Non-clear Cell Histology Research Articles

Should CARMENA Really Change our Attitude Towards Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma? A Systematic Review and Meta-Analysis Evaluating Cytoreductive Nephrectomy in the Era of Targeted Therapy.

Cytoreductive nephrectomy in metastatic renal cell carcinoma (mRCC) patients has been common clinical practice due to evidence that resection of the primary tumor results in a survival benefit regardless of systemic treatment. Recently, the first large phase III randomized, non-inferiority prospective clinical trial evaluating this surgical approach demonstrated that systemic treatment alone was not inferior to primary surgery plus systemic treatment. Our aim was to evaluate if cytoreductive nephrectomy results in a survival benefit over systemic treatment alone in patients with mRCC and in specific subgroups, including patients with brain metastases, poor performance status, poor prognosis according to IMDC or MSKCC criteria, and clear cell and non-clear cell histologies. We identified 16 published studies providing complete data for the comparison between cytoreductive nephrectomy + systemic treatment versus systemic treatment alone, and selected 9 for subgroup analysis. The inverse variance technique was applied for the meta-analysis of hazard ratios (HR), and, due to the intrinsic heterogeneity of the data, we adopted a random effects model. Risk of bias among the studies was estimated by the Newcastle-Ottawa Scale (NOS). Our analysis suggested a survival benefit for patients receiving cytoreductive nephrectomy (pooled HR of 0.48, 95% confidence interval of 0.42-0.56) in the overall population. Survival advantages were also observed in patients with clear cell and non-clear renal cell carcinoma, while no benefit was evident in patients with brain metastasis, poor performance status, and poor risk. Cytoreductive nephrectomy seems to result in a survival benefit in both clear cell and non-clear cell histology, while no survival advantage was found in patients with specific clinical features. Despite a high level of heterogeneity, our results highlight the importance of a good selection of patients to whom a primary surgical approach could be proposed.

Pathological staging of renal cell carcinoma: a review of 300 consecutive cases with emphasis on retrograde venous invasion.

Pathological staging of renal cell carcinoma (RCC) can be challenging compared to other cancer types, as invasion often manifests as finger-like protrusions into vascular spaces or renal sinus tissue. Although prior studies have shown larger tumour size to be correlated highly with renal sinus invasion, prospective data on evaluating pathological stage are limited. We evaluated a large series reported by one urological pathologist. Three hundred consecutive specimens were reviewed. Tumours larger than 5 cm were routinely sampled extensively or grossly re-reviewed when no extrarenal extension was identified on initial examination. Apparent multifocal disease was assessed critically for intravascular spread. Retrograde venous invasion was reported in 15 of 300 (5%) cases, 13 of 15 of which were clear cell RCC. Of a total of 163 specimens with clear cell histology, only five of 34 (15%) tumours 7 cm or larger were reported as pT2, all of which had an explanatory comment indicating the absence of definitive extrarenal spread. In contrast, 15 of 20 (75%) pT2 tumours were non-clear cell histology (papillary, chromophobe and translocation-associated). Comparing pT3a or higher tumours, the median tumour size in cases with retrograde venous invasion was 8.0 cm, compared to 6.2 cm in cases without retrograde venous invasion (P = 0.005). Our findings support that retrograde venous invasion should be considered carefully before diagnosing multifocal clear cell RCC, which is rare in the sporadic setting. In the absence of vascular invasion, multifocal clear cell papillary RCC can be a mimic. pT2 occurs more frequently with non-clear cell histology (particularly papillary or chromophobe RCC).

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with first-line systemic tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma.

To examine the prognostic role of the pretreatment aspartate transaminase/alanine transaminase or De Ritis ratio in patients with metastatic renal cell carcinoma receiving first-line systemic tyrosine kinase inhibitor therapy. We retrospectively searched the medical records of 579 patients with metastatic renal cell carcinoma who visited Samsung Medical Center, Seoul, Korea, from January 2001 through August 2016. After excluding 210 patients, we analyzed 360 patients who received first-line tyrosine kinase inhibitor therapy. Cancer-specific survival and overall survival were defined as the primary and secondary end-points, respectively. A multivariate Cox proportional hazards regression model was used to identify independent prognosticators of survival outcomes. The overall population was divided into two groups according to the pretreatment De Ritis ratio as an optimal cut-off value of 1.2, which was determined by a time-dependent receiver operating characteristic curve analysis. Patients with a higher pretreatment De Ritis ratio (≥1.2) had worse cancer-specific survival and overall survival outcomes, compared with those with a lower De Ritis ratio (<1.2). Notably, a higher De Ritis ratio (≥1.2) was found to be an independent predictor of both cancer-specific survival (hazard ratio 1.61, 95% confidence interval 1.13-2.30) and overall survival outcomes (hazard ratio 1.69, 95% confidence interval 1.19-2.39), along with male sex, multiple metastasis (≥2), non-clear cell histology, advanced pT stage (≥3), previous metastasectomy and the Memorial Sloan Kettering Cancer Center risk classification. Our findings show that the pretreatment De Ritis ratio can provide valuable information about the survival outcomes of metastatic renal cell carcinoma patients receiving first-line tyrosine kinase inhibitor therapy.

PD12-07 PREDICTORS OF PATHOLOGICALLY NODE POSITIVE DISEASE IN PATIENTS UNDERGOING RETROPERITONEAL LYMPH NODE DISSECTION (RPLND) FOR RENAL CELL CARCINOMA (RCC): RESULTS FROM THE CANADIAN KIDNEY CANCER COLLABORATION

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy II1 Apr 2018PD12-07 PREDICTORS OF PATHOLOGICALLY NODE POSITIVE DISEASE IN PATIENTS UNDERGOING RETROPERITONEAL LYMPH NODE DISSECTION (RPLND) FOR RENAL CELL CARCINOMA (RCC): RESULTS FROM THE CANADIAN KIDNEY CANCER COLLABORATION Andrea Kokorovic, Rodney Breau, Antonio Finelli, Simon Tanguay, Anil Kapoor, Jun Kawakami, Adrian Fairey, Alan So, Darrel Drachenberg, Luke T. Lavallée, Jean-Baptiste Lattouf, Frederic Pouliot, Ranjeeta Mallick, and Ricardo A. Rendon Andrea KokorovicAndrea Kokorovic More articles by this author , Rodney BreauRodney Breau More articles by this author , Antonio FinelliAntonio Finelli More articles by this author , Simon TanguaySimon Tanguay More articles by this author , Anil KapoorAnil Kapoor More articles by this author , Jun KawakamiJun Kawakami More articles by this author , Adrian FaireyAdrian Fairey More articles by this author , Alan SoAlan So More articles by this author , Darrel DrachenbergDarrel Drachenberg More articles by this author , Luke T. LavalléeLuke T. Lavallée More articles by this author , Jean-Baptiste LattoufJean-Baptiste Lattouf More articles by this author , Frederic PouliotFrederic Pouliot More articles by this author , Ranjeeta MallickRanjeeta Mallick More articles by this author , and Ricardo A. RendonRicardo A. Rendon More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.643AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES A randomized trial demonstrated that patients with clinically low risk RCC do not benefit from RPLND, but the role of RPLND at time of nephrectomy for higher risk tumors remains controversial. We hypothesize that patients with locally advanced disease have a worse prognosis and may benefit from nodal dissection. Here we identify predictors of pathologically node positive (pN1) disease in patients treated with RPLND at time of nephrectomy. METHODS We analyzed data from a prospectively maintained multi-institutional cohort of patients in the Canadian Kidney Cancer Information System (CKCis) who underwent nephrectomy for RCC with or without RPLND from 2011 to 2017. Analysis was used to determine: (a) preoperative predictors of undergoing RPLND (b) predictors of pN1 in patients receiving RPLND. RESULTS 6084 patients with cTanyNanyMany RCC treated with partial (N=2788) or radical (N=3296) nephrectomy were identified. 886 (16%) patients had clinical T3-T4 disease, 322 (6%) had clinically positive nodes (cN1) and 504 (9%) had metastatic (M1) disease. 1777 (29%) patients underwent RPLND. Of patients treated with RPLND, 248 (14%) had pN1 disease. Patients with ECOG performance status (PS) >1, larger tumor size, stages cT2-T4 vs. T1, cN1, M1 and histologic grades 3-4 were more likely to undergo RPLND at time of surgery. Predictors of pN1 disease were BMI 20-30 vs. BMI >30, ECOG PS >1, larger tumor size, stages cT2-T4 vs. cT1, cN1, M1, histologic grades 3-4, and non-clear cell histology (Table 1). CONCLUSIONS In the largest study of its kind to date, several risk factors for pN1 status were identified. Of interest, BMI 20-30 and non-clear cell histology have not been previously identified as predictors of pN1 disease and may therefore represent a novel subset of patients that could benefit from nodal dissection. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e241 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Andrea Kokorovic More articles by this author Rodney Breau More articles by this author Antonio Finelli More articles by this author Simon Tanguay More articles by this author Anil Kapoor More articles by this author Jun Kawakami More articles by this author Adrian Fairey More articles by this author Alan So More articles by this author Darrel Drachenberg More articles by this author Luke T. Lavallée More articles by this author Jean-Baptiste Lattouf More articles by this author Frederic Pouliot More articles by this author Ranjeeta Mallick More articles by this author Ricardo A. Rendon More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP28-19 DERMATOLOGIC FINDINGS AND FAMILY HISTORY ARE THE ONLY PREDICTORS OF A POSITIVE GENETIC TEST RESULT IN PATIENTS WITH A SUSPECTED HEREDITARY KIDNEY CANCER SYNDROME: EXPERIENCE FROM A PROVINCIAL GENETICS UNIT

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging I1 Apr 2018MP28-19 DERMATOLOGIC FINDINGS AND FAMILY HISTORY ARE THE ONLY PREDICTORS OF A POSITIVE GENETIC TEST RESULT IN PATIENTS WITH A SUSPECTED HEREDITARY KIDNEY CANCER SYNDROME: EXPERIENCE FROM A PROVINCIAL GENETICS UNIT Andrea Kokorovic, Aidan Thomas, Meghan Ferguson, and Ricardo A Rendon Andrea KokorovicAndrea Kokorovic More articles by this author , Aidan ThomasAidan Thomas More articles by this author , Meghan FergusonMeghan Ferguson More articles by this author , and Ricardo A RendonRicardo A Rendon More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.919AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors (ACMG/NSGC) recommend genetic assessment for patients with renal cell carcinoma (RCC) who have high risk features: young age, bilateral/multifocal tumors, strong family history, non-clear cell histology, features suspicious for Cowden syndrome (CS) or tuberous sclerosis (TS). These recommendations are based on studies with individuals carrying known gene mutations but data assessing the outcomes of patients referred for genetic testing as per current guidelines are very limited. The only study available to date is from a single center (MSKCC) that found an association between young age and a positive genetic test in 43 patients evaluated for hereditary RCC. The purpose of our study is to delineate risk factors associated with a positive genetic test in a real-life cohort of patients referred to Medical Genetics for evaluation of hereditary RCC. METHODS A retrospective chart review of patients referred for genetic evaluation of a hereditary kidney cancer from 2006 to 2016 at the Division of Medical Genetics in Nova Scotia, Canada was performed. Univariate and multivariate analyses using Fisher's exact test were used to determine predictors of a positive test result. RESULTS 109 patients were referred to Medical Genetics, 85 were evaluated and 64 underwent testing. 5 were excluded from analysis (4 non-RCC; 1 unavailable result). 5 patients (8.5%) had a positive genetic test (3 Birt-Hogg-Dube, 1 CS, 1 TS). Mean age at time of RCC diagnosis was 54. 32 (54%) patients had multifocal/bilateral tumors, 26 (44%) had a positive family history, 26 (44%) had non-clear cell histology and 10 (17%) had tumors outside the kidney. Dermatologic findings (facial fibrofolliculomas) (p=0; OR=42) and family history of RCC or a genetic syndrome (p=0.037; OR=7.2) were the only predictors of a positive test. CONCLUSIONS This study identifies dermatologic findings and family history as the only predictors of a positive genetic test in patients undergoing evaluation for hereditary RCC. To date, our patient population represents the largest of its kind in the literature. A recent SEER database study reveals that 1 in 5 patients diagnosed with RCC should be referred for genetic counselling as per ACMG/NSGC guidelines. Our study suggests that current referral criteria may be too broad for application in a real-life patient population, however further evaluation with prospective trials is needed. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e364 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Andrea Kokorovic More articles by this author Aidan Thomas More articles by this author Meghan Ferguson More articles by this author Ricardo A Rendon More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Fourth-Line Therapy in Metastatic Renal Cell Carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC)1

Background: Fourth-line therapy (4LT) in the treatment of metastatic renal cell carcinoma (mRCC) varies significantly due to the lack of data and recommendations to guide treatment decisions. Objective: To evaluate the use and efficacy of 4LT in mRCC patients. Methods: The International mRCC Database Consortium (IMDC) dataset was used to identify patients with mRCC treated with 4LT. This is a multicenter, retrospective cohort study. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier curves. Patients were evaluated for overall response. The six prognostic variables included in the IMDC prognostic model were used to stratify patients into favorable-, intermediate- and poor-risk groups. Exploratory analyses were performed examining the elderly (&gt;70 years old) and non-clear cell RCC subgroups. Proportional hazards regression modelling was performed adjusting these covariates by IMDC criteria measured at initiation of 4th line therapy. Results: 7498 patients were treated with first line targeted therapy and out of these 594 (7.9%) received 4LT. Everolimus was the most frequently used 4LT (16.8%). Sorafenib, axitinib, pazopanib, sunitinib and clinical trial drugs were also used in &gt;10% of patients. The OS of patients on any 4LT was 12.8 months, with a PFS of 4.4 months. The overall response rate (ORR) was 13.7%. Favorable-risk patients using IMDC criteria (5%) displayed an OS of 23.1 months, intermediate-risk patients (66%) had an OS of 13.8 months and poor-risk patients (29%) had an OS of 7.8 (p &lt; 0.0001) months. Age &gt;70 years and non-clear cell histology did not impact OS. Our study is limited by its retrospective design. Conclusions: 4LT use appears to have activity in mRCC patients. The IMDC continues to be of prognostic value in the fourth-line setting for OS. This study helps to set a benchmark for response rate and survival for which clinical trials can plan sample size calculations and aim to improve upon.

Antibiotic use and outcomes with systemic therapy in metastatic renal cell carcinoma (mRCC).

607 Background: Antibiotic (Abx) use is shown to alter commensal gut microbiota, a key regulator of immune homeostasis. We conducted the largest investigation to date on the impact of Abx use on outcomes in mRCC patients treated with systemic agents. Methods: Two cohorts were analyzed: an institutional cohort (DFCI, n = 146) of patients receiving PD-1/PD-L1-based immune checkpoint inhibitors (ICI), and an external cohort from pooled phase II/III clinical trials (Pfizer, n = 4144) of patients treated with interferon (IFN, n = 510), mTOR inhibitors (n = 660), and VEGF inhibitors (n = 2974). Abx use was defined as Abx treatment at any time between 8-weeks pre- and 4-weeks post the start of systemic therapy. We examined the associations of Abx use and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using Cox/logistic regression models, adjusted for prognostic factors including risk groups. Results: In the DFCI cohort, 15% had non-clear cell histology, 43% had first-line ICI, 45% had combotherapy. Baseline characteristics were balanced between Abx users (n = 31, 21%) and non-users (p &gt; 0.15). Abx users had a lower ORR (12.9 vs 34.8%, p = 0.026) and shorter PFS compared to non-users (Table). In the external cohort, Abx users (n = 709) had lower ORR (19.3 vs 24.2%, p = 0.005). IFN treated patients (current or prior cytokines) had worse OS if they received Abx compared to those who did not. However, there was no OS difference by Abx use in mTOR or VEGF treated patients without prior cytokines. Conclusions: Abx use was independently associated with worse outcomes in mRCC patients receiving contemporary ICI or historic cytokine immunotherapy. We hypothesize that concurrent use of Abx may reduce the efficacy of ICI due to a complex interplay with the host microbiome. [Table: see text]

Application of Canadian hereditary renal cell carcinoma risk criteria to a population database.

621 Background: Canadian criteria for identifying patients (pts) and families at risk for hereditary renal cell carcinoma (RCC) were published in 2013. They included characteristics for pts with RCC (age ≤ 45 years, bilateral or multifocal tumours, associated medical conditions and non-clear cell histologies with unusual features) and for any pts who have a family history of specific clinical or genetic diagnoses associated with renal neoplasms. The clinical impact of these criteria on genetic testing had yet to be evaluated. Methods: The Canadian hereditary RCC risk criteria were applied to pts from 16 centres in the Canadian Kidney Cancer Information System prospective database. The primary endpoint was the proportion of pts who met at least one criterion. Secondary endpoints included the number of pts with more than one criterion and the number of pts receiving genetic testing (with or without at risk criteria). Results: From January 2011 to May 2017, 8097 pts were entered in the database. 2827 (35%) met at least one criterion for genetic testing. The majority (83%) met just 1 criterion, while 16% met 2 criteria. The criterion of non-clear cell histology with unusual features contributed the largest proportion of at risk pts (59%), followed by age ≤ 45 years (29%), then first or second degree relative with renal tumour (16%). 69 pts underwent genetic testing, with 59 being classified at risk ( &lt; 3% of at risk). Details about the genetic testing results will be presented. Conclusions: The application of the Canadian hereditary RCC risk criteria to a population database resulted in 35% of pts being identified at risk for hereditary RCC. However, the true incidence of hereditary RCC in this population is unknown as most pts did not undergo genetic testing, and thus the sensitivity or specificity of the criteria cannot be determined. The low proportion of at risk pts that underwent genetic testing was disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing. The results have helped determine the proportion of at risk pts in Canada, what criteria are most common, and importantly, have established a foundation and benchmark to improve upon.

Relationship of tumor mutational burden (TMB) to immunotherapy response in metastatic renal cell carcinoma (mRCC).

662 Background: Multiple studies across histologies (e.g., lung cancer, melanoma and bladder cancer) have linked TMB to response to checkpoint inhibition (CPI). However, the association in patients with mRCC remains unclear. Methods: From an institutional database, consecutive patients (pts) with mRCC who had comprehensive genomic profiling (CGP) done in the course of routine clinical care were assessed. Data pertaining to systemic therapy was collected, and for each patient, duration of therapy (DOT) on 1st immunooncology agent (DOT-IO) was computed. Furthermore, best response data (using a RECIST v1.1 defintion) was collected, and patients were characterized as either having clinical benefit (CB; defined as complete/partial response or stable disease) or no clinical benefit (NCB; progressive disease). CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 718X for up to 315 cancer-related genes plus introns from up to 28 genes frequently rearranged in cancer. TMB was estimated using the cumulative number of non-variant of unknown significance (non-VUS) and VUS genomic alterations (GAs). The correlation between TMB and DOT-IO as well as CB rate was assessed. Results: Of 31 patients (26:5 M:F) who received IO, 25 pts and 6 pts had clear cell and non-clear cell (papillary = 4; sarcomatoid = 1; chromophobe = 1) histologies, respectively. The most common 1st IO agent rendered was nivolumab (77%), and this was administered most commonly in the post-2nd-line setting (60%). The median number of GAs in the cohort was 10, with the most frequent GAs encountered being VHL (21%), TERT (10%) and PBRM1 (10%). When segregated in groups by estimate of TMB, DOT-IO was similar in high TMB and low TMB pts (71 days and 70 days, respectively; P = 0.39). The median estimated TMB was similar in pts with CB and NCB (11 and 10, respectively; P = 0.84). Conclusions: While previous studies in other histologies have suggested an association between TMB and IO response, our study fails to confirm these findings in mRCC. Given our limited sample size, this association warrants exploration in larger series.

The Efficacy of Conventionally Fractionated Radiation in the Management of Osseous Metastases from Metastatic Renal Cell Carcinoma.

Background There is little data regarding the effectiveness of palliative radiation with conventional fractionation for metastatic renal cell carcinoma (RCC), which has been described as radioresistant. We conducted a retrospective analysis of patients with metastatic bony disease from RCC treated with radiation therapy at our institution. Methods Forty patients with histologically confirmed RCC with a total of 53 treatment courses were included. Pain response after radiotherapy was recorded and freedom from progression was generated using posttreatment radiographs. Patient data was analyzed to assess influence on local control. Results Patients had a median age of 63. Median follow-up was 9.3 months. The most common radiation dose was 30 Gy in 10 fractions. Pain control after radiotherapy was achieved in 73.6% of patients. Increasing age was associated with nonresponse at the initial pain assessment post-RT (p = 0.02). In lesions with initial pain response, nonclear cell histology was associated with increased pain recurrence (p = 0.01) and a shorter duration to pain recurrence (p = 0.01). Radiographic control at 1 year was 62%. Conclusions Pain response and control rates for osseous metastatic disease in RCC are comparable to other histologies when treated with conventional fractionation. These appear to be inferior to reported control rates from stereotactic treatments.

Endometriosis-associated malignant transformation in abdominal surgical scar: A PRISMA-compliant systematic review.

Background:Endometriosis-associated malignant transformation in abdominal surgical scar (EAMTAS) is a very rare and aggressive phenomenon. Our current article aims to provide a clinical overview, focusing on risk factors affecting survival.Methods:We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review based on prior reviews and case reports regarding the phenomenon published as abstracts in English, from January 1980 to November 2016. Overall, we identified 47 cases, and we included another case from our institution. We further contacted previous investigators to receive updated follow-up regarding their patients. We analyzed the data, focusing on risk factors that might affect overall survival.Results:All the patients reported in the literature had a uterine surgery, mainly caesarean section. The median time-lag from first surgery to the diagnosis of cancer was about 19 years. Clear-cell carcinoma (CCC) was the most prevalent histology (67%), followed by endometrioid adenocarcinoma (15%). Most of the patients were treated by extensive surgery and chemotherapy and/or radiation. Overall 5 years survival was about 40%. Median overall survival was 42 months (95% confidence interval of [18.7, 65.3]). Although our review is currently the largest in the literature, we cannot draw any statistical significant results due to the limited number of patients reported. According to univariate Cox-regression models, a tendency toward worse prognosis was shown for 3-year disease-free survival clear cell histologic-type (P = .169), and tumor diameter ≥8 cm in nonclear-cell histology, 18 months postdiagnosis (P = .06).Conclusion:EAMTAS is a rare and aggressive disease. It is mostly related to cesarean section scars and is diagnosed many years postsurgery. Clear-cell histology tends to endure from the worse prognosis. The treatment is mainly extensive surgery and adjuvant chemotherapy and/or radiotherapy.

Non-Clear Cell Renal Cell Carcinoma: Current Management and Best Practice.

The treatment of metastatic renal cell carcinoma (mRCC) has evolved markedly over the past several decades; first with the introduction of targeted therapies and more recently with data supporting checkpoint inhibition. However, the vast majority of studies to date have explored the benefit of agents specifically in the context of clear cell disease. For the estimated 15–20% of patients with non-clear cell histology, there is little consensus around best practice. Herein, we discuss emerging datasets providing biologic characterization of non-clear cell RCC and identify trials that exploit this biology.

The Evolution of Clinical Trials in Renal Cell Carcinoma: A Status Report for 2013-2016 from the ClinicalTrials.gov Website.

Background:We previously published an analysis of clinical trials in renal cell carcinoma (RCC) using the publicly available ClinicalTrials.gov registry. Here we present a 3-year update to understand clinical research current trends in RCC compared to 2013.Methods:The Website’s advanced search function was used to search for RCC trials. The characteristics of the trial were extracted, summarized and compared to 2013 data using Fisher’s exact tests.Results:We locked our search on May 26, 2016 with 165 trials eligible, compared with 169 trials on Sep 25, 2013. There were more phase I and I/II trials in 2016 compared to 2013 (40.8% vs 24.9%, p = 0.05). More clinical trials in 2016 compared to 2013 used immunotherapy (IT) alone or in combination with other drugs (24.2% vs 10.7%, p = 0.001), and the use of targeted therapy alone (TT) declined (32.9% vs 47.9%, p = 0.005). TT+IT combination trials more than doubled (6.7% vs 2.3%, p = 0.07). The number of trials with treatment in (neo)adjuvant settings in 2016 and 2013 were similar (9.7% vs 10.6%, p = 0.77), respectively. Compared to 2013, the number of trials with non-clear cell histology remained low (n = 10). Many more trials were sponsored by the pharmaceutical industry in 2016 vs 2013 (41.5% vs 16.0%, p = <0.001).Conclusion:IT-based and industry sponsored clinical trials significantly increased from 2013 to 2016 with a concomitant drop in TT only trials. The increase in industry-sponsored studies may reflect the rapid uptake of expensive IT drugs. There continues to be a paucity of (neo)adjuvant studies and for non-clear cell histologies.

902P - Prognostic factors for overall survival of patients with advanced renal cell carcinoma – data from the German prospective RCC-Registry

Background: The identification of prognostic factors is a central question in oncology. They help to predict the course of disease and ideally support the oncologist in treatment decision making in clinical practice. We analysed prognostic factors identified by MSKCC and additional factors for the overall survival (OS) of patients (pts) treated with currently approved agents. Methods: The prospective German renal cell carcinoma (RCC) Registry includes pts with advanced or metastatic renal cell carcinoma at start of systemic first-line therapy. > 300 oncologists are recruiting pts since 2007. Pts and tumour characteristics, data on all systemic therapies and outcome are collected. The prognostic factors for OS were assessed using a multivariate cox regression model. Results: Median OS of the 1039 pts (median age 70 years) was 18.6 months (95% CI 16.0 - 20.5 months, 55% events). Median OS in months for low, intermediate and high risk pts according to MSKCC 1999 was 27.3 (23.7-33.8, 48% events), 16.0 (12.7-18.8, 58% events) and 5.3 (3.7-7.2, 74% events). The following factors were significantly associated with shorter OS (p < 0.05: *; p < 0.01: **; p < 0,001: ***): higher age*, non-clear cell histology**, grading G3/4 at diagnosis*, Karnofsky Performance Status <80%***, haemoglobin < lower limit of normal (LLN)***, LDH >1.5x upper limit of normal (ULN)***. Factors significantly associated with longer OS were time from primary diagnosis to metastasis***, BMI 25-30 versus (vs) <25***, BMI>30 vs < 25***, lung metastasis only at start of treatment*, non-visceral metastasis only at start of treatment* and hypertension*. Factors not significantly associated with OS were sex, tumour stage at diagnosis (IV vs <IV), total calcium >ULN, tumour localisation (right/left), congestive heart failure, renal disease, diabetes and total nephrectomy. Conclusions: 3 out of 5 MSKCC factors were significantly associated with OS in our cohort. Still, a clear separation of OS between pts with low, intermediate and high risk according to MSKCC could be confirmed. In addition, we identified novel factors also associated with OS. Clinical trial identification: ClinicalTrial.gov registry: study number: NCT00610012 Legal entity responsible for the study: iOMEDICO AG Funding: Bayer Vital GmbH, GlaxoSmithKline GmbH & Co. KG, Novatis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG Disclosure: P.J. Goebell: Received honoraria for paticipation in expert rounds and honoraria/support as a speaker from Astellas, AstraZeneca, Bayer, Bristol-Myers Squib, Eisai, Ipsen, Janssen, Novartis, Pfizer, Sanofi. M. Staehler: Consultant, Honoria and Research Funding: Pfizer, GlaxoSmithKline, Novartis, Bayer, AVEO, Ipsen, Exelixis, EISAI Consultant and Honoria: EUSAPharm, Astellas, Pelloton Consultant and Research funding: Roche Research funding: Immatics, Wilex. N. Marschner: Employed by iOMEDICO which performs the tumorregistry RCC as an CRO Member of advisory boards regarding RCC treatment and Travel grants: Roche, Novartis, Pfizer, Bayer, GSK Corporate sponsored research: Novartis, Pfizer Roche. All other authors have declared no conflicts of interest.

883P - Synchronous vs metachronous metastatic disease: Impact of time to metastasis on outcome in metastatic renal cell carcinoma patients treated with targeted therapy

Background: Patients (pts) with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of timing of metastatic disease outbreak on outcomes from targeted therapy (TKI) is unclear. Methods: We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to assess overall survival (OS) and time to treatment failure (TTF) on first line TKI, and performed Cox regression analyses comparing synchronous (metastases ≤ 3 mo of initial diagnosis of cancer) vs metachronous disease (metastasis diagnosed post initial diagnosis, evaluated by intervals >3-12 mo, >1-2 yrs, >2-7 yrs, and >7yrs). Results: In 7386 pts with mRCC treated with first line TKI, 3906 pts (53%) had synchronous and 3480 pts (47%) had metachronous metastases. Synchronous vs metachronous disease by intervals >3-12 mo, >1-2 yrs, >2-7 yrs, >7yrs correlated with lower age at TKI initiation (mean 61 yrs vs 61, 62, 63, 66 yrs, respectively, p < 0.0001), higher rate of non-clear cell histology (14% vs 12%, 10%, 10%, 7%, respectively, p < 0.0001), and higher rate of IMDC risk features (mean 2.3 vs 1.6, 0.9, 0.9, 0.8, p < 0.0001). Compared with synchronous disease, the longer time to metastases was significantly associated with improved OS and TTF from TKI therapy initiation in multivariable Cox regression, adjusted for nephrectomy status, histology (cc vs ncc), IMDC risk factors (Hgb, Corrected calcium, Neutrophil, platelets, Karnofsky performance status), number of metastasis (1 vs > 1), age at TKI initiation and year of TKI initiation (2003-2007, 2008-2012, 2013-2016).Table883P Association of time to metastases with OS and TTF from TKI initiationOSTTFtime to metastasesTotalFailedMedian, months 95%CIAdjusted Hazard ratio (95%CI)Adjusted P-valueTotalFailedMedian, months 95%CIAdjusted Hazard ratio (95%CI)Adjusted P-value0-3mo3906(53%)285216.7(15.9-17.5)1.00(reference)–388034835.6(5.5-5.8)1.00(reference)–>3∼12mo1055(14%)72623.8(21.6-26.1)1.06(0.98-1.16)0.16210509417.3(6.6-8.0)1.02(0.95-1.1000.551>1∼2yrs638(9%)40130.2(26.7-32.5)0.84(0.76-0.94)0.0026355648.0(7.3-8.9)0.99(0.90-1.08)0.767>2∼7yrs1155(16%)72934.8(32.4-38.1)0.76(0.70-0.83)<.00011151101110.8(9.6-11.5)0.83(0.77-0.89)<.0001>7yrs632(9%)35941.7(36.3-46.0)0.65(0.58-0.73)<.000162752713.3(11.5-14.9)0.67(0.61-0.74)<.0001Total7386(100%)506773436526 Open table in a new tab Conclusions: Timing of metastases post initial RCC diagnosis impacts outcome with targeted therapy in mRCC. This may need to be taken into consideration in clinical trial designs. Legal entity responsible for the study: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Funding: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Disclosure: F. Donskov: Research funding (to institution) from Novartis, GSK and Pfizer. C. Porta: Consulting or advisory role: Novartis, Bristol-Myers Squib, Pfizer, Jannsen, Eisai, Pelefon, Ipsen, Speaker bureau: Novartis, Bristol-Myers Squib, Pfizer, Ipsen; Eisai Research funding: Pfizer. J.L. Lee: Honoraria from Pfizer and Astellas; consulting fees from Astellas; research funding from Pfizer, Bayer, Janssen, Novartis, and Exelixis. T. Yuasa: Honoraria from Astellas, Novartis, and Pfizer. I.D. Davis: Supported by an Australian National Health and Medical Research Council Practitioner Fellowship (APP1102604) and research funding from Astellas and Exelixis. C. Pezaro: Honoraria from Janssen, Pfizer, Sanofi, Novartis, and Astellas; consulting fees from Novartis; and travel and accommodation funding from Pfizer and Sanofi. R. Kanesvaran: Honoraria from Pfizer, Novartis, Bayer, Astellas, Janssen, Mundipharma, and Sanofi; research funding from Sanofi; and travel and accommodation expenses from Pfizer and Astellas. N. Agarwal: Consulting fees from Pfizer, Exelixis, Cerulean, Argos, and Medivation. C.M. Canil: Advisory Boards for Janssen, Pfizer, Astellas and Amgen; speaking fees from Janseen and Astellas and travel grants from Novartis and Janssen. T.K. Choueiri: Consulting or advisory role for Bayer, Bristol-Myers Squib (institutional), GSK, Merck, Novartis, and Pfizer; and institutional research funding from AstraZeneca, Bristol-Myers Squib, Exelixis, GSK, Merck, Novartis, Peloton Therapeutics, Pfizer, Roche/Genentech, and TRACON Pharma. D.Y.C. Heng: Advisory boards Pfizer, Novartis, Bristol-Myers Squib, Exilexis. All other authors have declared no conflicts of interest.

The evolution of clinical trials in renal cell carcinoma: A status report for 2013-2016 from the clinicaltrials.gov website.

e16050 Background: The treatment paradigm for renal cell carcinoma (RCC) continues to rapidly evolve. We previously published a snapshot analysis of clinical trials in RCC using the publicly available ClinicalTrials.gov registry. Here we present a 3 year update in order to understand the current trends in RCC clinical research, to identify opportunities for improvement, and to compare this data to the landscape in 2013. Methods: The Website’s advanced search function was used to search for the terms “renal cell carcinoma”, “kidney cancer”, “kidney neoplasm” or “renal neoplasm”. The search was further refined to “open studies”, “interventional” and “age ≥18”. Basket trials with ≥7 tumors with non-RCC tumor histologies, terminated studies and pediatric studies were excluded. The phase, stage, treatment setting, type of intervention, study design, histologies, use of biomarkers, studied outcomes, sponsors and location of the trials were recorded. Results: We locked our search on May 26, 2016 and 165 trials were eligible, compared with 169 trials on Sep 25, 2013. There were more phase I and I/II trials in 2016 compared to 2013 (p = 0.05): phase I (25.6% vs 15.4%) and phase I/II (15.2% vs 9.5%). More clinical trials in 2016 compared to 2013 used immunotherapy (IT) alone or in combination with other drugs (24.2 % vs 10.7%, p = 0.001), and the use of targeted therapy alone (TT) declined (32.9% vs 47.9%, p = 0.005). IT alone was used in 15.2% of current trials, compared to 5.96% in 2013. TT+IT combination trials more than doubled (6.7% vs 2.3%, p = 0.07). The number of trials with treatment in neoadjuvant/adjuvant settings in 2016 and 2013 were similar (9.7% vs 10.6%, p = 0.77), respectively. Compared to 2013, the number of trials with non-clear cell histology remained low (n = 10). Many more trials were sponsored by pharmaceutical industry in 2016 vs 2013 (41.5% vs 16.0%, p = &lt; 0.001). Conclusions: More clinical trials included immunotherapy in 2016 compared to 2013, and there was a significant increase in industry sponsored trials. The increase in industry sponsored studies may reflect use of new expensive drugs. More studies in (neo)adjuvant settings and for non-clear cell histologies are needed.

Nivolumab treatment for patients with non-clear cell renal cell carcinoma: A multicenter retrospective analysis.

4586 Background: Nivolumab (Nivo) is approved for metastatic renal cell carcinoma (mRCC) refractory to prior antiangiogenic therapy. However, the clinical activity of Nivo in non-clear cell RCC subtypes remains unknown as these patients were not part of the trial population. Methods: Patients (pts) from 3 centers who received at least one dose of Nivo as monotherapy for mRCC between 12/2015 and 01/2017 were identified. All patients had histologically-confirmed non-clear cell histology. A retrospective analysis focusing on patient and treatment characteristics, objective response according to RECIST v1.1 and adverse events (AEs) was undertaken. Results: Twenty-three patients were identified. Median age was 59 years (33-82), 78% were male, 61% were white, 30% black and 9% Hispanic. MSKCC risk groups were 19% favorable, 67% intermediate, 14% poor. Most common histologies were Unclassified (48%) and Papillary (44%), followed by Collecting duct and Mucinous tubular and spindle cell carcinoma (MTSCC) (4% each). The majority of pts had ECOG PS 0 (57%) or 1 (33%). At diagnosis, 65% had metastatic disease; most common sites were lung (57%), retroperitoneal lymph nodes (35%), and liver or bone (26% each). Most pts (74%) had prior nephrectomy and had received one (74%) or &gt; 1 (26%) prior systemic therapy, most commonly sunitinib (65%), pazopanib (30%) or axitinib (17%). No pts had prior IL-2, but one pt had atezolizumab on trial. After a median follow-up of 6.5 months (mos) and 8 Nivo doses, median PFS was 4.2 mos and median OS was not reached. Among 21 pts evaluable for best response, 6 (29%) had PR and 4 (19%) had SD. Median time to best response was 5.1 mos. At the time of analysis, 9 pts were still on Nivo, 2 were on treatment break, 8 pts had subsequent treatment after PD on Nivo, and 2 were lost to follow-up. Two of 23 pts died. Most common AEs ( &gt; 10%, any grade) were fever (13%) and fatigue (13%). Nivo treatments were postponed in 6 pts due to intolerance and stopped in3 pts. There were no treatment-related deaths. Conclusions: Nivolumab monotherapy demonstrated a substantial objective response rate and was well tolerated in a heterogeneous population of treatment-refractory patients who had mRCC with non-clear cell histology.

Clinical outcomes according to ethnicity in patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeted therapy (TT).

e16065 Background: Discrepancies in clinical outcomes between different ethnic groups are well known in cancer patients. Differences in mRCC patients receiving VEGF-TT are less well characterized. We thought to report on baseline characteristics and treatment outcomes in African-Americans (AA) and Hispanic patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Methods: Caucasians, AA and Hispanics with mRCC treated with 1stline VEGF-TT were identified from the IMDC. We created 2 matched cohorts: 1) AA vs. Caucasians and 2) Hispanics vs. Caucasians, both matched for age (&lt;50; 50-59; 60-69; &lt;70-year-old), gender, years of treatment (2003-07; 2008-12; 2013-16) and geography (Canada, USA, Europe). Weighted Cox and logistic regressions were used to compare OS, time-to-treatment failure (TTF) and best response, adjusted for nephrectomy status, IMDC risk groups, number of metastatic sites (1 v. &gt;1) and histology (clear-cell vs. else). Results: 73 AA and 71 Hispanics met eligibility criteria and were matched with 1236 and 901 eligible Caucasians, respectively. AA had more non-clear cell histology (26% v. 11%), time from diagnosis to therapy&lt;1 year (67% v. 55%) and anemia (75% v. 54%) vs. Caucasians. Differences were not significant for Hispanics. Clinical outcomes are presented in Table. Conclusions: Adjusted for clinical prognostic factors, Hispanics with mRCC have statistically shorter TTF and survival than Caucasians. AA had a trend toward shorter TTF (not significant) but similar survival than Caucasians. Underlying genetic/biological differences, along with potential cultural variations, may impact survival in Hispanic mRCC patients. [Table: see text]

A novel preoperative inflammatory marker prognostic score in patients with localized and metastatic renal cell carcinoma

ObjectiveSeveral inflammatory markers have been studied as potential biomarkers in renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score (RISK) could serve as a rigorous prognostic indicator of overall survival (OS) in patients with clear cell and non-clear cell RCC. MethodsCombination of preoperative C-reactive protein (CRP), albumin, erythrocyte sedimentation rate (ESR), corrected calcium, and aspartate transaminase to alanine transaminase (AST/ALT) ratio was used to develop RISK. RISK was developed using grid-search methodology, receiver-operating-characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. Prognostic value of RISK was analyzed using the Kaplan–Meier method and Cox proportional regression models. Predictive accuracy was compared with RISK to Size, Size, Grade, and Necrosis (SSIGN) score, University of California-LOS Angeles (UCLA) Integrated Staging System (UISS), and Leibovich Prognosis Score (LPS). ResultsAmong 391 RCC patients treated with nephrectomy, area under the curve (AUC) for RISK was 0.783, which was comparable to SSIGN (AUC 0.776, p = 0.82) and UISS (AUC 0.809, p = 0.317). Among patients with localized disease, AUC for RISK and LPS was 0.742 and 0.706, respectively (p = 0.456). On multivariate analysis, we observed a step-wise statistically significant inverse relationship between increasing RISK group and OS (all p < 0.001). ConclusionRISK is an independent and significant predictor of OS for patients treated with nephrectomy for clear cell and non-clear cell RCC, with accuracy comparable to other histopathological prognostic tools.