High-risk Muscle-invasive Bladder Cancer Research Articles

Study Protocol of the Bladder Adjuvant RadioTherapy (BART) Trial: A Randomised Phase III Trial of Adjuvant Radiotherapy Following Cystectomy in Bladder Cancer

AimsTo assess the efficacy and safety of adjuvant radiotherapy in patients with high-risk muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC) and chemotherapy. Materials and methodsThe BART (Bladder Adjuvant RadioTherapy) trial is an ongoing multicentric, randomised, phase III trial comparing the efficacy and safety of adjuvant radiotherapy versus observation in patients with high-risk MIBC. The key eligibility criteria include ≥pT3, node-positive (pN+), positive margins and/or nodal yield <10, or, neoadjuvant chemotherapy for cT3/T4/N+ disease. In total, 153 patients will be accrued and randomised, in a 1:1 ratio, to either observation (standard arm) or adjuvant radiotherapy (test arm) following surgery and chemotherapy. Stratification parameters include nodal status (N+ versus N0) and chemotherapy (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy). For patients in the test arm, adjuvant radiotherapy to cystectomy bed and pelvic nodes is planned with intensity-modulated radiotherapy to a dose of 50.4 Gy in 28 fractions using daily image guidance. All patients will follow-up with 3-monthly clinical review and urine cytology for 2 years and subsequently 6 monthly until 5 years, with contrast-enhanced computed tomography abdomen pelvis 6 monthly for 2 years and annually until 5 years. Physician-scored toxicity using Common Terminology Criteria for Adverse Events version 5.0 and patient-reported quality of life using the Functional Assessment of Cancer Therapy – Colorectal questionnaire is recorded pre-treatment and at follow-up. Endpoints and statisticsThe primary endpoint is 2-year locoregional recurrence-free survival. The sample size calculation was based on the estimated improvement in 2-year locoregional recurrence-free survival from 70% in the standard arm to 85% in the test arm (hazard ratio 0.45) using 80% statistical power and a two-sided alpha error of 0.05. Secondary endpoints include disease-free survival, overall survival, acute and late toxicity, patterns of failure and quality of life. ConclusionThe BART trial aims to evaluate whether contemporary radiotherapy after standard-of-care surgery and chemotherapy reduces pelvic recurrences safely and also potentially affects survival in high-risk MIBC.

LBA02-08 RESULTS FROM THE EXTENDED FOLLOW-UP IN PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER IN THE CHeckMATE 274 TRIAL

You have accessJournal of UrologyCME1 Apr 2023LBA02-08 RESULTS FROM THE EXTENDED FOLLOW-UP IN PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER IN THE CHeckMATE 274 TRIAL Matthew Milowsky, Matthew D. Galsky, Dean F. Bajorin, Johannes Alfred Witjes, Jürgen E. Gschwend, Michael Schenker, Craiova Romania, Begoña P. Valderrama, Yoshihiko Tomita, Aristotelis Bamias, Thierry Lebret, Shahrokh F. Shariat, Se Hoon Park, Mads Agerbaek, Frank Stenner, Margarita Askelson, Federico Nasroulah, Joshua Zhang, Lynne Brophy, and Gautam Jha Matthew MilowskyMatthew Milowsky More articles by this author , Matthew D. GalskyMatthew D. Galsky More articles by this author , Dean F. BajorinDean F. Bajorin More articles by this author , Johannes Alfred WitjesJohannes Alfred Witjes More articles by this author , Jürgen E. GschwendJürgen E. Gschwend More articles by this author , Michael SchenkerMichael Schenker More articles by this author , Craiova RomaniaCraiova Romania More articles by this author , Begoña P. ValderramaBegoña P. Valderrama More articles by this author , Yoshihiko TomitaYoshihiko Tomita More articles by this author , Aristotelis BamiasAristotelis Bamias More articles by this author , Thierry LebretThierry Lebret More articles by this author , Shahrokh F. ShariatShahrokh F. Shariat More articles by this author , Se Hoon ParkSe Hoon Park More articles by this author , Mads AgerbaekMads Agerbaek More articles by this author , Frank StennerFrank Stenner More articles by this author , Margarita AskelsonMargarita Askelson More articles by this author , Federico NasroulahFederico Nasroulah More articles by this author , Joshua ZhangJoshua Zhang More articles by this author , Lynne BrophyLynne Brophy More articles by this author , and Gautam JhaGautam Jha More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003361.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite radical resection, patients with muscle-invasive urothelial carcinoma (MIUC) remain at high risk for lethal metastatic recurrence, mostly within 2–3 years of surgery. CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in high-risk MIUC after radical resection. The 2 primary endpoints (disease-free survival [DFS] in intent-to-treat [ITT] patients [pts] and in pts with tumor programmed death ligand 1 [PD-L1] expression ≥ 1%) were met. At minimum follow-up of 11.0 months (median: 23.3 months), DFS benefit with NIVO vs PBO was observed in ITT pts (HR 0.70; 95% CI 0.57–0.85) and in pts with PD-L1 ≥ 1% (HR 0.53; 95% CI 0.38–0.75); efficacy benefits (DFS [HR 0.61; 95% CI 0.49–0.77], non-urothelial tract recurrence-free survival [NUTRFS], and distant metastasis-free survival [DMFS]) were also seen in pts with muscle invasive bladder cancer (MIBC). We report extended follow-up results for pts with MIBC (minimum: 31.6 months [median: 36.1 months] in the ITT population). METHODS: Pts were randomized 1:1 to NIVO 240 mg IV Q2W or PBO for ≤1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection±neoadjuvant chemotherapy and were at high risk of recurrence. Primary endpoints are DFS in ITT pts and in pts with PD-L1 ≥1%. NUTRFS is a secondary endpoint. DMFS and safety are exploratory endpoints. Analysis of the MIBC subgroup is exploratory. RESULTS: Of 709 randomized pts, 560 had MIBC (NIVO, n=279; PBO, n=281). DFS was improved with NIVO vs PBO in all pts with MIBC (HR 0.63), and in the PD-L1 ≥1% (HR 0.44) and PD-L1 <1% (HR 0.74) subgroups (Table). HR favored NIVO vs PBO for NUTRFS (HR 0.64) and DMFS (HR 0.70) (Table). Grade 3–4 treatment-related adverse events occurred in 17.3% and 5.8% of NIVO and PBO arm pts, respectively. CONCLUSIONS: With extended 3-year median follow-up, continued improvement in DFS, NUTRFS, and DMFS were observed with NIVO vs PBO in pts with MIBC. DFS benefit was evident regardless of tumor PD-L1 expression. Safety was consistent with previous data in the ITT population with no new safety signals identified. These results further support NIVO as a standard of care for high-risk MIBC after radical resection. Source of Funding: Bristol Myers Squibb © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1189 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Matthew Milowsky More articles by this author Matthew D. Galsky More articles by this author Dean F. Bajorin More articles by this author Johannes Alfred Witjes More articles by this author Jürgen E. Gschwend More articles by this author Michael Schenker More articles by this author Craiova Romania More articles by this author Begoña P. Valderrama More articles by this author Yoshihiko Tomita More articles by this author Aristotelis Bamias More articles by this author Thierry Lebret More articles by this author Shahrokh F. Shariat More articles by this author Se Hoon Park More articles by this author Mads Agerbaek More articles by this author Frank Stenner More articles by this author Margarita Askelson More articles by this author Federico Nasroulah More articles by this author Joshua Zhang More articles by this author Lynne Brophy More articles by this author Gautam Jha More articles by this author Expand All Advertisement PDF downloadLoading ...

IMvigor011: a study of adjuvant atezolizumab in patients with high-risk MIBC who are ctDNA+ post-surgery.

The standard-of-care for muscle-invasive bladder cancer is radical surgery with neoadjuvant cisplatin-based chemotherapy. Despite curative intent from these interventions, relapse rates post-surgery remain high, with approximately 50% of patients developing local or distant recurrence within 2years of surgery and a 5-year survival of only50-60%. Identifying patients who are high risk for relapse post-surgery is a priority. Monitoring patients for circulating tumor DNA (ctDNA) is a minimally invasive approach that appears attractive for selecting patients potentially suitable for adjuvant treatment with checkpoint inhibitors. IMvigor011 (NCT04660344) is a global, double-blind, randomized phase III study assessing the efficacy of atezolizumab (anti-PD-L1) versus placebo in patients with high-risk muscle-invasive bladder cancer who are ctDNA positive post-cystectomy. The primary end point is disease-free survival in participants who are ctDNA positive within 20weeks of cystectomy.

Neural network analysis of tumor and germline profiling to predict survival of muscle-invasive bladder cancer following radical cystectomy: An analysis of the Cancer Genome Atlas (TCGA).

546 Background: Following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), recurrence is suboptimally associated with pathologic stage. A prognostic model that incorporates information from comprehensive genomic and transcriptomic data from germline and tumor tissues will improve the selection of high-risk patients (pts) for adjuvant therapy and tailored surveillance. Methods: Pts with MIBC in TCGA who underwent RC (without neoadjuvant chemotherapy) and with whole exome sequencing (WES) of tumor + normal, and tumor RNA-Seq were eligible. Germline variants were called and annotated using GATK4 and Variant Effect Predictor (VEP). Only high and moderate VEP-Impact variants contributed to burdens. Given that recurrence is associated with 5-year survival, pts were required to have data for survival at a landmark of 5 years post-RC or may have died within 5 years of RC. Patients who died &lt;4 months of diagnosis were excluded since they may have died from post-operative complications. Dead patients were propensity-matched against alive patients by pathologic stage, adjuvant chemotherapy, gender, race, age and smoking. A linear artificial neural network was trained to predict 5-year survival using Artificial Intelligence Quality Control (AIQC)-a deep learning experience tracker. The samples were divided into 3 equally distributed subsets of alive and dead pts. The algorithm was trained on 50% of the dataset, evaluated on 40% and tested on 10%. The remaining 39 dead pts were used for additional holdout validation. The accuracy (percentage of correct prediction of death or survival) was reported. Results: A cohort of 117 pts were evaluable for 5 year survival. The cohort included 39 survivors that satisfied inclusion criteria, and 78 dead pts that were propensity matched against them (one set of 39 dead pts for training &amp; evaluation, and a second set of 39 dead pts as an additional holdout). The binary classification neural network was trained on 38 samples to predict survival based on their most differentiated: germline alteration burdens + tumor alteration burdens + tumor gene expression. The differentially mutated genes most important to the algorithm were: PTPRN(n-m), TECTA(t-m), BPIFB1(n-m), SORL1(n-m), SLC39A5(n-m), and RBBP6(n-h) [t=tumor/ n=normal tissue origin | m=moderate/ h=high VEP impact]. The algorithm was 97% accurate on the 38 training samples, and 94% accurate across the 79 evaluation (validation, test and holdout) samples. Conclusions: Neural network analysis of germline and tumor profiling was validated to optimally differentiate between dead and surviving pts at 5 years following RC for MIBC. Further validation and application of this promising algorithm may advance precision medicine by permitting the selection of the most appropriate pts with high-risk MIBC for adjuvant therapy.

Progression-free survival is an adequate endpoint for clinical trials of locally advanced and metastatic urothelial carcinoma.

To evaluate intermediate clinical endpoints that have been proposed as potential surrogates for overall survival amongst patients with locally advanced and metastatic urothelial carcinoma. Several endpoints have been proposed as potential surrogates for overall survival. They are: pathologic downstaging or complete response after neoadjuvant treatments and progression-free survival in the adjuvant setting and metastatic setting. Formal surrogacy, as per Prentice, has not been established among any of the aforementioned intermediate clinical endpoints and overall survival. Despite that, regulatory agencies have recently approved adjuvant nivolumab for patients with high-risk muscle invasive bladder cancer, based on the results of a trial that had disease-free survival as primary endpoint. Despite the lack of proven surrogacy between progression-free survival and overall survival, this endpoint seems adequate for trial design and medication approval, as the recent case of adjuvant nivolumab demonstrates.

Results for patients with muscle-invasive bladder cancer (MIBC) in the CheckMate 274 trial.

4585 Background: In the CheckMate 274 trial, disease-free survival (DFS) was significantly improved with nivolumab (NIVO) vs placebo (PBO) both in intent-to-treat (ITT) patients (pts) (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P &lt; 0.001) and in pts with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% (HR, 0.55; 98.72% CI, 0.35–0.85; P &lt; 0.001). We report results for the subgroup of pts with bladder cancer, the most predominant type of urothelial carcinoma. Methods: CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant NIVO vs PBO in high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis) after radical resection. Pts were randomized 1:1 to NIVO 240 mg intravenously every 2 weeks or PBO for ≤ 1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection ± neoadjuvant chemotherapy and were at high risk of recurrence on final pathologic staging. Primary endpoints were DFS in ITT pts and in pts with PD-L1 ≥ 1%. Non–urothelial tract recurrence-free survival (NUTRFS) was a secondary endpoint, and distant metastasis-free survival (DMFS) was an exploratory endpoint. This exploratory analysis focused on the subgroup of pts with muscle-invasive bladder cancer (MIBC) after radical resection. Results: Of 709 randomized pts in the trial, 560 had MIBC (NIVO, n = 279; PBO, n = 281). With a minimum follow-up of 11.0 months, a DFS benefit was observed with NIVO vs PBO in these pts, regardless of tumor PD-L1 expression (Table). DFS probability at 12 months in all MIBC pts was 66% with NIVO and 45% with PBO. DFS was improved with NIVO vs PBO across subgroups according to age, sex, ECOG performance status, nodal status, and PD-L1 expression status. Improvement in NUTRFS and DMFS with NIVO vs PBO was also observed (Table). Grade 3–4 treatment-related adverse events occurred in 17% and 6% of pts in the NIVO and PBO arms, respectively. Conclusions: Improvement in DFS was observed with NIVO over PBO in pts with MIBC after radical resection regardless of tumor PD-L1 expression. The DFS benefit was observed in all prespecified subgroups. These results further support adjuvant NIVO as a standard-of-care treatment for pts with high-risk MIBC after radical resection ± neoadjuvant cisplatin-based chemotherapy. Clinical trial information: NCT02632409. [Table: see text]

Adjuvant Radiotherapy After Radical Cystectomy for Patients with High-risk Muscle-invasive Bladder Cancer: Results of a Multicentric Phase II Trial

BackgroundHigh-risk muscle-invasive bladder cancer (MIBC) has a poor prognosis. Old trials showed that external beam radiotherapy (EBRT) after radical cystectomy (RC) decreases the incidence of local recurrences but induces severe toxicity. ObjectiveTo evaluate the toxicity and local control rate after adjuvant EBRT after RC delivered with volumetric arc radiotherapy. Design, setting, and participantsThis is a multicentric phase 2 trial. From August 2014 till October 2020, we treated 72 high-risk MIBC patients with adjuvant EBRT after RC. High-risk MIBC is defined as ≥pT3-MIBC ± lymphovascular invasion, fewer than ten lymph nodes removed, pathological positive lymph nodes, or positive surgical margins. InterventionPatients received 50 Gy in 25 fractions with intensity-modulated radiotherapy to the pelvic lymph nodes ± cystectomy bed. Outcome measurements and statistical analysisThe primary outcome is acute toxicity. We report on local relapse-free rate (LRFR), clinical relapse-free survival (CRFS), overall survival (OS), and bladder cancer–specific survival (BCSS). Results and limitationsThe median follow-up is 18 mo. Forty-two patients (61%) developed acute grade 2 gastrointestinal (GI) toxicity. Four patients (6%) had acute grade 3 GI toxicity. One patient had grade 5 diarrhea and vomiting due to obstruction at 1 mo. Two-year probabilities of developing grade ≥3 and ≥2 GI toxicity were 17% and 76%, respectively. Urinary toxicity, assessed in 17 patients with a neobladder, was acceptable with acute grade 2 and 3 urinary toxicity reported in 53% (N = 9) and 18% (N = 3) of the patients, respectively. The 2-yr LRFR is 83% ± 5% and the 2-yr CRFS rate is 43% with a median CRFS time of 12 mo (95% confidence interval: 3–21 mo). Two-year OS and BCSS are 52% ± 7% and 62% ± 7%, respectively. Shortcomings are the nonrandomized study design and limited follow-up. ConclusionsAdjuvant EBRT after RC can be administered without excessive severe toxicity. Patient summaryIn this report, we looked at the incidence of toxicity and local control after adjuvant external beam radiotherapy (EBRT) following radical cystectomy (RC) in high-risk muscle-invasive bladder cancer patients. We found that adjuvant EBRT was feasible and resulted in good local control. We conclude that these data support further enrollment of patients in ongoing trials to evaluate the place of adjuvant EBRT after RC.

716TiP IMvigor011: A global, double-blind, randomised phase III study of atezolizumab (atezo; anti–PD-L1) vs placebo (pbo) as adjuvant therapy in patients (pts) with high-risk muscle-invasive bladder cancer (MIBC) who are circulating tumour (ct)DNA+ post cystectomy

MIBC has few adjuvant treatment (tx) options. ctDNA analysis is a promising approach for selecting pts potentially suitable for checkpoint inhibitors. In IMvigor010, ctDNA positivity identified pts with high-risk muscle-invasive urothelial cancer who may derive disease-free and overall survival (DFS/OS) benefit from adjuvant atezo. ctDNA– pts had a low relapse risk without improved outcomes with atezo vs observation, suggesting they may be spared adjuvant tx (Powles ESMO IO 2020). Following on these data, IMvigor011 is studying adjuvant atezo vs pbo in pts with high-risk MIBC who are ctDNA+ post cystectomy.

Adjuvant Systemic Therapy for High-risk Muscle-invasive Bladder Cancer After Radical Cystectomy: Current Options and Future Opportunities

We describe the case of a 71-yr-old woman with locally advanced muscle-invasive bladder cancer and stage III chronic kidney disease due to an obstructed nonfunctional left kidney. She was started on neoadjuvant immunotherapy, but had to stop treatment because of acute worsening of renal function. Radical cystectomy was then performed uneventfully, revealing pT3aN1 urothelial carcinoma of the bladder. Adjuvant chemotherapy in high-risk locally advanced bladder cancer after radical cystectomy currently poses several challenges, especially for cisplatin-ineligible candidates. Recent data on adjuvant immunotherapy trials suggest a disease-free survival advantage for this subgroup of patients. The current and future role of immuno-oncology agents in this setting is discussed. Patient summaryPatients with advanced bladder cancer might benefit from further chemotherapy or immunotherapy following bladder removal, but it is still unclear which patients benefit the most from this strategy. Measurement of biomarkers and scans to show urinary function will probably help in optimising patient selection for this treatment in the near future.

Complete Transurethral Resection before Radical Cystectomy May Improve Oncological Outcomes

Objectives: The objective of this study was to assess the impact of complete transurethral resection of bladder tumors (TURBTs) before radical cystectomy on pathological and oncological outcomes of patients with muscle-invasive bladder cancer (MIBC) and high-risk non-MIBC. Materials and Methods: The charts of all patients who underwent radical cystectomy for bladder cancer in 2 academic departments of urology between 1996 and 2016 were retrospectively reviewed. Patients were divided into 2 groups according to the completeness of the last endoscopic resection before radical cystectomy: macroscopically complete transurethral resection (complete) or macroscopically incomplete transurethral resection (incomplete). The primary end point was the recurrence-free survival (RFS). Secondary end points included cancer-specific survival (CSS) and rates of pT0 and downstaging. Results: Out of 486 patients included for analysis, the TURBT immediately preceding radical cystectomy was considered macroscopically complete in 253 patients (52.1%) and incomplete in 233 patients (47.9%). In multivariate analysis, macroscopically complete TURBT was the strongest predictor of both pT0 disease (OR = 3.1; p = 0.02) and downstaging (OR = 7.1; p < 0.0001). After a median follow-up of 41 months, macroscopically complete TURBT was associated with better RFS (5-year RFS: 57 vs. 37%; p < 0.0001) and CSS (5-year CSS: 70.8 vs. 54.5%; p = 0.002). In multivariate analysis adjusting for multifocality, weight of endoscopic resection specimen, cT4 stage on preoperative imaging, interval between endoscopic resection and radical cystectomy, neoadjuvant chemotherapy, pT stage, and associated carcinoma in situ, macroscopically complete endoscopic resection remained the main predictor of better RFS (HR = 0.4; p = 0.0003) and the only preoperative factor associated with CSS (HR = 0.5; p = 0.01). Conclusion: A macroscopically complete TURBT immediately preceding radical cystectomy may improve pathological and oncological outcomes in patients with MIBC and high-risk MIBC.

A TP53-based immune prognostic model for muscle-invasive bladder cancer.

Background: Muscle-invasive bladder cancer (MIBC) patients are subject to unfavorable treatment options and a high recurrence rate. The status of TP53 mutations played an essential role in the progression and the prognosis of MIBC. The present study proposed to investigate the association between TP53 mutations and immunophenotype in MIBC.Results: We established an immune prognostic model (IPM) ground on the immune-associated genes derived from variation analysis between wild-type TP53 and mutated TP53 TCGA-MIBC patients, and validated in another cohort from GEO database. Based on IPM, we divided MIBC patients into low and high risk subgroups. The high risk MIBC patients had higher proportions of macrophages M1, and lower proportions of T cells regulatory (Tregs) and activated dendritic cells than the low risk MIBC patients. Moreover, the expression of immune checkpoints genes (PD1, CTLA4, LAG3, HAVCR2 and TIGIT) was higher in the high risk patients than the low risk patients. In clinical application, IPM exhibited better survival prediction than conventional clinical characteristics.Conclusions: Our investigation presented practical prognostic significance for MIBC patients and displayed the overarching landscape of the immune response in the MIBC microenvironment.Methods: Data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) analysis between the TP53 mutated and wild-type MIBC patients was conducted. The CIBERSORT algorithm was performed to evaluate the proportion of immune cell types. Gene expression profiles from the TCGA and GEO were used as training and testing cohorts to build and validate an immune-related prognostic model (IPM). Genes in the IPM model were first screened by univariate Cox analysis, then filtered by the least absolute shrinkage and selection operator (LASSO) Cox regression. A nomogram was finally established and evaluated by combining both the IPM and other clinical factors.

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the recommended treatment, with the highest level of evidence, for patients with muscle-invasive bladder cancer (MIBC). However, only a minority of patients receive this treatment, mainly due to patient comorbidities, the relatively small survival benefit, and the lack of predictive biomarkers to select those patients most likely to benefit from this multimodal approach. In addition, adjuvant chemotherapy has been recommended for patients with high-risk MIBC, although randomized trials have not provided conclusive evidence on the impact of this approach. At present, however, this situation is changing, largely due to our improved knowledge of the molecular biology of bladder cancer, which has enabled us to identify new prognostic and predictive biomarkers that can be used to select the most appropriate treatment for each patient. Moreover, new active treatments, especially immunotherapy, have shown promising results in the neoadjuvant setting. In addition, the gene expression profile of bladder tumors can be used to classify them into different subtypes, which correlate with specific clinical-pathological characteristics and with treatment response or resistance. Therefore, the main objective for the near future is to introduce these translational breakthroughs into routine clinical practice in order to personalize treatment for each patient.

Systematic analysis of gene expression profiles reveals prognostic stratification and underlying mechanisms for muscle-invasive bladder cancer

BackgroundMuscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice.MethodsThis study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways.ResultsIn the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC.ConclusionsIn summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.

924P - Pathologic outcomes after neoadjuvant chemotherapy for high-risk muscle invasive bladder cancer

BackgroundNeoadjuvant chemotherapy (NAC) with cisplatin-based chemotherapy for muscle invasive bladder cancer (MIBC) has improves overall survival as compared to radical cystectomy (RC) alone. Our group has previously reported high risk features of MIBC that increase benefit of NAC. We report our institutional experience with NAC for patients with high-risk MIBC. MethodsThe records of consecutive high-risk, clinically node negative MIBC patients who underwent RC at our institution between 2005 and 2017 were reviewed. Pre-operative high-risk criteria included one or more of lymphovascular invasion, hydronephrosis, extravesical disease, and/or variant histology. Clinicopathologic and demographic information was collected, including eGFR and a previously validated frailty index. The primary outcomes were pathologic complete response (pCR=pT0N0M0) and downstaging to <pT2N0M0. ResultsIn our cohort (n=674), 74.3% (n=501) of patients received any NAC, most commonly dose dense MVAC (39.3%, n=265) followed by gemcitabine/cisplatin (GC) (13.1%, n=88), other cisplatin-based regimens (OCBR) (10.4%, n=70), and non-cisplatin regimen (NCBR) (11.6%, n=78) were used with similar frequency. The pCR rate was significantly lower without NAC at only 7.5% (n=13, p<0.01), while ddMVAC (30.2%, n=80), GC (25%, n=22), OCBR (25.7%, n=18), and NCBR (23.1%, n=18) all yielded similar results (p=0.55). When controlling for age, baseline eGFR, frailty index, and clinical T stage the chemotherapeutic regimen was not significantly predictive of achieving <ypT2N0M0 when ddMVAC was used as the reference group: GC (OR 0.75, p=0.28), other cisplatin-based regimens (OR 1.25, p=0.44), and non-cisplatin regimens (OR 0.80, p=0.4). At 5-years, cancer specific and overall survival were: 90% and 63% (MVAC); 85% and 47% (GC); 86% and 54% (OCBR); 81% and 50% (NCBR); 81% and 47% (none). ConclusionsThe benefits of NAC for MIBC have been repeatedly demonstrated, however, the rate of pathologic CR in high-risk muscle invasive disease has not been reported in a large series. In our high risk MIBC group, NAC led to significant higher pCR rate as compared to upfront surgery. These findings will serve as a benchmark for future neoadjuvant studies for evaluation of novel regimens. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureM.T. Campbell: Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Apricity health; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Janssen; Non-remunerated activity/ies: BMS; Non-remunerated activity/ies: Roche; Non-remunerated activity/ies: Merck. A.Y. Shah: Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self): Oncology Information Group; Honoraria (self): Roche Pharmaceuticals; Research grant / Funding (institution): BMS; Research grant / Funding (institution): EMD Serono. J. Gao: Travel / Accommodation / Expenses: AstraZeneca. A.O. Siefker-Radtke: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Sharp & Dohme; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy: Bavarian Nordic. C.P.N. Dinney: Advisory / Consultancy: FKD Therapies Oy; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (self): NCI; Research grant / Funding (self): The University of Eastern Finland, Faculty of Health Sciences (UEFHS). A.M. Kamat: Advisory / Consultancy: Photocure; Advisory / Consultancy: FKD; Advisory / Consultancy: Abbott Molecular; Advisory / Consultancy: Theralase; Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy: BioClin Therapeutics; Advisory / Consultancy: Cold Genesys; Advisory / Consultancy: Roviant; Advisory / Consultancy: Sessen Bio; Advisory / Consultancy: Asieris; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: US Biotest; Advisory / Consultancy: Ferring; Advisory / Consultancy: MDxHealth; Leadership role: IBCG; Advisory / Consultancy: TMC Innovation. N. Navai: Shareholder / Stockholder / Stock options: Allogene; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pacira. All other authors have declared no conflicts of interest.

Impact of Adjuvant Radiotherapy on Survival of Patients with Pathological High-Risk Muscle Invasive Bladder Cancer: A Propensity Scored Match Paired Analysis

Radical cystectomy (RC) and pelvic lymph-node dissection (LND) is standard treatment for non-metastatic muscle-invasive urothelial bladder cancer (MIBC). However, loco-regional recurrence (LRR) is a common early event associated with poor prognosis. We tested the hypothesis that the impact of adjuvant radiotherapy (aRT) on oncological outcomes in these individuals is related to tumor characteristics. We retrospectively evaluated 490 patients with muscle invasive bladder cancer (MIBC) with a pT3-4 and/or N+ and/or positive surgical margins (PSM) disease treated with RC with or without aRT between 2000 and 2013 at five tertiary care centers. A 1:1 propensity score matched cohort was built to adjust for age, gender, and neoadjuvant chemotherapy. Multivariable Cox regression analyses on the matched cohort tested the relationship between aRT and LRR, cancer specific mortality (CSM) and overall mortality (OM). 5 years-recurrence-free survival risk stratification-tree analysis was built on the whole matched cohort. Acute Gastro-Intestinal (GI), Genito-Urinary and Blood Count Disorders (BCD) toxicities were recorded according to CTCAE V4.0 scale. Median follow-up was 25 months (Interquartile range: 11-55). Overall, 16% of patients received aRT. At multivariable analysis, aRT was associated with more favorable RR rate (hazard ratio [HR] 0.49, 95% Confidence Interval [CI]: 0.24-0.99), p=0.04). When patients were stratified into risk groups, only those with PSM benefited from aRT. These results were confirmed when 5-years recurrence-free survival was examined as an end point. Moreover, 5 % and 4 % of patients presented grade > 2 acute GI or GU toxicities, respectively. Because of poor prognosis, an effective post-operative standard of care is needed for pathological high-risk MIBC. aRT seems feasible and may have oncological benefits. Prospective trials evaluating this approach with current RT techniques should be undertaken.

A pilot pre-surgical study evaluating anti-PD-L1 durvalumab (durva) plus anti-CTLA-4 tremelimumab (treme) in patients with muscle-Invasive, high-risk urothelial bladder carcinoma who are ineligible for cisplatin-based neoadjuvant chemotherapy.

e16524 Background: In patients with muscle-invasive bladder cancer (MIBC), especially those with high risk features including lymphovascular invasion, hydronephrosis, T3b disease, or variant histology, cisplatin-based neoadjuvant chemotherapy followed by cystectomy improves overall survival as compared to cystectomy alone. However, it is estimated that over 50% of patients with MIBC are ineligible for cisplatin-containing therapy. Therefore, we propose to use durva plus treme as neoadjuvant therapy for this population of patients. Methods: We carried out a single-arm, pre-surgical clinical trial with durva + treme in patients with localized, high-risk MIBC who are ineligible for cisplatin-containing chemotherapy due to decreased renal function, neuropathy, hearing loss, or heart failure (NCT02812420). Each patient will receive durva (1500 mg) plus treme (75 mg) on weeks 1 and 5. Patients will then undergo surgery at week 9-11. Pre- and post-treatment blood and tumor samples will be collected for immunological and genomic analyses for clinical correlation. Results: Twelve patients have been enrolled on this trial. Six patients have completed cystectomy as of January 30, 2018. Of these 6 patients, 3 (50%) had pathologically complete response (pCR); one (17%) did not respond; two (33%) had upstaging of disease. Of the two upstaged patients, one was found to have tumor progression in a pre-existing pelvic lymph node and was taken off trial, treated with chemotherapy, then had cystectomy with pCR. Only 1 of 12 patients developed grade 3 immune related toxicity. Immunologic and molecular analyses are ongoing on all collected samples. Conclusions: To date, out data indicate that durva plus treme may be an effective and well tolerated neoadjuvant therapy for patients with MIBC ineligible for cisplatin-based therapy. Based upon these data, we have expand this pilot trial from 15 to 35 patients. We will also report correlative biomarker data. Clinical trial information: NCT02812420.

A decision-support tool to assist muscle-invasive bladder cancer patients choosing between radical cystectomy and chemoradiotherapy.

505 Background: Patients with high-risk muscle-invasive bladder cancer (MIBC) who are borderline medically operable for radical cystectomy (RC) face a difficult decision between RC which has higher short-term treatment-related morbidity/mortality &amp; chemoradiotherapy (CRT) which is better tolerated in the short-term but may have worse long-term cancer control outcomes. There are no existing decision support tools to assist patients &amp; providers in understanding these trade-offs. Herein, we developed a visualization tool to inform patients &amp; providers how the relative risks &amp; benefits of RC &amp; CRT vary over time with respect to overall survival (OS). Methods: We identified cT2-3 N0 M0 urothelial bladder cancer patients ≥65 y/o treated with RC +/- chemo (n = 5981) or definitive-dose CRT after TURBT (n = 793) in the National Cancer Database, 2003-2011. The database was split into a development &amp; validation cohort. Multivariate Cox regression with time-varying hazard ratio was performed to assess pre-treatment factors associated with OS. The inverse probability of treatment weighting method using the propensity score was employed to reduce selection bias. External validation was performed. Visualization tool showing adjusted survival curves based on pre-op patient features was generated with input from patients &amp; a multidisciplinary expert panel. Tool calculates median OS &amp; the “break-even point,” where the short-term OS disadvantage of RC equals the long-term advantage of RC (i.e. the point where the restricted mean survival for RC &amp; CRT are equal). Results: On MVA, significant predictors of OS were age, Charlson Deyo comorbidity index, &amp; cT stage (p &lt; 0.001 for all). Using these results, we iteratively developed a web application that utilizes clinical inputs to generate patient-specific survival curves that display estimated OS differences over time. Median OS, the break-even point, &amp; percent alive at the break-even point are provided. Conclusions: This is the first decision-support tool developed to assist high-risk borderline operable MIBC patients &amp; their providers in understanding the short-term &amp; long-term trade-offs between RC &amp; CRT. Additional testing is underway.

Adjuvant pelvic radiotherapy for pathological high-risk muscle-invasive bladder cancer: A multicenter retrospective study.

369 Background: Radical cystectomy (RC) and pelvic lymph-node dissection (PLND) are standard procedures in the management of non-metastatic muscle invasive bladder cancer (MIBC). Loco-regional recurrence (LRR) is a common early event associated with a poor prognosis. The aim of this study is to evaluate adjuvant radiotherapy (RT) for pathological high-risk MIBC. Methods: We retrospectively reviewed data from patients treated by RC from 3 institutions. Inclusion criteria were MIBC, histologically proven urothelial carcinoma treated by RC and adjuvant RT. Patients with conservative surgery were excluded. LRR free-survival, overall survival (OS) and metastasis-free survival (MFS) were evaluated. Acute toxicities were recorded according to CTCAE V4.0 scale. Results: Between January 2000 and December 2013, 57 patients with a median age of 66 years (45-84) were included. Post-operative pathological staging was pT2, pT3 and pT4 in 16%, 44%, and 39%, respectively. PLND revealed 28% of pN0, 26% of pN1 and 42% of pN2. For 2 patients, no PLND was performed. Median number of lymph-nodes retrieved was 10 (2-33). Forty-eight patients (84%) received platin-based chemotherapy, 7 in neo-adjuvant and 41 in adjuvant setting. For RT, clinical target volume 1 (CTV 1) alwyas encompasses pelvic lymph nodes and cystectomy bed for 37 patients (65%). Median dose for CTV 1 was 45 Gy (4-50). Dose complement of 16 Gy (5-22) corresponding to CTV 2 was achieved in 53 of cases, depending on pathological features. Intensity Modulated RT was performed in one third of patients. With a median follow-up of 40.4 months, LRR occurred in 8 patients (14%). Three-year loco-regional free survival, MFS and OS were 45% (IC 95%: 0.30-0.60), 39% (IC 95%: 0.25-0.52) and 49% (IC 95%: 0.33-0.63), respectively. Acute grade ≥ 3 toxicities were observed in 5 patients (9%). One patient died with intestinal fistula in septic context. No survival or toxicity predictive factor was identified. Conclusions: Adjuvant radiotherapy for pathological high-risk MIBC is safe and may have oncological benefits. Thus, new prospective trials evaluating this approach with modern RT techniques should be undertaken.

1050 FDG-PET/CT improves staging in patients with high-risk muscle-invasive bladder cancer scheduled for radical cystectomy

1050 FDG-PET/CT improves staging in patients with high-risk muscle-invasive bladder cancer scheduled for radical cystectomy

[18F]Fluorodeoxyglucose – positron emission tomography/computed tomography improves staging in patients with high-risk muscle-invasive bladder cancer scheduled for radical cystectomy

Objective. The aim of this study was to evaluate the clinical use of [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in addition to conventional preoperative radiological investigations in a defined group of patients with high-risk muscle-invasive bladder cancer. Materials and methods. In total, 103 patients with high-risk muscle-invasive bladder cancer defined as stage T3/T4 disease or as stage T2 with hydronephrosis or high-risk histological features, who were provisionally scheduled to undergo cystectomy, were prospectively recruited to the study. The patients were referred to FDG-PET/CT in addition to standard preoperative investigation with computed tomography (CT). The final treatment decision was reached at a multidisciplinary conference based on all available information including the FDG-PET/CT findings. Results. Compared to CT alone, FDG-PET/CT provided more supplemental findings suggesting malignant manifestations in 48 (47%) of the 103 patients. The additional FDG-PET/CT findings led to an altered provisional treatment plan in 28 out of 103 patients (27%), detection of disseminated bladder cancer and subsequent cancellation of the initially intended cystectomy in 16 patients, and identification of disseminated disease and treatment with induction chemotherapy before radical cystectomy in 12 patients. Conclusions. Preoperative FDG-PET/CT changed the treatment plan for a considerable proportion (27%) of the present patients. Accordingly, such examination can potentially improve the preoperative staging of cystectomy patients with high-risk features, and may also reduce the number of futile operations in patients with advanced disease who are beyond cure.