Treatment Of Muscle-invasive Bladder Cancer Research Articles

Long-Term Results of Bladder Preservation with Twice-Daily Radiation plus 5-Flourouracil/Cisplatin or Daily Radiation plus Gemcitabine for MIBC – Updated Report of NRG/RTOG 0712: A Randomized Phase 2 Trial

Purpose5-FU/cisplatin and twice-daily radiation (FCT) or gemcitabine and once daily radiation (GD) are effective chemoradiation (CRT) regimens for bladder sparing treatment of muscle-invasive bladder cancer (MIBC). This trial evaluated these regimens and demonstrated efficacy with either regimen at 3 years. With further follow-up, longer term results are reported here. Methods and MaterialsPatients with cT2-4a MIBC were randomized to FCT or GD. Patients had a transurethral resection and induction CRT to 40 Gy. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others had cystectomy. Adjuvant gemcitabine/cisplatin chemotherapy was administered. The primary endpoint was freedom from distant metastasis (FDM). This updated analysis reports 7-year data. Toxicity and efficacy endpoints, including bladder intact distant metastasis free survival (BI-DMFS) were also assessed. ResultsFrom 12/2008 to 4/2014, 70 patients were enrolled; 66 eligible for analysis, 33 per arm. Median follow-up was 9.1 years for eligible living patients. At 7 years, FDM was 65% and 73% for FCT and GD, respectively. BI-DMFS was 58% (95% CI: 41 – 76) and 68% (95% CI: 51-84), respectively. The post-hoc hazard ratio of 0.75 (95% CI: 0.37-1.55) showed no difference between treatments (p=0.44). Overall survival at 7 years was 48% and 59%. There were 4 and 5 cystectomies performed for FCT and GD, respectively. In the FCT arm, there were 5 (16%), 1 (3%) and 0 grade 3, 4 and 5 late toxicities reported. In the GD arm, there were 7 (23%), 0 and 0. ConclusionsBoth regimens maintained high FDM rates at 7 years. Cystectomy rates were low and overall survival rates high on both arms. Late toxicity rates were low. Either gemcitabine and daily radiation or a cisplatin-based regimen are effective bladder sparing therapies.

Efficacy and safety of radical cystectomy with ileal conduit for muscle-invasive bladder cancer in the elderly: a multicenter retrospective study.

Radical cystectomy with ileal conduit is the current mainstay of treatment for muscle-invasive bladder cancer and is also a high-risk procedure. Existing studies have limited targeted assessment of the efficacy and safety of this procedure, and the patient population appropriate for this procedure is still poorly defined. We sought to longitudinally analyze differences in the efficacy and safety of radical cystectomy with ileal conduit by age subgroups to assess whether the age factor should be used as an exclusion criterion when selecting this procedure. We retrospectively examined the clinicopathological data of patients with MIBC treated with RC with IC at the Cancer Hospital of Harbin Medical University between February 2014 and October 2023. Additionally, we utilized clinical and pathological data from the SEER database (2000-2020) for external validation of our findings. Patients were categorized into elderly (≥70 years at diagnosis) and non-elderly (<70 years) groups. Statistical analyses included t-tests, non-parametric tests for continuous data, chi-square tests for categorical data, and Kaplan-Meier survival analysis. In this study, 152 patients were included: 119 were categorized as non-elderly and 33 as elderly. For external validation, data from 416 patients in the SEER database were analyzed, with 172 classified as non-elderly and 244 as elderly. The results indicated that elderly patients were more likely to require ICU transfer postoperatively but exhibited a lower incidence of stoma inflammation. Additionally, both the data from our center and the external validation from the SEER database showed a concordance in cancer-specific survival (CSS) between the elderly and non-elderly groups. The efficacy of RC with IC was comparable in both elderly and non-elderly patients. For longitudinal age subgroups, RC with IC for both elderly and non-elderly MIBC had good efficacy and safety, and good quality of life after surgery. Although there are surgical and perioperative risks in elderly patients, there is no significant difference compared with non-elderly patients. In elderly patients requiring RC for bladder cancer, IC should remain the preferred mode of urinary diversion, and old age should not be used as an absolute exclusion criterion for IC.

Utilization of neoadjuvant chemotherapy for muscle-invasive bladder cancer in elderly patients: a retrospective cohort study.

Neoadjuvant chemotherapy (NAC) improves overall survival in muscle-invasive bladder cancer (MIBC). Older patients often do not receive NAC due to its potential toxicities. We examined treatment patterns of elderly MIBC patients as well as impact of NAC on survival in this population. The National Cancer Database was queried from 2006 to 2019 for stage T2-T4a MIBC patients ≥ 80years old. Treatment exposures (extirpative surgery; chemotherapy; radiation) were ascertained. Kaplan-Meier survival curves were generated based on treatment modalities (no treatment; radiation only; chemotherapy only; chemoradiation; surgery only; NAC with surgery). Multivariable Cox proportional hazards regression assessed associations with overall survival (OS). The cohort included 16,391 patients (mean age 86years); 51% received treatment. MIBC treatment was less common with advancing age; patients receiving NAC then surgery were younger and had lower comorbidity scores. From 2006 to 2019, more patients received chemoradiation, while rates of NAC rose modestly. Median OS for the NAC with surgery group was 48months versus 9months for the no treatment group. Log-rank tests showed significantly improved survival in the NAC with surgery group compared to the surgery only group, while Cox proportional hazards regression analysis showed highest survival benefit in the NAC with surgery group. Only half of elderly MIBC patients received treatment, with fewer undergoing curative intent. NAC with surgery was associated with the greatest survival benefit. While our findings should be taken in the context of potential selection bias and patient preferences, they support NAC as part of shared-decision making regardless of age.

Abstract IA006: Towards ctDNA-guided treatment of muscle-invasive bladder cancer

Abstract Cancer cells release cell-free DNA with tumor-specific molecular alterations into circulation, known as circulating tumor DNA (ctDNA). Numerous studies have underscored the biomarker potential of ctDNA in detecting minimal residual disease across various cancer types, including bladder cancer. The rapid clearance of ctDNA from circulation, typically under two hours, makes it an ideal candidate for real-time monitoring of tumor burden following surgical interventions and throughout oncological treatments. For ctDNA measurements to be effectively incorporated into clinical decision-making, it is crucial to conduct ctDNA-guided intervention trials that demonstrate tangible clinical benefits. Current trials focusing on muscle-invasive bladder cancer (MIBC) are supported by recent exploratory sub-analyses of completed clinical trials, which have shown that ctDNA can effectively guide treatment decisions in this context. Beyond guiding adjuvant treatments, ctDNA holds potential for directing bladder preservation strategies, potentially in combination with urinary tumor-derived DNA (utDNA) measurements. The need for treatment de-escalation, such as in neoadjuvant chemotherapy (NAC), is underscored by the observation that a significant proportion of patients undergo treatments that result in considerable adverse effects without achieving pathologic response. Traditional decision-making in cancer treatment, largely reliant on imaging-based criteria like the Response Evaluation Criteria in Solid Tumors (RECIST), often does not adequately reflect the ultimate clinical endpoint of overall survival. A ctDNA-based measure that considers ctDNA dynamics during treatment could serve as a superior tool or complement to current strategies. In conclusion, ctDNA has demonstrated significant promise as a biomarker in both retrospective and prospective studies for risk assessment in MIBC. The clinical value of ctDNA-guided treatment will soon be determined by ongoing clinical trials (TOMBOLA, IMvigor011, MODERN). In my presentation I will address the potential clinical impact of ctDNA analyses, the technological aspects involved, how urine analyses may supplement these findings, and future directions in the field. Citation Format: Lars Dyrskjøt. Towards ctDNA-guided treatment of 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 IA006.

Abstract B020: Development of novel Src-targeting strategies to block bladder cancer invasive progression

Abstract Background: Treatment of muscle-invasive bladder cancer remains challenging and, BCG, one of the few treatments that prevents progression of high-risk non-muscle invasive tumors to invasive metastatic disease, is difficult to obtain. Thus, development of new treatment approaches to block progression to muscle invasive disease is essential. We find that TRIM29 (tripartite motif containing 29, also known as ATDC), drives bladder cancer invasive progression through modulation of focal adhesions containing FAK and c-Src (Src). Despite this, literature has reported conflicting effects of Src knockdown and Src kinase inhibition on migration, perhaps due to separable pro- and anti-invasive functions of Src in bladder cancer. Hypothesis: Src drives bladder cancer invasive progression specifically through its tyrosine kinase activity within focal adhesions. Methods: We used 2D live cell migration assays and 3D spheroid invasion assays to test dasatinib, highly specific, novel conformation inhibitors of Src, a novel Src PROTAC, and siRNA against Src on bladder cancer migration and invasion. Results: Dasatinib and our novel conformation-specific inhibitors inhibited Src kinase activity and both siRNA and the novel PROTAC reduced total Src expression in vitro. Neither dasatinib, conformation inhibitors, siRNA, nor the PROTAC impacted bladder cancer cell viability in UM-UC5, UM-UC9 or UM-UC14 cell lines. Interestingly, we found that inhibiting Src’s kinase activity with either dasatinib or conformation-specific inhibitors abrogated bladder cancer migration. Conclusion: These results point to the selective importance of Src in regulating bladder cancer migration and invasion. They also suggest that novel Src targeting agents have potential clinical utility in the prevention of bladder cancer invasive progression. Citation Format: Nicole A. Jerome, Yin Wang, Marian L. Henderson, Luke Broses, Kathleen C. Day, Mark L. Day, Matthew B. Soellner, Phillip L. Palmbos. Development of novel Src-targeting strategies to block bladder cancer invasive progression [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 B020.

Robot-Assistant Radical Cystectomy as a Modern Method of Personalized Treatment for Patients with Muscle-Invasive Bladder Cancer

Introduction. Radical cystectomy (RC) is the “gold standard” treatment for muscle-invasive bladder cancer (MIBC). Robot-assisted RC (RARC) can act as a safe and effective method of treating MIBC.The aim of the study was to analyze our own experience with the use of RARC with intraoperative indocyanine green fluorescence (ICG) and postoperative determination of tumor macrophage levels in the treatment of patients with MIBC.Materials and methods. A study was conducted at the Clinic of the Bashkir State Medical University with the participation of 202 patients aſter RARC. 30 patients underwent intraoperative ICG fluorescence testing. The levels of tumor macrophages in the removed macropreparations were determined in all patients. In the postoperative period, a survival analysis was performed.Results. The sensitivity of the ICG fluorescence method was 94.4 %, and the specificity was 83.3 %. High levels of expression of macrophage markers CD68 and CD163 significantly predominate in the group with the cN+ stage (according to the clinical TNM classification, there are signs of damage) (p = 0.027 and p = 0.018, respectively). ICG fluorescence of regional lymph nodes (100 %) was observed in all patients with high CD68 and CD163 levels. A significant decrease in survival was recorded in patients with high pathomorphological stage T (pT according to the TNM classification) (r = 0.952, p &lt; 0.05) and statistically significant survival rates were obtained for pT1–pT4 groups (p &lt; 0.05 for overall, cancer-specific and recurrence-free survival (OS, CSS, RFS, respectively)).Discussion. More and more studies are appearing in the world literature proving the effectiveness of RARC in the treatment of patients with MIBC. Compared with open and laparoscopic techniques, better surgical and comparable oncological results are demonstrated.Conclusion. The results of the analysis of the RARC’s own experience indicate the effectiveness of this method of treating MIBC. The use of ICG fluorescence and verification of tumor macrophages makesit possible to provide personalized care to oncourological patients.

Advances in Urinary Diversion: From Cutaneous Ureterostomy to Orthotopic Neobladder Reconstruction-A Comprehensive Review.

Bladder cancer ranks as the 10th most prevalent cancer globally with an increasing incidence. Radical cystectomy combined with urinary diversion represents the standard treatment for muscle-invasive bladder cancer, offering a range of techniques tailored to patient factors. Overall, urinary diversions are divided into non-continent and continent. Among the first category, cutaneous ureterostomy and ileal conduit represent the most common procedures while in the second category, it could be possible to describe another subclassification which includes ureterosigmoidostomy, continent diversions requiring catheterization and orthotopic voiding pouches and neobladders. In this comprehensive review, urinary diversions are described in their technical aspects, providing a summary of almost all alternatives to urinary diversion post-radical cystectomy.

Abstract LB256: New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer

Abstract The standard of care for eligible patients with muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. However, platinum-based treatments leave up to 70% of MIBC patients with residual disease, and the 5-year survival rate for these individuals is under 30%. Understanding cisplatin resistance mechanisms will improve MIBC treatment by developing more effective therapeutics and precision medicine strategies. We previously identified NPEPPS, an M1 aminopeptidase, as a novel and potentially targetable mediator of platinum drug response. Recently, we have established that NPEPPS controls platinum drug import through its interactions with volume regulated anion channels (VRACs), which have been shown to import cisplatin to cells directly. We have shown that NPEPPS interacts with key VRAC subunit SWELL1 at the cell membrane and that intact SWELL1 is required for NPEPPS-mediated platinum resistance. We further discovered that NPEPPS cannot bind SWELL1 when its enzymatic aminopeptidase function is disrupted genetically or pharmacologically. In vivo studies showed that catalytic-dead NPEPPS-mutant MIBC xenografts were sensitive to cisplatin treatment compared to NPEPPS-wildtype xenografts. Patient cohort data analysis supported the model that the expression of NPEPPS and its relative expression with VRAC proteins are associated with overall survival in treatment-resistant MIBC patients. These findings shed light on how bladder cancer cells resist chemotherapy by disrupting the transport of drugs into cells and suggest new ways to target NPEPPS to enhance the effectiveness of platinum-based therapeutics in treating bladder cancer. Citation Format: Lily Elizabeth R. Feldman, Saswat Mohapatra, Robert Jones, Charlene Tilton, Tahlita Zuiverloon, James Costello, Dan Theodorescu. New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB256.

MIR145 Core Promoter Methylation in Pretreatment Cell-Free DNA: A Liquid Biopsy Tool for Muscle-Invasive Bladder Cancer Treatment Outcome.

The lack of personalized management of bladder cancer (BlCa) results in patients' lifelong post-treatment monitoring with invasive interventions, underlying the urgent need for tailored and minimally invasive health care services. On the basis of our previous findings on miR-143/145 cluster methylation in bladder tumors, we evaluated its clinical significance in pretreatment cell-free DNA (cfDNA) of patients with BlCa. Methylation analysis was performed in our screening cohort (120 patients with BlCa; 20 age-matched healthy donors) by bisulfite-based pyrosequencing. Tumor recurrence/progression for patients with non-muscle-invasive bladder cancer, and progression and mortality for patients with muscle-invasive bladder cancer (MIBC) were used as clinical end point events in survival analysis. Bootstrap analysis was applied for internal validation of Cox regression models and decision curve analysis for assessment of clinical benefit on disease prognosis. Decreased methylation of MIR145 core promoter in pretreatment cfDNA was associated with short-term disease progression (multivariate Cox: hazard ratio [HR], 2.027 [95% CI, 1.157 to 3.551]; P = .010) and poor overall survival (multivariate Cox: HR, 2.098 [95% CI, 1.154 to 3.817]; P = .009) of patients with MIBC after radical cystectomy (RC). Multivariate models incorporating MIR145 promoter methylation in cfDNA with tumor stage clearly ameliorated patients' risk stratification, highlighting superior clinical benefit in MIBC prognostication. Reduced pretreatment cfDNA methylation of MIR145 core promoter was markedly correlated with increased risk for short-term progression and worse survival of patients with MIBC after RC and adjuvant therapy, supporting modern personalized and minimally invasive prognosis. Methylation profiling of MIR145 core promoter in pretreatment cfDNA could serve as a minimally invasive and independent predictor of MIBC treatment outcome and emerge as a promising marker for blood-based test in BlCa.

Ileoneocystoplasty After Radical Cystectomy – Modification of the Method and Immediate Results

The objective: is to evaluate the effectiveness of the treatment of muscle-invasive bladder cancer (MIBC) by creating an artificial reservoir for the derivation of urine from segments of the small intestine of patients and to study urination and other functions of the urinary system in the postoperative period. Material and methods. During 2019-2020, the SI «Academician O.F. Vozianov Institute of Urology National Academy of Sciences of Ukraine» conducted examinations and treatments on nine patients diagnosed with MIBC at clinical stages T2aN0M0–T3bN0M0. All patients underwent laparoscopic cystectomy and lymphadenectomy, while a third of them underwent open bladder resection at other medical facilities. Among these, three patients received intracorporeal ileoneocystoplasty, whereas in six patients, the procedure involved a change in access from a median laparotomy. The implemented method of orthotopic ileoneocystoplasty during radical cystectomy involves creating an orthotopic artificial bladder from a previously resected segment of the ileum and anastomosing it with the proximal part of the urethra and the distal segments of the ureters. Notably, this method introduces several innovations: firstly, it allows for instrumental intestinal suturing in cases of endoscopic variants of radical cystoprostatectomy, and reduces the necessary length of the ileo-intestinal fragment to 50 cm. Secondly, it involves complete detubularization of the intestine fragment, asymmetrically during its middle 5 cm to form a cervical flap, and symmetrically along the contramesenteric edge for the remaining length. Thirdly, the medial edges of the right and left intestinal segments are initially fixed to the upper edge of the middle segment. Fourthly, after creating the eye of the neck of the future reservoir, the upper and middle thirds of the lateral edge of the right and left intestinal segments are fastened together. Fifthly, the original neck of the intestinal bladder is formed by performing vertical incisions of the pre-created eye of the neck of the reservoir at 12 and 6 o’clock to expand its diameter to 1.0–1.5 cm, followed by eversion and tubularization of the formed semicircles on the urethral catheters using 3–5 nodal sutures and a neck duplication maneuver with two nodal, superimposed parallel to the axis of the neck, sero-muscular sutures with a step between injection and needle puncture of 0.3–0.5 cm. Sixth, after forming the vesico-urethral anastomosis, the free edge of the cervical flap and the lower thirds of the lateral edge of the right and left intestinal segments are sutured, the adoral nd aboral intestinal openings are sealed, a cystostomy drainage is installed through the latter, and a reversible peritonization maneuver is performed. Results. According to the type of intervention, patients were divided into 2 groups: 1 group of open ileoneocystoplasty – 6 patients, 2 group of intracorporeal ileoneocystoplasty – 3 patients. According to the results of the operation, the average volume of the artificial reservoir immediately after the operation was: in group 1 – 180 ml ± 23 ml, in group 2 160 ml ± 50 ml. After 6 months, this volume increased and was 420 ± 68 ml in group 1, 380 ± 50 ml in group 2, which allowed patients to urinate 6-8 times a day and 2-3 times a night in some cases. The postoperative bed-day in group 2 was shorter on average by 7 days (7.2 ± 1.5 vs. 14.2 ± 4.2). In this study, there were no registered cases of leakage of the vesico-urethral anastomosis or its stenosis. Conclusions. Application of the proposed method of orthotopic ilioneocystoplasty during radical cystectomy will allow: – to reduce the total time of the operation in connection with the use of modern methods of intestinal suture provided for in its framework; – to compensate for the possible tension of the vesico-urethral anastomosis, which will lead to a decrease in the frequency and intensity of such postoperative complications and negative consequences as: leakage of the vesico-urethral anastomosis or its stenosis, as well as urinary incontinence at night; – thanks to the original maneuver of forming the neck of the ileal reservoir, reduce the hypermobility of the reconstructed bladder-urethral segment; – reduce the likelihood of metabolic disorders in the postoperative period due to the reduction of the length of the ileal segment removed from the patient; – to unify the technology of orthotopic ilioneocystoplasty within the framework of various approaches to performing radical cystectomy, among them: traditional «open», laparoscopic or robot-assisted.

Successful pre-surgical treatment with carboplatin and gemcitabine chemotherapy for a patient with muscle-invasive bladder cancer and severe renal dysfunction.

Radical cystectomy is the standard treatment for muscle-invasive bladder cancer, and pre-surgical treatment can improve survival. Carboplatin and gemcitabine chemotherapy is considered an effective, safe treatment for patients ineligible for cisplatin-based chemotherapy owing to reduced renal function. However, there is limited evidence on pre-surgical treatment with carboplatin and gemcitabine chemotherapy with glomerular filtration rates < 30mL/min. We discuss the treatment of a patient who did not undergo surgery owing to bladder tumor size of 12cm (cT3bN0M1a) and severe renal dysfunction (serum creatinine: 2.57mg/dL, estimated glomerular filtration rate: 20.2mL/min/1.73 m2). After the patient received two courses of carboplatin and gemcitabine chemotherapy, the bladder tumor size had reduced by 60%. No nausea or renal dysfunction was observed; febrile neutropenia improved with antibiotic therapy and granulocyte colony-stimulating factor. Then, he could undergo robot-assisted radical cystectomy after the pre-surgical chemotherapy treatment. Pre-surgical treatment with carboplatin and gemcitabine chemotherapy is a viable treatment option for patients with muscle-invasive bladder cancer and severe renal dysfunction.

Disitamab Vedotin Alone or in Combination With Immune Checkpoint Inhibitors in Bladder-Sparing Treatment of Muscle-Invasive Bladder Cancer: A Real-World Study

PurposeTo evaluate the efficacy and safety of a novel humanized anti-HER2 antibody, RC48-ADC (Disitamab vedotin, DV), the combination of RC48-ADC with PD-1 inhibitors was used to treat muscle-invasive bladder cancer (MIBC). This combination therapy has potential applications in both bladder preservation and neoadjuvant therapy for MIBC. MethodsPatients with MIBC underwent transurethral resection of bladder tumors followed by RC48-ADC alone or in combination with PD-1 inhibitors. Radiological and endoscopic evaluations were conducted 3 months later. The primary endpoint was objective response rate (ORR), with secondary endpoints including complete response rate (CR), partial response rate (PR), and bladder preservation rate. Treatment safety was assessed according to RECIST v1.1 criteria. ResultsEleven patients were enrolled, with a median follow-up of 19.0 months. Nine patients achieved objective response, including 6 CR and 3 PR cases. The pathological ORR was 81.8%. Eight patients continued combined treatment after 3 months, maintaining a 72.7% bladder preservation rate at 16 months. One elderly patient progressed from ypT2N0M0 to ypT3N0M0 and underwent radical cystectomy but had no recurrence or metastasis 12 months postoperation. All patients reported varying degrees of treatment-related adverse reactions, which were largely manageable. ConclusionThe combination of RC48-ADC and PD-1 inhibitors proves to be a viable and safe option for bladder-sparing therapy, particularly for T2-stage MIBC patients who are ineligible for surgery and chemotherapy. This approach offers a promising new direction for bladder preservation or neoadjuvant therapy in MIBC patients.

A narrative review of management of muscle-invasive bladder cancer perioperative period: will continuous and combined treatment be the new trend?

With the emergence of immunotherapy and targeted therapies, there are more options for the perioperative period management of muscle-invasive bladder cancer (MIBC), and various types of clinical studies are emerging, leading to the need to explore ways to choose the optimal treatment modality. This review aims to synthesize past and present treatment modalities and to explore future trends in the perioperative period cares of MIBC for the benefit of clinical practitioners. A non-systematic, literature search was conducted between March 5, 2023 and November 30, 2023 on PubMed using "perioperative period", "MIBC", "chemotherapy", "radiotherapy", "immunotherapy", "targeted treatment" and "combination" as keywords, along with a search for ongoing clinical studies that were related to the perioperative period of MIBC on classic.clinicaltrials.gov, some latest conference abstracts were also included as references. The trend towards benefit from adjuvant chemotherapy in perioperative chemotherapy is gradually being recognized. Neoadjuvant immunotherapy, including single-agent immunization, like programmed cell death protein 1 (PD-1) inhibitors, programmed cell death 1 ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, and double-immunization, has been confirmed by several clinical studies to be beneficial to clinical remission rates, and the combination regimen is superior to single-agent therapy. Targeted therapies such as antibody-drug conjugate (ADC) are entering MIBC perioperative studies. Multiple sequential and combination clinical studies are gradually disclosing preliminary data on efficacy and safety. Immunotherapy would become an essential perioperative treatment for MIBC, and continuous and integrated perioperative management may become the MIBC treatment mode of the future. ADC medicines will also be a hot research focus in the coming years.

A bibliometric insight into neoadjuvant chemotherapy in bladder cancer: trends, collaborations, and future avenues.

Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) remains the cornerstone of treatment for muscle-invasive bladder cancer (MIBC). While platinum-based regimens have demonstrated benefits in tumor downstaging and improved long-term survival for selected patients, they may pose risks for those who are ineligible or unresponsive to chemotherapy. We undertook a bibliometric analysis to elucidate the breadth of literature on NAC in bladder cancer, discern research trajectories, and underscore emerging avenues of investigation. A systematic search of the Web of Science Core Collection (WoSCC) was conducted to identify articles pertaining to NAC in bladder cancer from 1999 to 2022. Advanced bibliometric tools, such as VOSviewer, CiteSpace, and SCImago Graphica, facilitated the examination and depicted the publication trends, geographic contributions, institutional affiliations, journal prominence, author collaborations, and salient keywords, emphasizing the top 25 citation bursts. Our analysis included 1836 publications spanning 1999 to 2022, indicating a growing trend in both annual publications and citations related to NAC in bladder cancer. The United States emerged as the predominant contributor in terms of publications, citations, and international collaborations. The University of Texas was the leading institution in publication output. "Urologic Oncology Seminars and Original Investigations" was the primary publishing journal, while "European Urology" boasted the highest impact factor. Shariat, Shahrokh F., and Grossman, H.B., were identified as the most prolific and co-cited authors, respectively. Keyword analysis revealed both frequency of occurrence and citation bursts, highlighting areas of concentrated study. Notably, the integration of immunochemotherapy is projected to experience substantial growth in forthcoming research. Our bibliometric assessment provides a panoramic view of the research milieu surrounding neoadjuvant chemotherapy for bladder cancer, encapsulating the present state, evolving trends, and potential future directions, with a particular emphasis on the promise of immunochemotherapy.

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.

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (GDFather-Neo).

TPS712 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Neoadjuvant immunotherapy (I/O) demonstrated clinical safety and efficacy in various solid tumors including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for treatment of MIBC. Increasing evidence emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive role. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. The Neo-GDFather trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: Multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. Other inclusion criteria comprise an ECOG performance status 0-1 and a pure/predominant UC histology. No statistical assumptions were undertaken at this stage.Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations of EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., #2501 ASCO Annual Meeting 2023 Oral Abstract Session. Clinical trial information: Not yet available.

PRDX2 regulates stemness contributing to cisplatin resistance and metastasis in bladder cancer.

Cisplatin (CDDP)-based chemotherapy has emerged as the primary treatment for muscle-invasive bladder cancer and metastatic bladder cancer. Nevertheless, a significant proportion of patients experience rapidly developed chemoresistance, leading to treatment ineffectiveness. Existing evidence suggests that chemoresistance is governed by various factors, including tumor stem cells, epithelial mesenchymal transition, and reactive oxygen species (ROS). However, limited research has been conducted on the role of PRDX2, a crucial ROS scavenger, in the modulation of chemoresistance in bladder cancer. Cisplatin-resistant cell lines were established using the concentration gradient overlay method, and differentially expressed genes in resistant cells were screened through RNA sequencing. The expression of PRDX2 in cells and tissues was assessed using RT-qPCR, Western Blot, and immunohistochemistry. The expression of PRDX2 in bladder cancer and adjacent tissues was evaluated using a bladder cancer tissue microarray. Furthermore, the impact of PRDX2 knockdown on tumor formation and metastasis was investigated in vivo by applying subcutaneous tumor xenografts tail vein metastasis assays. We demonstrated that PRDX2 is significantly upregulated in bladder tumors and cisplatin-resistant bladder tumor cell lines. Overexpression of PRDX2 can promote tumor proliferation, migration, and invasion both in vitro and in vivo. We have found that knockdown of PRDX2 expression can effectively reverse cell resistance to cisplatin. Mechanistically, our findings suggest that PRDX2 is involved in regulating tumor stemness and epithelial-mesenchymal transition (EMT). Knockdown of PRDX2 affects the PI3K-AKT and mTOR signaling pathways, thereby influencing tumor stemness and EMT, ultimately impacting the chemotherapy resistance of the tumor. This study provides a new insight into the regulation of chemotherapy resistance in bladder cancer by PRDX2. Targeting PRDX2 can serve as a potent therapeutic target for chemotherapy resistance.

Patient experience of surveillance following radical treatment for muscle-invasive bladder cancer.

Patient experience of surveillance following radical treatment for muscle-invasive bladder cancer.

Comparative Outcomes of Radical Cystectomy in Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis.

Muscle-invasive bladder cancerposes a significant clinical challenge that necessitates effective therapeutic interventions. Radical cystectomy is a primary treatment option, but a comprehensive understanding of its outcomes is crucial for informed clinical decision-making.This systematic review and meta-analysis aimed to investigate and summarize the outcomes associated with radical cystectomy as a primary treatment for muscle-invasive bladder cancer with a focus on survival rates, complications, and quality of life.A systematic search across databases-PubMed, Google Scholar, and others-covered studies from 2017 onwards. Included were studies reporting survival rates, complications, and quality of life post-radical cystectomy in muscle-invasive bladder cancer patients, including randomized controlled trials, cohort, and observational studies. Multidimensional analysis revealed promising findings regarding the efficacy of radical cystectomy in muscle-invasive bladder cancer. Survival outcomes, including overall survival and disease-specific mortality, have demonstrated significant improvements, particularly in recent randomized controlled trials and cohort studies. Complications associated with the surgical procedure, such as positive surgical margins and lymph node yields, were generally acceptable. Quality of life outcomes post-radical cystectomy exhibited positive trends, although variations were noted in the emotional and social domains. This review underscores radical cystectomy's role in enhancing overall survival and reducing disease-specific mortality in muscle-invasive bladder cancer. Despite reported complications, recent studies support its acceptable risk profile. Detailed examination of various factors contributes to a comprehensive understanding of the procedure. These findings emphasize the importance of individualized treatment approaches in the management of muscle-invasive bladder cancer, considering both oncological efficacy and perioperative outcomes.Radical cystectomy remains fundamental in urological oncology, with ongoing advancements refining its significance.

Radical cystectomy in the geriatric population. Tools for screening postoperative complications

Radical cystectomy is the gold standard for the treatment of muscle-invasive bladder cancer. Advanced age is only a relative criterion when selecting patients eligible for radical cystectomy, and to reduce post-operative complications, the management of an elderly patient requires a multidisciplinary approach. The role of the geriatrician is therefore essential, in collaboration with the urologist, to ensure appropriate follow-up. A series of preoperative screening tests should be used to identify frailer patients who are at high risk of developing complications, so that appropriate follow-up can be carried out.