bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacist-led monitoring program for patients on sunitinib for metastatic renal-cell carcinoma: A Canadian experience.
Authors: Edwards Scott , Wood Lori , McCarthy Joy S. , Collins Andrew , Hartery Lynn , Abbott Rick , Whelan Maria
Published: February 2017

479

Background: Sunitinib is a standard of care for first-line treatment of metastatic clear cell renal-cell carcinoma (mRCC). Despite having a relatively good safety profile, Sunitinib does have several clinically important toxicities. With the rapid rise in the use of Sunitinib and other oral cancer agents, we instituted a pharmacist-led monitoring program in the ambulatory care setting to prospectively document, monitor, and manage toxicities in our Canadian province. Methods: The pharmacist-led monitoring program consisted of patient assessments in clinic with the oncology team combined with a call back program. The program consisted of a patient assessment in the oncology clinic on day 1 of a Sunitinib cycle followed with a call back on day 14. A chart review of consecutive patients who were prospectively monitored by this progam after receiving Sunitinib for mRCC was conducted. Treatment specific data for the first six cycles of therapy included dose reductions, therapy delays/interruptions, therapy discontinuation, and reason for each was recorded. Toxicity data including the occurrence and severity grade was collected. The time to treatment failure (TTF) defined as the time from therapy initiation to treatment discontinuation for any reason was measured. Results: Fifty six patients are included in the study cohort. Of these, 52 (92.86%) started at the standard 50 mg once daily and the remainder at a reduced dose. Additionally, 15 patients experienced hypertension requiring drug therapy adjustment or additional antihypertensive therapy. Two patients required drug therapy for hypothyroidism. There were a total of 39 dose reductions in this patient population over a six cycle period. The majority of dose reductions (46.2%) and therapy interruptions (34.5%) occurred during cycle one. The time to treatment failure for the 45 patients that discontinued therapy was 9.72 months. Conclusions: Pharmacist-Led monitoring of oral cancer therapies is a practical and feasible method of monitoring patients on Sunitinib for mRCC. The success has led to its implementation with other agents and disease sites.
Brain metastasis from renal cell carcinoma: Are we missing our chance to treat?
Authors: Hanzly Michael
Published: February 2017

485

Background: Brain metastasis from renal cell carcinoma (RCC) occurs approximately 8% of patients with metastatic RCC. The guidelines from the NCCN, EAU, and AUA recommendcerebral imaging only in patients who have symptomatology. The purpose of our study was to review the presenting symptomatology that led to their diagnosis of brain metastases followed by their overall treatment and survival. Methods: Our IRB-approved prospectively-maintained kidney cancer data base was reviewed between from 1995 to 2012. Brain metastases from a primary RCC was identified in 52 patients. Patient demographics including family and social history, primary treatment for RCC, elapsed time between primary diagnosis and brain metastasis, associated symptomatology, treatment of metastatic site and overall survival following diagnosis of brain metastasis were examined. Results: Primary RCC was diagnosed in 986 patients between 1995 and 2012. Brain metastases were identified in 52 patients, 79% were male and 100% Caucasian, 87% had no family history of renal malignancy. Primary treatment for RCC included 75% radical nephrectomy, 10% observation, 7.6% cytoreductive nephrectomy, 5.4% sunitinib, 2% interleukin-2 treatment. Central nervous system (CNS) symptoms were absent in 37% of patients diagnosed with brain metastases, while 73% presented with symptoms. The average number of metastases was 1.78 per patient in the asymptomatic group, and 2.7 metastases in patients with CNS symptoms (p=.18). Elapsed time from primary RCC treatment to diagnosis of brain metastases was an average of 730 days in the asymptomatic group and 1170 days for the symptomatic group (p=0.02). The symptomatic group has overall survival (OS) at one year of 81% and 69% at three years, while the asymptomatic group had an OS of 81% at one year and 31% at 3 years. Pulmonary involvement existed in 75% of both cohorts of patients (p=0.003). Conclusions: Our findings suggest that patients without CNS symptoms with brain metastases had a worse overall survival. The urologic guidelines recommending CNS imaging only in patients with symptoms may be missing a subset of the metastatic RCC population who could potentially benefit from early intervention, thus prolonging overall survival.
Patients with metastatic papillary renal cell carcinoma (RCC) who may benefit from sunitinib therapy (tx): Results from an international metastatic RCC database.
Authors: Kejzman Daniel , Gottfried Maya , Maimon Natalie , Hammers Hans J. , Eisenberger Mario A. , Carducci Michael Anthony , Sinibaldi Victoria J. , Neiman Victoria , Rosenbaum Eli , Sarid David , Gez Eliahu , Peer Avivit , Sella Avishay , Mermershtain Wilmosh , Rouvinov Keren , Berger Raanan , Lee Jae-Lyun
Published: February 2017

486

Background: The VEGFR inhibitor sunitinib is a standard tx for metastatic clear cell RCC. Data on the activity of sunitinib in metastatic non clear cell RCC, is limited by small or heterogeneous (mixed histology or targeted therapies) studies, that revealed a lower antitumor activity than in patients with clear cell histology. We aimed to analyze the activity of sunitinib in a large international cohort of patients with metastatic papillary RCC, and to characterize patients who may benefit for this therapy. Methods: Records from metastatic papillary RCC patients treated with sunitinib in 10 centers across 3 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and clinical outcome were performed using Cox regression. Results: Between 2004-2013, 74 patients (median age 60, 68% male) with metastatic papillary RCC were treated with sunitinib. 78% had a prior nephrectomy. HENG risk was good 11%, intermediate 56%, and poor 33%. 21% were active smokers, and 31% users of angiotensin system inhibitors. 24% and 41% had liver and bone metastases, respectively. 55% had a pre-treatment neutrophil to lymphocyte ratio (NLR) >3. 40% had dose reduction/treatment interruption. Sunitinib induced hypothyroidism and hypertension (HTN) occurred in 30% and 43%, respectively. 70% achieved a clinical benefit (partial response + stable disease), while 30% had disease progression within the first 3 months of therapy. Median progression free survival (PFS) and overall survival (OS) were 5 and 12 months, respectively. 27% had a PFS ≥ 1 year, and 26% survived ≥ 2 years. Factors associated with PFS were sunitinib induced HTN (HR 0.31, p=0.002), pre-treatment NLR >3 (HR 5.3, p=0.001), and active smoking (HR 2.5, p=0.01). Factors associated with OS were sunitinib induced hypothyroidism (HR 0.4, p=0.024), past nephrectomy (HR 0.41, p=0.02), pre-treatment NLR >3 (HR 2.25, p=0.036), and active smoking (HR 2.3, p=0.027). Conclusions: Clinicopathologic factors may be used to identify patients with metastatic papillary RCC who may benefit from sunitinib tx. A prolonged PFS and OS were noted in 26-27% of patients.
Salivary markers in renal cell carcinoma.
Authors: Dudek Alexandra , Appleyard Lauren , O'Brien Tim S. , Chowdhury Simon , Champion Penny , Challacombe Ben , Kooiman Gordon , Carpenter Guy
Published: February 2017

489

Background: Kidney cancer ranks number 8 among cancer diagnoses in the UK with around 9,600 new diagnoses made each year (Cancer Research UK. Risks and causes of kidney cancer. http://www.cancerresearchuk.org/cancer-help/type/kidney-cancer/about/risks-and-causes-of-kidney-cancer). This study aimed to identify overexpressed proteins in human saliva that could serve as markers for renal cell carcinoma. Methods: Saliva was collected from 144 participants (95 male and 28 female).; 123 RCC patients (85%) and 21 healthy controls (15%), Total salivary protein levels were determined by BCA protein assay. Then 10ug of total saliva protein were evaluated via Western blotting on 4-12% Bis-Tris SDS-PAGE gels. Blots were probed for albumin as well as for three proteins associated with RCC; profilin1, 14-3-3 zeta, and endogenous avidin binding protein (EABP). Additionally, 6 saliva samples were evaluated via quantitative proteomics in a Tandem mass tag (TMT) labelling experiment comparing 4 RCC patients vs. 2 renal cyst patients. Results: Profilin1 levels were determined visually on a scale of 0 to 3 depending on band intensities on Western blots. Cancer patients had a higher percentage of levels 2 and 3 with 62 patients (50.4%). The control group only had 2 patients at level 2 (9.5%) and none at level 3. No difference in profilin1 levels was seen between metastatic vs. non-metastatic disease. Differences were seen in gender and histology, with female and non-CC patients having higher profilin levels. There is a potential link between profilin1 levels and surgical or drug treatment. 14-3-3 zeta could not be detected in saliva with these analyses. Albumin was present across all samples. EABP was found in 40.6% of cancer patients vs. 0% of controls; however no clear trend was seen with respect to disease burden, histology, or gender. Proteomic analysis gave a total of 33 hits showing raised protein levels of up to 20x higher in cancer patients vs. controls. Profilin1 was 2x and 14-3-3 zeta 5x more prevalent. Conclusions: This study has successfully identified profilin1 as a detectable salivary marker for renal cell carcinoma. [Table: see text]
Dysregulation of the beta-catenin complex as an independent predictor of oncological outcomes in patients with ccRCC.
Authors: Krabbe Laura-Maria , Westerman Mary Elizabeth , Bagrodia Aditya , Gayed Bishoy A. , Darwish Oussama M. , Haddad Ahmed Q , Khalil Dina , Kapur Payal , Sagalowsky Arthur I. , Lotan Yair , Margulis Vitaly
Published: February 2017

493

Background: Epithelial to mesenchymal transition (EMT) is thought to play a crucial role in cancer progression and development of metastasis. Thus, we evaluated dysregulation of beta-catenin as a part of EMT and its clinical implications in patients with clear cell renal cell carcinoma (ccRCC). Methods: Immunohistochemical staining was performed for beta-catenin on tissue microarrays of patients with ccRCC. Membranous and cytoplasmatic beta-catenin expression patterns were assessed separately. Beta-catenin was considered normal if none or only one component was abnormal and was considered dysregulated if both components were abnormal. Differences in pathological characteristics between both groups were investigated. Differences in recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with the Kaplan-Meier method. Uni- and multivariate Cox proportional hazard models were used to assess independent predictors of oncological outcomes. Results: 406 patients with a median follow-up of 58 months were included. Overall, 52 (12.8%) and 25 (6.2%) patients recurred and died of ccRCC. Beta-catenin was dysregulated in 70 (17.2%) patients. Dysregulation of beta-catenin was significantly associated with adverse pathologic features, such as higher T-stage, nodal positivity, higher grade, presence of tumor thrombus, sarcomatoid features, necrosis and LVI (all p<0.001). Patients with dysregulated beta-catenin had inferior RFS and CSS (both p<0.001). In multivariate analysis adjusting for tumor stage, nodal status and grade, dysregulation of beta-catenin was an independent predictor of RFS (HR 2.2, 95%CI 1.2-3.9, p=0.008) and CSS (HR 2.4, 95%CI 1.1-5.6, p=0.044). Conclusions: Our results indicate that dysregulation of beta-catenin may be an important phenomenon in ccRCC carcinogenesis. These findings support further study of beta-catenin and systematic assessment of EMT in ccRCC.
U.S. regional practice patterns in metastatic renal cell carcinoma (mRCC) patients: A real-world retrospective analysis.
Authors: Pal Sumanta Kumar , Gorritz Magdaliz , Sherman Steven A. , Liu Zhimei
Published: February 2017

505

Background: The treatment landscape for metastatic renal cell carcinoma (mRCC) has changed in recent years, with several targeted therapies becoming available for 1st and 2nd line use. The rapidly evolving treatment landscape has left physicians with an abundance of choices for the treatment of mRCC patients. This study aimed to understand whether this has resulted in varying treatment patterns across US regions in 1st and 2nd line targeted therapy for mRCC. Methods: RCC patients who initiated 1st line targeted therapy with a vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFr) or mammalian target of rapamycin (mTOR) inhibitor between January 1, 2004 and June 30, 2011 were identified in the MarketScan database. First-line therapy was defined as the first claim in the database for a targeted therapy. One drug claim was sufficient to establish a line of therapy and a new line was defined as switching to another agent. Treatment patterns in the 1st and 2nd line settings were assessed in patients who initiated 2ndtherapy line after FDA approval of everolimus (Ev) (March 30, 2009) and stratified by geographic region. Results: Of the 6,524 patients included in the study, 1,298 (36%) received a 2nd line targeted therapy after March 30, 2009. Although all possible permutations of treatment sequences were observed, overall, sunitinib (Su) and temsirolimus (Te) combined made up 80% to 83% of the 1st line regimens across regions. The most common sequence was Su->Ev, observed in 18% of patients in the North Central US to 31% in the Northeast; Su->Te was the next most common sequence in all regions. Among patients who received 1st line temsirolimus, the majority initiated 2ndline on either bevacizumab (Be) (7%-12%) or Su (6%-10%) across regions. Conclusions: The most common treatment sequences across all regions were Su->Ev and Su->Te. Although a consistent pattern of sequential therapy emerged across regions, a wide range of on- and off-label strategies was observed outside of the predominant pattern of care. Furthermore, very few patients in this study received additional targeted therapy after 1st line. Further research is needed to identify factors influencing these treatment strategies.
Population-based comparison of surgical margin status for robotic versus open radical prostatectomy.
Authors: Hu Jim C. , Gandaglia Giorgio , Nguyen Paul Linh , Trinh Quoc-Dien , Shih Ya-Chen T. , Abdollah Firas , Chamie Karim , Wright Jonathan L. , Karakiewicz Pierre I. , Sun Maxine
Published: February 2017

51

Background: Robotic-assisted radical prostatectomy (RARP) remains controversial due to exaggerated marketing claims, higher costs, hidden risks, and few clinically significant benefits, including an absence of improved cancer control compared to open radical prostatectomy (ORP). The purpose of our study is to compare surgical margin status by surgical approach. Methods: We identified 13,434 men with a histologically confirmed, non-metastatic prostate cancer treated with RARP versus ORP during 2004 and 2009 from Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data. Propensity-based analyses were performed to minimize treatment selection biases. Generalized linear regression models were computed for comparison of radical prostatectomy surgical margin status by surgical approach. Results: During the study period, 5,556 and 7,878 men underwent RARP and ORP, respectively. In the propensity-adjusted cohort, the incidence of positive surgical margins was significantly lower among men undergoing RARP versus ORP (13.7% vs. 18.4%, odds ratio [OR]: 0.68, 95% confidence interval [CI]: 0.63–0.73, p<0.001). This reduction in the incidence of positive surgical margins of RARP over ORP was more pronounced among men with more advanced disease—6.6% lower absolute incidence of positive margins among men with intermediate- and high-risk disease (p<0.001, respectively) and 15.4% lower absolute incidence of positive margins among men with extracapsular extension (p<0.001). Moreover, RARP was associated with lower odds of positive surgical margins compared to ORP for pT2 (Odds Ratio [OR] 0.67, 95% Confidence Interval [CI] 0.61–0.74, p<0.001) and pT3a (OR 0.72, 95% CI 0.60–0.85, p<0.001) disease. Additionally, RARP was associated with lower odds of positive surgical margins for intermediate (OR 0.66, 95% CI 0.58–0.74) and high-risk (OR 0.69, 95% CI 0.64–0.75) disease. Conclusions: RARP was associated with improved surgical margin status among men with intermediate and high-risk disease. This has important implications for cancer control, patient quality of life, health care delivery and additional costs of downstream therapies.
Glandular metastasis as a surrogate for long survivors in metastatic renal carcinoma.
Authors: Chanez Brice , Brachet Pierre-Emmanuel , Laguerre Brigitte , Walz Jochen , Joly Florence , Esterni Benjamin , Dermeche Slimane , Salem Naji , Brunelle Serge , Thomassin Jeanne , Gravis Gwenaelle
Published: February 2017

510

Background: Metastatic renal cell carcinoma (RCC) is still associated with a poor prognosis with an overall survival (OS) of 37 months, although some patients are long survivors despite a disseminated disease. The purpose of this study was to determine whether the presence of at least one glandular metastasis (GM), defined by metastasis in pancreas, thyroid, breast or adrenal contralateral, affect survival outcome in patients with metastatic clear cell RCC (cc-RCC). Methods: In this retrospective analysis, we included patients treated for GM and non GM (NGM) metastatic RCC at the Institut Paoli Calmettes (IPC), Marseille, France between January 2004 and May 2013. Two more centers provided data for GM cc-RCC. GM were authentified using CTscan and/or by histopathological analysis obtained at biopsy or at surgery. Patients were analyzed from the time of metastatic disease to last follow up or death. The purpose of this study was to analyze patients outcomes based on the presence or absence of GM. We analysed survival using a log rank test from the time of the diagnosis of GM to the death or last follow-up visit. Results: Among 180 patients analysed, 59 had GM. Median age 65.2 vs 61.8 years old, male 55% vs 72%, 90% vs 78% prior nephrectomy in GM and NGM group. GM sites were pancreas for 45.5%, adrenal 44.5%, thyroid: 10%, breast10%. GM was the only site of metastasis for 10% of pts. For GM group, 55.5% had histopathology proven RCC metastasis. The median follow up was 72 months and the median survival is 114 months (IC95% [62.9-NR.]) in GM group vs 33.2 months (IC95% [23-41.9]; p<0.0001, HR 2.7 [1.7-4.3]) in non GM group. Conclusions: This retrospective study in a rare metastatic localization finds a longer survival in patients with GM. Despite some obvious limitations, this study questions GM as a surrogate for a better prognosis in RCC. Prospective follow-up and the collection for biological and genomic markers are needed to confirm and extend our present findings.
Late onset of bone metastases as a prognostic parameter in metastatic renal cell cancer (mRCC): A single-center experience in 82 mRCC patients treated with sunitinib.
Authors: Ivanyi Philipp , Koenig Jasper , Trummer Arne , Reuter Christoph W. , Ganser Arnold , Grünwald Viktor
Published: February 2017

523

Background: Bone metastasis (BM) is considered a negative prognostic marker in metastatic renal cell carcinoma (mRCC). Here, we address the impact of BM onset on overall survival (OS) in mRCC patients during targeted therapy. Methods: Patients with BM who received sunitinib (SU) as 1st targeted treatment at our center between May 2005 and December 2012 were included in this retrospective analyzes. Treatment was performed according to local standard and patients were followed for survival. Spine surgery, fracture or irradiation were considered skeletal related events (SRE). Results: Out of 128 mRCC patients with BM, 82 patients had SU as 1st line targeted agent. 57 (69.5%) patients suffered from BM at initial diagnosis of mRCC (=synchronous BM [sBM]), while 25 (30.5%) patients developed BM during treatment course (=metachronous BM [mBM]). Baseline characteristics showed different histological gradings for sBM compared to mBM patients (p=0.029) and higher frequency of ≥3 metastatic organ sites prior to SU for sBM patients (sBM: n=40 [70.2%] vs. mBM: n=10 [40%], p=0.016). In Kaplan-Meier analysis, sBM patients showed a reduced mean OS from SU start (sBM 23.5 [95%CI:18.6-28.3] vs. mBM 41.3 [95%CI:31.7-50.9] month, p=0.001), whereas PFS during SU treatment was similar (sBM: 8.1 [95%CI:3.9-12.3] vs. mBM: 8.7 [95CI:2.7-14.8] months, p=0.93). Bisphosphonate treatment and SRE revealed no differences between subgroups (p=0.62), while spinal compression occurred in 6 patients with sBM, but none with mBM (p=0.153). 2nd-line targeted agents were less frequently administered in sBM patients (sBM n=17 vs. mBM: n=10). Multivariate Cox-regression confirmed MSKCC score (OR: 2.6 [95%CI:0.99-7.28], p=0.052), liver metastases (OR: 2.66 [95%CI:1.28-5.51], p=0.009], and sBM [OR: 2.45 [95%CI:1.19-5.08], p=0.016) as independent prognostic parameters for reduced OS after SU start. Conclusions: In our cohort, OS in patients with sBM was significantly reduced compared to mBM patients, despite similar PFS with SU and SRE rate. Despite the lower incidence of subsequent therapies in sBM, a more aggressive biology is likely to be the cause of these findings.
The degree of preoperative hydronephrosis to predict pathologic features and oncologic outcomes in high-grade upper tract urothelial carcinoma.
Authors: Darwish Oussama M. , Krabbe Laura-Maria , Chung Paul H. , Westerman Mary Elizabeth , Bagrodia Aditya , Gayed Bishoy A. , Haddad Ahmed Q , Kapur Payal , Sagalowsky Arthur I. , Lotan Yair , Margulis Vitaly
Published: February 2017

525

Background: There have been multiple reports implicating the role of hydronephrosis (HN) as a predictor of outcome in patients diagnosed with upper tract urothelial carcinoma (UTUC). However, this was done in mixed populations (low-/high-grade) and degree of HN (DOH) was not taken into account. We evaluated the impact of severity of hydronephrosis on systemic and bladder relapse in patients with UTUC. Methods: We retrospectively reviewed the records of 141 patients with localized UTUC that underwent extirpative surgery. Preoperative imaging was used to evaluate ipsilateral DOH. We analyzed the association between DOH (none/mild vs. moderate/severe), pathological findings and oncological outcomes in high-grade vs. low-grade patients. Bladder recurrence was assessed separately from local or systemic (L/S) recurrence. Results: High-grade UTUC was present in 80% of patients, 35% had muscle-invasive disease (≥pT2), and 29% had non-organ-confined disease. At a median follow-up of 34 months (range, 1-149), 35% of patients experienced intravesical recurrence, 20% developed L/S recurrence, and 17% died of UTUC. No difference in outcomes was seen between patients without HN and mild HN. DOH was none/mild in 55% and moderate/severe in 45% of cases. In patients with high-grade UTUC, moderate/severe HN was associated with advanced pathologic stage (p<0.001) and positive lymph node status (p=0.01). On Kaplan-Meier analysis, DOH was a predictor of L/S recurrence-free survival (RFS) (HR 5.5, p=0.019) and cancer-specific survival (CSS) (HR 5.2, p=0.022) but not intravesical recurrence. On multivariable analysis with preoperatively known factors controlling for grade and tumor location, DOH was independently associated with L/S RFS (HR 2.8, p=0.016) and CSS (HR 2.5, p=0.044). Conclusions: Moderate/severe HN was associated with features of advanced disease and predicted worse oncological outcomes in patients with high-grade UTUC. Since preoperative imaging is a routinely available diagnostic tool, this can serve as a surrogate parameter for advanced disease and can help to counsel patients towards preoperative chemotherapy and radical surgery.
Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted-therapy era.
Authors: Kalra Sarathi , Verma Jonathan , Atkinson Bradley J. , Matin Surena F. , Wood Christopher G. , Karam Jose A. , Tamboli Pheroze , Sircar Kanishka , Rao Priya , Corn Paul Gettys , Tannir Nizar M. , Jonasch Eric
Published: February 2017

528

Background: Bone metastases (BM) occur commonly in patients with metastatic renal cell carcinoma (mRCC). Tyrosine kinase inhibitors (TKIs) have improved outcomes for patients with mRCC. Data on outcomes of mRCC patients with BM treated with TKIs are limited, but suggest a worse outcome compared to non-BM groups. Herein, we describe outcomes of patients with BM treated with TKI therapy, and compare to outcomes in a pre-TKI control group. Methods: Retrospective review of patients with mRCC in the intervals of 2002-2003 and 2006-2007 was performed using the institutional tumor registry. Patient characteristics including demographics, laboratory data, and outcomes were analyzed. Overall survival (OS) was estimated using Kaplan-Meier methods. Predictors of OS were analyzed using Cox regression. Results: 375 patients were reviewed; 187 patients (50%) started treatment with TKIs and 188 patients (50%) started treatment in pre-TKI era. Distribution of patient characteristics was similar. Organ metastases were equally distributed, including BM in 48% of patients in each cohort. Median OS of patient treated with TKI therapy was 22 mo (95% CI: 17-25) compared to 14 mo (95% CI: 10-19; p<0.01) for historical controls. Subset analysis of patients with BM treated with TKI therapy demonstrated a median OS of 24 mo (95% CI: 17-28) compared to 18 mo (95% CI: 10-21; p<0.01), in non TKI treated group. Predictors of shorter OS were higher MSKCC score; liver, lung, and brain metastases; and multiple sites of BM (HR 1.38; 95% CI: 1.02-1.91; p=0.04). Rate of new BM development was the same in the pre-versus-post TKI era. Conclusions: Median survival of patients with BM appears to be slightly longer than the median, irrespective of systemic therapy received. Rate of BM development was the same in the pre-versus post-TKI era. The slightly prolonged OS with BM contradicts published data. The management of bone metastases in mRCC remains a challenge. [Table: see text]
Retrospective study assessing the association of single nucleotide polymorphisms in VEGFR3 and on-target toxicity in patients with advanced renal-cell carcinoma (RCC) treated with sunitinib.
Authors: Rodriguez-Moreno Jf. , Esteban Emilio , Leandro-García Luis Javier , Castellano Daniel E. , Gonzalez del Alba Aranzazu , Climent Miguel Angel , Arranz Jose Angel , Gallardo Enrique , Puente Javier , Bellmunt Joaquim , Mellado Begoña , Martínez Esther , Moreno Fernando , Font Albert , Robledo Mercedes , Polo Susana Hernando , García-Donas Jesús , Rodriguez-Antona Cristina
Published: February 2017

537

Background: Sunitinib is a tyrosine kinase inhibitor approved as first line therapy of RCC. Some Adverse Events (AEs) of sunitinib are due to its inhibition of VEGFR and could be considered as “on-target” toxicity. They are a class-effects and have been observed even with the most selective antiangiogenic drugs. We aimed to correlate such secondary effects with germline SNPs in VEGFR3. Methods: In order to define “on target ” toxicity we considered any AEs ≥ Grade II (CTCAE 4.0) recorded in more than 10% of the patients included the pivotal studies of axitinib and tivozanib (the most selective tyrosin kinase inhibitors targeting VEGF(R). We assessed associations between polymorphisms in VEGFR3 and on-target toxicity for patients with advanced RCC treated with sunitinib prospectively included in the SUTRENT Study. Results: Polymorphisms in VEGFR3 are associated with less on-target toxicity. Probably these genetic changes confer a reduced susceptibility to the action of sunitinib. This could explain, at least partially, the worse outcome showed in this population. Conclusions: Polymorphisms in VEGFR3 are associated with less on-target toxicity. Probably these genetic changes confer a reduced susceptibility to the action of sunitinib. This could explain, at least partially, the worse outcome showed in this population.
Axitinib: Common questions related to real-world use of a new treatment option in advanced renal cell carcinoma.
Authors: Borst Diane Lorraine , Arruda Lillian Shahied , MacLean Elizabeth A. , Pithavala Yazdi K. , Morgado James E. , Sharma Nikhil
Published: February 2017

538

Background: Axitinib is a next generation VEGFR inhibitor approved in the US in Jan 2012 for advanced RCC after failure of one prior systemic therapy. Post approval questions may arise in the medical community regarding clinical scenarios which may not have been addressed in the clinical trials. We present the most common inquiries for axitinib submitted to Pfizer US Medical Information (MI) during the first 18 months post FDA approval and review available information that addresses these questions. Methods: MI inquiries were analyzed during the 6-mo period immediately post FDA approval and a second 6-mo period approximately 1 yr later. To gain insight into real-world dosing patterns, de-identified prescription data from Feb 2012-July 2013 obtained from the 21 specialty pharmacies (SP) in the US that distribute axitinib (Inlyta) were analyzed. Algorithms were developed to define dose modifications using dosage strengths dispensed and time between prescription fills over 2 day and 14 day windows. Results: The most frequent inquiries (>5%) common to both time periods included use in patients (pts) who were unable to swallow medication, use in patients with renal impairment (RI), and general dosage and administration questions. A method for preparation of an axitinib oral suspension for NG tube administration was developed for use in pts unable to swallow axitinib tablets. No dose adjustments are recommended for pts with RI; however axitinib should be used with caution in pts with end stage renal disease. The most common dose dispensed, using a 2 day window, was 5 mg bid, comprising 9659 (70%) of all dispensed prescriptions, with 789 (6%) at the 10 mg bid dose. An assessment of the most recent 7 months in the evaluation period shows that 16% and 19% of prescriptions were for doses >5 mg bid or <5 mg bid, respectively. Similar findings were observed using a 14 day window. Conclusions: Axitinib questions in the medical community revolve primarily around use in specific populations and dosing. Analysis of SP data revealed that dose modifications occurred at a lower frequency than observed in clinical trials. Further analysis is needed to understand outcomes associated with the dose modifications made in these patients.
Major histocompatibility complex class I (MHC 1) expression in clear cell renal cell carcinoma: Correlation with clinical outcome.
Authors: Master Viraj A. , Holzman Sarah , Pollack Brian , Osunkoya Adeboya O.
Published: February 2017

541

Background: Most patients with clear cell renal cell carcinoma (ccRCC) initially present with localized disease but a fraction subsequently develop metastases. Current predictive models of ccRCC recurrence are imperfect, suggesting a need for additional predictors. Metastatic ccRCC may be modulated by the immune system, suggesting that the immune system plays a role in tumor progression. Major histocompatibility complex class I (MHC I) expression on tumor cells is critical for immune system recognition. Here, we analyzed MHC I expression in ccRCC and its correlation with clinical outcomes. Methods: ccRCC patients who underwent radical nephrectomy with a ≥4 years of follow-up, without T4 disease or metastasis at presentation were included. All slides were re-reviewed by a single Urologic Pathologist and blocks with tumor and adjacent renal parenchyma were selected for each case for immunohistochemical staining for MHC I . Whole slide scanning and automated image analysis was used; representative areas of tumor and normal kidney were selected and averaged with Aperio image analysis software (positive pixel count v. 9). Unpaired t-test and one-way ANOVA were performed in GraphPad Prism. Results: 34 patients were analyzed. Fuhrman nuclear grades (FNG) were: FNG 2 10/34 (29%), FNG 3 20/34 (59%) and FNG 4 4/34 (11%). Although there was no correlation with FNG and MHC1 (ANOVA, p=0.800), patients who were alive at follow up had increased MHCI expression (80.1% average positivity score) than those who died (53% average positivity score; t-test, p<0.0001). Patients living with recurrence had increased MHCI expression (81.3% positivity score) compared to those who succumbed to their disease (53.2% positivity score; t-test, p<0.0001). Conclusions: MHCI expression may be an important prognostic factor in ccRCC for recurrence free survival, and also for prognosis of those patients with recurrence. This is the first study to show that increased MHCI expression is a favorable prognostic indicator in metastatic ccRCC. These results suggest that MHCI expression plays an important role in tumor-host immune system interaction of ccRCC and merits further study.
Results from the seminal vesicle sparing prostatectomy trial.
Authors: Gilbert Scott Michael , Dunn Rodney , Montgomery Jeffrey Scott , Miller David , Skolarus Ted A. , Weizer Alon , Wood David Peter , Hollenbeck Brent K.
Published: February 2017

55

Background: Prostate cancer accounts for greater than 200,000 cases each year. Although cancer control is generally favorable with treatment, side effects are common. Among men treated with surgery, nerve-sparing prostatectomy is associated with lower rates of incontinence and erectile dysfunction. Seminal vesicle sparing (SVS) may further limit damage to the neurovascular tissue surrounding the prostate. Although some surgeons practice SVS, evidence supporting its use is lacking. We implemented a randomized control trial to determine if SVS is associated with better functional outcomes compared to non-SVS prostatectomy. Methods: 140 men with early-stage (T1c/T2N0M0, Gleason score <= 7) prostate cancer and adequate erectile function (IIEF >= 21) were enrolled in the Seminal Vesicle Sparing Prostatectomy Trial (NCT01825642) and randomized to either SVS or non-SVS prostatectomy between 2006 and 2011. The Expanded Prostate Cancer Index Composite (EPIC) was used to assess quality of life outcomes following surgery. Results: 71 and 69 men were enrolled in the SVS and non-SVS arms, respectively. The predominant surgical approach was robotic assisted prostatectomy (>97% in both arms). Men in the SVS arm were slightly younger (56 vs 58 years, p = 0.02); however, there were no significant differences in other clinical or demographic factors. There were no cases of seminal vesicle invasion. PSA recurrence was noted in 3 patients (1 in SVS group and 2 in non-SVS group). At 12 months postoperatively, sexual (76 vs 75) and urinary incontinence (92 vs 94) scores were similar among SVS and non-SVS patients (both p > 0.2). Conclusions: Recovery of urinary and sexual function was common among men undergoing SVS or non-SVS prostatectomy. SVS did not negatively impact cancer control, but was not associated with enhanced recovery of sexual or urinary function, perhaps due to the high level of recovery of the control arm. Clinical trial information: NCT01825642. [Table: see text]
Using MRI/ultrasound fusion biopsy to detect clinically significant prostate cancer in the African American population.
Authors: George Arvin , Rais-Bahrami Soroush , Rothwax Jason , Siddiqui Minhaj , Stamatakis Lambros , Su Daniel , Okoro Chinonyerem , Raskolnikov Dima , Shakir Nabeel , Walton-Diaz Annerleim , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Merino Maria , Pinto Peter A.
Published: February 2017

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Background: African-American (AA) men are at greater risk for prostate cancer (CaP) and experience increased prostate cancer-specific mortality. We aimed to determine racial disparities in CaP incidence, pathology, and anatomy identified on MRI/US fusion biopsy. Methods: Patients who underwent MP-MRI with targeted MRI/US fusion biopsy at our institution between May 2007 and June 2013 were reviewed. AA patients undergoing fusion biopsy were matched by age and PSA with a Caucasian cohort at a 1:2 ratio. MRI and pathologic parameters including lesion location, number of lesions, and Gleason score. Bivariate comparisons were made with the Student’s t-test and Χ2 analysis. Results: 822 patients had MRI/US fusion biopsy. 127 AA men were paired with a matched cohort of 254 Caucasians. Mean age was 60.2 and 61.4 years and mean PSA was 11.6 and 10.7ng/ml in AAs and Caucasians, respectively. We identified significantly more AA with CaP (49.6% vs 37.4%, p=0.03; Table). AAs also had higher grade disease (Gleason 7-10) versus white men (20.5% vs. 11.8%, p=0.04). Additionally, the diagnostic yield for the AA cohort was significantly higher per sampled lesion (37.5% vs 24.5%, p<0.01), despite no significant differences in % core involvement of the highest risk lesion between the groups. While there was no significant difference in presence of anterior lesions between the groups (15.7% vs 12.9%, p=NS), anterior lesions equally represented the highest risk lesions in both cohorts. Conclusions: MRI/US Fusion-guided biopsy demonstrates increased diagonostic yield/incidence of CaP and higher risk disease in the AA population in an age and PSA matched cohort of Caucasian patients. [Table: see text]
Enzalutamide monotherapy: Extended follow-up of a phase II study in hormone-naive prostate cancer patients.
Authors: Tombal Bertrand , Borre Michael , Rathenborg Per , Werbrouck Patrick , Van Poppel Hendrik , Heidenreich Axel , Iversen Peter , Braeckman Johan , Heracek Jiri , Baskin-Bey Edwina , Ouatas Taoufik , Perabo Frank , Phung De , Smith Matthew R.
Published: February 2017

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Background: The efficacy and safety of enzalutamide (ENZA) monotherapy was assessed in hormone-naive men with prostate cancer (PC; any stage) eligible for androgen-deprivation therapy (ADT). The primary end point of prostate-specific antigen (PSA) response rate (80% or more decline), assessed at 25 weeks (wks), was 92.5% with a median (range) maximum decrease of –99% (–100, –86.5) (Tombal et al. ASCO-GU 2013). Here we present data from the extended follow-up at 49 wks. Methods: In an open-label, single-arm phase II study, men age 18 or older with histologically confirmed PC requiring ADT, non-castrate testosterone (8 nmol/L or more), PSA 2 ng/mL or more at screening and a life expectancy of 12 months or more, received 160 mg ENZA once daily (NCT01302041). Treatment continued until disease progression or unacceptable toxicity. Secondary end points included changes in endocrine levels, metabolic parameters, bone mineral density (BMD), quality of life, and safety. Results: Sixty seven men were enrolled. Median (range) age was 73 (48 to 86); 38.8% had prior metastases; 35.8% and 23.94% had undergone prior prostatectomy and radiotherapy, respectively. Fifty nine men continued treatment beyond wk 25, and 54 completed wk 49. PSA response rate (80% or more reduction from baseline) at wk 49 was 80.6%, with a median (range) maximum decrease of –100% (–100, –86.5). Luteinizing hormone and testosterone were increased from baseline to wk 49 by 215.2% and 101.7%, respectively. Mean changes from baseline for metabolic outcomes at wk 49 were: +5.02% (total cholesterol), +8.86% (triglycerides), –3.54% (HbA1c), and +19.72% (HOMA-IR). Total body BMD was maintained at 49 wks (–0.30% from baseline). The most frequently reported treatment-emergent adverse events (AEs) were gynecomastia (47.8%) and fatigue (38.8%). Seven men had serious AEs, none of which were drug related. Data on patient reported outcomes will be presented. Conclusions: ENZA monotherapy was associated with significant PSA reductions after 49 wks of treatment in men with hormone-naive PC. Endocrine changes and AEs were consistent with potent AR inhibition. Outcomes for all end points at 49 wks were consistent with those reported at 25 wks. Clinical trial information: NCT01302041.
Using whole-genome sequencing to implicate the androgen receptor as the predominant driver of DNA breakpoints and fusion events in prostate cancer.
Authors: Corcoran Niall , Macintyre Geoff , Hong Matthew , Slogget Clare , Naeem Haroon , Cmero Marek , Pedersen John , Haviv Izhak , Ryan Andrew , Phal Pramit , Costello Anthony , Hovens Christopher
Published: February 2017

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Background: Structural rearrangements in cancers genomes have the potential to disrupt normal gene function and result in a selective growth advantage, either by inactivating tumour suppressors or creating novel gene fusions with oncogenic gain-of-function. Specific fusion genes identified to date are found in particular tumor types rather than being present in all cancers suggesting there are tissue-specific mechanisms underlying these events. The most well-known fusion event in prostate cancer is TMPRSS2-ERG. Recent studies have suggested that androgen receptor may play a role in the formation of TMPRSS2-ERG fusions, bringing the two loci in close proximity in the nucleus and facilitating DNA strand break and repair along with AR associated enzymes. Methods: To explore this mechanism more comprehensively, we performed whole-genome sequencing of 14 prostate cancers from seven patients as well as paired whole blood controls. Results: Across the cancer genomes we identified approximately 4,500 high confidence DNA breakpoints and found that a large proportion of these breakpoints were in close proximity to curated androgen receptor binding sites. Furthermore, when we examined breakpoints in 11 other cancers from the TCGA and ICGC projects, we identified a similar association with androgen (and estrogen) receptor binding sites specifically in hormone-dependent tumour types, suggesting a role for steroid hormone receptors in the formation of cancer driving structural rearrangements. In addition, in at least one patient, the formation of a novel gene fusion contributed directly to the lethal evolution of his tumour. Conclusions: These data suggest that the androgen receptor drives genome wide breakpoints and novel fusion events in prostate cancer.
Metabolic response by choline positron emission tomography (cPET) to enzalutamide (ENZ) in castration-resistant prostate cancer (CRPC) patients (pts): Preliminary results of a monoinstitutional prospective study.
Authors: Maines Francesca , Caffo Orazio , Donner Davide , Veccia Antonello , Chierichetti Franca , Galligioni Enzo
Published: February 2017

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Background: ENZ is a new generation hormone therapy, able to produce a survival improvement in CRPC pts pre-treated with docetaxel. In Italy, ENZ is not approved yet for the daily clinical practice but until few months ago it was available through a named patient programme (NPP). Since in our Hospital CRPC pts are regularly assessed by cPET to evaluate the treatment response, so pts treated with ENZ were monitored in the same way. Methods: Eligible pts received ENZ at the standard dose of 160 mg po daily until progression. The cPET was performed at baseline, at the 3rd treatment month and thereafter every 4 mos. For each cPET we recorded the median of the maximum standard uptake values (SUVmax) of the 5 most choline-avid region of interest (ROI) and the overall number of ROIs with SUVmax > 2.5. A progressive disease (PD) was defined as the increase ≥ 30% of median SUVmax or the appearance of at least two new ROIs; a partial response (PR) as the reduction ≤ 30% of median SUVmax compared to the baseline; otherwise we considered the disease as stable (SD). Results: Out of the 31 CRPC pts treated with ENZ in our hospital from 09/12 to 03/13, 28 had complete cPET data for evaluation. The baseline median SUVmax of all evaluable pts was 10.82. At 3 mos the median SUVmax decreased to 9.30 (7 PR, 12 SD, 9 PD). Among the 19 pts evauable at 7 mos, the median SUVmax was 7.15 (8 PR, 9 SD, 2 PD). The correlation between the best metabolic response and the prostate specific antigen (PSA) response is showed in the Table. Conclusions: Our preliminary data showed a good concordance between the cPET response and biochemical response in either responding or progressing pts, while most of the pts with stable metabolic parameters showed a good PSA reduction. This is to our knowledge the first report concerning the metabolic response to ENZ and its correlation to PSA response. Further studies are required to define the role and use of cPET in monitoring the treatment efficacy in pts receiving ENZ. [Table: see text]
Evaluation of the prostate health index (phi) as a novel biomarker in active surveillance of prostate cancer.
Authors: Eichholz Andrew , McCarthy Frank , Dennis Nening , Thomas Karen , Howlett Tim , Iqbal Jhangir , Amin Jan , Tan Mildred , Singhera Mausam , Selvadurai Elizabeth , Huddart Robert Anthony , Dearnaley David Paul , Parker Chris
Published: February 2017

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Background: Phi is calculated from serum PSA, free/total (f/t) PSA and [-2]proPSA using the Beckman Coulter assay kit, and has been approved for use in patient selection for diagnostic prostate biopsy. We hypothesized that phi might also predict outcome of active surveillance. Methods: From 2002, we have done a prospective cohort study of active surveillance for men with T1/2, Gleason <= 3+4, PSA < 15ng/ml prostate cancer. Serum was banked at baseline. Monitoring included 6 monthly PSA and 2-yearly repeat biopsy. Treatment was indicated for PSA velocity > 1ng/ml/yr or Gleason >= 4+3 on repeat biopsy. We analyzed baseline phi with respect to time to treatment. A multivariate model was fitted using total PSA, PSA velocity, PSA density, Gleason score, % biopsy cores positive, T stage, and maximum % cancer in any biopsy core. The fit of this model was then compared with the addition of % f/t PSA and phi. Results: 370 patients were evaluable with a median follow-up of 5 years. The table shows the association between baseline phiand time to treatment. On multivariate analysis, the model with % f/t PSA was a significant improvement over base model (change in fit 41.1, p<0.001), and the model with % f/t PSA and phi was a significantly better fit than % f/t PSA alone (change in fit 11.1, p=0.001). Conclusions: In men with favorable risk prostate cancer, phi at diagnosis was a significant predictor of the outcome of active surveillance. The data require validation, but suggest that active surveillance is particularly attractive to men with a low phi. [Table: see text]