bluuebunny/crossref_metadata_2025 huggingface dataset:
Dosing patterns for octreotide LAR in neuroendocrine tumor (NET) patients: NCCN NET outcomes database.
Authors: Strosberg Jonathan R. , Bobiak Sarah , Zornosa Carrie C. , Choti Michael A. , Bergsland Emily K. , Benson Al Bowen , Bloomston Mark , Kulke Matthew , Shah Manisha H. , Yao James C.
Published: March 2020

4142

Background: Among patients (pts) with neuroendocrine histology, 10 mg – 30 mg of octreotide-LAR administered intramuscularly every 4 weeks is FDA-approved for the long term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and pancreatic VIPomas. In clinical practice, higher doses and/or more frequent administration is often prescribed for pts who experience refractory symptoms (e.g., flushing and/or diarrhea) on the maximal labeled dose. Methods: National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize pts treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions, from 2004 to 2010, with a confirmed carcinoid or pancreatic NET (pNET) diagnosis who received octreotide LAR. The primary aim of this analysis was to describe octreotide LAR dosing patterns when beyond label recommendations, clinical characteristics, reasons for dose increase, and maximal dose. Results: Among 1,886 pts in the database, 271 carcinoid and pNET pts received octreotide LAR. 40% of carcinoid pts (n=82) and 23% of pNET pts (n=15) received octreotide LAR above-label dosing, defined by dose and/or frequency greater than 30 mg every 4 weeks. The primary tumor sites among carcinoid pts receiving above label dosing were small bowel (n=40), colorectal (n=4), and unknown (n=34). Reasons for above label dosing among carcinoid pts included uncontrolled symptoms (n=53, 65%), tumor progression (n=21, 25%), high urine 5-HIAA (n=1, 1%) and unknown (n=7, 9%). The most common dose/frequency combinations for carcinoid pts were 40 mg every 4 weeks (32 pts, 39%), 40 mg every 3 weeks (15 pts, 18%), and 30 mg every 2 weeks (14 pts 17%). Among pNET pts, reasons for change included uncontrolled symptoms (n=5, 33%), tumor progression (n=9, 60%), and unknown (n=1, 7%). The most common maximal dose/frequency combinations among pNET pts were 40mg every 4 weeks (n=5, 33%), 30mg every 2 weeks (n=4, 27%), and 60 mg every 4 weeks (n=4, 27). Conclusions: Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome. Prospective studies are planned to validate this strategy.
Pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer: A clinical and biomarker study.
Authors: Powles Thomas , Sarwar Naveed , Stockdale Andrew , Boleti Ekaterini , Jones Robert J. , Protheroe Andrew , Chowdhury Simon , Peters John , Oades Grenville , O'Brien Tim S. , Sullivan Mark , Stewart Grant , Aitchison Michael , Sarker Shah-Jalal , Berney Dan , Rofe Charlotte , Sharpe Kevin , Crabb Simon J.
Published: March 2020

4508

Background: The safety and efficacy of upfront pazopanib, prior to nephrectomy in metastatic clear cell renal cancer (mRCC), has not been prospectively evaluated. The toxicity profile of pazopanib potentially makes it an attractive agent in this setting. Methods: A single arm phase II study (2009-016675-29) evaluated 12-14 weeks of pazopanib prior to planned nephrectomy in 102 untreated patients with mRCC. Patients had MSKCC intermediate (n=80) and poor risk disease (n=22). The Primary endpoint of the trial was to achieve at least a 75% clinical benefit rate (absence of disease progression) with pazopanib at the time of surgery. Sequential tissue was used for biomarker analysis (exploratory endpoint). Tissue from a previous sunitinib trials with a similar design was included for comparative purposes. Results: Overall 81% of patients obtained clinical benefit prior to surgery. The partial response rate of the primary tumor was 14% by RECIST v1.1. The median reduction in the size of the primary tumor was 14% (range 33% to - 41%). No patients became inoperable due to local progression of disease. A nephrectomy was performed in 66% of patients. The two commonest reasons for not having surgery were patient choice (9%) and progression of disease (16%). There were 2 (3%) post operative surgical death. Delayed wound healing occurred in 5%. Progression during the treatment free interval for surgery was 26%. Median PFS has not been reached. Results from biomarker analysis of sequential tissue revealed therapy resulted in a significant decrease in CD31 (-49%), PDL-1 (-31%) and pS6K (-26%), while FGF-2 (+147%), MET (+34%) and Ki-67 expression increased with therapy. Increased ki-67 and CD31 correlated with a poor outcome. Conclusions: Nephrectomy after upfront pazopanib can be performed safely in mRCC and obtains control of disease in the majority of patients. Biomarker analysis shows dynamic changes some of which are prognostically significant. Clinical trial information: NCT01512186.
Randomized phase II CTEP study of MK2206 versus everolimus in VEGF inhibitor refractory renal cell carcinoma patients.
Authors: Jonasch Eric , Corn Paul Gettys , Pagliaro Lance C. , Lara Primo , Wang Xuemei , Do Kim-Anh , Garza Racheal , Bird Shelly , Drabick Joseph J. , Marcott Valerie , Quinn David , Doyle Austin , Tannir Nizar M.
Published: March 2020

4517

Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poorer prognosis in pts with advanced RCC. We hypothesized that optimal blockade of AKT in pts refractory to anti-VEGF therapy eliminates key drivers of tumor growth and proangiogenic signaling, and will prolong progression-free survival (PFS). We tested whether MK-2206, a selective allosteric inhibitor of AKT, will yield superior PFS to everolimus in anti-VEGF therapy refractory RCC pts. Methods: Eligible pts with metastatic RCC who progressed on an anti-VEGF agent were randomized (2:1 ratio) to receive MK2206 or everolimus. Up to two prior therapies allowed. Primary endpoint was PFS. The study had 80% power to detect a 67% increase in PFS with MK2206 over everolimus (8.2 vs. 4.9 mo) with a 1-sided log-rank at alpha= 0.10. One interim futility analysis was planned. Secondary endpoints: safety, overall survival, & response rate. Tumor tissue was collected in correlative analyses. Results: A total of 43 patients were accrued; 42 were evaluable for efficacy. Demographics: Male, 77%;White, 81%; median age 62 (range 41-83). MK2206 was held in 3 pts due to grade 3 rash; 1 came off study for rash. No everolimus pt discontinued study drug due to AEs. 30 events had occurred at first futility analysis. The 1-sided log-rank p-value for rejecting null hypothesis was 0.979, exceeding p-value boundary of 0.6413 for stopping trial. Median PFS for MK2206 was 3.65 mo (95%CI 1.77-5.52) and 7.43 mo for everolimus (95%CI 1.84-13.27). Two out of 29 MK2206 pts demonstrated dramatic response with greater than 50% disease regression and PFS of 8 months and 6 months (ongoing). Conclusions: Monotherapy with MK2206 was not superior to everolimus in this randomized, phase II study. However, dramatic response to MK2206 was seen in a subset of patients. Planned translational studies to allow genotype-phenotype correlations may help explain this observation. Clinical trial information: NCT01239342.
Preliminary HER2 expression data from NeuACT, the phase II randomized, open-label trial of DN24-02 in patients (pts) with surgically resected HER2+ urothelial cancer (UC) at high risk for recurrence.
Authors: Press Michael F. , O'Donnell Peter H. , Plimack Elizabeth R. , Hoffman-Censits Jean H. , Quinn David I. , Sharma Padmanee , DeVries Todd , Chen Melissa , Locker Michael , Bajorin Dean F.
Published: March 2020

4527^

Background: HER2 overexpression may be a prognostic factor for poor outcomes in pts with high-risk UC. Publications report a wide variability of HER2 expression in UC, with ≥2+ HER2 expression by immunohistochemistry (IHC) reported in <10% to >50% of cases. DN24-02 is an investigational autologous immunotherapy targeting HER2, based on the same manufacturing platform used for sipuleucel-T. NeuACT (N10-1; NCT01353222) is designed to evaluate whether DN24-02 can prolong survival when given as adjuvant therapy following surgical resection in pts with high risk HER2-expressing UC (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples, and covariate analyses. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest system. Results: As of December 2012, tumor specimens from 114 pts have been screened. Of these pts, 84 (74%; 95% CI: 65–82%) had a HER2 expression score ≥1+ in the primary tumor, with 36 (32%) having a 2+ score and 5 (4%) having a 3+ score. Thirty-eight pts also had HER2 expression levels evaluated in lymph node samples. Of these 38 pts, 35 (92%; 95% CI: 79–98%) had a HER2 expression score ≥1+ in the lymph nodes, with 17 (45%) having a 2+ score and 4 (11%) having a 3+ score. Gender, primary tumor site, nodal stage and prior neoadjuvant chemotherapy were not significantly correlated with HER2 expression (p≥0.10). Conclusions: To date, high frequencies (≥74%) of HER2 expression ≥1+ in primary tumor and lymph node samples of UC pts have been observed. No baseline variables, including prior neoadjuvant chemotherapy, appear to affect the rate of HER2 expression. Although preliminary, these data are consistent with prior studies that have noted a higher incidence of HER2 expression in UC lymph node tumor vs. primary tumor and suggest that HER2 protein expression is common in high-risk UC. Clinical trial information: NCT01353222.
Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: A randomized phase II trial: An update.
Authors: Haggag Rasha Mohamed , Farag Kamel , Abu-Taleb Fouad , Shamaa Sameh , Zekri Abdel-Rahman , ELBolkainy Tarek , Khaled Hussein Mustafa
Published: March 2020

4537

Background: Bladder carcinoma is still one of the foremost oncologic problems in Egypt. In previous single-arm and double-arm phase II studies, prolonged infusion of low dose gemcitabine and cisplatin proved to be an effective treatment for such patients with advanced disease. Methods: To compare efficacy and safety of both prolonged infusion and standard gemcitabine-cisplatin combination, we updated the data and duplicated the number of patients of our previously published phase II randomized study to 120 untreated patients with stage III/IV bladder cancer. Patients were randomized to receive either gemcitabine (250 mg/m2) 6-hour infusion on days 1 and 8, and cisplatin (70 mg/ m2) on day 2 every 21-day cycle (Arm1) or gemcitabine (1,250 mg/ m2) 30-min infusion on days 1 and 8, and cisplatin (70 mg/ m2) on day 2 every 21-day cycle (Arm 2). Results: The 92 males and 28 females had a median age of 62 years (range 40-85 years). A total of 87 patients had transitional cell, 28 had squamous cell, and 5 had undifferentiated cell carcinoma. Among the 105 evaluable patients (52patients in arm1 and 53patients in arm 2), complete response rate was achieved in 13.5% (7/52 patients of arm 1) and 5.7% (3/53 patients of arm 2). Eighteen patients in arm 1 (34.6%) and 17 patients (32.1%) in arm 2 had partial response on therapy. Thus the overall response rate of patients in arm1 and arm 2 was 48% (25/52 patients) and 37.7% (20/53patients), respectively (p = 0.26). No significant difference in median time to disease progression (26 months versus 24 months, p =0.4), median survival (12 months versus 16 months, p =0.8), and 1-year survival (49.9 % versus 54.7%, p = 0.8) was detected between arms 1 and 2, respectively. No treatment- related deaths occurred. Main hematologic and nonhematologic toxicities were similar in both arms with no statistically signiﬁcant differences. Conclusions: In the treatment of advanced bladder cancer, gemcitabine in low dose and prolonged infusion in combination with cisplatin is not inferior to high-dose short infusion gemcitabine and cisplatin in terms of overall survival, time to disease progression, and response rates with favorable toxicity profile and less financial costs.
A STAT3- and p63-dependent transcriptional network to define a lethal basal subset of human bladder cancers.
Authors: Dinney Colin P.N. , Choi Woonyoung , Porten Sima P. , Roth Beat , Cheng Tiewei , Willis Daniel Levi , Tran Mai Ngoc-Ahn , Lee I-Ling C. , Bondaruk Jolanta E. , Majewski Tadeusz , Zhang Shizhen , Pretzsch Shanna M. , Baggerly Keith A. , Siefker-Radtke Arlene O. , Czerniak Bogdan , McConkey David James
Published: March 2020

4538

Background: Muscle-invasive bladder cancers (MIBCs) are a heterogeneous group of tumors that display widely variable clinical outcomes and responses to conventional chemotherapy. Methods: We used whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 flash frozen primary tumors to identify 3 distinct subsets of muscle-invasive bladder cancer (MIBC). We confirmed the existence of these 3 subsets in a second cohort of 57 formalin-fixed, paraffin-embedded (FFPE) MIBCs and in 2 other public datasets. Analysis of primary tumors and mechanistic studies in human bladder cancer cell lines identified tumors that respond to FGFR inhibitors or chemotherapy. Results: The first subset was driven by an active "basal" EGFR-STAT3-p63 transcriptional network, and was associated with poor clinical outcomes. High miR-200c expression stratified the survival of these basal tumors. The second subset was characterized by active p53 pathway activation, and tumors and cell lines with these features were resistant to cis-platinum based chemotherapy. The third subset expressed "luminal" markers and active estrogen receptor (ER) and PPARγ signaling, and luminal cell lines were sensitive to fibroblast growth factor receptor (FGFR) inhibition. Conclusions: Molecular subtyping of MIBCs can be used to identify lethal cancers and enrich for tumors that will respond to FGFR inhibitors or conventional chemotherapy.
Introduction of a tobacco-screening initiative for those at risk for bladder cancer in a high volume urology clinic.
Authors: Bassett Jeffrey C. , Gore John L. , McCarthy William J. , Morrison Christopher , Kwan Lorna , Bennett Carol J. , Cookson Michael S. , Penson David F. , Saigal Christopher
Published: March 2020

4540

Background: Tobacco use is causal or contributory in 50% of bladder cancer diagnoses. Continued use after diagnosis may negatively impact recurrence, progression, and mortality. Despite its relevance, tobacco screening was infrequently occurring in a regional urology clinic. We hypothesized that the clinic was fertile ground for a tobacco-screening initiative given the number of referrals for bladder cancer, hematuria, and other tobacco-related urologic conditions. Methods: An EMR-based tobacco-screening prompt was designed using the same informatics architecture and clinical reporting system used in primary care. The prompt was introduced for all new patient encounters beginning January 2010. We prospectively collected the proportion of patients asked about tobacco use, advised to quit, and assisted with smoking cessation. Results: For the two years ending December 2011, 4,617 patients were seen in urologic consultation; 31% (n = 1,444) were referred for tobacco-related urologic diagnoses, 36% (n = 518) of whom were referred for bladder cancer or hematuria. The tobacco-screening prompt was used 57% (n = 2,626) of the time. Attending physicians utilized the template in 17% of their encounters, resident physicians in 71%, and nurse practitioners in 97% (p < 0.001). 49% (n = 255) of those referred for bladder cancer or hematuria were screened for tobacco use. Active smokers comprised 21% (n = 558) of screened patients. Relative to former and never smokers, active smokers were more likely referred for bladder cancer or hematuria (p = 0.005). 40% (n = 225) of active smokers desired to quit. Those counseled by an attending physician were more likely ready to quit and trended toward a more intensive cessation program (p = 0.004 and p = 0.07, respectively). Conclusions: Our data suggest that urology clinics may be important sites for tobacco-screening initiatives, particularly for those with tobacco-related urologic diagnoses. Screening patients referred for bladder cancer or hematuria is likely high yield due to the increased proportion of active smokers. Given the disparate utilization of the prompt, identification of provider-level facilitators and barriers to tobacco screening is worthy of study.
A novel phase I trial design featuring a two-dimensional dose-finding algorithm optimizing the dose of gemcitabine and doxorubicin with bortezomib in metastatic urothelial carcinoma (UC).
Authors: Siefker-Radtke Arlene O. , Wen Sijin , Shen Yu , Stigall Kristi , McConkey David James , Millikan Randall E.
Published: March 2020

4548

Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR < 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase 1 design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.
Investigating serum β-HCG as an independent prognostic factor in patients (pts) receiving chemotherapy (Ct) for transitional cell carcinoma (TCC) of the urothelial tract.
Authors: Crabb Simon J. , Sharp Adam , Head Julia , Chau Caroline , Wheater Matthew , Geldart Thomas R. , Mead Graham
Published: March 2020

4549

Background: Serum human chorionic gonadotrophin β subunit (β-HCG) has prognostic value in TCC but has not been investigated in pts receiving Ct for this disease. Furthermore prior studies lacked statistical power to test independence from other prognostic variables. Methods: A single institution retrospective clinical database was constructed of pts receiving Ct between 2005 and 2011 for cancer of the urothelial tract. Eligible pts had pure or a component of TCC. Prognostic variables were tested by univariate Kaplan Meier analyses. Statistically significant variables were then assessed by multivariate cox regression analysis. A prospectively defined β-HCG cut-point of < versus ≥ 2 iu/L, either prior to (β-HCGp), or on completion of (β-HCGc) Ct was used. Results: 235 pts were eligible (72% male, 55% ≤70 years, 83% bladder primary). Initial Ct was perioperative (CtPeri) in 46% (7% adjuvant, 39% neoadjuvant). 63% had first line palliative Ct for metastatic disease (CtMet). For CtPeri, ECOG performance status (PS), haemoglobin (Hb), CtPeri regimen and T stage were statistically significant prognostic factors in univariate analyses for overall survival (OS), as were β-HCGp (median OS (mOS) 8.50 v. 1.86 years, p<0.001) and β-HCGc (mOS 4.27 v. 0.66 years, p=0.003). β-HCGp and β-HCGc after CtPeri were also prognostic for relapse free survival and in multivariable analysis remained statistically significant as a prognostic factor for OS (β-HCGp: hazard ratio (HR) 3.13, p=0.001; β-HCGc: HR 4.26, p=0.007). In pts treated with CtMet, PS, alkaline phosphatase, prior CtPeri, visceral metastases, CtMet regimen and β-HCGc (mOS 1.70 v. 1.07 years, p=0.005) were prognostic in univariate analyses for OS. β-HCGc after CtMet was also prognostic for progression free survival and in multivariable analysis remained statistically significant as a prognostic factor for OS (HR 3.47, p<0.001). Conclusions: β-HCG, and specifically its post-Ct level, is an independent prognostic factor for TCC treated with Ct in both curative and palliative settings. Prospective evaluation is warranted for incorporation into treatment selection strategies.
The impact of clinically significant discrepancies from primary pathological review of transurethral bladder resection specimens upon repeat review at a tertiary care center.
Authors: Barlow Lamont J. , Shapiro Edan , Ahn Jennifer , Benson Mitchell C. , McKiernan James M.
Published: March 2020

4552

Background: Internal review of outside pathology slides is a common practice among urologic oncologists at tertiary care facilities, and discrepancies have a potential to directly affect the choice of treatment. While repeat prostate biopsy review has been extensively studied, there is little data available on the impact of repeat reviews of bladder biopsies. The purpose of the current study is to perform a standardized comparison of original and internal pathology reviews of identical bladder specimens to characterize the impact of repeat review on treatment decisions. Methods: Using the Columbia Urologic Oncology Database, a retrospective analysis of 91 consecutive patients who underwent bladder resections at outside institutions from 2008-2012 with secondary referral to a single urologist and internal review at our institution was conducted. Characteristics of both original pathology reports and internal reviews were collected and compared by blinded reviewers. A discrepancy in one of the following characteristics was considered treatment-altering: presence of muscularis in specimen or tumor involvement in muscularis. Additional clinically-significant discrepancies including presence of secondary histology, carcinoma in situ, lymphovascular invasion, micropapillary features, tumor stage, and overall accumulative discrepancy rate were also analyzed. Results: Median time from original procedure to internal review was 34 days (range: 9-368). 56/91 (62%) patients had at least one of the predefined clinically-significant discrepancies. 27/91 (30%) patients had at least one treatment-altering discrepancy, including 25 with discrepant muscle in specimen and 11 with discrepant muscle invasion. Regarding tumor stage, 8 patients were upstaged, 71 were unchanged, and 12 were downstaged on internal review. Conclusions: Repeat pathologic review of primary bladder specimens at a tertiary care center has the potential to alter clinical care for the majority of patients. Further studies are needed to determine if these discrepancies and the decisions they influence have a significant impact on patient outcomes.
A retrospective analysis of patients with poor-risk germ cell tumor (PRGCT) treated at Indiana University from 2000 to 2010.
Authors: Adra Nabil , Albany Costantine , Sonnenburg Daniel , Tong Yan , Hanna Nasser H. , Einhorn Lawrence H.
Published: March 2020

4557

Background: PRGCT represents 14% of germ cell tumors, with 2-year PFS of 50%. PRGCT is defined by primary mediastinal non-seminomatous germ cell tumor (PMNSGCT), non-pulmonary visceral metastasis (NPVM), AFP > 10,000 or hCG > 50,000. This analysis attempts to identify subsets of patients with more or less favorable outcomes among the poor risk groups. Methods: Retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) from 2000-2010. 291 patients with PRGCT identified of whom 79 received initial therapy at IU. We analyzed the following variables: primary site testis/retroperitoneal (T/RP) vs. PMNSGCT, pulmonary vs. NPVM, and the amplitude of serum tumor markers. We identified groups of patients according to the level of tumor marker elevation with cutoff points of AFP 20,000 and hCG 200,000. Results: Mean age 29, mean AFP 8,283, mean hCG 185,667. 24% had PMNSGCT, 48% NPVM, 11% AFP>20,000, and 25% hCG>200,000. When hCG was analyzed as a continuous variable, every 10,000 unit increase in hCG caused the hazard of progression to increase by 1% (p value 0.01). Patients with NPVM had significantly worse PFS. NPVM with elevated hCG had worse outcome than NPVM with normal hCG. This did not correlate as well with AFP. PFS was worse with NPVM than elevated pre-chemotherapy tumor markers. Multiple different criteria for poor risk disease carried significantly worse impact on PFS and OS when compared to having a single criterion for poor risk disease. Conclusions: Our data indicate that patients with NPVM or more than one criteria for PRGCT have a worse outcome compared to other PRGCT subgroups. [Table: see text]
Two cycles of carboplatin as adjuvant therapy in stage I seminoma: 8-year experience by the Hellenic Co-operative Oncology Group (HECOG).
Authors: Koutsoukos Konstantinos , Liontos Michael , Lykka Maria , Rigakos Georgios , Andreadou Anna , Efstathiou Eleni , Koutras Angelos , Papatsoris Athanasios , Chrisofos Michael , Stravodimos Kostas , Adamakis Ioanis , Alamanis Christos , Karavasilis Vasilios , Makatsoris Thomas , Galani Eleni P. , Klouvas George , Kosmidis Paris A. , Fountzilas George , Dimopoulos Meletios A. , Bamias Aristotelis
Published: March 2020

4558

Background: Adjuvant chemotherapy is used in stage I testicular seminoma. We have reported a risk-adapted strategy of 2 cycles of cisplatin/etoposide (EP) in 64 patients with age < 34 and/or tumor diameter > 4cm) (Bamias et al, Urology 2007), resulting in no relapses over a median follow up of 5 years. Following the establishment of adjuvant carboplatin as a standard, we adopted this treatment for all patients with stage I seminoma. We report our 8-year experience and compare these results with our previous EP strategy. Methods: Patients with stage I seminoma, treated with 2 cycles of carboplatin AUC 6 and a minimum follow up of 1 year after chemotherapy were selected. All patients consented for the use of their medical information and the analysis was approved by the centers involved. Survival functions were presented using Kaplan-Meier curves. The log-rank test was used to test for survival differences across different categories. Results: 137 patients (Median age: 34; Age<34: 49%, tumor diameter>4cm: 42%; rete testis invasion: 24%), treated between 11/2003-12/2011 were selected. During a median follow up of 4 years, there were 5 relapses (5-y relapse rate [RR]: 97% [SE: 2%]): retroperitoneal lymph nodes (n=4) and isolated brain (n=1). All patients with relapse had tumor diameter > 4cm and/or age < 34. No relapse was associated with rete testis invasion. Patients with at least 1 of the above risk factors (n=94) had a significantly higher relapse rate compared with a similar population (n=64) treated with 2 cycles of adjuvant EP: 5-y RR was 95% (SE: 2%) vs.100% (SE 0%), (p=0.033). All relapsed patients were treated with BEP chemotherapy and are currently alive with no evidence of relapse. Neutropenia and nausea/vomiting were less frequent with carboplatin than with EP (11% vs. 36% and 15% vs. 65%). Conclusions: Our analysis confirms the association of age and tumor diameter with relapse in stage I seminoma treated with adjuvant carboplatin. Although adjuvant carboplatin in patients with age<34 and/or tumor diameter> 4 cm is associated with higher RR than EP, the prognosis of these patients is excellent with salvage chemotherapy and, therefore, the use of less toxic treatment is justified.
Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer (mRCC) patients (pts).
Authors: Kim Jenny J. , Labots Mariette , Marchionni Luigi , Begum Shahnaz , Meijer Gerrit A. , Verheul Henk M.W. , Carducci Michael Anthony , Hammers Hans J. , Allaf Mohammad , Netto George J. , Hoque Mohammad
Published: March 2020

4566

Background: There exists a significant heterogeneity in the clinical response to sunitinib among pts treated for mRCC and, thus, a biomarker which would predict pts’ response up front would be an invaluable tool in the clinical management of these pts. In this regard, whole genome methylation array was performed between 2 extreme groups: sunitinib responders (RES) and non-responders (NRES) to identify differentially methylated genes between these subsets of pts. Methods: mRCC pts who received sunitinib therapy with available frozen nephrectomy tissues (stored at -80°C) and clinical data were identified. RES were identified as pts with progression free survival (PFS) of > or =11 months (mos) and NRES as those with PFS < or = 3 mos. After DNA extraction and quality assurance according to standard protocol, whole genome methylation array was performed using Infinium Humanmethylation450 BeadChip Kit - Illumina. Data normalization was achieved by subset-quantile within array normalization (PMID: 22703947). Differentially methylated regions were identified using logit transformed Beta values, using an F-test after shrinking variance via empirical Bayes (PMID: 21118553). Results: Total of 13 pts who received sunitinib therapy with available frozen nephrectomy tissues were identified. Of the 13, 5 pts qualified for each RES and NRES cohort as described in methods section. All pts in RES group had clear cell subtype. Two pts of the NRES group were of non-clear cell subtype. The QC plots showed that all arrays were successful. For RES vs. NRES, one genomic location, DENND2D, was significantly hypermethylated in the RES group with a false discovery rate (FDR) of <10%. DENND2D has been identified as a tumor suppressor-like gene in non-small cell lung cancer and melanoma cell lines in the recent past. Conclusions: In this study, DENND2D was significantly hypermethylated in sunitinib RES compared to NRES among mRCC pts. Data analysis with a less stringent FDR is also being pursued. Technical validation as well as clinical validation of DENND2D utilizing a larger pt cohort are ongoing.
Prognostic significance of bone metastases (BM) and bisphosphonate (BIS) therapy in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs).
Authors: McKay Rana R. , Lin Xun , Perkins Julia Jane , Simantov Ronit , Choueiri Toni K.
Published: March 2020

4572

Background: BM are frequently present in patients with mRCC. BM cause significant morbidity and are associated with high rates of skeletal related events (SREs). The purpose of this retrospective analysis was to assess the impact of BM and BIS use on outcomes including progression-free survival (PFS) and overall survival (OS) in patients with mRCC. Methods: We conducted a pooled analysis of patients with mRCC treated from 2003-2011 on phase III (NCT00083899, NCT00065468, NCT00678392) and phase II trials (NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423). Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: We identified 2,749 patients treated with sunitinib (n=1,059), sorafenib (n=335), axitinib (n=359), temsirolimus (TEM) (n=208), TEM + interferon-alfa (IFN) (n=208), or IFN (n=560). Most patients were male (71%), had baseline ECOG PS of 0 (47%) or 1 (51%), clear cell histology (91%), and prior nephrectomy (84%). 285 patients (10.4%) received treatment with BIS (zoledronic acid n=233, pamidronate n=57, unspecified n=1). No patients received denosumab. Of the 2,504 patients with data regarding site of metastasis at diagnosis, 31.9% (n=781) had BM. The rate of SREs in patients with BM compared to patients without BM was 6.4% versus 1.4% (p<0.0001). Presence of BM was associated with shorter PFS (5.1 vs. 6.7 months (mo), HR 1.195, 95% CI 1.076-1.328, p<0.0008) and OS (13.2 vs. 20.2 mo, HR 1.292, 95% CI 1.145-1.456, p<0.0001) when compared to those without BM. In patients with BM, the use of BIS was not associated with improved PFS (5.1 vs. 4.9 mo, HR 0.867, 95% CI 0.704-1.067, p=0.1785) or OS (13.3 vs. 13.1 mo, HR 0.904, 95% CI 0.722-1.132, p=0.3801) when compared to patients who did not receive BIS. In patients with BM stratified by type of first-line MTA (TKI, mTOR inhibitor, or IFN-based), use of BIS was not associated with improved PFS or OS. Conclusions: In this analysis, we confirm that the presence of BM is an adverse risk factor for shorter PFS and OS in patients with mRCC treated with MTAs. Treatment with BIS did not have a positive impact on survival in this cohort.
Association analysis of polymorphisms in genes related to sunitinib pharmacokinetics.
Authors: Diekstra Meta , Klümpen Heinz Josef , Lolkema Martijn P. J. K. , Yu Huixin , Kloth Jacqueline S.L. , Gelderblom Hans , van Schaik Ron H.N. , Gurney Howard , Swen Jesse J , Huitema Alwin D.R. , Steeghs Neeltje , Mathijssen Ron H.J.
Published: March 2020

4580

Background: Sunitinib is approved as systemic therapy for mRCC, GIST and pNET. Interpatient variability in the pharmacokinetics (PK) of sunitinib is high, which may have serious consequences for efficacy and toxicity of the drug. The objective of this study was to evaluate whether polymorphisms in candidate genes involved in sunitinib metabolism are related to the PK of sunitinib and its active metabolite SU12662. Methods: In this multicenter study, steady state sunitinib plasma concentrations and genotypes were prospectively obtained from 115 patients. Single nucleotide polymorphisms (SNPs) and haplotypes in 8 genes encoding CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3, and PORwere evaluated as covariates in a population pharmacokinetic model describing both sunitinib and SU12662 PK using NONMEM. First, candidate genotypes/haplotypes were individually tested for a potential association with sunitinib or SU12662 clearance. Next, potential significant SNPs (p<0.05) were simultaneously included in a multivariate model and tested by backward elimination with a significance threshold of p<0.0005. Results: Four out of 37 screened genotypes (from 14 different SNPs) were related to sunitinib clearance (CYP3A4*22 CC and CT, CYP3A5*3 GG, and ABCB1 (2677 TT)). CYP3A5*3 AG genotype was associated with clearance of SU12662. In the multivariate analysis, none of the SNPs reached the predefined significance threshold of p<0.0005. Nevertheless, CYP3A4*22T allele carriers showed a 22.5% decreased clearance of sunitinib (p<0.01). Conclusions: Our data suggest that individual SNPs or haplotypes in CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3 and POR are not clearly associated with sunitinib or SU12662 clearance. Several (environmental) factors may also influence the PK of sunitinib. Interestingly, the recently identified CYP3A4*22 SNP potentially has an impact on drug exposure. Replication studies in larger groups of patients are needed to verify the role of CYP3A4*22 for sunitinib clearance.
Contrasting vascular response to sunitinib as measured by DCE-CT, DCE-MRI, and DCE-US in renal cell carcinoma (RCC) patients (pts).
Authors: Hudson John M. , Williams Ross , Milot Laurent M. , Bailey Colleen , Kiss Alex , Atri Mostafa , Stanisz Greg J. , Burns Peter N. , Bjarnason Georg A.
Published: March 2020

4583

Background: Imaging (DCE-MRI, DCE-CT, DCE-US) provides information about the integrity and hemodynamics of the tumor microvasculature. Methods: 34 treatment (Rx) naive pts with RCC and abdominal tumor suitable for imaging received sunitinib 50 mg on a standard 4/2 schedule. DCE-US, DCE-CT, and DCE-MRI were done at baseline, during the first course and after 2wks off Rx. Imaging parameters included vessel permeability (Ktrans), extracellular volume fraction (ve) and Ktrans/ve=Kep (by DCE-MRI), permeability surface product (PS) by DCE-CT, blood volume (BV), by DCE-CT and DCE-US and blood perfusion (by DCE-US). A morphology parameter (MP) was developed that relates flow kinetics of the microbubble contrast agent to tumor vascular morphology by DCE-US. Results: Several imaging parameters predicted for progression free survival (PFS) in responding pts (N=26). Baseline imaging parameters correlated with PFS: Ktrans by DCE-MR (Spearman r= 0.53, p=0.01, N=24), BV by DCE-CT (r=0.48, p=0.02, N=25) and disorganized vessel morphology (large MP) by DCE-US (r= - 0.45, p=0.02, N=24). Changes from baseline imaging parameters correlated with PFS: BV by DCE-US at 2 wks (r= -0.46, p=0.02, N=24), Kep by DCE-MR at 2 wks (r= -0.45, p=0.03, N=24) and MP at 1wk (r=0.67, p=0.02, N=12). There was a correlation between imaging methods: BV measured by DCE-CT correlated with BV by DCE-US (r=0.46, p=0.03, N=23) and Kep by DCE-MR (r=0.59, p=0.003, N=22); Permeability measured by DCE-MR (Ktrans) and DCE-CT (PS) correlated at 2wks (r=0.56, p=0.01, N=21). A combination of baseline US and MR parameters identified responders and non-responders with a sensitivity of 83% and specificity of 90%. Conclusions: This is the first study to contrast DCE-US, DCE-CT and DCE-MRI imaging in pts receiving antiangiogenic therapy. Baseline parameters for all three methods can predict for PFS. Changes from baseline in DCE-US and DCE-MRI parameters also predict for PFS. There is a correlation between imaging methods in parameters that measure BV and permeability. A novel DCE-US parameter was developed (MP) that quantifies the degree of tumor vascular disorganization. Baseline values in MP and changes during Rx correlate with PFS. Clinical trial information: OCT1205.
ERG rearrangements and association with clinical outcome in patients (pts) receiving abiraterone acetate (AA): Results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC).
Authors: Attard Gerhardt , De Bono Johann Sebastian , Li Weimin , Molina Arturo , Griffin Thomas W. , Kheoh Thian San , Ricci Deborah Sokol , Zelinsky Kathy , Rathkopf Dana E. , Scher Howard I. , Ryan Charles J.
Published: March 2020

5004

Background: ERG rearrangements result in androgen receptor-modulated up-regulation of ERG and may predict for AA response in mCRPC. Concordance has been shown between ERG status in archival samples and fresh CRPC biopsies (Attard et al., Cancer Res. 2009;69:2912). In this prospectively defined biomarker sub-study, the association between ERG subtypes and clinical outcome in chemo-naïve mCRPC pts receiving AA was evaluated. Methods: COU-AA-302 is a randomized double blind study of AA (1 g) + prednisone (P) (5 mg BID) vs placebo + P in chemo-naïve mCRPC. Fluorescence in situ hybridization (FISH) assays to evaluate ERG subtypes (Attard et al., Oncogene. 2008;27:253) were conducted on 524 archival prostate tissue samples (365 biopsies, 107 RPEs, 44 TURPs, 3 bone marrows, 5 lymph nodes) from 497 pts. Clinical outcome measures included radiographic progression-free survival (rPFS) (central [CEN] and investigator [INV] reviewed), time to PSA progression (TTPP), and PSA ≥ 50% decline. Cox regression was used to evaluate association with time to event endpoints and Cochran-Mantel-Haenszel for PSA response. Results: 337 of 497 pts with tumor samples had evaluable FISH results. An ERG rearrangement was present in 117 of 337 (35%) pts. 112 pts were class Edel, 50 were 2+Edel (interstitial deletion with duplication of fusion sequences) and 18 were ESplit. A trend for an association with greater improved rPFS (CEN) and TTPP in 2+ Edel pts treated with AA + P vs ERG non-rearranged was observed (22 months [m] vs 16 m [HR: 0.59, 95% CI: 0.30-1.16], p = 0.12, and 14 m vs 8 m [HR: 0.68; 95% CI: 0.41-1.15], p = 0.15, respectively). No differences in 2+ Edel vs ERG non-rearranged were observed in the P-alone arm. No association between any ERG sub-class and either rPFS [INV] or PSA ≥ 50% decline in either treatment arm was observed. Conclusions: This represents the largest study to date to molecularly characterize CRPC pts participating in a therapeutic phase 3 trial. These data suggest that chemo-naïve mCRPC pts with a 2+ Edel rearrangement may derive a slightly greater benefit from AA and P than other pts. Clinical trial information: NCT00887198.
Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy (COU-AA-302).
Authors: Rathkopf Dana E. , Smith Matthew R. , De Bono Johann Sebastian , Logothetis Christopher , Shore Neal , De Souza Paul L. , Fizazi Karim , Mulders Peter , Mainwaring Paul N. , Hainsworth John D , Beer Tomasz M. , North Scott A. , Fradet Yves , Griffin Thomas W. , Park Youn Choi , Kheoh Thian San , Small Eric Jay , Scher Howard I. , Molina Arturo , Ryan Charles J.
Published: March 2020

5009

Background: AA, a CYP17 inhibitor, prolongs the lives of men with progressive pre- or post-chemotherapy treated mCRPC with a favorable safety profile (Rathkopf et al. ASCO-GU 2013. Abstr 5). This post hoc analysis examines the safety and tolerability of long-term treatment (≥ 24 mos) in study COU-AA-302. Methods: 1,088 pts were randomized 1:1 to AA 1000 mg + P 5 mg po BID vs placebo + P. Co-primary endpoints were radiographic progression-free survival (rPFS) and OS. Median times with 95% CI of the end points were estimated using the Kaplan-Meier (KM) method. Post hoc analysis of adverse events (AEs) was performed at pre-specified interim analysis (IA3) (55% OS events). Results: At a median follow-up = 27.1 mos (IA3): rPFS HR (95% CI) = 0.53 (0.45, 0.62), p < 0.0001 and OS was improved over P [0.79 (0.66, 0.96), p = 0.0151]; the latter did not reach the pre-specified efficacy boundary (p = 0.0035). All secondary endpoints favored the AA arm (Rathkopf et al. ASCO-GU 2013. Abstr 5). The incidence rate of selected AEs by duration of exposure is shown below (Table). There was no clinically relevant increase in the incidence rate of AEs with longer exposure using AA + P versus P alone; although pts on treatment for ≥ 24 mos may have had greater tolerability. The percentage of patients who came off study due to an AE was 8% (AA) versus 6% (P). Conclusions: The updated IA3 of COU-AA-302 in pts without prior chemotherapy confirms the delay in progression and prolongation of life with a favorable safety profile including pts treated for ≥ 24 mos with AA + P or P. Clinical trial information: NCT00887198. [Table: see text]
Relationship of baseline PSA and degree of PSA decline to radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.
Authors: Ryan Charles J. , Londhe Anil , Molina Arturo , Smith Matthew R. , De Bono Johann Sebastian , Mulders Peter , Rathkopf Dana E. , Saad Fred , Logothetis Christopher , Fizazi Karim , Scher Howard I. , Small Eric Jay , Matheny Shannon , Kheoh Thian San , Griffin Thomas W.
Published: March 2020

5010

Background: Abiraterone acetate (AA), an androgen biosynthesis inhibitor, prolongs overall survival (OS) in mCRPC patients and is approved for use in this population. The relationship of PSA kinetics to rPFS was evaluated in an exploratory analysis of patients from COU-AA-302, a randomized phase III study of AA in chemotherapy-naive mCRPC patients. Methods: 1,088 patients were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or P alone. rPFS and OS were co-primary endpoints. rPFS was defined as time to first occurrence of bone scan progression by PCWG2 criteria, progression by CT/MRI by modified RECIST 1.0 criteria, or death from any cause; PSA changes were not a factor in determining rPFS. Quartiles of baseline PSA and % PSA decrease from baseline to nadir were analyzed. Stratified Cox regression models were used with factors for treatment, PSA outcomes, and baseline covariates performed at 55% of OS events. Results: 54/546 patients (10%) in AA + P arm achieved undetectable PSA vs 14/542 patients (3%) in the P arm; at median follow-up of 27.1 mos, radiographic progression was observed in 28% (AA + P) vs 50% of patients (P). There was a consistent trend of decreasing hazard of progression with decreasing baseline PSA and increasing % PSA decline (Table). Treatment effect of AA + P vs P with decreasing baseline PSA or % PSA decline remained significant (p=0.001) after adjusting for other factors (PSA, LDH, alk phos, hemoglobin, bone metastasis) in the model. Conclusions: rPFS was positively associated with the magnitude of PSA decline and inversely associated with baseline PSA. These effects remained after correcting for covariates. In all analyses, treatment with AA led to rPFS outcomes superior to P. Clinical trial information: NCT00887198. [Table: see text]
A prognostic model for predicting overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) after docetaxel.
Authors: Chi Kim N. , Kheoh Thian San , Ryan Charles J. , Molina Arturo , Bellmunt Joaquim , Vogelzang Nicholas J. , Rathkopf Dana E. , Fizazi Karim , Kantoff Philip W. , Li Jinhui , De Bono Johann Sebastian , Scher Howard I.
Published: March 2020

5013

Background: COU-AA-301 was a multinational, randomized, controlled, phase III trial comparing AA + prednisone (P) (n = 797) versus placebo + P (n = 398) in mCRPC pts post-docetaxel. Using data from that trial, we developed a prognostic model for predicting OS in pts treated with AA post-chemotherapy, with a focus on readily assessable clinical parameters. Methods: The analyses used data from pts treated with AA in the COU-AA-301 trial for whom relevant baseline data were available (n = 729). Baseline variables were assessed for association with OS through a univariate Cox proportional hazards regression model. High/low values for accepted normal ranges were used for laboratory parameters. The Cox proportional hazards regression was used with a stepwise procedure to identify independent prognostic factors for OS. The model was subject to sensitivity analyses and the C-index was utilized as a measure of model accuracy. Results: The following risk factors were associated with a poor prognosis: ECOG performance status (only pts with scores of ≤ 2 were eligible for this trial) of 2 (HR = 2.19, p < 0.0001), presence of liver metastases (HR = 2.00, p < 0.0001), time from start of initial LHRH agonist therapy to start of AA treatment ≤ 36 months (HR = 1.30, p = 0.0078), low albumin (HR = 1.54, p < 0.0001), high ALP (HR = 1.38, p = 0.0016), and high LDH (HR = 2.31, p < 0.0001). Patients were categorized into 3 risk groups (good prognosis, n = 369; intermediate prognosis, n = 321; poor prognosis, n = 107) based on total number of risk factors and median OS calculated for each group (table). The C-index was 0.74 (95% CI: 0.68, 0.80). Conclusions: This prognostic model uses readily available clinical parameters to conveniently assess risk for mCRPC pts previously treated with docetaxel and initiating treatment with AA + P. If validated, the model will be useful in clinical practice and clinical trials. Clinical trial information: NCT00638690. [Table: see text]