bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world economic outcomes among patients (pts) who initiated sunitinib or pazopanib as first targeted therapy (TT) for advanced renal cell carcinoma (aRCC): A retrospective analysis of Medicare data.
Authors: Vogelzang Nicholas J. , Pal Sumanta K. , Ghate Sameer , Li Nanxin , Swallow Elyse , Peeples Miranda , Zichlin Miriam , Meiselbach Mark , Perez Jose Ricardo , Agarwal Neeraj
Published: March 2017

475

Background: Evidence on economic outcomes could provide insight on comparative economic benefit of TTs. This study assessed all-cause healthcare resource utilization (HRU) and costs among aRCC patients who initiated pazopanib and sunitinib, two commonly-used first TTs. Methods: Pts with aRCC who initiated sunitinib or pazopanib as first TT (index therapy/index date) were identified in this 100% Medicare data + Part D linkage (1/1/2006-12/31/2014). Characteristics were assessed during the 1 year prior to index date (baseline period) and pts were followed until death, end of eligibility, or end of data (study period), whichever was earliest. Pts were stratified by first TT initiated and 1:1 matched using propensity scores based on age, sex, race, year of RCC diagnosis, metastatic sites, comorbidities, and baseline inpatient, outpatient, emergency room, and pharmacy costs. Study period all-cause HRU and costs (2015 USD) were assessed on a per pt per month (PPPM) basis and compared between the matched cohorts. Results: Before matching, the cohorts were similar in baseline characteristics; however, the pazopanib cohort (n=526) was associated with higher outpatient visits and costs and lower pharmacy costs during the baseline period than the sunitinib cohort (n=1,185; all p<0.05). After matching, all baseline characteristics were balanced (n=522 for both). First TT with pazopanib was associated with significantly lower total healthcare costs ($10,416 vs. $8,845, mean difference [MD]):$1,571, p<0.01), total medical costs ($6,904 vs. $5,460, MD:$1,444, p<0.01), inpatient costs ($4,035 vs. $2,914, MD:$1,120, p<0.01), inpatient admissions (0.26 vs. 0.18, MD:0.08, p<0.01), and inpatient days (1.9 vs. 1.4, MD:0.5, p<0.01) compared with the sunitinib cohort. Conclusions: In this retrospective analysis of Medicare aRCC pts, treatment first line with pazopanib compared to sunitinib had lower follow-up all-cause healthcare costs and resource use, particularly with lower inpatient admissions and shorter length of stay.
Impact of immune checkpoint protein expression in tumor cells and tumor infiltrating CD8+ T cells on clinical benefit from PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Mahoney Kathleen M. , Moreira Raphael Brandao , Novak Jesse , Conen Hilla , Norton Craig , Harshman Lauren Christine , Van Allen Eliezer Mendel , Wu Catherine J. , Atkins Michael B. , Freeman Gordon J. , Catalano Paul J. , Choueiri Toni K. , McDermott David F. , Signoretti Sabina
Published: March 2017

477

Background: PD-1 blockade with nivolumab has demonstrated efficacy in mccRCC patients who have failed prior therapy; however, durable benefit is observed only in a subset of patients. Correlative studies have demonstrated that tumor PD-L1 expression alone fails to reliably identify patients likely to benefit. Therefore, the development of more robust predictive markers is warranted. Methods: We studied 20 mccRCC patients treated with nivolumab (n=17) or atezolizumab (n=3) with distinct clinical outcomes: 8 pts who experienced durable clinical benefit (DCB) for ≥ 12 months and 12 pts with limited clinical benefit (LCB) for ≤ 6 months from start of therapy. Expression of PD-L1 and PD-L2 on tumor cells and density of tumor infiltrating CD8+ T cells and Foxp3+ cells were evaluated by immunohistochemistry. Percentages of tumor infiltrating CD8+T cells expressing the immune-inhibitory molecules PD-1, TIM-3, or LAG-3 either alone or in combination were determined by multiplex immunofluorescence, using the Inform algorithm (Perkin Elmer). The association between clinical benefit (CB) and biomarker expression was assessed using Fisher exact test. Results: Baseline patient characteristics were similar in the DCB and LCB groups. When analyzed separately, tumor cell expression of PD-L1 or PD-L2 showed no association with CB. However, when positivity was defined as expression of either or both PD-L1(≥ 1% cutoff) and PD-L2 (≥ 5% cutoff), a significant association with CB was found (7/8 DCB vs 4/11 LCB, p = 0.04). A low percentage of tumor infiltrating CD8+PD-1+ T cells co-expressing either or both TIM-3 and LAG-3 (75thpercentile cutoff) was also significantly associated with CB (8/8 DCB vs 7/12 LCB, p = 0.05). Conclusions: Our results suggest that expression of a PD-1 ligand on tumor cells (PD-L1 and/or PD-L2), and a low percentage of severely exhausted T cells, i.e. CD8+PD-1+ T-cells co-expressing the immune-inhibitory receptors TIM-3 and/or LAG-3, might represent valuable predictive biomarkers for response to PD-1 blockade in mccRCC. Independent validation in a larger patient cohort is ongoing.
Epigenetic targeting of clear cell renal cell carcinoma (ccRCC) with ascorbic acid (AA) via upregulation of Ten-Eleven Translocation (TET) methylcytosine dioxygenase activity.
Authors: Shenoy Niraj Konchady , Bhagat Tushar , Pagliaro Lance C. , Witzig Thomas E. , Verma Amit
Published: March 2017

479

Background: We and others have previously shown that the ccRCC epigenome is characterized by widespread DNA hypermethylation (CCR 2014, Nature 2014). Various important tumor suppressor genes (TSGs), such as SMAD7 (inhibitor of oncogenic TGF-β signaling), are under-expressed due to aberrantly methylated promoters or enhancers. We hypothesized that the hypermethylation in ccRCC could be due to low activity of the TET enzymes, which convert methylcytosine (5-mc) to hydroxymethylcytosine (5-hmc). Loss of function of TET enzymes can occur with an inactivating mutation (TET-2 is mutated in about 6% of ccRCC (Science Signaling 2013) or hypoactivity of normal TET enzymes, through inhibition by metabolic intermediates. AA is an essential co-factor for TET enzymes (JACS 2015). We hypothesized that high dose AA treatment of ccRCC could potentially increase the functional activity of TET enzymes leading to demethylation of the RCC genome, and enhance expression of TSGs. Methods: In vitro TET activity was performed on ccRCC cell line 769P with increasing doses of AA (L-AA). Genome wide quantitative 5-mc and 5-hmc was evaluated using mass spectrometry. SMAD7 expression was determined using qRT-PCR. Proliferation assay (MTT) was performed with AA in combination with pazopanib. Cell cycle and apoptosis assays were performed. Results: AA, at doses achieved only by the intravenous route (1-10mM), increased TET activity in ccRCC cell line 769P. Genome wide 5-mc was significantly reduced and 5-hmc was increased, correlating with increase in TET activity. SMAD7 expression was increased with AA treatment. High dose AA led to proliferation inhibition with a cell cycle arrest in the G1 phase, and had a synergistic effect with pazopanib. Since AA leads to the generation of H2O2 in-vitro, catalase was used as control. This did not reverse the effect of AA on epigenetic changes; and proliferation inhibition was seen despite catalase control. Conclusions: High dose AA causes TET mediated DNA demethylation of the hypermethylated RCC genome, resulting in the re-expression of TSGs, and proliferation inhibition. Sequencing and xenograft studies are underway.
Intraoperative conversion from partial to radical nephrectomy: Predictive factors and outcomes.
Authors: Petros Firas G. , Keskin Sarp K. , Yu Kai-Jie , Fellman Bryan M. , Metcalfe Michael J. , Matin Surena F. , Karam Jose A. , Wood Christopher G.
Published: March 2017

483

Background: Predictive risk factors for intraoperative conversion from partial to radical nephrectomy (RN) are poorly quantified. We evaluated preoperative predictors of conversion in a cohort of patients undergoing planned partial nephrectomy (PN). Methods: A prospectively maintained database was reviewed to identify patients who were scheduled to undergo (open, laparoscopic, or robot-assisted) PN that were converted to RN between 1990 and 2015. Reasons for conversion were collected from the operative report. Patient demographics and perioperative variables were evaluated including body mass index (BMI), tumor size, nephrometry score, hilar tumors, procedure type, intraoperative complications, and oncologic outcome. Results: A total of 2298 patients underwent successful PN. The rate of conversion to RN was 4% (n=99) patients. The median patient age was 60 years and median BMI was 30 kg/m2. The median American Society of Anesthesiologists (ASA) score was 3 and median Charlson Comorbidity Index (CCI) was 2. The median tumor size for the converted cases was 4.5 cm (1.0-10.1) and median nephrometry score was 9. Histology was clear cell-RCC in 79% of the tumors. A total of 30 patients had completely endophytic tumors. The most common reasons for conversion were hilar/renal sinus extension of the renal mass in 38 (38%) patients, positive surgical margin on frozen section or gross assessment in 27 (27%) patients, insufficient renal remnant in 27 (27%) patients, and excessive intraoperative bleeding in 7 (7%) patients. RN was performed open in 79, laparoscopically in 9, and robot-assisted in 11 cases. Intraoperative complications occurred in 1 (1%) patient underwent an attempted robot-assisted PN resulted in an injury to a major renal artery branch requiring conversion to RN. Patients were followed up for a median of 33 months. In the converted cohort, evidence of disease at last follow-up was found in 13 (13%) patients. Conclusions: The rate of conversion to RN was low in patients undergoing PN in this series. The most common reason for conversion was hilar/renal sinus extension of these complex renal masses while positive surgical margin and insufficient renal remnant were contributing equally at lower rates.
Is RECIST-defined progression free-survival a meaningful endpoint in the era of immunotherapy?
Authors: Johal Sukhvinder , Santi Irene , Doan Justin , George Saby
Published: March 2017

488

Background: Progression-free survival (PFS) is often used as a primary endpoint in oncology clinical trials as a surrogate for overall survival. Traditionally, the Response Evaluation Criteria in Solid Tumors (RECIST) have defined disease progression as a significant increase in the size of tumor lesions and the development of new lesions. However, some patients starting immunotherapy have shown initial increased size of tumor lesions followed by tumor regression, due to the unique mechanism of action of immunotherapies. This initial “pseudo-progression” could be classified inaccurately as disease progression, as evidenced by benefit from the treatment beyond progression approach ( JAMA Oncol 2016). The phase III CheckMate 025 trial of nivolumab versus everolimus in patients with advanced renal cell carcinoma allowed treatment beyond progression if there was investigator-assessed clinical benefit and tolerability. The purpose of our study was to test if treatment duration for an immunotherapy was different from RECIST-defined PFS, and as such, could potentially explain the apparent lack of correlation between RECIST progression and overall survival shown in CheckMate 025. Methods: Using 1-year data from CheckMate 025, Kaplan–Meier methodology was used to estimate the median duration of PFS and time to treatment discontinuation (TTD). Stratified log-rank test was used to assess the difference in treatments. Results: For all patients, the median PFS with nivolumab was 4.6 months (95% CI, 3.7–5.4 months) and median TTD was 6.2 months (95% CI, 5.6–7.7 months). For everolimus, the median PFS was 4.4 months (95% CI, 3.7–5.5 months) and median TTD was 3.9 months (95% CI, 3.7–4.6 months). Conclusions: Patients in CheckMate 025 had significantly longer survival with nivolumab than with everolimus, but with similar PFS. Our analysis demonstrated that while PFS was similar to TTD with everolimus, there was a significant difference between the 2 measures for nivolumab, suggesting that RECIST-defined PFS may not be the proper endpoint to define progression for immunotherapies. Further evaluation of the association of TTD and other immune-related progression endpoints with overall survival is warranted. Clinical trial information: NCT01668784.
Real world experience of immuno-oncology agents in metastatic renal cell carcinoma: Results from the IMDC.
Authors: Yip Steven , Wells Connor , Moreira Raphael Brandao , Wong Alex , Srinivas Sandy , Beuselinck Benoit , Porta Camillo , Sim Hao-Wen , Ernst D. Scott , Rini Brian I. , Yuasa Takeshi , Basappa Naveen S. , Kanesvaran Ravindran , Wood Lori , Soulieres Denis , Canil Christina M. , Kapoor Anil , Fu Simon Yuen Fai , Choueiri Toni K. , Heng Daniel Yick Chin
Published: March 2017

492

Background: Immuno-oncology (IO) checkpoint inhibitors have demonstrated efficacy in metastatic renal cell cancer (mRCC) treatment. Real world data is required to assess outcomes when applied to the general population. Methods: A retrospective analysis was performed using the IMDC database. It included mRCC patients treated with IO agents, including atezolizumab (Atezo), avelumab, ipilimumab, nivolumab (Nivo), and pembrolizumab (Pembro). Some patients were treated with combination therapy with a targeted agent. Patients may have received IO therapy as first-, second-, third-, or fourth-line treatment. Overall survival (OS), treatment duration, and overall response rates (ORR) were calculated. Results: 255 patients with mRCC treated with IO therapy were included. The ORR to IO therapy in those patients who were evaluable was 29% (32% first-, 22% second-, 33% third-, and 32% fourth-line therapy). Patients treated with second-line IO therapy were divided into favorable, intermediate, and poor risk using IMDC criteria; the corresponding median OS rates were not reached, 26.7 mo, and 12.1 mo, respectively (p<0.0001). Conclusions: Response rates to IO therapies appear to remain consistent no matter which line of therapy it is used in. Within second-line treatment, IMDC criteria appear to stratify patients appropriately into favorable, intermediate, and poor risk groups. Survival data are premature and will be updated. In contrast to Nivo clinical trial data, where median treatment duration was 5.5 mo, longer treatment length is observed in real world practice. [Table: see text]
Proton pump inhibitors (PPIs) and survival outcomes in patients with metastatic renal cell carcinoma (mRCC).
Authors: Lalani Aly-Khan A. , McKay Rana R. , Lin Xun , Simantov Ronit , Kaymakcalan Marina D. , Choueiri Toni K.
Published: March 2017

493

Background: PPIs are potent inhibitors of gastric acid secretion and can affect the bioavailability of orally administered cancer targeting therapies, such as vascular endothelial growth factor tyrosine-kinase inhibitors (VEGF-TKIs). Smaller preclinical and clinical studies have attempted to assess the interaction between VEGF-TKIs and PPIs in patients with advanced cancers; however, these studies are limited and larger analyses from rigorous datasets have been lacking. We investigate the impact of PPI use on survival in patients with mRCC treated with oral VEGF-TKIs. Methods: A pooled analysis of mRCC patients treated on phase II and III clinical trials was conducted. The primary outcome was to assess overall survival (OS) between PPI users, defined as patients receiving a PPI at baseline, compared to non-PPI users. Secondary outcomes included progression-free survival (PFS), objective response rates (ORR), and adverse events. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. Results: Our cohort consisted of 2,188 patients treated with sunitinib (n = 952), axitinib (n = 626), or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users demonstrated similar OS compared to non-PPI users (median 24.1 vs. 21.3 months, adjusted hazard ratio [aHR] 1.051, 95% confidence interval (CI) 0.769-1.438, p = 0.754). Similarly, PFS (5.5 vs. 8.0 months, aHR 1.016, 95% CI 0.793-1.301, p = 0.902) and ORR (23.3% versus 27.4%, p = 0.344) were not different between PPI users and non-users. These findings were consistent across International mRCC Database Consortium risk groups and by line of therapy. Adverse events were also similar between both groups. Conclusions: In this analysis, we demonstrate that PPI use does not appear to negatively impact the efficacy of VEGF-TKIs in mRCC patients treated in the targeted therapy era. Given the current landscape expanding to include more self-administered treatments, documentation of concomitant medications, and patient education on potential drug interactions are critical for optimizing the utilization of oral cancer targeting therapy.
Correlations between tumor-infiltrating and circulating lymphocyte subpopulations in mRCC patients treated with immune-checkpoint inhibitors.
Authors: Bersanelli Melissa , Gnetti Letizia , Vaglio Augusto , Sverzellati Nicola , Campanini Nicoletta , Galetti Maricla , Incerti Monia , Varotti Elena , Parziale Raffaele , Corrado Michele , Bottarelli Lorena , Azzoni Cinzia , Rapacchi Elena , Caruso Giuseppe , Cosenza Agnese , Ferri Leonarda , Silini Enrico Maria , Leonardi Francesco , Buti Sebastiano
Published: March 2017

494

Background: In clinical trials with immune-checkpoint inhibitors (CKI), histological features such as tumor-infiltrating lymphocites (TILs) are investigated as potential predictive biomarkers, with the possible limit of an outdated parameter for a typically dynamic element. Methods: This explorative study compared, in metastatic renal cell carcinoma (mRCC) patients, basal pathological data about TILs on diagnostic histological specimens with circulating lymphocyte subpopulations measured before and during therapy with nivolumab, with the primary aim to assess their concordance. Secondarily, with the limit of a small sample size, a possible relation with treatment outcome was explored. Results: Of 11 mRCC patients, 5 had low presence of TILs (L-TILs), 3 moderate amount (M-TILs), and 3 high number (H-TILs). Overall, 8 patients had low intratumoral pathological CD4+/CD8+ ratio (LIPR) ≤ 1 and 3 cases high intratumoral pathological ratio (HIPR) ≥ 2. Of 8 patients with LIPR, only 2 cases matched with low circulating CD4+/CD8+ ratio (LCR) ≤1, whilst 5 cases had high circulating ratio (HCR) ≥ 2 (1 undetermined). All 3 cases with HIPR (≥ 2) conversely had LCR (≤ 1). Unexpectedly, independently from the clinical outcome, circulating CD4+/CD8+ ratio remained unchanged during therapy with CKI in each patient, maintaining the same value after 8 weeks (mean -0.12). The respective percentage values of CD4+ and CD8+ circulating T cells also remained stable during treatment (mean variation 0%); the absolute value of CD4+ was more likely to increase (mean +46.3/mm3); the level of CD8+ tended to slightly decrease (mean -6.5/mm3). No correlation of lymphocyte subpopulations with treatment outcome was found. Conclusions: Of note, this study did not evidence any correspondence between histopathological and circulating findings in terms of T-lymphocyte subpopulations in mRCC patients undergoing treatment with CKI, also suggesting the inconsistency of circulating data in terms of relative variations. Considering the likely high dynamism of TILs, rebiopsy before CKI therapy might be the most reliable way to assess the utility of TILs characterization for predictive purpose.
Second line axitinib in metastatic renal cell carcinoma: Evaluation of prognostic factors influencing outcome.
Authors: Brooks Helen , Challapalli Amarnath , Reed Hannah , Masson Susan , Hilman Serena , Bahl Amit
Published: March 2017

495

Background: Axitinib has been approved for 2nd line treatment in the UK for patients with advanced renal cell carcinoma on the basis of the AXIS study, which showed improved progression free survival (PFS) and a trend towards overall survival (OS) benefit. There is no randomised data to support the use of Axitinib after first line Pazopanib. Hence, we compared the efficacy of Axitinib after first line Pazopanib or Sunitinib. The influence of Heng prognostic risk score (HPRS) at initiation of Axitinib, previous nephrectomy, and haemoglobin (Hb) rise during Axitinib treatment on outcome was also evaluated. Methods: Thirty one patients were commenced on Axitinib between May 2013-May 2016. Patient demographics, laboratory parameters, and survival data were collected retrospectively. Data were analysed in October 2016, which served as a censor date for patients who were alive. Analysis of PFS and OS was performed by Kaplan-Meier estimates and log-rank test. Results: All 31 patients received axitinib as 2nd line treatment. At the time of analysis, 14 patients were alive and 7 remained on axitinib. The prognostic factors influencing outcome are shown in the table. Conclusions: There was no significant difference in PFS or OS regardless of first line treatment, supporting the use of axitinib post pazopanib or sunitinib. Prior nephrectomy, and favourable HPRS significantly predict better PFS and OS. The impact of Hb rise needs further validation in a larger cohort.[Table: see text]
Perinephric white adipose tissue inflammation in clear cell renal cell carcinoma (ccRCC).
Authors: Furberg Helena , Hakimi A. Ari , Gucalp Ayca , Iyengar Neil M. , Williams Samantha , Petruzella Stacey , Tennenbaum Daniel M. , Samson Marguerite , Mannino Nicole , Giri Dilip D. , Zhou Xi K. , Russo Paul , Dannenberg Andrew J.
Published: March 2017

507

Background: High body mass index (BMI) is an established risk factor for developing ccRCC but is associated with better survival in clinical studies. The obesity paradox may be influenced by metabolically healthy patients classified as obese, and metabolically unhealthy patients classified as normal weight. We evaluated white adipose tissue inflammation (WATi) in perinephric fat as a new marker of metabolic dysregulation and examined its association with clinicopathological characteristics. Methods: In July 2015, we established a prospective cohort study at Memorial Sloan Kettering Cancer Center to investigate the prognostic significance of perinephric WATi among patients undergoing nephrectomy. Perinephric WAT is collected during surgery and patients are followed for clinical outcomes. WATi is defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) and detected through immunohistochemistry. Clinicopathological data are abstracted from the electronic medical record. Wilcoxon rank-sum, Chi-square, or Fisher’s exact tests describe the relationship between CLS status and clinicopathological characteristics on the first 38 ccRCC patients. Results: The study cohort had a median age of 56 years (range 47-64 years) and was predominantly male (71%). CLS were detected in 50% of patients, did not differ by age or sex, and were present in all BMI levels; 59% of obese, 38.5% of overweight, and 33% of normal weight patients (p = 0.47). CLS was significantly associated with advanced disease characteristics including higher stage (p = 0.03) and local invasion (p = 0.02). Median tumor size was larger in patients who were CLS+ (3.5 cm, range 2.65-5.75) than CLS- (2.2 cm, range 1.55-3.00; p = 0.02). Conclusions: Perinephric WATi was found in ccRCC patients of all BMI levels and associated with factors related to poor prognosis. Patients with occult inflammation may be at higher mortality risk, regardless of their BMI. Recruitment of additional cases and analyses to examine how CLS influences ccRCC survival are on-going.
Predictors of mortality in metastatic papillary renal cell cancer.
Authors: Sidana Abhinav , Jain Amit L , Kadakia Meet , Krane Spencer , Friend Julia C. , Muthigi Akhil , Ninos Martha , Shih Joanna H. , Srinivasan Ramaprasad
Published: March 2017

509

Background: While studies have established several prognostic factors determining mortality in metastatic clear cell renal cell cancer patient, similar analysis has been lacking in metastatic papillary renal cell cancer (pRCC) patients. We aim to determine the predictors of mortality in metastatic pRCC patients. Methods: Retrospective evaluation of the medical records of patients with metastatic pRCC seen at National Cancer Institute (2000-2014) was undertaken. Patient demographics, tumor characteristics, and outcomes were studied. Kaplan-Meier Survival analysis was done to estimate overall survival (OS). Cox proportional-hazards regression analysis was done to identify predictors of All cause mortality (ACM) in this population. Results: 106 consecutive patients with metastatic pRCC were identified. The median age and follow up time after the diagnosis of metastases was 50 years (11-80) and 33.8 mon (2.3-246.7) respectively. Twenty one (19.8%) and 42 (39.6%) patients had papillary type 1 and papillary type 2 renal cancers respectively; in 43 (40.5%) patients, tumors were classified as papillary, not otherwise specified. Half (53) of patients had hereditary origin of pRCC. Median estimated OS of entire cohort was 37.5 mon. There was no difference in survival between patients with hereditary or sporadic pRCC (p = 0.80) or among patients with different subtypes of pRCC (p = 0.79). On univariate analysis, elevated serum corrected calcium elevated lactate dehydrogenase, Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and presence of malignant ascites significantly affected the patients’ prognosis. Corrected Calcium (p = 0.03) and NLR (p = 0.004) were found to be independent predictors of ACM on multivariate analysis. Conclusions: To our knowledge, this is the largest single center series evaluating survival and predictors of survival in metastatic pRCC. Metastatic pRCC patients with elevated NLR and serum corrected calcium are significantly associated with relatively poor OS when compared to patients without these findings. If validated in larger multi-institutional cohorts, it might be reasonable to incorporate corrected calcium and NLR in nomograms predicting ACM in metastatic pRCC.
Immune cell phenotyping of clear cell renal cell carcinoma.
Authors: Ghanaat Mazyar , Liu Ming , Manley Brandon , Kashan Mahyar , Becerra Maria , Redzematovic Almedina , Coleman Jonathan , Russo Paul , Hsieh James , Li Ming , Hakimi A. Ari
Published: March 2017

511

Background: Clear cell renal cell carcinoma (ccRCC) tumors develop mechanisms that impair function and/or prevent entry of the host infiltrating immune cells (immune exclusion) within the tumor microenvironment. The goal of immunotherapy is to overcome this immune resistance. We aim to characterize the T−cell populations in a cohort of largely untreated high risk patients with ccRCC. Methods: We prospectively collected ccRCC tumor and adjacent normal kidney (NK) from patients undergoing surgical resection at our institution from 6/2015-8/2016. Immune cell phenotyping was performed by immune cell staining of single cell suspensions. Analysis of immune cell populations were determined by CD45+ staining and corresponding proportions of different T−cell populations (CD3+, CD4+, CD4+Treg, and CD8+ T cells). Staining for CD4+Treg was not available for two patients. Student t−test was utilized to compare the immune populations between tumor and adjacent NK tissue. Analysis was also conducted by stratifying patients who presented with localized versus metastatic disease. Results: A total of 31 tumor and adjacent NK were analyzed. Median tumor pathological size was 8.5cm (2.9cm−18cm), 27(87%) had pT3a−pT3b and 13(42%) presented with metastatic disease. Overall 84% of tumors had higher immune infiltrate with an average ratio of four-fold increase compared to adjacent NK as determined by CD45+ cells. Intriguingly, the other 16% presented with metastatic (4) or rapidly metastatic disease (1). Orthogonal validation with inferred immune populations using RNAseq data from the The Cancer Genome Atlas (TCGA) demonstrated similar aggressive behavior in tumors with lower immune infiltrate compared to NK. Comparison of immune cell populations of tumor and NK tissue is shown in table 1. No specific T-cell subtype was associated with specific clinical outcomes in this cohort. Conclusions: Our data shows a general trend of immune infiltration in ccRCC when compared to adjacent NK with a diversity of T-cell subsets and possible evidence of immune exclusion. Further genomic characterization of these tumors is currently underway. [Table: see text]
Does dose modification affect efficacy of first-line pazopanib in metastatic renal cell carcinoma?
Authors: Grassi Paolo , Procopio Giuseppe , Ratta Raffaele , Porcu Luca , Martinetti Antonia , Mennitto Alessia , Verzoni Elena
Published: March 2017

512

Background: Pazopanib is a standard treatment for metastatic renal cell carcinoma (mRCC) and 800 mg/day is considered the optimal dose for mRCC patients (pts). However, some pts require a dose reduction due to toxicity. It remains unclear whether reduced-dose pazopanib is as effective as the standard dose in achieving a response. Methods: We retrospectively evaluated treatment duration, objective response rate (ORR), progression-free survival (PFS), and discontinuation rate in consecutive pts with mRCC treated with first-line pazopanib between 2011 and 2016 at the Istituto Nazionale Tumori of Milano, Italy. Three patient groups were compared: group 1 received the standard starting dose of 800 mg/day continously, group 2 received a dose reduced to 400 or 600 mg/day after starting with 800 mg/day, and group 3 received a reduced starting dose of 400 or 600 mg/day because of ECOG performance status = 2-3 and/or comorbidities. Results: We included 69 pts, with 34 in group 1, 19 in group 2, and 16 in group 3. Median age at diagnosis was 62 years, and 64% were male. Overall 13% and 87% of pts were classified as Heng good and intermediate-risk respectively. In 10 and 9 pts of the group 2, the dose was reduced to 600 and 400 mg/day respectively while 12 and 4 pts in the group 3 received a reduced initial dose of 400 and 600 mg/day respectively. After a median follow-up of 13.9 months (range 0.3-43.8), 27 (39.1%) pts showed progressive disease (PD) and 3 (4.3%) pts were dead. Incidence rate of PD or death was 2.5 (95% CI: 0.6-4.4; Hazard ratio [HR]:1) per 100 person-months in group 1; 4.0 (95% CI: 0-11.4; HR: 1.45) per 100 person-months in group 2 and 3.3 (95% CI: 0-6.8; HR: 1.19) per 100 person-months in group 3. Rates of discontinuation due to PD were 28% in group 1, 42% in group 2, and 44% in group 3. ORR was 44%, 11% and 19% in group 1, group 2, and group 3 respectively. Conclusions: Our results suggest that mRCC pts receiving a lower dose of first-line pazopanib might not have a meaningful PFS advantage compared with those receiving standard dose. These data highlight the importance of management of the treatment-related side effects that may eventually lead to optimal drug exposure.
Characterization of patients (pts) with poor risk metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.
Authors: Hamieh Lana , McKay Rana R. , Lin Xun , Simantov Ronit , Choueiri Toni K.
Published: March 2017

515

Background: Survival outcomes are heterogeneous across different subsets of mRCC pts. Poor risk pts have grim outcomes and are less likely to be enrolled in clinical trials, hence the lack of prospective data characterizing this pt population. We provide a comprehensive analysis of poor risk pts, as defined by three widely used prognostic models, in the era of targeted therapy. Methods: We conducted a pooled retrospective analysis of 4,736 mRCC pts treated on phase II and III clinical trials. Pts were defined as poor risk according to the Memorial Sloan Kettering Cancer Center (MSKCC), International Metastatic Database Consortium (IMDC), and Hudes prognostic risk models. We evaluated overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) in poor risk pts in each of the risk models in the total cohort and in a subset of pts who remained on treatment for >12 months (mos). The models’ concordance (c-) index was used to assess their prognostic performance. Results: We identified 1145 (24.2%), 904 (19.1%), and 1901 (40.1%) poor risk pts by IMDC, MSKCC, and Hudes models, respectively. The majority were <65 years of age (70-73%) with clear-cell histology (85-88%), prior nephrectomy (62-66%), and no prior systemic therapy (80-86%). The efficacy and toxicity outcomes as well as the c-indexes for each of the models are reported in the table below. Additionally, 9-14% of poor risk pts remained on therapy for >12 mos and had higher OS (29.8-35.2 mos) and ORR (42-53%). Conclusions: In this large database of poor risk mRCC pts, we highlight that the models have similar predictive accuracy in the targeted therapy era. We also demonstrate that poor risk pts continue to have dismal outcomes and should be considered for trials of novel agents and combinations. A subset of these pts appears to derive prolonged clinical benefit and should be further explored.[Table: see text]
Use of liquid biopsy for detection of renal cell carcinoma.
Authors: Laganosky Dean , Lorentz Charles , Al-Qassab Usama , Ogan Kenneth , Master Viraj A. , Issa Muta , Pattaras John , Roberts David , Bergquist Sharon , Rossi Michael R. , Arnold Rebecca , Goecks Jeremy , Petros John
Published: March 2017

521

Background: Circulating tumor DNA (ctDNA) displays characteristics of an ideal serum biomarker. We sought to develop whole-exome sequencing of ctDNA to interrogate commonly mutated genes in renal cell carcinoma (RCC) for early tumor detection through a single blood sample. Methods: Patients with solid renal tumors and healthy controls provided 40 mL blood from which purified plasma cell-free DNA was prepared. A multiplex bar-coded polymerase chain reaction amplification using the Fluidigm Access Array was performed to prepare sequencing libraries for the Illumina HiSeq platform. Galaxy workflow was then utilized to identify mutations within the plasma cell-free DNA samples and results were compared to buffy coat sequencing containing control DNA for each individual’s sample. The following genes were queried: VHL, PBRM1, SETD2, BAP1, KDM5C, KIT, NFE2L2, MET, TP53, CDKN2A, FGFR3, PIK3CA, BRAF, and MUC4. Criteria for calling mutations included adequate frequency by overall count and percentage of reads, identification in all overlapping sequences and presence of buffy coat-derived control DNA for comparison with <0.5% containing the mutation. Results: Of the preoperative RCC patients, 20/30 (67%) had detectable somatic mutations compared to 2/48 (4.2%) controls. These included nonsynonymous, frameshift, stop-gain, and splice site mutations. Mutations were detected in RCC patients with both early and advanced stage disease, including a patient with a 1.1 x 0.7 x 0.5 cm tumor. Mutations were seen in all genes assayed. Conclusions: The majority of RCC patients of various stages and histology had ctDNA detected in a single preoperative blood sample. Comparatively, only two of the control patients sampled were ctDNA positive. Controls will be followed to identify the possible sources of ctDNA. Developing such non-invasive methods for RCC detection has the potential to enhance both diagnosis and surveillance of renal malignancy, even in the setting of small renal masses.
CLOVIZ: Clinical outcomes visualization of IMDC criteria in metastatic renal cell carcinoma for patient-centered decision making.
Authors: Odisho Anobel Y. , Pal Sumanta K. , Shapiro Michael , Dixon Ashley , Wells Connor , Ruiz Morales Jose Manuel , Choueiri Toni K. , Heng Daniel Yick Chin , Gore John L.
Published: March 2017

527

Background: The International Metastatic Renal Cell Carcinoma Database (IMDC) Criteria (Heng Criteria) is a validated risk prediction tool for patients with metastatic renal cell carcinoma (mRCC). It provides valuable prognostic data but clinical application can be challenging due to limited available tools. We created an interactive visualization to facilitate clinical application of IMDC Criteria. Methods: A multi-institutional cohort of 436 patients with mRCC was used to create an interactive visualization depicting IMDC Criteria at the patient level. Usability testing was performed with non-medical lay-users and medical oncology fellows. Subjects used the tool to calculate median survival times based on IMDC Criteria in six increasingly complex clinical scenarios. Confidence using the tool was surveyed and measured along a 5-point Likert scale. Results: The interactive visualization is available at http://faculty.washington.edu/odisho . 400 lay-users and 15 medical oncology fellows completed clinical scenarios and surveys. Overall, lay-users were able to obtain the exact correct answer in 48% of scenarios, compared to 60% of medical oncology fellows. The proportion of exact correct answers decreased with increasing task complexity, but the proportion of answers within 25% of the expected answer remained stable at 68-78% for lay-users and 73-93% for medical oncology fellows. When surveying usability, 65% of lay-users felt it was easy to use, compared to 80% of fellows, and 83%-87% felt it became intuitive with increasing use. Among lay-users, 69-77% were confident selecting lab values and drugs, compared to 87-93% of medical oncology fellows. 75% of lay-users felt it helped them better understand survival in mRCC. 68% of lay-users wanted to use a similar tool with their doctor, while 87% of medical oncologists wanted to use this with patients, and 93% wanted to incorporate it into their clinical practice in some way. Conclusions: A graphical method of interacting with a validated nomogram for mRCC outcomes provides real-time individual level data that can be used by untrained nonmedical users and medical oncologists, with potential for use in the clinic setting.
Biomarker study of early death in patients with intermediate and favorable risk metastatic renal cell carcinoma.
Authors: Harris Wayne , Zhang Chao , Liu Yuan , Kucuk Omer , Carthon Bradley Curtis , Master Viraj A.
Published: March 2017

530

Background: The primary objective of this study was to determine whether severe systemic inflammation (SSI) could serve as a biomarker for terminal disease progression and early death in patients with intermediate and favorable risk metastatic renal cell carcinoma (mRCC). Methods: Retrospective chart reviews of patients treated with targeted therapy for mRCC were conducted at the Winship Cancer Institute of Emory University (WCIEU) and the Atlanta Veterans Administration Medical Center (AVAMC) after obtaining institutional authorizations. The modified Glasgow Prognostic Score (mGPS) was used to quantify intensity of systemic inflammation (ISI) at baseline and at least two additional time points that were at least 10 days apart. Early death was defined as death within two years of Day 0, the first day ISI was quantified. Descriptive statistics were employed along with Kaplan-Meier survival analysis. Results: ISI was quantified 2,428 times in 135 patients at the WCIEU with a median of 16 per patient and a range of 3 to 51 versus 758 times in 46 patients at the AVAMC with a median of 12 per patient and a range of 3 to 48. Baseline risk stratification was as follows: favorable (mGPS=0), intermediate (mGPS=1) and poor (mGPS=2) with 96 (51%), 36 (19%), and 53 patients (29%) in the respective risk groups of the combined cohort (n=181). Sixty eight of the 90 patients who died in the time frame of the study did so within 2 years of Day 0. Of these early deaths, only 34 (50%) were among patients with poor risk at baseline versus 18 (26%) and 16 (24%) of the intermediate and favorable risk patients, respectively. Furthermore, 90% of these early deaths were associated with SSI as a terminal event as were 87% of all deaths in spite of the fact that 64% of poor risk patients had died as of Year 2 versus only 27% of patients in the combined group of intermediate and favorable baseline risk. Conclusions: Severe acquired systemic inflammation is a promising biomarker for terminal disease progression and early death in patients with intermediate and favorable risk mRCC. Prospective confirmatory studies are required.
Additive prognostic impact of elevated De Ritis ratio and renal score in predication of survival outcomes in localized renal cell carcinoma.
Authors: Hamilton Zachary , Bloch Aaron , Field Charles , Fero Katherine Elaine , Berquist Sean , Hassan Abd−elrahma , Han Daniel , Proudfoot James , Derweesh Ithaar
Published: March 2017

532

Background: Renal Cell Carcinoma (RCC) is a metabolically driven neoplasm. Inflammatory markers and morphometric measures have been suggested to be predictive for prognosis. We investigated the impact of a novel combination of preoperative tumor morphology (RENAL score) and a laboratory based inflammatory marker (DeRitis Ratio, AST/ALT) on survival outcomes in localized RCC. Methods: Single center, retrospective analysis of 264 patients with RCC (112 PN, 152 RN, mean follow-up 45 months) from 2003−2015. A priori, we assigned a positive marker score of “1” if RENAL >8 or DeRitis >1.5. Patients were stratified by increasing positive markers (“0”=RENAL ≤8 and DeRitis ≤1.5, “1”=RENAL >8 or DeRitis >1.5, “2”=RENAL >8 and DeRitis>1.5). Primary outcome was overall survival (OS). Cox models and Kaplan−Meier curves were utilized. Results: 264 patients, 61.7% male, mean age 64.5 ± 12.8 years, mean BMI 28.5 ± 5.6, mean AST/ALT 1.1 ± 0.4. With regards to tumor characteristics, mean clinical tumor size 4.7 ± 3.2cm and median RENAL score 9 (IQR 7−10). For clinical staging, 75.7% were cT1, 17.4% were cT2, and 6.9% were >cT2. 32.6% had 0 positive markers, 60.2% had 1 marker, and 7.2% had 2 markers. Kaplan−Meier analysis for “0”, “1”, and “2”demonstrated significantly worsened OS (log−rank p=0.03). On Cox model for OS, RENAL >8 (HR 2.13, p=0.01) or AST/ALT >1.5 (HR 2.25, p=0.028) were significantly associated with worsened survival, as was combined RENAL >8 and DeRitis > 1.5 (HR 5.1, p<0.001). Conclusions: Novel combination of a morphological score (RENAL) and an inflammatory marker (DeRitis ratio) was associated with worsened OS in localized RCC. Our findings point toward development and validation of a prognostic index to assist in risk stratification for localized RCC.
Comparison of multiparametric MRI to PSA kinetics as an indication of prostate cancer progression in men on active surveillance.
Authors: Maruf Mahir , Kongnyuy Michael , George Arvin Koruthu , Siddiqui Mohummad Minhaj , Sidana Abhinav , Jain Amit L , Calio Brian P. , Sugano Dordaneh , Chelluri Raju , Valayil Subin , Muthigi Akhil , Frye Thomas P , Choyke Peter L. , Turkbey Baris , Wood Bradford J. , Pinto Peter A.
Published: March 2017

59

Background: Pathologic progression is identified in > 25% of prostate cancer (CaP) patients on active surveillance (AS). Yet, identifying patients at risk for progression is limited to PSA based biomarkers with variable utility. Multiparametric MRI (mpMRI) with fusion-guided prostate biopsy (FBx) has shown utility in risk stratification for patients considering AS. We compared mpMRI characteristics with PSA kinetics for the prediction of pathologic progression in AS patients. Methods: A review of men on AS with serial mpMRI and 2 or more FBx sessions was performed. FBx sessions consisted of targeted biopsies and a 12 core systematic biopsy. Men who met NIH Expanded AS criteria included those with low and intermediate risk CaP, Gleason score ≤ 3+4 = 7 with no restriction on percent core involvement or number of cores positive. Progression was defined by patients with initial Gleason 3+3 = 6 to any Gleason 4, and Gleason 3+4 = 7 to a primary Gleason 4 or higher. MRI progression was defined as increase in suspicion score, size, or new lesion on follow-up. PSA velocity (PSAV) > 0.75ng/ml/yr, PSA doubling time (PSAdt) < 3 yrs, and imaging characteristics were examined for association with pathologic progression at surveillance biopsy. Results: A total of 164 men, median age of 63 yrs [58-67], were included. Median length of follow up was 19.4 months [IQR 14.3-30.0]. Median PSA, and prostate volume of our cohort were 4.9ng/ml [3.3-7.3] and 47.0ml [36.5-59.8]. The sensitivity and specificity of predicting pathologic progression by mpMRI, PSAV and PSAdt were 45% and 65%, 30% and 76%, and 17% and 86% respectively. A combination of MRI, and PSAV or PSAdt yielded a sensitivity and specificity of 61% and 49% or 54% and 56% respectively. Using a decision curve analysis, mpMRI offers minimal benefit for predicting pathologic progression of CaP. Conclusions: MpMRI alone marginally outperforms PSA kinetics for predicting pathologic progression in men on AS for CaP. The combination of mpMRI along with PSA parameters increase the sensitivity of prostate imaging in identifying progression in AS patients. Research in combinations of imaging with other biomarkers will be needed to more accurately risk stratify AS patients.
Quality of life evaluation of the effect of decapeptyl compared with zoladex preradiotherapy: Final results of randomised controlled trial.
Authors: Bahl Amit , Challapalli Amarnath , Greenwood Rosemary , Hurley Katrina , Persad Rajendra
Published: March 2017

62

Background: Hormone therapy in combination with radiotherapy is a curative treatment option for prostate cancer (CaP). There is paucity of data regarding quality of life (QoL) evaluation of neoadjuvant Decapeptyl. We reported on the equivalence of cytoreductive efficacy of neoadjuvant Decapeptyl and Zoladex previously. Here we present the final QoL evaluation of the effect of Decapeptyl compared with Zoladex preradiotherapy. Methods: Seventy-one patients with localised CaP who have chosen radical radiotherapy had been randomised by stratified block design, toreceive either Decapeptyl (D: n = 37) or Zoladex (Z: n = 34) with bicalutamide cover. All the patients had subsequent radical radiotherapy and followed up as per departmental protocol. The effect of Decapeptyl and Zoladex on QoL was assessed using EQ5D, QLQ-PR25, QLQ-C30 questionnaires, which were completed at baseline, 6, 10 & 14 weeks after start of therapy. QoL scores were analysed as mean scores over the 4 treatment time points for all domains, controlling for baseline scores using Analysis of Covariance. Results: There was no clinically significant difference or trend towards worsening QoL with either Z or D in the global (EQ5D) and cancer-specific (QLQ-C30) domains. The cancer-specific (QLQ-C30) symptom score also showed no trend towards worsening QoL with either Z or D. Symptom scores in the QLQ-PR25 questionnaire did not show a significant difference between Z and D arms with the exception of hormone symptoms. The hormone symptoms showed an increasing trend over the 4 treatment time points, with those in the Z arm significantly (p = 0.02) more affected (3 points higher on average) than patients in the D arm, despite equivalence in cytoreductive effect and achieving castrate levels of testosterone. Conclusions: There were no clinically significant differences in QoL domains between Zoladex and Decapeptyl, apart from hormones symptoms which were worse with Zoladex. Further validation is required with affect on hormone symptoms as the primary outcome measure. To our knowledge this is the first reported prospective randomised data demonstrating the effect of Zoladex and Decapeptyl, on QoL in the neoadjuvant setting. Clinical trial information: EduraCT: 2008-007028-25.