Biochemical assessment of the neurotoxicity of gold nanoparticles functionalized with colorectal cancer-targeting peptides in a rat model.

The application of gold nanoparticle-peptide conjugates as theranostic agents for colorectal cancer shows much promise. This study aimed at determining the neurotoxic impact of 14 nm gold nanoparticles (AuNPs) functionalized with colorectal cancer-targeting peptides (namely p.C, p.L or p.14) in a rat model. Brain tissue samples, obtained from Wistar rats that received a single injection of citrate-capped AuNPs, polyethylene glycol-coated (PEG) AuNPs, p.C-PEG-AuNPs, p.L-PEG-AuNPs or p.14-PEG-AuNPs, and sacrificed after 2- and 12-weeks, respectively, were analysed. Inflammation marker (tumour necrosis factor-α, interleukin-6, interleukin-1ß), oxidative stress (superoxide dismutase, catalase, glutathione peroxidase) and apoptotic biomarker (cytochrome c, caspase-3) levels were measured. Gold nanoparticle-treated groups sacrificed after 2-weeks did not exhibit any significant inflammatory, oxidative stress or apoptotic effects in brain tissue compared to the untreated control group. In brain tissue from rats that were exposed to citrate-capped AuNPs for 12-weeks, tumour necrosis factor-α and interleukin-6 levels were significantly increased compared to the untreated control. Exposure to PEG-AuNP, p.C-PEG-AuNP, p.L-PEG-AuNP and p.14-PEG-AuNP did not elicit significant toxic effects compared to the control after 12-weeks, as evidenced by the absence of inflammatory, oxidative stress and apoptotic effects in brain tissue. We thus report on the safety of PEG-coated AuNP-peptide conjugates for potential application in the diagnosis of colorectal cancer; however, exposure to citrate-capped AuNPs could induce delayed neuro-inflammation, and as such, warrants further investigation.

Radiological assessment of response and adverse events associated with novel systemic oncological therapies.

The last decade has seen a paradigm shift in medical oncology treatment with the rise of novel systemic agents, principally molecular targeted therapy and immunotherapy. These new groups of anti-cancer treatment have revolutionised the prognostic landscape for certain patient cohorts with advanced disease, and it is hoped that through ongoing extensive clinical research, significant survival benefits may be demonstrated in the majority of tumour types. However, radiological response assessment of these new agents has become more nuanced for radiologists, as the behaviour of both responding and progressing tumour burden can be more diverse than with conventional chemotherapy. Additionally, radiologists need to be aware of adverse events associated with these treatments as some side effects carry a high morbidity/mortality and may manifest radiologically before they become clinically apparent. This review discusses radiological response assessment and adverse events associated with these novel agents, which have become fundamental aspects of systemic oncological therapy.

What's the Price? Toxicities of Targeted Therapies in Breast Cancer Care.

Agents with mechanisms novel to breast cancer care have been approved to treat breast cancer. These agents include drugs that target cyclin-dependent kinases, phosphoinositide 3-kinase PI3KCA gene mutations, PARP, checkpoint regulation, and novel antibody-drug conjugates. However, these novel approaches bring a risk of toxicities quite different from those of conventional cytotoxic chemotherapy. Here, we review these agents and discuss related adverse events, with particular attention to endocrine, pulmonary, and dermatologic toxicities. Endocrine toxicities associated with novel cancer therapies for breast cancer are distinct and often present with symptoms related to the specific hormonal deficiencies and rarely hormonal excess. Given the complex and sometimes irreversible nature of these toxicities, once recognized, transdisciplinary management with an endocrinologist experienced with managing drug-related toxicities is encouraged. Drug-related pneumonitis is a serious concern with new targeted therapies. Presentation may not be easily distinguished, and a multidisciplinary team approach can optimize patient care. Heightened awareness is crucial for early detection and treatment. Management should follow recommendations provided by the National Cancer Institute Common Terminology Criteria for Adverse Events and agent-specific guidelines. Cutaneous toxicities from anticancer therapies represent a common and often poorly characterized challenge for patients with breast cancer. Although our understanding of dermatologic effects from novel therapies continues to improve, the breadth of toxicities spans all dermatologic conditions. Targeted therapies offer effective and often novel therapeutic strategies for patients with breast cancer but also bring new adverse event profiles. In this era, it will be important both to closely follow monitoring recommendations and to remain vigilant for emerging toxicities.

Taking advantage of drug resistance, a new approach in the war on cancer.

Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit.We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.

Real-World Treatment Patterns for Lung Neuroendocrine Tumors: A Claims Database Analysis.

OBJECTIVE: The aim of this study was to describe real-world lung neuroendocrine tumor (NET) treatment patterns. METHODS: This study examined cytotoxic chemotherapy (CC), somatostatin analogues (SSA), targeted therapy (TT), interferon, and liver-directed therapies in 2 US claims databases. Patients ≥18 years with ≥1 inpatient or ≥2 outpatient claims for lung NET, initiating pharmacologic treatment between July 1, 2009, and June 30, 2014, were identified and followed until the end of enrollment or study end, whichever occurred first. RESULTS: A total of 785 newly pharmacologically treated lung NET patients were identified: mean (SD) age was 58.6 (9.1) years; 54.0% were female; 78.2% started first-line therapy with CC, 18.1% with SSA, and 1.1% with TT. Mean duration of first-line treatment was 397 days for SSA, 142 days for CC, and 135 days for TT. 74.1% of patients received no pharmacological treatment beyond first-line. The most common second-line treatment was SSA. CONCLUSIONS: Most patients received CC as first-line treatment, with SSA being less common. SSA-treated patients remained on therapy for > 1 year, compared to < 5 months for CC. The high proportion of patients using chemotherapy and the low proportion receiving second-line treatment seems consistent with treatment guidelines for small cell lung cancer rather than for NET. Future studies are warranted to describe reasons for treatment choice, discontinuation, and switching.

Use of targeted therapy in patients with metastatic renal cell carcinoma: clinical and economic impact in a Canadian real-life setting.

Introduction: Outside of randomized controlled clinical trials, the understanding of the effectiveness and costs associated with targeted therapies for metastatic renal cell carcinoma (mrcc) is limited in Canada. The purpose of the present study was to use real-world prospective data to assess the effectiveness and cost of targeted therapies for patients with mrcc. Methods: The Canadian Kidney Cancer Information System, a pan-Canadian database, was used to identify prospectively collected data relating to patients with mrcc. First- and subsequent-line time to treatment termination (ttt) was determined from therapy initiation time (sunitinib or pazopanib) to discontinuation of therapy. Kaplan-Meier survival curves were used to estimate the unadjusted and adjusted overall survival (os) by treatment. Unit treatment cost was used to estimate the cost by line of treatment and the total cost of therapy for the management of patients with mrcc. Results: The study included 475 patients receiving sunitinib or pazopanib in the first-line setting. Patients were treated mostly with sunitinib (81%); 19% of patients were treated with pazopanib. The median ttt in the first line was 7.7 months for patients receiving sunitinib and 4.6 months for those receiving pazopanib (p < 0.001). The adjusted os was 32 months with sunitinib and 21 months with pazopanib (hazard ratio: 1.61; p < 0.01). The total median cost of first- and second-line treatments was $56,476 (interquartile range: $23,738-$130,447) for patients in the sunitinib group and $46,251 (interquartile range: $28,167-$91,394) for those in the pazopanib group. Conclusions: For the two therapies, os differed significantly, with a higher median os being observed in the sunitinib group. The cost of treatment was higher in the sunitinib group, which is to be expected with longer survival.

Detection of adverse drug reactions: evaluation of an automatic data processing applied in oncology performed in the French Diagnosis Related Groups database.

The aim of this study was to assess an automated detection method of serious adverse reactions induced by oral targeted therapy (OTT) in patients with cancer, performed in the French Diagnosis Related Groups (DRG) database. Patients with cancer of the Poitiers hospital who started an OTT between 2014 and 2015 were included. This study focused on adverse drug reaction which required inpatient hospitalization (ADRh ). All diagnoses coded in the DRG database for hospital stays that occurred within 3 months after OTT initiation were collected (potential ADRh ). Filters (exclusion criteria) were automatically applied on potential ADRh to exclude diagnoses that were not adverse drug reactions (false positives). A pharmacovigilance review was carried out to identify ADRh in the medical records (reported ADRh ). The sensitivity and specificity of the detection method were estimated for each filter combinations by comparison between potential and reported ADRh . This study included 129 patients. The medical records review led to identify 19 ADRh (all coded in the DRG database) in 14 patients. To maintain a 100% sensitivity of the method detection, the best specificity obtained was 58.3% (95% IC: [55.2-61.4]).The use of restrictive filters ('drug' in the diagnostic label, specific diagnosis code for adverse cancer drug reaction) resulted in a 97.8% specificity (95% IC: [96.6-98.5]) with a 38.2% sensitivity (95% IC: [23.9-55.0]). Our method has detected the third of ADRh with an excellent specificity. Complementary experimentations in pharmacovigilance centers are necessary to evaluate the interest of this tool in routine in addition to spontaneous reporting.

Treatment Patterns and Burden of Illness in Patients Initiating Targeted Therapy or Chemotherapy for Pancreatic Neuroendocrine Tumors.

OBJECTIVE: The aim of this study was to characterize treatment patterns and burden of pancreatic neuroendocrine tumors (PNET). METHODS: Using 2 claims databases, we identified patients with PNET initiating targeted therapy (everolimus, sunitinib) or chemotherapy from 2009 to 2012. The first targeted/cytotoxic therapy was considered index treatment. Treatment patterns were graphically evaluated from index treatment initiation until enrollment or study end, whichever occurred first. Disease burden was examined by index group for first follow-up year. RESULTS: In treatment pattern analyses (582 newly treated patients with PNET), 72.2% received chemotherapy index treatment, 16.2% everolimus, and 11.7% received sunitinib. Median index treatment duration was 242, 146, and 126 days for everolimus, sunitinib, and cytotoxics (P < 0.01). Sunitinib initiators switched most often followed by everolimus and cytotoxic initiators. In disease burden analyses, 338 patients met inclusion criteria, with mean age of 54.5 (standard deviation, 9.9) years, 45.6% were female, and there were no significant between-group differences. Targeted therapy initiators had more prior somatostatin analog use versus cytotoxics (53.4% vs 25.1%, P < 0.001); 72.5% had comorbidities after treatment initiation; 42.9% had 1 or more inpatient hospitalization; and 47.9% had 1 or more emergency department visit. CONCLUSIONS: Pancreatic neuroendocrine tumor treatment patterns varied; cytotoxics were more often used as early therapy than targeted agents, but for less time. Patients had high health care utilization, irrespective of treatment, potentially from burdensome symptoms and comorbidities.

Molecular Targeted Therapy in Modern Oncology: Imaging Assessment of Treatment Response and Toxicities.

Oncology is a rapidly evolving field with a shift toward personalized cancer treatment. The use of therapies targeted to the molecular features of individual tumors and the tumor microenvironment has become much more common. In this review, anti-angiogenic and other molecular targeted therapies are discussed, with a focus on typical and atypical response patterns and imaging manifestations of drug toxicities.

Skin toxicities and unmet supportive care needs of patients with cancer undergoing EGFR-inhibitor therapy / Toxische Hautreaktionen und Unterstützungsbedarf von KrebspatientInnen im Zuge einer EGFR-Antikörpertherapie. Eine deskriptive Studie

Background: Targeted therapies, such as the EGFR (epidermal growth factor receptor) inhibitor therapy, are being used to treat patients with various solid and metastatic tumours. Skin toxicities are a common side effect of this therapy. Aim: The aim of this study was to assess the effects of skin toxicities on quality of life of patients with cancer undergoing EGFR inhibitor therapy, as well as their unmet supportive care needs. Method: Embedded design. A standardised quantitative survey was administered and analysed. In addition, memos and audiotaped material of insightful conversations with the patients after survey administration were included in the analyses. Results: Among the three domains of the effects of skin toxicities on quality of life, physical symptoms (e. g. itching skin, rash) were most frequently reported to impair quality of life, while associated emotional and functional impairments were less frequently reported. Patients don't consider the management of skin toxicities to be a priority during their treatment, skin toxicities are rather perceived in context of the total symptom burden. Yet, we observed significant correlations between the assessed quality of life and unmet supportive care need domains, especially concerning physical and psychological needs. Conclusions: Although no clinically significant impairment of quality of life of patients undergoing EGFR inhibitor therapy was found, skin changes should be addressed in supportive interventions embedded in routine symptom management.

New Paradigm in Treating Cancer: Right on Target.

Cancer prevalence is increasing every year and now cancer is the third highest cause of death in developing countries. Effective anticancer treatment can prolong life and improve the patient's quality of life. Targeted therapy is a new therapeutic modality which targets specific molecules in the cancer cell and disrupts dysregulated signaling pathways involved in carcinogenesis. Since targeted therapy does not attack normal cells, its side effects are considered low compared to chemotherapy. More than 15 drugs have been approved for treatment in various human cancers. These drugs can largely be grouped into tyrosine kinase inhibitors and monoclonal antibodies. This review will focus on the most common agents within both groups.

Precision Medicine in Gastrointestinal Pathology.

CONTEXT: -Precision medicine is the promise of individualized therapy and management of patients based on their personal biology. There are now multiple global initiatives to perform whole-genome sequencing on millions of individuals. In the United States, an early program was the Million Veteran Program, and a more recent proposal in 2015 by the president of the United States is the Precision Medicine Initiative. To implement precision medicine in routine oncology care, genetic variants present in tumors need to be matched with effective clinical therapeutics. When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. OBJECTIVE: -To present the current state of precision medicine using gastrointestinal oncology as a model. We will present currently available targeted therapeutics, promising new findings in clinical genomic oncology, remaining quality issues in genomic testing, and emerging oncology clinical trial designs. DATA SOURCES: -Review of the literature including clinical genomic studies on gastrointestinal malignancies, clinical oncology trials on therapeutics targeted to molecular alterations, and emerging clinical oncology study designs. CONCLUSIONS: -Translating our ability to sequence thousands of genes into meaningful improvements in patient survival will be the challenge for the next decade.

Towards using a full spectrum of early clinical trial data: a retrospective analysis to compare potential longitudinal categorical models for molecular targeted therapies in oncology.

Following the pattern of phase I clinical trials for cytotoxic drugs, dose-finding clinical trials in oncology of molecularly targeted agents (MTA) aim at determining the maximum tolerated dose (MTD). In classical phase I clinical trials, MTD is generally defined by the number of patients with short-term major treatment toxicities (usually called dose-limiting toxicities, DLT), occurring during the first cycle of study treatment (e.g. within the first 3weeks of treatment). However, S. Postel-Vinay (2011) highlighted that half of grade 3 to 4 toxicities, usually considered as DLT, occur after the first cycle of MTA treatment. In addition, MTAs could induce other moderate (e.g. grade 2) toxicities which could be taken into account depending on their clinical importance, chronic nature and duration. Ignoring these late toxicities may lead to an underestimation of the drug toxicity and to wrong dose recommendations for phase II and III clinical trials. Some methods have been proposed, such as the time-to-event continuous reassessment method (Cheung 2000 and Mauguen 2011), to take into account the late toxicities. We suggest approaches based on longitudinal models (Doussau 2013). We compare several models for longitudinal data, such as transitional or marginal models, to take into account all relevant toxicities occurring during the entire length of the patient treatment (and not just the events within a predefined short-term time-window). These models allow the statistician to benefit from a larger amount of safety data which could potentially improve that accuracy in MTD assessment.

Changing the cost of care for chronic myeloid leukemia: the availability of generic imatinib in the USA and the EU.

Imatinib is an oral tyrosine kinase inhibitor and considered to be the most successful targeted anti-cancer agent yet developed given its substantial efficacy in treating chronic myeloid leukemia (CML) and other malignant diseases. In the USA and the European Union (EU), Novartis' composition of matter patent on imatinib will expire in 2016. The potential impact on health system spending levels for CML after generic imatinib becomes available is the subject of significant interest among stakeholders. The extent of the potential savings largely depends on whether and to what extent prices decline and use stays the same or even increases. These are also empirical questions since the likely spending implications following generic imatinib's availability are predicated on multiple factors: physicians' willingness to prescribe generic imatinib, molecule characteristics, and health system priorities. This article discusses each of these issues in turn. We then review their implications for the development of country-specific cost-effectiveness models to predict the implications for cost and quality of care from generic imatinib.

Fluid retention associated with imatinib treatment in patients with gastrointestinal stromal tumor: quantitative radiologic assessment and implications for management.

OBJECTIVE: We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. MATERIALS AND METHODS: In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. RESULTS: The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. CONCLUSION: Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management.

QTc prolongation induced by targeted biotherapies used in clinical practice and under investigation: a comprehensive review.

In anticancer drug development, there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can influence decision making during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. In this comprehensive review, we will analyze potential effects on QTc prolongations of targeted agents approved by regulatory agencies and under investigation. A thoughtful risk management plan was generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development program essential for oncology agents with cardiac safety concerns.

Assessment and management of gastrointestinal toxicities and lab abnormalities related to targeted therapy.

OBJECTIVES: To identify the most common gastrointestinal toxicities and laboratory abnormalities associated with targeted therapies, as well as the assessment and management necessary to minimize adverse events related to these side effects. DATA SOURCES: Peer-reviewed articles and national guidelines for oncology practice. CONCLUSION: Common toxicities of diarrhea, mucositis, and laboratory abnormalities are often associated with the use of targeted agents and require skilled assessment and early management interventions to prevent severe complications or treatment interruption. IMPLICATIONS FOR NURSING PRACTICE: Emerging trends focused on targeted therapy increase the importance of the oncology nurse's role in assessment, education, and evidenced-based recommendations to meet patient needs.

Role of toxicogenomics in the development of safe, efficacious and novel anti-microbial therapies.

Over the last two decades, occurrence of bacterial resistance to commonly used antibiotics has necessitated the development of safer and more potent anti-microbial drugs. However, the development of novel antibiotics is severely hampered by adverse side effects, such as drug-induced liver toxicity. Several antibacterial drugs are known to have the potential to cause severe liver damage. The major challenge in developing novel anti-microbial drugs is to predict, with certain amount of probability, the drug-induced toxicity during the pre-clinical stages, thus optimizing and reducing the time and cost of drug development. Toxicogenomics approach is generally used to harness the potential of genomic tools and to understand the physiological basis of drug-induced toxicity based on the in-depth analysis of Metagenomic data sets, i.e., transcriptional, translational or metabolomic profiles. Toxicogenomics, therefore, represents a new paradigm in the drug development process, and is anticipated to play an invaluable role in future to develop safe and efficacious medicines, by predicting the toxic potential of a new chemical entity (NCE) in early stages of drug discovery. This review examines the toxicogenomic approach in predicting the safety/toxicity of novel anti-microbial drugs, and analyses the promises, pitfalls and challenges of applying this powerful technology to the drug development process.

Natalizumab: a review of its use in the management of relapsing-remitting multiple sclerosis.

Natalizumab (Tysabri®) is a humanized monoclonal antibody against the α4 chain of integrins and was the first targeted therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab acts as a selective adhesion molecule antagonist, which binds very late antigen (VLA)-4 and inhibits the translocation of activated VLA-4-expressing leukocytes across the blood-brain barrier into the CNS. In a pivotal phase III clinical trial, natalizumab 300 mg intravenously every 4 weeks for 2 years in adults with RRMS significantly reduced the annualized relapse rate and the risk of sustained progression of disability compared with placebo, as well as significantly increasing the proportion of relapse-free patients at 1 and 2 years. Natalizumab also significantly reduced the number of T2-hyperintense, gadolinium-enhancing and T1-hypointense lesions on magnetic resonance imaging, and significantly reduced the volume of T2-hyperintense and T1-hypointense lesions compared with placebo. Natalizumab recipients generally experienced improved health-related quality of life at 1-2 years. Natalizumab was generally well tolerated in pivotal trials. The only adverse events that were more frequent with natalizumab monotherapy than with placebo were fatigue and allergic reactions. The main safety and tolerability issue with natalizumab is the incidence of progressive multifocal leukoencephalopathy (PML). As long as the risk of PML is managed effectively, natalizumab is a valuable therapeutic option for adults with highly active relapsing forms of multiple sclerosis.