Memorial Sloan-Kettering Cancer Center Risk Research Articles

Second-Line Treatment of Metastatic Renal Cell Carcinoma in the Era of Predictive Biomarkers.

Over the past few years, significant advancements have been achieved in the front-line treatment of metastatic renal cell carcinomas (mRCCs). However, most patients will eventually encounter disease progression during this front-line treatment and require further therapeutic options. While treatment choices for mRCCs patients are determined by established risk classification models, knowledge of prognostic factors in subsequent line therapy is essential in patient care. In this retrospective, single-center study, patients diagnosed with mRCCs who experienced progression after first-line therapy were enrolled. Fifteen factors were analyzed for their prognostic impact on survival using the Kaplan-Meier method and the Cox proportional hazards model. Poor International Metastatic RCCs Database Consortium (IMDC) and Memorial Sloan-Kettering Cancer Center (MSKCC) risk scores, NLR value > 3, clinical benefit < 3 months from a therapeutic line, and the presence of sarcomatoid differentiation were found to be poor independent prognostic factors for shortened overall survival. This study provided new insights into the identification of potential prognostic parameters for late-line treatment in mRCCs. The results indicated that good IMDC and MSKCC prognostic scores are effective in second-line therapy. Moreover, patients with NLR < 3, no sarcomatoid differentiation, and clinical benefit > 3 months experienced significantly longer overall survival.

Long-term survivorship rates among patients with previously treated advanced renal cell carcinoma receiving nivolumab: Analyses based on ≥ 7 years of follow-up from CheckMate 025 trial.

729 Background: The phase 3 CheckMate 025 study has shown sustainable and superior long-term survival outcomes for previously treated aRCC patients receiving NIVO over everolimus. This exploratory analysis investigated the survival heterogeneity within the NIVO arm of CheckMate 025 borne by the underlying fraction of potential long-term survivors (LTS). Methods: OS and PFS outcomes from the trial with minimum 7-years of follow-up were analyzed separately using mixture cure models (MCMs). In MCMs, patients were probabilistically classified in mutually exclusive subgroups as LTS or non-LTS, where LTS were assumed to be free of disease-related mortality risk. In the analysis of PFS outcomes, LTS were also assumed to be free of progression risk. In the MCMs, the survival trend for LTS was estimated using age- and sex-adjusted background mortality rates reported by the World Health Organization and patients’ enrolment distribution across the countries participating in the trial. Time-to-event outcomes for non-LTS were modelled using candidate parametric distributions, which were estimated simultaneously with the proportion of LTS by maximum likelihood methods. Model selection was based on statistical goodness-of-fit metrics, visual comparison to observed survival curves, and longer-term clinical plausibility. Effects of selected baseline covariates on the proportion of LTS were also analyzed using OS data. Results: The best-fitting models indicated that the proportion of LTS was 17.5% (95% confidence interval (CI): 13.0%-23.2%) from the OS data and 4.7% (95% CI: 2.5%-8.4%) from the PFS data. Across all clinically plausible candidate models, estimated proportion of LTS ranged between 15.2%-18.0% where the range of progression-free LTS was 2.6%-6.7%. Lifetime mean OS and PFS projected by the best-fitting MCMs over a 30-year time horizon was 64.6 (95% CI: 56.0-77.1) and 19.1 (95% CI: 15.0-25.3) months, respectively. Estimated 10- and 30-year OS rates from the best-fitting MCMs were 14.7% (95% CI: 11.9%-20.3%) and 4.6% (95% CI: 3.6%-6.4%), respectively. Corresponding 10- and 30-year PFS rates were 3.9% (95% CI: 2.0%-6.4%) and 1.2% (95% CI: 0.5%-2.0%), respectively. Odds ratios for likelihood of being LTS between subgroups classified by Memorial Sloan Kettering Cancer Center (MSKCC) Risk Criteria (intermediate/poor vs favourable) was 0.37 (95% CI: 0.28-0.48), by PD-L1 status (&lt; 1% vs ≥ 1%) was 0.58 (95% CI: 0.45-0.75), and by number of sites with metastases (≥ 2 vs 1) was 0.25 (95% CI: 0.19-0.33). Conclusions: A moderate proportion of aRCC patients treated with NIVO in CheckMate 025 can be projected as LTS with a smaller fraction subject to no risk of progression. Having a favourable MSKCC risk score, positive PD-L1 status, or only one site of metastasis were associated with improved odds of long-term survivorship.

Prognostic factors for patients with advanced renal cell carcinoma (aRCC) in the era of first-line (1L) treatment with immune checkpoint inhibitors (ICIs).

4544 Background: The most commonly used prognostic models in aRCC, the Memorial Sloan-Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, were developed when cytokines and VEGF targeted monotherapies were standard of care, respectively. aRCC 1L treatment now includes combination therapy with 2 ICIs or ICI+VEGF receptor inhibitor. Re-evaluation of the MSKCC and IMDC prognostic models in the era of ICI therapy and identification of additional prognostic factors are overdue. Methods: Data from 1052 patients with aRCC treated on the CheckMate-214 (CM214) clinical trial with 1L nivolumab/ipilimumab (NIVO/IPI) or sunitinib (SUN) were analyzed retrospectively at median follow-up 5 yrs. For each treatment group, multivariable Cox model hazard ratios (HR) were compared to the published MSKCC and IMDC model HRs. Discrimination (c index) was assessed based upon the continuous scores obtained as the weighted combination of regression parameters from the published MSKCC &amp; IMDC models. Results: KPS &lt; 80% remained highly prognostic in both treatment groups (HRs &gt; 2.5). With the exception of high calcium, the other factors of time from dx to treatment &lt; 1 yr, hemoglobin &lt; lower limit of normal (LLN), neutrophils &gt; upper limit of normal (ULN), platelets &gt; ULN and LDH &gt; 1.5xULN consistently retained prognostic value for SUN (HRs ≥ published model HRs) but had diminished prognostic value for NIVO/IPI (each HR &lt; published model HR). High calcium had diminished prognostic value for SUN and retained prognostic value for NIVO/IPI. The c-indices for discrimination were 0.61 and 0.64 for the MSKCC model in the NIVO/IPI and SUN treatment groups, respectively, and were 0.63 and 0.67 for the IMDC model in the NIVO/IPI and SUN treatment groups compared to reported IMDC c-index of 0.73 (Heng 2009). (Table) Conclusions: The prognostic ability of the MSKCC and IMDC risk models is reduced with combination ICI treatment. Evaluation of additional prognostic factors and development of new risk scores are needed and this work is ongoing. [Table: see text]

MP14-12 DISAGREEMENTS BETWEEN MEMORIAL SLOAN KETTERING CANCER CENTER (MSKCC) AND THE INTERNATIONAL METASTATIC RCC DATABASE CONSORTIUM (IMDC) PROGNOSTIC SCORE AND THEIR IMPACT ON SURVIVAL OUTCOMES IN CLEAR-CELL METASTATIC RENAL CELL CARCINOMA (mRCC) PATIENTS TREATED WITH TYROSINE-KINASE INHIBITORS (TKI)

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) I (MP14)1 Sep 2021MP14-12 DISAGREEMENTS BETWEEN MEMORIAL SLOAN KETTERING CANCER CENTER (MSKCC) AND THE INTERNATIONAL METASTATIC RCC DATABASE CONSORTIUM (IMDC) PROGNOSTIC SCORE AND THEIR IMPACT ON SURVIVAL OUTCOMES IN CLEAR-CELL METASTATIC RENAL CELL CARCINOMA (mRCC) PATIENTS TREATED WITH TYROSINE-KINASE INHIBITORS (TKI) Florian Janisch, Phillip Marks, Philipp Gild, Christian P. Meyer, Constantin Fühner, Roland Dahlem, Shahrokh F. Shariat, Margit Fisch, and Michael Rink Florian JanischFlorian Janisch More articles by this author , Phillip MarksPhillip Marks More articles by this author , Philipp GildPhilipp Gild More articles by this author , Christian P. MeyerChristian P. Meyer More articles by this author , Constantin FühnerConstantin Fühner More articles by this author , Roland DahlemRoland Dahlem More articles by this author , Shahrokh F. ShariatShahrokh F. Shariat More articles by this author , Margit FischMargit Fisch More articles by this author , and Michael RinkMichael Rink More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001995.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clear-cell histology is the most common histologic subtype in patients with metastatic renal cell carcinoma (mRCC) in the tyrosine-kinase era. Treatment strategies are dependent on proper risk stratification. Differential risk stratification between the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic RCC Database Consortium (IMDC) prognostic score complicates clinical decision-making. We aimed to assess the specifics and impact of disagreement between IMDC and MSKCC risk scores on survival outcomes in patients with clear-cell mRCC (ccmRCC) treated with TKIs METHODS: 215 patients with ccmRCC treated with TKIs were analyzed. Calculation of MSKCC and IMDC was performed based on clinical data and patients were grouped according to disagreement between the scores. Cohen’s kappa was used to assess overall agreement between the risk scores. We used descriptive analysis to assess differences between the two groups as well as Kaplan-Meier estimates to assess the association of disagreement on overall (OS) and progression-free survival (PFS) as primary co-endpoints. RESULTS: Overall, 169 (78.6%) of patients were in agreement between risk scores, with a Cohen’s kappa of 0.624 (p<0.01). 8 patients (22.4%) were upgraded to higher, and 38 patients (77.6%) were downgraded to a lower risk group from MSKCC to IMDC score. Neutrophil leucocyte serum levels were the most frequent score-relevant factors involved in upgrading in 7 patients (87.5%) and LDH serum levels were the most frequent reason for downgrading in 38 patients (100%), respectively. Patients with agreement in prognostic risk scores had significantly worse IMDC score groups (p<0.01), more frequently time to systematic therapy <1 year (p=0.03), and had more frequently a LDH ≤1.5 fold of the upper normal level (p≤0.01). There was no association between agreement of the scores and OS (HR: 0.94; 95%-CI=0.64-1.38; p=0.7) or PFS (HR: 1.20; 95%-CI=0.80-1.79; p=0.4) in univariable analyses. CONCLUSIONS: There was a moderate agreement between IMDC and MSKCC score groups ccmRCC patients treated with TKI. OS and PFS were not impacted by disagreement between the score. Despite the preferred role of the IMDC for risk stratification, results of studies using the MSKCC score can be used for comparison of results in research and the clinical setting. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e257-e258 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Florian Janisch More articles by this author Phillip Marks More articles by this author Philipp Gild More articles by this author Christian P. Meyer More articles by this author Constantin Fühner More articles by this author Roland Dahlem More articles by this author Shahrokh F. Shariat More articles by this author Margit Fisch More articles by this author Michael Rink More articles by this author Expand All Advertisement Loading ...

A Novel Prognostic Marker for Primary CNS Lymphoma: Lactate Dehydrogenase-to-Lymphocyte Ratio Improves Stratification of Patients Within the Low and Intermediate MSKCC Risk Groups.

BackgroundPrimary central nervous system lymphoma (PCNSL) is a highly aggressive and rare extranodal non-Hodgkin lymphoma (NHL). The MSKCC and the IELSG scores represent the most widely used prognostic models, but many changes have occurred in therapeutic protocols since their development. Moreover, many PCNSL patients cannot be classified using the IELSG score. We thus aimed to create a novel, effective and feasible prognostic model for PCNSL.MethodsWe included 248 PCNSL patients diagnosed with PCNSL. Our primary endpoint was the overall survival (OS) and we used the receiver operating characteristic (ROC) analysis to determine the optimal prognostic cut-off value for LLR (lactate dehydrogenase-to-lymphocyte ratio), neutrophil-to-lymphocyte ratio (NLR) and derived neutrophil-to-lymphocyte ratio (dNLR). Variable associated with OS were evaluated by univariate and multivariate analyses. 124 out of 248 patients were randomly selected as the internal validation cohort.ResultsBy univariate analysis, an age >60 years, Eastern Cooperative Oncology Group performance status (ECOG PS) >1, treatment with radiotherapy alone, high-risk groups of Memorial Sloan Kettering Cancer Center (MSKCC) score, NLR >4.74, dNLR >3.29, and LLR >166.8 were significantly associated with a worse OS. By multivariate analysis, the MSKCC score and LLR were confirmed as independent prognostic parameters for poorer OS. OS, however, was not significantly different between low- and intermediate-risk groups according to the MSKCC score, while LLR proved to be prognostically relevant and was thus used to develop a novel, effective three-tier PCNSL scoring system. Of 124 patients, 84 patients with survival data and LLR data were successfully validated by newly established PCNSL LLR scoring system.ConclusionsIn the present study, we demonstrate that a high LLR represents an independent unfavorable prognostic parameter in PCNSL patients which can be integrated into an effective prognostic model.

Prognostic significance of the controlling nutritional status score in patients with metastatic renal cell carcinoma diagnosed before an era of first-line immune-oncology combination therapies.

To explore the prognostic role of the controlling nutritional status score in patients with metastatic renal cell carcinoma. We retrospectively analyzed 107 patients with metastatic renal cell carcinoma who received their diagnosis between 2007 and 2018 and were treated with or without a first-line interferon or tyrosine kinase inhibitor at a single cancer center. The controlling nutritional status score was based on values for albumin, lymphocyte count and total cholesterol at the metastatic renal cell carcinoma diagnosis. Association of the controlling nutritional status score and clinical variables, including the Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium risk classifications, with overall survival was examined using the Cox proportional hazard model. Predictive accuracy of the prognostic factors was assessed using Harrell's concordance index. First-line interferon and tyrosine kinase inhibitor were given to 48 (45%) and 41 (38%) patients, respectively, and 28 (26%) and 33 (31%) patients underwent cytoreductive nephrectomy and metastasectomy, respectively. During follow-up (median: 36.3months), 64 patients died. The median controlling nutritional status score was 2 (range: 0-8). A controlling nutritional status score≥2 was significantly associated with shorter overall survival (P<0.01) independently of the Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium risk classifications. Integration of the controlling nutritional status score into the Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium risk classifications improved concordance index from 0.702 to 0.770 and from 0.698 to 0.749, respectively. The controlling nutritional status score may serve as a prognostic biomarker objectively reflecting the general physical condition of patients with metastatic renal cell carcinoma treated with or without first-line interferon or tyrosine kinase inhibitor in terms of nutritional and immuno-inflammatory status.

Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: the STAR-TOR registry.

Aim: Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors. Patients &methods: Patients enrolled in STAR-TOR registry (n=327). End points included overall survival, progression-free survivaland objective response rate. Results: Overall survival was similar for IMDC 0 versus 1 (p=0.238)or 2 versus ≥3 (p=0.156), but different for MSKCC (0 vs 1, p=0.037; 2 vs ≥3, p=0.001). Progression-free survival was similar for IMDC 2 versus 3 (p=0.306), but different for MSKCC (p=0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Conclusion: Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. Clinical trial registration: NCT00700258 (ClinicalTrials.gov).

Prognostic Value of Systemic Inflammatory Biomarkers in Patients with Metastatic Renal Cell Carcinoma.

Metastatic renal cell carcinoma (mRCC) encompasses a heterogeneous group of neoplasms with distinct clinical behavior and prognoses. As a result of the increasing number of therapeutic options in the metastatic setting, it is crucial to improve prognostic stratification ability. We aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and combination platelet count and neutrophil lymphocyte ratio (COP-NLR) in patients with mRCC. We evaluated a cohort of mRCC patients treated with first-line pazopanib or sunitinib. Levels of NLR, PLR and COP-NLR were measured prior to systemic treatment and evaluated as prognostic predictors. Primary endpoint was overall survival (OS). Data from 276 patients were included, of which 54.7% received first-line pazopanib and 45.3%, sunitinib. Memorial Sloan-Kettering Cancer Center risk classification was intermediate and poor in 50% and 42.6% of patients, respectively. High NLR (> 3.5) was associated with inferior OS (median 9.6 vs 17.8months, P < 0.001). A high PLR (> 200) was associated with inferior OS (median 10.3 vs 17months, P = 0.002). The median OS in the COP-NLR 1, 2 and 3 groups were 19.0months (95% CI 15.3-26.0), 13.1months (95% CI 9.8-17.0) and 7.4months (95% CI 3.6-11.9), respectively (P < 0.001). In the multivariate analysis, high NLR and high COP-NLR were associated with inferior OS. Both high NLR and high COP-NLR were associated with poorer OS in our cohort of patients with mRCC treated with first-line pazopanib or sunitinib.

Outcomes According to MSKCC Risk Score with Focus on the Intermediate-Risk Group in Metastatic Renal Cell Carcinoma Patients Treated with First-Line Sunitinib: A Retrospective Analysis of 2390 Patients.

Background: The Memorial Sloan–Kettering Cancer Center (MSKCC) prognostic model has been widely used for the prediction of the outcome of metastatic renal cell carcinoma (mRCC) patients treated with systemic therapies, however, data from large studies are limited. This study aimed at the evaluation of the impact of the MSKCC score on the outcomes in mRCC patients treated with first-line sunitinib, with a focus on the intermediate-risk group. Methods: Clinical data from 2390 mRCC patients were analysed retrospectively. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were analysed according to the MSKCC risk score. Results: ORR, median PFS, and OS for patients with one risk factor were 26.7%, 10.1, and 28.2 months versus 18.7%, 6.2, and 16.2 months, respectively, for those with two risk factors (ORR: p = 0.001, PFS: p < 0.001, OS: p < 0.001). ORR, median PFS, and OS were 33.0%, 17.0, and 44.7 months versus 24.1%, 9.0, and 24.1 months versus 13.4%, 4.5, and 9.5 months in the favourable-, intermediate-, and poor-risk groups, respectively (ORR: p < 0.001, PFS: p < 0.001, OS: p < 0.001). Conclusions: The results of the present retrospective study demonstrate the suitability of the MSKCC model in mRCC patients treated with first-line sunitinib and suggest different outcomes between patients with one or two risk factors.

Tumor response criteria for assessing pazopanib first-line therapy in patients with metastatic renal cell carcinoma (mRCC).

To identify the optimum response criteria for first-line targeted pazopanib therapy in patients with mRCC using solid tumor response criteria and clinical risk factors. Pre- and post-treatment CTs of patients (n = 43) with mRCC treated with first-line pazopanib therapy were analyzed retrospectively. Treatment response was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Choi, modified Choi (mChoi), revised Choi (rChoi), MASS (Morphology, Attenuation, Size, and Structure), 10% threshold criteria, and subjective assessment. Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium clinical risk factors were also used to define response groups. Response evaluations were correlated with overall survival (OS) and progression-free survival (PFS) using log-rank test. Patients with partial response (PR) by mChoi and rChoi had longer OS than those with stable disease (SD) (P < 0.001). Responders by 10% threshold criteria also had better OS, without or combined with clinical criteria. Patients with PR by rChoi, mChoi, RECIST v1.1, MASS criteria, and by subjective assessment had longer PFS than those with SD. rChoi and mChoi criteria best delineated the difference in PFS for patients with PR versus SD, without or combined with clinical criteria. For mRCC patients treated with pazopanib, OS and PFS for PR and SD groups were best predicted by rChoi and mChoi criteria, without or combined with clinical risk factors. 10% threshold criteria also predicted OS and PFS, whereas RECIST did so only in a limited number of patients.

Impact of the Charlson Comorbidity Index on dose-limiting toxicity and survival in locally advanced and metastatic renal cell carcinoma patients treated with first-line sunitinib or pazopanib.

Anti-angiogenic tyrosine kinase inhibitors, sunitinib and pazopanib, have proven efficacy in advanced renal cell carcinoma, with specific adverse events occurring during treatment process. Comorbidities can reflect functional status and have prognostic value in oncology patients. We aimed to assess the association of the Charlson Comorbidity Index with severe toxicities and mortality in renal cell carcinoma cases treated with front-line sunitinib or pazopanib. Files of locally advanced and metastatic renal cell carcinoma patients who received first-line sunitinib or pazopanib were retrospectively examined. Charlson Comorbidity Index of each patient was calculated. Patients were also stratified into Memorial Sloan-Kettering Cancer Center risk groups. Predictors of dose-limiting toxicity were evaluated with binomial logistic regression analysis. Univariate and multivariate Cox regression models were utilized to determine prognostic factors for survival. The study included 102 patients, 64 were treated with first-line sunitinib and 38 with pazopanib. In 42 patients (41.9%), Charlson Comorbidity Index was 9 or more. Dose-limiting toxicities were significantly more frequent in Charlson Comorbidity Index ≥9 group (69% vs. 40%, p = 0.004), and Charlson Comorbidity Index independently predicted dose-limiting toxicity (Hazard ratio (HR) = 4.30, p = 0.002). After adjusting for other variables, a Charlson Comorbidity Index of ≥9 is also a significant prognostic factor for progression-free (HR = 1.76, p = 0.02) and overall survival (HR = 1.75, p = 0.03). Charlson Comorbidity Index may be a valuable method to estimate prognosis and optimize therapy in patients with advanced renal cell carcinoma receiving first-line sunitinib or pazopanib.

Biomarkers in renal cell carcinoma

We have entered a new era for patients with mRCC with multiple treatment options including VEGF(Vascular Endothelial Growth Factor)-, MET(Mesenchymal-eptihelial Transition)-, AXL(AXL-Rezeptortyrosinkinase)-, mTOR(mechanistic Target of Rapamycin)-targeted TKIs (tyrosinekinaseinhibitors) as well as PD-1(programmed cell death protein 1)-, PD-L1(Programmed cell death 1 ligand)- and CTLA4(cytotoxic T-lymphocyte-associated Protein 4)-targeted IOs and their combinations, respectively. However, the possibility to select patients based on predictive biomarkers for the different treatment options is still lacking. The TCGA (Cancer Genome Atlas) consortium conducted comprehensive analyses of genomic and metabolic features of RCC (renal cell carcinoma) and these findings demonstrated significant differences between the major histological subtypes of RCC like differences in immune signatures and their course of disease. The increasing knowledge on the genomic landscape of RCC supports stratification of patients for targeted therapies. Biomarker development for future therapeutic approaches will require integration of multiple biologic components like PD-L1 expression, tumor-infiltrating lymphocytes and mutations in addition to the prognostic risk scores. However, no single molecular marker has been shown to improve the accuracy of MSKCC (Memorial Sloan Kettering Cancer Center) or IMDC (International Metastatic RCC Database Consortium) prognostic risk scores. Large-scale biomarker-driven prospective trials with consensus methodologies on biomarker assessment and scoring are needed to obtain clinically validated new prognostic and predictive biomarkers as described above. The integration of routinely available parameters and new biomarkers could hold the key for personalized treatment strategies of patients with RCC.

Prognostic value of risk stratification using blood parameters for nivolumab in Japanese patients with metastatic renal-cell carcinoma.

Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma. However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic renal-cell carcinoma. We retrospectively reviewed the medical records of 65 patients with previously treated metastatic renal-cell carcinoma and who received nivolumab. Inflammation-based prognostic scores, including neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, lymphocyte/monocyte ratio, and Glasgow prognostic score before and 6weeks after the treatment were recorded. Categorical variables influencing disease-specific survival were compared using Cox proportional-hazards regression models. Univariate analysis showed that Memorial Sloan-Kettering Cancer Center risk score (P=0.0052), lactate dehydrogenase (P=0.0266), lymphocyte/monocyte ratio (P=0.0113), and platelet/lymphocyte ratio (P=0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that platelet/lymphocyte ratio and lactate dehydrogenase were found to be independent prognostic factors for disease-specific survival (P=0.0008, risk ratio (RR)=7.95, 95% confidence interval, 2.16-51.64 and P=0.0123, RR=3.92, 95% confidence interval, 1.37-10.80, respectively). The combination of platelet/lymphocyte ratio and lactate dehydrogenase was the most significant prognostic biomarker in metastatic renal-cell carcinoma (P<0.0001). Changes in lymphocyte/monocyte ratio and platelet/lymphocyte ratio in response to nivolumab were significant prognostic factors for disease-specific survival (P<0.0001 and P=0.0477, respectively). The combination of platelet/lymphocyte ratio and lactate dehydrogenase may be a potential biomarker for estimating disease-specific survival in Japanese patients with metastatic renal-cell carcinoma treated by nivolumab.

957P - Overall and progression-free survival according to MSKCC scores in 1st line sunitinib treatment of metastatic renal cell carcinoma (mRCC)

BackgroundData on the efficacy and safety of all targeted therapies for metastatic renal cell carcinoma (mRCC) including sunitinib are collected in the Czech RENIS patient registry. RENIS thus provides a uniquely large sample of long-term effectiveness and prognostic data of sunitinib according to adverse/risk factors measured by the Memorial Sloan Kettering Cancer Center (MSKCC) score. The aim of this study was to analyze the long-term overall (OS) and progression-free survival (PFS) of sunitinib, when used as 1st line treatment, based on MSKCC risk group scores including MSKCC scores for two intermediate subgroups. MethodsData from mRCC patients treated using sunitinib in the 1st line were collected in RENIS between 06/2007 and 02/2018. OS/PFS were then stratified based on MSKCC scores: a) favorable risk (0 adverse factors (AF)), b) intermediate risk (pooled 1–2 AFs), and c) poor risk (3+ AFs). The OS/PFS of the intermediate risk group was further stratified into two subgroups: i) 1AF and ii) 2 AFs. All OS/PFS data were analyzed using Kaplan-Meier estimates. Differences in OS/PFS between risk groups were assessed using median survival, 95% confidence intervals (CI), and the log-rank test. Then we assessed the OS/PFS for 1-, 3-, and 5-year survival. ResultsOver the 11-year follow-up, 2390 patients were treated using sunitinib with 806, 1450, and 134 patients in the favorable, intermediate, and poor MSKCC risk groups. The more favorable MSKCC risk group was accompanied by an improved OS and PFS (p<0.001). Regarding the MSKCC for the two intermediate sub-groups, 1AF was associated with improved survival compared to 2 AFs (p<0.001) (Table).Table957P OS and PFS results for sunitinib treatment based on MSKCC risk groupsTableMSKCC favorableMSKCC intermediateMSKCC poorMSKCC intermediateAll patients1AF2 AFsOverall survivalMedian survival (95% CI)44.7months (40.9-50.5)24.1months (21.9-26.0)9.5months (7.2-14.1)28.2months (25.9-30.7)16.2months (14.5-20.2)28.5months (26.3-30.5)1-year survival (95% CI)85.0% (82.4-87.6)69.1% (66.6-71.7)44.3% (35.0-53.7)74.3% (71.4-77.2)58.0% (53.1-62.9)73.3% (71.4-75.2)3-year survival (95 %CI)57.3% (53.4-61.3)37.1% (34.1-40.1)9.6% (3.1-16.2)42.0% (38.3-45.7)26.3% (21.4-31.2)42.9% (40.5-45.2)5-year survival (95% CI)35.6% (31.2-40.1)23.4% (20.4-26.4)3.2% (0.0-8.8)26.5% (22.7-30.3)16.5% (11.8-21.2)26.8% (24.3-29.2)n80614501349694812390Log-rank p-value< 0.001< 0.001-Progression-free survivalMedian survival (95% CI)17.0months (15.4-18.8)9.0months (8.3-9.5)4.5months (3.9-6.1)10.1months (9.4-11.4)6.2months (5.5-7.5)10.6months (9.9-11.5)1-year survival (95% CI)61.8% (58.3-65.3)40.7% (38.0-43.4)20.8% (13.1-28.5)45.1% (41.8-48.4)31.6% (27.1-36.1)46.9% (44.7-49.0)3-year survival (95 %CI)25.1% (21.7-28.5)13.0% (11.0-15.1)1.8% (0.0-5.1)15.9% (13.2-18.6)7.0% (4.2-9.7)16.6% (14.9-18.4)5-year survival (95% CI)10.4% (7.7-13.2)8.0% (6.2-9.8)1.8% (0.0-5.1)9.7 (7.3-12.0)4.5% (2.1-6.9)8.4% (7.0-9.9)n80614501349694812390Log-rank p-value< 0.001< 0.001- ConclusionsBetter MSKCC risk scores were associated with significantly longer OS and PFS. To our knowledge, this is the largest published sunitinib mRCC cohort described relative to MSKCC risk groups. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureJ. Finek: Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Bayer; Honoraria (self): Teva; Honoraria (self): MSD; Honoraria (self): Merck; Honoraria (self): Sanofi; Honoraria (self): Pierre Fabre. A. Poprach: Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): Bayer. B. Melichar: Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Astellas Pharma; Honoraria (self): Pfizer; Honoraria (self): Bayer. J. Kopecky: Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): Pfizer. M. Zemanova: Advisory / Consultancy: Novartis; Honoraria (self): Eli Lilly; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. Buchler: Honoraria (self): Amgen; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Janssen. K. Kopeckova: Honoraria (self): Novartis; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Pfizer. T. Mlcoch: Full / Part-time employment: Value Outcomes. T. Dolezal: Full / Part-time employment: Value Outcomes. All other authors have declared no conflicts of interest.

The prognostic effect of immunoscore in patients with clear cell renal cell carcinoma: preliminary results.

This study aimed to evaluate the density of CD8+ and CD3+ tumor-infiltrating lymphocytes (TILs) and determine whether the immunoscore has any prognostic effect on the oncological outcomes in patients with clear cell renal cell carcinoma (RCC). A total of 129 patients diagnosed with clear cell RCC following radical or partial nephrectomy between 2009 and 2014 were retrospectively analyzed. Both tumor core (CT) and the invasive margin of nephrectomy specimens were assessed. The specimens were immunostained for anti-CD8+ and anti-CD3+ TILs. The patients were divided into three groups (favorable, intermediate, and poor risk) according to immunoscore levels. In the multivariate analysis, a favorable immunoscore (I3-4) was associated with prolonged disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) (HR 2.652, 2.848, and 2.933, respectively; all p < 0.001). The lower Fuhrman grade and pathological tumor-node-metastasis (TNM) stage had better DFS, PFS, and OS, whereas prolonged PFS was associated with a higher density of CD8+ CT (HR 1.602, 95% CI 0.934-3.470; p = 0.014). The shorter DFS, PFS, and OS were observed in the group with poor immunoscore (I0-1) at the early TNM stage of RCC (p < 0.001). In the metastatic subgroup analysis, the immunoscore showed better estimation than the International Metastatic RCC Database Consortium model and the Memorial Sloan-Kettering Cancer Center risk model for progression and OS (p < 0.001). The additional contributions of immunoscore to TNM stage, Fuhrman grade, and the WHO/ISUP 2016 grade for estimating oncological outcomes were found in ROC analysis. According to our preliminary results, immunoscore can be a promising prediction tool in clear cell RCC for postoperative oncological outcomes following nephrectomy.

Use of Memorial Sloan Kettering Cancer Center nomogram to guide intraoperative sentinel lymph node frozen sections in patients with early breast cancer.

We implemented selective use of frozen section (FS) to optimize accuracy and cost control in the intraoperative diagnosis of sentinel lymph node (SLN) in patients with breast cancer, guided by the Memorial Sloan Kettering Cancer Center (MSKCC) nodal metastasis risk prediction nomogram. Surgical pathology records were reviewed, examining 2582 consecutive biopsies from 2552 patients with breast cancer to compare intraoperative FS diagnoses with postoperative final reports. We calculated sensitivity, specificity, and false-negative rates (FNRs) for various MSKCC risk levels, also analyzing axillary reoperation rates, with and without FS, and the number needed to treat (NNT) to avoid separate axillary lymph node dissection. The sensitivity, specificity, and FNR of FS were 84.7%, 99.9%, and 15.3%, respectively. FNR and MSKCC risk level negatively correlated (r = -0.86; P = .002). Axillary reoperation rate significantly declined if FS was done (FS: 4.0%; no FS: 36.4%; P = .002). In grouping patients by quartile of MSKCC risk, axillary reoperation rates were 16.7%, 25.1%, 38.7%, and 58.7% without FS, compared with 4.3%, 3.2%, 5.6%, 3.3% with FS and NNT correspondingly fell from 8.1 to 4.6, 3.0, and 1.8. A stratified decision-making algorithm based on the MSKCC risk prediction model improved the effectiveness of FS during SLN biopsy to avoid axillary reoperation.

Efficacy and safety of cytokines versus first-line sunitinib and second-line axitinib for patients with metastatic renal cell carcinoma (ESCAPE study): A study protocol for phase III randomized sequential open-label study

Appropriate protocol for the sequential treatment of metastatic renal cell carcinoma (mRCC) has not been established yet. Some mRCC cases with favorable risk were reported to achieve complete remission and durable response using interferon alfa (IFNα) + low dose interleukin-2 (IL-2). Cytokine therapies may be suitable for some patients with mRCC as first-line therapy. The present study is a phase III, investigator-initiated, multicenter, prospective randomized controlled trial investigating patients with low and intermediate risk mRCC classified by Memorial Sloan-Kettering Cancer Center risk criteria to evaluate the efficacy and safety of sequential treatment with cytokine (IFNα + IL-2) as first-line and axitinib as second-line therapy versus sequential treatment with sunitinib as first-line and axitinib as second-line therapy, which is the current standard treatment for patients with favorable risk. The target sample size was set at 72 patients per group (total 144 cases). The study duration is 7 years, and the duration for recruitment is 4 years. Our expectation of this trial is to clarify first- and second-line sequential treatment for mRCC better, especially in patients with favorable risk and some with intermediate risk. The results of this trial will certainly contribute to new information for the strategy of first- and second-line sequential treatment for mRCC. Trial registrationUniversity hospital Medical Information Network (UMIN) Center identifier UMIN 000012522.

Real-world Effectiveness and Safety of Pazopanib in Patients With Intermediate Prognostic Risk Advanced Renal Cell Carcinoma.

The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778). Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients. Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS≥ 2 (vs. PS< 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar. Outcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs.≥ 2) to more accurately predict outcomes.

Impact of disagreement between the IMDC and MSKCC risk groups on prognosis in patients with metastatic renal cell carcinoma.

556 Background: As the clinical implication of the risk group disagreement between the risk models remains unclear, we aimed to investigate the impact of the risk group disagreement between the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models on prognosis. Methods: We retrospectively evaluated 176 patients with metastatic renal cell carcinoma (mRCC) who were treated with tyrosine kinase inhibitors as first-line therapy in five hospitals between October 2008 and August 2018. The risk group classification differences between the MSKCC and the IMDC models were evaluated using criteria of agreement (identical risk group in both the MSKCC and IMDC models) and disagreement (not identical risk group in both the MSKCC and IMDC models). The agreement of risk stratification between the MSKCC and IMDC models was evaluated using Cohen’s k coefficient. Oncological outcomes were compared between the agreement and disagreement groups. Results: The number of patients with agreement, upgrade, and downgrade was 135/176 (77%), 39/176 (22%), and 2/176 (1.1%), respectively. Of 41 patients with disagreement, reclassification from the MSKCC-intermediate to the IMDC-poor-risk group was most frequent (n = 34/176, 19%). The Cohen’s k coefficient for agreement of the two risk models was substantial with k value of 0.613 ( P &lt; 0.001). Significantly poorer prognosis was observed in patients with disagreement than in those with agreement. Conclusions: Disagreement between the MSKCC and IMDC models may have a negative impact on prognosis in patients with mRCC. Further study is necessary to validate our findings.

Prognosis of renal cell carcinoma with bone metastases: Experience from a large cancer centre

BackgroundBone metastases (BMs) are associated with significant morbidity and shorter survival in renal cell carcinoma (RCC). Our purpose was to identify prognostic factors for overall survival (OS) in RCC patients with BMs. MethodsData from patients with BMs from RCC treated at Gustave Roussy between April 1992 and March 2016 were retrospectively collected. Age, sex, Eastern Cooperative Oncology Group-Performance Status, Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups, histology, number and site of bone lesions, concomitant metastases (presence and sites), therapy for BMs (radical resection or palliative surgery, radiotherapy and other local and systemic treatments) and time from diagnosis to BMs were analysed. Synchronous solitary bone metastasis (SSBM) was defined as a single BM without concomitant visceral lesions at the initial diagnosis of RCC. OS was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan–Maier method and modelled with Cox regression analysis. ResultsFrom 1750 patients with diagnosis of RCC followed at Gustave Roussy Cancer Campus, 300 patients with BMs were identified. Median time from diagnosis to BMs was 32.4 months (range 0–324 months). In 64 patients (21%), bone was the only metastatic site, and 22 patients (7%) had an SSBM and 236 patients (79%) had concomitant metastases in other sites. Median OS was 23.2 months (95% confidence interval 19.9–26.2). SSBM patients had better OS than those with concomitant metastases (40 vs 20 months; P < 0.001). At multivariate analysis, concomitant metastases remained predictor of poor prognosis, while MSKCC risk group, radical resection and SSBM were predictors of better OS. ConclusionsThis study suggests that MSKCC score, numbers of BMs and radical resection are important prognostic factors for RCC patients with BMs. Additionally, in the presence of solitary BM without concomitant metastases at the initial diagnosis of RCC, bone surgery should be considered to achieve local tumour control and likely increase OS.