Therapy For Muscle-invasive Bladder Cancer Research Articles

The Impact of Histologic Subtypes on Clinical Outcomes After Radiation-Based Therapy for Muscle-Invasive Bladder Cancer.

Outcomes of radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC) with histologic subtypes of urothelial cancer (HS-UC) are lacking. Our objective was to compare survival outcomes of pure urothelial carcinoma (PUC) to HS-UC after RT. A multicenter retrospective study of 864 patients with MIBC who underwent curative-intent RT to the bladder for MIBC (clinical T2-T4aN0-2M0) between 2001 and 2018 was conducted. Regression models were used to test the association between HS-UC and complete response (CR) and survival outcomes after RT. In total, 122 patients (14%) had HS-UC. Seventy-five (61%) had HS-UC with squamous and/or glandular differentiation. A CR was confirmed in 69% of patients with PUC and 63% with HS-UC. There were 207 (28%) and 31 (25%) patients who died of metastatic bladder cancer in the PUC and HS-UC groups, respectively. There were 361 (49%) and 58 (48%) patients who died of any cause in the PUC and HS-UC groups, respectively. Survival outcomes were not statistically different between the groups. The HS-UC status was not associated with survival outcomes in multivariable Cox regression analyses. In our study, HS-UC responded to RT with no significant difference in CR and survival outcomes compared to PUC. The presence of HS-UC in MIBC does not seem to confer resistance to RT, and patients should not be withheld from bladder preservation therapy options. Due to low numbers, definitive conclusions cannot be drawn for particular histologic subtypes.

Abstract IA013: Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer

Abstract Many muscle-invasive bladder cancer (MIBC) patients are not getting curative treatment, there remains an undertreated/underserved population and a huge unmet need. Some are not good surgical candidates and others decline a radical cystectomy given concerns regarding its morbidity. Trimodality therapy (TMT), comprising of a maximal transurethral resection of bladder tumor (TURBT) followed by chemoradiation (with salvage cystectomy reserved for those that incur a muscle-invasive recurrence), has emerged as a viable bladder-preserving alternative to radical cystectomy for selected patients. In clinically-matched cohorts, survival is comparable to radical cystectomy in the modern era. More than 85% of contemporary patients keep their own native bladder and long-term quality of life after bladder preservation is good. Salvage cystectomy is feasible and can be curative for those with MIBC recurrences. TMT is now supported by numerous clinical guidelines, including NCCN (category 1 recommendation for stage II and IIIA). There are opportunities to continue to optimize clinical staging of disease (e.g. MRI), delivery of RT (e.g. image guidance, adaptive delivery, dose escalation, hypofractionation, field design) and systemic therapies (e.g. concurrent, neoadjuvant and adjuvant, including possibly immunotherapy) to improve outcomes. Ongoing trials (such as SWOG/NRG 1806 which recently closed to accrual) will inform the addition of immunotherapy to TMT. Validation of biomarkers in independent cohorts and in prospective trials is necessary to further guide bladder preservation therapy for MIBC and for personalized treatment selection. Ultimately, MIBC patients should be seen in a multidisciplinary environment where informed decision making by the patient is key. Citation Format: Jason A. Efstathiou. Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA013.

Abstract 3701: Urine-based liquid biopsy test for the detection of residual bladder cancer in radical cystectomy patients

Abstract The gold standard therapy for muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy (RC) and urinary diversion. Some patients may have their disease completely eradicated by chemotherapy as ~35% of patients achieve a pathologic complete response (pCR) when evaluated from RC specimens. RC with urinary diversion is a life-altering operation with high complication rates and therefore determining who are complete responders would improve quality of life and could decrease costs and still achieve a high cure rate via RC avoidance. Unfortunately, current methods cannot accurately identify complete responders. Our lab has developed a urine-based liquid biopsy test in which DNA isolated from urine and germline is isolated and subjected to panel exome sequencing for enumeration of somatic variants. This occurs under the premise that tumor DNA identified (as mutant alleles) is a marker of residual disease while the absence of tumor DNA (meaning the absence of mutant alleles) can indicate a pCR. A 55 gene panel was designed to be used for exonic sequencing of urinary DNA (uDNA) to identify mutations indicative of bladder cancer or therapeutic targets. We have shown that most mutations in tumor tissue are detectable as mutations in urine (Mu). We also showed that the presence or absence of residual Mu after completion of chemotherapy strongly associates with residual disease or pCR at the time of RC, respectively. Therefore, this test could be used after neoadjuvant therapy to better identify patients for RC avoidance. To optimize this test, we are currently evaluating pre-analytical factors affecting the yield, purity, and integrity of uDNA and the quality of sequencing data using prospectively collected samples from patients with MIBC. We are also testing commercial and novel preservatives to identify one that maintains cell-free DNA integrity, yield, and mutation detection accuracy to enable temporary ambient temperature storage without compromising mutation detection, permitting shipping/centralized testing. Lastly, we are comparing two library preparation approaches: classical hybrid capture-based (Agilent SureSelect XTHS) and amplicon+hybrid capture-based (Agilent HaloPlexHS) to determine which performs the best for identifying the variants in a sample. Our results showed that both sequencing depth and the quality bases mapped was higher when utilizing the SureSelect XTHS kit as compared to HaloPlexHS using approximately the same number of reads. This improvement may also increase the power to detect rare alleles. Studies described herein will enable liquid biopsy tests to accurately identify patients with pCR after neoadjuvant therapy and might safely avoid radical cystectomy. Citation Format: Rhea Arya, Henkel Valentine, Uttam Satyal, Raju Chelluri, Mengmeng Li, Philip Abbosh. Urine-based liquid biopsy test for the detection of residual bladder cancer in radical cystectomy patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3701.

Patterns of concurrent chemotherapy selection in US patients undergoing trimodality therapy for muscle-invasive bladder cancer.

554 Background: Trimodality therapy (TMT) consists of concurrent chemoradiation following maximal transurethral resection of the bladder tumor for muscle-invasive bladder cancer (MIBC). Current TMT treatment guidelines allow for several different radiosensitizing chemotherapy regimens, however there is limited data on existing use patterns. Methods: Using data from CancerLinQ Discovery, 71,499 patients with a bladder tumor diagnosed between 2000-2022 were included. Patients with documented radiation to “bladder” or “pelvis” with no known metastatic disease and a documented chemotherapy regimen started within a 30-day window of radiation, were included in the final analyses (n=233). Chemotherapy regimens included cisplatin, gemcitabine, 5FU+ mitomycin, taxanes, and other. Through bivariate analyses, patient characteristics and TMT treatment patterns were characterized. Results: The most commonly utilized TMT chemotherapy regimen was cisplatin alone (42.5%) followed by gemcitabine (19.3%), 5FU+ mitomycin (15.8%), taxanes (12.5%) and other (9.9%). These data demonstrated a significant relationship between age at diagnosis and chosen TMT regimen (p=0.017). Patients <65 were more likely to receive cisplatin (27.3%), 5FU mitomycin (29.7%) or other (30.4%) while patients 85+ were more likely to receive gemcitabine (28.9%). Patients more frequently received cisplatin alone prior to 2017 (before 2011: 28.3% vs. 2011-2016: 53.5% vs. 2017-2022:18.2%, p-value <.001), with a trend towards more gemcitabine use in the most recent period between 2017-2022 (51.1% vs. before 2011: 20.0% vs 2011-2016: 28.9%, p-value <.001). Additionally, there was less taxane use over time (before 2011: 37.9% vs. 2011-2016: 55.2% vs 2017-2022: 6.9%, p-value <.001). Finally, the association between TMT regimen and Charlson Comorbidity Index (CCI) trended toward significance—those treated with cisplatin alone were most likely to have a CCI of 0 (62.6%, p-value = 0.081) while patients receiving gemcitabine alone or 5FU + mitomycin were more likely to have a CCI of 1+ (gemcitabine alone: 51.1%, 5FU + mitomycin 51.4%, p-value = 0.081). Conclusions: There remains wide variation in the use of chemotherapy regimens in TMT with cisplatin monotherapy as the most utilized radiosensitizing agent overall. Since 2000, there has been a shift away from taxane therapy and increased gemcitabine use. Patients with lower CCI had a trend to more frequently receive cisplatin and older patients more frequently received gemcitabine. Further investigations are needed to better characterize patient characteristics as well as toxicity and survival by drug regimen to better help inform treatment guidelines.

Predictive roles of NETs and IgG in neoadjuvant chemotherapy for muscle-invasive bladder cancer.

659 Background: Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC), in the neoadjuvant setting. However, the efficacy of MIBC for chemotherapy is only about 40%. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. Besides, NETs and IgG could reflect the immune response, even may induce immune tolerance. In MIBC, the predictive role of NETs or IgG in chemotherapy resistance is unclear. Methods: This study included 54 patients with MIBC undergoing neoadjuvant chemotherapy. Immunohistochemical staining with NETs was performed on tumor primary lesions before chemotherapy, and the staining intensity was scored. Serum IgG levels in the pre-treatment baseline and 1 month after chemotherapy were also measured for these patients. Results: Citrullinated histone H3 (H3Cit) as a hallmark of NETs, was an independent predictor of chemotherapy resistance as determined by the multivariate logistic regression analyses [OR=5.94, 95% CI 1.20–45.50, P=0.045]. Additionally, in patients with favorable chemotherapy response, serum IgG levels significantly decreased after 1 month of treatment (P=0.0018), while in those with poor response, there was no significant change. Conclusions: The baseline levels of NETs and the change of IgG after 1-month treatment demonstrated predictive capabilities during neoadjuvant chemotherapy, possibly reflecting the immune status. MIBC patients with high NETs and IgG levels were resistant to neoadjuvant chemotherapy, providing new insights into the treatment of MIBC. However, these results require further validation through larger sample studies. Further validation of our findings could provide a theoretical basis regarding NETs inhibitors or IgG antibodies combined with chemotherapy strategy.

Radical cystectomy or trimodality therapy for muscle-invasive bladder cancer: a qualitative study exploring patient priorities and counselling needs when making a treatment choice

BackgroundThis study aims to explore the priorities and counselling needs of patients with muscle-invasive bladder cancer faced with a decision between radical cystectomy and trimodality therapy.MethodsWe performed a qualitative study according to the phenomenological approach. Sixteen muscle-invasive bladder cancer survivors who underwent radical cystectomy or trimodality therapy completed a semi-structured interview between May 2022 and February 2023. Patients were recruited via Ghent University Hospital and a patient organisation. Data were analysed with inductive thematic analysis by a multi-disciplinary team using an iterative approach and investigators’ triangulation.ResultsFour main priorities determining the treatment decision were identified. (1) curing the disease; (2) health-related quality of life (physical, mental and social); (3) confidence in the treatment, which was mainly based on trust in the clinician; and (4) personal attributes. Trust in the clinician can be achieved by fulfilling the patient’s information needs (accurate, complete, clear, impartial, personalised, realistic, and transparent information), ensuring accessibility of the clinician, and creating a clear and personalised treatment plan, involving patients to the extend they desire. Many patients considered a patient decision aid as a valuable asset in this process.ConclusionPriorities vary between patients with muscle-invasive bladder cancer. Identifying individual priorities and offering personalised information about them is crucial for ensuring trust in the clinician and confidence in the treatment. Use of a patient decision aid can be beneficial in this process.

Phase II Trial of Concurrent Nivolumab and Radiation Therapy for Muscle-Invasive Bladder Cancer of Older or Chemotherapy-Ineligible Patients

Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.

Early Experience with CBCT-Guided Online Adaptive Radiotherapy for Muscle Invasive Bladder Cancer.

Radiation therapy for muscle-invasive bladder cancer (MIBC) requires substantial planning target volume (PTV) margins to account for variability in bladder filling as well as other anatomic changes. We hypothesized that CBCT-guided online adaptive RT (oART) may both improve target coverage and reduce normal tissue exposure as compared to non-adaptive RT. The purpose of this study is to report the dosimetric results of our initial experience utilizing oART for treatment of MIBC. Seven patients with MIBC were treated with oART over a 1-year period. Patients were simulated with an empty bladder and were asked to void prior to each treatment. Five patients received 55 Gy in 20 fractions to a clinical target volume (CTV) expanded from the TURBT bed and 46 Gy simultaneously to the remaining bladder and for 2 patients the high dose CTV was the entire bladder. PTVs consisted of a 7mm isometric expansion of the CTV. The oART delivery process initially coregisters the daily CBCT to the treatment planning CBCT using skeletal alignment. Target volumes and organs-at-risk (OARs) were modified at each treatment session and the plan re-optimized to meet prespecified clinical goals. Target coverage and OAR dosimetric parameters for the adaptive were compared non-adaptive (scheduled) plan for each fraction using the Wilcoxon paired test of means. The adapted plan was selected for delivery for all fractions across all patients. Daily bladder volumes differed from the bladder volume at simulation by a mean of 60cc ± 66cc. At least 95% of the high dose CTV was covered by the prescription dose for 139 (99.3%) fractions with the oART plan as compared to 70 (50%) fractions with scheduled. A portion of the high dose CTV was outside of the 80% isodose line for 13 (9.3%) of scheduled fractions and was outside of the 50% isodose line for 2 (0.01%) of scheduled fractions. There were no cases of oART plans where any portion of the high dose CTV was outside of the 90% isodose line. A comparison of selected target and OAR dosimetric parameters is shown in the Table. oART treatment plans were associated with greater target coverage and less OAR exposure for all metrics. In this initial experience, oART resulted in acceptable delivered dosimetry to target volumes with a reduced PTV margin of 7mm despite considerable daily variation in bladder volume. As expected, oART plans were associated with improved target coverage and OAR dosimetry. Future patient-centered studies should explore the clinical impact of reduced margin oART for patients with MIBC.

CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway

Systemic therapy for muscle-invasive bladder cancer (BC) remains dominated by cisplatin-based chemotherapy. However, resistance to cisplatin therapy greatly limits long-term survival. Resistance to cisplatin-based chemotherapy still needs to be addressed. In this study, we established three cisplatin-resistant BC cell lines by multiple cisplatin pulse treatments. Interestingly, after exposure to cisplatin, all cisplatin-resistant cell lines showed lower reactive oxygen species (ROS) levels than the corresponding parental cell lines. Using proteomic analysis, we identified 35 proteins that were upregulated in cisplatin-resistant BC cells. By knocking down eleven of these genes, we found that after CAB39 knockdown, BC cisplatin-resistant cells were more sensitive to cisplatin. Overexpression of CAB39 had the opposite effect. Then, the knockdown of six genes downstream of CAB39 revealed that CAB39 promoted cisplatin resistance in BC through LKB1. Moreover, a key cause of cisplatin-induced cell death is damage to mitochondria and increased ROS levels. In our study, cisplatin-resistant cells exhibited higher autophagic flux and healthier mitochondrial status after cisplatin exposure. We demonstrated that the CAB39-LKB1-AMPK-LC3 pathway plays a critical role in enhancing autophagy to maintain the health of mitochondria and reduce ROS levels. In addition, the autophagy inhibitor chloroquine (CQ) can significantly enhance the killing effect of cisplatin on BC cells. Compared with gemcitabine plus cisplatin (GC), GC plus CQ significantly reduced tumor burden in vivo. In conclusion, our study shows that CAB39 counteracts the killing of cisplatin by enhancing the autophagy of BC cells to damaged mitochondria and other organelles to alleviate the damage of cells caused by harmful substances such as ROS.

Selective multimodal bladder-sparing therapy for muscle-invasive bladder cancer: the present and the future

ABSTRACT Introduction Despite the lack of level 1 evidence, selective bladder-sparing therapy using trimodal therapy is currently recommended by guidelines as a standard of care in patients with non-metastatic, muscle-invasive bladder cancer who are eligible for the treatment. Areas covered This article reviews major studies of selective, bladder-sparing therapy utilizing multiple modalities for muscle-invasive bladder cancer and those comparing the oncological outcomes between bladder-sparing therapy and radical cystectomy. Also discussed are predictive biomarkers potentially capable of guiding treatment decisions by patients with muscle-invasive bladder cancer and a novel strategy for boosting the antitumor immune response in bladder-sparing therapy. PubMed databases were searched for records of 30 June 2023 or earlier. Expert opinion Selective, bladder-sparing therapy appears to be underutilized at present. To promote its use, measures should be taken to facilitate the referral of eligible patients to specialist centers and broaden the number of facilities providing the therapy. Recent studies have suggested a prognostic benefit of radiotherapy for the primary lesion in patients with metastatic bladder cancer. Given that irradiation can induce the abscopal effect, particularly in combination with immune checkpoint inhibitors, demand for bladder-sparing therapies may increase in the context of treatments for metastases.

Integrating angiogenesis signature and tumor mutation burden for improved patient stratification in immune checkpoint blockade therapy for muscle-invasive bladder cancer

BackgroundMuscle-invasive bladder cancer (MIBC) patients have benefitted greatly from immune checkpoint blockade (ICB) therapy. However, there is a pressing need to identify factors underlying the heterogeneity of clinical responses to ICB. MethodsWe conducted a study on 848 MIBC patients from 4 independent cohorts to investigate the key biological characteristics affecting ICB responses. The IMvigor210 cohort (n = 234) was used to identify the key factor, followed by exploration of the correlation between tumor angiogenesis and immune suppression in the IMvigor210, TCGA (n = 391), and UNC-108 (n = 89) cohorts. The ZSHS cohort (n = 134) was used for validation. Additionally, we integrated angiogenesis signature with tumor mutation burden (TMB) to decipher the heterogeneity of clinical outcomes to ICB in MIBC patients. ResultsOur analysis revealed that nonresponders to PD-L1 blockade were enriched with angiogenesis signature. Furthermore, we observed a correlation between angiogenesis signature and decreased neoantigen load, downregulated T-cell antigen recognition, and noninflamed immunophenotype. We identified a subgroup of patients resistant to ICB, characterized by high angiogenesis signature and low tumor mutation burden (TMB), and found the activation of TGF-β signaling and downregulation of T-cell cytolytic signatures in this subgroup. ConclusionsThe study concluded that angiogenesis signature is closely associated with an immunosuppressive microenvironment, leading to resistance to ICB therapy in MIBC patients. The study further suggested that the combination of angiogenesis signature and TMB can serve as an integrated biomarker for better stratification of patients' clinical outcomes to ICB therapy.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer

Re: Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis

Re: Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis

Molecular classification of muscle-invasive bladder cancer based on a simplified immunohistochemical panel using GATA3, CK5/6 and p16.

The choice of therapy for muscle-invasive bladder cancer (MIBC) could be influenced by the tumor's molecular subtype. Currently, well-defined consensus subtypes are based on tumor microarray mRNA data. Clearly defined and easy-to-use surrogate molecular subtypes, based on immunohistochemistry (IHC) performed on whole slides, are needed to make subtyping cost-effective and useful in routine work and future research. To aid in the development of a simple immunohistochemical classifier, a retrospective single-center series of 92 cases of localized bladder cancer was identified. Routine IHC for GATA3, cytokeratins 5 and 6 (CK5/6), and p16 was performed on whole tissue blocks containing muscle-invasive disease. Electronic medical records were retrieved and searched for clinical variables, treatment, and survival data. The mean age was 69.6 years, and 73% were males. Conservative treatment was used in 55% of cases, while cystectomy with chemotherapy was used in 45%. GATA3 and CK5/6 expression divided cases into broad luminal and basal subtypes, respectively, while p16 expression was used to subclassify luminal cases into luminal papillary and luminal unstable types according to the consensus molecular classification. When subtyped in this way, GATA3 and CK5/6 negative cases showed worse overall survival. Molecular subtyping of MIBC on whole slides containing muscle-invasive tumor using only three commonly used, consensus-based antibodies, is a feasible and cost-effective method for detecting subtypes of invasive bladder cancer. Future work combining morphological analysis and IHC is needed to fully translate the consensus molecular classification into a comprehensive, cost-effective subtyping strategy.

Recent developments in perioperative combination therapy in muscle-invasive bladder cancer.

A summary of recent literature to provide a comprehensive overview of the current state of systemic perioperative treatment combinations for muscle-invasive bladder cancer (MIBC). We discuss recent developments in standard and experimental treatment modalities. The VESPER trial has shown that six cycles of neoadjuvant dose-dense MVAC are superior to four cycles of gemcitabine/cisplatin (GC), though it is unclear whether the superiority is derived from the specific regimen or number of cycles. Adjuvant cisplatin-based chemotherapy, a subject of longstanding debate, was shown to have comparable overall survival-benefit to neoadjuvant chemotherapy in an updated meta-analysis. Neoadjuvant chemotherapy and anti-PD-(L)1 show encouraging results, but with no comparative studies to standard care, context is lacking. Immunotherapeutic neoadjuvant anti-CTLA-4/PD-(L)1 combinations or combinations of checkpoint inhibitors with antibody-drug-conjugates are in early stages of development and show promising preliminary results. Six cycles of neoadjuvant dose-dense MVAC are superior to four cycles of gemcitabine/cisplatin. Adjuvant cisplatin-based chemotherapy is a viable option for patients with high-risk tumours who did not receive prior neoadjuvant treatment. The added value of anti-PD-(L)1 to chemotherapy still needs to be established. Novel developments in immunotherapy combinations, while promising, are still in an early stage and randomized studies are ongoing.

Neutrophil extracellular trap as a predictive marker to cisplatin-based chemotherapy for patients with muscle-invasive bladder cancer.

e16600 Background: Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC), in both the neoadjuvant and first-line settings. However, the efficacy of MIBC for chemotherapy is only about 40%~60%. Patients without clear benefits from cisplatin-based chemotherapy still suffer from the potential toxicity, possibly missing the timing for other effective treatments. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. In bladder cancer, NETs were involved in radio-resistance, but the predictive role of chemotherapy is unclear. This study constructed a NET-related signature that predicted chemotherapy efficacy for MIBC patients. Methods: Transcriptome datasets were obtained from the transurethral resection of bladder tumor (TURBT) and metastatic lesion specimens. A dataset (GSE169455) of 149 MIBC patients who received preoperative cisplatin-based chemotherapy (neoadjuvant or induction) was enrolled for the training cohort. We used the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model to select candidate molecules based on the 250 NETs-initial biomarkers collected from the literature, and further developed a NETs-associated signature score (NETs-score) for therapeutic response prediction. The dataset reported by Taber A et al. of 96 MIBC patients who received cisplatin-based chemotherapy (neoadjuvant or first-line) was used as a validation cohort. Immunohistochemistry (IHC) was conducted to evaluate the potential role of NET-related genes in 51 patients who received neoadjuvant chemotherapy at our center from 2012 to 2019. Results: We constructed the NETs-score with 11 NETs-related genes by the LASSO Cox model. A higher NET score was observed in non-responders compared to responders in the training cohort (P<0.001). These results were confirmed in the validation cohort (P=0.006). Moreover, high NETs-score indicated reduced recurrence-free survival (RFS) [HR=2.07, 95% CI (1.26-3.40), P=0.003], cancer-specific survival (CSS) [HR=1.87, 95% CI (1.12-3.12), P=0.014], and overall survival (OS) [HR=1.83, 95% CI (1.13-2.94), P=0.012] among MIBC patients. Furthermore, in the IHC cohort, citrullinated histone H3 (H3Cit) as a hallmark of NETs, was an independent predictor of chemotherapy resistance as determined by the multivariate logistic regression analysis [OR=5.94, 95% CI 1.20–45.50, P=0.045]. Conclusions: In conclusion, our study suggested that NET was a predictive and prognostic biomarker for MIBC patients with cisplatin-based chemotherapy. [Table: see text]

ANTICIPATE phase I: Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).

e16607 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: ANTICIPATE Phase I was a dose escalation study to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of APL-1202. Eligible patients had newly diagnosed MIBC, were cisplatin-ineligible or refused cisplatin-based neoadjuvant chemotherapy, and were planned for radical cystectomy (RC). A standard 3+3 dose-escalation design was employed. On day 1 of each cycle, a single dose of 200 mg tislelizumab was administered intravenously. APL-1202 was administered orally 3 times daily and with the dose escalated in 3 successive cohorts (375 mg, 750 mg, and 1,125 mg). Intra-patient dose escalation was not allowed. Blood samples were collected for pharmacokinetics and other translational studies. Results: Nine patients have been enrolled in phase I: 3 patients each at 375 mg, 750 mg, and 1125 mg of APL-1202. All patients had predominant urothelial cancer with cT2 (6/9) and cT3 (3/9); PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay and 1/9 (11.1%) patients was positive. No dose-limiting toxicities were observed at either 375 mg, 750 mg, or 1125 mg daily dose of APL-1202. Treatment-related adverse events (TRAE) were observed in 6 patients. All AEs were grade 1, except 1 grade 2 T wave abnormality on ECG and 1 grade 3 liver dysfunction. No grade 4 or 5 related AEs were observed. The patient with grade 3 liver dysfunction recovered to baseline within 2 weeks and underwent RC. Pathologic downstaging to < pT2 was observed in 5/8 (62.5%) and 1/8 (12.5%) with pT0 in 8 evaluable patients; 1 patient refused RC. Conclusions: APL-1202 plus tislelizumab was well tolerated. The RP2D of APL-1202 was identified as 1125 mg daily dose. Early efficacy signals were observed including pathologic downstaging to < pT2 (5/8, 62.5%) and pT0 (1/8, 12.5%). Phase 2 trial was ongoing. (NCT04813107). Clinical trial information: NCT04813107 .

A single institution experience of multimodality radiation therapy for muscle-invasive bladder cancer.

e16614 Background: We studied a cohort of patients with localized muscle invasive bladder cancer (MIBC) who received organ preserving trimodality therapy (TMT) as definitive treatment at a single high-volume institution. Methods: A retrospective cohort analysis was performed for 231 bladder cancer patients treated with definitive radiation or chemoradiation therapy from 2006 to 2022 at a single institution. We assessed overall and disease-free survival as defined by any type of cancer recurrence. We analyzed survival outcomes based on stage, pathologic features, and patient characteristics. Results: 184 of 231 patients in this cohort received either definitive radiation therapy alone or with chemoradiation and had adequate follow-up data for analysis. The median overall survival for these 184 patients was 37mo (95%CI 28-67). Disease free survival (DFS) had a median time of 36mo (95% CI 23-69). On univariate analysis neither tumor size nor hydronephrosis showed a significant association with local recurrence. The presence of carcinoma in situ (CIS) was associated with shorter time to local recurrence (Log-Rank p = 0.039). Nine patients (4.9%) required cystectomy after initial definitive radiation therapy. When overall survival was compared between patients offered radical cystectomy who proceeded with definitive multimodal radiation therapy and radical cystectomy ineligible patients, there was a significantly longer overall survival for the cystectomy eligible patients (median 86mo (95%CI 35-206) vs median 31mo (95%CI 24-44), Log-Rank p = 0.0016). No differences were observed in cancer specific survival between cystectomy eligible and ineligible patients. Conclusions: Multimodality bladder preservation demonstrated cancer specific survival outcomes comparable to published radical cystectomy series. The presence of CIS at baseline was associated with increased local recurrence, but not CSS or OS. Eligibility for radical cystectomy was associated with longer overall survival in patients treated with TMT, highlighting the limitations of retrospective comparisons of all-cause mortality between different treatment approaches. Disease specific survival endpoints, propensity matching analyses, or randomized prospective trials are needed to draw comparative efficacy conclusions.

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers

BackgroundRadiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). ObjectiveTo analyze predictors of complete response (CR) and survival after RT for MIBC. Design, setting, and participantsThis was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. Outcome measurements and statistical analysisRegression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). Results and limitationsThe median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3–4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29–0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034–0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46–2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25–3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79–3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46–0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51–0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01–1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34–2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17–1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49–0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51–0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12–1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. ConclusionsRT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. Patient summaryWe investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

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.