bluuebunny/crossref_metadata_2025 huggingface dataset:
Branched evolution and intratumor heterogeneity of urothelial carcinoma of the bladder.
Authors: Cha Eugene K. , Sfakianos John P. , Al-Ahmadie Hikmat , Scott Sasinya N. , Kim Philip H. , Iyer Gopa , Bajorin Dean F. , Rosenberg Jonathan E. , Berger Michael F. , Bochner Bernard H. , Solit David B.
Published: February 2017

293

Background: Genomic characterization of urothelial carcinoma of the bladder (UCB) has begun to reveal significant intertumor heterogeneity when comparing samples from different subjects. As in other malignancies, intratumor heterogeneity, which may allow for tumor evolution and adaption, poses a significant challenge to personalized-medicine strategies. Methods: To examine UCB tumor evolution and heterogeneity, we performed next-generation targeted sequencing on multiple temporally and spatially separated bladder tumors obtained at time of transurethral resection (TUR) and radical cystectomy (RC). Specimens were analyzed using a next-generation, targeted sequencing assay designed to identify point mutations, indels, and copy number alterations in 300 cancer-associated genes. Results: Phylogenetic reconstruction revealed evidence of branched evolutionary growth. Evaluation of multiple tumors from individual subjects identified both shared and unique potential driver mutations. Evidence of convergent phenotypic evolution was detected through analysis of multiple distinct tumors from several subjects. For example, three separate tumors in one subject shared a common PIK3CA mutation (E453K) and had unique second mutations in PIK3CA (E542V, E545K, and E545Q, respectively). In another subject, distinct inactivating mutations of EP300 were identified in two temporally separated tumor samples. Macrodissection of single tumors into non-invasive and invasive components revealed significant intratumor heterogeneity; one case illustrates how analysis of a muscle-invasive TUR specimen could result in undersampling and thereby miss the tumor clone that persisted at time of RC. Conclusions: We demonstrate branched evolution of UCB through genomic analyses of multiple temporally and spatially distinct bladder tumors from individual subjects. Macrodissection of individual tumor samples identified significant intratumor heterogeneity. These concepts may present major challenges to personalized-medicine approaches that rely on sampling of a single tumor at a specific timepoint in the evolution of a patient’s UCB.
Phase II trial of pazopanib and weekly paclitaxel in metastatic urothelial cancer (UC).
Authors: Srinivas Sandy , Narayanan Sujata , Harshman Lauren Christine , Lam Anthony P. , Vaishampayan Ulka N. , Haas Denise , Poushnejad Shermeen , Pachynski Russell
Published: February 2017

299

Background: Currently, there are no standard treatments for relapsed or refractory urothelial carcinoma (UC). Discouraging results have been achieved in trials evaluating drugs as single agents or in combination regimens. Paclitaxel has activity when used alone and in combination in urothelial cancer, and pazopanib is active in solid tumors secondary to its potent anti-angiogenic effect. We report the results of an ongoing multicenter phase II study evaluating the combination of paclitaxel with pazopanib in refractory UC. Methods: Patients (pts) eligible for the study have histologically confirmed UC, with relapse after receiving up to 2 chemotherapeutic regimens. Pazopanib (800 mg) is administered daily, with weekly paclitaxel (80mg/m2) for 3 weeks in a 28 day cycle. Treatment is continued until disease progression or unacceptable toxicity. Primary endpoint of the study is the response-rate (RR) based on RECIST criteria. Secondary endpoints include safety, and progression free-survival (PFS). For designing the study, Simon’s two-stage method was applied, and 9 pts were recruited in the first stage. After having ≥1 response in the first group, a full enrollment of 32 pts has been initiated. Results: 25 pts were enrolled from April 2010 to September 2013. Their median age was 67 years (47-89), with a median ECOG performance status of 1 (0-2). 10 pts (40%) had UC of the upper urinary tract and 15 had primary bladder/ureter tumors. All pts had multiple metastatic sites, including 11 (44%) with liver metastases. Median number of prior cytotoxic regimens was 2, and 50% were considered cisplatin responsive. Based on RECIST (v1.1) criteria,13 pts (52%) had partial response (PR), 5 (20%) had stable disease (SD), and 2 (8%) had complete response (CR) (80% clinical benefit). The side effects included grade 3 hypertension (n=2), grade 3 fatigue (n=4), grade 3 thrombosis (n=2) and grade 4 neutropenia (n=2). 14 pts required growth factor support. Conclusions: Our phase II study combining paclitaxel and pazopanib demonstratedsignificant anti-tumor activity of combining paclitaxel in relapsed/refractory UC. This combination is safe, and is worthy of evaluation in larger studies. Clinical trial information: 1108055.
Racial disparities in the morbidity of radical cystectomy in the United States.
Authors: Borza Tudor , Feng Chen Chen , Leow Jeffrey , Chung Benjamin I. , Chang Steven L.
Published: February 2017

304

Background: Racial disparities in the management of bladder cancer have been previously reported. However, limited data exists on inequalities in the morbidity of radical cystectomy. We performed a contemporary population-based analysis to examine the association between race and surgical complications among patients undergoing radical cystectomy. Methods: We analyzed the Prospective Rx Comparative Database (Premier, Inc., Charlotte, NC), which collects data from over 600 non-federal hospitals throughout the US. We identified patients who underwent radical cystectomy between 2003 and 2010 based on ICD-9 code (57.71). Primary outcome measure was 90-day major complication rates, defined as Clavien Classification System Grade 3-5, derived from ICD-9 codes. Multivariable logistic regression models were developed adjusting for clustering by hospitals and survey weighting to ensure nationally representative estimates to evaluate 90-day major complication for all patients (Model 1), patients ≥65 years (Model 2), and Medicare only patients (Model 3). Results: Our study cohort included 50,175 patients. The majority of patients were Caucasion (76%), men (83.5%), with Medicare (64.2%). Major complication rates were 16% for Caucasions, 17% for African American, 24% for Hispanics, and 16% for Other. Compared to Caucasians, the odds ratio (OR) of major complications for Hispanics was 1.9 (p=0.03) and 2.6 (p<0.0001) in Models 1 and 2, and 1.7 (p=0.1) for Model 3. None of the other racial groups had significantly different odds of major complications compared with Caucasians. Conclusions: In the United States, Hispanic patients are the least likely to undergo radical cystectomy but have the highest rate of major complication following surgery. Our analysis shows that this disparity is uniquely absent among Hispanic patients with Medicare suggesting that barriers to healthcare may underlie the observed phenomenon. Therefore, the worse outcomes for Hispanic patients with bladder cancer may be secondary to challenges in accessing medical treatment at earlier stages of disease arising from language differences and non-U.S. citizenship status.
Influence of age on incident diabetes (DM) and cardiovascular disease (CVD) among prostate cancer survivors receiving androgen deprivation therapy (ADT).
Authors: Morgans Alicia Katherine , Fan Kang-Hsien , Koyama Tatsuki , Albertsen Peter C. , Goodman Michael , Hamilton Ann S. , Hoffman Richard M. , Stanford Janet L. , Stroup Antoinette M. , Resnick Matthew , Barocas Daniel Ari , Derleth Christina Louise , Penson David F.
Published: February 2017

31

Background: Androgen deprivation therapy (ADT) has been associated with an increased risk of developing diabetes (DM) and cardiovascular disease (CVD), though this is controversial, particularly for CVD. We prospectively assessed the relationship between ADT and incident DM and CVD in the Prostate Cancer Outcomes Study (PCOS), a population-based cohort of prostate cancer survivors followed longitudinally for 15 years from diagnosis. Methods: We identified men in the PCOS with non-metastatic prostate cancer diagnosed from 1994 to 1995 and followed through 2009 to 2010. We used multivariable logistic regression models to compare groups receiving short-term ADT (less than 2 years), prolonged ADT (2 years or more) and no ADT to assess the relationship between ADT exposure and subsequent diagnoses of DM and CVD (determined by patient report and cause of death data). We evaluated the effects of age at diagnosis, race, stage, and comorbidity on the development of DM and CVD. Results: Among 3,526 men with comorbidity and treatment data, 2,985 men without baseline DM and 3,112 men without baseline CVD constituted the DM and CVD cohorts, respectively. Regardless of duration of ADT exposure, there was not an increased risk of DM or CVD in men younger than 70 at diagnosis. Compared to no ADT exposure, prolonged ADT was associated with an increased risk of DM and CVD that increased steadily over age 76 at diagnosis for DM (OR 2.11 at age 74, 95% CI 1.02 – 4.36; OR 2.65 at age 80, 95% CI 1.09 – 6.47) and age 74 at diagnosis for CVD (OR 1.89 at age 74, 95% CI 1.02 - 3.49; OR 3.19 at age 80, 95% 1.25 – 8.17). Increasing comorbidity burden modified risk of DM and CVD (for 3 or more comorbidities vs. no comorbidities; for DM, OR 4.25, 95% CI 2.3 - 7.9; and for CVD, OR 8.1, 95% CI 4.3 -15.5 P<0.001). Conclusions: The relationship between ADT and development of CVD and DM may be dependent upon age at diagnosis in addition to length of ADT administration, with longer ADT exposure predominantly increasing risk among older men only. Men with greater comorbid burden had increased risk of developing DM and CVD. Closer monitoring for development of DM and CVD may be most important among older men receiving prolonged ADT, especially those with other comorbidities.
Decreasing length of hospital stay following radical cystectomy using multimodal enhanced recovery protocol.
Authors: Djaladat Hooman , Ahmadi Hamed , Schuckman Anne , Daneshmand Siamak
Published: February 2017

313

Background: To evaluate a peri-operative protocol to expedite recovery and decrease length of stay (LOS) without increasing readmission and complication rates after cystectomy for bladder cancer. Methods: From 5/2012 to 8/2013, a peri-operative protocol used in 126 unselected consecutive patients who underwent open cystectomy for bladder cancer with prospective follow-up. The enhanced recovery after surgery (ERAS) protocol focused on avoiding bowel prep and NGT, early feeding, minimizing narcotics and use of a μ-opioid antagonist. Exclusion was any adjunct surgery (10), previous diversion (2) and prolonged intubation (4). Time to bowel movement (BM) and regular diet, LOS, 30-day readmission and complication rates were captured. The outcomes of interest were compared to a historical cohort. Results: A total of 110 (84 male) patients were included. Median age was 69 y/o (range, 31-90). 40 (36%) patients were ≥ 75 y/o and 75 (68%) patients underwent continent diversion. 90 (82%) patients had BM and 87 (79%) were advanced to regular diet by postop day (POD) 2. Median LOS was 4 days and 63/110 (57%) discharged at or before POD 4. Five patients needed NGT due to ileus. Most common 30-day complications were anemia requiring transfusion (19%), UTI (13%) and dehydration (9%), with the latter two also being the most common etiologies for readmission. Major complications (≥ Clavian grade III) were seen in 15 (13%) patients and were significantly higher in patients ≥75 y/o than younger (22% vs. 8%; P=0.05). There was no difference in other measured outcomes with respect to age (≥75 vs. <75 y/o) and type of diversion (continent vs. incontinent). Conclusions: Our current ERAS protocol resulted in significant reduction in time to BM and LOS without increasing early readmission and complication rates. [Table: see text]
The high incidence of vascular thromboembolic events (VTE) in advanced urothelial cancer (UC) patients (pts) treated with carboplatin (Cb): Analysis of treatment with gemcitabine (G)/cb (GCb), gcb/bevacizumab (GCbBev), or gemcitabine/cisplatin (GCis).
Authors: Tully Christopher Michael , Apolo Andrea Borghese , Zabor Emily C. , Regazzi Ashley Marie , Ostrovnaya Irina , Rosenberg Jonathan E. , Bajorin Dean F.
Published: February 2017

316

Background: VTE occur in ~13% of pts receiving Cis-based therapy for UC. Cb-based therapy is considered less thrombogenic but no definitive data exist to support this conclusion. While Bev added to chemotherapy (Ch) increases VTE in other tumors, VTE impact when added to UC Ch is unknown. This study evaluated the incidence of and etiologic factors for VTE in UC pts treated with GCb, GCbBev and GCis. Methods: UC pts treated from 6/2006 to 6/2010 on a GCbBev protocol were analyzed prospectively. Planned therapy was 6 cycles of GCbBev then Bev alone; pts who had ≥ 3 cycles were included. Similar UC pts treated with GCb or GCis during the same time were retrospectively evaluated. Type of VTE and potential contributing clinical factors were collected. VTE was defined as pulmonary embolism, vascular thrombosis, myocardial infarction or cerebral vascular accident. Associations with Ch regimen were tested using Fisher’s exact test or linear regression. Factors associated with VTE were analyzed using conditional logistic regression stratified by Ch regimen. Results: 198 pts were analyzed. VTE occurred in 13/51 (26%) GCbBev pts, 22/92 (24%) GCb pts, and 8/55 (15%) GCis pts. Age (≤65 vs >65; p<0.001), having had a prior cystectomy (p<0.001), mass near pelvic vessels (p=0.027), Khorana risk group (p=0.025) and anti-platelet therapy (p=0.036) were significantly associated with the Ch regimen reflecting cohort-specific differences. Type of Ch was not associated with any VTE (p=0.3) or type of VTE (arterial vs venous) (p=0.11). Having had a prior cystectomy was associated with increased risk of VTE (OR 2.2, 95% CI 1.0-5.0, p=0.047). Conclusions: This is the largest series reporting VTE in Cb-treated UC pts; the VTE rate of 24% (95% CI 17, 32%) is higher than expected. Bev does not appear to increase this risk. VTE in Cis-treated pts (15%) was similar to prior reports. The finding that pts with advanced UC are at high risk of VTE regardless of the specific platinum agent warrants further study of Cb therapy-related risk and analysis for contributing factors including prior pelvic surgery.
Biologic activity of dasatinib administered as neoadjuvant therapy preceding radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC).
Authors: Knudsen Beatrice , Hahn Noah M. , Daneshmand Siamak , Posadas Edwin M. , Muhanty Sambit , Lerner Seth P. , Sonpavde Guru
Published: February 2017

324

Background: Dasatinib (D) is an oral tyrosine kinase inhibitor of Src mediated signaling, and has demonstrated promising preclinical anti-tumor activity in bladder cancer with activated Src (Sonpavde G, Mol Cancer Ther, 2010). We previously reported the feasibilty of neoadjuvant D before RC for MIBC in a phase II trial (Hahn NM, ASCO, 2012). Here, we report correlative tumor tissue studies. Methods: A phase II trial (N=25) was conducted to assess the safety and biologic activity of neoadjuvant D in cT2-T4a, N0, M0 bladder cancer patients (pts) unsuitable for or willing to forego platinum-based neoadjuvant therapy. Patients received D 100 mg po once daily for 28 +/- 7 days followed by RC 8-24 hours after the last dose. Correlative studies evaluated tissues from baseline biopsy and RC for expression of phosphorylated (p) SRC family kinases (SFK) by immunohistochemistry (IHC). pSFK expression was scored on a scale from 0 - 3 by 2 pathologists. Results: The study completed accrual with enrollment of 25 patients. Both baseline and RC tumor were available and adequate for correlative studies in 14 cases. In 5 additional cases, carcinoma was available for baseline or RC tumor only. All pre- and post-treatment tissue samples demonstrated positive staining by IHC in inflammatory cells, which were used as the internal positive control. In all cases, the cancer cells were positive before treatment and the staining decreased after treatment. In 6 cases there was no detectable staining after treatment. In 9 cases (66%), pSFK levels decreased by 2 units from 2.5-3 pre-treatment to 0.5-1 post-treatment. In 5 cases, levels declined <2 units and of these, 2 demonstrated weak staining before treatment (0.5 and 1).In a separate tissue microarray from 20 RC specimens, 15 (75%) bladder cancers demonstrated pSFK expression, while all 40 control kidney and prostate cancers were negative. Conclusions: Neoadjuvant D demonstrated biologic activity in MIBC with marked decrease of pSFK in 66% of cases, while the remaining showed smaller decreases. This study also demonstrates frequent and high expression of pSFK at baseline in MIBC, suggesting that evaluation of D may be justified in a broad population.
Radical cystectomy versus trimodality bladder-preserving therapy for muscle-invasive bladder cancer among elderly (80-84 years old) patients.
Authors: Hatakeyama Shingo , Yamamoto Hayato , Okamoto Akiko , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

340

Background: Management of muscle-invasive bladder cancer (MIBC) in elderly patients is issue of vital importance. The aim of the present study was to compare the oncological outcome of radical cystectomy to trimodality bladder preservation therapy. Methods: Between 1996 and 2013, we treated consecutive 419 patients with MIBC. Of these, we identified 44 patients with MIBC (cT2-4aN0M0) aged 80-84 years. We retrospectively reviewed the clinical charts of these patients. All patients received maximally safe transurethral resection of the bladder tumor before definitive therapy. The patients were categorized according to the treatment options into 2 cohorts; radical cystectomy cohort (RCx, n = 22), or radiotherapy with chemotherapy cohort (Trimodality, n = 22). All patients in trimodality cohort received at least 2 courses of gemcitabine plus carboplatin chemotherapy. Each patient was evaluated every 3-6 months by blood test, urine cytology, and computed tomography. Overall survival (OS), progression free survival (PFS) was estimated by Kaplan-Meier method. Multivariate analysis was used to identify independent factors to predict OS or PFS. Results: There were no significant differences in patient backgrounds between the groups, except for ECOG performance status (ECOG-PS), Charlson comorbidity index (CCI) and eligibility for cisplatin. The mean ECOG-PS, CCI and the number of cisplatin-unfit patients were significant higher in trimodality cohort (p = 0.001, p = 0.034, and p = 0.003, respectively). There were no significant differences in OS and PFS between the groups. On multivariate analysis, ECOG-PS >1 was the independent prognostic factors for OS and PFS. Conclusions: Trimodality bladder preservation therapy for MIBC in elderly patients is comparable to those who received radical cystectomy. For patients with MIBC who are non-cystectomy candidates, or select patients who are motivated to keep their native bladders, trimodality bladder preservation therapy should recognized as an effective alternative to radical cystectomy, and be considered.
Trends in the utilization of diagnositics for upper-tract urothelial carcinoma.
Authors: Vemana Goutham , Bhayani Sam , Baty Jack , Vetter Joel , Strope Seth A.
Published: February 2017

348

Background: The evolution and adoption of better endoscopes and imaging allow for improved diagnostic capacity for upper tract urothelial cancer (UTUC). We evaluated the changes in diagnostic modalities used to establish a diagnosis of UTUC. Additionally, we assessed how these changes affected the stage of patients receiving definitive surgery. Methods: Using linked SEER-Medicare data from 1992-2009, we identified patients between the age of 66-90 who underwent surgical treatment for UTUC. Among this cohort we assessed the types of diagnostics: endoscopy, computed tomography urogram (CTU), magnetic resonance urography (MRU), intravenous pyelogram (IVP), and retrograde pyelogram (RGP), used to evaluate their disease. Additionally, we dichotomized the final stage at surgery as lower stage disease (Ta, CIS, or unknown stage) or higher-stage disease (T1 or greater). Tests for trend were calculated for the five diagnostic modalities. Logistic regression models were fit to determine the impact of diagnostic modalities on stage at surgery. Results: We found a downward trend in utilization of IVP and RPG over time (p < 0.001, p = 0.011) with IVP having largest decline in use. Endoscopy, CTU and MRU all demonstrated increased utilization over time (p <0.0001). The incidence of lower stage disease was not found to be changing over time (p = 0.123). Logistic regression analysis demonstrated that among modern use (2000-2009), only the use of endoscopy and IVP were associated with smaller tumors (CI 1.310-1.996, CI 1.150-1.720). Conclusions: Modern diagnostics (endoscopy, CTU, MRU) have supplanted traditional methods of establishing a diagnosis of UTUC. Although these newer adopted technologies have a greater sensitivity in diagnosis of UTUC, only the use of endoscopy prior to definitive management has been associated with the diagnosis of smaller tumors.
Heterogeneity of circulating tumor cells isolated from bladder cancer patients using ApoStream and biomarkers of epithelial-mesenchymal transition.
Authors: Dinney Colin P. N. , Melnikova Vladislava O. , Pretzsch Shanna M. , Garza Miguel , Wu Weiguo , Davis Darren W. , Anderes Kenna Lynn
Published: February 2017

349

Background: Elucidating the molecular pathways that drive the progression of metastatic bladder cancer (BC) from local disease to metastatic may provide insight into prognosis and potentially treatment. The frequency of detection of circulating tumor cells (CTCs) in metastatic BC patients is only 30% using EpCAM based methods. Reports have shown that EpCAM based methods detect only a fraction of CTCs and miss the heterogeneous subpopulations of CTCs related to epithelial to mesenchymal transition (EMT). EMT is a hallmark of cellular invasion and metastasis and CTCs undergoing EMT may have prognostic value in BC if reliable detection and characterization methods were developed. Here we used ApoStream, a novel antibody-free CTC isolation device to isolate CTCs and perform molecular characterization. Methods: Blood samples from 13 early stage or metastatic BC patients were collected and processed using ApoStream. Isolated cells were immunophenotyped using a multiplexed immunofluorescence assay for CK, CD45, DAPI, uroplakin, vimentin and Twist. Laser scanning cytometry analysis was applied to identify subsets of CK+CD45-DAPI+ or CK-CD45-DAPI+ cells for the expression and distribution of uroplakin, vimentin and Twist. Urovysion FISH analysis was performed on CTCs from 6 BC patients. Results: CK+CD45- DAPI+ cells were detected in 4/13 (31%) of patients with vimentin detected in this subset. CK-CD45-DAPI+ cells were detected in 9/12 (75%) of patients with Twist expression detected in this subset. Uroplakin expression was not detected. Chromosomal abnormalities were detected in CK-CD45-DAPI+ cells isolated from the blood of 3/6 (50%) BC patients. Conclusions: ApoStream isolated cells from the blood of BC patients with phenotypic and genotypic characteristics of CTCs. The CK+/-CD45-DAPI+ Twist and vimentin phenotype indicates a population of circulating cells with relevant biomarkers of EMT and may represent an important population of CTCs mediating disease progression. Detection of chromosomal abnormalities on non-canonical CTCs highlights heterogeneity and underscores the need for expanded definitions of CTCs in BC.
Evaluation of the neutrophil-lymphocyte ratio (NLR) during neoadjuvant chemotherapy (NC) for muscle-invasive bladder cancer (MIBC) and correlation with pathologic response to treatment.
Authors: Seah Jo-An , Leibowitz-Amit Raya , Atenafu Eshetu G. , Alimohamed Nimira , Joshua Anthony Michael , Knox Jennifer J. , Sridhar Srikala S.
Published: February 2017

351

Background: Cancer associated inflammation, as measured by markers such as NLR, appears to impact on outcome. In MIBC, an elevated NLR> 2.5 prior to radical cystectomy (RC) is associated with a poorer prognosis (Gondo, 2011). We evaluated the pattern of change in NLR before (pre-NC), during (mid-NC) and after NC (pre-RC) and correlated this with pathological outcomes, to determine if NLR is of predictive value in this setting. Methods: AllMIBC pts treated with NC and RC between Jan 2005 – April 2013 were evaluated. Standard demographic, disease-related and biochemical parameters (Hb, LDH, albumin) and NLR were analyzed with univariate and multivariable logistic regression. The continuous variable pre-RC NLR was dichotomized using a cut-off of 2.5 based on area under the receiver-operator-curve analysis. Generalized linear mixed model was used to account for the time trend and co-linearity when assessing NLR change between pts who achieved pathological response (pathR) and non-responders. Results: Twenty-three patients were evaluable. Age, gender, ECOG, smoking, clinical stage, and hydronephrosis did not significantly predict for pathR. Pre-NC and mid-NC NLR did not predict for pathR. Pre-RC NLR <2.5 showed a trend towards association with pathR (p=0.05). The pattern of NLR change between responders and non-responders was significantly different (p=0.039). Non-responders exhibited a transient decrease in NLR during NC, followed by an increase in NLR pre-RC above its baseline; responders exhibited a sustained decrease in NLR which remained suppressed until RC (Figure: http://bit.ly/1bYC2wR). Conclusions: While there was no significant difference in pre-NC NLR between responders and non-responders, there was a significant difference in the pattern of NLR change during NC. We speculate that a sustained decrease in inflammatory burden during NC, as manifested by NLR, is associated with pathR. Despite limitations of a small retrospective study, our results may have potential translational and clinical implications.
Preoperative pitfalls: Prediction of pathologic lymph node status in patients undergoing neoadjuvant chemotherapy and radical cystectomy.
Authors: Espiritu Patrick , Luchey Adam , Lin Hui-Yi , Yue Binglin , Lockhart Jorge , Pow-Sang Julio , Spiess Philippe E. , Sexton Wade Jeffers , Poch Michael Adam
Published: February 2017

352

Background: Category 1 evidence supports neoadjuvant chemotherapy (NC) prior to radical cystectomy (RC) in patients with muscle invasive urothelial carcinoma of the bladder (UC). In addition, patients with clinical node (cN) positive disease may undergo RC after consolidative chemotherapy. Pathologic node (pN) positive disease at the time of radical cystectomy for UC portends a poor prognosis but is often challenging to predict. The purpose of this study was to investigate clinical predictors of pN positive disease in patients receiving NC followed by RC. Methods: After IRB approval, a retrospective analysis was performed on all patients who underwent neoadjuvant chemotherapy followed by RC from 2001-2013. Chi-square, Fisher’s exact, and logistic regression analyses were performed to analyze relationships between preoperative variables including clinical grade, stage, lymphovascular invasion, histologic variance, concomitant carcinoma in−situ, cycles of NC, smoking status with pN status. Overall survival (OS) and progression free survival (PFS) analysis was performed using Kaplan-Meier methodology. Results: 158 patients met inclusion criteria for the study. Fifty-five (35%) patients had pN positive disease at the time of RC. Of all of the preoperative variables assessed, cN positive disease was the only factor associated with pN positive disease (p <0.001). Of the 129 patients with cN negative disease 36 (28%) patients had pN positive disease. Six patients (32%) who were cN positive were pN negative at RC. Overall survival for the cohort was 30 months. Compared to pN negative disease, patients with pN positive disease had a worse PFS (p <0.01) and OS (p <0.01). Compared to non−organ confined (≥ pT3) pN positive disease, patients with organ confined (≤pT2) pN positive tumors had an improved PFS (p<0.01) and OS (p<0.01). Conclusions: Clinical node status is the only preoperative variable associated with pN status at the time of RC for patients receiving NC. A large percentage of patients who are cN negative will be pN positive at RC. As expected, patients who are pN positive had poor PFS and OS compared to pN negative patients.
Response to second-line chemotherapy (Ctx) in advanced urothelial carcinoma: A pooled retrospective analysis of the correlation between objective response rate (ORR) and progression-free survival (PFS) and overall survival (OS).
Authors: Jayaram Anuradha , Teo MinYuen , McDermott Raymond S.
Published: February 2017

354

Background: Second-line ctx for advanced urothelial carcinoma (UC) constitutes a substantial unmet need. A commonly used endpoint in phase II studies is ORR, however it is unclear whether this translates to a benefit in OS and PFS. We previously examined pooled OS, PFS, ORR and DCR in second line ctx in advance UC. We now are now determining whether increased ORR correlates with improved PFS and OS. Methods: Published second-line studies were identified from PubMed between 1997- 2012 and were reviewed for data extraction. Pearson correlation coefficient was used to determine correlation between ORR and OS and PFS. Results: 25 prospective studies of second-line ctx for progressive advanced UC were identified (22 non-randomised, 3 randomised) (n= 1,297). The majority of studies (88%) were phase II. 12 studies investigated combination regimens and 13 studies monotherapy. All studies allowed adjuvant and primary chemotherapy as first-line but only 7 studies reported median time from last chemotherapy. The range of reported response rates were 1% - 29%. ORR is moderately correlated to PFS (r= 0.42 {0.01 - 0.71} p = 0.04) and OS (r=0.67 {0.39 - 0.84} p = <0.01) in the entire cohort. When we compared the combination regimens to monotherapy the ORR was 27.7% versus 12.3% (p<0.01). The reported response rate for monotherapy was 8.6% - 27.7% and there was no correlation between ORR and PFS (r=0.26 {-0.37 - 0.72} p=0.42) and OS (r = 0.35 {-0.25 - 0.76} p=0.24). Conversely with combination regimens, response rates were 7% - 60% and ORR strongly correlated to PFS (r= 0.78 {0.40 - 0.93} p =<0.001) and OS (r=0.80 {0.43 - 0.94}, p=<0.001). Conclusions: The analysis revealed that ORR translated to a survival benefit. In second line ctx for advanced UC, responses to combination therapy only yielded a survival benefit. This may be appropriate approach in patients with a good performance status.
Vinflunine maintenance therapy versus best supportive care after platinum combination in advanced bladder cancer: A phase II, randomized, open label, study (MAJA study, SOGUG 2011-02)—Interim analysis on safety.
Authors: Polo Susana Hernando , Gonzalez del Alba Aranzazu , Perez-Valderrama Begoña , Villa Guzman José Carlos , Climent Miguel Angel , Lainez Nuria , Font Albert , Duran Ignacio , Mellado Begoña , Castellano Daniel , García-Donas Jesús , Virizuela Juan Antonio , Leon Luis , LLorente Maria del Mar , Domenech Montserrat , Morales Rafael , Gallardo Enrique , Puente Javier , Maciá Sonia , Bellmunt Joaquim
Published: February 2017

359

Background: Vinflunine (VFL) is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. We evaluated whether maintenance vinflunine delays progression after response to CT. Methods: Multicenter, randomized, open label, proof-of-concept study that is being performed in 21 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects are randomized to receive (arm A) VFL 320 mg/m2 (280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr <60ml/min) every 21 days plus best supportive care (BSC) vs. (arm B) BSC alone until disease progression. Main inclusion criteria: Subjects ≥18 and< 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease whith radiological response or stabilization after 4 to 6 cy of a cisplatin-containing doublet for metastasic/advanced disease (carboplatin allowed on cy 5-6). Primary objective: progression free survival (PFS). A sample size of 86 patients allocated in a 1:1 ratio is planned. Recruitment started on April 2012. A pharmacogenomic translational study will be conducted. Results: To September 2013, 46 pts have been enrolled, 20 in the VFL+BSC group, 26 in the BSC group. We present the results of the interim analysis including data from first 25 patients who have completed at least 2 cycles. Median age 65.6 years (range 54-77); PS 0/1, 44%/56%; CrCl <60 ml/min 16%; liver metastasis 16%; prior pelvic RT 8%. Primary tumour location: bladder 76%, upper urinary tract 20%, urethra 4%. Pure transitional cells 84%. Metastatic/locoregional disease, 72% / 28%. We analyzed 63 cy in the chemotherapy arm. Most common G3/4 (% cycles) AEs on vinflunine were constipation (12.7%), neutropenia (7.9%), fatigue (4.8%), myalgia (3.2%). One death was reported due to dyspnea, not related to the treatment. No febrile neutropenia was reported at the time of the analysis. Conclusions: Maintenance with vinflunine presented an acceptable security profile leading to trial continuation. Clinical trial information: 2011-001271-39.
Craniocaudal retroperitoneal node length as a risk factor for relapse from clinical stage I testicular germ cell tumor.
Authors: Howard Stephanie Anne Holler , Gray Kathryn P. , O'Donnell Elizabeth , Fennessy Fiona M. , Beard Clair , Sweeney Christopher
Published: February 2017

363

Background: To investigate if retroperitoneal craniocaudal nodal length (CCNL) or nodal volume (NV) predicts relapse risk in clinical stage I testicular cancer. Methods: This institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study retrospectively reviewed 826 patients with testicular cancer. One hundred eighteen out of 826 patients forming the analytic cohort had stage I disease and either more than or equal to 2 years surveillance or retroperitoneal lymph node dissection with no adjuvant chemotherapy. 3D NVs and CCNL were measured by two attending physicians in consensus. Association between relapse risk and CCNL/NV was evaluated using univariable/multivariable logistic regression analysis adjusted for known prognostic factors. Results: Sixty six out of 118 patients (56%) had nonseminomatous germ cell tumor (NSGCT) and 52 (44%) had seminomatous germ cell tumor (SGCT). Twenty one percent (25 out of 118) of patients relapsed: 24% (16 out of 66) for NSGCT and 17% (9 out of 52) for SGCT. Eighty percent of relapses were limited to the retroperitoneum; 90% of these were at the site of the largest lymph node. CCNL proved to be an independent risk factor in NSGCT using a multivariable logistic regression model adjusting for other potential known risk factors of embryonal predominance (EP) and lymphovascular invasion (LVI). For every 3 mm increase in CCNL, the risk of relapse increased by 52% (odds ratio [OR]=1.52; 95% CI=1.03- 2.25). For patients with SGCT, only the primary tumor size was an independent risk factor for relapse (OR=1.34; 95% CI=1.02-1.75). Conclusions: In NSGCT, CCNL was shown to be associated with increased risk of relapse independently of other known risk factors. If validated in a larger cohort, CCNL could provide important additional information used to inform management decisions in these patients.
Modern patterns of care in testicular seminoma: Results from the National Cancer database.
Authors: Gray Phillip John , Lin Chun Chieh , Paly Jonathan J. , Jemal Ahmedin , Efstathiou Jason Alexander
Published: February 2017

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Background: The management of testicular seminoma (TS) is evolving with guidelines supporting differential use of chemotherapy (CT) and radiotherapy (RT) depending on stage and presentation. We examined modern practice patterns in TS using the National Cancer Data Base. Methods: Data on 41,745 patients with TS treated between 1998 and 2010 were analyzed. Patients were grouped by stage based on National Comprehensive Cancer Network treatment guidelines. Multivariate generalized estimating equation models were used to assess factors associated with treatment paradigms. Results: Rates of surveillance after orchiectomy for those with stage IA/B TS increased from 21.4% during 1998-2001 to 40.4% from 2006-2010. Despite this, RT remained the most common adjuvant therapy (47.9% in 2006-2010). Use of adjuvant CT increased from 1.7% to 10.6% during this time. Patients with stage IS TS most commonly received RT; however, in 2006-2010, 32.4% of patients received surveillance and 15.6% received CT. Receipt of surveillance for those with stage IIA/B TS remained flat at ~12% while the use of CT rose (34.4% in 2006-2010 vs. 22.5% in 1998-2001). For patients with stage IA/B TS, Medicare or uninsured patients were more likely to receive surveillance vs. CT/RT (OR 1.54, p<0.0001 and OR 1.26, p<0.0001 respectively). Adjuvant CT/RT was more common at high volume centers (OR 0.63 vs. low volume, p<0.0001) and in patients with larger tumors (OR 0.80 for tumors ≥ 4 cm, p<0.0001). Among patients with stage IA/B TS who received adjuvant RT/CT, Medicaid or uninsured patients (OR 0.55, p<0.0001 and OR 0.68, p<0.0001 respectively) and those treated at NCI network cancer centers (OR 0.40 vs. community centers, p<0.0001) were less likely to receive RT vs. CT. For stage IIA/B TS patients, facility type was the strongest predictor for the receipt of RT vs. CT (OR 0.54 at NCI network centers, p<0.0001). Conclusions: Management of TS appears at least partially driven by economic concerns and facility type, especially in regards to selection of stage I patients for surveillance, the preferred management for this group. Many patients with stage IS are not managed according to published guidelines. Action is needed to ensure all patients with TS receive guideline supported care.
To what degree is there interobserver variability among pathologists for T1 penile cancer?
Authors: Luchey Adam , Espiritu Patrick , Agarwal Gautum , Protzel Chris , Dhillon Jasreman , Spiess Philippe E.
Published: February 2017

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Background: Molecular and genetic markers have yet to be developed to predict those patients that are at risk for lymph node metastasis. Currently, the grading of penile cancer plays a critical role in the determination of which patients receive an inguinal lymph node dissection (ILND) along with other treatment modalities. We sought out to determine the variance among genitourinary (GU) pathologists at a tertiary cancer center for penile cancer based on a European model. Methods: Nine patients that were diagnosed with stage pT1 primary penile squamous cell carcinoma were selected who underwent either a partial (8) or radical penectomy (1) from 10/2000 to 09/2009. All slides from each case were reviewed by each of the 3 reviewing pathologists, independently, who diagnosed the subtype of squamous cell carcinoma according to WHO criteria, assigned a grade, noted whether lymphovascular invasion was present or not and finally staged the tumor according to the AJCC Cancer Staging Manual, 7th edition. No access to the original, final pathological diagnosis was allowed. Interobserver variance between the 3 GU pathologists and each variable was calculated using Cohen’s kappa coefficient. Results: Complete agreement was reached in 3 cases for tumor grade and 4 cases for tumor stage out of 9. Overall, the 3 GU pathologists only displayed fair agreement at 30% for tumor grade (ê = 0.30, p = 0.018) and trended towards fair agreement at 24% (ê = 0.24, p = 0.077) and 25% (ê = 0.250, p = 0.097) for tumor stage and LVI respectively. Conclusions: The variance displayed herein demonstrates the difficulty in identifying individuals that would benefit from a diagnostic/therapeutic lymph node dissection based on pathological staging. This corroborates that of the European model and calls for novel methods to determine reproducible prognostic markers.
Integrated comprehensive high-throughput kinomics profiling and whole exome sequencing of penile squamous cell cancer (PSCC).
Authors: Mehta Amitkumar N. , Willey Christopher , Crowley Michael , Anderson Joshua , Chen Dongquan , Crossman David , Necchi Andrea , di Lorenzo Giuseppe , Eigl Bernhard J. , Lee Richard J. , Harshman Lauren Christine , Dorff Tanya B. , Galsky Matt D. , Milowsky Matthew I. , Bolger Graeme , DeShazo Mollie , Naik Gurudatta , Grizzle William E. , Sonpavde Guru
Published: February 2017

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Background: Molecular drivers in penile squamous cell cancer (PSCC), an orphan malignancy, remain unclear. The Cancer Genome Atlas (TCGA) is not studying PSCC and the Catalogue of Somatic Mutations in Cancer (COSMIC) investigators have reported only targeted analyses of PSCC. We report the first integrated analyses of comprehensive kinomics and whole exome sequencing (seq) in tumors from patients (pts) with PSCC . Methods: We performed integrated functional kinomics profiling and comprehensive exome-seq of two frozen tissue samples from men with PSCC with a matched normal tissue procured from the Cooperative Human Tissue Network (CHTN). Kinomic profiling was performed using the PamStation 12 high-content phospho-peptide substrate microarray system (PamGene International). The protein tyrosine kinome and serine/threonine kinome PamChips were used to measure global kinase activity by detecting phosphorylation of various peptides through FITC-labeled antibodies. Upstream kinase prediction was performed using a scoring algorithm that incorporates the phosphonet database (www.phosphonet.ca). Exome capture was performed with the Agilent SureSelect v5 kit and whole exome-seq was done on the Illumina HiSeq2000 with paired end 100bp chemistry. Results: In the single patient, paired kinomics analysis comparing the tumor sample to adjacent normal tissue, the HER family (EGFR, ERBB2, 3 and 4), AXL, TYRO3 and SYK kinases were the most active. When combining the two tumors in an unpaired analysis against the normal sample, the HER (EGFR, ERBB2, 3 and 4), MER, FRK, and FAK, kinases showed increased activity. When comparing whole exome-seq of the two PSCC samples with normal, among the affected genes were CCDC181, ZNF717, MUC4, HGC6.3, NOTCH1, STK11, SIRPB1, SKA3, PDE6B, FAT1, CACNA2D1, USP17L11, MNT, and CEP89. We are evaluating 10 PSCC tumors and matched normal tissue by kinomics and whole exome-seq and will present these complete data and analysis at the conference. Conclusions: In our preliminary analysis of pts that underwent the first reported integrated kinomics and whole exome-seq performed in PSCC, we identified multiple potential therapeutic targets in tumors.
SWITCH: A randomized sequential open-label study to evaluate efficacy and safety of sorafenib (SO)/sunitinib (SU) versus SU/SO in the treatment of metastatic renal cell cancer (mRCC).
Authors: Michel Maurice Stephan , Vervenne Walter , de Santis Maria , Fischer von Weikersthal Ludwig , Goebell Peter J. , Lerchenmueller Juergen , Zimmermann Uwe , Bos Monique M.E.M. , Freier Werner , Schirrmacher-Memmel Silke , Staehler Michael D. , Pahernik Sascha , Los Maartje , Schenck Marcus , Flörcken Anne , Van Arkel Cornelis , Hauswald Kirsten , Indorf Martin , Gottstein Dana , Eichelberg Christian
Published: February 2017

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Background: The sequential use of SO and SU has been investigated retrospectively in patients with mRCC. We report here results from the first randomized study to prospectively compare SO/SU versus SU/SO. Methods: Pts with mRCC unsuitable for cytokines without prior systemic therapy, ECOG PS 0/1, MSKCC score low or intermediate, and ≥1 measurable lesion were randomized to receive open-label SO/SU (arm A) or SU/SO (arm B) in standard dosage. Primary endpoint: total PFS (T-PFS) from randomization to event during 2nd line therapy. Therapy continued until progression or intolerability. The study was powered to detect a 47% increase in T-PFS with SO/SU compared to SU/SO using log-rank testing and Cox proportional hazard regression model. ( NCT00732914 ). Results: A total of 365 pts were enrolled: 182 arm A, 183 arm B.The two arms were well balanced: median age (A/B): 64/65 yrs; prior nephrectomy: 74/65%; MSKCC intermediate: 59/51%, low: 39/45%; clear cell histology: 90/84%. At time of final T-PFS analysis 220 events had occurred (A, n=117 [64%]; B, n=103 [56%]). There was no statistically significant difference in T-PFS across arms: HR 1.01, p=0.54, arm A and arm B, respectively. Likewise, there was no statistically significant difference in OS: HR 0.997, p=0.49, nor in the first PFS across arms: HR 1.19, p=0.92. Fewer pts crossed over to receive SO in arm B (n=76) than to receive SU in arm A (n=103). Overall DCR was 72/67%. There was a marked difference in AEs leading to permanent discontinuation between the two groups (18.6/29.5%). Most frequent (>20%) side effects under 1st-line treatment SO vs SU were alopecia (29/4%), diarrhea (43/29%), dysgeusia (8/21%), fatigue (21/34%), HFSR (37/20%), hypertension (24/24%), nausea (18/24%) and rash (22/3%). AEs were generally lower during 2nd-line therapy. Conclusions: There was no significant difference in T-PFS, OS, DCR and 1st-line PFS between the two sequential treatments. Both drugs provided overall benefit regardless of sequence. Side effect profiles differ, but were generally less frequent during 2nd-line therapy. More patients reached 2nd-line in the SO/SU arm. Clinical trial information: NCT00732914.
Results of the MARS study on the management of antiangiogenics’ renovascular safety in renal cell carcinoma.
Authors: Ray-Coquard Isabelle Laure , Janus Nicolas , Goldwasser Francois , Mir Olivier , Oudard Stephane , Scotte Florian , Spano Jean-Philippe , Thery Jean Christophe , Beuzeboc Philippe , Daniel Catherine , Rey Jean-Baptiste , Jouannaud Christelle , Gligorov Joseph , Morere Jean F. , Azizi Michel , Dorent Richard , Deray Gilbert , Launay-Vacher Vincent
Published: February 2017

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Background: MARS is a prospective multicentric study conducted to assess the renovascular tolerance of anti-VEGF drugs (AVD) in the clinical setting in France, in a number of different tumor types. Methods: Patients (pts) from 8 centres were included when they were 1) naïve of any AVD and 2) about to start treatment with an AVD, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit during f/u. This sub-group analysis presents the results for renal cell carcinoma (RCC) pts receiving sunitinib. Results: 1,124 pts were included. 137 had RCC and 112 received sunitinib. Median age: 61.0 years. Visceral, bone and cerebral metastasis frequencies were 71.4, 42.0 and 12.5%, respectively. All except 3 pts, had at least one kind of metastasis. At inclusion, HTN prevalence was 43.8%. Baseline renal assessment retrieved: Pu 15.6%, Hu 8.1%, mean aMDRD 69.4 ml/min/1.73m2. The incidence of de novo Pu and HTN during f/u was 75.0 and 21.4% (Table). All pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 75.8% afterwards improved/normalized. Mean aMDRD was 72.2 at the end of f/u. 0.7% had grade 3 SCr increase (no grade 4). No thrombotic micro-angiopathy (TMA) was reported. Conclusions: These results on the renovascular safety of AVD in RCC patients showed that 1) TMA is rare, 2) Pu develops in 75.0% of the pts, 3) 21.4% developed HTN, Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]