Management Of mRCC Research Articles

RENO Study: Clinical characteristics, treatment patterns and survival results in patients with metastatic renal cell carcinoma in Northern Spain

BackgroundThe current available evidence on the management of metastatic renal cell cancer (mRCC) in real life is scarce in our environment. We present a summary of the existing real-world data and the results of an analysis describing the clinical characteristics, treatments, and health outcomes of patients with mRCC in northern Spain. MethodsRetrospective observational study. Adult patients diagnosed with mRCC between Jan 2007 and Dec 2019 were included. Epidemiological, efficacy and toxicity data were collected. Median overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method. ResultsA total of 829 patients were included (median age at diagnosis:63 years;73% men). Median follow-up was 180 months. The preponderant histology was clear cell (85%). In 50% the initial diagnosis was advanced disease. The distribution according to IMDC prognosis was good (24%), intermediate (50%) and poor (26%). The most frequent metastatic locations were lung (68.3%) and lymph node (41.0%). Most patients (95%) received a first line (1L) systemic treatment, 60% were treated with a second line (2L) of therapy and 37% received third line (3L). A VEGFR-TKIs was the most common treatment (1L: 90%, n = 507; 2L: 49%, n = 233; 3L: 54%, n = 156) followed by mTOR inhibitors (1L: 2%, n = 4; 2L: 27%, n = 126; 3L: 23%, n = 68) and immunotherapy (1L: 3.7%, n = 25; 2L: 27%, n = 126). Median OS was 24.5 months in the general population. According to IMDC prognostic groups, OS was 52.5, 25.7 and 9 months respectively. From the start of the 1L, 2L, and 3L treatment, median PFS was: 1L: 7.8 (6.8–9.0); 2L: 4.9 (4.3–5.5); 3L: 4.3 (3.8–4.8) months. No unexpected toxicity was reported. ConclusionsThe Real-World Data on the management of mRCC in Northern Spain are comparable in epidemiology, efficacy, and safety to studies conducted in other areas of the world. The significant reduction in the number of patients receiving second and subsequent lines of therapy hampers the access to new therapies developed in this context.

Emerging resistance vs. losing response to immune check point inhibitors in renal cell carcinoma: two differing phenomena.

The introduction of immune checkpoint inhibitor (ICI) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and has dramatically improved the outcomes of patients. The use of monotherapy or combinations of ICIs targeting PD-1/PD-L1 and CTLA-4, as well as the addition of ICIs with tyrosine kinase inhibitors, has significantly enhanced the overall survival of mRCC patients. Despite these promising results, there remains a subset of patients who either do not respond to treatment (primary resistance) or develop resistance to therapy over time (acquired resistance). Understanding the mechanisms underlying the development of resistance to ICI treatment is crucial in the management of mRCC, as they can be used to identify new targets for innovative therapeutic strategies. Currently, there is an unmet need to develop new predictive and prognostic biomarkers that can aid in the development of personalized treatment options for mRCC patients. In this review, we summarize several mechanisms of ICI resistance in RCC, including alterations in tumor microenvironment, upregulation of alternative immune checkpoint pathways, and genetic and epigenetic changes. Additionally, we highlight potential strategies that can be used to overcome resistance, such as combination therapy, targeted therapy, and immune modulation.

Understanding and integrating cytoreductive nephrectomy with immune checkpoint inhibitors in the management of metastatic RCC.

Cytoreductive nephrectomy became accepted as standard of care for selected patients with metastatic renal cell carcinoma (mRCC) because of improved survival observed in patients treated with cytoreductive nephrectomy in combination with interferon-α in two randomized clinical trials published in 2001. Over the past two decades, novel systemic therapies have shown higher treatment response rates and improved survival outcomes compared with interferon-α. During this rapid evolution of mRCC treatments, systemic therapies have been the primary focus of clinical trials. Results from multiple retrospective studies continue to suggest an overall survival benefit for selected patients treated with nephrectomy in combination with systemic mRCCtreatments, with the notable exception of one debatedclinical trial. The optimal timing for surgery is unknown, and proper patient selection remains crucial to improving surgical outcomes. As systemic therapies continue to evolve, clinicians have an increasing need to understand how to incorporate cytoreductive nephrectomy into the management of mRCC.

Evaluation of deep learning techniques (DL) in RNA sequencing data for the prediction of response to immune checkpoint inhibitors in patients with metastatic renal cell cancer m(RCC).

641 Background: Immune checkpoint inhibitors have become a cornerstone in the management of mRCC. However, to identify the most suitable patients for this treatment is an unmet medical need. We aimed to explore the utility of DL integrating clinical and molecular data to predict response to immunotherapy. Methods: We conducted a retrospective analysis using publicly available data from patients treated with nivolumab in the clinical trials Checkmate 009, 010 and 025. The primary objective was to assess the performance of different DL models (autoencoder and convolutional neural network (CNN)) predicting the PFS of these patients. With that scope, we followed several research lines including the creation of combined datasets with clinic and RNA sequencing and comparing the results of the DL models against the performance of traditional machine learning (ML) models. Finally, we came up with an interpretability analysis of those black-box models using LIME and SHAP values. Results: Clinical and transcriptomic data were available from 181 nivolumab-treated patients. Outcomes achieved confirmed that we can model the response for NIVOLUMAB using RNA sequencing data. (Table) However, DL models have not demonstrated to be significantly better than traditional ML methods when predicting response (p= 0.068). Deep autoencoder provided 68.9% accuracy, but the most accurate model was logistic regression classifier which achieved 86.4% of hit rate. Interpretability results revealed that most relevant genes for the decision making were related with the immune response and the regulation of kinases. Regarding interpretability, best results were achieved integrating both transcriptomic and clinical data (7 out of 10 DL and ML tested models achieved higher hit rates with combined data set. Logistic regression classifier improved its accuracy in 11%). Conclusions: The integration of clinical and molecular data could lead to more accurate predictions of outcome than any dataset by its own. However, further research is intended in the field of the DL analysis, as data codification and data structure could bias the results. The ongoing study ART (Artificial Intelligence in Renal Tumors) will address this issue prospectively. [Table: see text]

Theranostic Applications of Glycosaminoglycans in Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) makes up the majority of kidney cancers, with a poor prognosis for metastatic RCC (mRCC). Challenges faced in the management of mRCC, include a lack of reliable prognostic markers and biomarkers for precise monitoring of disease treatment, together with the potential risk of toxicity associated with more recent therapeutic options. Glycosaminoglycans (GAGs) are a class of carbohydrates that can be categorized into four main subclasses, viz., chondroitin sulfate, hyaluronic acid, heparan sulfate and keratan sulfate. GAGs are known to be closely associated with cancer progression and modulation of metastasis by modification of the tumor microenvironment. Alterations of expression, composition and spatiotemporal distribution of GAGs in the extracellular matrix (ECM), dysregulate ECM functions and drive cancer invasion. In this review, we focus on the clinical utility of GAGs as biomarkers for mRCC (which is important for risk stratification and strategizing effective treatment protocols), as well as potential therapeutic targets that could benefit patients afflicted with advanced RCC. Besides GAG-targeted therapies that holds promise in mRCC, other potential strategies include utilizing GAGs as drug carriers and their mimetics to counter cancer progression, and enhance immunotherapy through binding and transducing signals for immune mediators.

IJU this issue

This issue of International Journal of Urology contains two Review Articles, 13 Original Articles, three Urological Notes, nine Editorial Comments, one Letter to the Editor, and three Author's Replies. Prostate biopsy is one of the most frequently performed urological procedures. Despite being generally safe and well-tolerated, it is sometimes associated with complications including acute bacterial prostatitis especially in transrectal approach. In the last decade, an increased number of fluoroquinolone-resistant and extended-spectrum beta-lactamase-producing Escherichia coli have been reported in cases of acute prostatitis. In the Review Article by Acosta et al. (Okayama, Japan), the authors emphasized the clinical value of the isolation of these pathogens from rectal bio-flora samples, which can be easily obtained through the fingertip of a sterile glove or a cotton swab, with selective media before transrectal prostate biopsy. As the authors described, this preventive measure may allow us to offer a tailored prophylactic treatment that benefits patients and reduces the economic burden for the hospital. The treatment paradigm for metastatic renal cell carcinoma (mRCC) has been dramatically changed by the introduction of immune checkpoint inhibitors (ICIs). Recent clinical trials have demonstrated the survival advantages of several kinds of the first-line ICI combination therapy compared with sunitinib, suggesting that substantial improvements in survival for patients with mRCC could be achieved during the ICI era compared with the tyrosine kinase inhibitor (TKI) era. Besides the advancement of systemic anticancer therapy, surgical resection of the primary tumor or metastases remains an important option in the management of mRCC although the clinical implications of these surgeries have changed in the TKI era. In the Review Article by Naito et al. (Yamagata, Japan), the authors provided an excellent overview about cytoreductive nephrectomy, metastatectomy, and radiotherapy for metastatic lesions in the ICI era. At present, this topic has minimal evidence and further investigations are needed. This review will give some hints to the readers for tomorrow's practice. A difficult ureter (DU) is defined as a ureter that requires prestenting because a ureteroscope or a ureteral access sheath needed for treatment cannot be inserted during retrograde intervention. In the Original Article by Waseda et al. (Tokyo, Japan), the authors focused on risk factors and predictive models for ureteral difficulty during retrograde ureteroscopic lithotripsy in clinical practice. It is meaningful and important to predict DU prior to surgery because the presence or absence of DU is related to the success of the procedure. Interestingly, the absence of stone history was the greatest risk factor for developing DU, followed by age 45 years or younger and renal stones only. As the authors suggested, preoperative assessment of the risk of DU may be helpful in the informed consent for patients requiring retrograde lithotripsy. Surgical resection of RCC with inferior vena cava (IVC)–tumor thrombus (TT) is the standard of care for nonmetastatic patients and confers long-term survival. However, it is a technically challenging procedure with a high risk of morbidity (40–50%) and mortality (5–10%). One of the serious complications is intraoperative tumor embolism (iTE) of pulmonary artery. Currently, there is no consensus on whether it is optimal to perform thrombectomy before kidney mobilization (“thrombus first”) or vice versa (“thrombus last”). In the Original Article by Ishiyama et al. (Tokyo, Japan), the authors compared these two techniques focusing on iTE prevalence and other early surgical outcomes in 130 patients with RCC and IVC-TT. In this retrospective study, there were four cases (3.1%) of iTE, all from the thrombus-last group. Additionally, those who underwent the thrombus-first technique experienced shorter operation time, smaller estimated blood loss, fewer complications, and shorter in-hospital stay. “Thrombus-first” approach may be preferred when performing nephrectomy and caval thrombectomy under open procedures. Unfortunately, the limited space does not allow me to introduce all the articles. However, all the papers are interesting, informative, and well-illustrated. I hope you enjoy this issue of International Journal of Urology. None declared.

A network meta-analysis of efficacy and safety of first-line and second-line therapies for the management of metastatic renal cell carcinoma.

Metastatic renal cell carcinoma (mRCC) is the most common type of kidney cancers. Disease-specific survival for mRCC has been significantly improved with the introduction of new targeted agents since 2005. However, there is a lack of head-to-head clinical trials comparing the efficacy between therapies. This study compared indirectly progression-free survival (PFS) and overall survival (OS) among first-line and second-line therapies in patients with mRCC using network meta-analysis (NMA). The PubMed, MEDLINE, Cochrane Library and Web of Science were searched to identify phase II or phase III randomized controlled trials (RCTs) of targeted and biological therapies in patients with mRCC published between January 2000 and June 2020. The Bayesian fixed-effect NMA was performed to evaluate relative PFS and OS of first-line and second-line therapies of axitinib, bevacizumab, cabozantinib, everolimus, lenvatinib, nivolumab, ipilimumab, pazopanib, sorafenib, sunitinib, temsirolimus, tivozanib, avelumab and pembrolizumab, which were approved by the Food and Drug Administration or European Medicines Agency. End points were compared using hazard ratio (HR) and 95% credible interval (CrI). The surface under the cumulative ranking curve (SUCRA) was estimated to assess the probability of being the best treatment. A total of 26 RCTs (first line: 19, second line: 9) with 13893 patients were included in the NMA. For the first-line therapy, cabozantinib was associated with the highest improved PFS (HR=0.26, 95% CrI=0.14-0.44) followed by avelumab+axitinib and pembrolizumab+axitinib (HR=0.27, SUCRA=90%). Pembrolizumab+axitinib had a high likelihood of being the preferred treatment when using OS as the outcome measure (HR=0.41, 95% CrI=0.16-0.85). Avelumab+axitinib had the lowest HR compared with placebo+interferon on discontinuations due to AE (HR=1.04, 95% CrI=0.54-1.86). For second-line therapy, cabozantinib was identified as the most effective treatment option when assessing PFS (HR=0.17, 95% CrI=0.12-0.24). Axitinib had the lowest HR of OS and discontinuation due to AE (HR=0.54, 95% CrI=0.40-0.71; HR=0.98, 95% CrI=0.42-1.97, respectively). Pazopanib was the second choice in terms of OS (HR=0.56, 95% CrI=0.28-1.00; SUCRA=76%) compared with placebo. With respect to PFS and OS improvement, cabozantinib, avelumab+axitinib and pembrolizumab+axitinib are likely to be the preferred options for the first-line therapy and cabozantinib and axitinib for the second-line therapy in the management of mRCC. Regarding safety, avelumab+axitinib and temsirolimus were considered preferred treatment options in first-line and second-line therapies. More future research is needed to establish subgroup analyses, allowing evaluation of the impact of some of the differences in patient characteristics, including treatment effect modifiers.

Disparities in utilization of oral anticancer agents and related costs in elderly patients with metastatic renal cell carcinoma in the United States.

106 Background: Although survival among patients with metastatic renal cell carcinoma (mRCC) has improved with the introduction of targeted therapies, substantial disparities in mRCC survival persist. The purpose of this study was to identify patient characteristics associated with differential adoption of emerging oral anticancer agents (OAAs) and related costs in the management of mRCC. Methods: SEER-Medicare patients diagnosed with mRCC aged 65 years or older from 2007-2015 continuously enrolled in Medicare Part D benefits for at least 1 year after diagnosis or until death were included. Associations between patient-level characteristics and OAA receipt were analyzed using univariable and multivariable log-binomal regression; associations between patient characteristics, OAA receipt, and total, cancer-specific, and OAA-specific costs in the 12 months following diagnosis were modeled as relative cost ratios using generalized linear regression with a gamma link. Reported costs were adjusted to 2015 dollars. Results: 2,792 patients with mRCC met inclusion criteria; 32.4% received an OAA in the 12 months following diagnosis. The majority of patients receiving an OAA used either sunitinib or pazopanib. Receipt increased slightly over the study period from 2007 (31% of patients) to 2015 (37%). In multivariable-adjusted models, patients of advanced age ( > 80 years RR 0.50; 95% CI 0.42-0.60) or residing in the Southern US (RR 0.83 95% CI 0.70-0.98) were less likely to receive OAAs. Married patients were 20% more likely (RR 1.19; 95% CI 1.04-1.37) to receive OAAs. After multivariable adjustment, receipt of OAAs was associated with higher total and cancer-specific costs, as was Hispanic ethnicity. Among patients receiving an OAA, the cost of OAAs to Medicare increased approximately 7% per year (95% CI 4%-9%), while patient out-of-pocket spending for OAAs decreased approximately 10% per year (95% CI 7%-14%). Out-of-pocket OAA costs were consistently lower for Black, Hispanic, and Other patient race/ethnicity categories compared to the White Non-Hispanic category. Conclusions: Patient characteristics including age at metastatic diagnosis, marital status, geographic region, and certain comorbidities are related to the likelihood of receiving OAAs. Future research is warranted to investigate if such differences in OAA use lead to differences in survival.

Redefining the Role of Surgical Management of Metastatic Renal Cell Carcinoma.

The treatment landscape for metastatic renal cell carcinoma (mRCC) continues to evolve with ongoing advancements in systemic therapy, raising further questions about the optimal role of surgery in the management of mRCC. Herein, we provide a context and review of the recent evidence concerning the role of surgical therapy for patients with mRCC including cytoreductive nephrectomy and distant metastatectomy. One randomized trial has been published in the targeted therapy era suggesting that initial systemic therapy is non-inferior to cytoreductive nephrectomy among patients with intermediate and poor-risk mRCC. Delaying cytoreductive nephrectomy until after systemic therapy may be a viable treatment approach, although a high level of evidence is lacking. Additional questions remain regarding the sequence of surgery with systemic therapy, utility of distant metastatectomy, as well as the application of these findings to the current generation of immunotherapy. Recent evidence challenges the need of upfront cytoreductive nephrectomy for unselected patients with mRCC. However, surgical therapy continues to play an important role in the management of the disease.

The role of active surveillance and cytoreductive nephrectomy in metastatic renal cell carcinoma

Treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by an expanding armamentarium of systemic therapies, which have resulted in improved patient outcomes. Multimodal approaches that include cytoreductive nephrectomy (CN), immunotherapy, and targeted therapy are necessary to optimize clinical care. Active surveillance (AS) and CN are two cornerstones of treatment in mRCC, which require reexamination in the context of new systemic therapies. Herein, we review the data and provide a practical approach for the incorporation of AS and CN in the management of mRCC.

Reassessing the Role of Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma in 2019.

Cytoreductive nephrectomy (CRN) has long been considered a standard of care in the management of mRCC. This is largely based on randomized trials in the era of interferon (IFN) that demonstrate an improvement in overall survival (OS). With the advent of targeted therapies, the role of CRN has been questioned and multiple retrospective analyses have shown a potential benefit, particularly in intermediate-risk disease. Two long-awaited prospective trials have been published in the past year that explore the role of CRN. The CARMENA trial randomly assigned patients to therapy with sunitinib with or without CRN, showing noninferiority of sunitinib alone versus sunitinib plus CRN with a median OS of 18.4 months versus 13.9 months, respectively (hazard ratio [HR] for mortality, 0.89; 95% CI, 0.71-1.1). The SURTIME trial randomly assigned patients to immediate CRN followed by sunitinib versus a deferred CRN after three cycles of sunitinib. Analysis is limited by early termination as a result of low accrual. Although there was no difference in progression-free survival (PFS), median OS was significantly improved among patients in the deferred CRN arm (HR, 0.57; 95% CI, 0.34-0.95; p = .032). Early systemic therapy is paramount, but there are patients who may derive benefit by incorporating the removal of the primary tumor in their multimodal therapy, perhaps in a deferred setting. As systemic treatment paradigms shift and immunotherapy again moves to the frontline setting with the potential for novel therapeutic approaches, the role of CRN will continue to evolve with the potential to offer surgical interventions with minimal, if any, delay in systemic treatment.

The current state of immune checkpoint inhibitors in the first-line treatment of renal cancer.

Until recently, tyrosine kinase inhibitors (TKI) were the only approved drugs for the first-line treatment of metastatic renal cell carcinoma (mRCC). Emerging trials of immune checkpoint inhibitors (ICI)-based regimens have shown survival benefits over the standard TKI. These studies challenge a paradigm shift in the management of mRCC concerning the identification of the subgroup of patients that would benefit from ICI in treatment-naive mRCC, the possibility of treatment discontinuation between TKI and ICI, and the sequencing of surgery and systemic treatment. This paper reviews the currently available data and discusses the paradigm shift concerning first-line treatments of mRCC.

Mortality trends and the impact of lymphadenectomy on survival for renal cell carcinoma patients with distant metastasis.

Current treatment paradigms for metastatic renal cell carcinoma (mRCC) invoke a combination of surgical and systemic therapies. We sought to quantify trends in mortality and performance of lymphadenectomy, as well as impact on survival for patients with mRCC. The Surveillance, Epidemiology, and End Results registry (SEER) (1988-2011) identified patients with mRCC. Kaplan-Meier curves and Cox proportional hazards models with competing risks regression were employed to assess survival. 15 060 patients with mRCC were identified, with 6316 (41.9%) undergoing cytoreductive nephrectomy. Mean number of lymph nodes removed was 6.2, with mean 3.3 positive nodes among 1018 (43.9%) patients with positive nodes. Median overall survival (OS) increased from seven to 11 months (1999-2010), and finding a positive node decreased median cancer survival from 22 to nine months. Cancer-specific survival (CSS) showed significant decreases in mortality after 2005 (hazard ratio [HR] 0.71 [0.60-0.83] comparing 2010 to 1990). Lymphadenectomy was associated with decreased OS (HR 1.10 [1.03-1.16]; p=0.002) due to decreased CSS (HR 1.10 [1.04-1.17]; p<0.001) without increase in other-cause mortality (HR 0.94 [0.79-1.11]; p=0.455). However, more extensive lymphadenectomy ≥3 lymph nodes removed did not significantly impact OS or CSS. Number of positive lymph nodes was associated with decreased CSS. mRCC continues to carry a poor prognosis, but current treatment paradigms have led to modest improvements in OS and CSS in recent years. Lymphadenectomy was found to play a prognostic rather than therapeutic role in the management of mRCC. The performance of lymphadenectomy should be limited based on clinical judgment and better incorporated into randomized trials of new systemic therapies to identify scenarios where implementation may improve survival.

Cytoreductive Surgery in the Management of Renal Tumours: Rationale, Current Evidence and Future Perspectives.

Renal cell carcinoma accounts for 3% of adult solid malignant tumours. Approximately 25% of the patients present with metastatic disease at presentation. In the era of immunotherapy (interferon alpha-2b and interleukin-2), studies showed significant survival benefit with cytoreductive nephrectomy (CRN) followed by interferon alpha-2b than interferon alpha 2-b alone. Introduction of targeted therapies (vascular endothelial growth factor receptor-tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors) in 2005 generated a great interest in the management of metastatic renal cell carcinoma (mRCC) as these drugs exhibited tumour shrinkage in the primary tumour as well as in the metastatic site/s. Though there is no level 1 evidence, many studies have shown the usefulness of cytoreductive nephrectomy along with targeted therapy as against to targeted therapy alone. This review is aimed at the rationale behind the cytoreductive nephrectomy in mRCC, the current evidence and what is in store for the future. A detailed search on the management of mRCC was carried out on MEDLINE, Embase, CANCERLIT and Cochrane Library databases using the key words "cytoreductive nephrectomy", "immunotherapy" and "targeted therapy" since 1980 till 2015. Original articles, review articles, monograms, book chapters on metastatic renal cancer and textbooks on urologic oncology, oncology and urology were reviewed. Various international guidelines on this issue were also studied. An identical search was performed using the American Society of Clinical Oncology Abstract database. Trials in the progress or recently completed that were relevant to this paper were identified through clinicaltrials.gov. The latest information for new articles ahead of publication was last accessed in November 2015. CRN has remained an integral part to the management of metastatic renal cell carcinoma mainly for the patients with good performance status, life expectancy of more than 12months and in the absence of adverse prognostic factors. It had shown measurable survival benefit in the era of immunotherapy (CRN + immunotherapy vs. immunotherapy alone). In the era of targeted therapy, many studies have shown significant survival benefit with CRN + targeted therapy. However, there is no clear level 1 evidence to support this. The ongoing trials (CARMENA and European Organisation for Research and Treatment of Cancer SURTIME) would perhaps guide us in the way in which we should manage mRCC disease in the future. Maybe we may find some answers on the issues of the effectiveness of targeted therapy, the timing of CRN and sequencing these treatment arms once the results of these ongoing and future trials are through.

Axitinib in the treatment of renal cell carcinoma: patient selection and perspectives.

BackgroundAxitinib is a next-generation, selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors. It is approved for the treatment of metastatic renal cell carcinoma (mRCC) based on a demonstrated progression-free survival advantage over sorafenib in the second-line treatment setting. However, given the variety of available targeted therapies for mRCC, appropriate patient selection for the available therapies remains a significant clinical challenge.PurposeThis review summarizes the available evidence on the clinical, toxicity, and pharmacologic considerations for determining appropriate patient selection for axitinib therapy. In addition, it describes recent data on the use of predictive biomarkers to guide clinical management. This paper consists of material obtained via PubMed and Medline literature searches through October 2015.ConclusionAxitinib has a well-established role in the management of mRCC. Consistent clinical efficacy has been demonstrated across prognostic risk groups and prior therapeutic exposures. Although axitinib is generally well tolerated, appropriate toxicity management is critical to maximizing drug delivery and optimizing treatment outcomes. Although incident hypertension has been associated with improved clinical outcomes on axitinib, there are currently no validated clinical or genetic predictive biomarkers to guide patient selection.

Physician treatment selection in the prospective Metastatic Renal Cell Cancer (MaRCC) Registry.

563 Background: Clinical trials mRCC pts are different from real world pts, resulting in bias in the literature. The MaRCC Registry is designed to survey questions not asked in tri als, such as why physicians make certain management decisions. This analysis describes reasons for physician treatment (tx) selection in the first 109 real world pts enrolled in a multicenter, prospective, observational registry. Methods: MaRCC Registry will enroll 500 pts from up to 60 US academic (ACAD) and community (COMM) sites with ~2 years of recruitment and ≥ 3 years of follow-up. Key inclusion criteria are age ≥ 18 years and diagnosis of mRCC with no prior systemic therapy (STx) for mRCC at study entry. Pts currently not on STx but who are being observed are permitted. Key endpoints include descriptive characteristics of txs, tx and patient outcomes, medication adherence, and health resource utilization. Results: At data cutoff, 105 pts have been accrued with known STx status; median age 64 (Q1-3 range, 56-70); 66% male; 75% ACAD; 87% clear cell histology; and 31% stage IV at diagnosis. Initial management decision was: 40% deferred systemic therapy (DSTx), 22% pazopanib, 18% clinical trial, 10% sunitinib, and 6% other. Among STx pts (N = 61), the most common categories for therapy choice as selected by providers were likelihood of clinical benefit (41%) followed by pt characteristics (30%). Within the clinical benefit category, the most common reason was OS/PFS (31%). Within the pt characteristic category the most common reasons included performance status/frailty (12%) or prognostic factors (12%). Common reasons for DSTx pts (N = 44) were active surveillance (AS) with disease present (39%), AS without disease present following a procedure (11%), or local therapy (7%). ACAD sites had higher percentages of pts with DSTx undergoing AS with disease present and local therapy. Conclusions: This is the first report describing factors driving physician decision making in management of mRCC. Management choices are not captured in other prospective or retrospective studies. Early experience suggests that clinical benefit and pt characteristics were common reasons for initial STx. Side effect profile rarely determined initial STx selection.

Initial compared to deferred cytoreductive nephrectomy for metastatic kidney cancer and its association with improved survival in the targeted therapy era.

607 Background: Since 2005 seven new agents were approved for metastatic renal cell carcinoma (mRCC), demarcating a transition from the cytokine to the targeted therapy era. Trials demonstrated a survival benefit for upfront cytoreductive nephrectomy (CN) pre-2005. However, upfront versus delayed CN relative to targeted therapy has not been reported in the trial arena. We hypothesized that upfront CN confers a survival benefit in the targeted therapy era. We analyze survival in a population based cohort exposed to targeted therapies with upfront CN compared to deferred CN. Methods: Patients from SEER registries (2005-2011) with mRCC were categorized into: 1.) CN followed by targeted therapy or 2). initial targeted therapy. Additional exclusions were age &lt; 66, due to chance of uncaptured non-Medicare care, competing non-renal stage IV cancer and non-clear cell histology. Targeted therapy was identified from Medicare Part D files (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib, temsirolmus, everolimus) and duration of use. Clinical data, including co-morbidities, were obtained from Medicare inpatient and outpatient files, and cancer data from Medicare-linked SEER files. Unadjusted and multivariable Cox proportional hazards regression determined association between survival in the two groups. Propensity matching with bootstrapping was performed to control for measurable confounding in treatment selection. Results: Of 1,326 mRCC cases screened, 491 met the inclusion criteria. Median survival in the initial CN group (N = 194) was 20 months (IQR 12-32) compared to 14 months (IQR 6-27) in the initial targeted therapy group (N = 297, p &lt; 0.01). On multivariable analysis upfront CN was associated with improved survival (HR 0.57 95% CI 0.44, 0.74). On propensity matched analysis the survival advantage (average treatment effect on the treated, ATT) for upfront CN was 7.4 months (95% CI 3.86, 11.21). Conclusions: This study population closely resembles the treatment groups in ongoing randomized trials on the surgical management of mRCC in the targeted therapy era and demonstrates a survival advantage for upfront CN.

Anti-Angiogenic Drugs in the Treatment of Metastatic Renal Cell Carcinoma: Advances in Clinical Application

The current paradigm in attempting to treat metastatic renal cell carcinoma (mRCC) is a first line treatment with a vascular endothelial growth factor (VEGF) antagonist and second and subsequent treatments with either a vascular endothelial growth factor receptor (VEGFR) or an mTOR (mammalian Target of Rapamycin) inhibitor, while conventional chemotherapeutic and hormonal treatments do not play a role in the management of mRCC. Several drugs directed against VEGF and VEGFR have been developed in recent times. Phase III data validates sunitinib, pazopanib and sorafenib as the best-supported drugs in firstline therapy. Second-line treatment possibilities include axitinib, everolimus and sorafenib. Choosing the right combination of first and second line treatments, however, is difficult, because the success of treatment depends on the precondition of the patient. Hence, biomarkers indicating the best choice of therapy in individual patients are searched and newer trials are set to determine the role of surgery and vaccination together with anti-angiogenic drugs in the treatment of mRCC. In this review, current guidelines in mRCC management are summarized and possibilities of future personalized therapies are pointed out.

Management of metastatic renal cell carcinoma - mini review.

The management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the last decade. A number of different systemic molecular targeted agents that have been recently approved have improved the survival of patients with mRCC. This mini-review focuses on the implementation of multi-modality therapy in the management of mRCC and the approved indications of the various available novel agents. These novel agents have expanded our armamentarium and improved clinical outcomes of this challenging disease that has considerable biological heterogeneity and clinical variability.

More than 10 years survival with sequential therapy in a patient with advanced renal cell carcinoma: a case report.

Although radical nephrectomy alone is widely accepted as the standard of care in localized treatment for renal cell carcinoma (RCC), it is not sufficient for the treatment of metastatic RCC (mRCC), which invariably leads to an unfavorable outcome despite the use of multiple therapies. Currently, sequential targeted agents are recommended for the management of mRCC, but the optimal drug sequence is still debated. This case was a 57-year-old man with clear-cell mRCC who received multiple therapies following his first operation in 2003 and has survived for over 10 years with a satisfactory quality of life. The treatments given included several surgeries, immunotherapy, and sequentially administered sorafenib, sunitinib, and everolimus regimens. In the course of mRCC treatment, well-planned surgeries, effective sequential targeted therapies and close follow-up are all of great importance for optimal management and a satisfactory outcome.