bluuebunny/crossref_metadata_2025 huggingface dataset:
Testosterone kinetics after proton therapy for low- and intermediate-risk prostate cancer.
Authors: Nichols Romaine Charles , Morris Christopher G. , Hoppe Bradford S. , Henderson Randal H. , Mendenhall William M. , Li Zuofeng , Williams Christopher R , Costa Joseph A , Harris Stephanie , Mendenhall Nancy Price
Published: February 2017

237

Background: Evaluate long term changes in serum testosterone levels in patients with low and intermediate risk prostate cancer treated with proton therapy (PT) on two prospective clinical trials. Methods: Between August, 2006 and October, 2007, 171 patients with low and intermediate risk prostate cancer were enrolled and treated on the University of Florida Proton Therapy Institute institutional review board (IRB) approved PR01 and PR02 protocols. Of the 171 patients, 20 were excluded for having received hormonal therapy prior to PT. The pretreatment serum testosterone level was available for 149 of the remaining 151 patients. These 149 patients were included in the present study. Proton doses ranged from 78 Cobalt Gray Equivalent (CGE) to 82 CGE to the prostate using passively scattered protons. No patient underwent pelvic nodal irradiation. Results: The median baseline serum testosterone level was 358ng/dL (range 112 to 791ng/dL). Immediately after completion of PT, median serum testosterone was 365ng/dL which was not significantly different from the pre-PT level (p=0.2039). Subsequent median testosterone levels with associate P-Values are shown in the Table. At no point in the 60 month follow up period was the median serum testosterone value significantly different from the baseline value. Conclusions: Conformal proton therapy to the prostate, as delivered using the University of Florida Proton Therapy Institute PR01 and PR02 protocols, did not appear to significantly affect serum testosterone levels within 60 months after PT. [Table: see text]
Generation of virtual control groups for single-arm prostate cancer (PCa) adjuvant trials.
Authors: Jia Zhenyu , Lilly Michael B. , Koziol James A. , Ruckle Herbert , McLaren Christine E. , Ahlering Thomas , Skarecky Douglas , Mercola Dan
Published: February 2017

239

Background: It is difficult to construct a control group for trials of adjuvant Rx of PCa after radical prostatectomy (RP) due to ethical issues, patient acceptance. We present an algorithm involving 8 regression models to generate virtual control groups based on the Kattan post-prostatectomy nomogram. Methods: The online Kattan nomogram gives the probability of being progression-free at 2, 5, or 7yr after RP without adjuvant Rx. For each subject we estimate the progression-free survival (PFS) from these data by applying 8 models that use curve fitting and estimation of time to relapse. The models estimated time to 60%, 65%, . . . 95% chance of relapse for each subject. To prepare a virtual control group for a single-arm adjuvant Rx trial, the predicted PFSs generated from the optimum model are compared with the observed PFSs by the logrank test. Results: The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx. The optimum model depended on the clinical features of the test population. Higher relapse risk required a higher stringency model. The algorithm was validated with an independent dataset of 155 post-RP patients. When analyzed by the optimum model there was high correlation between the group observed, predicted PFSs (p = 0.792 for no difference). We created a virtual control group for pts on a Ph II trial of adjuvant chemohormonal Rx post RP. The observed PFSs for these subjects were significantly longer than the PFSs predicted by the new algorithm, indicating that the adjuvant Rx is highly effective in prolonging PFS after RP in pts at high risk for PCa recurrence. This was confirmed by comparing observed PFSs with PFSs of a matched historical group. Conclusions: The algorithm can accurately generate control groups for single arm adjuvant Rx trials for PCa, facilitating development of new therapeutic strategies.
The effects of age, stage, treatment, and Charlson comorbidity index (CCI) on quality of life after prostate cancer diagnosis in a single cohort.
Authors: Cross Deanna S. , Islam Rezwan , Mullins C. Daniel , Hussain Arif , Jacobson Crystal , Foth Wendy , Ritter Mark A.
Published: February 2017

242

Background: Long term quality of life after diagnosis of prostate cancer (PC) is an important factor in determining treatment success and satisfaction. Here we investigate the quality of life in a rural cohort of individuals treated for PC within a single institution. Methods: The Expanded Prostate Cancer Index Composite (EPIC) and the Medical Outcomes Short-Form 36 (SF 36) were completed by a rural population based cohort diagnosed with prostate cancer between January of 2005 and December of 2010, enrolled in a population based biorepository. Medical records were interrogated electronically for information such as age at treatment, stage, CCI, and first course of treatment. Results: Of the 173 individuals within the cohort, we received 95 completed survey instruments. No differences in age group, stage at treatment, or treatment type between individuals who completed the survey and those who did not were observed. Median summary score for the sexual domain was 10 (min -6 max 77), median summary score for urinary domain was 85 (min 36 max 100), and median summary score for the bowel domain was 95 (min 68 max 100). Median physical health score was 80 (min 20 max 100) and median general health score was 67 (min 20 max 100). Overall satisfaction score was 75 (min 25 max 100). Scores for bowel and urinary function were not significantly associated with treatment, age, CCI, or stage at diagnosis. For the sexual domain, individuals with hormonal treatment scored worse than other treatments (ttest p=0.05). Overall physical health was associated (anova, p<=0.05) with treatment, age, CCI, and stage. In a multivariate model only treatment and an interaction term with treatment and CCI were significant. Satisfaction score varied with treatment, individuals who received radiation treatment had a higher mean satisfaction score (87 vs 68 for the other groups ANOVA p=0.03). Conclusions: The treatment for prostate cancer affected an individual's quality of life in the domains of physical function, and sexual health. Treatment also affected satisfaction score regardless of age or stage at diagnosis.
Rectal dose-volume differences for scanning proton beam therapy with or without an endorectal balloon for the treatment of prostate cancer.
Authors: Desai Anand , Stoker Joshua B. , Wages Cody A. , Zhu X. Ron , Lee Andrew
Published: February 2017

243

Background: Endorectal balloons (ERB) are routinely used in proton radiation for prostate cancer (PCa). The dosimetric implications, however, in conjunction with scanning proton beam therapy (SPT) have not been studied. We sought to describe dose-volume values with the use of an ERB vs no ERB for SPT for PCa. Methods: We analyzed 10 patients with localized PCa. Each patient underwent two CT simulations, one with a water-filled ERB (50-60 ml) and one with no ERB. For 8 patients, the prostate and proximal 1 cm of the seminal vesicles was the clinical target volume (CTV), with the prostate only as CTV for 2 patients. We defined 3 structures: rectum (R), anterior rectal wall (ARW) as a 3 mm rim of the anterior half of the rectum, and AR-CTV as the ARW only on slices with a contoured CTV. SPT plans were created in both cases for each patient, with the creation of a scanning target volume (STV), which expanded the CTV by 6 mm in all dimensions except 4 mm posteriorly and 12 mm laterally. Two opposed lateral beams were used to plan to the STV. Total dose was 78 Co-60 Gy equivalent in 39 fractions, to cover 95% of the STV. RBE was 1.1. We compared the dose-volume values for the R, ARW, and AR-CTV between the two arms. Results: The ERB significantly increased the R volume for all cases (61 ± 11 ml vs 105 ± 10 ml (p<0.01)). Rectal volumes radiated for all cases: V10, 55%; V50, 23%; and V70, 11%. The ERB significantly decreased the R volume radiated for all dose levels V5-V82 (p<0.05). The absolute difference was larger at low dose levels (8% at V10) and intermediate dose levels (5% at V50) compared to high dose levels (3% at V70). For the ARW, the ERB did not significantly change the volume radiated at any dose level. For the AR-CTV, the ERB significantly decreased the volume radiated for dose levels V20-V60 (p<0.05). Conclusions: The ERB provided a significant decrease in R volume radiated at all dose levels, and significantly decreased the AR-CTV volume, which represents a high risk volume, radiated at intermediate dose levels. Rectal doses with SPT, however, were low whether using an ERB or not. In the setting of the low rectal doses delivered, further study regarding the clinical benefit is warranted.
Evaluation of a novel irreversible pan-HER inhibitor in bladder cancer models.
Authors: Grivas Petros , Karatsinides Andreas , Day Kathleen C. , Kunju Priya , Paul Alyssa , Shakir Nazia , Keller Evan T. , Hussain Maha , Day Mark L.
Published: February 2017

253

Background: Human epidermal receptors (HER) are overexpressed and HER signaling is biologically relevant in bladder cancer and may mediate chemotherapy resistance. Dacomitinib is a novel, potent, irreversible pan-HER inhibitor with activity against several solid tumors, currently in a phase III clinical trial in NSCLC. We hypothesized that dacomitinib has antitumor activity in bladder cancer models. Methods: Expression level of EGFR and HER2 protein was measured semi-quantitatively in 8 bladder cancer cell lines. We treated UM-UC-3, UM-UC-6, UM-UC-9 cell lines with dacomitinib (1nM-10uM) for 24-72 hours, and measured cell viability, proliferation, apoptosis, and cell cycle effects. Correlations between dose and cell viability were measured by two-way ANOVA (GraphPad Prism 5.0). We injected age-matched male NOD/SCID mice SC with 1x106 UM-UC-6 and UM-UC-9 cells, respectively, generating xenografts. Mice were randomized and treated with dacomitinib, 6mg/kg p.o. daily, starting 1 day or 1 week after cell injection; controls were treated with vehicle. Mice were monitored daily, weighed weekly, sacrificed at 4 weeks and tumors weighed. Results: In vitro, significant cytostatic effect was noted with as low as 50nM in UM-UC6 cells and 100nM in UM-UC9 cells. UM-UC3 cells did not exhibit cytostatic effect even with 1000nM, corresponding to differential target protein (HER) expression. Dacomitinib (2uM) induced apoptosis (UM-UC-6), and G1 cell cycle arrest in both cell lines. These effects corresponded to dacomitinib-mediated inhibition of EGFR, ERK, AKT phosphorylation. In vivo, xenograft weights in both cell lines were significantly lower in dacomitinib-treated mice vs control (p<0.001), corresponding to pharmacodynamic effects (decreased E-cadherin, p-EGFR, p-ERK, mitotic count). Dacomitinib 6mg/kg p.o. daily resulted in significantly lower tumor weights vs lapatinib 50 mg/kg p.o. daily in UM-UC-9 xenograft model (p=0.0052). Conclusions: Dacomitinib demonstrated single-agent activity in bladder cancer cell lines and xenografts. Induction of apoptosis and G1 phase arrest are the suggested mechanisms for anti-tumor activity. Further investigation of this inhibitor in bladder cancer models is being pursued.
Cost-effectiveness analysis of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.
Authors: Stevenson Scott M. , Deibert Chris M. , McKiernan James M.
Published: February 2017

258

Background: Neoadjuvant chemotherapy (NAC) is an option for treating muscle invasive bladder cancer (MIBC), and is reported to increase survival for patients who obtain a complete response with no residual disease at the time of radical cystectomy (RC). However, NAC has additional costs and side effects. We seek to compare the effectiveness of NAC and RC for MIBC and to report the increase in cost and change in quality adjusted life years (QALYs) for patients who receive NAC. Methods: Patients were retrospectively reviewed from 2004 to 2011 to identify those with MIBC (stage T2 to T4a) who were treated with either RC alone or NAC. Costs for hospital admissions and surgical procedures were estimated from the Healthcare Cost and Utilization Project (HCUP) using specific Diagnosis Related Groups (DRG) or ICD-9-CM identifiers. Costs for outpatient procedures and urology visits were obtained from internal billing departments, and costs for chemotherapy were estimated based on published literature. QALYs were calculated based on clinical events and standard utility weights obtained from the medical literature. Results: 186 patients were identified, of which 64% received RC alone and 36% received NAC. Overall median survival for the RC group and the NAC group was 26.6 months and 38.3 months, respectively (p=0.056). Overall median survival in QALYs for the RC group and NAC group was 21.9 months and 32.9 months, respectively (p=0.057). 5-year overall survival in QALYs was 21.8% for the RC group and 39.8% for the NAC group (p=0.039). The mean total cost of treatment during follow-up for the RC and NAC groups was $42,890 and $52,336, respectively. The absolute increase in cost of therapy for patients receiving NAC compared to RC alone was $9,712. The increased cost per additional QALY gained for patients receiving NAC was $10,317. Conclusions: Neoadjuvant chemotherapy results in an increased overall survival for patients with muscle invasive bladder cancer. This treatment is associated with an increased cost of approximately $10,000/QALY gained. This cost effectiveness compares favorably with other cancer therapies.
Relationship of ERCC1 genotype variant with mRNA expression and ERCC1 protein levels in advanced urothelial carcinoma (UC).
Authors: Guancial Elizabeth A. , Werner Lillian , Bellmunt Joaquim , Nikitas Nikitas , Stack Edward C. , Lis Rosina , Signoretti Sabina , Loda Massimo , Regan Meredith M. , Park Rachel S. , O'Brien Robert , Berman David M. , Bamias Aristotelis , Rosenberg Jonathan E.
Published: February 2017

260

Background: DNA repair factors may be predictive for response to chemotherapies that produce DNA damage. While low ERCC1 protein and mRNA levels have been reported as associated with improved outcomes in metastatic UC patients treated with platinum-based chemotherapy, the relationship between genotype, mRNA expression, and protein level is unknown. The ERCC1 germline 19007C>T single-nucleotide polymorphism (SNP) is functionally associated with reduced translation of ERCC1 mRNA. We investigated the relationship between ERCC1 germline SNP, ERCC1 tumor mRNA and protein expression, in a cohort of patients with advanced UC who received first-line, platinum-based chemotherapy. Methods: A cohort of clinically annotated, uniformly-treated advanced UC patients with FFPE primary tumor tissue available was identified through the Hellenic cooperative Oncology Group (HECOG) (N=93). Genomic DNA extraction, nested PCR, and restriction fragment length polymorphism techniques for the 19007C>T SNP were performed to identify C/C, C/T and T/T genotypes. ERCC1 mRNA expression was interrogated using Nanostring nCounter profiling. IHC analysis was performed on tissue arrays using an ERCC1 antibody. Percent of positive nuclear staining was categorized as quartiles using previously identified cut-points. Results: ERCC1 C/T genotype was identified in 30/61 samples (49%) and T/T in 14/61 samples (23%). In 54 patients with both SNP and mRNA data available, T/T genotype was associated with the highest level of mRNA expression, followed by the C/T genotype (p=0.04). Neither ERCC1 genotype (N=44) nor ERCC1 mRNA expression (N=54) was associated with ERCC1 protein expression as measured by IHC (p=0.52 and p=0.13, respectively). Conclusions: ERCC1 19007C>T is associated with increased ERCC1 mRNA expression. However, neither genotype nor mRNA are surrogates for ERCC1 protein detected by IHC in advanced UC tumors. This suggests that while genotype influences mRNA expression of ERCC1, the use of the nucleotide excision repair pathway as a predictive biomarker of platinum-sensitivity may be more complex than previously appreciated and require the integrative use of proteomics, genomics and epigenomics.
Pathologic response rates between gemcitabine-cisplatin (GC) and methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin (MVAC) neoadjuvant chemotherapy in muscle-invasive urothelial cell carcinoma of the bladder.
Authors: Wright Jonathan Lawrence , Lee Franklin , Harris William Proctor , Cheng Heather H. , Zhao Song , Champion Thomas , Gore John L. , Dean James , Porter Michael P , Yu Evan Y.
Published: February 2017

267

Background: Neoadjuvant chemotherapy for muscle invasive urothelial carcinoma (UC) of the bladder is associated with higher rates of pathologic complete response (CR) and improved disease-specific survival compared to those treated with radical cystectomy (RC) alone. Two standard regimens used are (1) gemcitabine and cisplatin (GC); and (2) methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), with debate on whether there is a difference in clinical efficacy. In this analysis, we compare the pathologic outcomes at cystectomy between neoadjuvant GC and MVAC treatment. Methods: Data was retrospectively collected on patients with T2-T4 UC of the bladder who underwent RC between Sept 2003 and December 2011 at the University of Washington. Clinical and pathologic factors were recorded along with neoadjuvant chemotherapy and comorbidities. Pathologic outcomes included those with CR (pT0) and near CR (nCR = pT0/Ta/Tis). Odds ratio (OR) for CR and nCR were calculated using multivariate logistic regression adjusting for demographic (age, gender, race), medical (creatinine, diabetes mellitus, cardiac disease) and clinical factors (clinical T stage, prior BCG therapy, complete tumor debulking prior to chemotherapy). Results: A total of 78 patients received GC or MVAC neoadjuvant chemotherapy followed by RC, including 46 who received GC and 32 who received MVAC. There was no difference in gender, renal function, cardiac disease or clinical stage between the two groups. Patients over 70 years of age primarily received GC (17/18). CR was achieved in 30% and 25% (p = 0.15) of GC and MVAC patients, respectively (multivariate OR 0.42, 95% CI 0.11-1.63). nCR was more common in those receiving GC (50% vs. 38%, p = 0.04) although non-significant in the multivariate model (OR 0.30, 95% CI 0.07-1.16). Conclusions: We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of bladder cancer patients. These observations support the use of GC as an alternative regimen in the neoadjuvant setting.
Muscle invasive bladder cancer in the elderly: Treatment and prognosis in a prospective cohort study.
Authors: Slater Stephanie , Wright Thomas , Devall Adam , Pirrie Sarah , Billingham Lucinda , Cheng K K , Zeegers Maurice , Bryan Richard , James Nicholas David
Published: February 2017

275

Background: As the prevalence of bladder cancer increases amongst the elderly, nearly 1 in 3 muscle invasive bladder cancer (MIBC) cases are in patients aged >80 years (Taylor JA, III, Kuchel GA. Nat Clin Pract Urol 2009; 6(3):135-1440). However, radical cystectomy remains as the gold standard treatment for MIBC (Yafi FA, Kassouf W. Can Urol Assoc J 2009; 3(5):409-412). In this study we examined treatment patterns and outcomes patients aged >80 years from a prospective study of bladder cancer. Methods: The Bladder Cancer Prognosis Programme (BCPP) is a 5 year prospective cohort study (2006-2011) with 1191 patients confirmed as having newly-diagnosed bladder cancer. Recruitment took place at 9 urological centres within the West Midlands region, UK. From this cohort we identified 67 patients aged >/=80 years with newly diagnosed MIBC. Study records include overall and disease specific survival, time to disease recurrence and radiotherapy (RT) treatment. Simple descriptive statistics were used to describe the outcomes. Results: This cohort consisted of 46 male and 21 female patients with a median age of 83 (IQR=81, 87; range=80, 94). Only 4 (6%) patients underwent cystectomy and 36 (53%) underwent RT. Median survival data is summarised in the table below. Conclusions: Despite guidelines, practising urologists in the West Midlands region do not offer cystectomy to the vast majority of MIBC patients aged >80 years. Furthermore, in this patient cohort, OS was shorter than BCSS by 10 months, suggesting that quality of life after diagnosis will be far more important than cure rates due to deaths from other causes. Of particular note is that the group receiving RT had longer OS and BCSS than the rest of the cohort. This indicates that RT could be a far more appropriate standard of care in the elderly than surgery, which is clearly of limited applicability in this growing demographic. Clinical trial information: 06/MRE04/65. [Table: see text]
Thromboembolic events with cisplatin-based neoadjuvant chemotherapy for transitional cell carcinoma of urinary bladder.
Authors: Botten Joanne , Sephton Matt , Tillett Tania , Masson Susan , Thanvi Narottam , Herbert Christopher , Hilman Serena , Rowe Edward , Gillatt David , Persad Raj , Whittlestone Tim , Bahl Amit
Published: February 2017

277

Background: Cancer is associated with an increased risk of venous and arterial thrombo-embolic events (TEEs), including deep vein thrombosis, pulmonary embolism, cerebrovascular accident and unstable angina/myocardial infarction. Several factors are known to influence the incidence of TEEs including chemotherapy agents, particularly cisplatin. Czaykowski et al reported 12.9% of patients receiving multiagent cisplatin based chemotherapy for transitional cell carcinoma between 1986 and 1996 developed TEE. Moore et al found that the rate of TEE in a similar cohort of patients receiving the same treatment to be 18.2% (6/33 patients). Methods: Retrospective case note review from an electronic database of patients allocated a cisplatin based neo-adjuvant chemotherapy regimen for transitional cell carcinoma of the bladder between April 2009 and April 2012. TEE was recorded as a chemotherapy related event if it occurred between the first dose of cisplatin and 4 weeks after the last administered dose. Results: 44 received treatment in the neoadjuvant setting. 11 out of 44 patients (25%) receiving neo-adjuvant chemotherapy developed TEE. 7 out of these 11 patients were male, 4 were female. 9 of the 11 TEEs (82%) in the neoadjuvant setting were arterial or peripheral arterial thrombi, including pulmonary emboli and thrombi within the aorta, left ventricle and iliac arteries. 5 of these thrombi were asymptomatic and only discovered on routine scanning. 2 out of the 11 TEEs were leg deep vein thromboses – both of which were symptomatic. 64% of TEEs occurred after the second cycle of cisplatin, the remainder after the third cycle. Conclusions: Neo-adjuvant chemotherapy is being adopted as the standard of care for patients with muscle-invasive TCC of bladder. The higher rate of TEE in our series compared to previous publications probably reflects the asymptomatic TEE being diagnosed on scans done for assessing response to chemotherapy. The significant rates of TEEs in this setting highlights the need to consider this complication as it may have a bearing on outcome from treatment, in particular delay in radical cystectomy.
Overexpression of IGF1R to predict outcome in invasive urothelial carcinoma of urinary bladder.
Authors: Kim Jenny J. , Gonzalez-Roibon Nilda , Chaux Alcides , Munari Enrico , Faraj Shiela F. , Ellis Carla , Sharma Rajni , Bivalacqua Trinity , Schoenberg Mark , Carducci Michael Anthony , Netto George J.
Published: February 2017

280

Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed (OE) in several tumors including bladder cancer and is currently under investigation as a target of Rx. Here we explore IGF1R expression in urothelial carcinoma (UC), its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered OE in cases with score 1. Endpoints of the study included overall survival and cancer-specific survival. Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R was OE in 62% of UC. No differences were noted between normal urothelium and malignant counterparts (74% vs. 60%; P=0.14). IGFR1 was more frequently OE in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). pT4 tumors OE IGF1R more frequently than pT1-pT3 tumors (71% vs. 29%, P=0.005). No association was found with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis). Overall survival (OS) and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients whose tumors OE IGF1R had a lower OS and DSS compared to those whose tumors did not OE IGF1R (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R overexpression remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: Overexpression of IGF1R was found in 62% of UC. High stage tumors OE IGF1R more frequently than low stage tumors. More importantly, IGF1R overexpression was a significant independent predictor of OS and DSS.
Presence of carcinoma in situ (CIS) in bladder cancer biopsies and its relationship to pathologic complete response (pCR) rates to neoadjuvant chemotherapy (neo-CTx).
Authors: Thomas Derek E. , Rice Kevin , Pedrosa Jose Alexandre , Johnston Paul , Moore Marietta L. , Reed Angela D. , Cregar Dylan M. , Franklin Cindy , Koch Michael O. , Bihrle Richard , Foster Richard , Masterson Timothy A. , Gardner Thomas A. , Sundaram Chandru , Powell Charles R. , Beck Stephen , Grignon David A. , Cheng Liang , Hahn Noah M.
Published: February 2017

286

Background: Despite an improved overall survival with neo-CTx for muscle-invasive urothelial carcinoma (miUC) patients (pts) prior to cystectomy, the adoption of neo-CTx in suitable pts has been suboptimal. While associated with a more aggressive phenotype in early stage UC, the prognostic role of CIS in miUC is less clear. In particular, the effect of concurrent CIS in pts undergoing neo-CTx prior to cystectomy is unknown. Methods: A retrospective review of the Indiana University Simon Cancer Center urology and medical oncology clinical databases was performed spanning the years 1991 – 2012. Subjects with miUC, pathology reports available for both transurethral resection of bladder tumor (TURBT) and cystectomy procedures, and confirmed receipt of neo-CTx were included in this analysis. Pts with clinically positive lymph nodes (LN+) were included provided they underwent cystectomy with curative intent. Associations between pCR and pt baseline age, gender, race, clinical stage (T2N0 vs. T3/T4/N+), chemotherapy regimen received (cisplatin combination therapy (CisCTx) vs. non-cisplatin based), and presence of CIS on TURBT sample were tested by multinomial logistic regression analysis with statistical significance set at p<0.05. Results: 72 miUC pts satisfying the inclusion criteria were identified. Cohort demographics included: median age – 59 yrs, 76% male, 93% Caucasian, 63% T2N0, 32% LN+, 81% CisCTx neo-CTx regimen, 32% CIS on TURBT, pCR for entire cohort 18%. The presence of CIS on TURBT was significantly associated with decreased rates of pCR (1/23 vs. 12/49) p=0.002. TURBT CIS was not associated with decreased rates of less than pT2N0 (12/23 vs. 18/49) p=0.562. Seven pts (30%) with CIS on TURBT sample achieved pTisN0 at cystectomy. Conclusions: The presence of CIS in TURBT specimens is associated with decreased rates of pCR at cystectomy in miUC pts treated with neo-CTx. The finding of pTisN0 at cystectomy is common after neo-CTx in pts with CIS in preop TURBT specimens. Validation of the prognostic significance of TURBT CIS on pCR rates and characterization of pTisN0 clinical course in TURBT CIS pts after neo-CTx is warranted.
Effect of germ-line BRCA mutations in biochemical relapse and survival after treatment for localized prostate cancer.
Authors: Castro Elena , Olmos David , Goh Chee Leng , Saunders Ed , Leongamornlert Daniel , Tymrakiewicz Malgorzata , Bancroft Elizabeth , Page Elizabeth , Dadaev Tokhir , Govindasami Koveela , Guy Michelle , Ellis Steve , Frost Debra , Peock Susan , Antoniou Antonis C. , Easton Douglas , Kote-Jarai Zsofia , Eeles Ros A. ,   EMBRACE and UKGPCS Collaborators
Published: February 2017

29

Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter cause-specific survival (CSS). Germline BRCA mutations are associated with worse PrCa outcomes. In this study, we analyzed biochemical-progression free survival (bPFS) after conventional treatments for localized PCa in a cohort of BRCA patients from the UK. Currently, BRCA1/2 carriers are treated with the same protocols used for non-carriers. Methods: In this retrospective case-control study, each BRCA carrier (10 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by: age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment (RT or RP), androgen-deprivation therapy (ADT) and year of treatment (±5yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 176 patients (pts) were included. Median follow-up was 97 months (ms). Median age at diagnosis was 58.5 yrs (43-75). 80 pts received RT (16 BRCA2, 4 BRCA1, 60 NC) and 85% also received ADT≥6 ms. 96pts underwent RP (18 BRCA2, 6 BRCA1 and 72 NC). Following RT treatment, 5yrs-CSS was 96% in NC and 47% in BRCA carriers (p=2x10-5), whilst no difference was seen after RP (5yrs-CSS was 98.5% in NC vs 93.3% in BRCA). Five-years bFPFS after RT was 74% in NC and 24% in BRCA (p=0.002). No difference was observed in 5yrs-bPFS between BRCA carriers and NC treated with RP (52% vs 66% , p=0.346). The adjusted MVA (including tumour stage, local treatment, ADT and BRCA status) confirmed the independent prognostic value of BRCA status for bPFS and CSS. Among BRCA carriers, the independent risk was greater when the analysis was limited to BRCA2 pts . Conclusions: Our results suggest that BRCA carriers have worse local disease control than NC when conventionally treated with RT. No differences in bPFS were observed in pts treated with RP after >8 yrs median follow-up. These results may have implications for tailoring clinical management in these patients.
Prediction of pathologic complete response to neoadjuvant chemotherapy in urothelial cancer by genetic determinants of platinum sensitivity.
Authors: O'Donnell Peter H. , Alanee Shaheen , Cao Hongyuan , Ostrovnaya Irina , Garcia-Grossman Ilana Rebecca , Ganshert Cory , Smith Norm D. , Steinberg Gary D. , Offit Kenneth , Stadler Walter Michael , Bajorin Dean F.
Published: February 2017

290

Background: Despite level 1 evidence demonstrating survival benefit for cisplatin-based neoadjuvant chemotherapy in urothelial cancer, its utilization remains low, likely due to the modest benefit and potentially significant toxicities. To improve selection of patients (pts) most likely to benefit, we evaluated the association of pharmacogenomic markers of cisplatin sensitivity with neoadjuvant therapy outcome. Methods: Pts receiving standard neoadjuvant cisplatin-based chemotherapy for muscle-invasive disease were recruited to provide a germline DNA sample. Nine single nucleotide polymorphisms (SNPs) selected for their associations with platinum sensitivity in various clinical and pre-clinical studies were tested for association with complete pathologic response (pT0) rate at cystectomy. Results: Sixty-three Caucasian pts were analyzed (median age=64; 67% male; all bladder primary and cN0). The overall pT0 rate was 27%; 52% were <pT2. Using a multivariate, recessive genetic model, rs244898 in RARS (odds ratio [OR] 6.8 [95% CI 1.6-32.6], P=0.01) and rs7937567 in GALNTL4 (OR 5.2 [95% CI 1.1-26.2], P=0.03) were associated with likelihood of achieving pT0. For each SNP, pts carrying the favorable genotype achieved pT0 in >58% of cases. Demonstrating the apparent independent nature of the two SNPs, pts carrying either favorable genotype had pT0 OR=8.5 (95% CI 2.5-31.8, P=0.0008). The combined effect of detecting both SNPs was most informative, as 2/3 pts with both favorable genotypes achieved pT0 (67%), compared to 9/15 pts with one favorable genotype (60%), and only 6/43 lacking both favorable genotypes (14%). The negative predictive value considering both SNPs was 86%. Conclusions: Two germline SNPs having prior evidence of governing platinum sensitivity in pre-clinical and clinical models were demonstrated to confer strong associations with complete response to cisplatin-based neoadjuvant chemotherapy. Validation testing in an independent, multi-institutional cohort of urothelial cancer pts is underway. If reproducible, these SNPs deserve consideration as predictive clinical biomarkers to inform the use of neoadjuvant chemotherapy in this disease.
The preclinical anti-angiogenic and pro-apoptotic activity of lenalidomide in urothelial carcinoma (UC).
Authors: Jian Weiguo , Levitt Jonathan M. , Chan Keith S. , Lerner Seth P. , Sonpavde Guru
Published: February 2017

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Background: Lenalidomide (Len) is an immunomodulatory drug (IMiD) approved for hematologic conditions and demonstrates immune modulation, anti-angiogenic activity and direct anti-tumor cytotoxicity. A rationale can be made to evaluate the preclinical activity of Len in UC. Methods: The in vitro anti-tumor activity of Len was evaluated in 4 human (5637, TCC-SUP, RT4, RT112) and 1 murine (MB49) cell line. Anti-proliferative activity activity (MTT assay), apoptosis (Annexin-FITC immunohistochemistry [IHC], flow cytometry) and cell viability by colony forming assay were measured. In vivo activity of daily oral Len 10 mg/kg or placebo orally for 5 days a week for up to 4 weeks was examined in syngeneic immunocompetent C57BL/6 mice bearing subcutaneous (SC) MB49-Luc25 tumors and RT4 subcutaneous xenografts. Tumors underwent immunohistochemistry (IHC) for microvessel density (CD31), apoptosis (cleaved caspase [cc]-3) and CD3+/CD20+ lymphocyte infiltration. Cereblon, a molecular target of Len was analyzed by IHC. Results: In vitro cultures for 3 days with daily repletion of Len showed significant pro-apoptotic activity (flow cytometry) at low micromolar concentrations attainable in human subjects (2.2 µM) against RT4 cells, a superficially invasive human UC cell line. Long-term cultures of RT4 cells for 2 weeks with daily repletion of Len significantly reduced cell viability and colony forming ability. Cereblon expression was numerically lower in sensitive RT4 cells compared to resistant 5637 cells (p=NS). In the immunocompetent model in vivo, Len did not decrease tumor size, or increase cc-3 and CD3+/CD20+ lymphocytes, but post-Len tumors exhibited decreased CD31 (p<0.05). In RT4 xenografts, Len significantly decreased the size of tumors and CD31, and increased cc-3 (all p<0.05). Cereblon expression increased in Len treated RT4 xenografts (p=0.024). Conclusions: Lenalidomide demonstrated selective preclinical activity against superficially invasive low grade human UC cells attributable to direct tumor cell apoptosis and anti-angiogenic activity. Clinical evaluation in patients with low grade or non-invasive UC and further study of cereblon as a predictive biomarker may be warranted.
Current management and proposal for guidance of radiation cystitis (RC): Results of a British Uro-oncology Group (BUG) survey.
Authors: Bahl Amit K. , Huddart Robert Anthony , Payne Heather
Published: February 2017

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Background: Although RC is a potentially significant acute and/or chronic complication of radiotherapy to the pelvic area (15-20% incidence), there is limited information about how it is managed in practice. Methods: The BUG membership (comprising of consultant Uro-oncologists) was surveyed as to their perception on and management of RC. Results: 87% (45/52) of respondents supervise radiotherapy to the bladder/pelvis. Of these 45, most consider acute RC during or immediately after treatment a significant problem in ‘some' (56%) or the ‘majority' (11%) of cases (‘minority': 33%). Late RC was mostly considered a significant problem in the ‘minority' of cases (73%), with the rest feeling it was a significant problem in ‘some' cases (27%). During radiotherapy or at follow-up the majority ‘always' (22%) or ‘sometimes' (60%) record the grade of cystitis (‘never': 18%). 93% do not have local guidelines for managing RC. The treatments most frequently used to treat acute RC are: fluids (71%); cranberry juice (36%); analgesia (36%); non-steroidal anti-inflammatory drugs (NSAIDs; 29%); and anti-spasmodics (18%). Mild late RC is treated similarly (fluids: 29%; analgesia: 22%; cranberry juice: 18%; NSAIDs: 16%), although 20% might consider no treatment. For moderate/severe late RC, most refer to an urologist (64%), with grade ≥2 cases, those with haemorrhagic cystitis (20%), and symptoms >90 days post-radiotherapy (18%) being the most common reasons for referral. For those treating moderate/severe late RC, hyperbaric oxygen (38%), fluids (19%), and analgesia (19%) are most commonly used. Over half were not aware of alternative treatment options including mesna (69% not aware), sodium hyaluronate (62%), intravesical prostaglandin E1/E2 (62%), sodium pentosanpolysulphate (60%), or intravesical formalin (51%). All supported the development of national guidelines in collaboration with the British Association of Urological Surgeons and British Association of Urology Nurses. Conclusions: RC is acknowledged as a potentially significant issue, and, with the majority of cases managed by oncology, there is a recognised need for further guidance on optimal treatment and BUG has started this work.
Exome sequencing of extreme phenotypes to identify variants predictive of response to chemotherapy in bladder cancer.
Authors: Alanee Shaheen , Shah Sohela , Stratton Kelly Lynn , Garcia-Grossman Ilana Rebecca , Zabor Emily , Ostrovnaya Irina , Joseph Vijai , Pendse Deepa , Bajorin Dean F. , Offit Kenneth
Published: February 2017

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Background: Little is known about germline variants predictive of response to chemotherapy in bladder cancer (BC). We investigated germline variants in patients (pts) treated with neoadjuvant gemcitabine/cisplatin (GC) under the hypothesis that responders and non-responders may differ in rare alleles predictive of treatment outcome. Methods: The Hiseq platform (≥ 20x coverage) was used to sequence the exomes of muscle-invasive (≥cT2) BC pts representing “extreme phenotypes” defined by response to neoadjuvant GC (complete responders vs. non responders). Responders were pT0N0 at cystectomy and remained disease free >1 year. Non-responders had residual disease in the bladder at cystectomy and metastatic disease either at cystectomy or within 1 year. Rare, potentially deleterious single nucleotide variants (SNVs) unique to these phenotypes were confirmed with Sequenom and validated in an independent group of BC pts treated with GC in the neoadjuvant or first line setting. One-sided Fisher’s exact test and multivariate logistic regression were used to estimate association between SNVs and response. Results: The discovery cohort had 6 responders (4 male) with a mean age of 62 and 9 non-responders (6 male) with a mean age of 63. Filtered exome sequences identified 93 rare/potentially deleterious SNVs unique to non-responders and 45 unique to responders of which 84 and 35 were confirmed by Sequenom, respectively. The independent validation cohort consisted of 173 pts, mean age 60, 72% male, and 53% responders (complete or partial). Among 119 SNVs genotyped in this cohort, only 3 responder and 9 non-responder SNVs were identified in ≥ 3 pts. None of the responder SNVs were associated with response. One non-responder SNV (rs150721903) was significantly associated with resistance to GC (OR: 9.7, 90% CI: 1.7-56.8, p=0.011), and remained significant after adjusting for risk score (p= 0.017). rs150721903 is a missense variant in an uncharacterized protein on chromosome 8. Conclusions: Exome sequencing of extreme phenotypes identified a variant that predicts resistance to GC, demonstrating the feasibility of this pharmacogenomics approach. Further evaluation of this SNV is warranted.
Discovery of molecular biomarker signatures for the detection of bladder cancer.
Authors: Gomes Evan , Urquidi Virginia , Cai Yunpeng , Sun Yijun , Rosser Charles Joel , Goodison Steve
Published: February 2017

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Background: Bladder cancer (BCa) is among the five most common malignancies world-wide, and due to high rates of recurrence, one of the most prevalent. Improvements in non-invasive urine-based assays to detect BCa would benefit both patients and healthcare systems. In this study, the goal was to identify urothelial cell transcriptomic signatures associated with BCa. Methods: Gene expression profiling (Affymetrix U133 Plus 2.0 arrays) was applied to exfoliated urothelia obtained from a cohort of 92 subjects with known bladder disease status. Computational analyses identified candidate biomarkers of BCa and an optimal predictive model was derived. Selected targets from the profiling analyses were monitored in an independent cohort of 81 subjects using quantitative real-time PCR (RT-PCR). Results: Data analysis identified 52 genes associated with BCa (p≤0.001), and gene models that optimally predicted class label were derived. RT-PCR analysis of 48 selected targets in an independent cohort identified a 14-gene diagnostic signature that predicted the presence of BCa with a specificity of 100% at 90% sensitivity. Conclusions: Exfoliated urothelia sampling provides a robust analyte for the evaluation of patients with suspected BCa. The refinement and validation of the multi-gene urothelial cell signatures identified in this preliminary study may lead to accurate, non-invasive assays for the detection of BCa. The development of an accurate, non-invasive BCa detection assay would benefit both the patient and healthcare systems through better detection, monitoring and control of disease.
Pre-cystectomy serum levels of CA19-9, CA125, and CEA: Correlation with pathologic stage and oncologic outcome in urothelial carcinoma of bladder.
Authors: Ahmadi Hamed , Djaladat Hooman , Miranda Gus , Cai Jie , Daneshmand Siamak
Published: February 2017

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Background: To evaluate the association between pre-cystectomy carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and carcinoembryonic antigen (CEA) levels and pathologic stage and oncological outcome of urothelial carcinoma of bladder (UCB). Methods: Preoperative stored serum samples of 186 patients with UCB who underwent radical cystectomy at USC between 2004 and 2009 were randomly selected to measure CA19-9, CA125, and CEA levels. Laboratory cut-off point values were used to define abnormal marker levels (CA 19-9>35.5, CA125>35.5, CEA>3.8). Pathologic stage was categorized as organ confined (OC) (pT1,T2), extravesical (EV) (>pT2), and lymph node positive (LN+) UCB. Cox regression model was used to identify independent predictors of recurrence-free survival (RFS) and overall survival (OS). Results: The mean age of patients were 70 years (ranges, 36-91) and the median follow-up was 4 years (ranges, 0.1–7). 94 (50.5%) patients had OC, 45 (24%) had EV, and 47 (25.5%) had LN+UCB. The mean CA 19-9, CA125, and CEA levels were14 (0.6–278) U/mL, 11.8 (3–79) U/mL, and 2.3 (0.3–30) ng/mL. 30/186 (16%) patients had at least one abnormal marker. Percentage of abnormal CA19-9 was significantly higher in locally advanced UCB (EV and/or LN+) compared to OC UCB (85.7% vs. 48%; P=0.03). The percentage of abnormal CA125 and CEA levels were comparable between locally advanced and OC UCB.4-year RFS and OS were 66% and 65%, respectively. After controlling for pathologic stage, age, and adjuvant chemotherapy; Abnormal CA19-9 and CEA were independent predictors of worse 4-year OS (HR:2.7; P=0.04 and HR:2; P=0.03). Abnormal CA 19-9 was also an independent predictor of worse 4-year RFS (HR: 2.8; P=0.05). Pre-cystectomy CA 125 level had no correlation with oncological outcome. Conclusions: In patients with UCB, abnormal precystectomyserumCA19-9 is correlated with advanced pathological stage and is an independent predictor of worse oncological outcome. Precystectomy CEA and CA 125 showed no significant correlation with pathological stage and oncological outcome. Prospective studies are encouraged to elucidate the clinical value of these serum markers.
Management of cT1 micropapillary bladder cancer.
Authors: Willis Daniel Levi , Fernandez Mario , Dickstein Rian J. , Parikh Sahil , Shah Jay Bakul , Pisters Louis L. , Guo Charles , Czerniak Bogdan , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M.
Published: February 2017

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Background: We have previously reported that intravesical BCG is ineffective as therapy for micropapillary variant of bladder cancer. Since then, smaller reports have emerged with differing conclusions. Here we report our updated experience and expanded number of patients with micropapillary bladder cancer (MPBC), with emphasis on cT1 MPBC. Methods: An IRB approved institutional review of our bladder cancer database identified 255 patients presenting with MPBC with 72 patients staged as cT1N0M0 at the time of initial diagnosis. Statistical and descriptive analysis was performed using IBM SPSS Statistics version 20 and survival analysis was performed using the Kaplan-Meier estimator and compared using the log-rank test. Results: Of the 72 patients with cT1 MPBC, intravesical BCG was used in 38 patients (53%), while 32 (44%) proceeded directly to radical cystectomy. This included 15 (20%) who received neoadjuvant chemotherapy for lymphovascular invasion (LVI). Kaplan-Meier estimates of overall survival (OS) and disease specific survival (DSS) at 5 and 10 years were 66% and 45%, and 70% and 61%, respectively. Among those receiving BCG, 28 (74%) recurred at a median of 7 mo., and 17 (45%) progressed, including 8 (30%) who developed metastatic disease. Among the 10 post BCG patients who underwent cystectomy after progression, median DSS was 43 mo. (mean=53 mo.) and 5 year DSS was 33%, whereas among those proceeding directly to cystectomy, median DSS was not reached (mean=152 mo.) and the 5 year DSS rate was 92% (p<0.001). For OS, upfront cystectomy conferred a median survival of 170 mo. versus 92 mo. for those receiving BCG as initial therapy (p=0.05). There was no association of OS with the presence of CIS, repeat transurethral resection (TUR), or history of intravesical therapy prior to the diagnosis of MPBC. Interestingly, the extent of micropapillary component in the initial TUR specimen did have prognostic value for those treated with BCG as patients with focal MPBC were 2.3 times less likely to progress (p=0.02). Conclusions: Our updated findings support the use of upfront radical cystectomy prior to progression of disease in patients with cT1 MPBC. BCG therapy should be attempted only in select patients as there is a high risk of disease progression during BCG treatment.