Esophagogastric cancer: integration of targeted therapies into systemic chemotherapy.

Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER-2 status in the tumor. Trastuzumab in combination with cisplatin/5-fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer.

Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis.

BACKGROUND Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. METHODS This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. RESULTS Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6 %) patients were male, 64 (48.1 %) had pancreatic NET, 23 (17.3 %) had ECOG PS ≥2, 41 (30.8 %) had functioning tumours, 63 (47.7 %) underwent surgery of the primary tumour, 45 (33.8 %) had received prior chemotherapy, and 115 (86.5 %) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5 % (6 months), 68.6 % (12 months) and 57.0 % (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3 % (6 months), 73.0 % (12 months), and 67.4 % (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95 % CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. CONCLUSIONS The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.

Successes and limitations of targeted therapies in renal cell carcinoma.

Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results.

Review of therapeutic drug monitoring of anticancer drugs part two - Targeted therapies.

Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration-time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.

Hémato-oncologie pédiatrique: de la biologie cellulaire aux traitements ciblés et individualisés [Pediatric hemato-oncology: from cellular biology to individualized targeted therapies].

Progresses in pediatric oncology over the last decades have been dramatic and allow current cure rates above 80%. There are mainly due to multicentre clinical trials aiming at optimizing chemotherapy protocols as well as local therapies in a stepwise approach. Most of the new anticancer drugs currently in development are based on targeted therapies, directed to specific targets present only in or on tumor cells, like growth factor receptors, mechanisms involved in proliferation, DNA repair, apoptosis, tumor invasion or angiogenesis. Concerning bone marrow transplantation also, new strategic approaches are in advanced development. They aim at reducing treatment induced toxicity and enhancing efficacy at the same time. This short paper would like to point out these new technologies, which should be known by the general practitioner.

Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era.

PURPOSE OF REVIEW: Many chemotherapeutic drugs, including fluoropyrimidines, platinums, CPT-11, taxanes and adriamycin have single-agent activity in advanced gastric cancer. Although combination chemotherapy has been shown to be more effective than single agents, response rates between 30 and 50% have not fulfilled their promise as progression-free survival from the best combinations ranges between 3 and 7 months and overall survival between 8 and 11 months. The development of targeted therapies in gastric cancer clearly stays behind the integration of these novel agents into new treatment concepts for patients with colorectal cancer. This review summarizes the experience and major recent advances in the development of targeted therapies in advanced gastric cancer. RECENT FINDINGS: Recent publications on targeted therapies in gastric cancer are limited to nonrandomized phase I or II trials. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors epidermal growth factor receptor 1 and HER2. SUMMARY: Adequately powered, randomized phase III trials are necessary to define the clinical role of targeted therapies in advanced gastric cancer. Biomarker studies to correlate with treatment outcomes will be critical to identify patients who benefit most from chemotherapy and targeted therapy.

Novel targeted therapies for eosinophilic disorders

Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders.

Novel targeted therapies for eosinophil-associated diseases and allergy.

Eosinophil-associated diseases often present with life-threatening manifestations and/or chronic organ damage. Currently available therapeutic options are limited to a few drugs that often have to be prescribed on a lifelong basis to keep eosinophil counts under control. In the past 10 years, treatment options and outcomes in patients with clonal eosinophilic and other eosinophilic disorders have improved substantially. Several new targeted therapies have emerged, addressing different aspects of eosinophil expansion and inflammation. In this review, we discuss available and currently tested agents as well as new strategies and drug targets relevant to both primary and secondary eosinophilic diseases, including allergic disorders.

NOX3-Targeted Therapies for Inner Ear Pathologies

Inner ear pathologies are associated with major morbidity and loss of life quality in affected patients. In many of these conditions, production of reactive oxygen-species (ROS) is thought to be a key pathological mechanism. While the sources of ROS are complex (including for example mitochondria), there is increasing evidence that activation of NOX enzymes, in particular NOX3, plays a key role. NOX3 is a multi-subunit NADPH oxidase, functionally and structurally closely related to NOX1 and NOX2. In both the vestibular and the cochlear compartments of the inner ear, high levels of NOX3 mRNA are expressed. In NOX3 mutant mice, the vestibular function is perturbed due to a lack of otoconia, while only minor alterations of hearing have been documented. However, there is increasing evidence that activation of NOX3 through drugs, noise and probably also aging, leads to hearing loss. Thus, NOX3 is an interesting target to treat and prevent inner ear pathologies and a few first animal models based on drug - or molecular therapy have been reported. So far however, there are no specific NOX3 inhibitors with a documented penetration into the inner ear. Nevertheless, certain antioxidants and non-specific NOX inhibitors diminish hearing loss in animal models. Development of small molecules inhibitors or molecular strategies against NOX3 could improve specificity and efficiency of redox-targeted treatments. In this review, we will discuss arguments for the involvement of NOX3 in inner ear pathologies and therapeutic approaches to target NOX3 activity.

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.

Targeted therapies for small cell lung cancer: Where do we stand?

Small cell lung cancer (SCLC) accounts for 15% of lung cancer cases and is associated with a dismal prognosis. Standard therapeutic regimens have been improved over the past decades, but without a major impact on patient survival. The development of targeted therapies based on a better understanding of the molecular basis of the disease is urgently needed. At the genetic level, SCLC appears very heterogenous, although somatic mutations targeting classical oncogenes and tumor suppressors have been reported. SCLC also possesses somatic mutations in many other cancer genes, including transcription factors, enzymes involved in chromatin modification, receptor tyrosine kinases and their downstream signaling components. Several avenues have been explored to develop targeted therapies for SCLC. So far, however, there has been limited success with these targeted approaches in clinical trials. Further progress in the optimization of targeted therapies for SCLC will require the development of more personalized approaches for the patients.