Authors: David J Benjamin, Arash Rezazadeh Kalebasty, Vinay Prasad...

Recent findings reported for the phase 3 EV-302 trial indicate a survival benefit from enfortumab vedotin plus pembrolizumab versus chemotherapy in metastatic urothelial carcinoma. We discuss several key points regarding post-protocol therapies, extending the duration of therapy, toxicity, and costs, all of which may have a bearing on how physicians and patients balance the benefit against the potential harms associated with this regimen.

Topics: Humans; Antibodies, Monoclonal, Humanized; Carcinoma, Transitional Cell; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Urinary Bladder Neoplasms; Standard of Care; Urologic Neoplasms; Neoplasm Metastasis; Survival Rate; Antineoplastic Agents, Immunological

PubMed: 38485615
DOI: 10.1016/j.euo.2024.02.010

Authors: Wolfgang A Schulz, Karina D Sørensen

The major urological cancers comprise prostate adenocarcinoma, urinary bladder (or upper urinary tract) carcinoma, renal cell carcinoma, testicular cancer and penile carcinoma, in this order of incidence, each with various histological and molecular subtypes [...].

Topics: Epigenesis, Genetic; Epigenomics; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Prognosis; Urologic Neoplasms

PubMed: 31561442
DOI: 10.3390/ijms20194775

Clinical Trial

Authors: Matthew D Galsky, Xiangnan Guan, Deepali Rishipathak...

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

Topics: Humans; Antibodies, Monoclonal, Humanized; Carboplatin; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Gemcitabine; Urinary Bladder Neoplasms; Urologic Neoplasms

PubMed: 38280376
DOI: 10.1016/j.xcrm.2024.101393

Review

Authors: Cinzia Antognelli, Vincenzo Nicola Talesa

Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide. While advances have been made towards understanding the molecular bases of these diseases, a complete understanding of the pathological mechanisms remains an unmet research goal that is essential for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these malignancies for which no effective therapies are currently being used. Glyoxalases, consisting of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), are enzymes that catalyze the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggests that glyoxalases, especially Glo1, play an important role in the initiation and progression of urological malignancies. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-prostate cancer (PCa) therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis.

Topics: Antineoplastic Agents; Carcinogenesis; Female; Humans; Lactoylglutathione Lyase; Male; Prognosis; Prostatic Neoplasms; Signal Transduction; Thiolester Hydrolases; Urologic Neoplasms

PubMed: 29385039
DOI: 10.3390/ijms19020415

Randomized Controlled Trial

Authors: Alison Jane Birtle, Robert Jones, John Chester...

JCO POUT was a phase III, randomized, open-label trial, including 261 patients with muscle-invasive or lymph node-positive, nonmetastatic upper tract urothelial cancer (UTUC) randomly assigned after radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease-free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups, respectively, at a median follow-up of 65 months. The 5-year DFS was 62% versus 45%, univariable hazard ratio (HR), 0.55 (95% CI, 0.38 to 0.80, = .001). The restricted mean survival time (RMST) was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms, respectively. The 5-year OS was 66% versus 57%, with univariable HR, 0.68 (95% CI, 0.46 to 1.00, = .049) and RMST difference 11 months (95% CI, 1 to 21). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported, and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits.

Topics: Humans; Nephroureterectomy; Chemotherapy, Adjuvant; Female; Disease-Free Survival; Male; Aged; Middle Aged; Carcinoma, Transitional Cell; Antineoplastic Combined Chemotherapy Protocols; Urologic Neoplasms; Ureteral Neoplasms; Kidney Neoplasms

PubMed: 38350047
DOI: 10.1200/JCO.23.01659

Review

Authors: Francesca Khani, Brian D Robinson

CONTEXT

- Precursor lesions of urologic malignancies are established histopathologic entities, which are important not only to recognize for clinical purposes, but also to further investigate at the molecular level in order to gain a better understanding of the pathogenesis of these malignancies.

OBJECTIVE

- To provide a brief overview of precursor lesions to the most common malignancies that develop within the genitourinary tract with a focus on their clinical implications, histologic features, and molecular characteristics.

DATA SOURCES

- Literature review from PubMed, urologic pathology textbooks, and the 4th edition of the World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. All photomicrographs were taken from cases seen at Weill Cornell Medicine or from the authors' personal slide collections.

CONCLUSIONS

- The clinical importance and histologic criteria are well established for the known precursor lesions of the most common malignancies throughout the genitourinary tract, but further investigation is warranted at the molecular level to better understand the pathogenesis of these lesions. Such investigation may lead to better risk stratification of patients and potentially novel treatments.

Topics: Adenoma; Carcinoma in Situ; Diagnosis, Differential; Female; Humans; Kidney Neoplasms; Male; Mutation; Neoplasm Invasiveness; Neoplasms, Germ Cell and Embryonal; Precancerous Conditions; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Testicular Neoplasms; Urinary Bladder Neoplasms; Urologic Neoplasms

PubMed: 28767283
DOI: 10.5858/arpa.2016-0515-RA

Review

Authors: Michael P Rimmer, Christopher D Gregory, Rod T Mitchell...

Extracellular vesicles (EVs) are small lipid bound structures released from cells containing bioactive cargoes. Both the type of cargo and amount loaded varies compared to that of the parent cell. The characterisation of EVs in cancers of the male urogenital tract has identified several cargoes with promising diagnostic and disease monitoring potential. EVs released by cancers of the male urogenital tract promote cell-to-cell communication, migration, cancer progression and manipulate the immune system promoting metastasis by evading the immune response. Their use as diagnostic biomarkers represents a new area of screening and disease detection, potentially reducing the need for invasive biopsies. Many validated EV cargoes have been found to have superior sensitivity and specificity than current diagnostic tools currently in use. The use of EVs to improve disease monitoring and develop novel therapeutics will enable clinicians to individualise patient management in the exciting era of personalised medicine.

Topics: Animals; Biomarkers, Tumor; Extracellular Vesicles; Gene Expression Regulation, Neoplastic; Genital Neoplasms, Male; Humans; Male; Prognosis; Signal Transduction; Urologic Neoplasms

PubMed: 34019971
DOI: 10.1016/j.bbcan.2021.188570

Authors: Vicenç Ruiz de Porras, Albert Font

Urological cancer encompasses a diverse range of tumors, including bladder, prostate, renal, upper urinary tract, and germ cell tumors [...].

Topics: Male; Humans; Kidney Neoplasms; Urologic Neoplasms; Kidney; Urinary Bladder; Prostate; Urinary Bladder Neoplasms

PubMed: 37958779
DOI: 10.3390/ijms242115795

Review

Authors: Jeanny B Aragon-Ching, Ananya Choudhury, Vitaly Margulis...

Diagnostic and therapeutic challenges in the field of bladder and upper tract cancers provide opportunities for multidisciplinary care. Urothelial cancers make up the majority of the histologic subtype of bladder and upper tract cancers. Although the existence of variant histology, nonurothelial cancers, and urethral cancers is rare, these cancers pose a challenging clinical dilemma given the lack of well-defined consensus treatment guidelines. This review focuses on key issues of treatment: cisplatin ineligibility with emphasis on the definition, nuances of chemotherapy and frontline immune checkpoint inhibitor therapy, use of radiation in bladder-preservation strategies, upper tract urothelial cancer management, and highlights of urothelial variants and nonurothelial tumors and management.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Disease Management; Humans; Neoplasm Metastasis; Neoplasm Staging; Treatment Outcome; Urologic Neoplasms

PubMed: 31099661
DOI: 10.1200/EDBK_237451

Review

Authors: Omar Alhalabi, Hind Rafei, Amishi Shah...

PURPOSE OF REVIEW

Advanced urothelial carcinoma is a heterogeneous disease with high burden of morbidity, mortality, and cost. Significant progress has been made in understanding the biology of the disease and the development of immunotherapies and targeted therapies. In this review, we summarize the current and future therapeutic approaches in the management of urothelial carcinoma.

RECENT FINDINGS

Advances in immune checkpoint inhibitors resulted in the Food and Drug Administration (FDA) approvals of atezolizumab in 2016, and pembrolizumab, avelumab, durvalumab, and nivolumab in 2017 for the treatment of advanced urothelial carcinoma. More recently, development of inhibitors targeting the fibroblast growth factor receptor genetic alterations and antibody-drug conjugates targeting specific cell surface antigens (trop2, nectin4, and SLITRK6) resulted in several FDA breakthrough designations for urothelial carcinoma.

CONCLUSION

The development of novel therapies targeting the immune and molecular pathways of advanced urothelial carcinoma is promising for the improvement of outcomes in this lethal disease. Ongoing efforts are poised to optimize therapeutic options in the post-chemotherapy arena. In the era of precision medicine, the future of urothelial carcinoma lies in using less cytotoxic chemotherapy, more targeted therapy and immunotherapy, and possibly a combination of these therapeutic approaches.

Topics: Antibodies, Monoclonal; Carcinoma; Humans; Molecular Targeted Therapy; Randomized Controlled Trials as Topic; Receptors, Growth Factor; Urinary Bladder Neoplasms; Urologic Neoplasms

PubMed: 30844889
DOI: 10.1097/CCO.0000000000000532