Bladder-sparing Trimodality Therapy Research Articles

Comparing Long-Term Survival Outcomes for Muscle-Invasive Bladder Cancer Patients Who Underwent with Radical Cystectomy and Bladder-Sparing Trimodality Therapy: A Multicentre Cohort Analysis.

Background Although radical cystectomy (RC) is the clinical practice guideline-recommended treatment of muscle-invasive bladder cancer (MIBC), bladder-sparing trimodality therapy (TMT) has emerged as a valid treatment option. Findings comparing the survival outcomes for MIBC patients who underwent RC and TMT are inconclusive. Objective We designed a large hospital-based multicohort study to compare the effectiveness of TMT with RC. Methods Information on deaths was jointly retrieved from EMR (electronic medical record), cause of death registry, and chronic disease surveillance as well as study-specific questionnaire. To avoid the systematical difference between patients who received two modalities, RC-MIBC cohort was propensity score-matched to TMT-MIBC cohort, and the Cox proportional hazard regression was used to calculate the overall survival (OS) and disease-specific survival (DSS). Results There were 891 MIBC patients treated with RC and another 891 MIBC patients who underwent with TMT in the propensity score matching. Comparable effectiveness between two modalities was observed for DSS (HR, 1.20; 95% confidence interval (CI), 0.94 to 1.49) and OS (HR, 1.17; 95% CI, 0.91 to 1.43) according to multiple adjustment after a median follow-up of approximately 9.3 years. However, a relatively higher mortality rate around 5 years after TMT treatment was found compared to RC (HR, 1.26; 95% CI, 1.01 to 1.53). The respective 5-year OS rates were 69% and 73% for TMT cohort and RC cohort, respectively. Conclusions Our findings supported that MIBC patients with TMT yielded survival outcomes comparable to MIBC patients who underwent RC overall. Treatment options should be suggested considering patients' age and willingness.

Comparison of Trimodal Therapy Versus Radical Cystectomy for Each Stage of Muscle-invasive Bladder Cancer

Purpose: Radical cystectomy (RC) has long been the standard of care for the management of muscle-invasive bladder cancer (MIBC). However, an increasing trend of bladder-sparing trimodal therapy (TMT) using maximal transurethral resection of bladder tumor, followed by radiation therapy (RT) with concomitant radiosensitizing chemotherapy, has been advocated. We compared the differences regarding long-term oncological outcomes between patients who accepted RC or TMT for MIBC. Materials and Methods: Between January 2012 and December 2018, 207 patients were diagnosed with MIBC at our center. We excluded patients with metastasis disease, received other treatments, and lost to follow-up. The patients were categorized into Group 1 (TMT) and Group 2 (RC). Both the groups with each tumor stage were compared for disease-free survival (DFS) and overall survival (OS) rates, and the risk factors for recurrence and survival were assessed. Results: In total, 58 (48.7%) patients in Group 1 underwent TMT and 61 (51.3%) patients in Group 2 underwent RC. The mean follow-up was 39.8 months. The 3-year DFS rates were 44.1% and 69.7% for Groups 1 and 2, respectively (P = 0.003). The 3-year OS rates were 61.7% and 72.5% for Groups 1 and 2, respectively (P = 0.226). We also analyzed the DFS with each stage, and the results showed a lower DFS rate for T2 and N0 stages. Conclusion: There was no significant survival benefit for MIBC with either RC or TMT. However, RC is associated with better outcome of DFS rate, especially for patients with early stages of MIBC in stages T2 and N0.

Targeting barriers to wider use of trimodality therapy in localized muscle invasive bladder cancer.

Radical cystectomy with bilateral pelvic lymphadenectomy and trimodality bladder-sparing therapy or TMT, are both curative options for patients with nonmetastatic muscle invasive bladder cancer. Patients should be afforded the opportunity for a multidisciplinary evaluation with equipoise in discussing these options for eligible patients. We discuss the barriers to broader acceptance and utilization of TMT and encourage support of clinical trials of TMT.

Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in Muscle-Invasive Bladder Cancer

Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in Muscle-Invasive Bladder Cancer

Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada

BACKGROUND: Despite recent advances in the management of muscle-invasive bladder cancer (MIBC), treatment outcomes remain suboptimal, and variability exists across current practice patterns. OBJECTIVE: To promote standardization of care for MIBC in Canada by developing a consensus guidelines using a multidisciplinary, evidence-based, patient-centered approach who specialize in bladder cancer. METHODS: A comprehensive literature search of PubMed, Medline, and Embase was performed; and most recent guidelines from national and international organizations were reviewed. Recommendations were made based on best available evidence, and strength of recommendations were graded based on quality of the evidence. RESULTS: Overall, 17 recommendations were made covering a broad range of topics including pathology review, staging investigations, systemic therapy, local definitive therapy and surveillance. Of these, 10 (59% ) were level 1 or 2, 7 (41% ) were level 3 or 4 recommendations. There were 2 recommendations which did not reach full consensus, and were based on majority opinion. This guideline also provides guidance for the management of cisplatin-ineligible patients, variant histologies, and bladder-sparing trimodality therapy. Potential biomarkers, ongoing clinical trials, and future directions are highlighted. CONCLUSIONS: This guideline embodies the collaborative expertise from all disciplines involved, and provides guidance to further optimize and standardize the management of MIBC.

Abstract IA25: Molecular biomarkers of chemoradiation response in bladder preservation therapy

Abstract The standard definitive treatment options for muscle-invasive bladder cancer are radical cystectomy or bladder-sparing trimodality therapy (TMT), consisting of maximal transurethral resection of bladder tumor followed by chemoradiation therapy. Although multiple series show these two treatment approaches have similar overall long-term outcomes, recent studies suggest that molecular biomarkers may identify subgroups of patients who may preferentially benefit from one type of therapy over the other. Such biomarkers include tumor-intrinsic genes involved in DNA repair and signal transduction, which confer sensitivity or resistance to radiation therapy based on the intrinsic biology of the tumor. Emerging biomarkers also include molecular signatures of the tumor microenvironment, suggesting an important role for tumor-extrinsic factors in governing therapeutic sensitivity or resistance. This presentation will review the evidence and rationale underlying potential prognostic and predictive molecular biomarkers in bladder preservation therapy. A specific focus will be on our recent gene expression profiling of 136 muscle-invasive bladder cancer patients treated with bladder-sparing TMT. Our analysis showed that higher immune infiltration was associated with improved disease-specific survival after TMT, whereas higher stromal infiltration was associated with shorter disease-specific survival in a comparison cohort treated with radical cystectomy after neoadjuvant chemotherapy. These findings require validation studies in additional cohorts, which are currently ongoing. An additional focus of the presentation will be on emerging liquid biopsy biomarkers of minimal residual disease after bladder cancer therapy. The standard follow-up for patients after bladder-sparing TMT includes cystoscopies with biopsies and imaging studies at regular intervals. Liquid biopsy approaches such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) may enable noninvasive monitoring of response and detection of minimal residual disease after therapy, with a substantial lead time over conventional follow-up approaches including imaging. If validated in prospective clinical trials, molecular biomarkers may guide the tailored selection of appropriate treatments for individual patients with muscle-invasive bladder cancer, as well as enable noninvasive monitoring of patients after therapy. Such biomarkers also have potential to guide the use of synergistic combinations of immunotherapy with chemoradiation therapy for bladder cancer. Citation Format: David T. Miyamoto. Molecular biomarkers of chemoradiation response in bladder preservation therapy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA25.

Trimodality Therapy for Muscle-Invasive Bladder Cancer: Recent Advances and Unanswered Questions.

Bladder-sparing trimodality therapy (TMT) has become an accepted alternative to cystectomy for selected muscle invasive bladder cancer (MIBC) patients unfit for cystectomy or opting for bladder preservation. This review will summarize recent advances in TMT for MIBC. A growing body of literature has emerged which supports the use of TMT. However, its delivery is yet to be standardized. The role of chemotherapy and predictive biomarkers remain to be elucidated. Novel bladder-sparing approaches, drug combinations including immunotherapy and targeted therapies are under investigation in clinical trials, with the goal of ultimately enhancing survival and quality of life outcomes. Recent advances in TMT have made bladder preservation possible for MIBC patients seeking an alternative local therapy to cystectomy. With careful patient selection, TMT offers comparable survival outcomes to cystectomy, and improved quality of life as patients are able to successfully retain their bladder.

Bladder-sparing trimodal therapy versus radical cystectomy for muscleinvasive bladder cancer: A systematic review and meta-analysis of comparative studies

Objective: To compare oncologic outcomes between patients with muscle-invasive bladder cancer who were treated with radical cystectomy (RC) or trimodal therapy (TMT). Materials and Methods: The primary sources were the PubMed, Embase, and Cochrane Library electronic databases. Studies published between June 1990 and July 2017 that evaluated combination bladder-sparing surgery for a bladder tumour with radiotherapy (RT) and chemotherapy compared with RC surgery alone for MIBC were included. Published data were extracted and used to calculate the 5-year overall survival rates. The secondary efficacy endpoints were disease-free survival and local and distant recurrence. Results: Nine studies incorporating 15,160 cases were included in the final analysis. Pooled data from 8 studies that assessed overall survival rates for 15,089 patients showed no significant differences in this metric between the TMT and RC groups (HR: 1.27; 95% CI, 0.98-1.63; P=0.066). No significant differences were found between TMT and RC in the subgroup analyses according to the lymph node stage (Nx), age and physiclal status (PS) stage, but differences were found for patients with node-negative disease (HR: 1.36; 95% CI, 1.02-1.81; P=0.036). Disease-free survival and local and distant recurrence did not differ significantly between the techniques. Conclusion: RC seems to be suitable for node-negative disease patients. TMT yielded survival outcomes similar to those of patients who underwent RC. Given the inherent limitations of the included studies, future well-designed RCTs are needed to confirm and update the findings of this analysis.

Integrated Gene Expression Score in Circulating Tumor Cells to Predict Treatment Response in Muscle-Invasive Bladder Cancer

Muscle-invasive bladder cancer (MIBC) is often managed with radical cystectomy, but select patients are eligible for bladder-sparing trimodality therapy (TMT) with contemporary bladder preservation rates ∼85% and comparable long-term survival. There is an urgent need for reliable biomarkers to optimize treatment selection and detect recurrence early. Circulating tumor cells (CTCs) in the blood have potential as non-invasive, serial “liquid biopsies” to predict and monitor therapeutic response. Prior studies of CTCs in MIBC relied on enrichment of EpCAM-expressing CTCs. The purpose of this study is to use an unbiased negative-selection, microfluidic CTC isolation approach coupled with sensitive droplet digital PCR (ddPCR) to develop and validate a CTC gene expression score (CTC-GES) to monitor response to TMT. Candidate genes were identified by differential expression analysis comparing RNA-seq data from MIBC (TCGA; n = 67) to non-neoplastic bladder (GTEX; n = 11) and leukocytes (n = 20), as well as genes correlated with molecular subtypes in MIBC. ddPCR primer/probe sets were designed for each gene and validated using bladder cancer cell lines (RT4: luminal, HT-1376: basal) spiked into healthy donor blood and processed with the microfluidic CTC-iChip. Validated genes comprised the CTC-GES panel. Blood is being collected from a discovery cohort of MIBC patients undergoing TMT (n = 7 to date) at several time points (baseline, on-treatment, two-month follow-up). CTCs were isolated using the CTC-iChip and the CTC-GES assay was applied. The GES was computed as log(∑(positive droplets/mL blood)+1). In total, eight candidate genes (PPARG, UPK1A, UPK2, KRT14, EGFR, KRT19, TMEM129, DSG2) were analytically validated and comprised the CTC-GES. The assay lower limit of detection was 3 CTCs per 10 mL blood. In the discovery cohort to date, median age was 80 yo (6 males, 1 female), and all had T2/grade 3 MIBC, except one had T3 disease. Remarkably, the assay was able to predict a recurrence after TMT more than two months prior to clinical detection. Of the 3 patients with >6 months follow-up to date, there was an increase in the GES from baseline to on-treatment in two patients who developed metastatic disease (ΔGESprog = +3.12, +1.06), while it decreased in the patient who had no radiographic/pathologic evidence of disease (ΔGESNED = -0.78). We have developed and analytically validated a novel CTC gene expression score for MIBC pts undergoing TMT. In a small discovery cohort, our preliminary data suggests this biomarker can predict cancer recurrence more than two months prior to clinical detection. In contrast to circulating tumor DNA, CTC-GES does not require interpatient customization based on prior knowledge of specific mutations. With continued refinement and substantiation, the CTC-GES has potential as a universal biomarker in MIBC to predict early failures after TMT and enable treatment modification/intensification at a lower disease burden.

Outcomes of trimodality bladder-sparing therapy for muscle-invasive bladder cancer.

Although radical cystectomy is considered the standard of care for muscle-invasive bladder cancer (MIBC), recent data has suggested comparable survival outcomes for bladder-sparing trimodality therapy (TMT). We conducted a retrospective, single-institution analysis of MIBC patients to evaluate the efficacy of TMT as an alternative, curative approach to surgical intervention. We conducted a retrospective analysis of MIBC patients assessed by a multidisciplinary team at the Juravinski Cancer Centre from 2010-2016. Patients underwent transurethral resection of bladder tumor (TURBT) followed by radiotherapy with or without concurrent chemotherapy. Patients could receive neoadjuvant treatment. Clinical data and response rates were summarized, and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Our analytic cohort included 115 patients, of whom 53 underwent TMT and 62 underwent radiotherapy alone following TURBT. Median age at diagnosis was 79 years and median followup was 21 months. Complete response rates in those receiving TMT and radiation without chemotherapy were 84.4% and 66.7%, respectively. For TMT patients, three-year OS and DFS were 68.5% and 49.6%, respectively. Patients who received TMT had reduction in risk of mortality (hazard ratio [HR] 0.49; p=0.026) and disease recurrence (HR 0.55; p=0.017) compared to those who had radiation without chemotherapy. Overall, four patients had grade 3 or higher late toxicity. In this single-institution analysis, TMT appears to be a safe and effective approach in the short-term management of MIBC in appropriately selected patients. Extended followup and analysis are necessary to validate these results.

MP32-05 CLINICAL OUTCOMES OF TETRA-MODALITY BLADDER-PRESERVING THERAPY INCORPORATING CONSOLIDATIVE PARTIAL CYSTECTOMY IN MUSCLE-INVASIVE BLADDER CANCER PATIENTS WITH HYDRONEPHROSIS

INTRODUCTION AND OBJECTIVES:Trimodality bladdersparing therapy has become an accepted treatment for selected patients with muscle-invasive bladder cancer (MIBC). As the presence of hydronephrosis m...

Re: Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-sparing Trimodality Therapy for Muscle-invasive Bladder Cancer

Re: Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-sparing Trimodality Therapy for Muscle-invasive Bladder Cancer

Clinical outcomes of muscle-invasive bladder cancer patients with hydronephrosis treated with tetra-modality bladder sparing therapy incorporating consolidative partial cystectomy.

430 Background: Trimodality bladder sparing therapy has become an accepted treatment for selected patients with muscle-invasive bladder cancer (MIBC). As the presence of hydronephrosis may reduce complete response rate and survival in trimodality therapy, some investigators deem hydronephrosis as a contraindication for bladder sparing. We have developed a tetra-modality bladder sparing therapy (TeMT) consisting of maximal transurethral resection (TUR), induction chemoradiotherapy (CRT), and partial cystectomy (PC) (Koga et al, BJU Int 2012). TeMT which enables surgical consolidation of the original MIBC site, including uretero-vesical anastomosis if necessary, may provide more chance of bladder sparing for patients with hydronephrosis. Methods: In total, 151 patients with cT2-3N0M0 MIBC (median age 69 years, female/male = 33/118, cT2/3 = 100/51) entered tetra-modality bladder-sparing protocol. After maximal TUR and CRT (40 Gy + cisplatin), response was evaluated via cytology, imaging, and tumor-site rebiopsy. Consolidative PC was performed in complete responders, while radical cystectomy was recommended for others. Extension of ipsilateral intrapelvic ureter in pretreatment computed tomography was graded following the Society for Fetal Urology grading system, then patients with grade 2-3 were classified as with hydronephrosis. Response rate to CRT, MIBC recurrence-free survival, and cancer-specific survival (CSS) were compared between patients with or without hydronephrosis. Results: Hydronephrosis was found in 19 patients (14%), and was associated with lower response rate to CRT (42% in hydronephrosis vs 77% in normal, p = 0.03). On an intent-to-treat basis, patients with hydronephrosis (n = 19) had lower 5-yr CSS than those without it (n = 132) (62% vs 85%, p < 0.01). Among the 106 patients who underwent PC as per protocol, patients with (n = 9) and without hydronephrosis (n = 97) had comparable 5-yr MIBC recurrence-free survival (100% vs 97%, p = 0.11) and CSS (100% vs 93%, p = 0.46). Conclusions: Patients with hydronephrosis should not necessarily be excluded from tetra-modality bladder sparing therapy.

Editorial comment

Bladder-sparing trimodality therapy (TMT) as an acceptable alternative to radical cystectomy (RC) for the treatment of muscle invasive bladder cancer (MIBC) is the product of consecutive institutional and national protocols over decades and across continents. RC and TMT are now recognized as bona fide treatment options for MIBC by multiple international guidelines. 1 Chang SS et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017; 198: 552-559 Crossref PubMed Scopus (473) Google Scholar , 2 Alfred Witjes J et al. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2017; 71: 462-475 Abstract Full Text Full Text PDF PubMed Scopus (1066) Google Scholar

Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-Sparing Trimodality Therapy for Muscle-Invasive Bladder Cancer

BackgroundBladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. ObjectiveTo evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. Design, setting, and participantsWe used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5yr, and median follow-up time for patients without an event was 5.0yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. Outcome measurements and statistical analysisMolecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. Results and limitationsGene expression profiling of TMT cases identified luminal (N=40), luminal-infiltrated (N=26), basal (N=54), and claudin-low (N=16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14–0.65], p=0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p=0.006), but not in the TMT cohort. This study is limited by its retrospective nature. ConclusionsHigher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. Patient summaryWe used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.

Outcomes of Tri-Modality Bladder-Sparing Therapy for Muscle-Invasive Bladder Cancer

Although radical cystectomy is considered the standard of care for muscle-invasive bladder cancer (MIBC) in North America, the resultant urinary diversion or neobladder construction is a morbid and life-altering outcome for patients. Recent data has shown comparable survival results for bladder-sparing tri-modality therapy (TMT) involving complete transurethral resection of bladder tumor (TURBT), radiotherapy (RT), and chemotherapy. As there remains paucity in data to change clinical practice, we conducted a retrospective analysis of patients in our institution to better define clinical outcomes of TMT in the setting of MIBC. A retrospective chart review was performed of adult bladder cancer patients assessed by a multi-disciplinary team consisting of uro-oncologists, medical oncologists, and radiation oncologists. Included patients were diagnosed with MIBC (T2-T4) in the past 6 years and underwent curative intent treatment with maximal TURBT followed by concurrent chemoradiation (≥50 Gy; platinum-based agent or fluorouracil + mitomycin). Patients who underwent radical RT alone following TURBT were also included. Clinical and treatment data were summarized including resection status, pathological features, response to treatment, and salvage cystectomy rates. Overall survival (OS) and disease-specific survival (DSS) were estimated using the Kaplan-Meier method. Of 116 included patients, 54 underwent TMT and 62 underwent radical RT alone following TURBT. The median age at diagnosis was 79 years and the median follow-up was 1.9 years. Clinical T-stage was T2 in 84% of patients and maximum TURBT was performed in 72% of patients. Complete response rates in those receiving TMT and RT alone were 70% and 50%, respectively. The overall local recurrence rate was 12%. The local recurrence rates in the TMT and RT only groups were 11% and 13%, respectively. In the TMT cohort, 4% of patients had grade 3 or higher late toxicity and 2% of patients underwent salvage cystectomy. For TMT patients, median OS and DSS were 57.2 and 28.1 months, respectively. Two-year OS and DSS were 74.5% and 51.5%, respectively. Based on our data, TMT remains a safe and effective alternative to radical cystectomy and should be offered to appropriately selected patients with MIBC. This multi-disciplinary approach appears to yield similar survival outcomes with minimal toxicity, while avoiding the morbidity of surgical intervention especially in older patients. Confirmation in larger patient cohorts with longer follow-up is required.

Clinical outcomes of patients with histologic variants of urothelial carcinoma treated with tetra-modality bladder-sparing protocol incorporating consolidative partial cystectomy.

490 Background: Trimodality bladder-sparing therapy has become an accepted treatment for selected patients with muscle-invasive bladder cancer (MIBC). As some of the histologic variants of urothelial carcinoma (VUC) are more resistant to chemotherapy and radiotherapy compared with pure urothelial carcinoma (PUC), it is still controversial whether bladder-sparing therapy provides comparable disease control in VUC. We have developed a tetra-modality bladder-sparing therapy consisting of maximal transurethral resection (TUR), chemoradiotherapy (CRT), and consolidative partial cystectomy, which has theoretical advantage in locoregional control by surgically eliminating chemo- and radio-resistant cells (Koga et al, Urol Oncol 2013, BJU Int 2012). Methods: After maximal TUR and CRT (40Gy + cisplatin), treatment response was evaluated by cytology, imaging and tumor-site rebiopsy. Complete responders were candidate for consolidative partial cystectomy, while radical cystectomy was recommended for others. VUC identified in maximal TUR samples were categorized according to the 2004 World Health Organization Classification. Response rate to CRT, MIBC recurrence-free survival and cancer-specific survival (CSS) were compared between patients with PUC and VUC. Results: Between 1997 and 2016, 153 consecutive patients with cT2-3N0M0 bladder cancer (median age 69, female/male = 33/120, cT2/3 = 99/54) entered tetra-modality bladder-sparing protocol. VUC was identified in 37 (24%) of the patients, including glandular in 12 (8%), squamous in 11 (7%), micropapillary in 8 (5%), sarcomatoid in 2 (1%), microcystic in 2 (1%), and lymphoepithelioma-like in 1 (0.7%). There was no difference in the response rate to CRT between PUC and VUC (71% vs 84%, p = 0.13). Among the patients with PUC (n = 75) and VUC (n = 31) who underwent partial cystectomy, 5-yr MIBC recurrence-free rates were 92% and 100% (p = 0.21), and 5-yr CSS rates were 93% and 94% (p = 0.64), respectively. Conclusions: Tetra-modality bladder-sparing therapy incorporating partial cystectomy could provide favorable locoregional control and survival for patients with VUC.

Genomic profiling of muscle invasive bladder cancer to predict response to bladder-sparing trimodality therapy.

513 Background: Trimodality therapy with TURBT followed by chemoradiation is an acceptable alternative to cystectomy for muscle invasive bladder cancer (MIBC). Genomic profiling has demonstrated MIBC can be divided into molecular subtypes with differing responses to chemotherapy. We explored the utility of genomic data to select patients for bladder-sparing trimodality therapy. Methods: Transcriptome wide gene expression profiles were generated for 189 MIBC TURBT samples from patients treated with trimodality therapy at a single institution. Of these, 103 passed microarray QC. Molecular subtype and expression of bladder cancer genes were assessed for association with overall and disease-specific survival. Transcriptome wide differential expression analysis was used to explore gene set enrichment in trimodality therapy response groups. Results: The chemoradiation cohort (n = 103) had a median followup of 6.9 years for alive patients, and was classified into four subtypes: basal (n = 44), basal claudin-low (n = 12), infiltrated luminal (n = 17) and luminal tumors (n = 30). There was no significant difference in overall or disease-specific survival by subtype. However, higher expression of the luminal-associated PPARG was correlated with increased survival after adjusting for subtype and clinical factors (HR = 0.52, p = 0.002). In contrast, a p53 signature predicted worse survival after adjusting for clinical factors (HR = 1.92, p = 0.022). Elevated mRNA expression of the DNA damage repair gene MRE11 was associated with improved survival in the trimodality cohort (HR = 0.69, P = 0.031), consistent with its potential role as a predictive biomarker for radiation response. Gene set enrichment revealed differential regulation of immune pathways in trimodality therapy responders relative to non-responders, including enrichment of interferon gamma signaling (p = 0.01) and CXCL9 (p = 0.031), suggestive of an interplay between tumor immunologic microenvironment and response to chemoradiation. Conclusions: Transcriptional profiling of MIBC revealed gene signatures correlated with response to chemoradiation, suggesting the potential of genomics to guide use of trimodality therapy.

Re: Propensity Score Analysis of Radical Cystectomy Versus Bladder-sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic

Re: Propensity Score Analysis of Radical Cystectomy Versus Bladder-sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic

Outcomes and Tolerability of Selective Bladder Preservation by Combined Modality Therapy for Invasive Bladder Cancer in Elderly Patients

The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the United States is 73 years old, and only about half of those over 70 receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of the elderly are undertreated. To address this unmet clinical need, we examined the outcomes and tolerability of bladder-sparing trimodality therapy (TMT) in elderly patients 75 years or older. We retrospectively analyzed 475 patients with cT2-T4a disease treated at our institution between 1986 and 2013 on or per protocol. Patients underwent induction chemoradiation (CRT) after maximal transurethral resection of bladder tumor (TURBT), in most cases with cisplatin-based concurrent chemotherapy. Patients achieving a complete response (CR) received consolidation CRT. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. For comparison of elderly patients (defined as 75 years or older) with younger patients, propensity score matching was performed based on T-stage, presence of hydronephrosis, completion of TURBT, and use of neoadjuvant chemotherapy. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Multivariate analyses were performed using a Cox proportional hazards regression model. Median age was 67 years (range 27-94), and 112 patients (23.6%) were 75 years or older. Median follow-up was 7.2 years for surviving patients. In a propensity score matching analysis of 101 elderly and 101 younger patients, DSS at 5 and 10 years for the elderly was 61.2% and 47.3%, compared to 68.6% and 61.0% for younger patients (P = 0.20). CR to induction CRT was 72.3% in the elderly, compared to 80.2% in the younger cohort (P = 0.25). 23.8% of elderly and 29.7% of younger patients underwent a salvage radical cystectomy (P = 0.43). Elderly patients, in comparison to younger patients, had similar rates of ED visits during treatment (8.9% vs 6.9%, P = 0.80) and unplanned treatment breaks for any cause (20.8% vs. 17.8%, P = 0.72), but had a nonsignificant increase in hospital admissions for any cause (16.8% vs. 9.9%, P = 0.21) and early discontinuation of therapy due to toxicities (6.9% vs. 3.0%, P = 0.33). On multivariate analysis, T3/T4 disease, incomplete response to CRT, ED visits during treatment, and early treatment discontinuation were significantly associated with worse DSS in elderly patients. In elderly patients with MIBC, outcomes and tolerability of bladder-sparing TMT using cisplatin-based CRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.