bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum-based biomarkers and liver metastases in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Cotogno Patrick , Ranasinghe Lahiru , Ledet Elisa , Lewis Brian E. , Sartor A. Oliver
Published: February 2018

372

Background: Metastatic castrate-resistant prostate cancer patients with liver metastases have a poor prognosis. No large studies to date have investigated the clinical and biochemical parameters associated with liver metastases in this population. Methods: Patient data was obtained from 1,281 men with mCRPC that were enrolled on to three phase III clinical trials for the treatment of their disease. This clinical trial data was obtained from Project Data Sphere (www.projectdatasphere.org), an initiative of the CEO Roundtable on Cancer's Life Sciences Consortium. Multiple logistic regression was performed on clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline CT/MRI imaging. Variables assessed included prior docetaxel exposure, ECOG performance status, albumin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), hemoglobin, lactate dehydrogenase (LDH), prostate specific antigen (PSA), and total bilirubin. The investigation included lab variables when treated as both dichotomous (based on normal-abnormal ranges) and continuous. Results: Multiple variable analysis demonstrated that an abnormally elevated serum AST and/or LDH was associated with an increased likelihood of having documented radiographic liver metastases (p < 0.0001). The predicted probability of having liver metastases for an abnormally elevated AST or LDH was 13.90% (95% CI 9.12 – 20.59) and 16.80% (95% CI 13.19 – 21.16), respectively. Patients with both an elevated AST and LDH had a 31.31% (95% CI 24.0 – 39.73) probability of having liver metastases as compared to only 6.67% (95% CI 5.17 – 8.57) for those with normal values. The ROC curve for the final model (AST + LDH) containing dichotomous predictors was 0.6683 (p < 0.0001), which was not significantly different when treating the predictors as continuous (p = 0.4858). Conclusions: Our analysis demonstrated a significant association between the presence of liver metastases and elevated serum levels of AST and LDH. More research is needed to validate these biomarkers and determine their application in the clinical setting.
Opinions on the role of brachytherapy boost in management of high-risk prostate cancer: A survey of North American genitourinary expert radiation oncologists.
Authors: McClelland Shearwood , Sandler Kiri A , Degnin Catherine , Chen Yiyi , Mitin Timur
Published: February 2018

373

Background: Three randomized clinical trials have established brachytherapy (BT) boost in combination with external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT) as superior to definitive EBRT and ADT alone in terms of biochemical control (but not overall survival) at the expense of increased toxicity in men with high-risk (HR) prostate cancer (PCa). The current view regarding these two treatment algorithms among North American genitourinary (GU) experts is not known. Methods: A survey was distributed to 88 practicing North American GU physicians serving on decision-making committees of cooperative group research organizations. Questions pertained to opinions regarding BT as monotherapy for low-risk (LR) PCa and BT boost for HR PCa. Responders were asked to self-identify as BT experts vs non-experts. Treatment recommendations were correlated with practice patterns using Fisher’s exact test. Results: Forty-two radiation oncologists completed the survey, of whom 23 (55%) recommend EBRT and ADT alone and 19 (45%) recommend addition of BT boost. Twenty-five participants (60%) identified themselves as BT experts. Nearly 90% of those recommending BT boost were BT experts versus approximately 10% of non-BT experts (p < 0.001). Responders who recommended BT monotherapy as first-choice treatment for LR PCa were more likely to recommend BT boost for HR PCa (p < 0.0001). Conclusions: There is a dramatic polarization in opinions regarding incorporation of BT boost into EBRT+ADT therapy for patients with HR PCa among North American GU radiation oncology experts, who serve on decision-making committees and influence the national treatment guidelines and future clinical trials. Those who identify themselves as BT experts are significantly more likely to recommend BT boost, which may serve as a self-fulfilling prophecy regarding the role of BT in North American clinical practice. These findings are likely to influence the national guidelines and implementation of BT boost in current and future North American PCa clinical studies.
Metastases-directed therapy (MDT) for oligometastatic prostate cancer.
Authors: El-Modir Ahmed
Published: February 2018

375

Background: Stereotactic ablative radiotherapy (SABR) is emerging as a treatment option for patients with oligometastatic prostate cancer. The primary aim of this approach is to prolong disease free survival and delay the initiation of systemic therapies. This retrospective study is aimed to analyse local control, biochemical progression-free survival (b-PFS), toxicity and systemic therapy-free survival in a cohort of patients treated by a single clinician. Methods: Eighteen patients (26 lesions) in patients with relapsed oligometastatic prostate cancer ( 1-3 sites) were treated with SABR, delivered using both cyberknife and VMAT. Doses used were 24 Gy in 2 or 3 fractions for spine and 30 - 40 Gy in 3 fractions for lymph nodes and other bony metastases. All patients had either a Choline or PSMA- PET scan prior to treatment. Response was assessed with PSA testing and repeat scanning when feasible. CTCAE acute and late toxicity was prospectively recorded. Results: Mean age was 68. Previous treatments for the primary prostate cancer included surgery (7 patients), surgery and salvage prostate bed radiotherapy (6 patients), radical radiotherapy (4 patients) and cryotherapy (1 patient). Twelve patients had a single metastatic site, four patients had 2 sites and two patients had 3 sites. Six patients patients were treated with a short course of androgen deprivation therapy (ADT) in addition to SABR. All patients had a fall in PSA with a mean reduction of 75%. Median pre-SABR PSA was 1.83μg/L and median post-SABR PSA was 0.28μg/L. At a median follow-up of 14 months (range 2 - 28.5), 14 patients (78%) remained systemic therapy free. Three patients with a single pelvic lymph node metastases achieved a sustained undetectable PSA level. All 8 patients who had a post-treatment PET scan showed no residual activity at the treated site. One patient experienced G2 acute bowel toxicity, otherwise there was no toxicity above G1. Conclusions: MDT using SABR for relapsed prostate cancer is a safe treatment with promising results in terms of local control, b-PFS and delaying the initiation of systemic therapies. This minimally invasive approach has the potential to improve patients' quality of life, but requires further evaluation in randomised clinical trials.
Cause of radium 223 treatment discontinuation in elderly mCRPC patients.
Authors: Costa Renato Patrizio , Raiti Fabio , Bordonaro Sebastiano , Tripoli Vincenzo , Murabito Alessandra , Licari Maria , Tralongo Paolo
Published: February 2018

376

Background: Prostate cancer is the most common cancer among adult men. Bones are the main metastatic site of prostate cancer. Radium-223 is indicated to treat metastatic castrate-resistant prostate cancer ( mCRPC) with symptomatic skeletal metastases. We evaluate the tolerability of Ra223 treatment in real life setting. Methods: We reported the cases of 38 consecutive non-selected patients with mCRPC symptomatic bone metastases treated in two Italian hospital cancer center from August 2016 to October 2017. The cause of Ra 223 treatment discontinuation in elderly prostate cancer patients were evaluated. Results: due bones metastases, 38 patients were treated with Radium-223; 20 were ≥75 years old (range 75-85 yrs). Patients characteristics and main toxicity are reported (Table). Regarding the elderly patients, hematologic toxicity were the most common adverse events reported. Anemia G2-G3 was observed in 10 pts (50%), thrombocytopoenia G3 in 2 patients (10%) and neutropenia G3 in 4 patients (20%); 12/20 patients interrupted the treatment, of which 10 were ECOG PS2. The number of patients who discontinued the drug because of hematologic adverse events was higher than ALSYMPCA clinical trial. Fatigue G1-G2 incidence was 32%. Unexpectedly we did not record any cases of gastrointestinal toxicity (diarrhea, nausea or constipation). Conclusions: In patients ≥75 years old, anemia G2-G3 was more frequent than data reported in literature, while diarrhea is not found. The data of this experience suggest that elderly vulnerable patients are more exposed to hematologic toxicity that may compromise the outcome of the treatment. For these patients surveillance for early supportive care is relevant. Characteristics of patients with ≥75y. [Table: see text]
Immune checkpoint molecule expression measured using circulating cell-free RNA isolated from the blood of metastatic prostate cancer patients.
Authors: Kollengode Kanthi Athreya , Grussie Erwin , Danenberg Genevieve , Usher Joshua L. , DANENBERG KATHLEEN , Danenberg Peter , Pinski Jacek K.
Published: February 2018

380

Background: Recent studies have identified panels of immune-related genes linked to progression and survival. Expressions usually are measured using RNA from tissue samples. The aim of the present study was to utilize circulating RNA (cfRNA) isolated from hormone-naïve (HN) and castrate-resistant prostate cancer (CRPC) patients to measure gene expressions of PD-L1, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), T-cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte activated gene 3 (LAG-3). Androgen receptor (AR) and AR-variant 7 (AR-v7) expressions were also measured in these samples to test for any possible relationships with the immune checkpoint genes. Methods: Blood samples were collected from 53 metastatic prostate cancer patients. cfRNA was extracted from patients’ plasma and reverse transcribed into complementary DNA. The gene expressions (mRNA levels) of the above genes were determined by quantitative reverse transcription-PCR. Beta-actin was used to normalize gene expressions to total RNA content. Results: Each of the immune signatures tested (PD-L1, TIM-3, LAG-3, CTLA-4) was expressed in over 50% (29/53) of the patients’ blood samples. AR was expressed in 25/53 (47%) samples. Four of these patients (8%) expressed AR-v7, indicating resistance to anti-AR drugs. Patient disease status included: 25% (13/53) CRPC, 74% (39/53) HN, and 1 unknown. Within the CRPC group, a significant negative correlation was found between TIM-3 and CTLA-4 expression (-0.833), and CTLA-4 also correlated with disease progression (0.719). Within the HN group, a significant negative correlation was measured between TIM-3 and PD-L1 (0.589). AR expression did not correlate with other targets measured among all patients or within the CRPC or HN groups. Conclusions: This study demonstrates successful quantitation of immune checkpoint gene expressions as well the AR and AR-v7 genes in plasma of prostate cancer patients. This result opens the possibility of the use of a noninvasive method to measure, monitor and track the dynamic interplay of these genes with changing disease status. Clinical trial information: NCT02853097.
Prospective analysis of 4,474 prostate biopsies to evaluate potential treatment management impact of combined clinical-genomic risk classification.
Authors: Nguyen Paul L. , Zhang Jingbin , Yousefi Kasra , Davicioni Elai , Den Robert Benjamin , Feng Felix Y , Spratt Daniel Eidelberg
Published: February 2018

39

Background: Prior studies suggested integrated clinical-genomic risk grouping can more accurately prognosticate prostate cancer (PCa) outcome than NCCN clinical risk. We evaluated the potential for genomic testing to reclassify patients in a manner that could change management compared to NCCN risk groups. Methods: We evaluated 4,474 consecutive patients with PCa who received the Decipher Biopsy test between 01/2016-08/2017 and had information to determine NCCN risk. Genomic categorizations with the potential to change management were defined as NCCN very low/low to genomic intermediate or high (active surveillance to active treatment), NCCN favorable intermediate to genomic high (radiation therapy [RT] alone to RT plus androgen deprivation therapy [ADT]), NCCN unfavorable intermediate to genomic low (RT + ADT to RT alone), NCCN high risk to genomic low (RT + long term ADT to RT + short term ADT). Results: There were 927 NCCN low-risk, 2,427 intermediate, and 1,120 high-risk patients. Among NCCN low-risk, the incidence of genomic low, intermediate, and high risk was 58.7%, 25.0%, and 16.3% respectively, for NCCN intermediate it was 36.5%, 27.6%, and 35.8%, and for NCCN high risk it was 15.9%, 17.1%, and 67.1%. Management could have been changed in the 41.3% of NCCN low risk patients with intermediate or high genomic risk, 26.7% of favorable intermediate risk patients who had high genomic risk, 32.4% of unfavorable intermediate risk patients with low genomic risk, and 15.9% of high risk patients with low genomic risk. Conclusions: A slight majority (54%) of Decipher Biopsy users have NCCN intermediate-risk disease, likely reflecting a need for further prognostic information to refine recommendations in intermediate risk. Reclassification of NCCN groups by genomic risk was common and an integrated clinical-genomic risk system could have altered treatment recommendations in 41.3% of NCCN low, 26.7% of favorable intermediate, 32.4% of unfavorable intermediate risk, and 15.9% of high risk patients.
Life after prostate cancer diagnosis: One step beyond.
Authors: Glaser Adam , Downing Amy , Wright Penny , Hounsome Luke , Kind Paul , Selby Peter John , Wilding Sarah , Donnelly David , Butcher Hugh , Watson Eila , Richard Wagland , Catto James , Cross William , Mason Malcolm David , Sharp Linda , Velikova Galina , Mottram Rebecca , Allen Majorie , Kearney Therese , Anna Gavin
Published: February 2018

40

Background: Prostate cancer (PCa) outcome studies are frequently restricted to specific disease stage or treatments. Interpretation may be restricted through lack of population control data & selection bias. We report a whole population evaluation of health-related quality of life (HRQL) following diagnosis of PCa compared to a general population (GenPop) cohort. Methods: Cross-sectional postal survey of all men diagnosed with PCa in the UK 18-42 months earlier. Measures of generic HRQL (EQ-5D) and PCa specific outcomes (EPIC-26 & interventions for erectile dysfunction), as defined in ICHOM minimum dataset, were utilized. Comparable GenPop data was collected from men never diagnosed with PCa in Northern Ireland. Results: 35,823 PCa survivors responded (60.8% response rate), median age 71, and 2,995 from the GenPop (30%). Overall HRQL was slightly lower in the PCa men than the GenPop, this difference was significant only in stage 4 disease. Men with PCa were less likely to report problems in individual EQ5D domains than men in the GenPop (62.0% vs. 68.8%). Both populations were most likely to report pain/discomfort, this was lower in PCa men than the GenPop (42.1% vs. 60.8%). Problems increased with age in all domains, with the exception of anxiety/depression. Men generally reported good function on EPIC-26; however PCa survivors reported poorer sexual function (78.9% vs 48%) except in the oldest. Medications/devices/services to aid or improve erections were offered to 45.4%, 26.0% & 16.9% respectively (and considered helpful by 14.7%, 7.5% & 3.2%). Men with PCa reported more problems with urinary leakage (13.1% vs. 7.1%), particularly after surgery. Hormonal symptoms were linked with receiving Androgen Deprivation Therapy and, to a lesser extent, external beam radiation. Conclusions: 18-42 months following diagnosis of PCa significant sexual and urinary morbidity is experienced relative to the GenPop. Specialist support for sexual dysfunction is not always offered. With the exception of men with stage 4 disease, overall HRQL is only mildly reduced. Funding The Life After Prostate Cancer Diagnosis study was funded by the Movember Foundation, in partnership with Prostate Cancer UK, as part of the Prostate Cancer Outcomes programme, grant number BO26/MO.
RNA-sequencing to identify three different molecular grades and immune checkpoint cascades with distinct clinical behaviour in NMIBC.
Authors: Chandrasekar Thenappan , Zlotta Alexandre , Shen Jess , Noon Aidan , Jiang Haiyan , Erlich Annette , Kuk Cynthia , Ni Ruoyu , Sukhu Balram , Chan Kin , Roupret Morgan , Seisen Thomas , Comperat Eva , Sweet Joan , Kulkarni Girish S. , Fleshner Neil Eric , Azad Azar , van der Kwast Theodorus , Wrana Jeff L
Published: February 2018

412

Background: NMIBC has a highly variable clinical behavior not adequately predicted by histological grade or clinical parameters. Some are indolent; others quickly progress to MIBC. Discrepancies between phenotype and genotype is compounded further by interobserver variability in pathological grading. There is an unmet need to improve the prediction of NMIBC. Methods: Whole transcriptomic analysis of 178 bladder tumors (158 NMIBC, 20 MIBC/metastatic) was performed from FFPE tissue incorporating messenger RNA expression, splice variants, gene fusion, mutation detection and immune checkpoint inhibitor cascades. CTLA, PD-1, LAG3, TIM3, TIGIT and B7 were compiled as an index including all major cascade genes. Data were integrated and tested for correlations with pathological grading and clinical outcomes. Conventional pathological grading for WHO 1973 (Grade 1, 2, 3) and 2004 (LG vs HG) classifications was reviewed by 3 expert uro-pathologists. Kappa statistic for interobserver variability was calculated. For validation we used an independent RNA-seq dataset (n = 209, Hedegaard et al. 2016 Cancer Cell). Results: Unsupervised clustering of RNA-Seq data distinguished 3 molecular subtypes of NMIBC; Molecular Grade Related Index (MGRI) 1, MGRI2, MGRI3. MGRI1 comprised of almost exclusively LG tumors. MGRI3 clustered with HG MIBC. Kappa for interobserver variability of expert pathologists was 0.40 and 0.78 in 1973 and 2004 WHO classification, respectively. FGFR3 mutations, FGFR3::TACC3 fusion events and MGRI1 genes were associated with components of xenobiotic metabolism (p = 2.51x10-09) signalling systems, in particular, GTPase regulation (p = 0.002), respiratory cycle genes (p = 0.004), HOX cluster (p = 0.005). MGRI independently predicted progression to MIBC (n = 138, HR = 2.96, 95%CI = 1.70-5.13, p = 1.20x10-04). 5-year PFS in a combined data set (n = 347) differed significantly for MGRI1 (100%) vs MGRI2 (92.2%) vs MGRI3 (73.5%, p = 1.99x10-05, Gray’s test). PD-1 ICC independently predicted progression (OR = 2.85, p < 0.05). Conclusions: RNA-seq delineates 3 molecular classes of NMIBC with different risks of progression to MIBC compared to conventional histologic grading.
Real-world systemic therapy utilization in Medicare patients with locally advanced or metastatic urothelial carcinoma.
Authors: Dinan Michaela Ann , Georgieva Mihaela , Shenolikar Rahul , Scales Charles D.
Published: February 2018

415

Background: Several immunotherapies recently have been approved for the treatment of locally advanced or metastatic bladder cancer that is prevalent in older adults. Utilization patterns in Medicare patients have not been examined and can provide an important context for emerging therapies. Methods: We conducted a retrospective analysis of SEER-Medicare beneficiaries diagnosed with locally advanced (T3-T4, N1-N3, M0) or metastatic urothelial carcinoma (any T, any N, M1) of the bladder or upper urinary tract from 2008 to 2012 and further characterized patients undergoing initial chemotherapy (within 30 days of diagnosis). Individuals receiving neoadjuvant chemotherapy were excluded. Results: A total of 3569 patients met study criteria. Among these, 48% received chemotherapy within 2 years of diagnosis. Receipt of chemotherapy was associated with younger age (median 75 vs 80 years, P< .001) and fewer comorbid conditions, including diabetes (12% vs 16%), renal disease (6% vs 11%), and congestive heart failure (4% vs 8%). A total of 977 patients received chemotherapy, of which 38% had distant metastatic disease and 65% had locally advanced tumors. Most patients had no (70%) or only a single (14%) comorbid medical condition. These patients most commonly received doublet chemotherapy (67%) followed by single-agent (17%) or triple-agent (10%) treatment. Gemcitabine was the most common individual agent received as part of initial chemotherapy (81%), followed by carboplatin (50%), cisplatin (38%), and docetaxel or paclitaxel (each 13%). The most common combination received was gemcitabine/carboplatin (42%) followed by gemcitabine/cisplatin (36%). Conclusions: Only half of Medicare patients with advanced urothelial carcinoma received systemic therapy. Most received a platinum doublet regimen. Gemcitabine in combination with platinum-containing chemotherapy was the preferred treatment. Ongoing assessment of the risks and benefits of emerging treatments for Medicare patients may be warranted with the introduction of targeted and/or immune therapies.
Post-chemotherapy PD-L1 expression correlates with clinical outcomes in Japanese bladder cancer patients treated with total cystectomy.
Authors: Hashimoto Yasuhiro , Noro Daisuke , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Kawaguchi Toshiaki , Ohyama Chikara
Published: February 2018

416

Background: Programmed cell death ligand-1 (PD-L1) is a key target molecule of immunotherapy that is frequently overexpressed in bladder cancer. In the present study, we examined whether PD-L1 expression is associated with clinical outcomes in bladder cancer patients. Methods: We enrolled 102 bladder cancer patients treated with cystectomy at the Aomori Prefectural Hospital between April 2004 and May 2014. We conducted an immunohistochemical examination of PD-L1 expression using the SP142 assay. PD-L1 expression was scored at three diagnostic levels (0/1/2). Results: Of the 102 patients, 82 were men (81.0%) and 20 were women (19.0%) (mean age 60 years, range 43-84 years). Sixty-six patients (64.8%) had previously undergone neoadjuvant chemotherapy [neoadjuvant (+) group]. During the mean observation period of 54.5 months, 42 patients had recurring disease (41.1%) and 34 died (33.3%). The 5-year cause-specific survival (CSS) rate was 66.6%; the 5-year disease-free survival (DFS) rate was 59.7%. In the neoadjuvant (+) group, the 5-year DFS rate was 65.0% for PD-L1 (-) patients and 31.7% for PD-L1 (+) patients (log-rank p = 0.006). In the neoadjuvant (+) groups, the 5-year CSS rate was 69.6% for PD-L1 (-) patients and 48.1% for PD-L1 (+) patients. Differences in CSS and DFS rates between PD-L1 (-) and PD-L1 (+) patients in both treatment groups were statistically significant (log-rank p = 0.006 and 0.039, respectively.) Conclusions: Despite the small study size, our data suggest that post-chemotherapy PD-L1 expression is associated with poor prognosis in patients receiving neoadjuvant chemotherapy who had previously undergone cystectomy.
Comparative effectiveness of bladder-preserving tri-modality therapy versus radical cystectomy for muscle-invasive bladder cancer.
Authors: Royce Trevor Joseph , Feldman Adam S. , Mossanen Matthew , Yang Joanna C. , Shipley William U. , Pandharipande Pari , Efstathiou Jason A.
Published: February 2018

418

Background: Radical cystectomy (RC) has historically been considered the standard of care for muscle invasive bladder cancer (MIBC). An alternative is tri-modality therapy (TMT), a bladder-sparing approach that often achieves preservation of the native bladder. There are limited randomized data comparing these guideline-recommended approaches but, in appropriately selected patients, both are thought to have similar survival outcomes with different morbidity profiles. Therefore this study compared the effectiveness of TMT and RC using decision-analytic modeling with the primary endpoint of quality-adjusted life years (QALYs). Methods: We developed a Markov model simulating the lifetime outcomes for 67-year-old patients after definitive treatment for American Joint Committee on Cancer clinical Stage T2-T4aN0M0 MIBC using two strategies: TMT or RC +/- neoadjuvant chemotherapy (NAC). Probabilities and utilities were extracted from the literature to determine the incremental effectiveness in QALYs. Sensitivity analyses were performed. Results: TMT was the most effective strategy with an incremental gain of 1.13 QALYs over RC (8.37 versus 7.24 QALYs, respectively; Table). One-way sensitivity analyses demonstrated the model was most sensitive to the quality of life (QoL) parameters (i.e. the utilities) for RC and TMT; TMT was more effective than RC irrespective of the RC utility (the 95% confidence interval of the RC parameter demonstrated an incremental gain with TMT of 0.01 to 4.77 QALYs). The model was relatively less sensitive to the probability of death for either strategy. Probabilistic sensitivity analysis demonstrated that TMT was more effective than RC for 75% of model iterations. Conclusions: Treatment of MIBC with organ-sparing TMT in appropriately-selected patients may result in a gain of over 1 QALY relative to RC. Further prospective investigation into the QoL implications of these treatment modalities is warranted. [Table: see text]
Survival outcomes and costs of trimodal therapy compared with radical cystectomy among patients diagnosed with localized muscle-invasive bladder cancer.
Authors: Williams Stephen Bentley , Shan Yong , Jazzar Usama , Mehta Hemalkumar B , Baillargeon Jacques G. , Huo Jinhai (Stephen) , Orihuela Eduardo , Tyler Douglas S. , Swanson Todd A. , Kamat Ashish M.
Published: February 2018

421

Background: Radical cystectomy is the guideline-recommended treatment for muscle-invasive bladder cancer. Recently there has been a resurgence in trimodal therapy with limited data on comparative outcomes, and especially attributable costs. Methods: A total of 3,200 patients aged 66 years or older diagnosed with clinical stage T2-4a bladder cancer from January 1, 2002- December 31, 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data were analyzed. Cox regression analysis and propensity score matching methods were used to determine predictors for overall and cancer-specific survival. Results: A total of 3,200 patients met inclusion criteria. After propensity score matching, 687 patients underwent trimodal therapy and 687 patients underwent radical cystectomy. Patients who underwent trimodal therapy had significantly decreased overall (Hazard Ratio (HR) 1.49, 95% Confidence Interval (CI), 1.31-1.69, p < 0.001) and cancer-specific (HR 1.55, 95% CI 1.32-1.83, p < 0.001) survival, respectively. While there was no difference in costs at 30 days, median total costs were significantly higher with trimodal therapy than radical cystectomy at 90-d ($63,355 vs. $73,420, p < 0.001) and 180-d ($98,005 vs. $164,720, p < 0.001), respectively. Extrapolating these figures to the total US population results in excess spending of $179 million for trimodal therapy compared to less costly radical cystectomy for patients diagnosed in 2011. Conclusions: Trimodal therapy was associated with significantly decreased overall and cancer-specific survival resulting in excess national spending of $179 million in 2011 compared with radical cystectomy. These findings have important health policy implications regarding appropriate use of high-value based care among patients who are candidates for either treatment.
Novel small-molecule RORγ agonist immuno-oncology agent LYC-55716: Tumor selection and evaluation of renal cell and bladder cancer for inclusion in phase 2a expansion.
Authors: Hu Xiao , Liu Xikui , Li Hongxiu , Zawidzka Elizabeth , Weems Garry Alan , Gao Yilin , Fox Brian , Wilkins H. Jeffrey , Carter Laura
Published: February 2018

424

Background: The master transcription factor retinoic acid receptor–related orphan receptor γt (RORγ) controls Type 17 effector T cell differentiation and function. Synthetic RORγ agonists modulate gene expression to enhance immune effector functions and decrease regulatory T cell (Treg) development and expression of checkpoint pathways. RORγ agonists have shown promise as mono- and combination therapy in syngeneic tumor models. Translational and bioinformatics analyses were performed to evaluate renal cell carcinoma (RCC) and bladder cancer (BC) for inclusion in a Phase 2a expansion trial of the investigational RORγ agonist LYC-55716 (NCT02929862). Methods: A gene signature was identified through transcriptional profiling of murine and human T cells treated ± RORγ agonists. Bioinformatics analyses were then conducted using data on RCC and BC patients from The Cancer Genome Atlas (TCGA) to determine (a) RORγ and RORγ-inducing cytokine expression; (b) signature genes associated with RORγ biology, biomarkers for endogenous RORγ ligands, and correlations with patient survival rates; and (c) tumor microenvironment (TME) immune profiles. Results: Expression: RNA sequencing analysis identified RORγ+ cells in a significant fraction of RCC and BC samples. RORγ-inducing cytokines IL6, IL23a, and IL1b as well as other genes that support Type 17 differentiation were highly expressed in RCC and BC. Biology: Low expression of sterol efflux genes in RCC and BC tumors suggested low levels of endogenous RORγ ligands in the TME. Importantly, analysis revealed a positive correlation between patient survival and expression of RORγ (or the RORγ signature gene IL17A) for RCC. Immune profile: Analysis of RCC and BC tumors indicated high infiltration of CD3+, CD4+, and CD8+ T cells and high mutation burden, which are associated with immunotherapy efficacy. Conclusions: Translational and bioinformatics studies of RORγ expression, biology, and tumor immune profiles support the inclusion of RCC and BC patients in an ongoing Phase 2a expansion trial of LYC-55716.
Impact of number of cycles of platinum-based first-line chemotherapy for advanced urothelial carcinoma.
Authors: Necchi Andrea , Mariani Luigi , Lo Vullo Salvatore , Raggi Daniele , Giannatempo Patrizia , Bamias Aristotelis , Crabb Simon J. , Bellmunt Joaquim , Yu Evan Y. , Niegisch Guenter , Vaishampayan Ulka N. , Theodore Christine , Berthold Dominik R. , Srinivas Sandy , Sridhar Srikala S. , Plimack Elizabeth R. , Rosenberg Jonathan E. , Powles Thomas , Galsky Matthew , Sonpavde Guru
Published: February 2018

426

Background: 6 cycles of platinum-based chemotherapy (CT) are conventionally targeted to treat locally advanced unresectable or metastatic urothelial carcinoma (UC). However, cisplatin is associated with significant cumulative toxicities, which render it challenging to deliver 6 cycles. Since this issue has not been investigated prospectively, we conducted a retrospective analysis. Methods: The Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) database was used to conduct a retrospective analysis. The association of the number of cycles of platinum-based first-line CT with overall survival (OS) was investigated by a Cox regression utilizing multivariate analysis after controlling for previously recognized prognostic factors used in a nomogram ( Eur Urol, 2017). The primary analysis was a comparison of < 6 cycles vs. ≥6 cycles. Six-month landmark analysis was applied throughout, accounting for OS events. Additionally, we excluded patients (pts) receiving < 3 or > 9 cycles to reduce confounding due to early removal for toxicities, progression and patient decision and increased number of cycles due to response and pt-related factors. Results: Of 1020 pts available from RISC, 472 (cisplatin = 338, carboplatin = 134) were evaluable for the landmark analysis with 281 events. A total of 157 pts received 3-5 cycles (median 4) and 315 received 6-9 cycles (median 6). There was no significant difference between 3-5 vs. 6-9 cycles of platinum-based chemotherapy (HR 1.02, 95%CI: 0.77-1.33, p = 0.91). No significant interactions were observed with type of platinum (p = 0.09) and “completed planned CT” (p = 0.56). Comparison of 4 vs. 6 cycles (p = 0.57) and < 6 vs 6 vs 7-9 (p = 0.9) also yielded no significant differences for association with OS. No differential association was observed with survival for 3-5 vs. 6-9 cycles when examining by nomogram-defined risk group tertiles. Limitations of a hypothesis-generating retrospective analysis apply. Conclusions: 4 cycles of platinum based first-line CT appear adequate to treat advanced UC. The omission of excessive cycles will avoid unnecessary toxicities and facilitate better transition to second-line and switch maintenance therapy.
Effect of detecting asymptomatic recurrence after radical cystectomy on prognosis in patients with muscle invasive bladder cancer.
Authors: Hatakeyama Shingo , Kusaka Ayumu , Kodama Hirotake , Tokui Noriko , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2018

428

Background: The prognostic benefit of oncological follow-up to detect asymptomatic recurrence after radical cystectomy (RC) remains unclear. We aimed to assess whether routine follow-up to detect asymptomatic recurrence after RC improves patient survival. Methods: We retrospectively analyzed 581 RC cases for muscle invasive bladder cancer at four hospitals between May 1996 and February 2017. All patients had regular follow-up examinations with urine cytology, blood biochemical tests, and computed tomography after RC. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of recurrence (asymptomatic group vs. symptomatic group) was estimated using the Kaplan–Meier method with the log–rank test. Cox proportional hazards regression analysis via inverse probability of treatment weighting (IPTW) was used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: Of the 581 patients, 175 experienced relapse. Among those, 12 without adequate data were excluded. Of the remaining 163 patients, 76 (47%) were asymptomatic and 87 (53%) were symptomatic at the time of diagnosis. The most common recurrence site and symptom were lymph nodes (47%) and pain (53%), respectively. Time of overall survival after RC and from recurrence to death were significantly longer in the asymptomatic group than symptomatic group. A multivariate Cox regression analysis using IPTW showed that in the patients with symptomatic recurrence was an independent risk factor for overall survival after RC and survival from recurrence to death. Conclusions: Routine oncological follow-up for detection of asymptomatic recurrence contributes to a better prognosis after RC.
Oncological outcomes of neoadjuvant chemotherapy in patients with locally advanced upper tract urothelial carcinoma: A multicenter study.
Authors: Hatakeyama Shingo , Kubota Yuka , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2018

429

Background: The clinical impact of neoadjuvant chemotherapy (NAC) on oncological outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC) remains unclear. We investigated the oncological outcomes of platinum-based NAC for locally advanced UTUC. Methods: A total of 426 patients who underwent radical nephroureterectomy at five medical centers between January 1995 and April 2017 were examined retrospectively. Of the 426 patients, 234 were treated for a high-risk disease (stages cT3–4 or locally advanced [cN+] disease) with or without NAC. NAC regimens were selected based on eligibility of cisplatin. We retrospectively evaluated post-therapy pathological downstaging, lymphovascular invasion, and prognosis stratified by NAC use. Multivariate Cox regression analysis was performed for independent factors for prognosis. Results: Of 234 patients, 101 received NAC (NAC group) and 133 did not (Control [Ctrl] group). The regimens in the NAC group included gemcitabine and carboplatin (75%), and gemcitabine and cisplatin (21%). Pathological downstagings of the primary tumor and lymphovascular invasion were significantly improved in the NAC than in the Ctrl groups. NAC for locally advanced UTUC significantly prolonged recurrence-free and cancer-specific survival. Multivariate Cox regression analysis using an inverse probability of treatment weighted (IPTW) method showed that NAC was selected as an independent predictor for prolonged recurrence-free and cancer-specific survival. However, the influence of NAC on overall survival was not statistically significant. Conclusions: Platinum-based NAC for locally advanced UTUC potentially improves oncological outcomes. Further prospective studies are needed to clarify the clinical benefit of NAC for locally advanced UTUC.
Evaluating the cost-effectiveness of hydrogel spacer in radiotherapy (RT) of prostate cancer (PC).
Authors: Khairnar Rahul Ramesh , Levy Joseph , Mishra Mark
Published: February 2018

43

Background: A hydrogel rectal spacer (HRS) is an FDA-approved medical device used to increase the separation between the rectum and the prostate. A recent phase III trial demonstrated a small reduction in the incidence of RT toxicities associated with use of HRS. We conducted a cost-effectiveness analysis of HRS use in PC patients undergoing intensity modulated radiation therapy (IMRT). Methods: A multi-state Markov model was constructed to examine the cost-effectiveness of HRS in men with localized PC receiving IMRT in the US (arms: IMRT alone vs. IMRT + HRS). Subgroups included delivery site of IMRT (hospital vs. ambulatory) and baseline sexual function (SF) (general population vs. those with good SF). Based on previous studies, recurrence and survival were assumed equal for both arms. Data on SF, gastrointestinal and genitourinary toxicities incidence, as well as potential risks associated with HRS implantation were obtained from a recently published clinical trial. Health utilities and costs were derived from the literature and 2018 Physician Fee Schedule. Quality-adjusted life years (QALYs) and costs were modeled for a 5-year period from receipt of RT. Probabilistic sensitivity analysis (PSA) and value-based threshold analysis were conducted. Costs and utilities were discounted at 3% annually. Results: The per-person 5-year incremental cost for HRS administered in a hospital was $4,008 and the incremental effectiveness was 0.0273 QALYs. The incremental cost-effectiveness ratio (ICER) was $146,746 (95% credible interval from PSA $125,638 – $178,049) for PC patients undergoing HRS insertion in a hospital vs. $73,359 ($66,732 – $86,767) for patients undergoing HRS insertion in an ambulatory facility. For men with good SF, the ICER was $55,153 ($46,002 – $76,090) and $26,542 ($17,399 – $46,044) in hospital vs. ambulatory facility. Conclusions: This study is the first to evaluate the cost-effectiveness of HRS based on long-term toxicity data. Based on the current Medicare Physician Fee Schedule, HRS is cost-effective in men with good SF at a willingness to pay threshold of $100,000 and it is marginally cost-effective for the entire population depending on the facility where the HRS is inserted.
Risk-stratified surveillance and cost effectiveness of follow-up after radical cystectomy in patients with muscle-invasive bladder cancer.
Authors: Hatakeyama Shingo , Kusaka Ayumu , Hosogoe Shogo , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2018

430

Background: The cost effectiveness of oncological surveillance after radical cystectomy are not clear. We aimed to develop a risk stratification and a surveillance protocol with improved cost effectiveness after radical cystectomy. Methods: We retrospectively evaluated 581 patients with radical cystectomy for muscle-invasive bladder cancer at 4 hospitals. Patients with routine oncological follow-up were stratified into normal- and high-risk groups by a pathology-based protocol utilizing pT, pN, lymphovascular invasion, and histology. Cost effectiveness of the pathology-based protocol was evaluated and a risk-score-based protocol was developed to optimize cost effectiveness. Risk-scores were calculated by summing risk factors independently associated with recurrence-free survival. Patients were stratified by low-, intermediate-, and high-risk score. Estimated cost per one recurrence detection by the pathology and by risk-scores were compared. Results: Of 581 enrolled patients, 175 experienced disease recurrences. The pathology-based protocol presented significant differences in recurrence-free survival, but the medical expense was high, especially in normal-risk (≤pT2pN0) patients. Cox regression analysis identified six factors that associated with recurrence-free survival. Risk score-based 5-year follow-up was significantly more cost effective than the pathology-based protocol. Conclusions: Risk-score-stratified surveillance protocol has potential to reduce over-evaluation after radical cystectomy without adverse effects on medical cost.
Atezolizumab (atezo) and subsequent therapies in patients (Pts) with metastatic urothelial carcinoma (mUC) outside clinical trials.
Authors: Barata Pedro C. , Koshkin Vadim S. , Mendiratta Prateek , Gopalakrishnan Dharmesh , Karafa Matt , Allman Kimberly D , Martin Allison , Beach Jennifer , Profusek Pam , Tyler Allison Janine , Wood Laura S. , Ornstein Moshe Chaim , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I. , Grivas Petros
Published: February 2018

432

Background: The use of immune checkpoint inhibitors (ICI) has revolutionized treatment of mUC. Little is known about the outcomes and safety profile of pts treated with ICI outside of clinical trials, as well as about responses to subsequent therapies. Methods: A retrospective analysis of consecutive mUC pts who received ≥1 dose of atezo 1200 mg every 3 weeks from May 2016 through April 2017 was conducted. Exploratory assessments included overall response rate according to RECIST v1.1, progression-free survival (PFS) and overall survival (OS) since time of treatment initiation, and treatment-related adverse events (TRAE) according to CTCAE v4.03. Results: A total of 79 pts were identified; median age 72 (29-93), 71% men, 27% never smokers, 66% pure urothelial histology, 49% visceral disease, 76% ECOG PS 0-1 and 61% with 1-2 Bellmunt risk factors. Most pts (79%) had primary tumor in bladder, 62% prior surgery and 75% ≥ 1 prior treatment. Most pts (71%) had 1-2 prior lines of treatment, 4% of pts had 3 lines, and 25% of pts had no prior systemic treatment. Pts received a median of 4 atezo doses (1-18) and median treatment duration was 3.2 months (95%CI 1.9-4.5). In 55 pts evaluable for response, 25% had partial response, 36% stable disease and 38% progressive disease, with a median time to best response of 2.7 months (1.3-7.4) and median PFS 4.5 months (95%CI 3.4-5.6). Estimated OS for the entire cohort was 8.3 months (median not reached) and was not significantly different based on prior therapy. TRAE of any grade were noted in 89% of pts and mostly included fatigue (63%) and anorexia (28%). Two pts had grade 4 hyperbilirubinemia, and no toxic deaths were noted. At time of data analysis, 34% of pts remained on atezo, 16% received 1-2 subsequent treatments with median duration of 1.3 months ( 95%CI 0.5-2.2) and 8% PR as best response, 41% were referred to hospice or died, and 9% were lost to follow-up. Conclusions: Pts with mUC treated with atezo had comparable outcomes and toxicity to those reported in clinical trials. Pts who progressed on atezo were unlikely to receive subsequent treatment and the benefit of such treatment was limited. Results may impact clinical trial designs and timing in regard to ICI.
Apparent plasticity in the biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.
Authors: Seiler Roland , Gibb Ewan , Wang Natalie Qiqi , Oo Htoo Zarni , Lam Hung-Ming , van Kessel Kim E.M , Takhar Mandeep , Erho Nicholas , Winters Brian , Douglas James , Van Rhijn Bas W.G. , Sjödahl Gottfrid , Zwarthoff Ellen C , Thalmann George N. , Davicioni Elai , Boormans Joost L , Dall'era Marc , Van Der Heijden Michiel Simon , Wright Jonathan L. , Black Peter C.
Published: February 2018

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Background: After cisplatin-based neoadjuvant chemotherapy (NAC) almost two thirds of patients have residual muscle-invasive bladder cancer (MIBC) present at radical cystectomy (RC). The alterations induced by NAC in these cisplatin-resistant tumors remain largely unstudied. Here, we aim to investigate the characteristics of cisplatin-resistant tumors. Methods: RC samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. In addition, the tumor bed (scar tissue) of 21 post-NAC RC specimens with no residual tumor was profiled. Unsupervised consensus clustering (CC) was performed and the CC were investigated for their biological and clinical characteristics. H&E and immunohistochemistry (KRT5/6, GATA3, KI67 and CD8) were used to confirm tissue sampling and gene expression analysis. Results: Unsupervised consensus clustering yielded four distinct consensus clusters (CC). Consistent basal-(CC1) and luminal-like (CC2) phenotype similar to pre-NAC subtyping was observed in 42% of cases. One third of cases became immune-infiltrated (CC3) in the post-NAC setting but lacked basal and luminal markers. These tumors expressed a strong T-cell signature, chemokine signaling and checkpoint molecules. Conversely, CC4 was associated with healing/scarring. This ‘scar-like’ character of CC4 was consistent with the scar samples. Despite being pathological non-responders, the relative risk of death for CC4 was 2.8 and 3 times less than CC2-Luminal (p = 0.038) and CC3-Infiltrated (p = 0.018), respectively. Luminal-like pre-NAC samples were more likely to adopt a scar-like character (CC4) in the post-NAC setting, while the basal-like tumors were more likely to develop luminal features (CC2). Conclusions: This study expands our knowledge of cisplatin-resistant MIBC by suggesting molecular subtypes to understand the biology of these tumors. Clinical trials are necessary to test the impact of these molecular subtypes with respect to selection of adjuvant and salvage treatments. Post-NAC immune infiltration could have implications for subsequent immunotherapy.