bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival differences in metastatic bladder cancer by geography.
Authors: Mandal Rakesh , Shah Binay Kumar
Published: February 2017

314

Background: It is unknown if there is any geographical variation in survival among patients with bladder cancer. This study was conducted to evaluate the survival rates in the northern (latitude ≥40o) and southern regions (latitude < 40o) in the United States for the period of 2000-2008.

Methods: We used Z-test in the Surveillance, Epidemiology, and End Results (SEER*Stat) program to analyze 1-year and 5-year relative survival rates of bladder cancer patients included in SEER database. Several cohorts categorized by race, gender, and age groups (<60 and ≥60 years) were examined to compare the survival rates in the northern and southern regions of the U.S. Based on the counties’ centroid, northern (latitude ≥40o) and southern (latitude < 40o) regions were determined.

Results: The dataset comprised 6,501 and 664 patients with AJCC stage-IV bladder cancer among Caucasian and African Americans respectively. Among Caucasian men (<60 years), 1-year survival rates in the northern and southern regions were 66.2± 2.5% (n=372) and 57.5± 1.9% (n= 738) respectively. Similarly, 5-year year survival rates in the northern and southern regions were 27.5± 2.6% (n=372) and 20.1± 1.7% (n= 738) respectively. Thus the survival for this group was lower in the South compared to the North and was statistically significantly (1-year: Z-value = -2.723, p= 0.006; 5-year: Z-value = -2.909, p= 0.003). There was no significant difference in the survival rates among any other cohorts examined.

Conclusions: Caucasian men (<60 year) with stage IV bladder cancer had lower 1- or 5-year relative survival rates in the South compared to the North. The survival difference in young Caucasian men with bladder cancer by geography may be due to differences in tumor biology resulting from the differential exposure to environmental carcinogens.
Mapping patterns of nodal metastases in seminoma: Rethinking radiotherapy fields.
Authors: Paly Jonathan J. , Efstathiou Jason Alexander , Hedgire Sandeep , Chung Peter W. M. , O’Malley Martin , Shah Anand , Bekelman Justin E. , Harisinghani Mukesh , Zietman Anthony L. , Shipley William U. , Beard Clair
Published: February 2017

324

Background: Historically, radiation therapy for testicular seminoma has targeted the retroperitoneal (RPLN) and pelvic lymph nodes via standard anterior-posterior/posterior-anterior fields based upon skeletal anatomy. This study was undertaken to identify the location of involved lymph nodes and their relationship to both bony and vascular anatomy in stage II patients.

Methods: Scans of 69 patients with stage II seminoma diagnosed between 1996 and 2011 were reviewed. 55% of patients had left-sided, 44% right-sided, and 1% bilateral primaries. The position of each node was recorded and then transferred to a standardized CT template scan based upon its relation to skeletal and vascular anatomy. Para-aortic fields were overlaid on the template, extending from T10/T11 to L5/S1 and bounded laterally by the contralateral transverse processes and ipsilateral renal hilum. Extended fields included ipsilateral iliac lymph node chains. The location of involved nodes within these conventional fields was assessed.

Results: 113 nodes were identified as radiographically positive. 88% of involved nodes were located in the RPLN region with the remaining 12% in the pelvis. 98% of positive RPLN nodes were within a 2.2cm lateral and 1.8cm anterior expansion of the aorta between L1/L2 and L5/S1. No positive nodes were identified within the renal hilar region or superior to L1 for patients with left-sided seminomas. For right-sided seminomas, no positive nodes were superior to L2, though there was one renal hilar node. <2% of all nodes fell outside the extended treatment field.

Conclusions: Nodal metastases from a contemporary cohort of stage II seminoma patients generally localized to a smaller area than is targeted using conventional fields. Notably, no positive nodes were identified superior to L1, on the contralateral side of vertebral bodies, or in the left renal hilum. Modified treatment fields based on vascular rather than bony anatomy may allow for a significant decrease in normal tissue irradiation and its associated toxicities. Validation of these results may inform guidelines for a redefined clinical target volume and allow for more targeted radiation delivery in the treatment of seminoma.
Phase II trial of docetaxel, cisplatin, 5-fluorouracil (TPF) in locally advanced and metastatic squamous cell carcinoma (SCC) of the penis (CRUK/09/001).
Authors: Bahl Amit , Nicholson Steve , Harland Stephen John , Chester John D. , Pickering Lisa M. , Barber Jim , Cruickshank Clare , Burnett Stephanie M. , Waters Rachel , Hall Emma ,   Penile TPF Trial Management Group
Published: February 2017

326

Background: Chemotherapy for penis cancer is used to palliate metastatic disease and treat locally-advanced disease. Pathologic similarities to head and neck SCC suggest that adding docetaxel (T) to platinum-based regimens may enhance efficacy.

Methods: A single-stage single-arm phase II trial was conducted. Eligible patients had measurable, histologically proven penile SCC staged M1; or T4, any N, M0; or any T, N3/inoperable N2, M0; or any T, N1, M0 with Multi-Disciplinary Team agreement for chemotherapy as first-line therapy. Treatment was three 21-day cycles of TPF (day 1: T 75mg/m2, P 60mg/m2; days 1-5: F 750mg/m2/day). In 26 evaluable patients ≥14 responses were required to conclude a response rate of ≥60% (p0=0.35, p1=0.60, α=0.1, β=0.2; Fleming-A’Hern design). Primary endpoint was overall response rate at completion/discontinuation of trial treatment. Secondary endpoints included safety, tolerability, progression-free survival (PFS) and overall survival (OS).

Results: 29 patients (median age 61 years) were recruited from 9 UK centres between Sept 2009 and Dec 2010. 8 patients were M1. 17 patients had performance status (PS) 0, 11 PS1, 1 PS2. 3 patients discontinued treatment early for reasons other than progression. Dose reductions/delays were reported for 13 patients. 28 patients have on-treatment toxicity data: 19 (68%) experienced grade 3/4 toxicity, with neutropenia most common (n=13, 46%). 7 patients (25%) experienced febrile neutropenia and/or neutropenic sepsis. 10/26 patients (38.5%, 95% CI: 20.2% - 59.4%) in the evaluable population responded. Twelve month PFS was 39.1% (95% CI: 20.9% - 56.8%; median PFS (all 29 patients/M1/M0): 7.1/ 3.1/ 9.6- months). Twelve month OS was 54.6% (34.9% - 70.6%; median OS (all patients/M1/M0): 13.7/ 6.9/ not reached yet-months).

Conclusions: UK clinicians successfully recruited to a multi-centre trial in penis cancer, establishing a network of centres for future studies. Toxic effects of TPF were common but not unexpected. The trial did not reach its target response rate of ≥60% to justify further investigation although PFS and OS in this cohort compares favourably to reported data in literature.
Perineural versus lymphovascular invasion: Which is a better marker for unfavorable biochemical outcomes following prostatectomy? Results from the Duke Prostate Center Database.
Authors: Singh Abhay A , Banez Lionel Lloyds , Gerber Leah , Freedland Stephen J. , Robertson Cary N. , Ferrandino Michael , Polascik Thomas , Walther Philip John , Moul Judd W.
Published: February 2017

34

Background: Despite a substantial effort to study the clinical significance of perineural invasion in prostate biopsies (PNIb) its prognostic significance remains controversial. The limited data on perineural invasion in radical prostatectomy (RP) specimens (PNIp) suggests that biopsy specimens inadequately represent whole gland pathology thus rendering investigation of PNIp even more clinically relevant. While lymphovascular invasion in pathology specimens (LVIp) has been more rigorously investigated, studies have shown conflicting results. More importantly, there has been minimal comparison of PNIp and LVIp in the same cohort to determine which marker is the superior prognostic factor.

Methods: We retrospectively analyzed data from 1611 men who underwent RP from 1999 to 2010 from the Duke Prostate Center database. We evaluated PNIp and LVIp as predictors of time to BCR by comparing hazard ratios (HR) and 95% confidence intervals (CI) using crude and adjusted proportional hazards regression models that included both variables and controlled for demographic and clinico-pathological covariates.

Results: A total of 1304 (81%) men had PNIp while only 82 (5%) men had LVIp. On crude regression, both PNIp (HR=3.39; 95% CI=1.94-5.84; p<0.001) and LVIp (HR=2.33; 95% CI=1.49-3.64; p<0.001) were significant predictors of adverse BCR risk. After adjusting for clinico-pathological covariates, PNIp remained significantly associated with increased BCR risk (HR=1.85; 95%CI =1.04-3.31; p=0.04). Specifically, men with PNIp were 85% more likely to experience BCR relative to PNIp (-) men. In contrast, LVIp was not independently associated with BCR risk (p=0.23).

Conclusions: In a cohort of men who underwent RP, PNIp is predictive of adverse BCR outcomes independent of clinicopathological parameters that include LVIp. Consequently, LVIp is a poor predictor of BCR risk. PNIp may thus provide additional prognostic information for men treated with RP and its inclusion in predictive nomograms requires study. Further analyses to determine if PNIp is likewise associated with metastasis and cancer-specific survival are warranted.
Everolimus therapy for angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: Results from EXIST-2.
Authors: Bissler John J. , Kingswood J. Chris , Zonnenberg B. A. , Frost Michael , Belousova Elena , Radzikowska Elzbieta , Fischereder Michael , Nonomura Norio , Brakemeier Susan , de Vries Petrus , Sahmoud Tarek , Shah Gaurav , Miao Sara , Gray Diep , Budde Klemens
Published: February 2017

356

Background: We evaluated everolimus, an oral mTOR inhibitor, for treating angiomyolipoma (AML) in patients with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM).

Methods: EXIST-2 ( NCT00790400 ) is a prospective, international, randomized, double-blind, placebo-controlled, phase III study. Patients (≥1 AML with longest diameter ≥3 cm) were stratified by (i) TSC and enzyme-inducing anti-epileptic drug (EIAED) use, (ii) TSC and EIAED non-use, (iii) sLAM and randomized 2:1 to receive everolimus 10 mg daily (n=79) or placebo (n=39). Kidney CT/MRI was performed at baseline, at 12, 24, and 48 weeks, and then annually. Primary efficacy endpoint was the proportion of patients with AML response (best overall confirmed ≥50% reduction in sum of volumes of all target AML relative to baseline). Secondary efficacy endpoints included time to AML progression and skin lesion response rate in patients with >1 skin lesion at baseline (n=114). Adverse events (AE) were monitored every visit. Core phase results (6 months from last patient randomized) are presented.

Results: Patient characteristics were balanced across the 2 groups; median patient age was 31 years. Median treatment duration was 38.1 weeks (everolimus) and 34.0 weeks (placebo). Everolimus best overall response rate (41.8%) was superior to placebo (0%) for the primary efficacy endpoint (p<0.0001). Median time to AML progression was 11.4 months for placebo and was not reached for everolimus. The everolimus group had a significantly higher best overall skin lesion response rate (complete or partial response) than placebo (26% vs. 0%; p=0.0002). Everolimus was associated with an acceptable safety profile consistent with previous reports in TSC, with most AEs being grade 1 or 2. Serious AE incidence was similar in the treatment arms (everolimus 19.0% vs. placebo 17.9%).

Conclusions: Everolimus treatment produced a clinically and statistically significant reduction in AML volume compared with placebo and showed a safety profile consistent with previous reports. Everolimus represents the first potential pharmacologic treatment option for patients with AML.
Incidence of benign versus malignant renal tumors in selected studies.
Authors: Russo Paul , Uzzo Robert G. , Lowrance William Thomas , Asnis-Alibozek Aviva , LaFrance Norman David , Libertino John A. , Pryma Daniel A. , Divgi Chaitanya R.
Published: February 2017

357

Background: Use of cross-sectional imaging has increased the detection rate for small renal tumors; more patients now present with early-stage renal cell carcinoma (RCC) or benign or indolent renal masses. Histopathology after surgical resection is the definitive method for characterizing renal tumors. Stage migration of renal masses creates uncertainty about the percentage of resected masses that will be benign vs malignant. We sought to better define these proportions through a targeted review of the literature.

Methods: PubMed/select congresses were searched to identify the histologic classification of renal masses in a representative sample from the contemporary literature: [search] incidence AND (renal cell carcinoma AND benign); incidence AND (renal tumor AND benign); percentage AND (renal cell carcinoma AND benign); limit: 2003–2011.

Results: Most representative studies included procedures conducted in the mid-1990s to the mid-to-late 2000s. Studies origin was US (n=8), Korea (n=3), China, Japan, Germany, Austria, Australia, and multisite (Israel/France/US; all n=1). Only 8 studies had n≥500 (range, 70–10,404). The proportion of benign masses are shown (see Table); half of the studies reported values between 16% and 17%. The majority found that benign tumors were more likely to be smaller in size (<4 or <7 cm) than malignant tumors. 11 studies reported the RCC subtype (% clear cell range, 46%–83%).

Conclusions: Benign renal tumors occur ~15% of the time and are more prevalent among small masses. Nearly 25% of resected lesions are benign or indolent and may not require surgery. Preoperative discrimination of more aggressive renal masses would be an important clinical advance that could improve clinicians’ diagnostic confidence and guide patient management. Funding: Wilex AG/IBA Molecular.

[Table: see text]
Epithelial-mesenchymal transition: A mechanism of resistance to VEGF pathway inhibition in genitourinary cancers.
Authors: Hammers Hans , Fu Chenglai , Gerber Stephanie , Van Den Berg Susan , Steenwinkel Frans , Moriarty Whei , Keizman Daniel , Kachhap Sushant , Carducci Michael Anthony
Published: February 2017

390

Background: There is emerging clinical data that epithelial-mesenchymal-transition (EMT), a cellular phenotype observed with aggressive disease and metastasis, is associated with resistance to angiogenesis inhibitors targeting the VEGF pathway. To better study and characterize this clinical observation we set out to generate well-defined preclinical prostate and kidney cancer models of EMT mediated resistance to the angiogenesis inhibitor sunitinib with the overarching goal to develop more effective antiangiogenic therapies in genitourinary malignancies.

Methods: We screened a library of prostate and kidney cancer xenografts models for their response to the angiogenesis inhibitor sunitinib. By applying strict clinical criteria we identified models, which were refractory, resistant and also unambiguously sensitive to sunitinib. The sensitive cell lines were used to stably overexpress the EMT inducing transcription factors Twist1, Snail and ZEB1. The cell lines were then injected to form xenografts and their response to sunitinib was assessed. Correlative studies for microvascular density and cellularly mediated resistance through blood vessel maturation and myeloid cell recruitment were performed.

Results: EMT mediated resistance to sunitinib was seen in both, prostate and kidney cancer models. Interestingly, EMT mediated resistance was primarily associated with an increase in blood vessel maturation.

Conclusions: We present for the first time defined preclinical prostate and kidney cancer model of EMT mediated resistance to a multitargeted VEGF pathway inhibitor. These model could prove useful in our efforts to develop more effective antiangiogenic approaches in prostate cancer and kidney cancer and aid to predict response or the lack thereof to VEGF based therapies.
Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT.
Authors: Blank Christian U. , Bono Petri , Larkin James M. G. , Gogov Svetozar , Panneerselvam Ashok , Garay Carlos A. , Grünwald Viktor ,   on behalf of the REACT Study Group
Published: February 2017

402

Background: Metastatic non-clear cell renal cell carcinoma (mncRCC), which accounts for about 25% of all RCCs, is characterized by resistance to treatment and poor overall survival. Despite recent advances in targeted therapies for patients with mRCC, effective therapies for patients with mncRCC remain limited. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with mRCC of any histology refractory to VEGF-targeted therapy access to everolimus in advance of regulatory approval.

Methods: REACT, an open-label, international, expanded-access program (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy in order to evaluate the long-term safety of everolimus 10 mg daily. Overall incidence of grade 3/4 and serious adverse events (AEs) were recorded, as was tumor response to everolimus according to RECIST criteria. A subgroup analysis of safety and efficacy in patients with mncRCC was performed.

Results: Of 1367 patients enrolled, 75 patients (5.5%) had mncRCC. Median everolimus treatment duration in the mncRCC subgroup was 12.14 weeks (range, 0.9–49.0 weeks) and in the overall REACT population it was 14.0 weeks (range, 0.1–83.7 weeks). In the mncRCC subgroup, most commonly reported grade 3/4 AEs were anemia (17.3%), dyspnea (10.7%), pleural effusion (9.3%), fatigue (8.0%), and hyperglycemia (6.6%). Best overall response was similar in the mncRCC subgroup and overall population: respectively, 1.3% and 1.7% had partial response and 49.3% and 51.6% had stable disease.

Conclusions: Although patients with mncRCC had a slightly lower treatment duration than the overall REACT population, approximately 50% of these patients achieved disease control on treatment. In this subgroup, everolimus was well tolerated, no new safety issues were observed, and the AE profile was consistent with that of the overall population. These encouraging results of the safety and efficacy of everolimus in patients with mncRCC support further evaluation of everolimus in these patients.
Improving outcomes through the development of quality indicators in renal cell cancer.
Authors: Wood Lori , Bjarnason Georg A. , Black Peter C. , Cagiannos Ilias , Heng Daniel Yick Chin , Kapoor Anil , Kollmannsberger Christian K. , Mohammadzadeh Forough , Moore Ronald Brian , Rendon Ricardo A. , Soulieres Denis , Tanguay Simon , Venner Peter , Finelli Antonio
Published: February 2017

422

Background: Optimal quality of care is necessary for ideal outcomes, and quality indicators (QI) are increasingly being used to measure quality of care. In renal cell carcinoma (RCC), there is a paucity of information defining such optimal care. This is particularly important as care of RCC patients is becoming increasingly complicated with more options and requiring greater expertise. The goal of this study was to identify QI for RCC across the entire disease spectrum from presentation to palliation.

Methods: A multidisciplinary expert panel (13 members) of medical and urologic oncologists from across Canada reviewed potential QI. These potential QI were identified from a systematic review of the literature. In addition, panel members were encouraged to suggest additional potential QI. A modified Delphi technique was utilized to select QI that were both relevant and practical to RCC; this technique incorporated 2 email questionnaires and 1 in-person meeting.

Results: From 250 citations in the systematic review, 34 possible QI were identified; 24 additional potential QI were suggested by panel members. A final set of 23 QI were established by the expert panel. These were distributed across the RCC disease spectrum as follows (number of QI in parentheses): screening (1), diagnosis and prognosis (3), management of localized disease (7), surgical management of locally advanced or metastatic disease (3), systemic therapy (4), and follow-up (3). These 21 QI focused largely on the treatment of RCC. In addition, two QI related to survival outcomes (overall and progression-free) were selected. An example of a QI in localized disease is the proportion of patients undergoing partial nephrectomy for tumors < 4 cm. An example in advanced disease is the proportion of patients who are assessed by members of a multidisciplinary genitourinary cancer team. The final 23 QI selected will be presented in detail.

Conclusions: A systematic, consensus-based approach was used to determine relevant QI in RCC care. These 23 QIs will provide a means of evaluating the quality of RCC care in an effort to improve outcomes for our patients. The next step will be to establish a means of measuring each of these QI based on defined or yet to be defined benchmarks.
Phase I/II safety and pharmacokinetic (PK) study of ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.
Authors: Rathkopf Dana E. , Danila Daniel Costin , Morris Michael J. , Slovin Susan F. , Steinbrecher Jill Elise , Arauz Gabrielle , Rix Peter J. , Chow Maneval Edna , Chen Isan , Fox Josef J. , Fleisher Martin , Larson Steven M. , Scher Howard I.
Published: February 2017

43

Background: In CRPC, androgen receptor (AR) overexpression is associated with resistance to first-generation anti-androgen therapy such as bicalutamide. ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data shows that ARN-509 binds AR with 5-fold greater affinity than bicalutamide, and induces tumor regression in hormone-sensitive and CRPC xenograft models.

Methods: In this open-label, Phase 1/2 study, mCRPC patients received ARN-509 orally on a continuous daily dosing schedule. In Phase 1 , 7 doses (30, 60, 90, 120, 180, 240, 300 mg) were tested using standard 3x3 dose escalation criteria to assess safety, PK, and determine the recommended Phase 2 dose (RP2D). Preliminary anti-tumor activity was assessed by PSA kinetics, radiographic responses, circulating tumor cells (CTCs), and FDHT-PET imaging.

Results: Twenty-four patients (median age 68 yrs, Gleason Score 8; prior docetaxel 13%) were enrolled. The most common Grade 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related Grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden, which led to an additional 3 patients being enrolled at the highest dose with no further dose limiting toxicities. PK was shown to be linear and dose-dependent. Twelve patients (55%) had ≥ 50% PSA declines. To date, 7 patients have discontinued the study due to progression, with the longest patient still on study for more than 1 year. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Based on preclinical assessment of maximum efficacious dose, PK, and promising activity across all doses, 240 mg was selected as the RP2D.

Conclusions: In this Phase 1 study, ARN-509 was shown to be safe and well tolerated, with promising preliminary activity based on PSA and pharmacodynamic evidence of AR antagonism. The Phase 2 portion of the study will enroll up to 90 patients with treatment-naïve non-metastatic and mCRPC.
Treatment of metastatic renal cancer with high-dose interleukin-2 after targeted therapy.
Authors: Hawkins Robert E. , Galvis Victoria , Shanks Jonathan , Dalal Neha , Thistlethwaite Fiona , Spencer-Shaw Andrea
Published: February 2017

439

Background: High-Dose Interleukin-2 (HD IL2) remains a good option for treatment of metastatic renal cancer. As a first-line treatment, in carefully selected patients, it can produce high rates of response ( OR 50%; CR 25%) (Shablak A et al., J Immunotherapy 2011, 34(1):107-122). Its use after targeted therapies is controversial and there are reports of increased toxicity, particularly an increased incidence of cardiovascular toxicity (and possibly a reduced response rate (Cho DC et al., J Immunotherapy 2009, 32(2):181-520). However, there is potential to use it either in patients who have failed treatment with targeted therapy or as a consolidation therapy after successful treatment with a targeted agent.

Methods: Here we present the outcomes of 16 patients treated with first-line immunotherapy with HD-IL2 after targeted therapy: of these 8 had been treated after failure of 1-3 lines of targeted therapy and 8 have been treated as consolidation after initial response to sunitinib. The histological characteristics of the tumours all fitted into the “favourable” group as defined previously by us and all had high levels of expression of CAIX (> 80%). All had ECOG PS 0/1, a satisfactory baseline stress echo, an interval of at least 8 weeks from last dose of targeted agent to start of HD-IL2 and at most 2 organs of disease.

Results: Toxicity is indistinguishable from that of patients without prior treatment and no patient needed inotropic support or admission to intensive care. The number of doses given per cycle was also similar to that in unpretreated patients. Overall the response rates are excellent – with 9/13 evaluable patients having RECIST defined response and 6/13 having a complete remission. To date none of the patients in complete remission have realpsed but follow up is relatively short with the longest being 24 months. The responses have been particularly striking following treatment with mTor inhibitors.

Conclusions: Overall, HD IL2 can be given safely in carefully selected patients after targeted therapies. It appears to be effective as a salvage therapy and potentially as a consolidation therapy. Updated results will be presented.
A phase I study of S-1 in combination with sorafenib in metastatic renal cell carcinoma (mRCC).
Authors: Ozono Seiichiro , Takayama Tatsuya , Fujisawa Masato , Miyake Hideaki , Hashine Katsuyoshi , Ninomiya Iku , Tatsugami Katsunori , Sakai Hideki , Ohba Kojiro , Akaza Hideyuki , Tsukamoto Taiji , Naito Seiji
Published: February 2017

447

Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil, with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The purpose of this study was to confirm the recommended dose (RD) and maximum tolerated dose (MTD) of S-1 in combination with sorafenib, a small molecular inhibitor of several tyrosine protein kinase, in Japanese patients with mRCC. We assessed dose-limiting toxicities (DLTs) and pharmacokinetic interactions during the first cycle of treatment.

Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary mRCC, measurable lesions, a history of no previous treatment or not more than 1 regimen of cytokine treatment, an ECOG performance status of 0 or 1, prior nephrectomy, and adequate organ functions. In this study, four dose levels were prepared, and the starting dose was set at Level 1B. S-1 was administered on days 1 to 28, and sorafenib was given on days 1 to 42 as one cycle. The MTD was assessed using a “3 + 3” dose escalation design and was defined as the highest dose level for which the incidence of DLTs was less than 33%.

Results: Between August 2009 and March 2010, 9 patients were enrolled. Two DLTs occurred in patients assigned to level 2, which was the full therapeutic dose of each agent. Therefore, the MTD was not confirmed, but the RD was determined to be level 2. Although renal clearance affected the pharmacokinetics of S-1, there were no obvious drug interactions between S-1 and sorafenib. Details are shown in the Table.

Conclusions: This combination therapy can be administered with acceptable tolerability, no overlapping toxicity, and no drug interactions. The RD for phase II studies was fixed at level 2, and a phase II study is ongoing.

[Table: see text]
Use of Fuhrman grading system for Japanese patients with renal cell carcinoma.
Authors: Miyaji Yoshiyuki , Kanomata Naoki , Ohira Shin , Ohbatake Aya , Fujita Masaichiro , Fukumoto Kazuhiko , Fujii Tomohiro , Jo Yoshimasa , Yokoyama Teruhiko , Nagai Atsushi
Published: February 2017

452

Background: In Japan, the 3-tiered system compared with the size of nuclei of normal tubule cell was adopted as the histologic criteria for tumor grading of renal cell carcinoma (RCC) in “General Rule for Clinical and Pathological Studies on Renal Cell Carcinoma”. Fuhrman grading system is first adopted in the 4th edition (April, 2011). We evaluated the impact of these pathological features on RCC survival and recurrence in Japanese patients.

Methods: We identified 187 consecutive patients who underwent partial or radical nephrectomy at our institution from 1996 to 2009 for RCC. Specimens were re-reviewed by a single pathologist (NK) blinded to clinical outcome data. The data captured were histological type according to the 2004 WHO classification and conventional Fuhrman grading system.

Results: Median followup was 57 months (range 5 to 181). Median age at diagnosis was 65 years. The TNM stage (7th UICC) was I in 127 cases, II in 21, III in 20 and IV in 19. A total of 24 partial and 163 radical nephrectomies were performed. Of the specimens 144 (77.0%) were clear cell carcinoma. The metastasis-free survival rates in stage I, II and III at 5 years were 89.7% ,79.8% and 52.1%, respectively (p<0.001). Univariate analysis revealed that there were significant risk factors in T stage, in Furhman grade, in microscopic venous invasion, in capsular invasion and in tumor size more than 4.1cm diameter. On multivariate analysis Furhman grade (grade I and II vs. III, vs. IV) was the only significant risk factor (HR 4.35 (III vs. I and II), HR 3.33 (IV vs. I and II), p=0.037). The overall survival rates in stage I, II , III and IV at 5 years were 83.0%, 90.0%, 76.8% and 41.8%, respectively (p<0.001). On multivariate analysis T stage, capsular invasion and Furhman grade (p=0.003) were the significant risk factor.

Conclusions: Even Japanese patients with renal cell carcinoma undergoing nephrectomy, Fuhrman grading system is the most important predictive factor for survival and disease-free survival.
Non–clear cell histology in patients with metastatic RCC as a prognostic indicator in the targeted therapy era.
Authors: Rampersaud Edward N. , Birkhauser Frederic , Logan Joshua E , Sonn Geoffrey , Chan Yvonne , Anterasian Christine , Li David , Pouliot Frederic , Kabbinavar Fairooz F. , Pantuck Allan J. , Belldegrun Arie S.
Published: February 2017

454

Background: The role of targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) having non-clear cell histology (non-ccRCC) is still being defined. We sought to examine the factors associated with survival outcomes in patients presenting with various histological subtypes in the TT era.

Methods: The UCLA Kidney Cancer Program database containing records of over 2000 patients was queried. The clinicopathologic factors between patients with clear cell subtype (ccRCC) and those with non-clear cell histology were compared using the Student’s T-test and the chi-square test for continuous and categorical variables, where appropriate. Survival outcomes were estimated using Kaplan-Meier (log rank). Univariate and multivariate Cox regression models were used to identify independent associations with survival.

Results: Of 157 patients treated with FDA-approved TT, 132 (84%) had ccRCC while 25 (16%) had non-ccRCC. The two groups were balanced for baseline demographic variables, including gender, race, BMI, pack-years of smoking, T-stage, Fuhrman grade, performance status and UCLA Integrated Staging System (UISS) risk category. Median survival of patients with ccRCC and non-ccRCC was 41.6 and 18.1 months (p<0.001). In univariate analysis, non-ccRCC was associated with a 2.7-fold risk of cancer specific death compared to ccRCC patients. Among patients receiving TT-only, median survival of patients with ccRCC and non-ccRCC was 35 and 15.4 months (p=0.007). A subset of ccRCC patients treated sequentially with IMT followed by TT had a median survival of 73 months. Worsening UISS risk class and non-ccRCC histology, but not age, gender, race, tobacco exposure history, or tumor size, were independently associated with the risk of cancer death.

Conclusions: Non-clear cell histology remains a significant and independent risk factor for cancer specific death for mRCC patients treated by TT even after controlling for UISS risk category.

[Table: see text]
Lymphopenia as a prognostic factor in renal cell carcinoma.
Authors: Mozayen Mohammad , Tesfaye Anteneh , Katato Khalil
Published: February 2017

470

Background: Lymphopenia is known to be a negative prognostic marker for NHL and hematological malignancies, recent observational studies evaluated the presence of lymphopenia and its impact in solid tumor like colon, lung and pancreatic cancer. We aim to assess the effect of Lymphopenia at the renal cell carcinoma (RCC) survival.

Methods: A retrospective review of 207 patients diagnosed with RCC between 1995 and 2008 in a community hospital setting was done. Patients with additional malignancies, lymphoma of the kidneys, with no follow up data or no preoperative complete blood count test were excluded. Demographics, preoperative complete blood count, pathology, disease stage, operative note, and subsequent follow up data were reviewed. Lymphopenia was defined as absolute lymphocytic count < 1200/µl. Last follow up date was used to calculate the 3 year overall survival. The primary outcome was 3 year overall survival.

Results: A total of 207 patients were included in the study. Caucasians were 176(85.9%), African Americans were 13.7% and Asians were 1(0.5%). Males (M) were 127 (62.3%) and females (F) were 77(37.7%). The median age of the study population was 65 (22-91. Clear cell histology was seen in 79%. Stage I was seen in 53.9%, II in 23.5%, III in 13.7% and IV in 8.8% of the study population. Lymphopenia was seen in 81 (40%) patients (95 CI 34-48). Lymphopenia was seen in 31.8% of stage I; 50% of stage II, 41.4% of stage III, and 65% of stage IV patients (p=0.017). Lymphopenia was seen in 28.6% of African Americans and 42.7% of Caucasians (p=0.11). Lymphopenia was seen in 32.1% of females and 45.7% of males (p=0.03). The 3 year overall survival for the study population was 67.3% (95% CI: 60.4-73.7). The 3-year overall survival for patients with lymphopenia was 60.5%, compared to 73.6% in non-lymphopenic patients (p=0.04).

Conclusions: Lymphopenia was seen to be higher among males and Caucasians, more frequently at advanced stage at diagnosis. Patients with lymphopenia were observed to have significantly worse survival when compared to patients with normal lymphocytic count in RCC. We conclude that lymphopenia is considered as a negative prognostic factor for RCC, and needed to be studied in the correlation of other known prognostic factors.
Association of metabolic syndrome with reduced survival among men receiving androgen deprivation therapy for nonmetastatic prostate cancer.
Authors: Rudman Sarah Maria , Gray Kathryn P. , Kasperzyk Julie , Pitt Michael , Giovannucci Edward , Loda Massimo , Mucci Lorelei , Sweeney Christopher
Published: February 2017

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Background: The metabolic syndrome (MS) is a set of risk factors implicated in both the development of prostate cancer (PC) and as a recognized complication of androgen deprivation therapy (ADT). In our previous study of a Veterans’ Administration (VA) cohort of relapsed PC patients (pts) on ADT, MS was associated with a shorter duration of PC control.

Methods: We studied 347 patients (72 from VA and 275 from Health Professionals Follow up Study) treated with ADT for non-metastatic PC. 88% for biochemical relapse post definitive local therapy and 12% treated with primary ADT. MS was assessed by the modified Adult Treatment Panel III criteria prior to the commencement of ADT. Cox models tested for association between MS status and time to overall survival (OS) or time to PC specific survival, stratified by cohorts (VA vs. HPFS). Cumulative incidence of PC specific death (accounting for competing risk of death from other causes and co-morbidities) by MS status was estimated.

Results: 96 patients (28%) had MS. 62 patients (18%) died of PC during a median follow-up of 9.5 years. The median OS for patients with and without MS was 7.5 and 10.6 years respectively. A multivariate Cox model adjusted for age at start of ADT, diagnosis, stage, Gleason score and primary treatment showed MS was associated with a significant 53% increased risk of death from any cause (HR(95%CI) 1.53(1.05-2.22); p=0.03). MS patients tended to have increased risk of PC specific death (HR(95%CI) 1.6 (0.9-2.84); p=0.11). Individual MS components hypertension, dyslipidemia, obesity and diabetes were not associated with an increased risk of death from any cause or PC. The cumulative incidence of PC specific death did not differ by MS status.

Conclusions In men receiving ADT for androgen dependent PC without metastases, the presence of MS at the commencement of ADT is associated with an increased risk of death compared to those pts without MS. The shorter time to death appears to be at least in part due to shorter time to dying from PC.
Inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumors and bone turnover in prostate cancer (PCa) models in vivo compared with inhibition of either kinase alone.
Authors: Dayyani Farshid , Parikh Nila , Song Jian H. , Araujo John C. , Carboni Joan M. , Gottardis Marco M. , Trudel Geralyn C. , Logothetis Christopher , Gallick Gary E.
Published: February 2017

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Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases (SFK) and IR/IGF-1R, respectively. Based on a phase I/II clinical trial in which 9/19 pts treated with docetaxel + dasatinib were increased in serum IGF-1 levels after one cycle, the aim of this study was to establish potential antitumor cooperativity of inhibiting both IGF-1R and Src in experimental PCa models in vitro and in mice.

Methods: Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IR/IGF-1R) as well as by shRNA, in PC3 and LNCaP cells. In vivo studies were done after orthotopic and intratibial injection of PC3 cells in nude mice.

Results: SFK inhibition decreased proliferation and migration of PCa cells whereas IGF-1R blockade induced apoptosis. All anti-tumor effects were enhanced by dual blockade. IGF-1 induced phosphorylation of Akt1 and 2. Only Akt 1 phosphorylation was decreased by dasatinib; whereas Akt 1 and 2 phosphorylation were completely abrogated by the combination. Dasatinib and BMS-754807 inhibited orthotopic in vivo tumor growth of PC3 cells more potently than either inhibitor alone. Similarly, intratibial tumor growth and bone destruction was significantly reduced with the drug combination, accompanied by a decrease in serum bone turnover markers alkaline phosphatase and N-telopeptide.

Conclusions: Dual inhibition of Src and IGF-1R has greater anti-tumor effect in PCa cells compared to inhibiting either alone. In the presence of IGF-1, dasatinib and BMS-754807 are necessary to inhibit IGF-1-induced phosphorylation of Akt1 and 2 in tumor cells in culture. In intratibial models, decreased bone turnover markers in serum support the concept of targeting both the epithelial and bone microenvironment. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression.
Vitamin E and the risk of prostate cancer: Updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
Authors: Klein Eric A. , Thompson Ian , Tangen Catherine M. , Lucia M. Scott , Goodman Phyllis , Minasian Lori M. , Ford Leslie G. , Parnes Howard L. , Gaziano J. Michael , Karp Daniel D. , Lieber Michael M. , Walther Philip John , Parsons J Kellogg , Chin Joseph , Darke Amy K , Lippman Scott Michael , Goodman Gary E. , Meyskens Frank L. , Baker Laurence H.
Published: February 2017

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Background: The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a non-statistically significant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.

Methods: SELECT randomized 35,533 men from 427 study sites in the United States, Canada and Puerto Rico in a double-blind manner between August 22, 2001 and June 24, 2004. Eligible men were 50 years or older (African Americans) or 55 years or older (all others) with a PSA <4.0 ng/mL and a digital rectal examination not suspicious for prostate cancer. Included in the analysis are 34,887 men randomly assigned to one of four treatment groups: selenium (n=8752), vitamin E (n=8737), both agents (n=8702), or placebo (n=8696). Data reflect the final data collected by the study sites on their participants through July 5, 2011.

Results: This report includes 54,464 additional person-years of follow-up since the primary report. Hazard ratios (99% confidence intervals [CI]) and numbers of prostate cancers were 1.17 (99% CI 1.004-1.36, p=.008, n=620) for vitamin E, 1.09 (99% CI 0.93-1.27, p=.18, n=575) for selenium, 1.05 (99%CI 0.89-1.22, p=.46, n=555) for selenium + vitamin E vs. 1.00 (n=529) for placebo. The absolute increase in risk compared with placebo for vitamin E, selenium and the combination were 1.6, 0.9 and 0.4 cases of prostate cancer per 1,000 person-years.

Conclusions: Dietary supplementation with Vitamin E significantly increases the risk of prostate cancer among healthy men.
High-dose-rate (HDR) brachytherapy with external beam radiotherapy for localized high-risk prostate cancer: Five-year results in 122 patients.
Authors: Yamamoto Toshihiro , Kido Masahito , Sasaki Hiroshi , Miki Jun , Kimura Takahiro , Miki Kenta , Yamada Hiroki , Aoki Manabu , Egawa Shin
Published: February 2017

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Background: To present outcome and morbidity of high-dose-rate (HDR) brachytherapy with external beam radiotherapy (EBRT) for localized high risk prostate cancer.

Methods: Between May 2005 and April 2009, 122 patients underwent Ir-192 HDR brachytherapy with EBRT and passed after HDR bachytherapy more than one year. The median follow-up was 46 months (range 2-76 months). All patients were high risk and localized prostate cancer. Median PSA was 40.2ng/ml (range 4.1-366ng/ml). Median Gleason Score was 8 (range 6-10). All patients were treated over six months neo-adjuvant hormonal therapy and over twenty-four months adjuvant hormonal therapy.

Results: Only one patient had died of lung small cell carcinoma. 14 patients had revealed biochemical failure(BCF) by Phoenix definition. 5-year biochemical free rate was 78%. Clinical T3 group is significant worse than clinical T1-T2 group(5-y BCF 73% vs 81%, p<0.05). Of the 122 patients, only one patient displayed Grade 3 late GI toxicity. There were no other acute nor late severe toxicity.

Conclusions: HDR brachytherapy for localized high risk prostate cancer resulted in good outcomes and had comparatively minor toxicity. Clinical T3 patients was poor outcome than clinical T1-2.
Analysis of 45 patients treated with sipuleucel-T (SIP-T) in a community practice.
Authors: Shah Tushar , Vogelzang Nicholas J.
Published: February 2017

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Background: We reviewed our toxicity experience with Sip-T since its FDA approval in May 2010. 340 pts were screened and 100 satisfied the general eligibility criteria for Sip-T; metastatic castrate resistant prostate cancer (mCRPC), minimally or asymptomatic status, limited or no visceral mets and not on chemotherapy.

Methods: 45 were and 55 were not treated with Sip-T. As expected the characteristics of the 2 groups differed in that the untreated pts tended to be older, have higher ECOG scores, higher PSA, lower Hgb, fewer radical prostatectomies, more local radiation and TURPs, and more co-morbidities (HTN/diabetes/DVTor PE/TIA or CVA/CAD/AF/obesity/lipids). Prior systemic Rx to the Sip T pts included anti-androgens 93%, estrogens 33%, chemotherapy 31% and abiraterone 20%.

Results: Central lines were placed in 32 pts. 10 of the first 17 had tunneled lines (TLs). One pt had a 10 day hospitalization for MRSA infection, 2 pts were delayed due to TL technical issues and all 10 pts complained about the complexity of TL care ( ∼1000 hrs of carer for the line to be used for ∼ 9 hours) 22 subsequent pts with central lines had external jugular lines (EJs) placed by interventional radiology before leukapheresis and removed the same day. No line complications have subsequently occurred. One pt pre-treated with samarium and ERT had too few cells for Rx. Two pts underwent a 4th pheresis for technical issues. One pt (no pre-meds) had marked rigors post-infusion #2. No other >grade 1 adverse reactions were noted during or after Sip T. 18% could not be weaned off low dose steroids before Sip T. No vascular events occurred. Median follow up is ∼ 10 months. 6 SipT pts (13%) and 11 untreated pts (18%) died of progressive disease. 3 of the 6 Sip T pts died within 30 days, all of progressive disease.

Conclusions: Sipuleucel T administration in a community setting is generally uncomplicated. For pts requiring central lines, EJs are preferred. Pts with rapidly progressive disease should not receive Sip T.