Localized Muscle-invasive Bladder Cancer Research Articles

Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

Abstract 7041: Tumor-immune interactions and cisplatin resistance in localized muscle-invasive bladder cancer

Abstract Background: Cisplatin-based chemotherapy followed by radical cystectomy remains the standard-of-care treatment for patient with localized muscle-invasive bladder cancer (MIBC). Neoadjuvant clinical trials studying the combination of cisplatin-based chemotherapy and immune checkpoint blockade (ICB) in MIBC reported encouraging pathologic complete response rates. However, the molecular mechanisms and cellular programs involved in response and resistance to cisplatin and ICB in MIBC remain incompletely characterized. Our goal is to define cellular transcriptional programs and chromatin accessible regions in cancer cells and infiltrating immune cells associated with response and resistance to neoadjuvant systemic therapy. Methods: We performed single-cell Multiome ATAC and Gene expression sequencing (simultaneous identification of gene expression and open chromatin regions within the same cell) of tumors that had a complete response – “responders” – and tumors that had no response or progressed – “non-responders” – through neoadjuvant cisplatin-based chemotherapy (n=15). Single cell suspensions were prepared following the 10x Genomics protocol. Cell Ranger ARC was used for sequence alignment, peak calling, and generation of count matrices. Downstream single-cell gene expression analysis was performed with Scanpy and ATAC-seq with Seurat. Results: We identified two distinct urothelial cell populations in "responders" vs "non-responders" based on single cell gene expression and genome wide chromatin accessibility regions. Cancer cells in “non-responders” preferentially express basal cell gene expression signatures. “Non-responders” were significantly enriched in suppressive tumor-associated macrophages (TAMs). Interestingly, SPP1+ TAMs known to have a pro-tumoral role and promote resistance to ICB were exclusively identified in “non-responders”. Conclusion: Single cell and genome wide chromatin accessibility regions identify heterogenous urothelial cell populations expressing basal cell markers in tumors resistant to neoadjuvant cisplatin-based chemotherapy. “Non-responders” are significantly enriched with TAMs implicated in resistance to ICB. Future studies will better define the implications of these findings in cancer therapeutics for patients with MIBC. Citation Format: Filipe La Fuente De Carvalho, Jihyun Lee, Kevin Bi, Breanna Titchen, Konrad Stawiski, Jihye Park, Amanda Garza, Daniel Michaud, Jennifer Guerriero, Elizabeth Mittendorf, Kent Mouw, Eliezer Van Allen. Tumor-immune interactions and cisplatin resistance in localized muscle-invasive bladder cancer [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 7041.

Abstract 965: Urine cell-free DNA multi-omics combining copy number analysis with fragmentomics to detect minimal residual disease in bladder cancer patients

Abstract Background: Standard-of-care for patients with localized muscle-invasive bladder cancer (BC) is neoadjuvant chemotherapy followed by radical cystectomy (RC). Bladder-sparing treatments are limited by our current inability to sensitively detect minimal residual disease (MRD). Here, we analyzed urine, a noninvasive and proximal biofluid, from patients with bladder cancer and utilized an approach that incorporates copy number-derived tumor fraction as well as fragmentomics to sensitively detect MRD and predict pathologic complete response (pCR). Methods: We acquired urine preoperatively from 51 BC patients (80% muscle-invasive) on the day of standard-of-care RC, and after neoadjuvant chemotherapy in 57% of patients. We performed whole genome sequencing (WGS) of urine cfDNA (median depth: 10X) from all 51 BC patients and 13 healthy adults. Tumor fraction level based on genome-wide copy number alterations was estimated using ichorCNA. We inferred fragment size and genomic coverage of urine cfDNA using Picard Tools. Then, we computed the short-to-long (S/L) fragment ratio for genomic bins in each sample. The S/L ratio per bin was derived by partitioning the genome into 100 kb bins and evaluating the ratio of GC-corrected short fragments (50-150 bp) to long fragments (151-250 bp) within each bin. A normalized genome-wide S/L score was calculated by averaging across all bins. Results: In our cohort of 51 BC patients, 45% of patients achieved pCR (n = 23) while 55% had residual disease detected in their surgical sample (no pCR; n = 28). Patients with no pCR had significantly higher copy number-derived tumor fractions in urine compared to patients with pCR (median 10.6% vs 1.9%, p = 0.0002) and healthy adults (n = 12) (median 10.6% vs 1.8%, p = 0.003). Tumor fraction achieved an AUC of 0.89 for classification of No pCR from pCR with sensitivity of 82% and specificity of 92%. Presumed cancer-free patients (healthy and pCR) had significantly longer urine cfDNA median fragment sizes than patients with no pCR (median 177 bp vs 156 bp, p = 0.002). Presumed cancer-free patients (healthy and pCR) also had significantly lower S/L ratio scores than no pCR patients (mean .98 vs 1.5, p = 0.007). The top 100 bins with maximally differential S/L ratio between these two patient groups were enriched for genes involved in KEGG pathways implicated in cancer and immune signaling (autophagy, transcriptional misregulation in cancer, Th1 differentiation) indicating biological relevance. Conclusion: Copy number alteration-derived tumor fraction inference combined with fragmentomic analysis of urine cell-free DNA can enable sensitive detection of MRD to predict pCR and reveal potentially onco-relevant pathways. Citation Format: Arpit Panda, Irfan Alahi, Pradeep S. Chauhan, John Sheng, Nathan Colon, Cayce Nawaf, Alexander Shiang, Peter K. Harris, Faridi Qaium, Eric H. Kim, Melissa A. Reimers, Woodson Smelser, Zachary L. Smith, Aadel A. Chaudhuri. Urine cell-free DNA multi-omics combining copy number analysis with fragmentomics to detect minimal residual disease in bladder cancer 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 965.

Robot-assisted radical cystectomy with neobladder diversion in females: safety profile and functional outcomes

ObjectiveRadical cystectomy (RC) is a standard treatment for localized muscle invasive bladder cancer and high-risk or very high-risk non-muscle invasive bladder cancer. In women, traditionally RC is performed with hystero-adnexectomy and resection of the anterior vaginal wall, often resulting in sexual disorders. Vaginal-sparing techniques have been developed to improve functional outcomes. The present study explores the safety and the functional outcome of this approach. MethodsWe retrospectively analyzed all consecutive female patients undergoing robot-assisted RC (RARC) with neobladder diversion between October 2017 and February 2022. The indications for vaginal-sparing RC were absence of tumor on bladder neck or urethra and no sign of infiltration of posterior bladder wall at preoperative staging on MRI. Functional results were evaluated with the aid of five questions out of the Bladder Cancer Index (BCI) questionnaire. Complications were reported according to Clavien-Dindo classification and cancer control was evaluated for recurrence free and cancer specific survival. ResultsA total of 22 female patients underwent RARC with neobladder. Neoadjuvant chemotherapy was given in 17 (77%) cases. Clavien-Dindo III-IV complications occurred in four (18%) cases. After a mean follow-up of 29 (interquartile range 16–44) months, six patients (27%) developed distant metastases, and one woman (5%) loco-regional relapse. Sexual-sparing surgery was performed in 19 (86%) patients, in the others the anterior vaginal wall was resected, but neobladder was still performed. During daytime, no patients reported total incontinence and 73% reported total continence or only occasional leaks. Sexual results showed that 47% of women regained sexual activity after surgery, with a quality reported as “good” or “very good” in 40% of all 19 cases. ConclusionRARC in female with anterior vaginal wall preservation is feasible. The approach showed a good safety profile, with satisfying results on continence and sexual activity. Sexual-sparing approaches should be carried out after correct patient selection.

Efficiency of bladder-sparing strategies for bladder cancer: an umbrella review.

Bladder preservation (BP) has emerged as a clinical alternative to radical cystectomy (RC) for alleviating the substantial physical and psychological burden imposed on localized bladder cancer patients. Nevertheless, disparities persist in the comparative evaluations of BP and RC. We aimed to address the disparities between BP and RC. An umbrella review and meta-analysis were conducted to explore these disparities. We extracted data from meta-analyses and randomized controlled trials (RCTs) selected after searching PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. Review Manager 5.4.0 and R x64 4.1.3 were used to evaluate the collected data. Our study included 11 meta-analyses and 3 RCTs. In terms of progression-free survival, all the meta-analyses reported that patients with localized bladder cancer who underwent BP exhibited outcomes comparable to those who underwent RC. Meta-analyses regarding the outcomes of cancer-specific survival (CSS) and overall survival (OS) are controversial. To solve these issues, we conducted a pooled analysis of CSS data, which supported the similarity of CSS between BP and RC with no significant heterogeneity [odds ratio (OR): 1.2; 95% confidence interval (CI): 0.71-2.02; I2 = 26%]. Similarly, the pooled OS results extracted from three RCTs indicated the comparability of OS between BP and RC with no significant heterogeneity (OR: 1.12; 95% CI: 0.41-3.07; I2 = 33%). A combination of umbrella review and meta-analysis results suggested that BP had survival rates comparable to those of RC. We suggest that BP may be a more eligible therapy than RC for patients with localized muscle-invasive bladder cancer. This conclusion warrants further validation through randomized controlled trials.

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy

Background and objectiveNeoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. MethodsPatients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, <ypT2N0 rates, 2-yr recurrence-free survival (RFS), and OS. Key findings and limitationsAmong 43 patients enrolled (n = 13, cohort 1; n = 30, cohort 2), 13 and 29 completed intended neoadjuvant therapy, respectively, in cohorts 1 and 2, and 41 underwent RC. The median time from the last dose to RC was 4 wk. The G3 TRAEs occurred in 0% (90% confidence interval [CI] 0–21%) of patients in cohort 1 and 7% (90% CI 1–20%) in cohort 2; all these TRAEs resolved and no G4/5 TRAEs occurred. No patient had delayed RC for >6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, <ypT2N0 rates were 25% and 32%, 2-yr RFS rates were 73% and 71%, and 2-yr OS rates were 82% and 89%, respectively. CD8+ T-cell density increased significantly from TURBT to RC in cohort 2. Conclusions and clinical implicationsNeoadjuvant nivolumab-based immunotherapy was safe, feasible, and well tolerated in cisplatin-ineligible patients with MIBC. Although ypT0N0 rates were lower than expected, 2-yr survival rates seem to be comparable with those of other neoadjuvant immunotherapy trials. Nivolumab is being evaluated in the CA-017-078 trial (NCT03661320). Patient summaryFor patients with muscle-invasive bladder cancer unable to receive cisplatin-based chemotherapy, treatment with nivolumab without and with lirilumab prior to radical cystectomy was safe, feasible, and well tolerated. Nivolumab-based immunotherapy showed lower pathologic response rates than but similar survival rates to other neoadjuvant immunotherapy trials.

Transurethral Resection of Bladder Tumor: Novel Techniques in a New Era.

Transurethral resection of bladder tumor (TURBT) serves both diagnostic and therapeutic purposes in the management of bladder cancer. Attaining a high-quality TURBT is not always guaranteed due to various factors. En-bloc resection of bladder tumors (ERBT) holds promise to be a primary technique for removing bladder tumors in most non-muscle invasive bladder cancers. However, so far, no conclusive evidence indicates the superiority of any specific energy source used for ERBT. While laser energy can prevent the activation of obturator nerve reflex during ERBT, it poses challenges such as thermal injury and imprecise controllability. Needle-shaped electrodes offer high-level precision and controllability, without causing tissue deterioration or vaporization. The primary limitation of ERBT at present is the extraction/harvesting of large en-bloc specimens. Effective tools have been developed to overcome this limitation. Enhanced cystoscopy improves the detection of flat and small bladder tumors, allowing for better removal of cancerous tissues and significantly reducing recurrence rates. Advances in medical technology have brought forth a multitude of strategies to address the shortcomings of traditional TURBT. Appliances with large operating channel provide a platform for conducting laparoscopic procedures within the context of pneumocystoscopy, facilitating the execution of super TURBT and conferring comparable advantages to en-bloc resection. Moreover, the utilization of pneumocystoscopy enables the safe and effective performance of transurethral partial cystectomy for localized muscle-invasive bladder cancer. Novel techniques significantly improve the precision of the transurethral surgery and lower the risk of complications.

Trial in Progress: Adaptive RADiation Therapy with Concurrent Sacituzumab Govitecan (SG) for Bladder Preservation in Patients with MIBC (RAD-SG).

A substantial proportion of patients with muscle invasive bladder cancer do not receive curative intent therapy, especially if unfit for or refuse radical cystectomy. Concurrent chemoradiation is an effective alternative to radical cystectomy, however systemic radio-sensitizing chemotherapy may have off target side effects. A Phase I study is accruing which will investigate the concurrent administration of a bladder cancer targeted antibody drug conjugate (Sacituzumab Govitecan) with radiotherapy. This trial in progress is a Phase I study of Adaptive RADiation therapy with concurrent Sacituzumab Govitecan (SG) for bladder preservation in patients with muscle invasive bladder cancer (MIBC). Eligible patients will have localized muscle invasive bladder cancer (MIBC) confined to the bladder. The initial cohort is expected to accrue 20 patients. The primary endpoint is to establish the safety, tolerability, and feasibility of bladder preservation therapy treatment with concurrent SG and adaptive image-guided radiation therapy for patients with localized MIBC. The secondary endpoints are to determine the bladder intact event-free survival (BI-EFS) with concurrent SG and radiation therapy for MIBC and compare to historical controls with other concurrent chemoradiation regimens. BI-EFS is defined as the time from treatment to the first documented occurrence of residual/recurrent MIBC, nodal or distant metastases on imaging, radical cystectomy, or death from any cause. Sacituzumab Govitecan targets TROP-2, a surface protein expressed in urothelial cancers of the bladder. SG will be delivered IV, 10 mg/kg, 21-day cycles for 1 loading cycle prior to radiation and two subsequent cycles with concurrent adaptive radiotherapy over a period of 6 weeks (64 Gy). Correlative objectives (Supported by NCI/NIH U54) and will involve 1) elucidation of the genetic and microenvironmental mechanisms that drive efficacy and resistance to combined ADC plus radiation therapy and 2) characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following treatment with SG plus radiation. To be determined. To be determined.

Treatment patterns, survival, and healthcare utilisation and costs in patients with locally advanced and metastatic bladder cancer in Denmark 2015–2020

Background Treatment patterns in locally advanced and metastatic urothelial bladder cancer (La/mUBC) is changing, but little is known about current treatment patterns, survival, and costs of these patients. Our aim was to describe treatment patterns, survival, and healthcare utilisation/costs in Danish La/mUBC patients in a routine clinical care setting. Methods Registry-based nationwide cohort study including all bladder cancer patients aged 18 years or older with a La/mUBC tumour in the pathology register and a concomitant bladder cancer diagnosis in the Danish National Patient Registry in the period 2015–2020. We categorised the patients according to (1) La/mUBC at time of first bladder cancer diagnosis (de novo La/mUBC) and (2) non-invasive or localised muscle-invasive bladder cancer at time of diagnosis which had progressed to La/mUBC. All patients were included at date of pathology-confirmed La/mUBC. Follow-up ended 30 September 2022. Results We identified 1278 patients (69% men) with La/mUBC and no other previous cancer. Of these, 212 (17%) had de novo La/mUBC, while 1066 (83%) had progressed to La/mUBC. Median age was 72 years. Patients were followed for a median of 13.0 months (interquartile range 4.7;32.0). During follow-up, 651 (51%) patients started first-line treatment, of these, 285 progressed to second-line treatment, and 112 also started third-line treatment. Median survival was 13.0 months from La/mUBC diagnosis, 12.1 months from start of first-line treatment, 9.8 months from start of second-line treatment, and 8.6 months from start of third-line treatment. The mean number of days admitted to hospital was 3.47, 3.97, and 4.07 per month following initiation of first-line, second-line, and third-line treatment, respectively. Conclusion Patients with La/mUBC have a poor prognosis, and in routine clinical care only around half of the patients received systemic anti-cancer treatment suggesting an unmet need for novel treatments. The overall costs only increased slightly from first to third-line treatment.

Practice Patterns Regarding Female Reproductive Organ-Sparing and Nerve-Sparing Radical Cystectomy Among Urologic Oncologists in the United States.

Female reproductive organ-sparing (ROS) and nerve-sparing radical cystectomy (RC) techniques have been shown to be oncologically safe and to improve sexual function outcomes among select patients with organ-confined disease. We sought to characterize practice patterns regarding female ROS and nerve-sparing RC among US urologists. We conducted a cross-sectional survey of members of the Society of Urologic Oncology to assess provider-reported frequency of ROS and nerve-sparing RC in premenopausal and postmenopausal patients with non-muscle-invasive bladder cancer that failed intravesical therapy or clinically localized muscle-invasive bladder cancer. Among 101 urologists, 80 (79.2%) reported that they routinely resect the uterus/cervix, 68 (67.3%) the neurovascular bundle, 49 (48.5%) the ovaries, and 19 (18.8%) a portion of the vagina when performing RC in premenopausal patients with organ-confined disease. When asked about changes to approach in postmenopausal patients, 71 participants (70.3%) reported that they were less likely to spare the uterus/cervix, 44 (43.6%) were less likely to spare the neurovascular bundle, 70 (69.3%) were less likely to spare the ovaries, and 23 (22.8%) were less likely to spare a portion of the vagina. We identified significant gaps in adoption of female ROS and nerve-sparing RC techniques for patients with organ-confined disease, despite evidence that ROS and nerve-sparing techniques are oncologically safe and can optimize functional outcomes in select patients. Future efforts should improve provider training in and education about ROS and nerve-sparing RC to improve postoperative outcomes among female patients.

Downstaging and Survival Associated with Neoadjuvant Immunotherapy Before Radical Cystectomy for Muscle-invasive Bladder Cancer

BackgroundNeoadjuvant cisplatin-containing chemotherapy before radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer (MIBC). However, a large proportion of patients are ineligible for cisplatin. Single-arm phase 2 neoadjuvant immunotherapy trials have reported promising tumor response rates, but interpretation is limited owing to lack of a comparator arm. ObjectiveTo compare rates of pathologic downstaging and overall survival between patients receiving neoadjuvant immunotherapy (NAI), neoadjuvant chemotherapy (NAC), or no neoadjuvant therapy (NNAT). Design, setting, and participantsWe identified 18 483 patients in the National Cancer Data Base who were diagnosed with clinically localized MIBC and underwent radical cystectomy from 2014 to 2019. Outcome measurements and statistical analysisNearest-neighbor propensity-score caliper matching was used to create three demographically similar and equally sized cohorts stratified by NAT receipt. Logistic regression was used to examine the association of treatment received with pathologic downstaging to pT0N0 and pT < 2N0. Cox proportional-hazards regression was used to assess the association of treatment received with overall survival (OS). Results and limitationsPropensity score matching yielded three equally sized cohorts without significant differences in baseline characteristics (n = 840). The NAI group had a higher rate of pathologic downstaging to pT0N0 than the NNAT group and a similar rate to the NAC group (NNAT 6.7% vs NAC 26.4%, odds ratio 5.0, 95% confidence interval [CI] 2.9–8.3; NAI 22.5%, odds ratio 4.0, 95% CI 2.4–7.1). The NAI group had better OS than the NNAT group and similar OS to the NAC group (NAC: hazard ratio 0.62, 95% CI 0.42–0.92; NAI: hazard ratio 0.68, 95% CI 0.46–0.97, with NNAT as the reference). The primary limitation is selection bias from confounding by clinical indication. ConclusionsNAI is a promising alternative to NAC for patients with clinically localized MIBC, as evidenced by similar pathologic downstaging rates and OS benefits in comparison to no NAT. Phase 3 trials should be conducted to test the noninferiority of NAI to NAC. Patient summaryWe compared outcomes for patients with muscle-invasive bladder cancer according to whether they received chemotherapy, immunotherapy, or no medical therapy before surgical removal of their bladder. We found that preoperative immunotherapy improved patient survival and regression of the cancer stage in comparison to no medical therapy, similar to the outcomes seen with preoperative chemotherapy. Randomized clinical trials are needed to confirm these findings.

Survival after sequential neoadjuvant chemotherapy followed by trimodal treatment or radical cystectomy for muscle-invasive bladder cancer.

to assess the respective outcomes of patients with localized muscle-invasive bladder cancer (MIBC) treated by either radical cystectomy (RC) or trimodal treatment (TMT) depending on pathological response to previous neoadjuvant chemotherapy (NAC) assessed on cystectomy specimen or post-NAC transurethral resection (TURB) specimen, respectively. We retrospectively included all consecutive patients treated in one academic center with cisplatin-based NAC followed by RC or TMT for cT2-3N0M0 MIBC between 2014 and 2021. Primary endpoint was metastasis-free survival (MFS) in both treatment groups and according to pathological response to NAC. Local recurrence-free survival and conservative management failure (metastasis-free bladder-intact survival) for patients treated with TMT were assessed. 104 patients were included, 26 treated with TMT and 78 with RC. The rate of complete pathological response was 47.4% in patients treated with RC (ypT0) and 66.7% in patients treated with TMT (ycT0). Median follow-up was 34.9months. Four-year MFS was 72% in both treatment groups. Four-year MFS was 85% in both ypT0 RC patients and ycT0 TMT patients. ycT0 stage was associated with low rates of intravesical recurrence and conservative management failure. Patients with post-NAC ycT0 stage treated with TMT have favorable oncological outcomes similar to those of ypT0 patients treated with RC. Assessment of complete histological response with TURB after NAC may help in selecting the best candidates for bladder preservation with TMT.

Bladder-sparing strategies in patients with clinically localized muscle-invasive bladder cancer.

Radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer (MIBC). In this context, bladder-sparing strategies (BSS) have been investigated as viable alternatives for patients who are unfit for radical cystectomy or aim to preserve their bladder without compromising oncological outcomes. This review aims to provide the most up-to-date evidence on BSSs as an alternative treatment for patients with MIBC. Different studies have highlighted the long-term efficacy of trimodal therapy or chemoradiation protocols. However, due to the lack of randomized controlled trials, there is still a lack of high-level evidence on BSS efficacy as compared to radical cystectomy. Consequently, the adoption of these approaches is still limited. A possible turning point could be represented by the introduction of immunotherapy, as several studies are investigating the potential combination with chemoradiotherapy or radiotherapy alone. Patient selection, together with the implementation of new predictive biomarkers and imaging tools, may improve the efficacy of BSS in the near future. Radical cystectomy with perioperative chemotherapy remains the gold standard treatment for MIBC patients. Nevertheless, BSS can be considered a viable option in selected patients who desire to preserve their bladder. Further evidence is needed to clearly state the role of BSS in MIBC.

SWOG S1011: A phase III surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at time of radical cystectomy for muscle invasive urothelial cancer.

4508 Background: S1011 tested the hypothesis that an extended lymphadenectomy (ELND) is associated with improved disease-free and overall survival (DFS, OS) compared to standard (S) LND in patients with localized muscle invasive bladder cancer (MIBC) undergoing radical cystectomy (RC)(NCT01224665). Methods: Eligible patients with cT2-4a N0-2 were stratified by receipt and type of neoadjuvant chemotherapy (NAC), T2 vs T3-4a and PS 0-1 vs 2. Patients were randomized 1:1 after intraoperative exploration determined they did not have disease outside the pelvis. All patients then underwent a standard bilateral pelvic LND including external and internal iliac and obturator LNs. If randomized to the experimental arm additional ELND up to at least the aortic bifurcation including common iliac (CI), pre-sciatic, and pre-sacral nodes was performed. We hypothesized that patients in the ELND arm would have a 10% improvement in 3-year DFS compared to an estimated 55% for patients in the SLND arm (HR = 0.72). Assuming a 1-sided a=0.025 and 85% power, 564 eligible randomized patients were required. Final analysis was to occur at 184 DFS events in the SLND arm or after max follow-up (6 yrs) using a stratified logrank(LR) test with a=0.022 to account for interim testing. Hazard ratios from Cox model are adjusted for strat factors. Secondary endpoints included OS and safety. Results: 36 surgeons at 27 sites in US and Canada were credentialed prior to enrolling patients, 658 were registered from 8/11-2/17, and 618 eligible patients were randomized to ELND (n=292) or SLND (n=300). Median f/up was 6.1 years in both arms. Median age was 69, 21% female, and 9% non-White. Clinical stage was balanced in both arms: T2 (71%) and T3-4a (29%). NAC was given to 57% in both. Pathologic T stage was &lt;T2 in 39% in S and 37% in E and ³ T2 in 61% and 63%, respectively. Median lymph nodes removed was higher in ELND compared to SLND (41 vs 25), but there was no difference in node metastasis with 26% vs 24%, respectively. More ELND patients had N2 or N3 disease. ELND was associated with increased G3-4 AEs compared to SLND: 16% vs 8%. Deaths within 90 days of RC occurred in 26 (4.4%) patients, including 16 in ELND vs 9 in SLND. There was no difference in DFS between E vs S arms (HR 1.10; 95% CI 0.87, 1.42), 1-sided LR p=0.82. OS results were similar (HR 1.15 95% CI 0.89, 1.48), 1-sided LR p=0.87. Conclusions: Patients with MIBC undergoing RC and ELND had increased node yield and higher pathologic N stage, but no significant DFS or OS benefit compared to patients undergoing SLND. ELND was also associated with greater morbidity and higher peri-operative mortality. Clinical trial information: NCT01224665 . [Table: see text]

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.

Accuracy of genome-wide mutational analysis for tumor-informed ctDNA-guided MRD monitoring in bladder cancer.

4589 Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard management of localized muscle-invasive bladder cancer (MIBC). However, about 45% of patients develop metastases within 2 years after RC. Biomarkers for treatment efficacy evaluation and early detection of minimal residual disease (MRD) are needed for earlier treatment initiation and monitoring of treatment response. Tumor-informed detection of mutations in cell-free DNA (cfDNA) has shown promising results to monitor MRD. However, the low tumor fraction after surgery and limited input material obtained from a typical plasma sample limits the probability of detecting low metastatic burden scenarios. Here we implemented and applied a whole-genome sequencing (WGS) approach to monitor circulating tumor DNA (ctDNA) for sensitive ctDNA detection. Methods: 110 MIBC patients undergoing NAC and RC were enrolled. cfDNA was extracted from ~1mL plasma (n=978) and procured from longitudinal plasma sampling during NAC and pre-RC and post-RC. WGS of tumor/germline pairs (30x/20x) and plasma cfDNA (&gt;20x) was performed, facilitating detection of genome-wide genomic alterations and quantification of ctDNA using the C2inform method. Results: For each patient we developed a tumor-informed WGS model by integrating genome-wide mutation and copy number variation data coupled with advanced signal processing and AI-based error suppression. Patient-specific somatic variant patterns were used for detection and measuring ctDNA levels in low-input blood samples by WGS. Post-RC ctDNA analysis identified patients with recurrence with 78% sensitivity and 95% specificity and with a median lead time over radiographic imaging of 118 days (full follow-up included). When restricting follow-up time to 12 months following the latest ctDNA test, a sensitivity of 86% and specificity of 94% was achieved. ctDNA status was associated with recurrence-free (p&lt;0.0001) and overall survival (p&lt;0.0001). Furthermore, ctDNA clearance during NAC was also associated with recurrence-free survival (p=0.0051). The APOBEC associated signatures SBS2 and SBS13 were identified as the primary contributors to the mutational landscape of the primary tumors and TP53, KMT2D, PIK3CA, RB1 and KDM6A were the main affected driver genes. Half of the tumors displayed whole genome doubling. Moreover, our analysis of plasma samples after treatment showed the presence of chemotherapy-induced mutational signatures not present in the primary tumor, along with increases in copy numbers on chromosomes 19q and 20, and a focal amplification of the FGFR3 gene on chromosome 4. Conclusions: Our results highlight the clinical potential of personalized genome-wide mutation integration as an ultra-sensitive, non-invasive method for MRD detection and treatment response monitoring.

Evaluation of short-term outcomes of neoadjuvant chemotherapy followed by radical cystectomy in muscle-invasive bladder cancer: a single Egyptian institution experience

Background and aimNeoadjuvant chemotherapy (NAC) before radical cystectomy (RC) became the standard of care for muscle-invasive bladder cancer (MIBC) in the last few years. We aimed to evaluate the radiological, pathological responses to NAC, and the 30-day surgical outcomes after RC in MIBC.Patients and methodsA retrospective cohort study involving adult patients with localized urothelial MIBC who received NAC followed by RC at the National Cancer Institute of Egypt (NCI-E) for 2 years (2017 and 2018). Out of 235 MIBC cases, we recognized 72 patients (30%) who fitted the eligibility criteria.ResultsA cohort of 72 patients with a median age of 60.5 years (range 34–87). Hydronephrosis, gross extravesical extension (cT3b), and radiologically negative nodes (cN0) were depicted initially in 45.8, 52.8, and 83.3% of patients, respectively. Gemcitabine and cisplatin (GC) was the rampant NAC employed in 95.8%. Radiological evaluation post NAC using RECIST v1.1 revealed a response rate (RR) of 65.3% in bladder tumor and progressive disease in the former and lymph nodes encountered in 19.4 and 13.9%, respectively. The median time from the end of NAC to surgery was 8.1 weeks (range 4–15). Open RC and ileal conduit were the most common types of surgery and urinary diversion, respectively. Pathological down-staging was encountered in 31.9%, and only 11 cases (15.3%) achieved pathological complete response (pCR). The latter was significantly correlated with the absence of hydronephrosis, low-risk tumors, and associated bilharziasis (p = 0.001, 0.029, and 0.039, respectively). By logistic regression, the high-risk category was the only independent factor associated with a poor likelihood of achieving pCR (OR 4.3; 95% CI 1.1–16.7; p = 0.038). Thirty-day mortality occurred in 5(7%) patients, and 16(22%) experienced morbidity, with intestinal leakage being the most frequent complication. cT4 was the only significant factor associated with post-RC morbidity and mortality compared to cT2 and cT3b (p = 0.01).ConclusionsOur results are further supporting the radiological and pathological benefits of NAC in MIBC, evidenced by tumor downstaging and pCR. The complication rate after RC is still considerable; hence, more larger studies are necessary to postulate a comprehensive risk assessment tool for patients who would get the maximum benefit from NAC, hoping to accomplish higher complete response rates with ultimately increased adoption of the bladder preservation strategies.

Bladder-sparing approaches for muscle invasive bladder cancer: a narrative review of current evidence and future perspectives.

In recent years, the application of less-invasive "bladder-sparing" trimodal therapy (TMT) in selected muscle-invasive bladder cancer (MIBC) patients unfit for or who declined radical cystectomy (RC) has been increasing. This review aims to summarize the current evidence and future perspectives of bladder-sparing therapy for MIBC. A non-systematic Medline/PubMed literature search was conducted on July 2022 with the following keywords 'MIBC', 'bladder-sparing', 'chemotherapy', 'radiotherapy', 'trimodal', 'multimodal', and 'immunotherapy'. All monotherapies are inferior to RC or combination therapy and should not be routinely used for curative intent. Radiotherapy (RT) alone has been shown to have poorer outcomes when compared to chemoradiotherapy. The ideal selection criteria for TMT include good bladder function and capacity, clinical stage within cT2, complete transurethral resection of bladder tumor (TURBT), no prior history of pelvic RT, no extensive carcinoma in situ (CIS), and absence of hydronephrosis. The emergence of immunotherapy may further increase the effect of bladder-sparing therapy. Novel predictive biomarkers are awaited for more precise patient selection and better oncological outcomes. TMT is a well-tolerated and offers a curative alternative approach to RC for selected patients with localized MIBC. Appropriate patient selection and a multi-disciplinary approach is crucial in achieving good oncologic control with bladder-sparing therapy.

MP56-12 PROPENSITY SCORE MATCHED SURVIVAL ANALYSIS OF OCTOGENARIANS WITH MUSCLE-INVASIVE BLADDER CANCER: CHEMORADIATION COMPARED TO RADICAL CYSTECTOMY

You have accessJournal of UrologyCME1 Apr 2023MP56-12 PROPENSITY SCORE MATCHED SURVIVAL ANALYSIS OF OCTOGENARIANS WITH MUSCLE-INVASIVE BLADDER CANCER: CHEMORADIATION COMPARED TO RADICAL CYSTECTOMY Pushan Prabhakar, Hariharan Ganapathi, Nikhil Kulkarni, Ahmed Eldefrawy, Jorge Caso, and Murugesan Manoharan Pushan PrabhakarPushan Prabhakar More articles by this author , Hariharan GanapathiHariharan Ganapathi More articles by this author , Nikhil KulkarniNikhil Kulkarni More articles by this author , Ahmed EldefrawyAhmed Eldefrawy More articles by this author , Jorge CasoJorge Caso More articles by this author , and Murugesan ManoharanMurugesan Manoharan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003309.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION: AND OBJECTIVE: Radical cystectomy and chemotherapy are challenging in the elderly population with muscle-invasive bladder cancer (MIBC) due to comorbidities and limited physiological reserve. Very few studies compared outcomes between chemoradiation therapy (CRT) and radical cystectomy (RC) among the older population. Current management options for older patients are extrapolated from outcomes based on the younger population. This study aims to compare survival outcomes among octogenarians who underwent CRT and RC for localized MIBC reported in the National Cancer Database (NCDB). METHODS: Patients who underwent CRT or RC for urothelial MIBC (cT2-T4N0M0) were identified in the NCDB (2004-2017). Primary CRT was defined as a radiation dose of ≥39.6 Gy, and chemotherapy received within 90 days of radiation without any definitive surgery. RC was defined as those who underwent RC with or without perioperative chemotherapy. The initial analysis compared proportions between octogenarians and the younger group. Following this, a propensity-matched analysis was performed to compare survival outcomes among octogenarians who underwent CRT and RC. RESULTS: A total of 21095 patients met the inclusion criteria and underwent either primary CRT or RC (4840 were octogenarians, and 16255 were less than 80 years). Among the octogenarian group, 2064 (42.6%) underwent primary CRT, and 2776 (57.4%) had RC. Whereas, in the younger group, 2633 (16.2%) had CRT, and 13622 (83.8%) had RC (p<0.001). Demographic parameters, comorbidity index, and clinical stage were used to generate propensity scores for octogenarians. After a propensity score match of 1:1 using strict criteria, there were 1767 octogenarians in each of the CRT and RC groups. The median overall survival in the primary CRT group was 28.78 months 95% CI [26.55, 31.00] and 26.12 months 95% CI [23.88, 28.36] in the RC group (p=0.326). CONCLUSIONS: CRT and RC groups had comparable survival outcomes in this retrospective analysis of octogenarians in a large national database. Further survival outcomes research in elderly populations will help us to individualize treatment and improve outcomes. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e779 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pushan Prabhakar More articles by this author Hariharan Ganapathi More articles by this author Nikhil Kulkarni More articles by this author Ahmed Eldefrawy More articles by this author Jorge Caso More articles by this author Murugesan Manoharan More articles by this author Expand All Advertisement PDF downloadLoading ...

MP19-03 IMPACT OF SOCIAL VULNERABILITY ON RECEIPT OF NEOADJUVANT CHEMOTHERAPY IN PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP19-03 IMPACT OF SOCIAL VULNERABILITY ON RECEIPT OF NEOADJUVANT CHEMOTHERAPY IN PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR BLADDER CANCER Rishi Sekar, Avinash Maganty, Jeff Montgomery, and Lindsey Herrel Rishi SekarRishi Sekar More articles by this author , Avinash MagantyAvinash Maganty More articles by this author , Jeff MontgomeryJeff Montgomery More articles by this author , and Lindsey HerrelLindsey Herrel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003244.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) is standard- of-care in patients with muscle-invasive bladder cancer (MIBC); however, utilization remains suboptimal. Social determinants of health (SDOH) may impact access to NAC leading to disparities in cancer outcomes. We evaluated the association between a comprehensive community-level measure of SDOH, the CDC Social Vulnerability Index (SVI), and receipt of NAC. METHODS: We queried our institutional database for patients with localized MIBC treated with RC between 2000 and 2022. Patients with contraindications to platinum-based NAC were excluded. SVI, assessed at the county level, was assigned to each patient using their zip code of residence. Patients were then grouped by quintiles of SVI (i.e., least vulnerable to most vulnerable). Demographics, clinicopathologic characteristics, and receipt of NAC were compared across SVI quintiles. Multivariable logistic regression analysis was performed to evaluate the association between SVI quintile and receipt of NAC. A sub-analysis was performed evaluating the association between subthemes of SVI (socioeconomic status, household composition/disability, race/ethnicity/language, and housing/transportation) and receipt of NAC. RESULTS: Of the total cohort (n=878), 51.4% received NAC, with increasing rates over the study period. A greater proportion of patients living in the highest SVI quintile counties were of minority status (9.1%), underwent open RC (82.4%), and did not receive NAC (57.1%, all p<0.05). On multivariable logistic regression analysis, highest SVI quintile was associated with significantly decreased odds of receiving NAC (OR 0.56, 0.35–0.90). Analysis of subthemes of SVI demonstrated this association was predominantly driven by socioeconomic status (OR 0.53, 0.33–0.84) and household composition and disability (OR 0.56, 0.31–1.00). CONCLUSIONS: Patients living in communities with the highest social vulnerability had significantly decreased odds of receiving NAC prior to RC, mostly driven by socioeconomic status and household composition/disability. Adverse community-level SDOH may contribute to disparities in complex oncologic care and should be addressed towards achieving equitable care. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e264 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rishi Sekar More articles by this author Avinash Maganty More articles by this author Jeff Montgomery More articles by this author Lindsey Herrel More articles by this author Expand All Advertisement PDF downloadLoading ...