Sunitinib and other targeted therapies for renal cell carcinoma

Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years

An examination of semantic impairment in amnestic MCI and AD : What can we learn from verbal fluency?

Introduction The Verbal Fluency Test (VF) is commonly used in neuropsychology. Some studies have demonstrated a marked impairment of semantic VF compared to phonemic VF in Alzheimer’s disease (AD). Since amnestic Mild Cognitive Impairment (aMCI) is associated with increased risk of conversion to incident AD, it is relevant to examine whether a similar impairment is observed in this population. The objective of the present empirical study is to compare VF performance of aMCI patients to those of AD and elderly controls matched one-to-one for age and education. Method Ninety-six participants divided into three equal groups (N = 32: AD, aMCI and Controls) were included in this study. Participants in each group were, on average, 76 years of age and had 13 years of education. A repeated measures ANOVA with the Group (AD, aMCI, NC) as between-subject factor and the Fluency condition (“P” and “animals”) as within-subject factor was performed. T-tests and simple ANOVAs were also conducted to examine the interaction. Results There was a significant interaction between the groups and the verbal fluency condition. In AD, significantly fewer words were produced in both conditions. In contrast, participants with aMCI demonstrated a pattern similar to controls in the phonemic condition, but generated significantly fewer words in the semantic condition. Conclusion These results indicate a semantic memory impairment in aMCI revealed by a simple, commonly-used neuropsychological test. Future studies are needed to investigate if semantic fluency deficits can help predict future conversion to AD

Metastatic renal cell cancer treatments: An indirect comparison meta-analysis

Abstract Background Treatment for metastatic renal cell cancer (mRCC) has advanced dramatically with understanding of the pathogenesis of the disease. New treatment options may provide improved progression-free survival (PFS). We aimed to determine the relative effectiveness of new therapies in this field. Methods We conducted comprehensive searches of 11 electronic databases from inception to April 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, and sunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome was investigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatment comparison analysis. Results We included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1 sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS. Using indirect comparisons with interferon-α as the common comparator, we found that sunitinib was superior to both sorafenib (HR 0.58, 95% CI, 0.38–0.86, P = < 0.001) and bevacizumab + IFN-a (HR 0.75, 95% CI, 0.60–0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab +IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52–1.13, P = 0.23). Using placebo as the similar comparator, we were unable to display a significant difference between sorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58–1.12, P = 0.23). Temsirolimus provided significant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57–0.85). Conclusion New interventions for mRCC offer a favourable PFS for mRCC compared to interferon-α and placebo

Costo-Efficacia di cabozantinib nel trattamento di seconda linea del tumore a cellule renali metastatico (mRCC) in Italia:

Introduction: Renal cell carcinoma (RCC) is the most common form of kidney cancer with >30% already metastatic at diagnosis. For patients who fail tyrosine kinase inhibitor (TKI) therapy, the Italian Medical Oncology Association recommends (level IA) nivolumab and cabozantinib. The aim of this study was to compare the cost-effectiveness of cabozantinib with nivolumab for treatment of adult patients with mRCC following prior TKI therapy in Italy. Methods: A partitioned survival (area under the curve) model was developed for the Italian medical environment. Cost-effectiveness was assessed from the Italian National Healthcare Service (SSN) perspective over a 30-year time horizon (annual discount: 3% rate). In the absence of head-to-head studies, clinical evidence was based on results of network meta-analysis. Health-state-related utilities were informed by EQ-5D data from the METEOR study. Resource use and costs were obtained from published sources. Results: Treatment with cabozantinib dominates nivolumab across a 30-years time horizon. In the reference case, treatment with cabozantinib results in an incremental 0.268 quality-adjusted life years (QALY) and an incremental 0.349 life years (LY) gained with a total saving, for the Italian SSN, of €5,605 compared to nivolumab over 30 years. Cabozantinib is associated with gains in quality adjusted life years versus nivolumab, in all analyses. Results were shown to be sensitive to drug prices variation and robust when altering other parameters. Discussion: Cabozantinib represents an efficient option in the management of mRCC after initial TKI-therapy in Italy. Drug prices impact final results, and this must be carefully considered, especially considering the confidential discounts and outcome/financial-based agreements currently in place in Italy

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials

A subset of patients with metastatic renal cell carcinoma treated with sunitinib achieved long-term response (ie, progression-free survival [PFS] &gt; 18 months). Long-term responders had improved objective response rate, PFS, and overall survival versus others. Patient baseline characteristics predictive of long-term response to sunitinib were identified. Background: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) &gt; 18 months. Patients and Methods: A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months (“others”). PFS and overall survival (OS) were summarized using Kaplan–Meier methodology. Results: Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P &lt;.0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P =.0018) and greater median maximum on-study tumor shrinkage from baseline (−56.9 vs. −27.1; P &lt;.0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR. Conclusion: A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS

Long-term Safety of Sunitinib in Metastatic Renal Cell Carcinoma

Background Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive &gt;2 yr, with chronic treatment sometimes extending to ≥6 yr. Objective To analyze long-term safety with sunitinib in mRCC patients. Design, setting, and participants Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g. cytokine refractory or treatment-naïve). Outcome measurements and statistical analysis Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment. Results and limitations Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-&lt;6 mo to 42% at 5-&lt;6 yr and by cumulative analysis from 14% at 0-&lt;1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (&lt;5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients. Conclusions Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative. Patient summary More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk

Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

Background: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants: A total of 150 mRCC patients with rapidly PD on first- line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarco- matoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Pro- gression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations: Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 ever- olimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second- line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary: The present work collected data about 150 patients affected by meta- static renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases

New Prognostic factors for second-line targeted therapy (TT) in metastatic renal cell carcinoma (mRCC).

No abstract availabl

Colloquium: Theory of Drag Reduction by Polymers in Wall Bounded Turbulence

The flow of fluids in channels, pipes or ducts, as in any other wall-bounded flow (like water along the hulls of ships or air on airplanes) is hindered by a drag, which increases many-folds when the fluid flow turns from laminar to turbulent. A major technological problem is how to reduce this drag in order to minimize the expense of transporting fluids like oil in pipelines, or to move ships in the ocean. It was discovered in the mid-twentieth century that minute concentrations of polymers can reduce the drag in turbulent flows by up to 80%. While experimental knowledge had accumulated over the years, the fundamental theory of drag reduction by polymers remained elusive for a long time, with arguments raging whether this is a "skin" or a "bulk" effect. In this colloquium review we first summarize the phenomenology of drag reduction by polymers, stressing both its universal and non-universal aspects, and then proceed to review a recent theory that provides a quantitative explanation of all the known phenomenology. We treat both flexible and rod-like polymers, explaining the existence of universal properties like the Maximum Drag Reduction (MDR) asymptote, as well as non-universal cross-over phenomena that depend on the Reynolds number, on the nature of the polymer and on its concentration. Finally we also discuss other agents for drag reduction with a stress on the important example of bubbles.Comment: Invited Colloquium Paper for Reviews of Modern Physics, 24 pages, 18 Figs., submitte