International Metastatic Renal Cell Carcinoma Database Research Articles

Are markers of survival associated with perioperative outcomes for tumor thrombectomy patients?

Despite modern advances in surgical and perioperative technologies, management of renal cell carcinoma (RCC) with tumor thrombus (TT) is a morbid procedure that necessitates careful patient selection. It is not known whether established prognostic models for metastatic RCC are suitable prognostic tools for more immediate perioperative outcomes in patients with RCC with TT. We evaluated if established risk models for cytoreductive nephrectomy, as a potential extension of their purpose-built use, are associated with immediate perioperative outcomes in patients undergoing nephrectomy and tumor thrombectomy. Perioperative outcomes of patients who underwent radical nephrectomy and tumor thrombectomy for RCC were compared to presences of established predictors of long-term outcomes from prior risk models individually and as stratified by risk grouping (International Metastatic Renal-Cell Carcinoma Database Consortium [IMDC], Memorial Sloan Kettering Cancer Center [MSKCC], M.D. Anderson Cancer Center [MDACC], and Moffitt Cancer Center [MCC]). Wilcoxon rank-sum test or the Kruskal-Wallis test compared continuous variables and the chi-square test or Fisher's exact test compared categorical variables. Fifty-five patients were analyzed with 17 (30.9%) being cytoreductive. Eighteen (32.7%) patients had a level III or higher TT. Individually, preoperative variables were inconsistently associated with perioperative outcomes. Poorer risk patients per the IMDC model had more major postoperative complications (Clavien-Dindo grade≥3, P = 0.008). For the MSKCC model, poorer risk patients had increased intraoperative estimated blood loss (EBL), longer length of stay (LOS), more major postoperative complications, and more likely to discharge to a rehabilitation facility (P < 0.05). Less favorable risk patients per MDACC model had increased LOS (P = 0.038). Poorer risk patients per the MCC model had increased EBL, LOS, major postoperative complications, and 30-day hospital readmissions (P < 0.05). Overall, cytoreductive risks models were heterogeneously associated with perioperative outcomes in patients undergoing nephrectomy and tumor thrombectomy. Of available models, the MCC model is associated with more perioperative outcomes including EBL, LOS, major postoperative complications, and readmissions within 30 days when compared to the IMDC, MSKCC, and MDACC models.

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma

BackgroundThe efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.MethodsIn this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.ResultsOverall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P=0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.ConclusionsAmong patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.)

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

The Predictive Value of Three Variables in Patients with Metastatic Renal Cell Carcinoma Treated with Immune-Based Combination Therapies in Randomized Clinical Trials: A Systematic Review and Meta-Analysis.

Background Sex, age, and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic risk may influence the immune response. Nonetheless, the correlation between these factors and the survival benefits of immune-based combination therapies in patients with metastatic renal cell carcinoma (mRCC) is controversial and undefined. As a result, the purpose of this research is to evaluate the potential differences of immune-based combination therapies on survival benefits from mRCC subgroups. Methods PubMed, Cochrane Library, Embase, and http://www.clinicaltrials.gov were searched from inception to March 17, 2022. Randomized clinical trials (RCTs) comparing overall survival (OS) or progression-free survival (PFS) in patients with mRCC treated by immune-based combinations vs. contemporary first-line therapies were included. Results Five RCTs with a total of 4206 subjects were included. An OS and PFS benefit of immune-based combinations were found for patients of different sex, age, and IMDC intermediate/poor risk. No obvious difference in relative PFS benefit from immune-based combinations over the control group was found in patients of different genders (P=0.71, I2 = 0%), ages (P=0.55, I2 = 0%), or IMDC prognostic risks (P=0.38, I2 = 0%). However, the difference in OS benefit was significant regarding age (P=0.009, I2 = 85.5%) and IMDC prognostic risk (P=0.004, I2 = 82.2%). Conclusions This meta-analysis found that immune-based combination therapies should not be restricted to certain patients with mRCC in gender categories. However, age and IMDC prognostic risk of mRCC patients are associated with different outcomes of OS and thus help identify those patients most probably to benefit from immune-based combination therapies.

Clinicopathological characteristics and prognosis of metastatic collecting duct carcinoma

To investigate the clinicopathological characteristics, response to different treatment regimens, and prognostic factors of metastatic collecting duct carcinoma (CDC). Information of patients with metastatic CDC was retrieved from a database including clinical and survival data. Survival outcomes were analyzed with the Kaplan-Meier method, and prognostic factors were identified with the Cox proportional hazard model. Fifty patients with metastatic CDC were included in this study. Most patients had an advanced T stage (58% T3-4) and high WHO/ISUP grade (86% G3-4). Twenty-nine patients (58%) developed metastases from an early stage, 42% had distant metastases at diagnosis, and 28% received cytoreductive nephrectomy. In the first-line setting, the objective response rate was 27.0%, and the median progression-free survival was 6.4 months (95%CI 4.9-7.9) for 37 patients who received chemotherapy combined with sorafenib. One PR was seen in 4 patients who received anti-PD-1 antibody plus axitinib. The median overall survival for the whole population was 12.6 months (95%CI 7.8-17.4). In univariate analyses, advanced T stage, East Cooperative Oncology Group Performance Score ≥1, anemia, elevated lactate dehydrogenase, and no response to first-line treatment was associated with poor prognosis (P < 0.05). In multivariate analyses, advanced T stage and anemia were independently associated with a poorer prognosis. The Memorial Sloan-Kettering Cancer Center (MSKCC) model (P = 0.002) predicted the prognosis of metastatic CDC patients more accurately than the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) model (P = 0.063). T Stage and anemia were independent prognostic factors for metastatic CDC. MSKCC was more accurate than the IMDC model to predict the outcome. Chemotherapy plus sorafenib demonstrated substantial efficacy in the first-line setting. Anti-PD-1 plus axitinib showed a preliminary antitumor effect and is worthy of further exploration.

Comparison of First-Line Anti-PD-1-Based Combination Therapies in Metastatic Renal-Cell Carcinoma: Real-World Experiences from a Retrospective, Multi-Institutional Cohort

Introduction: The aim of this study was to test for differences in overall (OS) and progression-free survival (PFS) rates and toxicity in first-line immune checkpoint inhibition (IO) combination therapy in metastatic renal-cell carcinoma (mRCC) patients. Methods: Between November 2017 and April 2021, 104 patients with histologically confirmed mRCC from 6 tertiary referral centers with either IO + IO (nivolumab + ipilimumab, n = 68) or IO + tyrosine kinase inhibitor (TKI) (pembrolizumab + axitinib, n = 36) were included. Kaplan-Meier and Cox regression analyses tested for OS and PFS differences. Results: Of 104 mRCC patients, 68 received IO + IO (65.4%) and 36 IO + TKI (34.6%) therapy, respectively. Median age was 67 years (interquartile range: 57–70.3). Patients receiving IO + TKI were less likely to be poor risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium score (16.7 vs. 30.9%) and presented with lower T-stage, compared to IO + IO treated patients. Median PFS was 9.8 months (CI: 5.3–17.6) versus 12.3 months (CI: 7.7 – not reached) for IO + IO versus IO + TKI treatment, respectively (p = 0.22). Median OS was not reached, survival rates at 12 months being 73.9 versus 90.0% for IO + IO versus IO + TKI patients (p = 0.089). In subgroup analyses of elderly patients (≥70 years, n = 38), IO + TKI treatment resulted in better OS rates at 12 months compared to IO + IO (91.0 vs. 57.0%; p = 0.042). Conclusion: IO + IO and IO + TKI as first-line therapies in mRCC patients were both comparable as for the oncological outcome and toxicity.

Real-world evidence on first-line treatment for metastatic renal cell carcinoma with non-clear cell and sarcomatoid histologies: are sunitinib and pazopanib interchangeable?

IntroductionNon-clear cell renal cell carcinoma (nccRCC) and sarcomatoid renal cell carcinoma (sRCC) are underrepresented in clinical trials. Treatment approaches are frequently extrapolated from data of clear cell renal cell carcinoma, in which pazopanib is non-inferior to sunitinib. We aim to compare the effectiveness of first-line sunitinib and pazopanib for nccRCC and sRCC.MethodsWe evaluated a retrospective cohort of patients with metastatic nccRCC and sRCC treated with first-line sunitinib or pazopanib at an academic cancer centre. Overall survival (OS), progression-free survival (PFS) and response rate were measured. Kaplan–Meier and log-rank analyses were used for time-to-event data. Cox regression was used for prognostic factors.ResultsFifty-three patients were included; 16 (30.1%) treated with sunitinib and 37 (69.9%) with pazopanib. Forty-six (86.8%) patients had nccRCC and 7 (13.2%) had sRCC. The majority had intermediate or poor International Metastatic Renal-Cell Carcinoma Database Consortium risk (93%).Median PFS was 6.6 months with sunitinib and 4.9 months with pazopanib (HR 1.75; P = 0.078). Treatment with pazopanib was associated with inferior OS in comparison with sunitinib (median OS: 30.4 months versus 8.7 months; HR 2.71, 95% CI 1.31–5.58, P = 0.007). These results were confirmed in subgroup analysis of patients with papillary, chromophobe and MiT family translocation histologies (median OS: 38.7 months versus 14.7 months; HR 3.16, 95% CI 1.20–8.29, P = 0.019). Unclassified and sarcomatoid histologies had inferior OS (median: 6.9 and 1.1 months, respectively) regardless of the treatment used.ConclusionIn this patient cohort, pazopanib was associated with inferior OS in comparison with sunitinib for metastatic nccRCC. Larger trials are ideally warranted to confirm these results.

First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Results from the International Metastatic Renal-cell Carcinoma Database Consortium

BackgroundIn metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited. ObjectiveTo compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies. Design, setting, and participantsUsing the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo. InterventionAll patients received first-line IO combination therapies. Outcome measurements and statistical analysisFirst- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors. Results and limitationsIn total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] –8% to 22%, p = 0.4), TTF was 14.3 versus 10.2 mo (p = 0.2), TNT was 19.7 versus 17.9 mo (p = 0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46–1.12, p = 0.14), 0.65 (95% CI 0.38–1.11, p = 0.11), and 1.74 (95% CI 0.82–3.68, p = 0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3–57%, p = 0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p = 0.4; n = 55). Limitations include the study’s retrospective design and sample size. ConclusionsThere were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially. Patient summaryThere were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.

Validation of the IMDC Prognostic Model in Patients With Metastatic Renal-Cell Carcinoma Treated With First-Line Axitinib: A Multicenter Retrospective Study.

The objective of the study was to validate the characteristics of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model in patients treated with first-line axitinib in clinical practice. We retrospectively evaluated 143 patients with metastatic renal-cell carcinoma who were treated with axitinib as the first-line therapy between October 2008 and February 2019. Overall survival (OS) was evaluated according to the IMDC prognostic model. We investigated the intragroup heterogeneity in the intermediate-risk group and divided these patients according to abnormal C-reactive protein (CRP) levels. An inverse probability of treatment-weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate the effects of the CRP-risk model of OS in the patients in the IMDC intermediate-risk group. A significant difference in OS was observed in patients in the IMDC intermediate- and poor-risk group, although no significant difference was observed between the IMDC favorable- and intermediate-risk group. Significantly shorter prognosis was observed in patients in the IMDC intermediate-risk group who had 2 risk factors and CRP≥0.3 mg/dL (inter-high group) than in those with 1 risk factor or 2 risk factors with CRP<0.3 mg/dL (inter-low group). IPTW-adjusted Cox regression analysis revealed significant differences in the OS between the inter-low and inter-high groups. The IMDC prognostic model was active in patients who received first-line axitinib treatment. The combination of CRP value with the number of positive risk factors in the IMDC model might predict prognosis in patients with IMDC intermediate-risk treated with first-line axitinib.

The Value of Neutrophil to Lymphocyte Ratio in Patients Undergoing Cytoreductive Nephrectomy with Thrombectomy

BackgroundThe neutrophil-lymphocyte ratio (NLR) is an established signature of inflammation used for evaluating renal cell carcinoma (RCC). ObjectiveTo determine the utility of NLR and its relationship with known risk factors associated with poor survival in patients with metastatic RCC and tumor thrombus undergoing cytoreductive nephrectomy (CN). Design, setting, and participantsPrognostic variables were reviewed for patients undergoing CN with thrombectomy between 2000 and 2014 from six different institutions. Patients were stratified for NLR >4.0 based on cut point analysis. Outcome measurements and statistical analysisKaplan-Meier curves compared overall survival of the total cohort and established risk models (Memorial Sloan Kettering Cancer Center [MSKCC], International Metastatic Renal-Cell Carcinoma Database Consortium [IMDC], and M.D. Anderson Cancer Center [MDACC]) stratified by NLR. Multivariable Cox regression determined predictors of overall survival. Receiver operator characteristic curves tested the predictive accuracy of survival ≥12 mo, and area under the curve (AUC) was compared between models. Results and limitationsIn total, 332 patients were identified. Patients with NLR ≤4.0 had longer median survival (24.7 vs 15.2 mo, p=0.004). NLR >4.0 distinguished patients with significantly shorter survival for non-poor-risk groups defined by MSKCC, IMDC, and MDACC criteria. Systemic symptoms, low hemoglobin, elevated lactate dehydrogenase, retroperitoneal adenopathy, level IV thrombus, elevated absolute neutrophil count, and NLR >4 were independent predictors of decreased survival (p<0.05). These factors had higher predictive accuracy for survival at 12 mo (AUC=0.755) than MKSCC, IMDC, and MSKCC models. ConclusionsNLR >4.0 independently predicts poor survival and further distinguishes established risk model survival curves. We identified seven preoperative risk factors related to poor survival for patients with metastatic RCC with tumor thrombus undergoing CN. Patient summaryThe neutrophil-lymphocyte ratio and six additional preoperative variables can be used to better council patients regarding survival after surgery for metastatic renal cell carcinoma with tumor thrombus.

Tumor infiltrating CD19+ B lymphocytes predict prognostic and therapeutic benefits in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

ABSTRACTThe objective response rate (ORR) of tyrosine kinase inhibitors (TKIs) therapy in metastatic renal cell cancer (mRCC) patients was not satisfactory. Effective indicator of mRCC patient selection for TKI therapy is urgently needed. The function of tumor infiltrating B lymphocytes (TIBs) in tumor immune elimination is still unclear. We aim to investigate the prognostic and predictive value of TIBs for TKI therapy in mRCC patients in this study. 108 eligible patients treated with TKI were enrolled in this study. TIBs was estimated by immunohistochemical staining of CD19 in the resected tumor, and its relationship with clinicopathological features, clinical outcomes and CD8+ tumor infiltrating T lymphocytes (CD8+ TILs) were evaluated. Associations between the expression level of CD19 and CD8+ TILs associated cytotoxic effectors were also assessed in public databases. Results showed TIBs positive infiltration predicted better therapeutic response to sunitinib (p = 0.006), longer overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p = 0.028) in mRCC patients. Combining TIBs and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) model showed a better predict value of OS in TKI-treated mRCC patients than IMDC model alone. We also found a positive correlation between TIBs and CD8+ TILs (p < 0.001). Patients with both cells high infiltration showed markedly better OS compared with those infiltrated by CD8+ T cells alone (p = 0.015). To conclude, TIBs density was not only an independent prognostic factor for mRCC patients, but also a predictive marker for TKI therapy response. It may potently enhance the antitumor effect by recruiting and activating CD8+ TILs in mRCC.

CT texture analysis: a potential tool for prediction of survival in patients with metastatic clear cell carcinoma treated with sunitinib

BackgroundTo assess CT texture based quantitative imaging biomarkers in the prediction of progression free survival (PFS) and overall survival (OS) in patients with clear cell renal cell carcinoma undergoing treatment with Sunitinib.MethodsIn this retrospective study, measurable lesions of 40 patients were selected based on RECIST criteria on standard contrast enhanced CT before and 2 months after treatment with Sunitinib. CT Texture analysis was performed using TexRAD research software (TexRAD Ltd, Cambridge, UK). Using a Cox regression model, correlation of texture parameters with measured time to progression and overall survival were assessed. Evaluation of combined International Metastatic Renal-Cell Carcinoma Database Consortium Model (IMDC) score with texture parameters was also performed.ResultsSize normalized standard deviation (nSD) alone at baseline and follow-up after treatment was a predictor of OS (Hazard ratio (HR) = 0.01 and 0.02; 95% confidence intervals (CI): 0.00 – 0.29 and 0.00 – 0.39; p = 0.01 and 0.01). Entropy following treatment and entropy change before and after treatment were both significant predictors of OS (HR = 2.68 and 87.77; 95% CI = 1.14 – 6.29 and 1.26 – 6115.69; p = 0.02 and p = 0.04). nSD was also a predictor of PFS at baseline and follow-up (HR = 0.01 and 0.01: 95% CI: 0.00 – 0.31 and 0.001 – 0.22; p = 0.01 and p = 0.003). When nSD at baseline or at follow-up was combined with IMDC, it improved the association with OS and PFS compared to IMDC alone.ConclusionSize normalized standard deviation from CT at baseline and follow-up scans is correlated with OS and PFS in clear cell renal cell carcinoma treated with Sunitinib.

2602 Pazopanib (Pz) as first line for metastatic renal carcinoma (mRC): Updated validation of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (IMRCC). The SPAZO study (SOGUG)

2602 Pazopanib (Pz) as first line for metastatic renal carcinoma (mRC): Updated validation of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (IMRCC). The SPAZO study (SOGUG)

Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

Background:We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials.Methods:Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on–2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice.Results:A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15–17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8–10.0) and 18.7 months (95% CI: 17.5–19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand–foot syndrome (each 7%).Conclusion:Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Validation of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (IMRCC), in patients (pt) treated with pazopanib (Pz) as first line for metastatic renal carcinoma (mRC): First results of the SOGUG SPAZO study.

e15597 Background: The IMRCC prognostic model for mRCC treated with VEGF-targeted agents (Heng, JCO '09) has been externally validated (Heng, Lancet Oncol '13), however, pt treated with Pz were not...

05 Patients with metastatic papillary Renal Cell Carcinoma (RCC) who may benefit from sunitinib therapy (tx): Results from an international metastatic RCC database

05 Patients with metastatic papillary Renal Cell Carcinoma (RCC) who may benefit from sunitinib therapy (tx): Results from an international metastatic RCC database

Patients with metastatic papillary renal cell carcinoma (RCC) who may benefit from sunitinib therapy (tx): Results from an international metastatic RCC database.

Patients with metastatic papillary renal cell carcinoma (RCC) who may benefit from sunitinib therapy (tx): Results from an international metastatic RCC database.

Patients with metastatic papillary renal cell carcinoma (RCC) who may benefit from sunitinib therapy (tx): Results from an international metastatic RCC database.

486 Background: The VEGFR inhibitor sunitinib is a standard tx for metastatic clear cell RCC. Data on the activity of sunitinib in metastatic non clear cell RCC, is limited by small or heterogeneous (mixed histology or targeted therapies) studies, that revealed a lower antitumor activity than in patients with clear cell histology. We aimed to analyze the activity of sunitinib in a large international cohort of patients with metastatic papillary RCC, and to characterize patients who may benefit for this therapy. Methods: Records from metastatic papillary RCC patients treated with sunitinib in 10 centers across 3 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and clinical outcome were performed using Cox regression. Results: Between 2004-2013, 74 patients (median age 60, 68% male) with metastatic papillary RCC were treated with sunitinib. 78% had a prior nephrectomy. HENG risk was good 11%, intermediate 56%, and poor 33%. 21% were active smokers, and 31% users of angiotensin system inhibitors. 24% and 41% had liver and bone metastases, respectively. 55% had a pre-treatment neutrophil to lymphocyte ratio (NLR) &gt;3. 40% had dose reduction/treatment interruption. Sunitinib induced hypothyroidism and hypertension (HTN) occurred in 30% and 43%, respectively. 70% achieved a clinical benefit (partial response + stable disease), while 30% had disease progression within the first 3 months of therapy. Median progression free survival (PFS) and overall survival (OS) were 5 and 12 months, respectively. 27% had a PFS ≥ 1 year, and 26% survived ≥ 2 years. Factors associated with PFS were sunitinib induced HTN (HR 0.31, p=0.002), pre-treatment NLR &gt;3 (HR 5.3, p=0.001), and active smoking (HR 2.5, p=0.01). Factors associated with OS were sunitinib induced hypothyroidism (HR 0.4, p=0.024), past nephrectomy (HR 0.41, p=0.02), pre-treatment NLR &gt;3 (HR 2.25, p=0.036), and active smoking (HR 2.3, p=0.027). Conclusions: Clinicopathologic factors may be used to identify patients with metastatic papillary RCC who may benefit from sunitinib tx. A prolonged PFS and OS were noted in 26-27% of patients.

Prognostic Impact of Preoperative Neutrophil-to-Lymphocyte Ratio in Localized Nonclear Cell Renal Cell Carcinoma

The preoperative neutrophil-to-lymphocyte ratio was proposed as a prognostic factor for localized clear cell renal cell carcinoma. We evaluated its role in nonclear cell renal cell carcinoma. We queried 2 prospective kidney cancer databases. Patients who underwent full resection of localized (T1-3 N0/+ M0) nonclear cell renal cell carcinoma by radical or partial nephrectomy were included in analysis. Associations of the continuously coded neutrophil-to-lymphocyte ratio with disease-free survival were assessed with univariable and multivariable Cox regression models. Prognostic accuracy was evaluated with the Harrell concordance index. Our final cohort included 281 patients. The 5-year disease-free survival rate was 88.1%. The neutrophil-to-lymphocyte ratio was significantly associated with disease-free survival. With each 1.0 increase in the ratio the risk of recurrence increased by 15% (HR 1.15, p=0.028). On multivariable analysis TNM group (HR 2.84, p=0.025), Fuhrman grade (HR 3.40, p<0.001) and the neutrophil-to-lymphocyte ratio (HR 1.17, p=0.022) were independently associated with disease-free survival. Adding the neutrophil-to-lymphocyte ratio improved the accuracy of a base model to predict disease-free survival from 78.8% to 80.8%. The neutrophil-to-lymphocyte ratio is an independent prognostic factor for disease-free survival after surgery with curative intent for localized nonclear cell renal cell carcinoma. It significantly increases the accuracy of established prognostic factors. The neutrophil-to-lymphocyte ratio may provide a meaningful adjunct for patient counseling and clinical trial design.

External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study

The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy of the model in an external population and compared it with other prognostic models. We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium's database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit. Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6-21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status <80%, and <1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68-0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4-50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7-25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5-9·7) in the poor risk group (three or more risk factors; 252 patients; p<0·0001; concordance index 0·664, 95% CI 0·639-0·689). 672 patients had complete data to test all five models. The concordance index of the CCF model was 0·662 (95% CI 0·636-0·687), of the French model 0·640 (0·614-0·665), of the IKCWG model 0·668 (0·645-0·692), and of the MSKCC model 0·657 (0·632-0·682). The reported versus predicted number of deaths at 2 years was most similar in the Database Consortium model compared with the other models. The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis. None.