHD. Effective prophylaxis of GVHD while allowing some GVL effect is an important, yet currently elusive, therapeutic goal in HSCT. Strategies to prevent GVHD include T-cell depletion, immunosuppression, gut decontamination and appropriate donor selection. Cyclosporin (CsA) and/or methotrexate (MTX) have formed the basis of many GVHD prophylaxis strategies with no major advances on this gold standard for over twenty years. This review seeks to outline the most effective methods for the prevention of GVHD with a particular emphasis on large randomised trials. Evidence on standard regimens, appropriate dosing and emerging strategies for GVHD prophylaxis for both myeloablative and reduced intensity conditioning HSCT will be explored.

Ibandronate is a potent bisphosphonate which has been most thoroughly assessed in benign bone disease for use in the management of postmenopausal osteoporosis. Its use in corticosteroid-induced osteoporosis, Paget's disease and uncommon benign bone conditions such as localised transient osteoporosis (or bone marrow oedema syndrome) and sternocostoclavicular hyperostosis has also been explored. Recent randomised controlled trial evidence suggests that intermittent high dosage oral ibandronate may be as efficacious as a daily low dose regime for the treatment of post-menopausal osteoporosis, with only a mild increase in adverse events. Movement towards an extended gap between doses has implications for patient compliance and adherence and thus potential benefits for fracture prevention. This review aims to provide an overview of the evidence from randomised controlled trials in humans for the use of ibandronate in benign bone diseases. This includes a discussion of the development program and dosage regimens for the prevention and treatment of postmenopausal osteoporosis, as well as the use of ibandronate in corticosteroid induced osteoporosis, Paget's disease localised transient osteoporosis and sternoclavicular hyperostosis. Adverse effects and long-term safety data will also be reviewed.

Small cell lung carcinoma comprises approximately 10-20% of all lung cancers. At the time of diagnosis, 20-30% of patients have what is considered limited stage disease. Historically, chemotherapy has been the mainstay of treatment for small cell lung cancer, but more recent evidence from large meta-analyses have established the local control and overall survival advantages conferred by the addition of external beam thoracic radiotherapy in combination with chemotherapy for limited stage disease along with prophylactic cranial irradiation for complete responders. At present, radiotherapy is recommended to commence in concurrentoe with an earlier cycle of chemotherapy. Despite the established role of thoracic radiotherapy combined with chemotherapy for patients with limited stage disease, the optimal radiotherapy dose-fractionation schedule is still undefined. Recent investigational radiotherapy approaches applied to limited stage small cell lung cancer patients include hyperfractionated radiotherapy, dose-escalated daily radiotherapy, and hypofractionation. While several chemotherapy regimens and targeted systemic agents have been investigated in small numbers of small cell lung cancer patients, cisplatin with etoposide remains the current standard chemotherapy regimen for this cancer.