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Advances in Management of Urothelial Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 25 May 2025 | Viewed by 15068

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Special Issue Editor

Prof. Dr. Shomik Sengupta

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Guest Editor

Eastern Health Clinical School, Monash University, 5 Arnold Street, Box Hill, VIC 3128, Australia
Interests: bladder cancer; uro-oncology; clinical trial

Special Issue Information

Dear Colleagues,

Urothelial cancers, particularly arising from the bladder, represent a large healthcare burden. On the one hand, low-risk bladder cancers are common and can recur frequently, thus requiring long-term repetitive follow-up that is invasive and expensive. On the other hand, invasive bladder cancer and upper tract urothelial cancer (UTUC) are rarer but potentially lethal, hence require aggressive and morbid treatment in patients who are elderly or frail. New developments in diagnostic modalities of endoscopy, imaging, biomarkers and genomics have come about in recent years, achieving earlier diagnoses and precise classification and prognostication. In parallel, there is an increased availability of therapeutic options in terms of improved surgical tools and approaches as well as novel and targeted agents delivered systemically or endoluminally. This Special Issue will highlight many of these developments. We welcome reviews of the current status of this field, as well as original research related to the management of urothelial cancer.

Prof. Dr. Shomik Sengupta
Guest Editor

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Keywords

urothelial cancer
bladder cancer
upper tract urothelial cancer
diagnosis
treatment
surgery
chemotherapy
immunotherapy
imaging

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Published Papers (9 papers)

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Research

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12 pages, 966 KiB

Open AccessArticle

Sequential Endoluminal Doxorubicin and Gemcitabine Alternating Weekly with Sequential Mitomycin and Docetaxel for Recurrent Non-Muscle Invasive Urothelial Carcinoma

by Ian M. McElree, Vignesh T. Packiam, Ryan L. Steinberg, Helen Y. Hougen, Mohamad Abou Chakra, Sarah L. Mott and Michael A. O’Donnell

Cancers 2024, 16(24), 4126; https://doi.org/10.3390/cancers16244126 - 10 Dec 2024

Viewed by 1005

Abstract

Background: After first-line treatment failure, patients with non-muscle invasive urothelial carcinoma (NMIUC) are recommended to undergo radical cystectomy. However, those unable to pursue radical surgery or desiring bladder preservation require effective salvage therapies. Multi-agent treatment regimens are particularly useful for targeting the complex resistance mechanisms of recurrent UC. Herein, we report a regimen of sequential doxorubicin and gemcitabine alternating weekly with sequential docetaxel and mitomycin (Quad Chemo) for patients with recurrent high-risk NMIUC. Materials and Methods: We retrospectively identified all patients sequentially treated with 50 mg of doxorubicin followed by 1000 mg of gemcitabine alternating weekly with sequential 37.5 mg of docetaxel followed by 40 mg mitomycin-C between 2007–2024. Induction consisted of 8 weekly treatments, and, if disease-free, patients were initiated on monthly maintenance treatments for 2 years. Results: In total, 29 patients (39 treated units; 26 lower urinary tract, 13 upper urinary tract) with high-grade NMIUC were included in the final analysis. The cohort had high-risk features with a median of three prior induction therapies and with 38 (97%) units presented with either biopsy-proven CIS or presumed CIS in the context of high-grade urine cytology in the absence of tumorous lesions. There were 26 recurrences during follow-up, 17 in the lower tract and 9 in the upper tract. Among all of the treated units, the complete response rate was 80%, and 1- and 2-year recurrence-free survival was 60% and 43%, respectively. In total, 10 patients experienced disease progression yielding a 5-year progression-free survival of 57%. Five patients ultimately died due to bladder cancer yielding a 5-year cancer-specific survival of 83%. A total of 19 (66%) patients reported side effects during treatment, and 7 (24%) stopped treatment secondary to side effects. Conclusions: In a high-risk heavily pre-treated cohort, Quad Chemo rescued a significant portion of patients with recurrent NMIUC from disease relapse. However, progression events were considerable in the long term. Further prospective evaluation of this treatment regimen is warranted. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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11 pages, 1490 KiB

Open AccessArticle

Pre-Op Hydronephrosis Predicts Outcomes in Patients Receiving Robot-Assisted Radical Cystectomy

by Chris Ho-Ming Wong, Ivan Ching-Ho Ko, David Ka-Wai Leung, Seok Ho Kang, Kousuke Kitamura, Shigeo Horie, Satoru Muto, Chikara Ohyama, Shingo Hatakeyama, Manish Patel, Cheung-Kuang Yang, Kittinut Kijvikai, Ji Youl Lee, Hai-Ge Chen, Rui-Yun Zhang, Tian-Xin Lin, Lui Shiong Lee, Jeremy Yuen-Chun Teoh and Eddie Chan

Cancers 2024, 16(16), 2826; https://doi.org/10.3390/cancers16162826 - 12 Aug 2024

Viewed by 1248

Abstract

Introduction: Robot-assisted radical cystectomy (RARC) has gained momentum in the management of muscle invasive bladder cancer (MIBC). Predictors of RARC outcomes are not thoroughly studied. We aim to investigate the implications of preoperative hydronephrosis on oncological outcomes. Patients and Methods: This study analysed data from the Asian RARC consortium, a multicentre registry involving nine Asian centres. Cases were divided into two groups according to the presence or absence of pre-operative hydronephrosis. Background characteristics, operative details, perioperative outcomes, and oncological results were reviewed. Outcomes were (1) survival outcomes, including 10-year disease-free survival (DFS) and overall survival (OS), and (2) perioperative and pathological results. Multivariate regression analyses were performed on survival outcomes. Results: From 2007 to 2020, 536 non-metastatic MIBC patients receiving RARC were analysed. 429 had no hydronephrosis (80.0%), and 107 (20.0%) had hydronephrosis. Hydronephrosis was found to be predictive of inferior DFS (HR = 1.701, p = 0.003, 95% CI = 1.196–2.418) and OS (HR = 1.834, p = 0.008, 95% CI = 1.173–2.866). Subgroup analysis demonstrated differences in the T2-or-above subgroup (HR = 1.65; p = 0.004 in DFS and HR = 1.888; p = 0.008 in OS) and the T3-or-above subgroup (HR = 1.757; p = 0.017 in DFS and HR = 1.807; p = 0.034 in OS). Conclusions: The presence of preoperative hydronephrosis among MIBC patients carries additional prognostic implications on top of tumour staging. Its importance in case selection needs to be highlighted. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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9 pages, 651 KiB

Open AccessArticle

Impact of Pre-Operative Ureteroscopy on Bladder Recurrence Following Nephroureterectomy for UTUC

by Chris Ho-Ming Wong, Ivan Ching-Ho Ko, David Ka-Wai Leung, Kang Liu, Hongda Zhao, Mario Alvarez-Maestro, Maria del Pilar Laguna Pes, Jean de la Rosette and Jeremy Yuen-Chun Teoh

Cancers 2024, 16(15), 2683; https://doi.org/10.3390/cancers16152683 - 28 Jul 2024

Cited by 1 | Viewed by 1218

Abstract

(1) Introduction: Diagnostic ureteroscopy (URS) is an important component in the workup of upper tract urothelial carcinoma (UTUC). Whether URS was associated with increased recurrence in the bladder was not fully concluded. The current study aimed to evaluate the implication of URS on the incidences of intravesical recurrence following radical nephroureterectomy (RNU) in non-metastatic UTUC patients without prior history of bladder cancer via multi-institutional data. (2) Patients and Methods: Data were obtained from the Clinical Research Office of the Endourology Society Urothelial Carcinomas of the Upper Tract (CROES-UTUC) registry, a prospective, multicentre database. Patients with non-metastatic UTUC treated with RNU were divided into two groups: those undergoing upfront RNU and those having diagnostic URS prior to RNU. Intravesical recurrence-free survival (IVRS) was the primary endpoint, evaluated through Kaplan–Meier analysis and multivariate Cox regression. Cases with adequate follow-up data were included. (3) Results: The analysis included 269 patients. Of these, 137 (50.9%) received upfront RNU and 132 (49.1%) received pre-RNU URS. The URS group exhibited an inferior 24-month IVRS compared to the upfront RNU group (HR = 1.705, 95% CI = 1.082–2.688; p = 0.020). Multivariate analysis confirmed URS as the only significant predictor of IVR (p = 0.019). Ureteric access sheath usage, flexible ureteroscopy, ureteric biopsy, retrograde contrast studies, and the duration of URS did not significantly affect IVRS. (4) Conclusions: Diagnostic URS prior to RNU was found to be associated with an increased risk of IVR in patients with UTUC. The risk was not significantly influenced by auxiliary procedures during URS. Physicians were advised to meticulously evaluate the necessity of diagnostic URS. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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13 pages, 1966 KiB

Open AccessArticle

Oncologic Outcomes of Patients with Immune Checkpoint Inhibitor Resistant Urothelial Carcinoma Treated with Enfortumab Vedotin and the Impact of Neutrophil-to-Lymphocyte Ratio and Dysgeusia on Overall Survival: A Retrospective Multicenter Cohort Study in Japan

by Keita Nakane, Kazuki Taniguchi, Minori Nezasa, Torai Enomoto, Toyohiro Yamada, Risa Tomioka-Inagawa, Kojiro Niwa, Masayuki Tomioka, Takashi Ishida, Shingo Nagai, Shigeaki Yokoi, Tomoki Taniguchi, Makoto Kawase, Kota Kawase, Koji Iinuma, Yuki Tobisawa and Takuya Koie

Cancers 2024, 16(15), 2648; https://doi.org/10.3390/cancers16152648 - 25 Jul 2024

Cited by 1 | Viewed by 1389

Abstract

Randomized phase III trial results have demonstrated enfortumab vedotin (EV), an antibody–drug conjugate (ADC) consisting of an anti-Nectin-4 human IgG1 monoclonal antibody and monomethyl auristatin E, is a useful treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) that progressed after immune checkpoint inhibitor (ICI) therapies. This multicenter retrospective cohort study aimed to identify predictive factors for the efficacy of EV therapy and prolonged overall survival (OS) of patients in clinical practice. This study included patients with la/mUC who received ICI treatment. Patients who subsequently received EV treatment, those who received non-EV chemotherapy, and those who received no treatment were defined as EV, non-EV, and best supportive care (BSC) groups, respectively. The median OS was 20, 15, and 7 months in the EV, non-EV, and BSC groups, respectively (p < 0.001). Patients with la/mUC who had a complete or partial response after EV treatment had a significantly prolonged OS compared with those with stable or progressive disease. Univariate analysis showed age, neutrophil-to-lymphocyte ratio (NLR), dysgeusia, and rash as independent predictors of OS improvement. NLR and dysgeusia were independent predictors of OS after EV in multivariate analysis. Patients without these factors had a significantly prolonged OS compared to those with both factors. In real-world practice, EV therapy is an effective treatment for patients with la/mUC after ICI treatment. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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10 pages, 373 KiB

Open AccessArticle

Hyperthermic Intravesical Chemotherapy (HIVEC) Using Epirubicin in an Optimized Setting in Patients with NMIBC Recurrence after Failed BCG Therapy

by Julien Blanc, Jonathan Ruggiero, Ilaria Lucca, Nicolas Arnold, Bernhard Kiss and Beat Roth

Cancers 2024, 16(7), 1398; https://doi.org/10.3390/cancers16071398 - 2 Apr 2024

Viewed by 1621

Abstract

To evaluate hyperthermic intravesical chemotherapy (HIVEC) using conductive heating and epirubicin in an optimized setting as an alternative to radical cystectomy in patients with recurrent non-muscle invasive bladder cancer (NMIBC) who have failed bacillus Calmette-Guérin (BCG) therapy. We retrospectively analyzed our prospectively recorded database of patients who underwent HIVEC between 11/2017 and 11/2022 at two Swiss University Centers. Cox regression analysis was used for univariate/multivariate analysis, and the Kaplan–Meier method for survival analysis. Of the 39 patients with NMIBC recurrence after failed BCG therapy, 25 (64%) did not recur within the bladder after a median follow-up of 28 months. The 12- and 24-month intravesical RFS were 94.8% and 80%, respectively. Extravesical recurrence developed in 14/39 (36%) of patients. Only 7/39 (18%) patients had to undergo radical cystectomy. Seven patients (18%) progressed to metastatic disease, with five of these (71%) having previously developed extravesical disease. No adverse events > grade 2 occurred during HIVEC. Device-assisted HIVEC using epirubicin in an optimized setting achieved excellent RFS rates in this recurrent NMIBC population at highest risk for recurrence after previously failed intravesical BCG therapy. Extravesical disease during or after HIVEC, however, was frequent and associated with metastatic disease and consecutively poor outcomes. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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Review

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16 pages, 302 KiB

Open AccessReview

Nuclear Medicine and Molecular Imaging in Urothelial Cancer: Current Status and Future Directions

by Sam McDonald, Kevin G. Keane, Richard Gauci and Dickon Hayne

Cancers 2025, 17(2), 232; https://doi.org/10.3390/cancers17020232 - 13 Jan 2025

Cited by 1 | Viewed by 1400

Abstract

Background: The role of molecular imaging in urothelial cancer is less defined than other cancers, and its utility remains controversial due to limitations such as high urinary tracer excretion, complicating primary tumour assessment in the bladder and upper urinary tract. This review explores the current landscape of PET imaging in the clinical management of urothelial cancer, with a special emphasis on potential future advancements including emerging novel non-¹⁸F FDG PET agents, PET radiopharmaceuticals, and PET-MRI applications. Methods: We conducted a comprehensive literature search in the PubMed database, using keywords such as “PET”, “PET-CT”, “PET-MRI”, “FDG PET”, “Urothelial Cancer”, and “Theranostics”. Studies were screened for relevance, focusing on imaging modalities and advances in PET tracers for urothelial carcinoma. Non-English language, off-topic papers, and case reports were excluded, resulting in 80 articles being selected for discussion. Results: ¹⁸F FDG PET-CT has demonstrated superior sensitivity over conventional imaging, such as contrast-enhanced CT and MRI, for detecting lymph node metastasis and distant disease. Despite these advantages, FDG PET-CT is limited for T-staging of primary urothelial tumours due to high urinary excretion of the tracer. Emerging evidence supports the role of PETC-CT in assessing response to neoadjuvant chemotherapy and in identifying recurrence, with a high diagnostic accuracy reported in several studies. Novel PET tracers, such as ⁶⁸Ga-labelled FAPI, have shown promising results in targeting cancer-associated fibroblasts, providing higher tumour-to-background ratios and detecting lesions missed by traditional imaging. Antibody-based PET tracers, like those targeting Nectin-4, CAIX, and uPAR, are under investigation for their diagnostic and theranostic potential, and initial studies indicate that these agents may offer advantages over conventional imaging and FDG PET. Conclusions: Molecular imaging is a rapidly evolving field in urothelial cancer, offering improved diagnostic and prognostic capabilities. While ¹⁸F FDG PET-CT has shown utility in staging, further prospective research is needed to establish and refine standardised protocols and validate new tracers. Advances in theranostics and precision imaging may revolutionise urothelial cancer management, enhancing the ability to tailor treatments and improve patient outcomes. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

10 pages, 236 KiB

Open AccessReview

The Utility of Intraluminal Therapies in Upper Tract Urothelial Carcinoma: A Narrative Review

by Jack Tyrrell, William Chui, Joshua Kealey and Shomik Sengupta

Cancers 2024, 16(10), 1931; https://doi.org/10.3390/cancers16101931 - 18 May 2024

Cited by 2 | Viewed by 1771

Abstract

Nephron sparing surgery (NSS) is considered for selected cases of upper tract urothelial carcinoma (UTUC) as it maintains renal function and avoids morbidity associated with radical nephroureterectomy (RNU). The appropriate selection of patients suitable for NSS without compromising oncological outcomes can sometimes be difficult, given the limitations of diagnostic modalities. Recurrence rates for UTUC can be as high as 36 to 54% after NSS. Intraluminal adjuvant therapy can be attempted following NSS to reduce recurrence, but delivery to the upper tract is more challenging than into the bladder. Bacillus Calmette-Guerin (BCG) and chemotherapy such as Mitomycin (MMC) have been administered via nephrostomy or ureteric catheter, which requires invasive/repeated instrumentation of the upper urinary tract. Drug delivery by reflux from bladder instillation along indwelling stents has also been tried but can potentially be unreliable. Recently, a gel formulation of mitomycin has been developed for the controlled exposure of the upper urinary tract to treatment over a number of hours. Drug-eluting stents to deliver chemotherapy to the upper urinary tract have been developed but have not yet entered clinical practice. Endoluminal phototherapy utilising an intravenous photosensitising agent is another novel approach that has recently been described. Intraluminal therapies may be beneficial in decreasing recurrence rates in UTUC, but currently have some limitations in their usage. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

19 pages, 8570 KiB

Open AccessReview

Melanoma Antigen Family A (MAGE A) as Promising Biomarkers and Therapeutic Targets in Bladder Cancer

by Shiv Verma, Diya Swain, Prem Prakash Kushwaha, Smit Brahmbhatt, Karishma Gupta, Debasish Sundi and Sanjay Gupta

Cancers 2024, 16(2), 246; https://doi.org/10.3390/cancers16020246 - 5 Jan 2024

Cited by 4 | Viewed by 3289

Abstract

The Melanoma Antigen Gene (MAGE) is a large family of highly conserved proteins that share a common MAGE homology domain. Interestingly, many MAGE family members exhibit restricted expression in reproductive tissues but are abnormally expressed in various human malignancies, including bladder cancer, which is a common urinary malignancy associated with high morbidity and mortality rates. The recent literature suggests a more prominent role for MAGEA family members in driving bladder tumorigenesis. This review highlights the role of MAGEA proteins, the potential for them to serve as diagnostic or prognostic biomarker(s), and as therapeutic targets for bladder cancer. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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13 pages, 3100 KiB

Open AccessSystematic Review

Symptoms and Side Effects of Bacille Calmette–Guerin Therapy for Non-Muscle Invasive Bladder Cancer as Reported by Patients: A Systematic Review

by John Lahoud, Alfin Okullo, Claudia Rutherford, David P. Smith, Daniel S. J. Costa, Margaret-Ann Tait, Shomik Sengupta and Manish I. Patel

Cancers 2025, 17(2), 160; https://doi.org/10.3390/cancers17020160 - 7 Jan 2025

Viewed by 1013

Abstract

Background/Objectives: Knowledge of the symptoms and side effects (SSEs) of Bacille Calmette–Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) is critical when establishing selecting appropriate therapies for patients. The aim of our study was to systematically review the common patient-reported SSEs associated with BCG-based and other intravesical chemotherapy treatment options for NMIBC. Methods: A systematic search of AMED, MEDLINE, EMBASE, PsycINFO, Web of Knowledge, and Scopus was conducted from inception to July 2024. The PRISMA process was followed. Prospective studies with an adult cohort that assessed SSEs through direct patient reports with standardized patient-reported outcome measures were included in this study. A narrative synthesis was performed to compare the frequency of SSEs reported by treatment options. Statistical analysis was performed using chi square and Fisher’s exact tests, with statistical significance at p < 0.05. Results: Thirty-four studies met the eligibility criteria. The main findings indicated that BCG induction is more toxic than BCG induction with maintenance; however, severe SSEs resulting in treatment cessation occurred almost twice as often in patients on BCG induction with maintenance. Patients who received full-dose BCG were more likely to have SSEs compared to those receiving a low dose. BCG monotherapy alone caused more SSEs compared to BCG with chemotherapy. Patients reported more SSEs with BCG compared to chemotherapy alone for induction with maintenance. Limitations of the study include the varied length of maintenance regimes affecting nature of data reported. Conclusions: The findings of this study allow for improved counselling of patients regarding expected side effects in accordance with their recommended treatment options for NMIBC. Full article

(This article belongs to the Special Issue Advances in Management of Urothelial Cancer)

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