 Thank you very much for the opportunity over the next few minutes to share our project looking at the utilization of cyto-reductive nephrectomy and patient survival in the targeted therapy era. No financial disclosures outside of funding sources. We know that cyto-reductive nephrectomy has utility and benefit in patients treated in the cytokine era and we know this from randomized clinical data. But the utility of cyto-reductive nephrectomy in the targeted therapy era is not well established and is widely debated. We sought to look at the temporal trends of utilization of cyto-reductive nephrectomy as well as patient survival, comparing survival in the targeted therapy era with previous. We hypothesized that cyto-reductive nephrectomy continues to offer a survival benefit for patients and to evaluate this hypothesis we looked at SEER data encompassing more than 20,000 patients with metastatic renal cell carcinoma between 1993 and 2010. This is our table one showing the patient demographics stratified by the receipt of cyto-reductive nephrectomy. And as we've already talked about at this meeting earlier today, anytime you evaluate the benefit of a surgical procedure, in particularly in evaluating retrospective data, you have to control for selection bias and you have to be aware of its potential to confound the results. And as you can expect, patients that received cyto-reductive nephrectomy differed from the remainder of the cohort in every possible way that we could measure. So first, to evaluate the utility of cyto-reductive nephrectomy knowing that selection bias and other potential confounders exist in retrospective data, we evaluated the utilization of cyto-reductive nephrectomy by year. And cyto-reductive nephrectomy increased from its lowest value at the beginning of the study period and peaked in 2004 with 39 percent of patients receiving a cyto-reductive nephrectomy in that year. And when you perform joint point regression, you see that a single joint point best explains the data. And this occurred in 2004. And beginning in 2005, there was a modest reduction in the utilization of cyto-reductive nephrectomy coinciding with the introduction of targeted therapies. So next, we wanted to evaluate what patient and tumor factors were associated with the receipt of cyto-reductive nephrectomy. So we fit univariable and multivariable logistic regression models to predict patients' receipt of cyto-reductive nephrectomy. And we identified several interesting disparities. First, older patients were less likely to receive a cyto-reductive nephrectomy, and this does not come as a surprise. But black patients in other patient categories were also less likely to receive a cyto-reductive nephrectomy. But for the purpose of this study evaluating cyto-reductive nephrectomy in the targeted therapy era, I want to bring your attention to the year of the patient's diagnosis. And when this was evaluated as a continuous variable or stratified by treatment era, after adjusting for patient and tumor characteristics, it was not an independent predictor of receipt of cyto-reductive nephrectomy. And this suggests that the modest decline in utilization may not be due to physicians changing their selection criteria for patients for surgery. Next, we evaluated the overall unadjusted survival for patients that received cyto-reductive nephrectomy. And so here's our Kaplan-Meier curves, and in the blue you can see patients treated in the cytokine era, and in the red, the targeted therapy era. If you look at the dashed lines at the bottom, you can see that patients that did not receive a cyto-reductive nephrectomy experienced a mild benefit in the targeted therapy era, with their median overall survival increasing from three months to four months. For patients that did receive a cyto-reductive nephrectomy, we see a much more significant increase, ranging from 13 to 19 months in the targeted therapy era. And here on the right, I've plotted the median difference in survival for patients that did receive cyto-reductive nephrectomy by year again. And you can see that this difference has increased over time and has continued to increase in the targeted therapy era. So next, to adjust for selection bias, we employed several epidemiologic and econometric models. At first, we performed a multi-variable proportional hazards model. And this identified the benefit of cyto-reductive nephrectomy offering a 60% reduction in the hazard mortality of mortality. And the treatment era was also associated with an independent benefit in survival, a 13% reduction in the hazard. And if you plot the hazard associated with cyto-reductive nephrectomy in a fully adjusted model by year, you can see that the hazard or improved survival for patients that did receive a cyto-reductive nephrectomy has continued. And the lowest hazard ratios for cyto-reductive nephrectomy are in the most recent study years, which represent targeted therapy era. Next, we employed propensity score matching to further evaluate and control for selection bias. And what I'm shown here is the full cohorts, Kaplan-Meier curve on the left and the propensity score matched cohort on the right. And you can see that the overall survival curves are essentially unchanged. And similarly, when we evaluate the Cox proportional hazards models, the point estimates are very similar for the propensity score matched group. Third, we employed a difference in difference analysis. And this is an econometric method that's not commonly seen in clinical research, but is well suited to testing new therapies in differential eras. Essentially, we're taking advantage of a natural experiment, which is in the targeted therapy era. The systemic therapy for metastatic kidney cancer has changed. While the technical aspects of a cyto-reductive nephrectomy have not. So we can now compare the outcomes for patients that receive surgery from before and after using this model to see if there's an improvement or worsening of overall survival in the targeted therapy era for these patients. And what I can show you here is that cyto-reductive nephrectomy in this model retains its overall survival benefit. That patients treated in the targeted therapy era also had a survival benefit. But the interaction between cyto-reductive nephrectomy and targeted therapy era provided an additional benefit. In other words, patients that were treated in the targeted era lived longer. Patients that received a cyto-reductive nephrectomy lived longer. But the best survival was for patients that received a cyto-reductive nephrectomy in the targeted therapy era, even when compared to those that received surgery previously. So in conclusion, while we've done a lot of heavy lifting to try to address selection bias, we are still evaluating retrospective data. So for that reason, we still await the outcomes of prospective trials, such as the Carmina trial, to evaluate the true benefit of cyto-reductive nephrectomy in this patient population. We now know that approximately one in three patients receives a cyto-reductive nephrectomy and that in the targeted therapy era, at least through 2010, the utilization of cyto-reductive nephrectomy was declining slightly. But despite this slight decline in the use of cyto-reductive nephrectomy, the retrospective data after multiple attempts to adjust for selection bias suggests that there is a survival benefit for patients that receive surgery in the targeted therapy era, and a suggestion that this benefit actually may be greater in the targeted therapy era when compared with previous years. Thank you very much for your attention.