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Kattan J, Kattan C, Aoun F, Nemr E. The practical roadmap for peri-cystectomy approaches in muscle-invasive bladder cancer. Front Oncol 2025; 15:1543837. [PMID: 40276057 PMCID: PMC12018224 DOI: 10.3389/fonc.2025.1543837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
The management of muscle-invasive bladder cancer (MIBC) remains a challenging topic since it is witnessing rapidly evolving changes and new drug approvals. In fact, more effective approaches are now available to improve the outcomes of patients with MIBC who are candidates for cystectomy. Neo-adjuvant cisplatin-based chemotherapy was the standard approach for patients who were deemed cisplatin-eligible. Also, adjuvant cisplatin-based chemotherapy was considered for high-risk operated patients who did not receive the standard neo-adjuvant chemotherapy. It was only recently that adjuvant immune checkpoint inhibitors were proved effective in adjuvant settings and were approved for high-risk MIBC patients after neo-adjuvant chemotherapy followed by cystectomy or for those who did not receive neo-adjuvant chemotherapy and were not eligible for adjuvant cisplatin-based chemotherapy. More recently, adding immune checkpoint inhibitors to neo-adjuvant chemotherapy and to post-cystectomy adjuvant therapy seemed to be very promising. In this review article, all current peri-cystectomy options are briefly described with an attempt to guide and simplify choices by drawing a roadmap covering all the practical scenarios.
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Affiliation(s)
- Joseph Kattan
- Department of Hematology-Oncology, Hotel-Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, Lebanon
| | - Clarisse Kattan
- Department of Hematology-Oncology, Hotel-Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, Lebanon
| | - Fouad Aoun
- Department of Urology, Hotel-Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, Lebanon
| | - Elie Nemr
- Department of Urology, Hotel-Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, Lebanon
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Mamede I, Silva C, Alves AC, Oliveira JP, Maia M, Liz CDD, Oliveira ACD. Adjuvant Immunotherapy in High-Risk Muscle-Invasive Urothelial Cancer: An Updated Meta-Analysis of Randomized Controlled Trials. Clin Genitourin Cancer 2025; 23:102288. [PMID: 39732134 DOI: 10.1016/j.clgc.2024.102288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/26/2024] [Accepted: 12/01/2024] [Indexed: 12/30/2024]
Abstract
INTRODUCTION Neoadjuvant cisplatin-based chemotherapy followed by radical surgery is the standard treatment for muscle-invasive urothelial carcinoma (MIUC). The Checkmate-274 and AMBASSADOR trials have demonstrated improvements in disease-free survival (DFS) with adjuvant immunotherapy. Consequently, this meta-analysis aimed to assess the effectiveness of strategies involving checkpoint inhibitors in managing high-risk MIUC. PATIENTS AND METHODS We searched PubMed, Embase, Cochrane, ClinicalTrials.gov, EAU24, and ASCO GU abstracts for randomized controlled trials (RCTs) comparing adjuvant PD-1 and PD-L1 inhibitors against control (placebo or observation) for MIUC. Outcomes included DFS, grade ≥3 adverse events (AEs), and overall survival (OS). Heterogeneity was assessed using I2 statistics, employing a random-effects model for analysis. RESULTS In a cohort of 2220 patients from three RCTs, 1,113 (50.14%) underwent adjuvant immunotherapy. This treatment significantly increased DFS (HR 0.76; 95% CI, 0.65-0.90; P < .01), particularly in lower tract tumors (HR 0.71; 95% CI, 0.56-0.91; P < .01). No substantial DFS improvement surfaced in the upper tract subgroup (P = .28) (p-interaction = .01). PD-L1 status (p-interaction = .83) and previous neoadjuvant chemotherapy (p-interaction = .11) did not significantly affect outcomes. However, immunotherapy correlated with higher grade ≥3 AEs (RR 1.47; P < .01), with no notable difference in OS (P = .07). CONCLUSIONS Adjuvant PD-1/PD-L1 inhibitors notably enhance MIUC DFS, particularly in lower tract tumors, regardless of PD-L1 status. These findings support immunotherapy, especially anti-PD1, as a valuable adjuvant treatment strategy for high-risk MIUC patients.
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Affiliation(s)
- Isadora Mamede
- Federal University of Sao Joao del-Rei, Divinopolis, Minas Gerais, Brazil.
| | - Caroliny Silva
- Federal University of Rio Grande do Norte, Campus Universitario - Lagoa Nova, Natal, Rio Norte, Brazil
| | | | - Joao Pedro Oliveira
- Federal University of Rio de Janeiro, Centro de Ciencias da Saude, Rio de Janeiro, Brazil
| | - Melissa Maia
- Federal University of Ceara, Fortaleza, Ceara, Brazil
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Baudelin C, Sargos P, Dinart D, Hennequin C, Teyssonneau D, Meynard L, Vuong NS, Lefort F, Baboudjian M, Roubaud G. Concomitant chemotherapy in trimodal treatment of patients with muscle invasive bladder cancer: A systematic review of prospective trials. Crit Rev Oncol Hematol 2025; 205:104557. [PMID: 39580059 DOI: 10.1016/j.critrevonc.2024.104557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/01/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND AND OBJECTIVE For selected patients with muscle-invasive bladder cancer (MIBC), trimodal therapy (TMT) incorporating transurethral resection of the tumor and chemoradiotherapy is an alternative to radical cystectomy. Concurrent chemotherapy (CC) is a pivotal component of TMT, however, the optimal CC protocol remains unknown. This systematic review aims to assess efficacy and safety outcomes of CC protocols used in TMT. METHODS A systematic literature search in the PubMed and Embase databases was performed to identify eligible studies published between 1980 and March 2024. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Data extraction and risk of bias assessment were performed following predefined criteria. KEY FINDINGS AND LIMITATIONS 50 studies met the inclusion criteria. Cisplatin-based CC protocols were the most reported. The highest level of evidence was found for 5-fluorouracil and Mitomycin C and for Carbogen-Nicotinamide. However, significant heterogeneity in patient selection, treatment modalities, follow-up and reported outcomes precluded comparison between trials. Outcomes were similar regardless of CC, with 5-year overall survival around 50 %. Bladder preservation rates ranged from 60 % to 90 %. Distant metastasis rates varied from 10 % to 45 %. Locoregional control rates seemed improved with cisplatin combinations despite an increased acute toxicity. Acute and late toxicity were however relatively low across CC protocols. There was no decrease in gastro-intestinal or urinary Quality of Life. Scarce data were available for elderly patients. CONCLUSIONS AND CLINICAL IMPLICATIONS With similar efficacy and toxicity profiles, and in the absence of comparability among trials, our review does not provide sufficient data to determine the optimal CC for TMT of MIBC. TMT is a well-tolerated and efficient approach with tailored strategy available for patients with localized MIBC.
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Affiliation(s)
- Camille Baudelin
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
| | - Paul Sargos
- Department of Radiation Oncology, Institut Bergonié, Bordeaux, France; Amethyst Radiotherapy Group, La Garenne Colombes, France.
| | - Derek Dinart
- Clinical Research and Clinical Epidemiology Unit, Institut Bergonié, Bordeaux, France.
| | | | - Diego Teyssonneau
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
| | - Lucie Meynard
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
| | - Nam-Son Vuong
- Department of Urology, Clinique Saint-Augustin, Bordeaux, France
| | - Félix Lefort
- Department of Medical Oncology, University Hospital, Bordeaux, France.
| | - Michael Baboudjian
- Department of Urology, APHM, North Academic Hospital, Marseille, France.
| | - Guilhem Roubaud
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
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Flammia RS, Tuderti G, Bologna E, Minore A, Proietti F, Licari LC, Mastroianni R, Bove AM, Anceschi U, Brassetti A, Ferriero MC, Guaglianone S, Chiacchio G, Calabrò F, Leonardo C, Simone G. Stratifying the Risk of Disease Progression among Surgically Treated Muscle-Invasive Bladder Cancer Eligible for Adjuvant Nivolumab. J Clin Med 2024; 13:5466. [PMID: 39336951 PMCID: PMC11432608 DOI: 10.3390/jcm13185466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Background: Check-Mate 274 has demonstrated the disease-free survival (DFS) benefit of adjuvant nivolumab in surgically treated muscle-invasive bladder cancer (MIBC). Since immunotherapy represents an expensive treatment with potential side effects, a better understanding of patient-specific risks of disease progression might be useful for clinicians when weighing the indication for adjuvant nivolumab. Objective: To identify the criteria for risk stratification of disease progression among MIBC patients eligible for adjuvant nivolumab. Materials and methods: A single-institution, prospectively maintained database was queried to identify patients eligible for adjuvant nivolumab according to Check-Mate 274 criteria. To account for immortal bias, patients who died or were lost to follow-up within 3 months of undergoing a radical cystectomy (RC) were excluded. Kaplan-Meier and Cox regression analyses addressed DFS, defined as the time frame from diagnosis to the first documented recurrence or death from any cause, whichever occurred first. Regression tree analysis was implemented to identify criteria for risk stratification. Results: Between 2011 and 2022, 304 patients were identified, with a median follow-up of 50 (IQR 24-72) months. After multivariable adjustment, including NAC as a potential confounder, higher CCI (HR 1.56, 95%CI 1.10-2.21, p = 0.013), T stage (HR 2.06, 95%CI 1.01-4.17, p = 0.046), N stage (HR 1.73, 95%CI 1.26-2.38, p = 0.001) and presence of LVI (HR 1.52, 95%CI 1.07-2.15, p = 0.019) increased the risk of disease recurrence or death. Finally, a two-tier classification was developed. Here, five-year DFS rates were 56.1% vs. 18.1 for low vs. high risk (HR: 2.54, 95%CI 1.79-3.62, p < 0.001). Conclusions: The current risk classification, if externally validated on larger samples, may be useful when weighing the risk and benefit of adjuvant nivolumab treatment and making patients more aware about their disease and about the need for additional treatment after RC.
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Affiliation(s)
- Rocco Simone Flammia
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
- Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
| | - Gabriele Tuderti
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Eugenio Bologna
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
- Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
| | - Antonio Minore
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Flavia Proietti
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
- Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
| | - Leslie Claire Licari
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Riccardo Mastroianni
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Alfredo Maria Bove
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Umberto Anceschi
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Aldo Brassetti
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Maria Consiglia Ferriero
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Salvatore Guaglianone
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Giuseppe Chiacchio
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Fabio Calabrò
- Department of Oncology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy;
| | - Costantino Leonardo
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
| | - Giuseppe Simone
- Department of Urology, IRCCS “Regina Elena” National Cancer Institute, 00128 Rome, Italy; (R.S.F.); (G.T.); (E.B.); (L.C.L.); (R.M.); (A.M.B.); (U.A.); (A.B.); (M.C.F.); (S.G.); (G.C.); (G.S.)
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Swinton M, Devi A, Song YP, Hoskin P, Choudhury A. Beyond surgery: bladder preservation and the role of systemic treatment in localised muscle-invasive bladder cancer. World J Urol 2024; 42:210. [PMID: 38573431 PMCID: PMC10994870 DOI: 10.1007/s00345-024-04892-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 02/15/2024] [Indexed: 04/05/2024] Open
Abstract
Over the last two to three decades the non-surgical curative management of bladder cancer has significantly progressed. Increasing evidence supports the use of bladder preservation as an alternative to radical cystectomy (RC) for localised muscle-invasive bladder cancer (MIBC). Radiosensitisation with chemotherapy or hypoxia modification improves the efficacy of radiotherapy. Systemic treatments play an important role in the management of localised MIBC with the benefit of neoadjuvant chemotherapy prior to radical treatment well established. The use of immune checkpoint inhibitors (ICIs) in the radical treatment of bladder cancer, their safe combination with radical radiotherapy regimens and whether the addition of ICIs improve rates of cure are outstanding questions beginning to be answered by ongoing clinical trials. In this narrative review, we discuss the current evidence for bladder preservation and the role of systemic treatments for localised MIBC.
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Affiliation(s)
- Martin Swinton
- Christie Hospital NHS Foundation Trust, Manchester, UK
- University of Manchester, Manchester, UK
| | - Aarani Devi
- Christie Hospital NHS Foundation Trust, Manchester, UK
| | - Yee Pei Song
- Christie Hospital NHS Foundation Trust, Manchester, UK
| | - Peter Hoskin
- Christie Hospital NHS Foundation Trust, Manchester, UK
- University of Manchester, Manchester, UK
| | - Ananya Choudhury
- Christie Hospital NHS Foundation Trust, Manchester, UK.
- University of Manchester, Manchester, UK.
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Dason S, Lee CT. Paradigm Shifting Research: Key Studies in Urologic Oncology. Ann Surg Oncol 2024; 31:2529-2537. [PMID: 38300402 PMCID: PMC10908645 DOI: 10.1245/s10434-023-14838-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/12/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND Genitourinary malignancies have a substantial impact on men and women in the USA as they include three of the ten most common cancers (prostate, renal, and bladder). Other urinary tract cancers are less common (testis and penile) but still have profound treatment implications related to potential deficits in sexual, urinary, and reproductive function. Evidenced-based practice remains the cornerstone of treatment for urologic malignancies. METHODS The authors reviewed the literature in consideration of the four top articles influencing clinical practice in the prior calendar year, 2022. RESULTS The PROTECT trial demonstrates favorable 15-years outcomes for active monitoring of localized prostate cancer. The SEMS trial establishes retroperitoneal lymph node dissection as a viable option for patients with seminoma of the testis with limited retroperitoneal lymph node metastases. CheckMate 274 supports adjuvant immunotherapy following radical cystectomy for muscle-invasive bladder cancer with a high risk of recurrence. Data reported from the IROCK consortium reinforce stereotactic ablative radiotherapy as an option for localized renal cell carcinoma. CONCLUSION The care for patients with urologic cancers has been greatly improved through advances in surgical, medical, and radiation oncologic treatments realized through prospective randomized clinical trials and large multicenter collaborative groups.
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Affiliation(s)
- Shawn Dason
- Department of Urology, The Ohio State University, Columbus, OH, USA
| | - Cheryl T Lee
- Department of Urology, The Ohio State University, Columbus, OH, USA.
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Huang Y, Liao C, Shen Z, Zou Y, Xie W, Gan Q, Yao Y, Zheng J, Kong J. A bibliometric insight into neoadjuvant chemotherapy in bladder cancer: trends, collaborations, and future avenues. Front Immunol 2024; 15:1297542. [PMID: 38444854 PMCID: PMC10912866 DOI: 10.3389/fimmu.2024.1297542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/31/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND 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. OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Yi Huang
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Chengxiao Liao
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zefeng Shen
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yitong Zou
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Weibin Xie
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Qinghua Gan
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yuhui Yao
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - JunJiong Zheng
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jianqiu Kong
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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Cheng Z, Ye F, Liang Y, Xu C, Zhang Z, Ou Y, Chen X, Dai X, Mou Z, Li W, Chen Y, Zhou Q, Zou L, Mao S, Jiang H. Blood lipids, lipid-regulatory medications, and risk of bladder cancer: a Mendelian randomization study. Front Nutr 2023; 10:992608. [PMID: 38188874 PMCID: PMC10768687 DOI: 10.3389/fnut.2023.992608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/20/2023] [Indexed: 01/09/2024] Open
Abstract
Background The influences of blood lipids and lipid-regulatory medications on the risk of bladder cancer have long been suspected, and previous findings remain controversial. We aimed to assess the causality between blood lipids or lipid-regulatory medications and bladder cancer susceptibility by means of a comprehensive Mendelian Randomization (MR) study. Methods Genetic proxies from genome-wide association studies (GWAS) of four blood lipid traits and lipid-lowering variants in genes encoding the targets of lipid-regulatory medications were employed. The largest ever GWAS data of blood lipids and bladder cancer involving up to 440,546 and 205,771 individuals of European ancestry were extracted from UK Biobank and FinnGen Project Round 6, respectively. A two-sample bidirectional MR study was performed using the inverse variance weighted as the main method. The heterogeneity, horizontal pleiotropy, MR Steiger, and leave-one-out analyses were also conducted as sensitivity tests. Results There was indicative evidence that genetically predicted low-density lipoprotein cholesterol (LDL-C) affected bladder cancer susceptibility based on 146 single nucleotide polymorphisms (SNPs) with an odds ratio (OR) of 0.776 (95% confidence interval [CI] = 0.625-0.965, p = 0.022). However, this result became non-significant after two SNPs that possibly drove the effect were removed as demonstrated by leave-one-out analysis. The reversed MR analysis suggested that bladder cancer could not affect serum lipid levels. No causal relationship was found between the lipid-lowering effect of lipid-regulatory medications (fibrates, probucol, statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and evinacumab) and the risk of bladder cancer. No heterogeneity or pleiotropy was found (all p > 0.05). Conclusion This MR study revealed for the first time, using the most recent and comprehensive GWAS data to date, that genetically predicted total cholesterol (TC) and the lipid-lowering effect of lipid-regulatory medications had no causal association with bladder cancer susceptibility. We also verified claims from early studies that low-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride (TG) are not related to bladder cancer susceptibility either. The current study indicated that lipid metabolism may not be as important in the tumorigenesis of bladder cancer as previously believed.
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Affiliation(s)
- Zhang Cheng
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Fangdie Ye
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yingchun Liang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenyang Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zheyu Zhang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxi Ou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiyu Dai
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zezhong Mou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Weijian Li
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiling Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Quan Zhou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Lujia Zou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Shanhua Mao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
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9
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Giles M, Crabb SJ. Systemic Treatment-Decision Algorithms in Muscle-Invasive Bladder Cancer: Clinical Complexities and Navigating for Improved Outcomes. Res Rep Urol 2023; 15:321-331. [PMID: 37441525 PMCID: PMC10335269 DOI: 10.2147/rru.s386549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Muscle-invasive bladder cancer has poor prognosis. If organ confined, it is potentially curable; however, across all prognostic groups, approximately half of patients will relapse. For patients with advanced disease, the median overall survival remains under two years. Systemic treatment options are centered on the use of platinum-based combination chemotherapy, with the choice of cisplatin- or carboplatin-based regimens determined on the basis of criteria including performance status and renal function. PD-1/PD-L1 checkpoint-directed immunotherapy has been established for use in advanced disease with modest overall improvements in survival outcomes. Based on current data, optimal utilization appears to be a switch maintenance strategy on completion of chemotherapy. In the curative setting, cisplatin-based chemotherapy provides modest improvements in cure rates in those fit to receive it. Data on the use of adjuvant immunotherapy are currently contradictory, with disease-free survival demonstrated for adjuvant nivolumab, but not atezolizumab, and no overall survival benefit has yet been confirmed. The Nectin-4 directed antibody drug conjugate enfortumab vedotin is an established treatment option for patients previously treated with both chemotherapy and immunotherapy. The emerging therapeutic targets under evaluation include Trop-2 with sacituzumab govitecan, fibroblast growth factor receptors, HER2, and DNA repair deficiency in biomarker-selected patients. The development of properly validated predictive biomarkers has proven challenging for this disease and should be a central priority in the future development of treatment options. This review summarizes the available systemic treatment options in both palliative and curative disease settings, and highlights the available evidence and current limitations for making treatment recommendations.
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Affiliation(s)
- Megan Giles
- Department of Medical Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Simon J Crabb
- Department of Medical Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
- School of Cancer Sciences, University of Southampton, Southampton, UK
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10
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Nerli RB, Ghagane SC, Shadab R, Patil S, Mungarwadi A, Dixit NS. Neoadjuvant Chemotherapy Followed by Cystectomy: a Single-Center Experience. Indian J Surg Oncol 2023; 14:481-486. [PMID: 37324300 PMCID: PMC10267044 DOI: 10.1007/s13193-021-01386-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/12/2021] [Indexed: 11/28/2022] Open
Abstract
Nearly 50% of patients with muscle-invasive bladder cancer treated with cystectomy alone will progress to metastatic disease. Surgery alone is not a sufficient therapy in a large number of patients with invasive bladder cancer. Systemic therapy with cisplatin-based chemotherapy has been shown to provide response rates in several bladder cancer studies. There have been multiple randomized controlled studies undertaken to define further the effectiveness of neoadjuvant cisplatin-based chemotherapy in advance of cystectomy. In this study, we have retrospectively reviewed our series of patients who underwent neoadjuvant chemotherapy followed by radical cystectomy for muscle-invasive disease. Between Jan 2005 and Dec 2019, 72 patients underwent radical cystectomy following neoadjuvant chemotherapy over a 15-year period. The data was retrospectively collected and analyzed. The median age was 59.84 ± 8.967 years (range, 43 to 74), and the ratio of male to female patients was 5:1. Of the 72 patients, 14 (19.44%) completed all the three cycles, 52 (72.22%) completed at least two cycles, and the remaining 6 (8.33%) completed only one cycle of neoadjuvant chemotherapy. A total of 36 (50%) patients died during the follow-up period. The mean and median survival of the patients was 84.85 ± 4.25 months and 91.0 ± 5.83 months respectively. Neoadjuvant MVAC should be offered to patients with locally advanced bladder cancer and who are candidates for radical cystectomy. It is safe and effective in patients with adequate renal function. The patients need to be carefully monitored for chemotherapy-induced toxic effects, and appropriate intervention is necessary in the event of severe adverse effects.
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Affiliation(s)
- R. B. Nerli
- Department of Urology, JN Medical College, KLE Academy of Higher Education & Research (Deemed-To-Be-University), JNMC Campus, Nehru Nagar, Belagavi, 590010 India
- Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital & Medical Research Centre, Nehru Nagar, Belagavi, 590010 India
| | - Shridhar C. Ghagane
- Department of Urology, JN Medical College, KLE Academy of Higher Education & Research (Deemed-To-Be-University), JNMC Campus, Nehru Nagar, Belagavi, 590010 India
- Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital & Medical Research Centre, Nehru Nagar, Belagavi, 590010 India
| | - Rangrez Shadab
- Department of Urology, JN Medical College, KLE Academy of Higher Education & Research (Deemed-To-Be-University), JNMC Campus, Nehru Nagar, Belagavi, 590010 India
| | - Shivagouda Patil
- Department of Urology, JN Medical College, KLE Academy of Higher Education & Research (Deemed-To-Be-University), JNMC Campus, Nehru Nagar, Belagavi, 590010 India
| | - Amit Mungarwadi
- Department of Urology, JN Medical College, KLE Academy of Higher Education & Research (Deemed-To-Be-University), JNMC Campus, Nehru Nagar, Belagavi, 590010 India
| | - Neeraj S. Dixit
- Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital & Medical Research Centre, Nehru Nagar, Belagavi, 590010 India
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11
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Schlack K. [Perioperative systemic treatment of urothelial cancer]. UROLOGIE (HEIDELBERG, GERMANY) 2023; 62:407-417. [PMID: 36856789 DOI: 10.1007/s00120-023-02061-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/15/2023] [Indexed: 06/18/2023]
Abstract
In 2020 the number of cases of newly diagnosed urothelial cancer in Germany was approximately 35,000, making urothelial cancer the fifth most common form of cancer in this country in terms of incidence. If systemic recurrence occurs the risk of dying from urothelial cancer is high. For this reason, perioperative concepts that improve the overall survival around curatively intended cystectomy are becoming increasingly more important as part of multimodal concepts for urothelial cancer. In the neoadjuvant setting, platinum-based chemotherapy currently remains the gold standard and can also be used in the adjuvant setting. Recently, immunotherapy has gained in importance for adjuvant treatment. Further innovations, such as the use of immunotherapy in the neoadjuvant setting or combination therapies in both situations can be expected. This article provides insights into the current recommendations and highlights possible new concepts.
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Affiliation(s)
- Katrin Schlack
- Klinik für Urologie und Kinderurologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland.
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12
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Sridhar SS, North SA, Blais N. Predictive Biomarkers in Muscle Invasive Bladder Cancer: Are We There Yet? Eur Urol 2023; 83:318-319. [PMID: 36155158 DOI: 10.1016/j.eururo.2022.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/02/2022] [Indexed: 11/20/2022]
Affiliation(s)
| | | | - Normand Blais
- Hematology and Medical Oncology, Centre Hospitalier Universitaire de Montreal, Montreal, Quebec, Canada
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13
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Caramelo B, Zagorac S, Corral S, Marqués M, Real FX. Cancer-associated Fibroblasts in Bladder Cancer: Origin, Biology, and Therapeutic Opportunities. Eur Urol Oncol 2023:S2588-9311(23)00043-3. [PMID: 36890105 DOI: 10.1016/j.euo.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/28/2022] [Accepted: 02/08/2023] [Indexed: 03/08/2023]
Abstract
CONTEXT Bladder cancer (BLCA) is a highly prevalent tumour and a health problem worldwide, especially among men. Recent work has highlighted the relevance of the tumour microenvironment (TME) in cancer biology with translational implications. Cancer-associated fibroblasts (CAFs) are a prominent, heterogeneous population of cells in the TME. CAFs have been associated with tumour development, progression, and poor prognosis in several neoplasms. However, their role in BLCA has not yet been exploited deeply. OBJECTIVE To review the role of CAFs in BLCA biology and provide an understanding of CAF origin, subtypes, markers, and phenotypic and functional characteristics to improve patient management. EVIDENCE ACQUISITION A PubMed search was performed to review manuscripts published using the terms "cancer associated fibroblast" and "bladder cancer" or "urothelial cancer". All abstracts were reviewed, and the full content of all relevant manuscripts was analysed. In addition, selected manuscripts on CAFs in other tumours were considered. EVIDENCE SYNTHESIS CAFs have been studied less extensively in BLCA than in other tumours. Thanks to new techniques, such as single-cell RNA-seq and spatial transcriptomics, it is now possible to accurately map and molecularly define the phenotype of fibroblasts in normal bladder and BLCA. Bulk transcriptomic analyses have revealed the existence of subtypes among both non-muscle-invasive and muscle-invasive BLCA; these subtypes display distinct features regarding their CAF content. We provide a higher-resolution map of the phenotypic diversity of CAFs in these tumour subtypes. Preclinical studies and recent promising clinical trials leverage on this knowledge through the combined targeting of CAFs or their effectors and the immune microenvironment. CONCLUSIONS Current knowledge of BLCA CAFs and the TME is being increasingly applied to improve BLCA therapy. There is a need to acquire a deeper understanding of CAF biology in BLCA. PATIENT SUMMARY Tumour cells are surrounded by nontumoural cells that contribute to the determination of the behaviour of cancers. Among them are cancer-associated fibroblasts. The "neighbourhoods" established through these cellular interactions can now be studied with much greater resolution. Understanding these features of tumours will contribute to the designing of more effective therapies, especially in relationship to bladder cancer immunotherapy.
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Affiliation(s)
- Belén Caramelo
- Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain; Hospital Sierrallana, Torrelavega, Spain
| | - Sladjana Zagorac
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | - Sonia Corral
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | - Miriam Marqués
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain; CIBERONC, Madrid, Spain.
| | - Francisco X Real
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain; CIBERONC, Madrid, Spain; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
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14
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Zhang Y, Wang Z, Yang X, Zhao Q, He L. The influence of serum sodium concentration on prognosis in patients with urothelial carcinoma treated by radical cystectomy. Medicine (Baltimore) 2022; 101:e31973. [PMID: 36596074 PMCID: PMC9803414 DOI: 10.1097/md.0000000000031973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Serum sodium concentration has been found to be associated with poor survival in many solid tumors. This study investigated the effect of basal serum sodium concentration on prognostic in patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). MIBC patients with histologically proven urothelial carcinoma treated by RC were retrospectively reviewed. According to the optimal cutoff value, we divided the patients into 2 groups: high-serum sodium concentration group (≥140 mmol/L, n = 39) and low-serum sodium concentration group (<140 mmol/L, n = 32). Overall survival (OS) was estimated with the Kaplan-Meier method and the significance was examined by the log-rank test. Multivariable Cox regression for OS was performed for lymphatic metastasis, hypertension, diabetes mellitus, and tumor size. A total of 71 MIBC patients (60 males and 11 females) were included who underwent cystectomy between 2014 and 2018. The patients' ages at the time of operation ranged from 44 to 86 years (mean, 66.66 years). Patients' serum sodium concentration <140 mmol/L had shorter median OS (1224 days (HR: 2.454 [95% CI, 1.083-5.561; P = .031]). In multivariate analysis, lower serum sodium concentration was significantly associated with worse OS after adjusted (adjusted HR: 2.422 [95% CI, 1.055-5.561; P = .037]). Serum sodium concentration <140 mmol/L was independently associated with a poorer prognosis in patients with MIBC used who underwent RC.
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Affiliation(s)
- Yan Zhang
- College of Life Sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, China
| | - Zuojun Wang
- Pharmacy Department, General Hospital of Northern Theater Command, Shenyang, China
| | - Xue Yang
- College of Life Sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, China
| | - Qingchun Zhao
- Pharmacy Department, General Hospital of Northern Theater Command, Shenyang, China
| | - Long He
- Organ Transplantation Center, General Hospital of Northern Theater Command, Shenyang, China
- *Correspondence: Long He, Organ Transplantation Center, General Hospital of Northern Theater Command, No.5, Guangrong Street, Heping District, Shenyang City, Liaoning Province, 110003, P.R. China (e-mail: )
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15
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Ernandez J, Kaul S, Fleishman A, Korets R, Chang P, Wagner A, Kim S, Bellmunt J, Kaplan I, Olumi AF, Gershman B. Adjuvant Chemotherapy Plus Radiotherapy versus Chemotherapy Alone for Locally Advanced Bladder Cancer after Radical Cystectomy. Bladder Cancer 2022; 8:405-417. [PMID: 38994178 PMCID: PMC11181795 DOI: 10.3233/blc-220031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 08/09/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Survival with locally advanced bladder cancer (LABC) following radical cystectomy (RC) remains poor. Although adjuvant chemotherapy (AC) is standard of care, one small, randomized trial has suggested a potential survival benefit when combined with post-operative radiotherapy (PORT). OBJECTIVE We examined the association of AC + PORT with overall survival (OS) in patients with LABC after RC. METHODS Using a prior phase 2 trial to inform design, we conducted observational analyses to emulate a hypothetical target trial of patients aged 18-79 years with pT3-4 Nany M0 or pTany N1-3 M0 urothelial bladder carcinoma following RC who were treated with AC (multiagent chemotherapy within 3 months of RC) with or without PORT (≥45 Gy to the pelvis) from 2006-2015 in the NCDB. Patients who received preoperative chemotherapy or radiotherapy were excluded. The associations of treatment with OS were evaluated using multivariable Cox regression. RESULTS 1,684 patients were included, with 66 receiving AC + PORT and 1,618 AC alone. Compared to patients treated with AC alone, those treated with AC + PORT were more likely to have pT4 disease (52% vs 26%; p < 0.01), positive surgical margins (44% vs 17%; p < 0.01), and be treated at a non-academic facility (75% vs 53%; p < 0.01). Crude 5-year OS was 19% for AC + PORT versus 36% for AC alone (p = 0.01). Adjusted 5-year OS was 33% for AC + PORT versus 36% for AC alone (p = 0.49). After adjusting for baseline characteristics including pathologic features, AC + PORT was not associated with improved OS compared to AC alone (HR 1.11; 95% CI 0.82-1.51). CONCLUSIONS Although infrequently utilized, the addition of radiotherapy to AC is not associated with improved OS in LABC. These results highlight the need for prospective trials to better define the potential benefits from PORT with regard to symptomatic progression and oncologic outcomes.
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Affiliation(s)
| | - Sumedh Kaul
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Aaron Fleishman
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Ruslan Korets
- Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Peter Chang
- Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Andrew Wagner
- Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Simon Kim
- Division of Urology, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Joaquim Bellmunt
- Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Irving Kaplan
- Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Aria F Olumi
- Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Boris Gershman
- Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
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16
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Guo Y, Dong J, Ji T, Li X, Rong S, Guan H. A risk score for the prognosis prediction of the muscle-invasive bladder cancer patients who received gemcitabine plus cisplatin chemotherapy. Aging (Albany NY) 2022; 14:9715-9729. [PMID: 36470668 PMCID: PMC9792215 DOI: 10.18632/aging.204424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022]
Abstract
To develop an individualized gene-based risk score to predict the prognosis of muscle-invasive bladder cancer (MIBC) patients who received GC regimens. We downloaded transcriptome profiling data and clinical information from the Cancer Genome Atlas (TCGA) database. We identified 1854 survival-associated genes and then constructed the risk score based on six special genes selected from the survival-associated genes. We divided patients into high-risk and low-risk groups according to the median risk score. High-risk patients have significantly poorer overall survival than low-risk patients (log-rank test chi-square = 38.08, p = 7e-10, C-index = 0.785, se = 0.032). The risk score was evaluated by Kaplan-Meier survival curve, time-dependent ROC curves, and C-index. Multivariate Cox regression and nomogram suggested that the risk score was an independent prognostic indicator. Gene set enrichment analysis indicated that the survival-associated genes were significantly enriched in immune-related terms. Among six special genes, CHPF2, TRAV26-2, and BTF3P12 were found to be immune-related genes. In conclusion, our risk score provided an indicator to predict the prognosis of MIBC patients who received GC regimens and potential immunotherapeutic targets for MIBC.
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Affiliation(s)
- Yupeng Guo
- Department of Epidemiology and Statistics, School of Public Health of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province 157011, China
| | - Jing Dong
- Department of Epidemiology and Statistics, School of Public Health of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province 157011, China
| | - Tao Ji
- Department of Epidemiology and Statistics, School of Public Health of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province 157011, China
| | - Xiaoxia Li
- Department of Epidemiology and Statistics, School of Public Health of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province 157011, China
| | - Shengzhong Rong
- Department of Epidemiology and Statistics, School of Public Health of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province 157011, China
| | - Hongjun Guan
- Department of Epidemiology and Statistics, School of Public Health of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province 157011, China
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17
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Struck JP, Hupe MC, Heinisch A, Ozimek T, Hennig MJP, Klee M, von Klot C, Kalogirou C, Kuczyk MA, Merseburger AS, Kramer MW. RLC score (R status, lymphovascular invasion, C-reactive protein) predicts survival following radical cystectomy for muscle-invasive bladder cancer. Aktuelle Urol 2022; 53:545-551. [PMID: 33445183 DOI: 10.1055/a-1310-3583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND CRP-based scoring systems were found to correlate with survival in patients with urooncologic diseases. Our retrospective single-centre study aimed to confirm CRP as a prognostic parameter in patients with bladder cancer (BCa) undergoing radical cystectomy (RC) and, based on the findings, to develop our own outcome score for muscle-invasive bladder cancer (MIBC) patients undergoing RC in order to identify patients with a high risk of mortality. MATERIAL AND METHODS A total of 254 patients who underwent RC at Hanover Medical School between 1996 and 2007 were reviewed with a follow-up until autumn 2013. The clinicopathologic parameters assessed included age, co-morbidities, pre-/postoperative serum levels of CRP, leukocytes, haemoglobin, creatinine, urinary diversion, tumour grading, staging, lymph node status, lymph node density (LND), lymphovascular invasion (LVI), metastases, and resection margin status. The Chi-square test was used for univariate analyses. Kaplan-Meier estimates and the log-rank test were used for survival analyses. Regarding outcome, overall survival (OS) was assessed. RESULTS The multivariate analysis excluding lymph node (LN)-positive and metastatic patients at time of RC showed a significant association of R status (R; p < 0.001), LVI (L; p = 0.021) and preoperative CRP level > 5 mg/l (C; p = 0.008) with OS. Based on these parameters, the RLC score was developed. The median OS in the intermediate, high-risk and very high-risk groups according to the RLC score was 62, 22, and 6.5 months, respectively. The score had a high predictive accuracy of 0.752. CONCLUSION The RLC score identifies BCa patients at a higher risk of overall mortality after RC. Overall, our study supports the role of CRP in prognostic score models for BCa.
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Affiliation(s)
- Julian Peter Struck
- Department of Urology, University-Hospital Schleswig-Holstein, Campus Luebeck, Luebeck
| | - Marie Christine Hupe
- Department of Urology, University-Hospital Schleswig-Holstein, Campus Luebeck, Luebeck
| | - Annika Heinisch
- Department of Urology and Urologic Oncology, Medical School Hannover, Hannover.,Clinic for Obsterics and Gynecology, Muehlenkreiskliniken, Johannes Wesling Klinikum Minden, Minden
| | - Tomasz Ozimek
- Department of Urology, University-Hospital Schleswig-Holstein, Campus Luebeck, Luebeck
| | | | - Melanie Klee
- Department of Urology, University-Hospital Schleswig-Holstein, Campus Luebeck, Luebeck
| | - Christoph von Klot
- Department of Urology and Urologic Oncology, Medical School Hannover, Hannover
| | - Charis Kalogirou
- Department of Urology and Pediatric Urology, Julius-Maximilians-University of Wuerzburg, Wuerzburg
| | - Markus A Kuczyk
- Department of Urology and Urologic Oncology, Medical School Hannover, Hannover
| | - Axel S Merseburger
- Department of Urology, University-Hospital Schleswig-Holstein, Campus Luebeck, Luebeck
| | - Mario W Kramer
- Department of Urology, University-Hospital Schleswig-Holstein, Campus Luebeck, Luebeck
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18
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Marcq G, Afferi L, Neuzillet Y, Nykopp T, Voskuilen CS, Furrer MA, Kassouf W, Aziz A, Bajeot AS, Alvarez-Maestro M, Black P, Roupret M, Noon AP, Seiler R, Hendricksen K, Roumiguie M, Pang KH, Laine-Caroff P, Xylinas E, Ploussard G, Moschini M, Sargos P. Oncological Outcomes for Patients Harboring Positive Surgical Margins Following Radical Cystectomy for Muscle-Invasive Bladder Cancer: A Retrospective Multicentric Study on Behalf of the YAU Urothelial Group. Cancers (Basel) 2022; 14:cancers14235740. [PMID: 36497222 PMCID: PMC9739538 DOI: 10.3390/cancers14235740] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction: Adjuvant therapy has no defined role for patients with positive surgical margins (PSMs) following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). The aim of our study was to describe loco-regional recurrence-free survival (LRFS), metastatic-free survival (MFS), recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) and identify predictors of each endpoint in patients with PSMs following RC for MIBC. Methods: A collaborative retrospective cohort study was conducted on 394 patients with PSMs who underwent RC for MIBC between January 2000 and December 2018 at 10 tertiary referral centers. Patients receiving perioperative radiotherapy were excluded from the study. Kaplan−Meier curves were used to estimate patient survival. Cox regression analysis was used to identify predictors of survival. Results: Median age at surgery was 70 years (IQR 62−76) with 129 (33%) and 204 (52%) patients had pT3 and pT4 tumors, respectively. Nodal metastasis (pN+) was identified in 148 (38%). Soft tissue PSMs were found in 283 (72%) patients, urethral PSMs in 65 (16.5%), and ureteral PSMs were found in 73 (18.5%). The median follow-up time was 44 months (95% CI 32−60). Median LRFS, MRFS, RFS, CSS, and OS were 14 (95% CI 11−17), 12 (95% CI 10−16), 10 (95% CI 8−12), 23 (95% CI 18−33), and 16 months (95% CI 12−19), respectively. On multivariable Cox regression analysis, the pT3−4 stage, pN+ stage, and multifocal PSMs were independent predictors of LRFS, MRFS, RFS, and OS. Adjuvant chemotherapy improved all oncological outcomes studied (p < 0.05). The number of lymph nodes removed was independently associated with better LRFS, MRFS, and RFS. Advanced age at diagnosis was independently associated with worse OS. Conclusion: Patients with PSMs following RC have poor outcomes since half of them will recur within a year and will die of their disease. Among all PSMs types, patients with multifocal PSMs harbor the worst prognosis. We observed a benefit of adjuvant chemotherapy, but clinical trials evaluating innovative adjuvant strategies for these patients remain an unmet need.
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Affiliation(s)
- Gautier Marcq
- Division of Urology, McGill University Health Centre, McGill University, 1001 Decarie Blvd, D02.7210, Montreal, QC H4A 3J1, Canada
- Urology Department, Claude Huriez Hospital, CHU Lille, F-59000 Lille, France
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, F-59000 Lille, France
| | - Luca Afferi
- Department of Urology, Luzerner Kantonsspital, 6000 Luzern, Switzerland
| | - Yann Neuzillet
- Department of Urology, Foch Hospital, Paris-Saclay—UVSQ University, 92150 Suresnes, France
| | - Timo Nykopp
- Department of Surgery, Kuopio University Hospital and University of Eastern Finland, PL 100, 70029 Kuopio, Finland
| | - Charlotte S. Voskuilen
- The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Department of Urology, 1066 CX Amsterdam, The Netherlands
| | - Marc A. Furrer
- Department of Urology, University Hospital of Bern, University of Bern, 3012 Bern, Switzerland
- Department of Urology, The Royal Melbourne Hospital, Parkville 3050, Australia
- Department of Urology, The Guy's Hospital, London SE1 9RT, UK
| | - Wassim Kassouf
- Division of Urology, McGill University Health Centre, McGill University, 1001 Decarie Blvd, D02.7210, Montreal, QC H4A 3J1, Canada
| | - Atiqullah Aziz
- Department of Urology, München Klinik Bogenhausen, 81925 Munich, Germany
| | | | | | - Peter Black
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
| | - Morgan Roupret
- Sorbonne University, GRC 5 Predictive Onco-Uro, AP-HP, Urology, Pitie-Salpetriere Hospital, F-75013 Paris, France
| | - Aidan P. Noon
- The Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK
| | - Roland Seiler
- Department of BioMedical Research, University of Bern, 3012 Bern, Switzerland
| | - Kees Hendricksen
- The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Department of Urology, 1066 CX Amsterdam, The Netherlands
| | | | - Karl H. Pang
- Department of Oncology and Metabolism, Academic Urology Unit, University of Sheffield, Sheffield S10 2TN, UK
| | - Paul Laine-Caroff
- Department of Urology, Bichat-Claude Bernard Hospital, Assistance Publique-Hopitaux de Paris, Paris University, 75018 Paris, France
| | - Evanguelos Xylinas
- Department of Urology, Bichat-Claude Bernard Hospital, Assistance Publique-Hopitaux de Paris, Paris University, 75018 Paris, France
| | - Guillaume Ploussard
- Department of Urology, La Croix du Sud Hospital, 31130 Quint Fonsegrives, France
| | - Marco Moschini
- Department of Urology and Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Paul Sargos
- Department of Radiotherapy, Institut Bergonie, 33076 Bordeaux, France
- Correspondence:
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19
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Bharadwaj M, Kaul S, Fleishman A, Korets R, Chang P, Wagner A, Kim S, Bellmunt J, Kaplan I, Olumi AF, Gershman B. Adjuvant chemotherapy versus observation following radical cystectomy for locally advanced urothelial carcinoma of the bladder. Urol Oncol 2022; 40:274.e15-274.e23. [DOI: 10.1016/j.urolonc.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/12/2022] [Accepted: 02/04/2022] [Indexed: 10/18/2022]
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Abstract
Muscle invasive bladder cancer (MIBC) carries a poor prognosis with a 5-year overall survival rate of 40-50%. For localized disease, radical treatment options are cystectomy or radiotherapy with or without a radiosensitiser. Neoadjuvant or adjuvant chemotherapy is often delivered in addition to either. Metastatic disease can be treated with palliative systemic chemotherapy or immunotherapy. Standard clinicopathological information is insufficient to guide treatment decisions in several clinical scenarios in MIBC and there has been substantial effort to identify predictive and prognostic biomarkers. Despite this, no biomarker has been sufficiently qualified in prospective clinical trials to justify routine use. In this chapter we discuss these biomarkers and provide insight into the significant unmet need for robust biomarkers to inform treatment decisions and ultimately improve outcomes for bladder cancer patients.
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Affiliation(s)
- Fiona Wilson
- The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Nuradh Joseph
- Ministry of Health, Colombo, Sri Lanka; Sri Lanka Cancer Research Group, Colombo, Sri Lanka
| | - Ananya Choudhury
- The Christie NHS Foundation Trust, Manchester, United Kingdom; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
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21
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Bhattacharjee S, Sullivan MJ, Wynn RR, Demagall A, Hendrix AS, Sindhwani P, Petros FG, Nadiminty N. PARP inhibitors chemopotentiate and synergize with cisplatin to inhibit bladder cancer cell survival and tumor growth. BMC Cancer 2022; 22:312. [PMID: 35321693 PMCID: PMC8944004 DOI: 10.1186/s12885-022-09376-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Background Management of bladder cancer (BLCA) has not changed significantly in the past few decades, with platinum agent chemotherapy being used in most cases. Chemotherapy reduces tumor recurrence after resection, but debilitating toxicities render a large percentage of patients ineligible. Recently approved immunotherapy can improve outcomes in only a third of metastatic BLCA patients. Therefore, more options for therapy are needed. In this study, we explored the efficacy of PARP inhibitors (PARPi) as single agents or as combinations with platinum therapy. Methods We treated BLCA cells with PARPi (olaparib, niraparib, rucaparib, veliparib, or talazoparib) alone or as the combination of cisplatin with PARPi. We then measured their survival, proliferation, apoptosis, as well as their ability to form colonies. BLCA xenografts in male SCID mice were treated similarly, followed by the assessment of their growth, proliferation, and apoptosis. Results PARPi niraparib and talazoparib were effective in reducing BLCA cell survival as single agents. Combinations of Cisplatin with talazoparib and niraparib effectively reduced the survival of BLCA cells, while veliparib was not effective even at high concentrations. In vivo, the combinations of cisplatin with niraparib, rucaparib, or talazoparib reduced BLCA xenograft growth significantly. Conclusions We provide evidence that PARPi can be effective against BLCA as single agents or as combinatorial therapy with cisplatin. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09376-9.
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Affiliation(s)
- Sayani Bhattacharjee
- Department of Urology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA.,Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA
| | - Matthew J Sullivan
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA
| | - Rebecca R Wynn
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA.,Graduate Program in Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA
| | - Alex Demagall
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA.,Graduate Program in Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA
| | - Andrew S Hendrix
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA
| | - Puneet Sindhwani
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA.,Graduate Program in Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA
| | - Firas G Petros
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA.,Graduate Program in Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA
| | - Nagalakshmi Nadiminty
- Department of Urology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA. .,Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA. .,Graduate Program in Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA. .,College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA.
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22
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Giudici N, Bonne F, Blarer J, Minoli M, Krentel F, Seiler R. Characteristics of upper urinary tract urothelial carcinoma in the context of bladder cancer: a narrative review. Transl Androl Urol 2021; 10:4036-4050. [PMID: 34804846 PMCID: PMC8575564 DOI: 10.21037/tau-20-1472] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/08/2021] [Indexed: 11/20/2022] Open
Abstract
Urothelial carcinomas (UC) arise from the urothelium that covers the proximal urethra, urinary bladder, and the upper urinary tract. In daily routine and clinical trials UC originating from different locations are often treated and investigated in the same manner. However, differences between the two locations seem to be apparent and may question in handling them as a single oncologic entity. In this review we discuss similarities and differences between bladder and upper urinary tract UC and consider their potential impact on treatment strategies. Despite similarities of UC in the bladder (BC) and the upper urinary tract (UTUC), clinicopathologic and molecular differences may question to generally assemble both as a single tumor entity. Treatment standards for UTUC are often adopted from BC. However, a specific investigation in the former may still be meaningful as shown by the example of adjuvant cisplatin based chemotherapy. In conclusion, future investigations should prioritize the understanding of the tumor biology of both BC and UTUC. This may reveal which UTUC can be treated according to treatment standards of BC and in which cases, a separate approach may be more appropriate.
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Affiliation(s)
- Nicola Giudici
- Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Fieke Bonne
- Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Jennifer Blarer
- Department of Urology, Hospital Center Biel/Bienne, Biel/Bienne, Switzerland
| | - Martina Minoli
- Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Friedemann Krentel
- Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Roland Seiler
- Department of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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23
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Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis of Individual Participant Data from Randomised Controlled Trials. Eur Urol 2021; 81:50-61. [PMID: 34802798 PMCID: PMC8708165 DOI: 10.1016/j.eururo.2021.09.028] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022]
Abstract
Context Our prior systematic review and meta-analysis of individual participant data (IPD) suggesting a benefit of adjuvant chemotherapy for muscle-invasive bladder cancer was limited by the number and size of included randomised trials. We have updated results to include additional trials, providing the most up-to-date and reliable evidence of the effects of this treatment. Objective To investigate the role of adjuvant cisplatin-based chemotherapy in the treatment of muscle-invasive bladder cancer. Evidence acquisition Published and unpublished trials were sought via searches of bibliographic databases, trials registers, conference proceedings, and hand searching. Updated IPD were centrally collected, checked, and analysed. Results from individual randomised controlled trials (RCTs) were combined using a two-stage fixed-effect model. Prespecified analyses explored any variation in effect by trial and participant characteristics. Evidence synthesis Analyses of ten RCTs (1183 participants) demonstrated a benefit of cisplatin-based adjuvant chemotherapy on overall survival (hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70–0.96, p = 0.02). This represents an absolute improvement in survival of 6% at 5 yr, from 50% to 56%, and a 9% absolute benefit when adjusted for age, sex, pT stage, and pN category (HR = 0.77, 95% CI = 0.65–0.92, p = 0.004). There was no clear evidence that the effect varied by trial or participant characteristics. Adjuvant chemotherapy was also shown to improve recurrence-free survival (HR = 0.71, 95% CI = 0.60–0.83, p < 0.001), locoregional recurrence-free survival (HR = 0.68, 95% CI = 0.55–0.85, p < 0.001), and metastasis-free survival (HR = 0.79, 95% CI = 0.65–0.95, p = 0.01), with absolute benefits of 11%, 11%, and 8%, respectively. Conclusions This systematic review and meta-analysis demonstrates that cisplatin-based adjuvant chemotherapy is a valid option for improving outcomes for muscle-invasive bladder cancer. Patient summary We looked at the effect of cisplatin-based chemotherapy on outcomes in participants with muscle-invasive bladder cancer. We gathered this information from eligible randomised controlled trials. We demonstrated that cisplatin-based chemotherapy is a valid option for improving outcomes of muscle-invasive bladder cancer.
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24
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Chatterjee A, Bakshi G, Pal M, Kapoor A, Joshi A, Prakash G. Perioperative therapy in muscle invasive bladder cancer. Indian J Urol 2021; 37:226-233. [PMID: 34465951 PMCID: PMC8388335 DOI: 10.4103/iju.iju_540_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 05/17/2021] [Accepted: 06/18/2021] [Indexed: 12/24/2022] Open
Abstract
Radical cystectomy with bilateral pelvic lymph node dissection is the standard of care for muscle invasive bladder cancer (MIBC). The role of neoadjuvant and adjuvant therapy has evolved over the last 3–4 decades, and neoadjuvant chemotherapy (NACT) has now become the standard recommended treatment. However, there are many nuances to this and the utilization of chemotherapy has not been universal. The optimum chemotherapy regimen is still debated. Adjuvant radiation has a role in high-risk patients although not established and immunotherapy has shown promising results. We reviewed the evidence on NACT and adjuvant chemotherapy (ACT) regimens, NACT versus ACT, and the role of adjuvant radiotherapy and immunotherapy in MIBC.
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Affiliation(s)
- Ambarish Chatterjee
- Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Ganesh Bakshi
- Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Mahendra Pal
- Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Akhil Kapoor
- Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Amit Joshi
- Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Gagan Prakash
- Department of Uro-Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
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25
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GRIK2 is a target for bladder cancer stem-like cell-targeting immunotherapy. Cancer Immunol Immunother 2021; 71:795-806. [PMID: 34405274 DOI: 10.1007/s00262-021-03025-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 07/29/2021] [Indexed: 10/20/2022]
Abstract
Recent studies have revealed that treatment-resistant cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be targeted by cytotoxic T lymphocytes (CTLs). CTLs recognize antigenic peptides derived from tumor-associated antigens; thus, the identification of tumor-associated antigens expressed by CSCs/CICs is essential. Human leucocyte antigen (HLA) ligandome analysis using mass spectrometry enables the analysis of naturally expressed antigenic peptides; however, HLA ligandome analysis requires a large number of cells and is challenging for CSCs/CICs. In this study, we established a novel bladder CSC/CIC model from a bladder cancer cell line (UM-UC-3 cells) using an ALDEFLUOR assay. CSCs/CICs were isolated as aldehyde dehydrogenase (ALDH)-high cells and several ALDHhigh clone cells were established. ALDHhigh clone cells were enriched with CSCs/CICs by sphere formation and tumorigenicity in immunodeficient mice. HLA ligandome analysis and cap analysis of gene expression using ALDHhigh clone cells revealed a distinctive antigenic peptide repertoire in bladder CSCs/CICs, and we found that a glutamate receptor, ionotropic, kainite 2 (GRIK2)-derived antigenic peptide (LMYDAVHVV) was specifically expressed by CSCs/CICs. A GRIK2 peptide-specific CTL clone recognized GRIK2-overexpressing UM-UC-3 cells and ALDHhigh clone cells, indicating that GRIK2 peptide can be a novel target for bladder CSC/CIC-targeting immunotherapy.
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26
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Extranodal Extension Predicts Poor Survival Outcomes among Patients with Bladder Cancer. Cancers (Basel) 2021; 13:cancers13164108. [PMID: 34439261 PMCID: PMC8391350 DOI: 10.3390/cancers13164108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Several lymph node-related prognosticators were reported in bladder cancer patients with lymph node involvement and receiving radical cystectomy. However, extranodal extension (ENE) remained a debate to predict outcomes. METHODS A retrospective analysis of 1303 bladder cancer patients receiving radical cystectomy and bilateral pelvic lymph node dissection were identified in the National Taiwan Cancer Registry database from 2011 to 2017. Based on the 304 patients with lymph node involvement, the presence of ENE and major clinical information were recorded and calculated. The overall survival (OS) and cancer-specific survival (CSS) were estimated with Kaplan-Meier analysis and compared using the log-rank test. Hazard ratios (HR) and the associated 95% confidence intervals were calculated in the univariate and stepwise multivariable models. RESULTS In the multivariable analysis, ENE significantly reduced OS (HR = 1.74, 95% CI 1.09-2.78) and CSS (HR = 1.69, 95% CI 1.01-2.83) more than non-ENE. In contrast, adjuvant chemotherapy was significantly associated with better OS and CSS upon the identification of pathological nodal disease. CONCLUSIONS Reduced OS and CSS outcomes were observed in the pathological nodal bladder cancer patients with ENE compared with those without ENE. After the identification of pathological nodal disease, adjuvant chemotherapy was associated with better survival outcomes.
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27
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Patel A, Bisno DI, Patel HV, Ghodoussipour S, Saraiya B, Mayer T, Singer EA. Immune Checkpoint Inhibitors in the Management of Urothelial Carcinoma. JOURNAL OF CANCER IMMUNOLOGY 2021; 3:115-136. [PMID: 34263255 PMCID: PMC8276975 DOI: 10.33696/cancerimmunol.3.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Urothelial carcinoma is one of the most common cancers in the United States, yet outcomes are historically suboptimal. Since 2016, the approval of five programmed cell death 1 and programmed death-ligand 1 immune checkpoint inhibitors for locally advanced and metastatic urothelial carcinoma has led to improved oncologic outcomes for many patients in the second-line setting. Two checkpoint inhibitors, pembrolizumab and atezolizumab subsequently earned approval for first-fine therapy with restricted indications. More recently, pembrolizumab was approved for bacillus Calmette-Guérin-unresponsive high-risk non-muscle invasive bladder cancer, opening the door for other immune checkpoint inhibitors to be integrated into treatment in earlier disease stages. Recent bacillus Calmette-Guérin shortages have highlighted the need for alternative treatment options for patients with non-muscle invasive bladder cancer. Currently, there are no FDA-approved checkpoint inhibitors for non-metastatic muscle-invasive bladder cancer. Furthermore, many patients are ineligible for standard cisplatin-based chemotherapy regimens. Numerous ongoing clinical trials are employing immune checkpoint inhibitors for muscle-invasive bladder cancer patients in the neoadjuvant, adjuvant, perioperative, and bladder-sparing setting. Although up to 10% of urothelial carcinoma tumors arise in the upper urinary tract, few studies are designed for this population. We highlight the need for more trials designed for patients with upper tract disease. Overall, there are numerous clinical trials investigating the safety and efficacy of immune checkpoint inhibitors in all stages of disease as single-agents and combined with dual-immune checkpoint inhibition, chemotherapy, radiotherapy, and other pharmacologic agents. As the field continues to evolve rapidly, we aim to provide an overview of recent and ongoing immunotherapy clinical trials in urothelial carcinoma.
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Affiliation(s)
- Aakash Patel
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Daniel I Bisno
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Hiren V Patel
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Saum Ghodoussipour
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Biren Saraiya
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Tina Mayer
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Eric A Singer
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.,Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
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28
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Janev A, Ramuta TŽ, Tratnjek L, Sardoč Ž, Obradović H, Mojsilović S, Taskovska M, Smrkolj T, Kreft ME. Detrimental Effect of Various Preparations of the Human Amniotic Membrane Homogenate on the 2D and 3D Bladder Cancer In vitro Models. Front Bioeng Biotechnol 2021; 9:690358. [PMID: 34249888 PMCID: PMC8267883 DOI: 10.3389/fbioe.2021.690358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022] Open
Abstract
Despite being among the ten most common cancers with high recurrence rates worldwide, there have been no major breakthroughs in the standard treatment options for bladder cancer in recent years. The use of a human amniotic membrane (hAM) to treat cancer is one of the promising ideas that have emerged in recent years. This study aimed to investigate the anticancer activity of hAM homogenate on 2D and 3D cancer models. We evaluated the effects of hAM homogenates on the human muscle invasive bladder cancer urothelial (T24) cells, papillary cancer urothelial (RT4) cells and normal porcine urothelial (NPU) cells as well as on human mammary gland non-tumorigenic (MCF10a) cells and low-metastatic breast cancer (MCF7) cells. After 24 h, we observed a gradual detachment of cancerous cells from the culture surface, while the hAM homogenate did not affect the normal cells. The most pronounced effect hAM homogenate had on bladder cancer cells; however, the potency of their detachment was dependent on the treatment protocol and the preparation of hAM homogenate. We demonstrated that hAM homogenate significantly decreased the adhesion, growth, and proliferation of human bladder invasive and papillary cancer urothelial cells and did not affect normal urothelial cells even in 7-day treatment. By using light and electron microscopy we showed that hAM homogenate disrupted the architecture of 2D and 3D bladder cancer models. The information provided by our study highlights the detrimental effect of hAM homogenate on bladder cancer cells and strengthens the idea of the potential clinical application of hAM for bladder cancer treatment.
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Affiliation(s)
- Aleksandar Janev
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Taja Železnik Ramuta
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Larisa Tratnjek
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Žiga Sardoč
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Hristina Obradović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Slavko Mojsilović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Milena Taskovska
- Department of Urology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Chair of Surgery, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tomaž Smrkolj
- Department of Urology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Chair of Surgery, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Mateja Erdani Kreft
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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29
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Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2021; 384:2102-2114. [PMID: 34077643 PMCID: PMC8215888 DOI: 10.1056/nejmoa2034442] [Citation(s) in RCA: 594] [Impact Index Per Article: 148.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
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Affiliation(s)
- Dean F Bajorin
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - J Alfred Witjes
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Jürgen E Gschwend
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Michael Schenker
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Begoña P Valderrama
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Yoshihiko Tomita
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Aristotelis Bamias
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Thierry Lebret
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Shahrokh F Shariat
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Se Hoon Park
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Dingwei Ye
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Mads Agerbaek
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Deborah Enting
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Ray McDermott
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Pablo Gajate
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Avivit Peer
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Matthew I Milowsky
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Alexander Nosov
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - João Neif Antonio
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Krzysztof Tupikowski
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Laurence Toms
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Bruce S Fischer
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Anila Qureshi
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Sandra Collette
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Keziban Unsal-Kacmaz
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Edward Broughton
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Dimitrios Zardavas
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Henry B Koon
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
| | - Matthew D Galsky
- From the Memorial Sloan Kettering Cancer Center (D.F.B), Weill Cornell Medical College (S.F.S.), and Icahn School of Medicine at Mount Sinai (M.D.G.) - all in New York; Radboud University, Nijmegen, the Netherlands (J.A.W.); the Department of Urology, Technical University Munich, Munich, Germany (J.E.G.); Nectarie Oncology Center, Craiova, Romania (M.S.); Hospital Universitario Virgen del Rocío, Seville (B.P.V.), and Ramon y Cajal University Hospital, Madrid (P.G.) - both in Spain; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Y.T.); National and Kapodistrian University of Athens, Athens (A.B.); the Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France (T.L.); Medical University of Vienna, Vienna General Hospital, Vienna (S.F.S.); University of Texas Southwestern Medical Center, Dallas (S.F.S.); Charles University, Prague, Czech Republic (S.F.S.); the Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow (S.F.S.), and Federal State Budget Institution N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg (A.N.) - both in Russia; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea (S.H.P.); Fudan University Shanghai Cancer Center, Shanghai, China (D.Y.); Aarhus University Hospital, Aarhus, Denmark (M.A.); Guy's and St. Thomas' NHS Foundation Trust, London (D.E.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.); Rambam Health Care Campus, Haifa, Israel (A.P.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (M.I.M.); Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil (J.N.A.); the Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland (K.T.); and Bristol Myers Squibb, Princeton, NJ (L.T., B.S.F., A.Q., S.C., K.U.-K., E.B., D.Z., H.B.K.)
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Solanki AA, Venkatesulu BP, Efstathiou JA. Will the Use of Biomarkers Improve Bladder Cancer Radiotherapy Delivery? Clin Oncol (R Coll Radiol) 2021; 33:e264-e273. [PMID: 33867226 DOI: 10.1016/j.clon.2021.03.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 03/19/2021] [Indexed: 12/19/2022]
Abstract
Advances in the field of cancer biology and molecular techniques have led to a better understanding of the molecular underpinnings driving cancer development and outcomes. Simultaneously, advances in imaging have allowed for improved sensitivity in initial staging, radiotherapy planning and follow-up of numerous cancers. These two phenomena have led to the development of biomarkers that can guide therapy in multiple malignancies. In bladder cancer, there is extensive ongoing research into the identification of biomarkers that can help tailor personalised approaches for treatment based on the intrinsic tumour biology. However, the delivery of bladder cancer radiotherapy as part of trimodality therapy currently has a paucity of biomarkers to guide treatment. Here we summarise the existing literature and ongoing investigations into potential predictive and prognostic molecular and imaging biomarkers that may one day guide selection for utilisation of radiotherapy as part of trimodality therapy, guide selection of the radiosensitising agent, guide radiation dose and target, and guide surveillance for recurrence after trimodality therapy.
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Affiliation(s)
- A A Solanki
- Department of Radiation Oncology, Stritch School of Medicine Loyola University Chicago, Loyola University Medical Center, Maywood, Illinois, USA.
| | - B P Venkatesulu
- Department of Radiation Oncology, Stritch School of Medicine Loyola University Chicago, Loyola University Medical Center, Maywood, Illinois, USA
| | - J A Efstathiou
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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31
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Dong Y, Hao L, Fang K, Han XX, Yu H, Zhang JJ, Cai LJ, Fan T, Zhang WD, Pang K, Ma WM, Wang XT, Han CH. A network pharmacology perspective for deciphering potential mechanisms of action of Solanum nigrum L. in bladder cancer. BMC Complement Med Ther 2021; 21:45. [PMID: 33494738 PMCID: PMC7836472 DOI: 10.1186/s12906-021-03215-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Solanum nigrum L. decoction has been used as a folklore medicine in China to prevent the postoperative recurrence of bladder cancer (BC). However, there are no previous pharmacological studies on the protective mechanisms of this activity of the plant. Thus, this study aimed to perform a systematic analysis and to predict the potential action mechanisms underlying S. nigrum activity in BC based on network pharmacology. METHODS Based on network pharmacology, the active ingredients of S. nigrum and the corresponding targets were identified using the Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform database, and BC-related genes were screened using GeneCards and the Online Mendelian Inheritance in Man database. In addition, ingredient-target (I-T) and protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, and then the pathways directly related to BC were integrated manually to reveal the pharmacological mechanism underlying S. nigrum-medicated therapeutic effects in BC. RESULTS Seven active herbal ingredients from 39 components of S. nigrum were identified, which shared 77 common target genes related to BC. I-T network analysis revealed that quercetin was associated with all targets and that NCOA2 was targeted by four ingredients. Besides, interleukin 6 had the highest degree value in the PPI network, indicating a hub role. A subsequent gene enrichment analysis yielded 86 significant GO terms and 89 significant pathways, implying that S. nigrum had therapeutic benefits in BC through multi-pathway effects, including the HIF-1, TNF, P53, MAPK, PI3K/Akt, apoptosis and bladder cancer pathway. CONCLUSIONS S. nigrum may mediate pharmacological effects in BC through multi-target and various signaling pathways. Further validation is required experimentally. Network pharmacology approach provides a predicative novel strategy to reveal the holistic mechanism of action of herbs.
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Affiliation(s)
- Yang Dong
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China.,Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China
| | - Lin Hao
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China.,Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China
| | - Kun Fang
- Xuzhou Clinical Medical College of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Traditional Chinese Medicine, Xuzhou, China
| | - Xiao-Xiao Han
- Center of Reproductive Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hui Yu
- Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Jian-Jun Zhang
- Department of Urology, Suqian People's Hospital of Nanjing Drum-Tower Hospital Group, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Long-Jun Cai
- Department of Urology, Suqian People's Hospital of Nanjing Drum-Tower Hospital Group, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Tao Fan
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Wen-da Zhang
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Kun Pang
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Wei-Ming Ma
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Xi-Tao Wang
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China
| | - Cong-Hui Han
- Department of Urology, XuZhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Jiefang South Road, No. 199, Jiangsu, Xuzhou, China. .,Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China. .,Department of Biotechnology, College of Life Sciences, Jiangsu Normal University, Xuzhou, China.
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Tian J, Sun J, Fu G, Xu Z, Chen X, Shi Y, Jin B. Population-based outcome of muscle-invasive bladder cancer following radical cystectomy: who can benefit from adjuvant chemotherapy? Transl Androl Urol 2021; 10:356-373. [PMID: 33532324 PMCID: PMC7844522 DOI: 10.21037/tau-20-960] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background The benefit of adjuvant chemotherapy remains controversial in muscle-invasive bladder cancer (MIBC) after radical cystectomy. The present study’s primary objective was to construct a predictive tool for the reasonable application of adjuvant chemotherapy. Methods All of the patients analyzed in the present study were recruited from the Surveillance Epidemiology and End Results program between 2004 and 2015. Propensity score matching (PSM) was used to reduce inherent selection bias. Cox proportional hazards models were applied to identify the independent prognostic factors of overall survival (OS) and cancer-specific survival (CSS), which were further used to construct prognostic nomogram and risk stratification systems to predict survival outcomes. The prognostic nomogram’s performance was assessed by concordance index (C-index), receiver-operating characteristic (ROC) and calibration curves. Decision curve analysis (DCA) was performed to evaluate the clinical net benefit of the prognostic nomogram. Results A total of 6,384 patients with or without adjuvant chemotherapy were included after PSM. Several independent predictors for OS and CSS were identified and further applied to establish a nomogram for 3-, 5- and 10-year, respectively. The nomogram showed favorable discriminative ability for the prediction of OS and CSS, with a C-index of 0.709 [95% confidence interval (CI): 0.699–0.719] for OS and 0.728 (95% CI: 0.718–0.738) for CSS. ROC and calibration curves showed satisfactory consistency. The DCA revealed high clinical positive net benefits of the prognostic nomogram. The different risk stratification systems showed that adjuvant chemotherapy resulted in better OS (P<0.001) and CSS (P<0.001) than without adjuvant chemotherapy for high-risk patients; while the OS (P=0.350) and CSS (P=0.260) for low-risk patients were comparable. Conclusions We have constructed a predictive model and different risk stratifications for selecting a population that could benefit from postoperative adjuvant chemotherapy. Adjuvant chemotherapy was found to be beneficial for high-risk patients, while low-risk patients should be carefully monitored.
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Affiliation(s)
- Junjie Tian
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junjie Sun
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Guanghou Fu
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhijie Xu
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyi Chen
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yue Shi
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Baiye Jin
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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33
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Zucali PA, Cordua N, D'Antonio F, Borea F, Perrino M, De Vincenzo F, Santoro A. Current Perspectives on Immunotherapy in the Peri-Operative Setting of Muscle-Infiltrating Bladder Cancer. Front Oncol 2020; 10:568279. [PMID: 33194654 PMCID: PMC7609911 DOI: 10.3389/fonc.2020.568279] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/15/2020] [Indexed: 12/22/2022] Open
Abstract
Patients with muscle-infiltrating bladder cancer (MIBC) present a high risk of postoperative recurrence and death from metastatic urothelial cancer despite surgical resection. Before the use of peri-operative chemotherapy, about half (52%) of patients undergoing radical cystectomy had had a relapse of tumor disease within 5 years of surgery. However, when peri-operative cisplatin-based chemotherapy is added to radical cystectomy for patients with MIBC it provides limited benefit in terms of survival, disease recurrence and development of metastases, at the expense of toxic effects. In fact, a significant proportion of patients still recurs and die to metastatic disease. Given the success of immune-oncological drugs in metastatic urothelial cancer, several trials started to test them in patients with non-metastatic MIBC either in neo-adjuvant and adjuvant setting. The preliminary results of these studies in neo-adjuvant setting are showing great promise, confirming the potential benefits of immunotherapy also in patients with non-metastatic MIBC. The aim of this review is to present an overview of developments happening on the introduction of immunotherapy in peri-operative setting in non-metastatic urothelial cancer. Moreover, an analysis of the critical issues regarding how best customize the delivery of immunotherapy to optimize efficacy and minimize the adverse effects, with particular focus on potential prognostic and predictive molecular biomarkers, is done.
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Affiliation(s)
- Paolo Andrea Zucali
- Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Nadia Cordua
- Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy
| | - Federica D'Antonio
- Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy
| | - Federica Borea
- Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy
| | - Matteo Perrino
- Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy
| | - Fabio De Vincenzo
- Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy
| | - Armando Santoro
- Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Kim DK, Cho KS. Neoadjuvant chemotherapy for upper tract urothelial carcinoma. Transl Cancer Res 2020; 9:6576-6582. [PMID: 35117267 PMCID: PMC8798340 DOI: 10.21037/tcr.2020.03.08] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/15/2020] [Indexed: 01/05/2023]
Abstract
Upper tract urothelial carcinoma (UTUC) is a very uncommon disease that occupies for <5% of all urothelial cancers. Radical nephroureterectomy (RNU) remains the standard-of-care for UTUC; however, when patients with locally advanced UTUC are treated with RNU only, the recurrence rate is high. Therefore, perioperative chemotherapy has been proposed given the high systemic recurrence rate. Moreover, there is growing evidence that neoadjuvant chemotherapy (NAC) plays an important role in the treatment of UTUC. Several studies and meta-analyses have reported the beneficial effect of NAC on survival outcomes and pathologic downstaging of patients with UTUC. However, the recommendation of NAC for UTUC is primarily based on level 1 evidence that demonstrated a beneficial effect on survival outcomes in patients with bladder cancer. The chemotherapy regimen for patients with UTUC is also based on that used for patients with bladder cancer. Nevertheless, the use of NAC for UTUC has some limitations, including the possibility of overtreatment. Therefore, selection criteria for NAC are needed, as are further trials to identify the most suitable patients and validate its use in daily clinical practice.
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Affiliation(s)
- Do Kyung Kim
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University Medical College, Seoul, Republic of Korea
| | - Kang Su Cho
- Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
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Jiang DM, North SA, Canil C, Kolinsky M, Wood LA, Gray S, Eigl BJ, Basappa NS, Blais N, Winquist E, Mukherjee SD, Booth CM, Alimohamed NS, Czaykowski P, Kulkarni GS, Black PC, Chung PW, Kassouf W, van der Kwast T, Sridhar SS. Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada. Bladder Cancer 2020. [DOI: 10.3233/blc-200291] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND: Despite recent advances in the management of muscle-invasive bladder cancer (MIBC), treatment outcomes remain suboptimal, and variability exists across current practice patterns. OBJECTIVE: To promote standardization of care for MIBC in Canada by developing a consensus guidelines using a multidisciplinary, evidence-based, patient-centered approach who specialize in bladder cancer. METHODS: A comprehensive literature search of PubMed, Medline, and Embase was performed; and most recent guidelines from national and international organizations were reviewed. Recommendations were made based on best available evidence, and strength of recommendations were graded based on quality of the evidence. RESULTS: Overall, 17 recommendations were made covering a broad range of topics including pathology review, staging investigations, systemic therapy, local definitive therapy and surveillance. Of these, 10 (59% ) were level 1 or 2, 7 (41% ) were level 3 or 4 recommendations. There were 2 recommendations which did not reach full consensus, and were based on majority opinion. This guideline also provides guidance for the management of cisplatin-ineligible patients, variant histologies, and bladder-sparing trimodality therapy. Potential biomarkers, ongoing clinical trials, and future directions are highlighted. CONCLUSIONS: This guideline embodies the collaborative expertise from all disciplines involved, and provides guidance to further optimize and standardize the management of MIBC.
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Affiliation(s)
- Di Maria Jiang
- Department of Medicine, Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Scott A. North
- Department of Oncology, Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Christina Canil
- Department of Internal Medicine, Division of Medical Oncology, The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada
| | - Michael Kolinsky
- Department of Oncology, Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Lori A. Wood
- Department of Medicine, Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, NS, Canada
| | - Samantha Gray
- Department of Oncology, Saint John Regional Hospital, Department of Medicine, Dalhousie University, Saint John, NB, Canada
| | - Bernhard J. Eigl
- Department of Medicine, Division of Medical Oncology, BC Cancer - Vancouver, University of British Columbia, Vancouver, BC, Canada
| | - Naveen S. Basappa
- Department of Oncology, Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Normand Blais
- Department of Medicine, Division of Medical Oncology and Hematology, Centre Hospitalier de l’Université de Montréal; Université de Montréal, Montreal, QC, Canada
| | - Eric Winquist
- Department of Oncology, London Health Sciences Centre, University of Western Ontario, London, ON, Canada
| | - Som D. Mukherjee
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada
| | | | - Nimira S. Alimohamed
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
| | - Piotr Czaykowski
- Department of Medical Oncology and Hematology, Cancer Care Manitoba, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Girish S. Kulkarni
- Departments of Surgery and Surgical Oncology, Division of Urology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Peter C. Black
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Peter W. Chung
- Department of Radiation Oncology, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Wassim Kassouf
- Department of Urology, McGill University Health Centre, Montreal, QC, Canada
| | | | - Srikala S. Sridhar
- Department of Medicine, Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
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Mariappan P, Johnston A, Padovani L, Clark E, Trail M, Hamid S, Hollins G, Simpson H, Thomas BG, Hasan R, Bhatt J, Ahmad I, Nandwani GM, Mitchell IDC, Hendry D. Enhanced Quality and Effectiveness of Transurethral Resection of Bladder Tumour in Non-muscle-invasive Bladder Cancer: A Multicentre Real-world Experience from Scotland's Quality Performance Indicators Programme. Eur Urol 2020; 78:520-530. [PMID: 32690321 DOI: 10.1016/j.eururo.2020.06.051] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/22/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND Clinical outcomes from non-muscle-invasive bladder cancer (NMIBC) are partly determined by the quality of initial interventions. To improve and standardise treatment for cancer, Scotland implemented a national Quality Performance Indicator (QPI) programme for bladder cancer (BC). OBJECTIVE To evaluate compliance with specific quality indicators (QIs) related to transurethral resection of bladder tumour (TURBT) and to understand clinical outcomes from NMIBC following the introduction of the QPI programme. DESIGN, SETTING, AND PARTICIPANTS Within a robust governance framework, 12 mandatory evidence-based QPIs were implemented nationally in April 2014. We report prospectively collected data for all new BC patients (between April 2014 and March 2017). We include follow-up data for 2689 patients. INTERVENTION The TURBT-related QPIs were (1) using a bladder diagram, (2) single post-TURBT instillation of mitomycin C (SPI-MMC), (3) detrusor muscle (DM) in the specimen, and (4) early re-TURBT in high-risk NMIBC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We measured compliance with these QPIs and (1) recurrence rate at first follow-up cystoscopy (RRFFC), (2) rates of residual cancer, and (3) pT2 cancer at re-TURBT. Associations between QPI compliance, tumour features, and outcomes were assessed with multivariable logistic regression models. RESULTS AND LIMITATIONS Among 4246 new BC patients, SPI-MMC was used in 67% (2029/3023) NMIBC patients. In 1860 NMIBC patients undergoing TURBT, RRFFC, rate of residual cancer, and rate of pT2 at re-TURBT were 13% (116/888), 33% (212/653), and 2.9% (19/653), respectively. SPI-MMC was associated with lower RRFFC, independent of all variables including hospital volume and surgeon. Presence of DM in the specimen halved the likelihood of residual disease in pT1 cancers. The main limitation is the lack of a pre-QPI introduction cohort for comparison. CONCLUSIONS The implementation of a QI programme in Scotland appears to facilitate high-quality TURBT, which in a real-world setting is associated with low early recurrence/residual cancer and accurate pathological staging. PATIENT SUMMARY Following the first 3 yr of implementing a novel Quality Performance Indicator (QPI) programme in Scotland, we assessed compliance and outcomes in non-muscle-invasive bladder cancer. Evaluating over 4000 new bladder cancer patients, we found that the QPI programme was associated with low recurrence and accurate staging following the initial transurethral resection of bladder tumour.
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Affiliation(s)
- Paramananthan Mariappan
- Edinburgh Bladder Cancer Surgery, Department of Urology, Western General Hospital, Edinburgh, UK; University of Edinburgh, Edinburgh, UK.
| | - Allan Johnston
- Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Luisa Padovani
- Edinburgh Bladder Cancer Surgery, Department of Urology, Western General Hospital, Edinburgh, UK
| | | | - Matthew Trail
- Department of Urology, Ninewells Hospital, Dundee, UK
| | - Sami Hamid
- Department of Urology, Ninewells Hospital, Dundee, UK
| | | | - Helen Simpson
- Department of Urology, Victoria Hospital, Kirkcaldy, UK
| | - Benjamin G Thomas
- Edinburgh Bladder Cancer Surgery, Department of Urology, Western General Hospital, Edinburgh, UK; Department of Urology, Borders General Hospital, Melrose, UK
| | - Rami Hasan
- Department of Urology, University Hospital Ayr, Ayr, UK
| | - Jaimin Bhatt
- Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Imran Ahmad
- Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
| | | | | | - David Hendry
- Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
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Inokuchi J, Yokomizo A, Nishiyama N, Kitamura H, Eto M, Nishiyama H, Tomita Y. Perioperative therapies for urological cancers. Jpn J Clin Oncol 2020; 50:357-367. [PMID: 32115649 DOI: 10.1093/jjco/hyaa013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/04/2020] [Accepted: 01/23/2020] [Indexed: 12/25/2022] Open
Abstract
Although surgery with curative intent is critical for management of many localized cancers, multimodal therapy including neoadjuvant and adjuvant therapy has been introduced to increase the effectiveness of local control of surgery and prolong survival. However, strong evidence supporting the utility of such multimodal therapy is limited. The utility of perioperative chemotherapy has been extensively investigated in bladder cancer, and several randomized controlled trials have indicated the benefit of neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Regrettably, perioperative therapy for other urological cancers is controversial; therefore, no definitive conclusions have been drawn. Recently, the number of trials has rapidly increased due to the development of immune checkpoint inhibitors, used alone or in combination with other modalities. In this review, we summarize the current status and supporting evidence for perioperative therapies such as neoadjuvant and adjuvant therapies for urological cancers, including prostate cancer, urothelial cancer and renal cell carcinoma.
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Affiliation(s)
- Junichi Inokuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University
| | | | - Naotaka Nishiyama
- Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama
| | - Hiroshi Kitamura
- Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University
| | - Hiroyuki Nishiyama
- Department of Urology, Faculty of Medicine, University of Tsukuba, Ibaraki
| | - Yoshihiko Tomita
- Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Zhegalik AG, Polyakov SL, Rolevich AI, Volkov AN, Minich AA, Vasilevich VJ, Mokhort AA, Krasny SA, Sukonko OG. Long-term results of a single-center prospective randomized trial assessing efficacy of a shortened course of adjuvant chemotherapy after radical cystectomy in patients with locally advanced bladder cancer. Cent European J Urol 2020; 73:26-32. [PMID: 32395319 PMCID: PMC7203780 DOI: 10.5173/ceju.2020.0032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 02/23/2020] [Accepted: 02/23/2020] [Indexed: 12/24/2022] Open
Abstract
Introduction This study assesses the efficacy and tolerability of two cycles of adjuvant chemotherapy (AC) with gemcitabine and cisplatin after radical cystectomy in patients with a high risk of progression of muscle-invasive urothelial bladder cancer as compared to chemotherapy at relapse, in a prospective randomized study. Material and methods From 2008 to 2013, all patients after radical cystectomy at our institution for primary or recurrent urothelial bladder cancer with stage pT3-4 and/or pN+ on histopathology and without contraindications to combination cisplatin-based chemotherapy, were randomized either to two cycles of gemcitabine and cisplatin chemotherapy or to follow-up and chemotherapy at the time of relapse. The study endpoints were overall, cancer-specific, and disease-free survival. Results The study included 100 patients, of whom 53 received AC and the other 47 were assigned to the control arm. Out of 53 allocated to AC arm, 16 patients did not start chemotherapy or received only one cycle of AC. The median follow-up for patients in the AC and control arms was 88 and 86 months, respectively. In the AC arm the hazard ratio for death from any cause, death from bladder cancer, and disease relapse were 0.70 (95% CI 0.45-1.11; p = 0.13), 0.84 (95% CI 0.50-1.41; p = 0.51), and 0.77 (95% CI 0.46-1.28; p = 0.31), respectively. Conclusions Two cycles of AC with gemcitabine and cisplatin in patients with high-risk urothelial bladder cancer after radical cystectomy does not improve overall, cancer-specific, and disease-free survival. Only 53% of patients randomized to AC received the entire planned treatment.
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Affiliation(s)
- Alexander G Zhegalik
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
| | - Sergey L Polyakov
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
| | - Alexander I Rolevich
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
| | - Alexander N Volkov
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
| | - Alexander A Minich
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
| | | | - Andrey A Mokhort
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
| | - Sergey A Krasny
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
| | - Oleg G Sukonko
- Department of Urology, N.N. Alexandrov National Research Cancer Center, Minsk, Belarus
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Del Pozo Jiménez G, Herranz Amo F, Arranz Arija JA, Rodríguez Fernández E, Subirá Ríos D, Lledó García E, Bueno Chomón G, Cancho Gil MJ, Carballido Rodríguez J, Hernández Fernández C. Effect of adjuvant chemotherapy in locally advanced urothelial carcinoma of the bladder treated with cystectomy. Actas Urol Esp 2020; 44:94-102. [PMID: 31866159 DOI: 10.1016/j.acuro.2019.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 07/09/2019] [Accepted: 08/27/2019] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Currently, the role of adjuvant chemotherapy (ADJ) in muscle invasive bladder tumor remains controversial. OBJECTIVE To evaluate the effect of ADJ on cancer specific survival of muscle invasive bladder tumor after radical cystectomy (RC). MATERIAL AND METHODS Retrospective analysis of 292 patients diagnosed with urothelial bladder tumor pT3-4pN0 / + cM0 stage, treated with RC between 1986-2009. Total cohort was divided in two groups: 185 (63.4%) patients treated with ADJ and 107 (36.6%) without ADJ. Median follow-up was 40.5 months (IQR 55-80.5). Comparative analysis was performed with Chi-square test and Student's t test /ANOVA. Survival analysis was carried out with the Kaplan-Meier method and log-rank test. Multivariate analysis (Cox regression) was made to identify independent predictors of cancer-specific mortality (CSM). RESULTS 42.8% of the series presented lymph node involvement after RC. At the end of follow-up, 22.9% were BC-free and 54.8% had died due to this cause. The median cancer specific survival was 30 months. No significant differences were observed in cancer specific survival regarding the treatment with ADJ in pT3pN0 (p=.25) or pT4pN0 (p=.29) patients, but it was significant in pT3-4pN+ (p=.001). Multivariate analysis showed pathological stage (p=.0001) and treatment with ADJ (p=.007) as independent prognostic factors for CSM. ADJ reduced the risk of CSM (HR:0.59,95% CI 0.40-0.87, p=.007). CONCLUSIONS pT and pN stages were identified as independent predictors of CSM after RC. The administration of ADJ in our series behaved as a protective factor reducing the risk of CSM, although only pN+ patients were benefited in the stage analysis.
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Affiliation(s)
- G Del Pozo Jiménez
- Servicio de Urología, Hospital Universitario Puerta de Hierro, Madrid, España.
| | - F Herranz Amo
- Servicio de Urología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - J A Arranz Arija
- Servicio de Urología, Hospital Universitario Gregorio Marañón, Madrid, España
| | | | - D Subirá Ríos
- Servicio de Urología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - E Lledó García
- Servicio de Urología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - G Bueno Chomón
- Servicio de Urología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - M J Cancho Gil
- Servicio de Urología, Hospital Universitario Gregorio Marañón, Madrid, España
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Gakis G. Management of Muscle-invasive Bladder Cancer in the 2020s: Challenges and Perspectives. Eur Urol Focus 2020; 6:632-638. [PMID: 31987763 DOI: 10.1016/j.euf.2020.01.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/30/2019] [Accepted: 01/16/2020] [Indexed: 12/16/2022]
Abstract
Despite an increased use of neoadjuvant and adjuvant chemotherapy, the long-term survival rates after radical cystectomy or trimodal therapy (TMT) for muscle-invasive bladder cancer (MIBC) remain basically unchanged for decades. Detection and effective treatment of micrometastatic disease are still a clinical dilemma. Assessment of circulating tumor DNA in combination with improved imaging modalities may improve the prediction of micrometastatic disease. Different genetic subtypes of MIBC show varying degrees of chemosensitivity. Further progress needs to be made in order to develop a common molecular classifier that can be used easily for daily clinical decision making. With the advent on immuno-oncology, bladder-sparing protocols are on the rise as an alternative to surgery. The extent of transurethral bladder tumor resection has a marked impact on the response rates to TMT and neoadjuvant chemotherapy. This review focuses on strategies regarding how to integrate surgery, radiotherapy, and molecular-based systemic treatment for improved oncological outcomes of patients with MIBC. PATIENT SUMMARY: Effective treatment of micrometastatic disease is the key to improved oncological outcomes in muscle-invasive bladder cancer and requires a multidisciplinary approach.
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Affiliation(s)
- Georgios Gakis
- Department of Urology and Pediatric Urology, Julius Maximillians University, Würzburg, Germany.
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Font A, Luque R, Villa JC, Domenech M, Vázquez S, Gallardo E, Virizuela JA, Beato C, Morales-Barrera R, Gelabert A, Maciá S, Puente J, Rubio G, Maldonado X, Perez-Valderrama B, Pinto A, Fernández Calvo O, Grande E, Garde-Noguera J, Fernández-Parra E, Arranz JÁ. The Challenge of Managing Bladder Cancer and Upper Tract Urothelial Carcinoma: A Review with Treatment Recommendations from the Spanish Oncology Genitourinary Group (SOGUG). Target Oncol 2020; 14:15-32. [PMID: 30694442 DOI: 10.1007/s11523-019-00619-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bladder cancer is the fourth most common cancer in men and the ninth most common in women in the Western world. The management of bladder carcinoma requires a multidisciplinary approach. Optimal treatment depends on several factors, including histology, stage, patient status, and possible comorbidities. Here we review recent findings on the treatment of muscle-invasive bladder carcinoma, advanced urothelial carcinoma, upper tract urothelial carcinoma, non-urothelial carcinoma, and urologic complications arising from the disease or treatment. In addition, we present the recommendations of the Spanish Oncology Genitourinary Group for the treatment of these diseases, based on a focused analysis of clinical management and the potential of current research, including recent findings on the potential benefit of immunotherapy. In recent years, whole-genome approaches have provided new predictive biomarkers and promising molecular targets that could lead to precision medicine in bladder cancer. Moreover, the involvement of other specialists in addition to urologists will ensure not only appropriate therapeutic decisions but also adequate follow-up for response evaluation and management of complications. It is crucial, however, to apply recent molecular findings and implement clinical guidelines as soon as possible in order to maximize therapeutic gains and improve patient prognosis.
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Affiliation(s)
- Albert Font
- Medical Oncology Service, B-ARGO Group, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916, Badalona, Spain.
| | - Raquel Luque
- Medical Oncology Service, H.U. Virgen de las Nieves, Granada, Spain
| | - José Carlos Villa
- Medical Oncology Service, Hospital General Universitario Ciudad Real, Ciudad Real, Spain
| | - Montse Domenech
- Medical Oncology Service, Hospital Fundació Althaia, Manresa, Spain
| | - Sergio Vázquez
- Medical Oncology Service, Hospital Universitario Lucus Augusti, EOXI de Lugo, Cervo e Monforte, Spain
| | - Enrique Gallardo
- Oncology Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | | | - Carmen Beato
- Medical Oncology Service, Hospital Virgen de la Macarena, Seville, Spain
| | - Rafael Morales-Barrera
- Medical Oncology Service, Hospital Universitario Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Sonia Maciá
- Medical Oncology Department, CRO Pivotal, Madrid, Spain
| | - Javier Puente
- Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONC, Madrid, Spain
| | - Gustavo Rubio
- Medical Oncology Service, Hospital Universitario Fundación Jimenez Diaz, Madrid, Spain
| | - Xavier Maldonado
- Radiation Oncology Service, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | | | - Alvaro Pinto
- Medical Oncology Service, Hospital Universitario La Paz, Madrid, Spain
| | | | - Enrique Grande
- Medical Oncology, MD Anderson Cancer Center, Madrid, Spain
| | | | - Eva Fernández-Parra
- Medical Oncology Service, Hospital Universitario Nuestra Señora de Valme, Seville, Spain
| | - José Ángel Arranz
- Medical Oncology Service, Hospital General Universitario Gregorio Marañon, Madrid, Spain
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Tierney JF, Fisher DJ, Burdett S, Stewart LA, Parmar MKB. Comparison of aggregate and individual participant data approaches to meta-analysis of randomised trials: An observational study. PLoS Med 2020; 17:e1003019. [PMID: 32004320 PMCID: PMC6993967 DOI: 10.1371/journal.pmed.1003019] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 12/30/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND It remains unclear when standard systematic reviews and meta-analyses that rely on published aggregate data (AD) can provide robust clinical conclusions. We aimed to compare the results from a large cohort of systematic reviews and meta-analyses based on individual participant data (IPD) with meta-analyses of published AD, to establish when the latter are most likely to be reliable and when the IPD approach might be required. METHODS AND FINDINGS We used 18 cancer systematic reviews that included IPD meta-analyses: all of those completed and published by the Meta-analysis Group of the MRC Clinical Trials Unit from 1991 to 2010. We extracted or estimated hazard ratios (HRs) and standard errors (SEs) for survival from trial reports and compared these with IPD equivalents at both the trial and meta-analysis level. We also extracted or estimated the number of events. We used paired t tests to assess whether HRs and SEs from published AD differed on average from those from IPD. We assessed agreement, and whether this was associated with trial or meta-analysis characteristics, using the approach of Bland and Altman. The 18 systematic reviews comprised 238 unique trials or trial comparisons, including 37,082 participants. A HR and SE could be generated for 127 trials, representing 53% of the trials and approximately 79% of eligible participants. On average, trial HRs derived from published AD were slightly more in favour of the research interventions than those from IPD (HRAD to HRIPD ratio = 0.95, p = 0.007), but the limits of agreement show that for individual trials, the HRs could deviate substantially. These limits narrowed with an increasing number of participants (p < 0.001) or a greater number (p < 0.001) or proportion (p < 0.001) of events in the AD. On average, meta-analysis HRs from published AD slightly tended to favour the research interventions whether based on fixed-effect (HRAD to HRIPD ratio = 0.97, p = 0.088) or random-effects (HRAD to HRIPD ratio = 0.96, p = 0.044) models, but the limits of agreement show that for individual meta-analyses, agreement was much more variable. These limits tended to narrow with an increasing number (p = 0.077) or proportion of events (p = 0.11) in the AD. However, even when the information size of the AD was large, individual meta-analysis HRs could still differ from their IPD equivalents by a relative 10% in favour of the research intervention to 5% in favour of control. We utilised the results to construct a decision tree for assessing whether an AD meta-analysis includes sufficient information, and when estimates of effects are most likely to be reliable. A lack of power at the meta-analysis level may have prevented us identifying additional factors associated with the reliability of AD meta-analyses, and we cannot be sure that our results are generalisable to all outcomes and effect measures. CONCLUSIONS In this study we found that HRs from published AD were most likely to agree with those from IPD when the information size was large. Based on these findings, we provide guidance for determining systematically when standard AD meta-analysis will likely generate robust clinical conclusions, and when the IPD approach will add considerable value.
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Affiliation(s)
- Jayne F. Tierney
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom
| | - David J. Fisher
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom
| | - Sarah Burdett
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom
| | - Lesley A. Stewart
- Centre for Reviews and Dissemination, University of York, York, United Kingdom
| | - Mahesh K. B. Parmar
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom
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Wu WR, Lin JT, Pan CT, Chan TC, Liu CL, Wu WJ, Sheu JJC, Yeh BW, Huang SK, Jhung JY, Hsiao MS, Li CF, Shiue YL. Amplification-driven BCL6-suppressed cytostasis is mediated by transrepression of FOXO3 and post-translational modifications of FOXO3 in urinary bladder urothelial carcinoma. Theranostics 2020; 10:707-724. [PMID: 31903146 PMCID: PMC6929993 DOI: 10.7150/thno.39018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 10/17/2019] [Indexed: 01/14/2023] Open
Abstract
Muscle-invasive urinary bladder urothelial carcinoma (UBUC) is a lethal disease for which effective prognostic markers and potential therapy targets are still lacking. Previous array comparative genomic hybridization identified that 3q27 is frequently amplified in muscle-invasive UBUCs, one candidate proto-oncogene, B-cell CLL/lymphoma 6 (BCL6), mapped to this region. We therefore aimed to explore its downstream targets and physiological roles in UBUC progression. Methods: Specimens from UBUC patients, NOD/SCID mice and several UBUC-derived cell lines were used to perform quantitative RT-PCR, fluorescence in situ hybridization immunohistochemistry, xenograft, gene stable overexpression/knockdown and a series of in vitro experiments. Results: Amplification of the BCL6 gene lead to upregulation of BCL6 mRNA and protein levels in a substantial set of advanced UBUCs. High BCL6 protein level significantly predicted poor disease-specific and metastasis-free survivals. Knockdown of the BCL6 gene in J82 cells inhibited tumor growth and enhanced apoptosis in the NOD/SCID xenograft model. In vitro experiments demonstrated that BCL6 inhibited cytostasis, induced cell migration, invasion along with alteration of the expression levels of several related regulators. At molecular level, BCL6 inhibited forkhead box O3 (FOXO3) transcription, subsequent translation and upregulation of phosphorylated/inactive FOXO3 through phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) and/or epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase 1/2 (MAP2K1/2) signaling pathway(s). Two BCL6 binding sites on the proximal promoter region of the FOXO3 gene were confirmed. Conclusion: Overexpression of BCL6 served a poor prognostic factor in UBUC patients. In vivo and in vitro studies suggested that BCL6 functions as an oncogene through direct transrepression of the FOXO3 gene, downregulation and phosphorylation of the FOXO3 protein.
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Affiliation(s)
- Wen-Ren Wu
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jen-Tai Lin
- Surgery Department, Urology Division, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Cheng-Tang Pan
- Department of Mechanical and Electro-Mechanical Engineering
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Ti-Chun Chan
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Chen-Liang Liu
- Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Wen-Jeng Wu
- Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jim Jinn-Chyuan Sheu
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Bi-Wen Yeh
- Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Steven K. Huang
- Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Jheng-Yan Jhung
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Meng-Shin Hsiao
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chien-Feng Li
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
- Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
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Macleod LC, Fam MM, Yabes JG, Hale NE, Turner RM, Lopa SH, Gingrich JR, Borza T, Skolarus TA, Davies BJ, Jacobs BL. Comparison of Neoadjuvant and Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer. Clin Genitourin Cancer 2019; 18:201-209.e2. [PMID: 31917172 DOI: 10.1016/j.clgc.2019.12.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 12/05/2019] [Accepted: 12/09/2019] [Indexed: 12/01/2022]
Abstract
BACKGROUND We use observational methods to compare impact of perioperative chemotherapy timing (ie, neoadjuvant and adjuvant) on overall survival (OS) in muscle-invasive bladder cancer because there is no head-to-head randomized trial, and patient factors may influence decision-making. PATIENTS AND METHODS Using Surveillance, Epidemiology, and End Results-Medicare data, we identified patients receiving cystectomy for muscle-invasive bladder cancer diagnosed between 2004 and 2013. Patients were classified as receiving neoadjuvant or adjuvant chemotherapy. Propensity of receiving neoadjuvant chemotherapy was determined using gradient boosted models. Inverse probability of treatment weighted survival curves were adjusted for 13 demographic, socioeconomic, temporal, and oncologic covariates. RESULTS We identified 1342 patients who received neoadjuvant (n = 676) or adjuvant chemotherapy (n = 666) with a median follow-up of 23 months (interquartile range, 9-55 months). Inverse probability of treatment weighted adjustment allows comparison of the groups head-to-head as well as counterfactual scenarios (eg, effect if those getting one treatment were to receive the other). The average treatment effect (ie, "head-to-head" comparison) of adjuvant compared with neoadjuvant on OS was not significant (hazard ratio, 1.14; 95% confidence interval, 0.99-1.31). However, the average treatment effect of the treated (ie, the effect if the neoadjuvant patients were to receive adjuvant instead) was associated with a 33% increase in risk of mortality if they were given adjuvant therapy instead (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57). CONCLUSION Significant treatment selection bias was noted in peri-cystectomy timing, which limits the ability to discriminate differential efficacy of these 2 approaches with observational data. However, patients with higher propensity to receive neoadjuvant therapy were predicted to have increased OS with approach, in keeping with existing paradigms from trial data.
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Affiliation(s)
- Liam C Macleod
- Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Urology, Asante Rogue Regional Medical Center, Medford, OR.
| | - Mina M Fam
- Department of Urology, Jersey Shore University Medical Center, Neptune, NJ
| | - Jonathan G Yabes
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Nathan E Hale
- Department of Urology, Charleston Area Medical Center, Charleston, WV
| | - Robert M Turner
- Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Samia H Lopa
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | | | - Tudor Borza
- Department of Urology, University of Wisconsin, Madison, WI
| | - Ted A Skolarus
- Division of Oncology, Department of Urology, University of Michigan, Ann Arbor, MI; Dow Division for Urologic Health Service Research, Department of Urology, University of Michigan, Ann Arbor, MI; VA Health Services Research & Development, Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI
| | - Benjamin J Davies
- Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Bruce L Jacobs
- Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA
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Karim S, Mackillop WJ, Brennan K, Peng Y, Siemens DR, Krzyzanowska MK, Booth CM. Estimating the optimal perioperative chemotherapy utilization rate for muscle-invasive bladder cancer. Cancer Med 2019; 8:6258-6271. [PMID: 31472011 PMCID: PMC6797575 DOI: 10.1002/cam4.2449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 11/24/2022] Open
Abstract
Background Identifying optimal chemotherapy (CT) utilization rates can drive improvements in quality of care. We report a benchmarking approach to estimate the optimal rate of perioperative CT for muscle‐invasive bladder cancer (MIBC). Methods The Ontario Cancer Registry and linked treated records were used to identify neoadjuvant and adjuvant CT rates among patients with MIBC during 2004‐2013. Monte Carlo simulation was used to estimate the proportion of observed rate variation that could be due to chance alone. The criterion‐based benchmarking approach was used to explore whether social and health‐system factors were associated with CT rates. We also used the “pared‐mean” approach to identify a benchmark population of hospitals with the highest treatment rates. Hospital CT rates were adjusted for case mix and simulated using a multi‐level multivariable model and a parametric bootstrapping approach. Results The study population included 2581 patients; perioperative CT was delivered to 31% (798/2581). Multivariate analysis showed that treatment was strongly associated with patient socioeconomic status and hospital teaching status. The benchmark rate was 36%. Unadjusted CT rates were significantly different across hospitals (range 0%‐52%, P < .001). The unadjusted benchmark perioperative CT rate was 45% (95% CI 40%‐50%); utilization rate in nonbenchmark hospitals was 28% (95% CI 26%‐30%). When using simulated CT rates adjusted for case mix, the benchmark CT rate was 41% (95% CI 35%‐47%) and the nonbenchmark hospital CT rate was 30% (95% CI 28%‐32%). The simulation analysis suggested that the observed component of variation (38%) was outside the 95% CI (22%‐28%) of what could be expected due to chance alone. Conclusions There is significant systematic variation in perioperative CT rates for MIBC across hospitals in routine practice. The benchmark perioperative CT rate for MIBC is 36%‐41%.
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Affiliation(s)
- Safiya Karim
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Canada
| | - William J Mackillop
- Department of Oncology, Queen's University, Kingston, Canada.,Department of Public Health Sciences, Queen's University, Kingston, Canada.,Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Canada
| | - Kelly Brennan
- Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Canada
| | - Yingwei Peng
- Department of Public Health Sciences, Queen's University, Kingston, Canada.,Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Canada
| | | | - Monika K Krzyzanowska
- Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - Christopher M Booth
- Department of Oncology, Queen's University, Kingston, Canada.,Department of Public Health Sciences, Queen's University, Kingston, Canada.,Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Canada
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Propensity-matched analysis of stage-specific efficacy of adjuvant chemotherapy for bladder cancer. Urol Oncol 2019; 37:877-885. [PMID: 31420159 DOI: 10.1016/j.urolonc.2019.06.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 06/12/2019] [Accepted: 06/23/2019] [Indexed: 11/21/2022]
Abstract
BACKGROUND Contemporary randomized controlled trials exploring adjuvant chemotherapy (AC) for bladder cancer (BCa) have yielded inconsistent results due to premature termination and/or poor patient accrual. OBJECTIVE To compare efficacy of AC vs. observation after radical cystectomy stratified by disease stage in a propensity-matched cohort. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective study that included patients who underwent radical cystectomy for any pT, N0-1, M0 BCa from the National Cancer Data Base (2004-2014). Patients who underwent AC were 1:1 propensity matched with patients who received observation only. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival was assessed with multivariable Cox regression models where adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) were calculated. RESULTS AND LIMITATIONS After coarsened exact 1:1 propensity matching, 3,066 patients (AC 1,533; observation 1,533) were included in the analysis. There were no significant differences in patient-, facility-, or tumor-level characteristics among cohorts. Compared with patients who underwent observation, recipients of AC had improved overall survival (aHR 0.67; 95% CI 0.61-0.74). Patients with pT2-4, pN1 disease significantly benefited from AC. Among the pN0 cohort, improved survival from AC was observed only in stages pT3 (aHR 0.67; 95% CI 0.55-0.83) and pT4 (aHR 0.70; 95% CI 0.50-0.98). CONCLUSIONS AC was associated with improved survival in locally advanced (pT3-4, pN0) and regionally advanced (pT2-4, pN1) chemotherapy-naive BCa.
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Song YP, McWilliam A, Hoskin PJ, Choudhury A. Organ preservation in bladder cancer: an opportunity for truly personalized treatment. Nat Rev Urol 2019; 16:511-522. [PMID: 31197260 DOI: 10.1038/s41585-019-0199-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2019] [Indexed: 02/07/2023]
Abstract
Radical treatment of many solid tumours has moved from surgery to multimodal organ preservation strategies combining systemic and local treatments. Trimodality bladder-preserving treatment (TMT) comprises maximal transurethral resection of the bladder tumour followed by radiotherapy and concurrent radiosensitizing treatment, thereby sparing the urinary bladder. From the patient's perspective, the choice of maintaining quality of life without a negative effect on the chances of cure and long-term survival is attractive. In muscle-invasive bladder cancer (MIBC), the evidence shows comparable clinical outcomes between patients undergoing radical cystectomy and TMT. Despite this evidence, many patients continue to be offered radical surgery as the standard-of-care treatment. Improvements in radiotherapy techniques with adaptive radiotherapy and advances in imaging translate to increases in the accuracy of treatment delivery and reductions in long-term toxicities. With the advent of novel biomarkers promising improved prediction of treatment response, stratification of patients for different treatments on the basis of tumour biology could soon be a reality. The future of oncological treatment lies in personalized medicine with the combination of technological and biological advances leading to truly bespoke management for patients with MIBC.
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Affiliation(s)
- Yee Pei Song
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK. .,Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK.
| | - Alan McWilliam
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.,Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK
| | - Peter J Hoskin
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.,Mount Vernon Cancer Centre, Northwood, Middlesex, United Kingdom
| | - Ananya Choudhury
- Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.,Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK
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Clinical predictors and survival outcome of patients receiving suboptimal neoadjuvant chemotherapy and radical cystectomy for muscle-invasive bladder cancer: a single-center experience. World J Urol 2019; 37:2409-2418. [PMID: 30805684 DOI: 10.1007/s00345-019-02689-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 02/18/2019] [Indexed: 02/06/2023] Open
Abstract
PURPOSE To investigate the prevalence of and factors' association with receiving suboptimal neoadjuvant chemotherapy (NAC) and its impact on survival outcomes in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy (RC). METHODS We reviewed 1119 patients treated with NAC and/or RC for cT2-cT4N0M0 BC. Patients were segregated into three groups: (i) suboptimal NAC (received < 3 cycles of cisplatin-based NAC or non-cisplatin-based regimen), (ii) optimal NAC and (iii) no NAC. Clinical characteristics were compared among groups. Logistic regression analyses tested the association between clinical variables and the odds of receiving suboptimal NAC. To adjust for potential baseline confounders, propensity score matching was performed. Pathologic outcomes were compared between groups and Cox regression analyses tested the risk factors associated with recurrence, overall (OM) and cancer-specific mortality (CSM). RESULTS Before matching, 84/315 (26.6%) patients received a suboptimal NAC regimen. Lower general health status and impaired renal functions were the most significant factors associated with the administration of a suboptimal NAC. After matching, the optimal NAC group achieved higher rates of complete pathological response as compared to the suboptimal group (p = 0.03). Suboptimal NAC (HR 1.77; p = 0.015) and no NAC (HR 1.52; p = 0.03) were both associated with higher risk of recurrence and OM (HR 1.71; p = 0.02 and HR 1.61; p = 0.02) as compared to optimal NAC. CONCLUSION One out of four MIBC patients received a suboptimal NAC regimen before RC. Receiving a suboptimal NAC regimen was associated with worse disease recurrence and survival outcomes following surgery, as compared to an optimal NAC regimen.
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Kim DK, Lee JY, Jung JH, Hah YS, Cho KS. Role of adjuvant cisplatin-based chemotherapy following radical cystectomy in locally advanced muscle-invasive bladder cancer: Systematic review and meta-analysis of randomized trials. Investig Clin Urol 2019; 60:64-74. [PMID: 30838338 PMCID: PMC6397926 DOI: 10.4111/icu.2019.60.2.64] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 01/03/2019] [Indexed: 11/18/2022] Open
Abstract
Purpose We purposed to assess the effects of adjuvant chemotherapy (ACH) on survival outcomes in patients with locally advanced muscle-invasive bladder cancer (MIBC) who are treated with radical cystectomy (RC). Materials and Methods Literature search was conducted in PubMed, Embase, and Cochrane library databases for all articles that were published until February 2018. Systematic review and meta-analysis were performed by pooling the randomized controlled trials (RCTs) that compared patients with locally advanced MIBC who received ACH after RC to those who underwent cystectomy alone. Endpoints were progression free survival (PFS) and overall survival (OS). Results Four RCTs with a total of 490 patients were selected for the analysis. These four trials included patients with locally advanced MIBC. Pooled HRs for PFS and OS across the studies were 0.48 (95% confidence interval [CI], 0.39–0.60; p<0.00001) and 0.63 (95% CI, 0.48–0.83; p=0.0009), respectively. Absolute increases in PFS and OS for locally advanced MIBC were 17% and 10%, respectively (i.e., equivalent to numbers needed to treat of 5.9 and 10). Conclusions ACH following RC may improve the survival outcomes of locally advanced MIBC patients. Beneficial effect of ACH might be more marked in patients with locally advanced MIBC when comparing the previously reported meta-analysis with all MIBC patients.
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Affiliation(s)
- Do Kyung Kim
- Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Joo Yong Lee
- Department of Urology, Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hung Jung
- Department of Urology, Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Yoon Soo Hah
- Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Kang Su Cho
- Department of Urology, Gangnam Severance Hospital, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea
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Boeri L, Soligo M, Frank I, Boorjian SA, Thompson RH, Tollefson M, Quevedo FJ, Cheville JC, Karnes RJ. Cigarette smoking is associated with adverse pathological response and increased disease recurrence amongst patients with muscle-invasive bladder cancer treated with cisplatin-based neoadjuvant chemotherapy and radical cystectomy: a single-centre experience. BJU Int 2019; 123:1011-1019. [PMID: 30623554 DOI: 10.1111/bju.14612] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To investigate the association between smoking status and pathological response to cisplatin-based neoadjuvant chemotherapy (NAC) and survival outcomes in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy (RC). PATIENTS AND METHODS We reviewed 201 patients treated with NAC and RC for cT2-cT4N0M0 BC between 01/1999 and 01/2015. Smoking status was categorised as: 'never', 'former', and 'current' smoker. Pathological response to NAC was defined as: complete (ypT0N0), partial (ypTis/Ta/T1, N0), and no response (ypT2-4 or ypN+). Clinicopathological characteristics were analysed according to smoking status. Logistic regression analyses tested the association between smoking status and pathological response to NAC. Cox regression analyses tested risk factors associated with recurrence, overall (OM) and cancer-specific mortality (CSM). RESULTS Overall, there were 58 (28.9%) never smokers, 87 (43.3%) former smokers, and 56 (27.9%) current smokers. No response to NAC was more frequently noted in current smokers (73.2%; P = 0.007). Former smoker (odds ratio [OR] 2.28; P = 0.024) and current smoker statuses (OR 4.52; P < 0.001) were significantly associated with no response to NAC, after adjusting for age, gender, Charlson Comorbidity Index, and clinical stage. Similarly, current smoking status (hazard ratio [HR] 2.14; P = 0.03) and extravesical pathological tumour stage (HR 3.31; P < 0.001) were independently associated with an increased risk of recurrence after RC. CONCLUSION Cigarette smoking was significantly associated with adverse pathological response to cisplatin-based NAC in patients with MIBC treated with RC. Current smokers were at significantly higher risk of disease recurrence as compared to former and never smokers.
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Affiliation(s)
- Luca Boeri
- Department of Urology, Mayo Clinic, Rochester, MN, USA.,Department of Urology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Matteo Soligo
- Department of Urology, Mayo Clinic, Rochester, MN, USA
| | - Igor Frank
- Department of Urology, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | - John C Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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