Therapy For Muscle-invasive Bladder Cancer Research Articles

Current Status of Perioperative Therapy in Muscle-Invasive Bladder Cancer and Future Directions.

Cisplatin-based combination chemotherapy has been a standard of care in the perioperative management of muscle-invasive bladder cancer for years, but several novel therapies are under active investigation. This review aims to provide an update on recent relevant literature and a forward look at the future landscape of adjuvant and neoadjuvant therapy in muscle-invasive bladder cancer patients who opt for radical cystectomy. The recent approval of nivolumab as adjuvant therapy established a new treatment option for high-risk patients with muscle-invasive bladder cancer after radical cystectomy. Several phase II studies of chemo-immunotherapy combinations and immunotherapy alone have reported pathological complete responses in the 26-46% range, including studies in cisplatin-ineligible patients. Randomized studies of perioperative chemo-immunotherapy, immunotherapy alone, and enfortumab vedotin are ongoing. Muscle-invasive bladder cancer remains a challenging disease associated with significant morbidity and mortality; however, increasing options in systemic therapy and an increasingly personalized approach to cancer treatment suggest continued future improvements in patient care.

Combined Modality Bladder-Sparing Therapy for Muscle-Invasive Bladder Cancer: How (Should) We Do It? A Narrative Review.

Organ-sparing combined-modality treatment for muscle-invasive bladder cancer remains underutilized despite high-quality evidence regarding its efficacy, safety, and preservation of quality of life. It may be offered to patients unwilling to undergo radical cystectomy, as well as those unfit for neoadjuvant chemotherapy and surgery. The treatment plan should be tailored to each patient's characteristics, with more intensive protocols offered to patients who are fit for surgery but opt for organ-sparing. After a thorough, debulking transurethral resection of the tumor and neoadjuvant chemotherapy, the response evaluation should trigger further management with either chemoradiation or early cystectomy in non-responders. A hypofractionated, continuous radiotherapy regimen of 55 Gy in 20 fractions with concurrent radiosensitizing chemotherapy with gemcitabine, cisplatin, or 5-fluorouracil and mitomycin C is currently preferred based on clinical trials. The response should be evaluated with repeated transurethral resections of the tumor bed and abdominopelvic-computed tomography after chemoradiation, with quarterly assessments during the first year. Salvage cystectomy should be offered to patients fit for surgery who failed to respond to treatment or developed a muscle-invasive recurrence. Non-muscle-invasive bladder recurrences and upper tract tumors should be treated in line with guidelines for respective primary tumors. Multiparametric magnetic resonance can be used for tumor staging and response monitoring, as it may distinguish disease recurrence from treatment-induced inflammation and fibrosis.

Low CD8 T Cell Counts Predict Benefit from Hypoxia-Modifying Therapy in Muscle-Invasive Bladder Cancer.

As hypoxia can drive an immunosuppressive tumour microenvironment and inhibit CD8+ T cells, we investigated if patients with low tumour CD8+ T cells benefitted from hypoxia-modifying therapy. BCON was a phase III trial that randomised patients with muscle-invasive bladder cancer (MIBC) to radiotherapy alone or with hypoxia-modifying carbogen plus nicotinamide (CON). Tissue microarrays of diagnostic biopsies from 116 BCON patients were stained using multiplex immunohistochemistry (IHC) with the markers CD8, CD4, FOXP3, CD68 and PD-L1, plus DAPI. Hypoxia was assessed using CA9 IHC (n = 111). Linked transcriptomic data (n = 80) identified molecular subtype. Relationships with overall survival (OS) were investigated using Cox proportional hazard models. High (upper quartile) vs. low CD8 T cell counts associated with a better OS across the whole cohort at 16 years (n = 116; HR 0.47, 95% CI 0.28-0.78, p = 0.003) and also in the radiotherapy alone group (n = 61; HR 0.39, 95% CI 0.19-0.76, p = 0.005). Patients with low CD8+ T cells benefited from CON (n = 87; HR 0.63, 95% CI 0.4-1.0, p = 0.05), but those with high CD8 T cells did not (n = 27; p = 0.95). CA9 positive tumours had fewer CD8+ T cells (p = 0.03). Prognostic significance of low CD8+ T cells in the whole cohort remained after adjusting for clinicopathologic variables. Basal vs. luminal subtype had more CD8+ cells (p = 0.02) but was not prognostic (n = 80; p = 0.26). Exploratory analyses with other immune markers did not improve on findings obtained with CD8 counts. MIBC with low CD8+ T cell counts may benefit from hypoxia-modifying treatment.

Genomic Determinants of Response to Trimodality Therapy for Muscle-Invasive Bladder Cancer

<h3>Purpose/Objective(s)</h3> Trimodality therapy (TMT), which consists of transurethral resection of bladder tumor (TURBT) followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. We characterized the genomic and transcriptomic landscape associated with response to TMT through whole exome sequencing (WES) and expression profiling. <h3>Materials/Methods</h3> MIBC patients treated with TMT at a single institution were identified. DNA and RNA were extracted from available FFPE pre-treatment TURBT samples, and WES and transcriptome-wide expression profiling were performed. WES data were analyzed by standard mutation analysis pipelines with a common variant filter to account for lack of matched germline samples. Somatic mutations, insertion/deletions, and copy number variations were identified. Molecular subtypes and DNA damage response (DDR) pathway scores were derived from expression profiles. Responders (R) were defined as patients with complete response at post-treatment cystoscopy and no recurrence. Nonresponders (NR) were defined as patients with incomplete response at post-treatment cystoscopy, those who underwent salvage cystectomy, or those with regional/distant disease progression. <h3>Results</h3> Pre-treatment TURBT FFPE samples from 77 selected TMT patients were successfully sequenced and passed quality control metrics, 68 of which had matched transcriptomic profiling. The median age of the cohort was 72.7 years; 23% were female. All patients had MIBC (87% T2, 13% T3/T4) and the majority were treated with concurrent cisplatin-based chemotherapy. Median follow-up was 42 months in alive patients. Thirty-nine patients were classified as NR, while 38 were R. Mean somatic tumor mutational burden among R and NR was 13.5 (range, 4.2-31.5) and 11.3 (range, 3.4-26.8) mutations/megabase, respectively (p=0.08). Exploratory analyses of DDR pathways revealed more patients classified as R had mutations in <i>ERCC2</i> (n=7) as compared to NR (n=1), p=0.023. Six of these 8 patients with <i>ERCC2</i> mutations received cisplatin-based chemotherapy; of the 2 that did not, 1 was NR. Samples with <i>ERCC2</i> mutations had higher hallmark DNA repair scores (median 0.110 versus -0.310, p=0.02), suggesting dysregulation of DDR. <i>ERCC2</i> mutant tumors were also enriched for GSC luminal subtype compared to <i>ERCC2</i> wildtype (83% vs. 37% luminal; p=0.03). Patients with <i>ERCC2</i> mutations had improved disease-specific survival (HR 0.17 (95%CI: 0.064-0.41), p=0.04). Consistent with these results, <i>in vitro</i> studies showed <i>ERCC2</i> mutant bladder cancer cell lines are significantly more sensitive to cisplatin and radiation than isogenic <i>ERCC2</i> wildtype cells. <h3>Conclusion</h3> Our data demonstrate that alterations in <i>ERCC2,</i> a crucial DDR gene, may be associated with improved response to TMT. These findings require validation in larger cohorts.

Neoadjuvant immunotherapy, chemotherapy, and combination therapy in muscle-invasive bladder cancer: A multi-center real-world retrospective study

To parallelly compare the efficacy of neoadjuvant immunotherapy (tislelizumab), neoadjuvant chemotherapy (gemcitabine and cisplatin), and neoadjuvant combination therapy (tislelizumab+ GC) in patients with muscle-invasive bladder cancer (MIBC) and explore the efficacy predictors, we perform a multi-center, real-world cohort study that enrolls 253 patients treated with neoadjuvant treatments (combination therapy: 98, chemotherapy: 107, and immunotherapy: 48) from 15 tertiary hospitals. We demonstrate that neoadjuvant combination therapy achieves the highest complete response rate and pathological downstaging rate compared with neoadjuvant immunotherapy or chemotherapy. We develop and validate an efficacy prediction model consisting of pretreatment clinical characteristics, which can pinpoint candidates to receive neoadjuvant combination therapy. We also preliminarily reveal that patients who achieve pathological complete response after neoadjuvant treatments plus maximal transurethral resection of the bladder tumor may be safe to receive bladder preservation therapy. Overall, this study highlights the benefit of neoadjuvant combination therapy based on tislelizumab for MIBC.

Neoadjuvant Treatment in Muscle-Invasive Bladder Cancer: From the Beginning to the Latest Developments.

Urothelial carcinoma of the bladder is one of the most prevalent cancers worldwide, diagnosed as muscle invasive in 25% of cases. Although several studies have demonstrated an overall 5% absolute survival benefit at 5 years with cisplatin-based combination neoadjuvant treatment, administration of chemotherapy prior to radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC) patients is still a matter of debate. This may be due to the perceived modest survival benefit, cisplatin-based chemotherapy ineligibility, or fear of delaying potentially curative surgery in non-responders. However, immunotherapy and novel targeted therapies have shown to prolong survival in advanced disease and are under investigation in the neoadjuvant and adjuvant settings to reduce systemic relapse and improve cure rates. Genomic characterization of MIBC could help select the most effective chemotherapeutic regimen for the individual patient. Large cohort studies on neoadjuvant treatments with immune checkpoint inhibitors (ICIs) and molecular therapies, alone or combined with chemotherapy, are ongoing. In this review, we trace the development of neoadjuvant therapy in MIBC and explore recent advances that may soon change clinical practice.

Abstract 2060: Treatment combination strategies to improve radiation efficacy in immunologically cold tumors in vivo

Abstract Introduction: Radiation therapy (RT) is a promising bladder-sparing therapy in muscle-invasive bladder cancer (MIBC). However, 30% of patients exhibit radioresistant tumors requiring salvage surgery. Combining RT with immune checkpoint inhibitor was reported to have synergic effects on anti-tumor immunity. Yet, it is also met with treatment resistance. In addition, activation of the STING pathway was shown to induce cell death, cancer cell antigens release and presentation, and promote the priming, activation and trafficking of T cells into tumors. Previous in vivo results from our team using the MB49 murine bladder cancer cell line - and immunologically ‘hot’ tumor model - demonstrated significant improvement of survival and immune cell infiltration upon STING agonist treatment, when combined with RT and anti-PDL1 treatment. Oppositely, treating the ‘cold’ tumor model UPPL with a combination of RT and anti-PDL1 treatment did not improve survival compared to RT alone. Consistently, UPPL tumors present low T cell and high neutrophil infiltration in vivo. Thus, the main objective of the present study is to evaluate whether combining RT, anti-PDL-1 and STING agonist treatments can improve the immunogenicity of UPPL tumors. Methods: Seven-week-old male C57BL/6 mice were subcutaneously injected with 5.106 UPPL tumor cells. Once tumors reached 0.1-0.15 cm3, mice were randomized into the following treatment groups : 1) Untreated; 2) PDL-1; 3) STING; 4) PDL-1 + STING; 5) RT; 6) RT + PDL-1; 7) RT + STING; 8) RT + STING + PDL-1. Midpoint (~0.6-0.8 cm3, n=5) and endpoint (2 cm3, n=8) tumors, spleens and draining lymph nodes (dLN) were harvested and dissociated for flow cytometry analysis of TME composition and cytokine production. Results: We report that RT and RT-combined treatments delayed tumor growth and prolonged survival in vivo compared to untreated. Additionally, our combination approaches shifted immune infiltration : compared to untreated, each strategy changed myeloid and T cells infiltrating cells in tumors. Combination of RT with anti-PDL-1 and STING agonist favored macrophages infiltration as well as increased MHC-II expression in dendritic cells (DC). Furthermore, we observed increased infiltration of cytotoxic CD8+ T cells (Granzyme B+ and IFN-γ+ CD8+) in these groups. Conclusions: Our results suggest RT and RT combination treatments in cold tumor affect antigen presentation potency in DCs, fine-tune the functionality of infiltrating CD8+ T cells. This preliminary study shows immunologically cold tumors can be modulated through treatment combination, which has relevance in human treatment-resistant tumors. It adds to the very small body of literature taking a deep dive into the immune modulation of a conventionally used ‘cold’ tumor cell line. Citation Format: Eva Michaud, Gautier Marcq, Sabina Fehric, JiaMin Huang, Jose Joao Mansure, Ciriaco Piccirillo, Wassim Kassouf. Treatment combination strategies to improve radiation efficacy in immunologically cold tumors in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2060.

ANTICIPATE: A phase I/II, open-label, multicenter study to evaluate the safety and efficacy of oral APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy (NAC) in patients with muscle invasive bladder cancer (MIBC).

TPS4613 Background: Standard treatment for muscle invasive bladder cancer (MIBC) is radical cystectomy (RC) and administration of NAC in patients who are eligible to receive cisplatin. Approximately 50% of patients are ineligible to receive cisplatin as a result of pre-existing contraindications, and some refuse to receive any chemotherapy due to concerns of toxicities. Immune checkpoint inhibitors (ICIs) have been shown to be highly active in metastatic urothelial cancer. APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Synergistic effects of APL-1202 and ICIs have been shown in model systems of bladder cancer. It is hypothesized that APL-1202 in combination with tislelizumab, a humanized IgG4 anti-PD-1 MAb, may be an effective neoadjuvant therapy in MIBC. This trial will evaluate the safety, efficacy, and pharmacodynamic effects of APL-1202 in combination with tislelizumab as neoadjuvant therapy for patients with MIBC who are cisplatin ineligible or refuse cisplatin-based chemotherapy. Methods: ANTICIPATE is an open-label, multi-center clinical trial enrolling 79 patients in two phases: Phase Ⅰ and Phase Ⅱ. Phase I is a dose escalation study to determine MTD (maximum tolerated dose) and/or RP2D. Phase II is an expanded proof-of-concept study to evaluate the safety and efficacy of APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy for MIBC as measured by pathological complete response (pCR). Phase Ⅰ and Phase Ⅱ both are divided into 3 periods: screening period of 4 weeks, neoadjuvant therapy comprising 3 cycles (each 21 days) prior to radical cystectomy; and a follow-up period of up to 90 days after surgery. The phase Ⅰ will determine the RP2D of APL-1202 in combination with tislelizumab as neoadjuvant therapy for MIBC. Eligible patients have newly diagnosed MIBC and are cisplatin ineligible or refuse cisplatin-based NAC and are planned for RC. In phase Ⅰ, a standard 3+3 dose-escalation design will be used. On day 1 of each cycle, a single dose of 200 mg tislelizumab will be administered intravenously. The daily dose APL-1202 will be escalated in successive cohorts (375 mg à 750 mg à 1,125 mg). The DLT observation window for any dose level will be treatment cycle 1. There will be no intra-patient dose escalation. In phase II patients will be randomly assigned to group 1 (APL-1202 + tislelizumab) or group 2 (tislelizumab only), stratified by PD-L1 expression. The IND has been approved by FDA and NMPA, and the study execution is under preparation both in US and China. Clinical trial information: NCT04813107.

Long term cost comparisons of radical cystectomy versus trimodal therapy for muscle-invasive bladder cancer.

Earlier studies on the cost of muscle-invasive bladder cancer treatments are limited to short-term costs of care. We determined the 2- and 5-year costs associated with trimodal therapy (TMT) vs. radical cystectomy (RC). We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Total Medicare costs at 2 and 5 years following RC vs. TMT were compared using inverse probability of treatment-weighted propensity score models. A total of 2,537 patients aged 66 to 85 years were diagnosed with clinical stage T2-4a muscle-invasive bladder cancer. Total median costs for patients that received no definitive treatment(s) were $73,780 and $88,275 at 2-and 5-years. Costs were significantly higher for TMT than RC at 2-years ($372,839 vs. $191,363, Median Difference $127,815, Hodges-Lehmann Estimate (H-L) 95% Confidence Interval (CI), $112,663-$142,966) and 5-years ($424,570 vs. $253,651, Median Difference $124,466, H-L 95% CI, $105,711-$143,221). TMT had higher outpatient costs than RC (2-years: $318,221 vs. $100,900; 5-years: $367,092 vs. $146,561) with significantly higher costs with radiology, medications, pathology/laboratory, and other professional services. RC had higher inpatient costs than TMT (2-years: $62,240 vs. $33,631, Median Difference $-29,174, H-L 95% CI, $-32,364-$-25,984; 5-years: $75,499 vs. $45,223, Median Difference $-29,843, H-L 95% CI, $-33,905-$-25,781). The excess spending associated with trimodal therapy vs. radical cystectomy was largely driven by outpatient expenditures. The relatively high long-term trimodal therapy costs are prime targets for cost containment strategies to optimize future value-based care.

Cancer genomic profiling identified dihydropyrimidine dehydrogenase deficiency in bladder cancer promotes sensitivity to gemcitabine

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

PD10-07 UPDATE OF TRUCE-01: NEOADJUVANT TISLELIZUMAB COMBINED WITH NAB-PACLITAXEL FOR MUSCLE-INVASIVE UROTHELIAL BLADDER CARCINOMA

You have accessJournal of UrologyCME1 May 2022PD10-07 UPDATE OF TRUCE-01: NEOADJUVANT TISLELIZUMAB COMBINED WITH NAB-PACLITAXEL FOR MUSCLE-INVASIVE UROTHELIAL BLADDER CARCINOMA Hailong Hu, Yuanjie Niu, Haitao Wang, Chong Shen, Gangjian Zhao, La Da, Lili Wang, Zhouliang Wu, Zhi Li, Houyuan Chen, Xuejian Zhan, Zhan Jiang, and Zhe Zhang Hailong HuHailong Hu More articles by this author , Yuanjie NiuYuanjie Niu More articles by this author , Haitao WangHaitao Wang More articles by this author , Chong ShenChong Shen More articles by this author , Gangjian ZhaoGangjian Zhao More articles by this author , La DaLa Da More articles by this author , Lili WangLili Wang More articles by this author , Zhouliang WuZhouliang Wu More articles by this author , Zhi LiZhi Li More articles by this author , Houyuan ChenHouyuan Chen More articles by this author , Xuejian ZhanXuejian Zhan More articles by this author , Zhan JiangZhan Jiang More articles by this author , and Zhe ZhangZhe Zhang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002536.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The PURE-01 and ABACUS studies has elucidated the administration of neoadjuvant immune checkpoint inhibitors in muscle-invasive bladder cancer (MIBC), with efficacy comparable to chemotherapy and less adverse events. However, the role of PD-1/PD-L1 inhibitor combining with chemotherapy remains unclear. We conduct a study to evaluate the outcome of pts treated with neoadjuvant PD-1 combined with second-line chemotherapy for MIBC. METHODS: TRUCE-01 is a phase II study of Tislelizumab combined with Nab-Paclitaxel before cystectomy or complete TURBT (cTURBT): the primary endpoint is pathologic complete response (pT0). Pts with clinical stage T2-4aN0-1M0 received tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 cycles followed by radical cystectomy or cTURBT. Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay) and tumor mutational burden (TMB). Comparisons between PD-L1 expression subgroups were made via Fisher’s exact tests for categorical variables. RESULTS: Between July 2020 and July 2021, 30 pts have completed neoadjuvant treatment and received radical cystectomy (n=9, 31%) or cTURBT (n=21, 69%). Finally, 16 pts achieved pT0 (53.3%; 95% CI, 36.7% to 73.3%). As a secondary end point, downstaging to pT <2 was achieved in 21 pts (70%; 95% CI, 53.3% to 86.7%). There were 2 pts experienced grade 3-4 adverse events (CTCAE), a grade 3 rash and a grade 4 acute renal failure, both of them recovered after treating by corticosteroid. In addition, The most common grade 1-2 adverse events include alopecia (96%), fatigue (63%), hyperglycemia (33%), rash (27%), fever (17%), and Creatinine increased (13%). There was no significant correlation between PD-L1 expression and therapeutic effect. pT0 was achieved in 8 pts (61.5%) with PD-L1 positive compared with 8 pts (47%) with PD-L1 negative (P=.484). As for tumor mutational burden (TMB), response pts show high lever (P=.067). CONCLUSIONS: The early efficacy data further support the role of Tislelizumab combined with Paclitaxel as neoadjuvant therapy in MIBC, benefiting them in a higher rate of pCR without increasing frequency of serve AEs. PD-L1 expression has no obvious correlation with the efficacy of immunotherapy combined chemotherapy. Patients with high TMB are more likely to respond to neoadjuvant therapy. Enrollment is ongoing. Source of Funding: The present study received financial support from the the Natural Science Foundation Project of Tianjin (grant no. 18PTLCSY00010) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e186 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hailong Hu More articles by this author Yuanjie Niu More articles by this author Haitao Wang More articles by this author Chong Shen More articles by this author Gangjian Zhao More articles by this author La Da More articles by this author Lili Wang More articles by this author Zhouliang Wu More articles by this author Zhi Li More articles by this author Houyuan Chen More articles by this author Xuejian Zhan More articles by this author Zhan Jiang More articles by this author Zhe Zhang More articles by this author Expand All Advertisement PDF DownloadLoading ...

Multi-institutional matched comparison of radical cystectomy to trimodality therapy for muscle-invasive bladder cancer.

433 Background: Prior randomized controlled trials (RCT) comparing bladder preservation to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC) closed early due to lack of accrual. Given that no future RCTs are foreseen, and in the absence of level 1 data, we aimed to provide the best evidence possible on outcomes of matched cohorts comparing trimodality therapy (TMT, maximal transurethral resection of bladder tumor followed by concurrent chemoradiation) to RC in order to guide management. Methods: This retrospective analysis included 703 patients with MIBC clinical stage T2-T3/4aN0M0 MIBC urothelial carcinoma of the bladder, 421 RC and 282 TMT who would have been eligible for both TMT or RC, treated at the Massachusetts General Hospital, Boston; Princess Margaret Cancer Centre, Toronto; and University of Southern California, Los Angeles between 2005-2017. To compare homogeneous cohorts, all patients included in this analysis had solitary tumors &lt; 7 cm, no or unilateral hydronephrosis, and no multifocal carcinoma in situ. Treatment propensity scores were estimated using logistic regression, and patients were matched 3:1 with replacement. Covariates included age, sex, clinical T stage, hydronephrosis, (neo)adjuvant chemotherapy, body mass index, smoking history, and ECOG status. Overall survival (OS) was estimated with adjusted Cox models; cancer-specific survival (CSS), distant failure-free survival, pelvic nodal failure-free survival and metastasis-free survival (combined distant and pelvic nodal failure) were estimated with adjusted competing risk models. Our primary endpoint of interest was metastasis-free survival. The analysis was performed as intent-to-treat. Results: The 3:1 matched cohort comprised of 1,116 patients (834 RC vs 282 TMT). After matching, age (71.3 vs 71.6), cT2 clinical stage (88 vs 90%), presence of hydronephrosis (12 vs 10%), and use of (neo)adjuvant chemotherapy (60 vs 65%) were similar between RC and TMT cohorts. Salvage cystectomy was performed in 38 patients (13%) treated by TMT. At 5 years, metastasis-free (73 vs 78%, p = 0.07), distant failure-free (78 vs 82%, p = 0.14), and pelvic nodal failure-free (96 vs 94%, p = 0.33) survival were not statistically different between RC and TMT, whereas CSS and OS favored TMT (78 vs 85%, p = 0.02; 70 vs 78%, p &lt; 0.001). Outcomes for RC and TMT were not different among centers. Final pT stage in the RC patients was: pT0 14%, pT1 7%, pT2 29%, pT3/4 42% and N+ 24%. Peri RC mortality was 2.1% and median number of nodes removed was 40. NMIBC recurrence occurred in 57/278 (20.5%) TMT patients. Conclusions: This large multi-institutional contemporary study provides the best evidence to date, in the absence of randomized trials, supporting TMT for select patients with MIBC. Oncologic outcomes seem to be equivalent between TMT and RC, affirming the position that TMT should be offered as an effective alternative.

Long-term cost comparisons of radical cystectomy versus trimodal therapy for muscle-invasive bladder cancer.

455 Background: Earlier studies on the cost of muscle-invasive bladder cancer treatments are limited to short-term periods of cost. Our study objective is to compare the 2- and 5-year costs associated with trimodal therapy (TMT) versus radical cystectomy (RC) benchmarked against costs for patients who received no curative treatment. Methods: This cohort study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Medicare expenditures were summed from inpatient, outpatient, and physician services within 2 and 5 years of diagnosis to determine total costs Total Medicare costs at 2-and 5-years following TMT versus RC were compared using inverse probability of treatment-weighted (IPTW) propensity score models. Results: A total of 2,537 patients aged 66-85 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer from January 1, 2002 through December 31, 2009. Total median costs for patients that received no definitive/systemic treatments (RC, TMT, radiotherapy alone, or chemotherapy alone) were $73,780 vs. $88,275 at 2-and 5-years respectively. Total median costs were significantly higher for TMT than RC at 2-years ($372,839 vs. $191,363, p&lt;0.001) and 5-years ($424,570 vs. $253,651, p&lt;0.001), respectively. TMT had higher outpatient median costs than RC (2-yr: $318,221 vs. $100,900; 5-yr: $367,092 vs. $146,561) with significantly higher costs largely associated with radiology, medications, pathology/laboratory, and other professional services. Conclusions: TMT vs. RC was associated with higher long-term costs among patients with muscle-invasive bladder cancer largely driven by outpatient expenditures. Reduction in costs associated with radiology, medications, pathology/laboratory, and other professional services may improve the value of TMT.[Table: see text]

A0763 - Management and outcomes of non-muscle invasive bladder recurrence after complete response to trimodality therapy for muscle-invasive bladder cancer: A monocentric experience

A0763 - Management and outcomes of non-muscle invasive bladder recurrence after complete response to trimodality therapy for muscle-invasive bladder cancer: A monocentric experience

Refining neoadjuvant therapy clinical trial design for muscle-invasive bladder cancer before cystectomy: a joint US Food and Drug Administration and Bladder Cancer Advocacy Network workshop.

The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials.

703P Camrelizumab in combination with gemcitabine plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer

Chemotherapy combined with immunotherapy before radical cystectomy (RC) is anticipated to improve survival of muscle-invasive bladder cancer (MIBC) patients(pts). We investigated the efficacy and safety of camrelizumab in combination with gemcitabine plus cisplatin (GC) as neoadjuvant therapy in MIBC pts.

Retrospective evaluation of planning margins for patients undergoing radical radiation therapy treatment for bladder cancer using volumetric modulated arc therapy and cone beam computed tomography.

IntroductionCurrent contouring guidelines for curative radiation therapy for muscle‐invasive bladder cancer (MIBC) recommend margins of 1.5–2.0 cm, applied to the clinical target volume (CTV). This study assessed whether the use of volumetric modulated arc therapy (VMAT), cone beam computed tomography (CBCT) and strict bladder preparation allowed for a reduced planning target volume (PTV) expansion, resulting in lower doses to surrounding organs at risk (OARs).MethodsDaily CBCT images for 12 patients (382 scans total) were retrospectively reviewed against four potential PTV margins created on and exported with the reference CT scan. To form the PTVs, three isotropic expansions of 0.5, 1.0 and 1.5 cm were applied to the CTV, as well as an anisotropic expansion of 1.5 cm superiorly and 1.0 cm in all other dimensions. Following treatment completion, the CBCTs were visually assessed to determine the margins encapsulating the bladder. For retrospective planning purposes, the 1.0‐cm and anisotropic margins were compared with the previously recommended margins to determine differences in OAR doses.ResultsThe 0.5‐, 1.0‐ and 1.5‐cm isotropic margins (IM) and the anisotropic margin (ANIM) covered the CTV in 46.1, 96.8, 100 and 100% of CBCTs retrospectively. Doses to OARs were significantly lower for the reduced margin plans for the small bowel, rectum and sigmoid.ConclusionBladder planning target volumes may be safely reduced. We endorse a PTV margin of 1.0cm anteriorly, posteriorly and inferiorly with 1.0–1.5 cm superiorly for radical whole bladder cases using strict bladder preparation, VMAT and pretreatment CBCTs.

Patterns and predictors of treatment in muscle-invasive bladder cancer (MIBC): A real-world study.

e16531 Background: Among the approaches to curative-intent therapy for MIBC, neoadjuvant cisplatin-based chemotherapy (NAC) is recognized as the gold standard. The combined modality approach of concurrent chemo-radiation is also considered a standard of care. Despite guidelines recommending multidisciplinary care, studies have shown a low adoption rate of multidisciplinary approaches for MIBC. This study aimed to describe the treatment patterns for MIBC pts using real world data. Methods: Following the appropriate IRB approvals, investigators followed a common protocol under the auspices of the Rapid Case Ascertainment at the Yale Cancer Center. Manual chart review was performed on MIBC pts diagnosed in Connecticut from 2004 –2015 and treated at investigator-affiliated hospitals. Information on medical history, comorbidity, and treatment types were recorded. This data set was linked to the Surveillance, Epidemiology, and End Results (SEER) database for demographic information. The descriptive and logistic regression were used to analyze treatment patterns and predicators in each treatment lines: surgery alone, chemotherapy alone, radiation alone and standard care (NAC followed by surgery; surgery followed by adjuvant chemotherapy and concurrent chemo-radiation). Results: The number of adult MIBC pts in the cohort was 1,198. Among them, 290 (24.2%) received surgery as the only treatment; 117 (9.8%) received chemotherapy only; 100 (8.3%) received concurrent chemo-radiation; 96 (8.0%) received NAC followed by surgery. Besides age ( OR: 0.546, 95% CI: 0.289-0.986), when comparing female to male patients on the likelihood of receiving NAC to the alternative treatment types (radiation or surgery), female pts were less likely to receive NAC than males (OR: 0.421, 95% CI: 0.184-0.930). Conclusions: Regardless of demographics, the overall adoption rate of standard care was low, consisting of 236 pts (19.7%) of the population. From the logistic regression results, age was consistently shown as a predictor for receiving NAC over the alternative treatment types, and sex was identified as another strong predictor. Older and female patients were less likely to receive NAC than younger males.[Table: see text]

Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

PurposeChemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model.Materials and MethodsCD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment.ResultsA significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay.ConclusionsUltrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.

Phase II trial of escalating doses of neoadjuvant atezolizumab for patients with non-metastatic urothelial carcinoma ineligible for cisplatin-based neoadjuvant chemotherapy.

442 Background: For patients (pts) with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy (cisplatin), the standard of care option is radical cystectomy (RC) alone. This prospective clinical trial investigated the safety and efficacy of escalating doses of atezolizumab (ATZ) as neoadjuvant therapy prior to RC in pts with non-metastatic urothelial cancer. Methods: This single-arm, single institution, phase II trial investigated the administration of one (n = 6), two (n = 5) or three (n = 9) cycles of ATZ (1200 mg IV given every 3 weeks) in pts with MIBC who are either ineligible for or refused cisplatin prior to RC. Key inclusion criteria were urothelial carcinoma of the bladder (T2-T4a,N0-1,M0) and inability to receive cisplatin-based treatment (eGFR &lt; 60 mL/min, G≥2 neuropathy/hearing loss, pt decision). Pts with high-risk disease ( &gt; pT2 or LN+) at the time of RC were eligible to receive adjuvant ATZ for up to 16 total cycles. Primary efficacy endpoint was pathologic complete response (pCR; pT0N0). Important secondary endpoints were safety of treatment, rates of pathologic downstaging and biomarker assessments in serial tissue samples. Pts were followed for up to 2 years following RC. Results: Among 20 pts with MIBC, median age was 69 (range 61-81) and 75% were male. Most commonly pts were cisplatin-ineligible due to low GFR (35%), hearing loss (25%) or neuropathy (10%); remainder refused cisplatin (30%). At trial enrollment, pT2, pT3, and pT4 was present in 80%, 15%, and 5% of pts and 10% had enlarged pelvic lymph nodes ( &gt; 10 mm) on scans. All pts completed intended treatment cycles and all had RC within the defined timeframe ( &gt; 3 weeks from last and &lt; 12 weeks from first treatment). pCR at RC was 10% (2/20 pts), and was observed in pts receiving 1 and 2 cycles of ATZ. Pathologic downstaging (≤pT1N0) was achieved in 25% (5/20 pts) and observed across all three dose levels. Adjuvant ATZ was given to 8 pts. TRAEs of any grade during perioperative period occurred in 75% and G3 TRAEs in 10% (diarrhea, fecal incontinence). There were no G4 or G5 events. Median follow-up from the time of RC was 21.4 months at the time of data cutoff in 10/2020. Among evaluable pts, 1-year RFS and OS were 71% and 94% while 2-year RFS and OS were 64% and 75%. Conclusions: This prospective trial supports the safety and efficacy of ATZ as neoadjuvant therapy in MIBC. Although pCR and rates of downstaging were lower than what was previously reported in comparable neoadjuvant trials of checkpoint inhibitors in MIBC, pCRs in this trial were seen even in pts receiving only 1-2 doses of ATZ. Many pts had a durable recurrence-free period and all 4 evaluable pts who had pathologic downstaging were alive and disease free at 2 years post RC. Translational and biomarker work from this study is also being pursued. Clinical trial information: NCT02451423.