EAU guidelines on renal cell carcinoma: the 2010 update. Methods for Development of the European Commission Initiative on Breast Cancer Guidelines A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma Systemic Therapy for Non-Clear Cell Renal Cell Carcinoma. Effect of temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies Prioritization of Research Addressing Management Strategies for Ductal Carcinoma In Situ Key Steps in Conducting Systematic Reviews for Underpinning Clinical Practice Guidelines: Methodology of the European Association of Urology. A phase III, randomized, controlled study to compare tivozanib with sorafenib in patients (pts) with advanced renal cell carcinoma (RCC). A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802 Sorafenib treatment of advanced renal cell carcinoma patients in daily practice: the large international PREDICT study. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Synopsis of the 2017 U.S. Department of Veterans Affairs/U.S. Department of Defense Clinical Practice Guideline: Management of Type 2 Diabetes Mellitus FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Phase II Trial and Correlative Genomic Analysis of Everolimus Plus Bevacizumab in Advanced Non-Clear Cell Renal Cell Carcinoma. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Characterization of indeterminate renal masses with molecular imaging: how do we turn potential into reality? Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Systemic therapy in the curative treatment of head-and-neck squamous cell cancer: Cancer Care Ontario clinical practice guideline. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. Depressive Symptoms and Cortisol Rhythmicity Predict Survival in Patients with Renal Cell Carcinoma: Role of Inflammatory Signaling Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. The use of sunitinib in renal cell carcinoma: where are we now?
CONTEXT AND OBJECTIVES The European Association of Urology Guideline Group for renal cell carcinoma ( RCC ) has prepared these guidelines to help clinicians assess the current evidence -based management of RCC and to incorporate the present recommendations into daily clinical practice . EVIDENCE ACQUISITION The recommendations provided in the current up date d guidelines are based on a thorough review of available RCC guidelines and review articles combined with a systematic literature search using Medline and the Cochrane Central Register of Controlled Trials . EVIDENCE SYNTHESIS A number of recent prospect i ve r and omised studies concerning RCC are now available with a high level of evidence , whereas earlier publications were based on retrospective analyses , including some larger multicentre validation studies , meta-analyses , and well- design ed controlled studies . CONCLUSIONS These guidelines contain information for the treatment of an individual patient according to a current st and ardised general approach . Up date d recommendations concerning diagnosis , treatment , and follow-up can improve the clinical h and ling of patients with RCC In December 2003 , the European Council identified best practice as key for ensuring development of high- quality cancer-screening programs . To support national policies on cancer control , the European Union institutions progressed several initiatives on cancer . The European Commission ( EC ) Initiative on Breast Cancer ( ECIBC ) is the most recent of these projects and the most implementation driven . Within this initiative , the European Guidelines for Breast Cancer Screening and Diagnosis ( in short , European Breast Guidelines ) are being developed ( http://ecibc.jrc.ec.europa.eu/ ) . Guidelines are approaches to generally improve prevention , diagnosis , treatment , and follow-up of diseases , overcoming inappropriate variations by providing recommendations for best care . The new era of guidelines promises recommendations that are based on the best available evidence summarized in systematic review s while providing the necessary flexibility needed to individualize decisions . The best methods for development of practice guidelines have experienced intense elaboration and attention during the past decades ( 17 ) . The impetus for this attention has been the change from expert- or consensus-based to evidence -based health care recommendations . Although this change in terminology should express the shift from un systematic development of guidelines to systematic and trustworthy recommendations , it is often misunderstood and misconstrued as meaning that experts are now meaningless in the process or as if consensus through discussion is a matter of the past . Neither is correct . Experts from various disciplines and consensus as a result of deliberation remain a mainstay of health care guideline development ( 810 ) . These experts are responsible for prioritization of questions that should be addressed in guidelines ; judgments that result from interpretation of evidence , including the rating of the certainty of the available evidence ; and decisions about how the judgments on the different criteria bear on recommendations . What has changed over time in guideline development are the rules , the structure and explicitness of the process , and the guideline product . Indeed , review s of guideline development methodology and how guidelines can be improved have led to more structured and documented processes that allow a reduction of bias and provide balanced views of appropriately composed guideline panels ( 2 , 5 , 6 ) . Core components for trustworthy guideline development ( 13 , 5 , 7 , 11 ) include that guidelines be developed by a knowledgeable , multidisciplinary panel of experts and representatives from key affected groups ; be based on a systematic review of the existing evidence ; consider important patient subgroups and patient preferences as appropriate ; be based on an explicit and transparent process that minimizes distortions , biases , and conflicts of interest ( 12 ) ; provide a clear explanation of the logical relationships between alternative care options and health outcomes and provide ratings of both the quality of evidence and the strength of the recommendations ( 1316 ) ; and be reconsidered and revised as appropriate when important new evidence warrants modifications . In addition , greater transparency in linking the considered research evidence and the recommendations , as well as the requirement of making structured expert judgments , represents a shift in the guideline development paradigm ( 5 , 11 , 1719 ) . At the same time , developing guidelines for a large number of member states and those that aim to adapt the guidelines poses challenges , such as the feasibility of implementing strategies that may exist in some member countries but not others ( for example , organized population -based screening in Italy but not Greece ) . Addressing these challenges requires considerations that extend beyond strictly clinical efforts in guideline development and mastering the many factors that influence recommendations and their implementation . This article describes the rationale , methods , and processes the ECIBC has adopted to develop the European Breast Guidelines in the context of evolving international st and ards . It also describes an innovative approach to presenting , disseminating , and accelerating implementation of recommendations . Guideline Methodology and Development To adhere to the core requirements for guideline development , the EC has taken several steps . First , it selected , via an open call ( https://ecibc.jrc.ec.europa.eu/ guidelines -team ) , a panel with broad representation of expertise , knowledge , and background , which includes patients , health care professionals , epidemiologists , guideline method ologists , and others ( Appendix ) . These individuals voluntarily participate in the ECIBC and compose the guidelines development group ( GDG ) . Second , it ensured that all recommendations were supported by systematic review s of the evidence conducted by independent scientists from Cochrane Iberoamricathe systematic review team (SRT)following st and ard Cochrane Collaboration methods ( 20 , 21 ) . Third , because this is a women-centered initiative , we included women advocates in the GDG as full voting guideline group members . We separately considered important subgroups of women during recommendation development ( for example , different age groups ) , and we specifically focused on evidence that supports best ways of communicating this information to women to inform their decisions . Fourth , we applied EC conflict of interest rules ( http://ecibc.jrc.ec.europa.eu/rules ) , which are consistent with international recommendations , and used GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) Evidence to Decision ( EtD ) frameworks to minimize the influence of competing interests on the recommendations ( 12 , 17 , 18 ) . These EtD frameworks help guideline panels use evidence in a structured , transparent way to inform decisions with a series of criteria , such as anticipated harms and benefits of the options considered , the certainty of the evidence for those effects , and the costs and feasibility of the options , to help them reach their decision . Fifth , using the GRADE approach to guideline development and its EtD frameworks , we focused our questions and recommendations on outcomes that matter to women and provided a rating of the certainty or quality of evidence and the strength of recommendations that is widely accepted as the reference st and ard ( Figures 1 and 2 ) . Sixth , our evidence review s are up to date when the recommendations are formulated , and we engage in international stakeholder feedback to ensure that recommendations remain timely and relevant to public health and clinical practice . The ECIBC is committed to review ing and updating the recommendations as required when new evidence becomes available . The general process is explained in Figure 3 and is based on the Guidelines International NetworkMcMaster Guideline Development Checklist ( https://hei grade .mcmaster.ca/ guideline -development/using-checklist ) ( 5 ) . Figure 1 . According to GRADE , certainty , quality , strength of evidence , or confidence in the estimate of effect is determined on the basis of a systematic review of the evidence for each outcome ( based on the domains risk of bias , indirectness , imprecision , inconsistency , and publication bias that lower certainty and , usually only for nonr and omized studies , large effects , doseresponse relations and opposing plausible residual confounding that may increase the certainty ) . For recommendations , the overall certainty is determined across outcomes based on the lowest certainty outcome among those critical for decision making for the specific context . The guidelines development group applies the GRADE Evidence -to-Decision frameworks to make recommendations that are made available on the European Commission Web site . ( Reproduced from reference 15 , with permission from Schnemann HJ . ) . GRADE = Grading of Recommendations Assessment , Development and Evaluation . Figure 2 . GRADE EtD frameworks . The GRADE EtD frameworks as available in the GRADE pro software ( www . grade pro.org ) . They help with structuring the entire guideline process into 4 sections and support the conduct of guideline group meetings , presentation , and implementation . They clarify the perspective that is taken by the guideline panel or decision maker and the type of question that is asked in the question section . The section on assessment includes the criteria if the problem is a priority , the balance of health benefits and harms , values and preferences related to the outcomes , cost , re sources and cost-effectiveness , equity , acceptability , and feasibility . Conclusions provide the decision or recommendation with a justification and implementation , as well as research considerations . The presentation function supports the conduct of guideline group meetings and facilitates the output of EtD frameworks to other implementation tools , such as Web sites , h and -held apps , and interactive decision aids . EtD = Evidence to Decision ; GRADE = Grading of Recommendations Assessment , Development and Evaluation ; HTA = health technology assessment ; PICO = population , intervention , comparators , and outcomes . Figure 3 . Approach to guideline development used by the European Commission Initiative on Breast Cancer . The European Commission JRC has oversight of the organization , budgeting , planning , and training . The JRC also manages conflicts of interest , documents all aspects of the work , and manages the membership and group processes . The guideline development group and JRC formulate the questions and work with the systematic review team on identifying and assessing the evidence . The guidelines development group is responsible for developing the recommendations . The JRC is responsible for most other aspects as described in the figure under dissemination , implementation , and updating . JRC = Joint Research Centre ; PICO = population , intervention , comparator , and outcomes . ( Reproduced with adaptation to the JRC process from Lessons Learned Our results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from pre clinical models . Because of toxicity and lack of efficacy , BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma . Background . Allosteric inhibitors of the mammalian target of rapamycin complex 1 ( mTORC1 ) are approved for advanced renal cell carcinoma ( RCC ) . Pre clinical models have suggested that dual inhibition of phosphatidylinositol 3-kinase ( PI3 K ) and mTOR kinase may establish superior anticancer effect . We aim ed to establish safety for BEZ235 , a potent inhibitor of both PI3 K and mTOR , in advanced RCC . Methods . Patients with advanced RCC who had previously failed st and ard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity . Primary endpoints were to identify the maximally tolerated dose ( MTD ) and to determine the recommended dose for the phase II study . Results . The study was terminated early because of high incidence of dose-limiting toxicities ( DLTs ) across all dose levels tested . Ten patients were treated with BEZ235—six  with clear cell and four with non-clear cell subtypes . Five of these patients suffered DLTs : 2 of 2 patients in the original 400 mg b.i.d . cohort , 1 of 6 in the 200 mg b.i.d . cohort , and 2 of 2 in the 300 mg b.i.d . cohort . DLTs included fatigue , rash , nausea and vomiting , diarrhea , mucositis , anorexia , and dysgeusia .  Five patients were evaluable for response : Two had stable disease as best response , and three had progressive disease . Conclusion . BEZ235 twice daily result ed in significant toxicity without objective responses ; further development of this compound will not be pursued in this disease Treatment options for metastatic clear cell renal cell carcinoma ( ccRCC ) have evolved markedly over the past decade , with multiple targeted therapies approved for the disease . In contrast , little improvement has been made in the management of metastatic non-clear cell RCC ( nccRCC ) . Non-clear cell disease is an umbrella term that encompasses multiple biologically distinct entities , including but not limited to papillary , chromophobe , and sarcomatoid RCC . To date , prospect i ve studies have largely explored treatments for ccRCC ( e.g. , VEGF- and mTOR-directed therapies ) in trials that aggregate non-clear cell histologies . However , the studies do not acknowledge the varying biology of each non-clear cell subtype . Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies . An example of this is SWOG 1500 , a r and omized phase II study that will compare a  VEGF-inhibitor  to one of three  MET-directed therapies  in patients with metastatic papillary RCC . Until the biologic diversity of nccRCC is appreciated , outcomes are likely to remain dismal Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma ( ARCC ) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus ( Torisel ™ ) or interferon-α ( IFN ) .  Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN ( 3 million units [ MU ] subcutaneously three times weekly , escalating to 18 MU ) or temsirolimus ( 25 mg intravenously weekly ) . Results Approximately 80 % of patients had clear cell and 20 % of patients had other histologies , the majority of which were papillary . Patients with clear cell and other RCC histologies , treated with temsirolimus , demonstrated comparable median overall and progression-free survival . In contrast , patients with other RCC histologies , treated with IFN , demonstrated shorter median overall and progression-free survival than patients with clear cell RCC . Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology . For patients treated with temsirolimus , 59 % with clear cell and 68 % with other RCC histologies experienced tumor reductions . For patients treated with IFN , 35 % with clear cell and 14 % with other RCC histologies had tumor reductions . However , temsirolimus did not appear to improve the objective response rate compared to IFN . Temsirolimus result ed in a superior clinical benefit rate compared with IFN , regardless of tumor histology . Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can , therefore , be used for the treatment of all types of RCC Ductal carcinoma in situ ( DCIS ) is a condition in which abnormal cells line the milk ducts of the breast but have not invaded the underlying breast tissue . Approximately 55000 new cases of DCIS were expected to occur among U.S. women in 2013 , which accounted for approximately 24 % of all new breast cancer diagnoses ( 1 ) . Although the annual incidence of DCIS is less than that of invasive breast cancer , exp and ed use of screening mammography has led to a dramatic increase in the diagnosis of DCIS ( 32.5 cases per 100000 women ) ( 2 ) . There is considerable uncertainty about the optimal clinical management of DCIS because of the lack of reliable methods for distinguishing DCIS that would never become symptomatic from DCIS that is likely to progress to life-threatening invasive cancer ( 3 ) . Current treatment options for DCIS include mastectomy , breast-conserving surgery ( BCS ) , and BCS plus radiation therapy ( 2 , 46 ) . There are limited r and omized , controlled trials ( RCTs ) on which to base decisions about the tradeoffs among DCIS treatment options , and the existing trials may not capture all relevant patient-centered outcomes . For example , 4 large RCTs comparing BCS alone with BCS plus radiation therapy all show similar , very high overall survival regardless of treatment ( 710 ) . The addition of radiation therapy significantly reduces the risk for local recurrence ; approximately one half of all recurrences are DCIS rather than invasive cancer ( 5 , 11 ) . The long-term benefit of preventing the recurrence of an asymptomatic condition that may or may not progress to cancer is difficult to quantify . In other conditions where screening may detect early cancer or cancer precursors that may not progress to a life-threatening stage , such as early-stage prostate cancer , active surveillance or watchful waiting ( an observation strategy ) is an acceptable option for some patients . A similar strategy may be acceptable for some women diagnosed with DCIS , although no studies have compared management strategies that involve no immediate treatment ( that is , observation or active surveillance ) versus immediate treatments . The most important potential benefit of treatment of DCIS is the reduction in the number of deaths due to invasive breast cancer . For many women with a DCIS diagnosis , this may be an unrealized benefit . Some proportion of DCIS may never progress to life-threatening invasive cancer , so these women only have the adverse outcomes of diagnosis and treatments . Both active management strategies and surveillance approaches present tradeoffs relevant to patient-centered outcomes , such as symptoms , function , and well-being . Given the clinical importance of DCIS , the diversity of available treatment strategies , variety of patient-centered outcomes of interest , and areas of uncertainty , we sought to create a prioritized research agenda for the Patient-Centered Outcomes Research Institute ( PCORI ) that would incorporate different stakeholders ' perspectives . A central goal of PCORI is to engage stakeholders in its work in a meaningful way . Between September 2012 and January 2013 , PCORI undertook a broad effort tosolicit research topics to consider for targeted funding from patients , caregivers , research ers , and results of previous prioritization processes by groups , such as the Institute of Medicine . In April 2013 , PCORI 's Assessment of Prevention , Diagnosis , and Treatment Options program , together with the program 's external advisory panel , have identified DCIS management as an important topic with unmet research needs . Then , PCORI tasked the Duke University Evidence Synthesis Group ( ESG ) to work with various stakeholders to identify and prioritize the future research that is most needed by patients and other decision makers on this topic . Methods Overview of Prioritization Approach Our approach to prioritizing future research and developing recommendations for targeted future funding by PCORI included several steps ( Figure 1 ) . These included appraisal s of recent systematic review s to preliminarily identify important evidence gaps , transformation of evidence gaps into research questions and organization of the questions within a comprehensive analytic framework , engagement of stakeholders to identify additional gaps and prioritize research needs or questions , scans of recently published and ongoing studies relevant to the stakeholders ' list of prioritized research needs , and identification of potential study design s to address prioritized research questions . Figure 1 . Overview of prioritization process Adapted from reference 12 . ESG = Evidence Synthesis Group ; PCORI = Patient-Centered Outcomes Research Institute . Identification of Evidence Gaps We used an iterative process to identify evidence gaps for DCIS management . First , we identified and appraised recent published systematic review s , clinical practice guidelines , and future research needs documents to develop an initial list of evidence gaps . This list was neither exhaustive nor prioritized . Next , we organized these gaps according to the population s , interventions , comparators , outcomes , timing , and setting of interest and transformed them into research questions informed by the criteria . Selection and Engagement of Stakeholders We convened a group of 9 stakeholders , including clinical experts and research ers in DCIS management strategies , representatives from federal and nongovernmental funding agencies , representatives from relevant professional societies , health care decision makers and policymakers , and representatives from related consumer and patient advocacy groups ( Table 1 of the Supplement ) . Within each of these categories , we sought to identify a person who was either familiar with the clinical area and its current uncertainties or brought a specific method ological expertise to the stakeholder panel . The University of Minnesota Evidence -based Practice Center , which did a comparative effectiveness review on DCIS management in 2009 ( 13 ) , and PCORI 's patient engagement group provided input on potential stakeholders . Each potential stakeholder completed a disclosure statement and was screened for conflicts of interest . We solicited and received stakeholder input at various points in the process through group discussion s via teleconferences detailing the process and outlining existing evidence gaps , Web-based surveys to obtain priority ranking of topics , and e-mail communications to solicit or provide further clarification of research gaps from teleconferences . Supplement . Supplementary Data for Prioritization of Research Addressing the Management of DCIS Development of an Analytic Framework On the basis of the exp and ed list of 30 evidence gaps and informed by an analytic framework in a recent evidence synthesis on DCIS ( 13 ) , we constructed an analytic framework that depicted the identified knowledge gaps within the context of the population s , interventions , comparators , outcomes , timing , and setting criteria ( Figure 2 ) . This framework shows that women diagnosed with DCIS may have pretreatment evaluations . After these evaluations , women may undergo several management strategies . These management strategies affect patient-centered outcomes ( such as development of comorbid conditions , DCIS recurrence , invasive cancer , and sexual functioning ) . Throughout the analytic framework , population factors ( such as socioeconomic , family history , and genetic factors ) and effects of decisional uncertainty about management strategies were highlighted as potential modifiers . Figure 2 . Analytic framework . DCIS = ductal carcinoma in situ ; FRN = future research need ; MRI = magnetic resonance imaging . Prioritization of Future Research After expansion of the identified research priorities , stakeholders were invited to rank the revised future research needs online . The survey used a forced-ranking prioritization method described by the Agency for Healthcare Research and Quality Evidence -based Practice Center 's Future Research Needs projects ( 14 ) , whereby participants were given 10 votes that could be allocated to any identified research priorities , with a maximum of 3 votes per item . The stakeholders were not given specific prioritization criteria to use but rather were told to decide , on the basis of their perspectives , which were the most important unanswered research questions in DCIS management . Only the priorities in the top tier ( n= 10 ) moved on to the final stage of horizon scan and study design determination . Stakeholders were informed of the final ranking of future research priorities . Horizon Scan of Studies Potentially Relevant to Top-Tier Research Questions We performed 2 data base search es to identify recently published and ongoing studies relevant to the top-tier future research questions result ing from the stakeholder forced-ranking prioritization exercise . We search ed PubMed to identify relevant literature published since 2008 and Clinical Trials.gov for ongoing studies . Members of the ESG team review ed the titles and abstract s identified by search ing PubMed for applicability to the top-tier research questions ; full texts were then obtained and screened for all citations passing the title- and - abstract screening . At both the title- and - abstract and full-text screening stages , articles were included if they met all of the following criteria : presented original data or secondary analysis of data from an RCT , prospect i ve or retrospective observational study , or relevant modeling study ; included data for a pretreatment evaluation or management strategy of interest ; included women with DCIS ; and had a stated objective that could be categorized according to our identified list of research priorities . We search ed Clinical Trials.gov using the keywords ductal carcinoma in situ and DCIS . A member of the ESG team review ed all study abstract s result ing from the search and coded them as potentially relevant to 1 or more of the identified research priorities . We then abstract ed study type ( such as CONTEXT The findings of systematic review s ( SRs ) and meta-analyses ( MAs ) are used for clinical decision making . The European Association of Urology has committed increasing re sources into the development of high quality clinical guidelines based on such SRs and MAs . OBJECTIVE In this paper , we have summarised the process of conducting SRs for underpinning clinical practice guidelines under the auspices of the European Association of Urology Guidelines Office . EVIDENCE ACQUISITION The process involves explicit methods and the findings should be reproducible . When conducting a SR , the essential first step is to formulate a clear and answerable research question . An extensive literature search lays the foundation for evidence synthesis . Data are extracted independently by two review ers and any disagreements are resolved by discussion or arbitration by a third review er . EVIDENCE SYNTHESIS In SRs , data for particular outcomes in individual r and omised controlled trials may be combined statistically in a meta- analysis to increase power when the studies are similar enough . Biases in studies included in a SR/MA can lead to either an over estimation or an under estimation of true intervention effect size , result ing in heterogeneity in outcome between studies . A number of different tools are available such as Cochrane Risk of Bias assessment tool for r and omised controlled trials . In circumstances where there is too much heterogeneity , or when a review has included nonr and omised comparative studies , it is more appropriate to conduct a narrative synthesis . The GRADE tool for assessing quality of evidence strives to be a structured and transparent system , which can be applied to all evidence , regardless of quality . A SR not only identifies , evaluates , and summarises the best available evidence , but also the gaps to be targeted by future studies . CONCLUSIONS SRs and MAs are integral in developing sound clinical practice guidelines and recommendations . PATIENT SUMMARY Clinical practice guidelines should be evidence based , and systematic review s and meta-analyses are essential in their production . We have discussed the key steps of conducting systematic review s and meta-analyses in this paper 310 Background : Drugs that block vascular endothelial growth factor ( VEGF ) pathway signaling , such as the tyrosine kinase inhibitor sorafenib , have become st and ard treatment for pts with RCC .  Tivozanib ( AV-951 ) is a potent , selective small-molecule pan-VEGF receptor ( VEGFR ) inhibitor , with activity against the VEGFR-1 , -2 , and -3 kinases at subnanomolar concentrations . Preliminary results from a phase II r and omized discontinuation trial of tivozanib ( 1.5 mg/d ; 3 wks on , 1 wk off ) in pts with RCC demonstrated an objective response rate ( ORR ) of 27 % and a median progression-free survival ( PFS ) of 11.8 mo by independent radiology review , with a favorable safety profile . Patients with clear cell RCC who had undergone nephrectomy had an ORR of 32 % and median PFS of 14.8 mo ( Bhargava , et al. ASCO 2010 . Abstract 4599 ) . Based on this antitumor activity a phase III , r and omized , controlled , global , multicenter trial is currently in progress to compare tivozanib with sorafenib in pts with advanced RCC . METHODS Approximately 500 adults with clear cell RCC who have undergone nephrectomy and received ≤ 1 prior systemic treatment ( no prior VEGF-targeted therapy ) were r and omized 1:1 to treatment with tivozanib or sorafenib . Pts are receiving 1.5 mg/d tivozanib orally in 4-week cycles ( 3 wks on , 1 wk off ) or continuous 400 mg sorafenib orally twice daily . The primary endpoint will be PFS by independent radiology review ; secondary endpoints will include overall survival , ORR , and duration of response . Safety is being monitored through adverse event reporting and laboratory analyses ; toxicities are grade d using the NCI Common Terminology Criteria for Adverse Events , version 3.0 . The effect of therapy on health-related quality of life will be compared between arms using kidney cancer-specific ( FKSI-DRS ) , oncology ( FACT-G ) , and general ( EQ-5D ) assessment s. Pharmacokinetics and biomarker analyses will be performed . RESULTS Pending . CONCLUSIONS Enrollment completed in August 2010 . An ongoing extension study will allow access to tivozanib for pts who demonstrate progressive disease on sorafenib , as well as long-term treatment with tivozanib or sorafenib for pts who demonstrate clinical benefit . [ Table : see text ] Sarcomatoid features can arise in renal cell carcinoma of any subtype and are associated with a poor prognosis . Doxorubicin and gemcitabine in a limited series showed activity in aggressive renal tumors and we wished to formally assess the combination in patients with renal cell carcinoma specifically containing sarcomatoid features . The Eastern Cooperative Oncology Group ( ECOG ) conducted a phase II trial of doxorubicin 50 mg/m2 IV push and gemcitabine 1,500 mg/m2 IV over 30 min every 2 weeks in 39 patients with locally advanced or metastatic renal cell carcinoma with sarcomatoid features . Ten patients ( 26 % ) had grade 3 toxicity , and four patients ( 11 % ) had grade 4 toxicities . Although most toxicity was from myelosuppression , one patient died on study from cardiac dysfunction after a cumulative dose of 450 mg/m2 doxorubicin . Six ( 16 % ) patients experienced responses ( 5 partial responses and 1 complete response ) , and ten ( 26 % ) patients had stable disease . In addition , another patient had an unconfirmed partial response and an additional patient experienced over 50 % decrease in her tumor burden after an initial progression . The median overall survival was 8.8 months , and the median progression-free survival was 3.5 months . We conclude that the combination of doxorubicin and gemcitabine , inactive in patients with mostly clear cell histology , demonstrated responses in patients with RCC with sarcomatoid features . We acknowledge the toxicity of this combination but note that limited treatment options exist for this aggressive histology . Only through prospect i ve multicenter trials with comprehensive central pathology review will better treatment options be identified BACKGROUND Patients with advanced renal cell carcinoma in routine clinical practice can differ considerably from those in phase III studies . PATIENTS AND METHODS PREDICT ( Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with sorafenib ) was a prospect i ve , noninterventional study of open-label sorafenib for the treatment of advanced RCC conducted in 18 countries . Patient characteristics , therapy duration , tumor status , and tolerability  were assessed at baseline and during routine follow-up . RESULTS Overall , 2599 patients were evaluable for safety and 2311 for efficacy . The diverse population included patients with brain metastases ( 5 % ) , non-clear-cell histologies ( 17 % ) , high Memorial Sloan-Kettering Cancer Center risk score ( 11 % ) , poor Eastern Cooperative Oncology Group performance status ( PS ≥ 2 , 29 % ) , and patients with no previous nephrectomy ( 16 % ) or no previous systemic therapy ( 37 % ) .  The median duration of sorafenib  therapy was 7.3 months and was similar in clinical ly relevant subgroups ( eg , patients with PS 2 , brain metastases , or concomitant hypertension or diabetes [ range , 6.7 - 7.0 months ] ) . The median duration of therapy was shorter for patients with PS 3 or non-clear-cell histologies ( 4.6 and 4.8 months , respectively ) . The most common drug-related adverse events were h and -foot skin reaction ( 20 % ) , diarrhea ( 17 % ) , and rash ( 8 % ) . CONCLUSION Sorafenib was generally well tolerated and provided clinical benefit in a large , diverse population of patients with advanced RCC treated in routine clinical practice BACKGROUND Most early stage kidney cancers are renal cell carcinomas ( RCCs ) , and most are diagnosed incidentally by imaging as small renal masses ( SRMs ) . Indirect evidence suggests that most small RCCs grow slowly and rarely metastasize . OBJECTIVE To determine the progression and growth rates for newly diagnosed SRMs stratified by needle core biopsy pathology . DESIGN , SETTING , AND PARTICIPANTS A multicenter prospect i ve phase 2 clinical trial of active surveillance of 209 SRMs in 178 elderly and /or infirm patients was conducted from 2004 until 2009 with treatment delayed until progression . INTERVENTION Patients underwent serial imaging and needle core biopsies . MEASUREMENTS We measured rates of change in tumor diameter ( growth measured by imaging ) and progression to ≥ 4 cm , doubling of tumor volume , or metastasis with histology on biopsy . RESULTS AND LIMITATIONS Local progression occurred in 25 patients ( 12 % ) , plus 2 progressed with metastases ( 1.1 % ) . Of the 178 subjects with 209 SRMs , 127 with 151 SRMs had>12 mo of follow-up with two or more images , with a mean follow-up of 28 mo . Their tumor diameters increased by an average of 0.13 cm/yr . Needle core biopsy in 101 SRMs demonstrated that the presence of RCC did not significantly change growth rate . Limitations included no central review of imaging and pathology and a short follow-up . CONCLUSIONS This is the first SRM active surveillance study to correlate growth with histology prospect ively . In the first 2 yr , the rate of local progression to higher stage is low , and metastases are rare . SRMs appear to grow very slowly , even if biopsy proven to be RCC . Many patients with SRMs can therefore be initially managed conservatively with serial imaging , avoiding the morbidity of surgical or ablative treatment Diabetes is the leading cause of major complications , such as end-stage renal disease and lower extremity amputations , and is a significant contributor to ischemic heart disease , stroke , peripheral vascular disease , and vision loss ( 1 ) . There has been increasing acceptance of the importance of individualizing glycemic management and assessment of risk for adverse events , especially hypoglycemia ( 26 ) . This is of great importance for all patients , especially older adults ( aged 65 years ) with comorbid conditions . In 2013 , 12.0 million older adults in the United States had diabetes , comprising 40 % of the 30.2 million persons with the disease ( 7 ) . Older adults account for an estimated 60 % to 70 % of the U.S. Department of Veterans Affairs ( VA ) and U.S. Department of Defense ( DoD ) diabetic population ( largely retirees ) ( VA/DoD. Unpublished data ) . These considerations make safe and effective diabetes management a policy priority for health care providers ( physicians , nurses , dietitians , and pharmacists ) and policymakers in both the VA and the DoD. The 2017 VA/DoD Clinical Practice Guideline ( CPG ) for the Management of Type 2 Diabetes Mellitus in Primary Care offers health care providers an evidence -based framework to evaluate , treat , and manage persons with type 2 diabetes  mellitus in the context of their individual needs and preferences ( 8) . The current article is a summary of key CPG recommendations , which was developed with multiple stakeholders to ensure representation by a broad spectrum of clinicians . It provides practice recommendations for the care of patients with diabetes , with an emphasis on shared decision making . Guideline Development and Review Process These recommendations were developed using methods established by the VA/DoD Evidence -Based Practice Work Group ( EBPWG ) ( 9 ) , which are aligned with st and ards for trustworthy guidelines ( 10 ) . The EBPWG and the U.S. Army Medical Comm and selected guideline panel cochairs ( 1 each from the VA and the DoD ) . The cochairs then selected a multidisciplinary panel of practicing clinician stakeholders , including primary care physicians ( family and internal medicine ) , endocrinologists , medical nutritionists , pharmacists , diabetes educators , and nurse practitioners . At the start of the CPG development process and at other key points throughout , all members were required to su bmi t disclosure statements for potential conflicts of interest in the previous 24 months . Verbal affirmations of no conflicts were used during meetings throughout the development process . The project team was also subject to r and om Web-based surveillance ( for example , ProPublica ) . The VA/DoD contracted with The Lewin Group , a third party with expertise in clinical practice guideline development , to facilitate meetings . The guideline panel , in collaboration with the ECRI Institute , developed 9 key questions using the PICOTS ( population , intervention , comparator , outcomes , timing of outcomes measurement , and setting ) format . A systematic search of the peer- review ed literature from January 2009 through March 2016 was conducted to find evidence relevant to the key questions that focused on r and omized trials , systematic review s , and meta-analyses of fair or better quality . One key question was up date d through 14 June 2016 . The search methods and results are detailed in the full guideline ( 8) . The guideline panel rated recommendations by using the GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) method ( 11 ) . The guideline panel focused on developing new and up date d recommendations using the evidence review for the key questions . The panel also considered , without a complete review of the relevant evidence , the current applicability of recommendations that were included in the 2010 CPG . As part of the development process , a patient focus group was also convened to better underst and the perspectives of patients receiving diabetes treatment in the VA and the DoD. Five patients were included , consistent with the requirements of the federal Paperwork Reduction Act . All patients had type 2 diabetes and were veterans receiving care in the VA . The focus group explored knowledge of treatment options , views on the delivery of care , patients ' needs and preferences , and the effect of diabetes on their lives . Important concepts that emerged from the focus group were shared with the panel and informed guideline development . It was acknowledged that this convenience sample may not be representative of all VA and DoD patients receiving treatment for type 2 diabetes . The draft guideline was sent to more than 15 expert review ers inside and outside the federal sector . Comments were review ed and , where appropriate , were incorporated into the final guideline based on panel consensus . The VA/DoD EBPWG approved the final document on 3 April 2017 and released it on 17 April 2017 . Recommendations are presented in the Table , and an algorithm for establishing a personalized glycemic goal and treatment plan is presented in the Figure . Key recommendations are review ed in this article . Table . Summary of Recommendations From the 2017 VA/DoD CPG on the Management of Type 2 Diabetes Mellitus Figure . Algorithmic approach to evaluating glycemic control risk factors , setting a personalized glycemic control target range , providing self-management ( including lifestyle and nutrition ) education , and initiating or reevaluating medication therapy . Recommendations Provide Patient-Centered Care and Incorporate Shared Decision Making The CPG strongly encourages clinicians to incorporate shared decision making and partner with their patients . Shared decision making is the process by which the patient and family , in conjunction with the care provider , reach an agreement about a plan of care and treatment . Key principles include readiness of the patient and family , tools with underst and able information about the benefits and harms of all options , and strategies to identify and incorporate patient preferences . Patients can not effectively participate in care and shared decision making unless they underst and diabetes and how they can be involved in planning and carrying out the jointly developed care plan . Shared decision making reinforces a trusted therapeutic relationship and increases patient satisfaction and treatment buy-in with regard to the methods used to reach a particular goal or treatment plan ( 1214 ) . It should be used not only for patients with stable glycemic control but also to assist those who are not able or willing to make lifestyle changes and decisions that affect their diabetes at any time during the course of treatment . At a minimum , shared decision making should be included at the time of diagnosis , during difficulties with management , and at times of transition or development of complications ( 14 ) . Benefits include greater knowledge of medications ( 13 ) and underst and ing of risks ( 14 ) . In addition , patient-centered care and shared decision making together may decrease patient anxiety , increase trust in clinicians ( 15 ) , and improve treatment adherence ( 16 ) . Family involvement should be considered if appropriate , especially in older adults ( 17 ) . Patient information should be culturally appropriate ; underst and able and actionable by people with limited literacy skills ; and accessible to those with physical , sensory , or learning needs ( 18 ) . As part of the patient-centered care approach to diabetes management , clinicians should explore with the patient the outcomes of previous opportunities for shared decision making , their ability to self-manage , prior efforts to change health behaviors , past treatment experiences ( including reasons for discontinuing treatment ) , and relevant clinical outcomes . In actively sharing decisions , they should involve the patient in prioritizing problems to be addressed and setting specific goals regardless of the setting or level of care . Assess Patient Characteristics and Nonglycemic Factors When Interpreting Results of Hemoglobin A1c , Fructosamine , and Other Glycemic Biomarker Testing Many factors affect measurement of hemoglobin A1c ( HbA1c ) besides the level of glycemia ( 19 ) . Because HbA1c level depends on the duration of erythrocyte exposure to glucose , conditions that alter erythrocyte life span affect the measured level of HbA1c ( 20 , 21 ) . Iron deficiency anemia , which prolongs erythrocyte life span and exposes the cell to glucose for a longer period , is associated with falsely elevated HbA1c levels ( 22 ) . In contrast , conditions that shorten erythrocyte life span ( such as hemolytic anemia ) may result in falsely low HbA1c levels . Various other conditions , such as chronic kidney disease , may alter HbA1c measurement . Hemoglobin variants can result in falsely elevated or falsely lowered HbA1c levels , depending on the assay used ( 2325 ) . In addition , oral hypoglycemic agents ( metformin or sulfonylureas ) may alter the relationship between blood glucose and HbA1c levels , although the clinical significance is unclear ( 26 ) . There are also racial/ethnic differences in HbA1c levels for a given level of glycemia . A previous study found that African Americans with prediabetes ( 27 ) had HbA1c values that were 0.4 % higher than among white persons ; those who were within 3 years of diagnosis ( 28 ) also had higher HbA1c values than white persons for any measure of glycemia . This difference can not be explained by measured differences in glycemia , clinical factors known to affect HbA1c measurement , or sociodemographic factors ( 27 , 28 ) . Therefore , it is recommended that a new diagnosis of diabetes be based on a confirmatory fasting blood glucose level of at least 7.0 mmol/L ( 126 mg/dL ) if the initial HbA1c value is 6.5 % to 6.9 % . How and where the HbA1c level is measured can also affect results because of intralaboratory variation ( variation in test accuracy and precision ) and interlaboratory variation ( variation related to use of different test methods ) . A single HbA1c measurement , even from a This report summarizes the U.S. Food and Drug Administration ( FDA ) 's approval of temsirolimus ( Torisel ) , on May 30 , 2007 , for the treatment of advanced renal cell carcinoma ( RCC ) . Information provided includes regulatory history , study design , study results , and literature review . A multicenter , three-arm , r and omized , open-label study was conducted in previously untreated patients with poor-prognosis , advanced RCC . The study objectives were to compare overall survival ( OS ) , progression-free survival ( PFS ) , objective response rate , and safety in patients receiving interferon (IFN)-alpha  versus those receiving temsirolimus alone or in combination with IFN-alpha . In the second planned interim analysis of the intent-to-treat population ( n = 626 ) , there was a statistically significant longer OS time in the temsirolimus ( 25 mg ) arm than in the IFN-alpha arm ( median , 10.9 months versus 7.3 months ; hazard ratio [ HR ] , 0.73 ; p = .0078 ) . The combination of temsirolimus ( 15 mg ) and IFN-alpha did not lead to a significant difference in OS compared with IFN-alpha alone . There was also a statistically significant longer PFS time for the temsirolimus ( 25 mg ) arm than for the IFN-alpha arm ( median , 5.5 months versus 3.1 months ; HR , 0.66 , p = .0001 ) . Common adverse reactions reported in patients receiving temsirolimus were rash , asthenia , and mucositis . Common laboratory abnormalities were anemia , hyperglycemia , hyperlipidemia , and hypertriglyceridemia . Serious but rare cases of interstitial lung disease , bowel perforation , and acute renal failure were observed . Temsirolimus has demonstrated superiority in terms of OS and PFS over IFN-alpha and provides an additional treatment option for patients with advanced RCC Purpose The decreased effectiveness of single-agent targeted therapies in advanced non-clear cell renal cell carcinoma ( ncRCC ) compared with clear cell renal cell carcinoma ( RCC ) supports the study of combination regimens . We evaluated the efficacy of everolimus plus bevacizumab in patients with metastatic ncRCC . Patients and Methods In this single-center phase II trial , treatment-naive patients received everolimus 10 mg oral once per day plus bevacizumab 10 mg/kg intravenously every 2 weeks . The primary end point was progression-free survival ( PFS ) at 6 months . Correlative analyses explored c and i date tissue biomarkers through next-generation sequencing . Results Thirty-five patients were enrolled with the following histologic subtypes : chromophobe ( n = 5 ) , papillary ( n = 5 ) , and medullary ( n = 2 ) RCC and unclassified RCC ( uRCC , n = 23 ) . The majority of patients had papillary growth as a major component ( n = 14 ) . For 34 evaluable patients , median PFS , overall survival , and objective response rate ( ORR ) were 11.0 months , 18.5 months , and 29 % , respectively . PFS varied by histology ( P < .001 ) , and ORR was higher in patients with significant papillary ( seven of 18 ) or chromophobe ( two of five ) elements than for others ( one of 11 ) . Presence of papillary features were associated with benefit , including uRCC , where it correlated with ORR ( 43 % v 11 % ) , median PFS ( 12.9 v 1.9 months ) , and overall survival ( 28.2 v 9.3 months ; P < .001 ) . Several genetic alterations seemed to segregate by histology . In particular , somatic mutations in ARID1A were seen in five of 14 patients with papillary features but not in other RCC variants . All five patients achieved treatment benefit . Conclusion The study suggests efficacy for this combination in patients with ncRCC characterized by papillary features . Distinct mutational profiles among ncRCCs vary according to specific histology OBJECTIVE Our aim was to present a summary of the 2010 version of the European Association of Urology ( EAU ) guidelines on the screening , diagnosis , and treatment of clinical ly localised cancer of the prostate ( PCa ) . METHODS The working panel performed a literature review of the new data emerging from 2007 to 2010 . The guidelines were up date d , and level of evidence and grade of recommendation were added to the text based on a systematic review of the literature , which included a search of online data bases and bibliographic review s. RESULTS A full version is available at the EAU office or Web site ( www.uroweb.org ) . Current evidence is insufficient to warrant widespread population -based screening by prostate-specific antigen ( PSA ) for PCa . A systematic prostate biopsy under ultrasound guidance and local anaesthesia is the preferred diagnostic method . Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy .  PSA doubling time in <3 yr or a biopsy progression indicates the need for active intervention . In men with locally advanced PCa in whom local therapy is not m and atory , watchful waiting ( WW ) is a treatment alternative to and rogen-deprivation therapy ( ADT ) with equivalent oncologic efficacy . Active treatment is mostly recommended for patients with localised disease and a long life expectancy with radical prostatectomy ( RP ) shown to be superior to WW in a prospect i ve r and omised trial . Nerve-sparing RP represents the approach of choice in organ-confined disease ; neoadjuvant and rogen deprivation demonstrates no improvement of outcome variables . Radiation therapy should be performed with at least 74 Gy and 78 Gy in low-risk and intermediate/high-risk PCa , respectively . For locally advanced disease , adjuvant ADT for 3 yr results in superior disease-specific and overall survival rates and represents the treatment of choice . Follow-up after local therapy is largely based on PSA , and a disease-specific history with imaging is indicated only when symptoms occur . CONCLUSIONS The knowledge in the field of PCa is rapidly changing . These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice Background The majority of enhancing renal masses are unable to be effectively characterized as benign or malignant using st and ard cross-sectional imaging modalities including multi-phase computed tomography ( CT ) [ 1 ] and magnetic resonance imaging ( MRI ) [ 2 ] . This is particularly unfortunate in light of the steady increase in the incidence of these lesions , many of which are discovered incidentally on imaging studies performed for nonurologic indications [ 3 , 4 ] . Moreover , it has been estimated that upwards of 5600 unnecessary partial and radical nephrectomies are performed each year in the USA for the false presumption of cancer [ 5 ] . In light of these data , recently , there has been a growing interest in the use of molecular imaging to characterize the aggressiveness of renal masses [ 6 , 7 ] . To date , several reports have been published on the ability of Tc-sestamibi planar and single photon emission computed tomography (SPECT)/CT imaging to differentiate mitochondrial-rich benign and indolent renal masses such as oncocytomas and hybrid oncocytic/ chromophobe tumors ( HOCTs ) from more aggressive renal tumor histologies including the clear cell subtype of renal cell carcinoma ( RCC ) [ 8–10 ] . In this issue of European Journal of Nuclear Medicine and Molecular Imaging Research , Tzortzakakis et al. [ 11 ] add to this body of literature with a prospect i ve study evaluating Tc-sestamibi SPECT/CT in 24 patients with 31 clinical ly localized T1 renal masses planned for biopsy or surgery . The authors reported that 11 of 12 ( 92 % ) oncocytomas and 3 of 3 ( 100 % ) HOCTs demonstrated Tc-sestamibi uptake , while all other lesions were negative for uptake with the exception of mild uptake in a single papillary RCC . These findings are concordant with earlier studies [ 9 , 10 ] and dramatically increase the number of Tc-sestamibi positive oncocytomas and HOCTs reported in the literature . As a brief aside , it should be mentioned that there is also a growing interest in the use of renal mass biopsy for determining the histology of renal tumors , particularly as data from two recent systematic review s have suggested that the rates of complications and nondiagnostic biopsies are tolerable [ 12 , 13 ] . However , limitations of renal mass biopsy remain , including the intrinsically invasive nature of this procedure , the inaccessibility of some tumors to safe approaches for biopsy , and the heterogeneous population of renal masses that can present as oncocytic neoplasms on biopsy [ 14 , 15 ] . As such , the non-invasive characterization of renal masses with molecular imaging techniques continues to be of interest and may serve as an adjunct to , or even a replacement of , biopsy in selected cases Purpose Provide evidence -based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer ( NSCLC ) . Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of r and omized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence -Based Care 's up date of a previous ASCO search . Results This guideline up date reflects changes in evidence since the previous guideline up date . Fourteen r and omized controlled trials provide the evidence base ; earlier phase trials also informed recommendation development . Recommendations New or revised recommendations include the following . Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma ( without positive markers , eg , EGFR/ALK /ROS1 ) , if the patient has high programmed death lig and 1 ( PD-L1 ) expression , pembrolizumab should be used alone ; if the patient has low PD-L1 expression , clinicians should offer st and ard chemotherapy . All other clinical scenarios follow 2015 recommendations . Regarding second-line treatment in patients who received first-line chemotherapy  , without prior immune checkpoint therapy , if NSCLC tumor is positive for PD-L1 expression , clinicians should use single-agent nivolumab , pembrolizumab , or atezolizumab ; if tumor has negative or unknown PD-L1 expression , clinicians should use nivolumab or atezolizumab . All immune checkpoint therapy is recommended alone plus in the absence of contraindications . For patients who received a prior first-line immune checkpoint inhibitor , clinicians should offer st and ard chemotherapy . For patients who can not receive immune checkpoint inhibitor after chemotherapy , docetaxel is recommended ; in patients with nonsquamous NSCLC , pemetrexed is recommended . In patients with a sensitizing EGFR mutation , disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy , and T790 M mutation , osimertinib is recommended ; if NSCLC lacks the T790 M mutation , then chemotherapy is recommended . Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib , or if they previously received crizotinib , they may be offered chemotherapy OBJECTIVE The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation ( rt ) or surgery , or both , for cure or organ preservation , or both , in patients with locally advanced nonmetastatic ( stages iii-ivb ) squamous cell carcinoma of the head and neck ( lascchn ) . METHODS The Meta- analysis of Chemotherapy in Head and Neck Cancer ( mach-nc ) reports have , de facto , guided practice since 2000 , and so we search ed the literature for systematic review s published from January 2000 to February 2015 in reference to five research questions . A search was also conducted up to February 2015 for r and omized trials ( rcts ) not included in the meta-analyses . Recommendations were constructed using the Cancer Care Ontario Program in Evidence -Based Care practice guidelines development cycle . RESULTS In addition to up date d mach-nc reports , five additional meta-analyses and thirty rcts were identified . Five recommendations for lascchn treatment were generated based on those data . Concurrent chemoradiation ( ccrt ) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment . The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence . For lascchn patients who are c and i date s for organ preservation strategies and would otherwise require total laryngectomy , either ccrt or induction chemotherapy , followed by rt or surgery based on tumour response is recommended . The addition of cetuximab to intensified rt ( concomitant boost or hyperfractionated schedule ) is an alternative to ccrt . Routine use of induction chemotherapy to improve overall survival is not recommended . CONCLUSIONS We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn . A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx . One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting . Concurrent chemoradiation provides one strategy for larynx preservation , but the best strategy is unclear . Use of induction chemotherapy does not improve overall survival , and its use should be limited to patients requiring immediate tumour downsizing before local therapy PURPOSE Sunitinib has shown antitumor activity with a manageable safety profile as metastatic renal cell carcinoma ( RCC ) treatment , when given by the st and ard intermittent schedule as well as a continuous daily dosing ( CDD ) schedule . A trial was conducted to compare the schedules . PATIENTS AND METHODS Patients with treatment-naive , clear cell advanced RCC were r and omly assigned 1:1 to receive sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment ( schedule 4/2 ; n = 146 ) or 37.5 mg/d on the CDD schedule ( n = 146 ) for up to 2 years . The primary end point was time to tumor progression . RESULTS Median time to tumor progression was 9.9 months for schedule 4/2 and 7.1 months for the CDD schedule ( hazard ratio , 0.77 ; 95 % CI , 0.57 to 1.04 ; P = .090 ) . No significant difference was observed in overall survival ( 23.1 v 23.5 months ; P = .615 ) , commonly reported adverse events , or patient-reported kidney cancer symptoms . Schedule 4/2 was statistically superior to CDD in time to deterioration , a composite end point of death , progression , and disease-related symptoms ( P = .034 ) . CONCLUSION ; There was no benefit in efficacy or safety for continuous dosing of sunitinib compared with the approved 50 mg/d dose on schedule 4/2 . Given the numerically longer time to tumor progression with the approved 50 mg/d dose on schedule 4/2 , adherence to this dose and schedule remains the treatment goal for patients with advanced RCC Purpose Evidence has supported the association between psychological factors and cancer biology ; however , findings are equivocal on the role of psychosocial factors in cancer progression . This study generates a hypothesis of mechanistic variables by examining the clinical effects of psychosocial factors and cortisol dysregulation in patients with metastatic renal cell carcinoma ( RCC ) and examines associated activation of transcription control pathways . Methods Patients with metastatic RCC ( n = 217 ) were prospect ively enrolled in this study . Patients completed question naires ( Centers for Epidemiologic Studies – Depression ; SF-36 Health Status Survey ; Duke Social Support Index ; Coping Operations Preference Enquiry ; organized and non-organized religious activity ; and intrinsic religiosity ) , and provided blood and saliva sample s. Cortisol levels and  whole genome transcriptional profiling  were assessed to identify potential alterations in circadian rhythms and genomic pathways . Results Separate Cox regression models , controlling for disease risk category , revealed that CES-D scores ( p = 0.05 , HR = 1.5 , 95 % CI for HR : 1.00–2.23 ) and cortisol slope ( p = 0.002 ; HR = 1.9 ; 95%CI for HR : 1.27–2.97 ) were significantly associated with decreased survival . Only cortisol slope and risk category remained significant in the complete model . Functional genomic analyses linked depressive symptoms to increased expression of pro-inflammatory and pro-metastatic genes in circulating leukocytes . 116 transcripts were found to be upregulated by an average of 50 % or more in high CES-D patients , and 57 transcripts downregulated by at least 50 % . These changes were also found in the tumor in a subset of patients . Conclusion These findings identify depressive symptoms as a key predictor of survival in renal cell carcinoma patients with potential links to dysregulation of cortisol and inflammatory biology Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) . Methods An Up date Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of r and omized controlled trials from January 2007 to February 2014 . Results This guideline up date reflects changes in evidence since the previous guideline . Recommendations There is no cure for patients with stage IV NSCLC . For patients with performance status ( PS ) 0 to 1 ( and appropriate patient cases with PS 2 ) and without an EGFR-sensitizing mutation or ALK gene rearrangement , combination cytotoxic chemotherapy is recommended , guided by histology , with early concurrent palliative care . Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 ( bevacizumab may be added to carboplatin plus paclitaxel if no contraindications ) ; combination or single-agent chemotherapy or palliative care alone for those with PS 2 ; afatinib , erlotinib , or gefitinib for those with sensitizing EGFR mutations ; crizotinib for those with ALK or ROS1 gene rearrangement ; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma . Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens , alternative chemotherapy , or a chemotherapy break . In the second-line setting , recommendations include docetaxel , erlotinib , gefitinib , or pemetrexed for patients with nonsquamous cell carcinoma ; docetaxel , erlotinib , or gefitinib for those with squamous cell carcinoma ; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib . In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended . There are insufficient data to recommend routine third-line cytotoxic therapy . Decisions regarding systemic therapy should not be made based on age alone . Additional information can be found at http://www.asco.org/ guidelines /nsclc and http://www.asco.org/ guidelines wiki . J Clin Oncol 33:3488 - 3515 . © 2015 by American Society of Clinical BACKGROUND Retrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma ( nccRCC ) . PATIENTS AND METHODS Eligibility criteria included advanced nccRCC except for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes . Patients were treated with 50 mg/day oral sunitinib for 4 weeks , followed by 2 weeks of rest . The primary end point was overall response rate ( RR ) . RESULTS Thirty-one eligible patients were enrolled . Twenty-four patients ( 77 % ) had prior nephrectomy . By Memorial Sloan-Kettering Cancer Center criteria , 8 patients ( 26 % ) had poor risk and 14 ( 45 % ) had intermediate risk . Twenty-two patients had papillary renal cell carcinoma ( RCC ) , and three had chromophobe RCC . Eleven patients had partial response with a RR of 36 % ( 95 % confidence interval ( CI ) 19 % to 52 % ) and an additional 17 patients ( 55 % ) had stable disease . Median duration of response was 12.7 months ( 95 % CI 6.3 - 19.1 months ) , and median progression-free survival was 6.4 months ( 95 % CI 4.2 - 8.6 months ) . At a median follow-up duration of 18.7 months ( 95 % CI 13.7 - 23.7 months ) , 13 patients ( 42 % ) had died , result ing in an estimated median survival of 25.6 months ( 95 % CI 8.4 - 42.9 months ) . Toxicity profiles were commensurate with prior reports . CONCLUSIONS Sunitinib has promising activity in patients with nccRCC ( NCT01219751 ) Sunitinib malate ( Sutent ™ ) is an inhibitor of multiple protein tyrosine kinases that shows antitumor and antiangiogenic activities . In a r and omized Phase III trial of treatment-naive patients with metastatic renal cell carcinoma ( mRCC ) , patients treated with sunitinib showed a significant improvement in progression-free survival compared with those treated with IFN-α . Sunitinib also exhibited antitumor activity in unselected RCC patients , including those with who were refractory to treatment , had non-clear cell histology brain metastases , or an Eastern Cooperative Oncology Group performance status > 1 . Typical side effects of sunitinib malate are fatigue , asthenia , diarrhea , skin rash , stomatitis , h and –foot skin syndrome , hypothyroidism and hematological abnormalities . Hypertension , other toxicities may serve as biomarkers for improved clinical outcomes in sunitinib treatment . Currently , sunitinib remains the gold st and ard of care in the treatment of mRCC
EVIDENCE SYNTHESIS The systematic review showed an absence of evidence for treating RKCs , with data only supporting sunitinib or MET inhibitors for some specific subtypes .
PATIENT SUMMARY Patients confronted with rare kidney cancers are often treated the same way as clear-cell renal cell carcinoma patients , despite little evidence from r and omized trials .
Molecular characterization of tumors to stratify patients may improve outcomes .
CONTEXT The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non-clear-cell renal cell carcinomas ( RCCs ) , which showed a substantial lack of evidence for management recommendations .
OBJECTIVE To improve the outcomes of patients with rare kidney cancers ( RKCs ) , we performed a subsequent unstructured review to determine current treatment strategies and druggable pathways , involving key stakeholders with a global perspective to generate recommendations .