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Urinary Bladder Neoplasms: HELP
Articles by Thomas Powles
Based on 20 articles published since 2009
(Why 20 articles?)

Between 2009 and 2019, Tom Powles wrote the following 20 articles about Urinary Bladder Neoplasms.
+ Citations + Abstracts
1 Guideline SIU-ICUD recommendations on bladder cancer: systemic therapy for metastatic bladder cancer. 2019

Merseburger, Axel S / Apolo, Andrea B / Chowdhury, Simon / Hahn, Noah M / Galsky, Matthew D / Milowsky, Matthew I / Petrylak, Daniel / Powles, Tom / Quinn, David I / Rosenberg, Jonathan E / Siefker-Radtke, Arlene / Sonpavde, Guru / Sternberg, Cora N. ·Department of Urology, Campus Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany. · Center for Cancer Research, National Cancer Institute, NIH Maryland, Bethesda, USA. · Guy's and St, Thomas' Hospital, Great Maze Pond, London, UK. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA. · Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA. · Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. · Yale Cancer Center, New Haven, CT, USA. · Barts Cancer Institute, London, USA. · Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. · Memorial Sloan Kettering Cancer Center, New York, USA. · Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Medical Oncology, Bladder Cancer Center, Dana Farber Cancer Institute, Boston, MA, USA. · Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy. cnsternberg@corasternberg.com. ·World J Urol · Pubmed #30238401.

ABSTRACT: The SIU (Société Internationale d'Urologie)-ICUD (International Consultation on Urologic Diseases) working group on systemic therapy for metastatic bladder cancer has summarized the most recent findings on the aforementioned topic and came to conclusions and recommendations according to the evidence published. In Europe and the United States, treatment for metastatic UC has changed a great deal recently, mainly involving a move from chemotherapy to immune checkpoint blockers. This is particularly true in platinum-refractory disease, where supportive randomized data exist. Five checkpoint blockers have been approved in this setting by the FDA: avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab. Nivolumab, pembrolizumab, and atezolizumab have been approved in Europe.

2 Review The Cancer Immunogram as a Framework for Personalized Immunotherapy in Urothelial Cancer. 2019

van Dijk, Nick / Funt, Samuel A / Blank, Christian U / Powles, Thomas / Rosenberg, Jonathan E / van der Heijden, Michiel S. ·Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Medical Oncology, Barts Cancer Institute, London, UK. · Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: ms.vd.heijden@nki.nl. ·Eur Urol · Pubmed #30274701.

ABSTRACT: CONTEXT: The abysmal outlook of urothelial cancer (UC) has changed with the introduction of immunotherapy. Still, many patients do not respond and distinctive biomarkers are currently lacking. The rise of this novel armamentarium of immunotherapy treatments, in combination with the complex biology of an immunological tumor response, warrants the development of a comprehensive framework that can provide an overview of important immunological processes at play in individual patients. OBJECTIVE: To develop a comprehensive framework based on tumor- and host-specific parameters to understand immunotherapy response in UC. This framework can inform rational, biology-driven clinical trials and ultimately guide us toward individualized patient treatment. EVIDENCE ACQUISITION: A literature review was conducted on UC immunotherapy, clinical trial data, and biomarkers of response to checkpoint inhibition. EVIDENCE SYNTHESIS: Here, we propose a UC immunogram, based on currently available clinical and translational data. The UC immunogram describes several tumor- and host-specific parameters that are required for successful immunotherapy treatment. These seven parameters are tumor foreignness, immune cell infiltration, absence of inhibitory checkpoints, general performance and immune status, absence of soluble inhibitors, absence of inhibitory tumor metabolism, and tumor sensitivity to immune effectors. CONCLUSIONS: Longitudinal integration of individual patient parameters may ultimately lead to personalized and dynamic immunotherapy, to adjust to the Darwinian forces that drive tumor evolution. Incorporating multiparameter biomarkers into quantitative predictive models will be a key challenge to integrate the immunogram into daily clinical practice. PATIENT SUMMARY: Here, we propose the urothelial cancer immunogram, a novel way of describing important immunological characteristics of urothelial cancer patients and their tumors. Seven characteristics determine the chance of having an immunological tumor response. Using this immunogram, we aim to better understand why some patients respond to immunotherapy and some do not, to ultimately improve anticancer therapy.

3 Review Anti-Programmed Cell Death 1/Ligand 1 (PD-1/PD-L1) Antibodies for the Treatment of Urothelial Carcinoma: State of the Art and Future Development. 2018

Powles, Thomas / Necchi, Andrea / Rosen, Galit / Hariharan, Subramanian / Apolo, Andrea B. ·Barts Cancer Institute, Queen Mary University of London, St Bartholomew's Hospital, London, UK. · Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · EMD Serono Inc, Billerica, MA, USA. · Global Medical Affairs, ImmunoOncology, Pfizer Oncology, New York, NY, USA. · Bladder Cancer Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: andrea.apolo@nih.gov. ·Clin Genitourin Cancer · Pubmed #29325739.

ABSTRACT: Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has expanded a previously limited pool of effective treatment options for patients with metastatic urothelial carcinoma, particularly those with recurring or refractory disease and those who are ineligible for cisplatin. This review reports key findings from completed and ongoing clinical trials that highlight the potential of PD-1/PD-L1 blockade in urothelial carcinoma. A literature search was performed of PubMed, Embase, ClinicalTrials.gov, and selected annual congress abstracts. Prospective studies, reviews, editorials, and descriptions of ongoing anti-PD-1/PD-L1 studies in bladder cancer were included. Anti-PD-1/PD-L1 monoclonal antibodies have shown efficacy and safety across patient subgroups with urothelial carcinoma, including those with poor prognostic factors. Efficacy was similar across different anti-PD-1/PD-L1 agents. Although these antibodies have demonstrated durable responses in a subset of patients with urothelial carcinoma, clinicians are currently unable to predict which patients may derive benefit from immune checkpoint blockade. Anti-PD-1/PD-L1 antibodies have shown favorable clinical activity and tolerability in patients with metastatic urothelial carcinoma refractory to platinum-based therapy or who are ineligible for cisplatin. The activity of PD-1/PD-L1 inhibitors is now also being studied as first-line monotherapy in cisplatin-eligible patients in combination with chemotherapy as maintenance therapy after first-line chemotherapy, and in earlier disease states, such as muscle-invasive and non-muscle-invasive bladder cancer. Better predictive tools to define target patient populations are needed, as are further investigations to define optimal combinations or sequencing of treatments.

4 Review A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. 2017

Bellmunt, Joaquin / Powles, Thomas / Vogelzang, Nicholas J. ·Bladder Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States; PSMAR-IMIM Lab, Barcelona, Spain. Electronic address: Joaquim_bellmunt@DFCI.HARVARD.edu. · Barts Cancer Institute, Queen Mary University of London, United Kingdom. · Comprehensive Cancer Centers of Nevada, Las Vegas, NV, United States. ·Cancer Treat Rev · Pubmed #28214651.

ABSTRACT: The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated. Several checkpoint targets (programmed death ligand-1 [PD-L1] programmed cell death protien-1 [PD-1], and cytotoxic T-lymphocyte associated protein 4 [CTLA4]) have received the most attention in the treatment of bladder cancer, and have inhibitor agents either approved or in late-stage development. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Atezolizumab is the only member of this class currently approved for the treatment of bladder cancer, but nivolumab, pembrolizumab, durvalumab, and avelumab all have positive results for this indication, and approvals are anticipated in the near future. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in immune system functioning.

5 Review A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. 2012

Meeks, Joshua J / Bellmunt, Joaquim / Bochner, Bernard H / Clarke, Noel W / Daneshmand, Siamak / Galsky, Matthew D / Hahn, Noah M / Lerner, Seth P / Mason, Malcolm / Powles, Thomas / Sternberg, Cora N / Sonpavde, Guru. ·Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. ·Eur Urol · Pubmed #22677572.

ABSTRACT: CONTEXT: Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC. OBJECTIVE: To review the data supporting perioperative chemotherapy and emerging regimens for MIBC. EVIDENCE ACQUISITION: Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included. EVIDENCE SYNTHESIS: The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed. CONCLUSIONS: Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.

6 Review The clinical advances of fluorine-2-D-deoxyglucose--positron emission tomography/computed tomography in urological cancers. 2010

Avril, Norbert / Dambha, Fatima / Murray, Iain / Shamash, Jonathan / Powles, Tom / Sahdev, Anju. ·Department of Nuclear Medicine, Barts and The London School of Medicine, Queen Mary University of London, London, UK. n.e.avril@qmul.ac.uk ·Int J Urol · Pubmed #20370848.

ABSTRACT: Fluorine-18 labeled fluorine-2-D-deoxyglucose (FDG) is the most frequently used positron emission tomography (PET) probe but it has certain limitations when used in urological cancers. The introduction of co-registered PET and computed tomography (PET/CT) represents a major advance in technology and FDG-PET/CT has now become the new standard. The diagnostic performance of FDG-PET and PET/CT depends on the metabolic activity of tumor tissue, which is generally low in primary renal cell and prostate cancers and often in their metastatic deposits. In contrast, both seminomatous and nonseminomatous germ cell tumors are characterized by upregulated glucose metabolism with subsequently increased FDG uptake in tumor sites. Generally, the metabolic activity provides accurate information regarding the presence of a viable tumor, except in patients with residual mature teratoma. Although bladder cancer demonstrates sufficiently increased FDG uptake, primary tumors are difficult to identify due to the renal excretion of FDG. The accuracy of FDG-PET/CT in metabolically active metastases is generally higher compared to conventional CT except for identifying small lung deposits. With disease progression and subsequent de-differentiation of prostate cancer, castrate resistant disease is more likely to present with lesions that have increased glucose metabolism.

7 Clinical Trial Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. 2017

Petrylak, Daniel P / de Wit, Ronald / Chi, Kim N / Drakaki, Alexandra / Sternberg, Cora N / Nishiyama, Hiroyuki / Castellano, Daniel / Hussain, Syed / Fléchon, Aude / Bamias, Aristotelis / Yu, Evan Y / van der Heijden, Michiel S / Matsubara, Nobuaki / Alekseev, Boris / Necchi, Andrea / Géczi, Lajos / Ou, Yen-Chuan / Coskun, Hasan Senol / Su, Wen-Pin / Hegemann, Miriam / Percent, Ivor J / Lee, Jae-Lyun / Tucci, Marcello / Semenov, Andrey / Laestadius, Fredrik / Peer, Avivit / Tortora, Giampaolo / Safina, Sufia / Del Muro, Xavier Garcia / Rodriguez-Vida, Alejo / Cicin, Irfan / Harputluoglu, Hakan / Widau, Ryan C / Liepa, Astra M / Walgren, Richard A / Hamid, Oday / Zimmermann, Annamaria H / Bell-McGuinn, Katherine M / Powles, Thomas / Anonymous1141202. ·Yale University School of Medicine, New Haven, CT, USA. Electronic address: daniel.petrylak@yale.edu. · Erasmus MC Cancer Institute, Rotterdam, Netherlands. · British Columbia Cancer Agency, Vancouver, BC, Canada. · David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · San Camillo and Forlanini Hospitals, Rome, Italy. · University of Tsukuba, Tsukuba, Ibaraki, Japan. · Hospital Universitario 12 de Octubre (CiberOnc), Madrid, Spain. · Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK. · Centre Léon Bérard, Lyon, France. · National and Kapodistrian University of Athens, Athens, Greece. · University of Washington, Seattle, WA, USA. · Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands. · National Cancer Centre Hospital East, Chiba, Japan. · PA Herzen Moscow Oncological Research Institute, Moscow, Russia. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · National Institute of Oncology, Budapest, Hungary. · Taichung Veterans General Hospital, Taichung, Taiwan. · Akdeniz University School of Medicine, Antalya, Turkey. · Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan. · University Hospital, Tübingen, Germany. · Florida Cancer Specialists, Port Charlotte, FL, USA. · Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea. · Division of Medical Oncology, Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy. · RBHI Ivanovo Regional Oncology Dispensary, Ivanovo, Russia. · Centre Oscar Lambret, Lille, France. · Rambam Health Care Campus, Haifa, Israel. · University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Tatarstan Regional Cancer Centre, Kazan, Russia. · Institut Català d'Oncologia L'Hospitalet, IDIBELL, University of Barcelona, Barcelona, Spain. · Hospital del Mar, Barcelona, Spain. · Trakya University, Edirne, Turkey. · Inonu University, Malatya, Turkey. · Eli Lilly and Company, Indianapolis, IN, USA. · Barts Cancer Institute, Queen Mary University of London, London, UK. ·Lancet · Pubmed #28916371.

ABSTRACT: BACKGROUND: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population. METHODS: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m FINDINGS: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96-4·47] vs 2·76 months [2·60-2·96]; hazard ratio [HR] 0·757, 95% CI 0·607-0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8-30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4-18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. INTERPRETATION: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. FUNDING: Eli Lilly and Company.

8 Clinical Trial Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2-Positive Metastatic Bladder Cancer. 2017

Powles, Thomas / Huddart, Robert A / Elliott, Tony / Sarker, Shah-Jalal / Ackerman, Charlotte / Jones, Robert / Hussain, Syed / Crabb, Simon / Jagdev, Satinder / Chester, John / Hilman, Serena / Beresford, Mark / Macdonald, Graham / Santhanam, Sundar / Frew, John A / Stockdale, Andrew / Hughes, Simon / Berney, Daniel / Chowdhury, Simon. ·Thomas Powles, Shah-Jalal Sarker, Charlotte Ackerman, and Daniel Berney, Queen Mary University of London · Simon Hughes and Simon Chowdhury, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, London · Robert A. Huddart, Institute of Cancer Research, Sutton · Tony Elliott, Christie Hospital NHS Foundation Trust, Manchester · Robert Jones, University of Glasgow, Glasgow · Syed Hussain, University of Liverpool, Liverpool · Simon Crabb, University of Southampton, Southampton · Satinder Jagdev, St James's University Hospital, Leeds · John Chester, Cardiff University, Cardiff · Serena Hilman, Bristol Haematology and Oncology Centre, Bristol · Mark Beresford, Royal United Hospitals Bath, Bath · Graham Macdonald, Aberdeen Royal Infirmary, Aberdeen · Sundar Santhanam, Nottingham University Hospitals NHS Trust, Nottingham · John A. Frew, Northern Centre for Cancer Care, Newcastle upon Tyne · and Andrew Stockdale, University Hospital, Coventry, United Kingdom. ·J Clin Oncol · Pubmed #28034079.

ABSTRACT: Purpose To establish whether maintenance lapatinib after first-line chemotherapy is beneficial in human epidermal growth factor receptor (HER) 1/HER2-positive metastatic urothelial bladder cancer (UBC). Methods Patients with metastatic UBC were screened centrally for HER1/HER2 overexpression. Patients who screened positive for HER1/2 and who did not have progressive disease during chemotherapy (four to eight cycles) were randomly assigned one to one to lapatinib or placebo after completion of first-line/initial chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS). Results Between 2007 and 2013, 446 patients with UBC were screened, and 232 with HER1- or HER2-positive disease were randomly assigned. The median PFS for lapatinib and placebo was 4.5 (95% CI, 2.8 to 5.4) and 5.1 (95% CI, 3.0 to 5.8) months, respectively (hazard ratio, 1.07; 95% CI, 0.81 to 1.43; P = .63). The overall survival for lapatinib and placebo was 12.6 (95% CI, 9.0 to 16.2) and 12.0 (95% CI, 10.5 to 14.9) months, respectively (hazard ratio, 0.96; 95% CI, 0.70 to 1.31; P = .80). Discontinuation due to adverse events were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3 to 4 adverse events for lapatinib and placebo was 8.6% versus 8.1% ( P = .82). Preplanned subset analysis of patients strongly positive for HER1/HER2 (3+ on immunohistochemistry; n = 111), patients positive for only HER1 (n = 102), and patients positive for only HER2 (n = 42) showed no significant benefit with lapatinib in terms of PFS and overall survival ( P > .05 for each). Conclusion This trial did not find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.

9 Clinical Trial Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle-invasive bladder cancer. 2015

Gurung, Pratik M S / Veerakumarasivam, Abhi / Williamson, Magali / Counsell, Nicholas / Douglas, James / Tan, Wei S / Feber, Andrew / Crabb, Simon J / Short, Susan C / Freeman, Alex / Powles, Thomas / Hoskin, Peter J / West, Catharine M / Kelly, John D. ·Division of Surgery and Interventional Science, University College London (UCL), London, United Kingdom. ·Int J Cancer · Pubmed #24917520.

ABSTRACT: The aim of this study was to test the utility of AIMP3, an upstream regulator of DNA damage response following genotoxic stress, as a clinical biomarker in muscle-invasive bladder cancer (MIBC). AIMP3 was identified from a meta-analysis of a global gene-expression dataset. AIMP3 protein expression was determined by immunohistochemistry on a customised bladder cancer tissue-microarray (TMA). The mechanism of gene silencing was probed using methylation-specific PCR. The association between AIMP3 expression, Tp53 transactivity and genomic stability was analysed. In vitro AIMP3 translocation to the nucleus in response to ionising radiation was demonstrated using immunofluorescence. Radiosensitisation effects of siRNA-mediated AIMP3-knockdown were measured using colony forming assays. TMAs derived from patients enrolled in BCON, a Phase III multicentre radiotherapy trial in bladder cancer (ISRCTN45938399) were used to evaluate the association between AIMP3 expression and survival. The prognostic value of AIMP3 expression was determined in a TMA derived from patients treated by radical cystectomy. Loss of AIMP3 expression was frequent in MIBC and associated with impaired Tp53 transactivity and genomic instability. AIMP3-knockdown was associated with an increase in radioresistance. Loss of AIMP3 expression was associated with survival in MIBC patients following radiotherapy (HR = 0.53; 95% CI: 0.36 to 0.78, p = 0.002) but was not prognostic in the cystectomy set. In conclusion, AIMP3 expression is lost in a subset of bladder cancers and is significantly predictive of survival following radiotherapy in MIBC patients.

10 Clinical Trial MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. 2014

Powles, Thomas / Eder, Joseph Paul / Fine, Gregg D / Braiteh, Fadi S / Loriot, Yohann / Cruz, Cristina / Bellmunt, Joaquim / Burris, Howard A / Petrylak, Daniel P / Teng, Siew-leng / Shen, Xiaodong / Boyd, Zachary / Hegde, Priti S / Chen, Daniel S / Vogelzang, Nicholas J. ·Barts Cancer Institute, Queen Mary University of London, Barts Experimental Cancer Medicine Centre, London EC1M 6BQ, UK. · Yale Cancer Center, 333 Cedar Street, WWW211, New Haven, Connecticut 06520, USA. · Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA. · Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, Nevada 89169, USA. · Gustave Roussy, 114 Rue Édouard Vaillant, 94805 Villejuif, France. · Vall d'Hebron Institute of Oncology (VHIO) and Vall d'Hebron University Hospital. Passeig Vall d'Hebron, 119-129, 08035, Barcelona, Spain. · Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. · Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, Tennessee 37203, USA. · University of Nevada School of Medicine and US Oncology/Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, Nevada 89169, USA. ·Nature · Pubmed #25428503.

ABSTRACT: There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.

11 Clinical Trial Gemcitabine, Cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer. 2013

Galsky, Matthew D / Hahn, Noah M / Powles, Thomas / Hellerstedt, Beth A / Lerner, Seth P / Gardner, Thomas A / Yu, Menggang / O'Rourke, Mark / Vogelzang, Nicholas J / Kocs, Darren / McKenney, Scott A / Melnyk, Anton M / Hutson, Thomas E / Rauch, Mary / Wang, Yunfei / Asmar, Lina / Sonpavde, Guru. ·US Oncology Research, McKesson Specialty Health, The Woodlands, TX, USA. matthew.galsky@mssm.edu ·Clin Genitourin Cancer · Pubmed #23228446.

ABSTRACT: BACKGROUND: Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials. PATIENTS AND METHODS: Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2. RESULTS: The initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m(2) intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m(2), respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small. CONCLUSIONS: Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.

12 Clinical Trial A phase II study of mitomycin, fluorouracil, folinic acid, and irinotecan (MFI) for the treatment of transitional cell carcinoma of the bladder. 2013

Bhattacharyya, Madhumita / Powles, Tom / Mutsvangwa, Katherine / Wilson, Peter / Oliver, Timothy / Shamash, Jonathan. ·Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London, United Kingdom. mbhattacharyya@doctors.org.uk ·Urol Oncol · Pubmed #21890383.

ABSTRACT: BACKGROUND AND OBJECTIVES: Cisplatin-based chemotherapy is standard care for metastatic transitional cell carcinoma (TCC) of the urinary tract. However it is not appropriate for all patients, particularly those with poor renal function. There is no clear consensus on the optimal regimen for these individuals or for those after cisplatin failure. Here we present data using mitomycin, 5-fluorouracil, and irinotecan (MFI) in these patients. MATERIALS AND METHODS: Patients with TCC, who had either received cisplatin-based chemotherapy previously or who were not deemed fit for cisplatin therapy (creatinine clearance was less than 60 ml/min) were eligible for treatment with the experimental combination chemotherapy regimen MFI. RESULTS: Thirty-six patients were treated with MFI between 2001 and 2004. Overall response rate was 19% and median overall survival (OS) was 5.4 months (95% CI 3.3-8.4 months). The response rate and overall survival in both groups was 19% and 5.4 months, respectively, (95% CI 2.9-7.1 months) in the pretreated and 2.5- 9.3 months in the untreated. The most common toxicity was malaise (grade 3 or 4 = 28%). CONCLUSIONS: MFI appear to be a combination which requires further investigation in patients where cisplatin and gemcitabine are not applicable.

13 Article Response Rate to Chemotherapy After Immune Checkpoint Inhibition in Metastatic Urothelial Cancer. 2018

Szabados, Bernadett / van Dijk, Nick / Tang, Yen Zhi / van der Heijden, Michiel S / Wimalasingham, Akhila / Gomez de Liano, Alfonso / Chowdhury, Simon / Hughes, Simon / Rudman, Sarah / Linch, Mark / Powles, Thomas. ·Barts Cancer Institute, Queen Mary University of London, London, UK; Department of Urology, University of Munich, Klinikum Grosshadern, Germany. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · Barts Cancer Institute, Queen Mary University of London, London, UK. · Guys and St Thomas' Hospital, London, UK. · University College London, London, UK. · Barts Cancer Institute, Queen Mary University of London, London, UK. Electronic address: Thomas.powles@bartshealth.nhs.uk. ·Eur Urol · Pubmed #28917596.

ABSTRACT: Immune checkpoint inhibitors (ICIs) are active in metastatic urothelial carcinoma (MUC). They have joined chemotherapy (CT) as a standard of care. Here, we investigate the activity of CT after progression on ICIs. Two cohorts of sequential patients with MUC were described (n=28). Cohort A received first-line ICIs followed by CT after progression. Cohort B received CT after failure of first-line platinum-based CT followed by ICIs. Response rate (RR) to CT was assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by a designated radiologist. Best RR for cohort A was 64%. Two patients experienced clinical progression and died before the first radiographic assessment. RR for cohort B was 21%, which was significantly lower than that for cohort A. Progression of disease occurred in 43% of cohort B patients by the end of CT. These data suggest a lack of cross resistance between CT and ICIs in MUC. Therefore, the sequencing of these drugs is likely to be important to maximise outcomes. This is particularly true after first-line ICIs as subsequent CT has significant activity. PATIENT SUMMARY: In this report, we studied the effect of chemotherapy in metastatic bladder cancer, which relapsed after immune checkpoint inhibitors. We found that the activity of chemotherapy was maintained despite previous exposure to immune therapy. This underlines the importance of sequencing these agents to maximise outcomes.

14 Article Radical cystectomy or bladder preservation with radiochemotherapy in elderly patients with muscle-invasive bladder cancer: Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators. 2018

Boustani, Jihane / Bertaut, Aurélie / Galsky, Matthew D / Rosenberg, Jonathan E / Bellmunt, Joaquim / Powles, Thomas / Recine, Federica / Harshman, Lauren C / Chowdhury, Simon / Niegisch, Guenter / Yu, Evan Y / Pal, Sumanta K / De Giorgi, Ugo / Crabb, Simon J / Caubet, Matthieu / Balssa, Loïc / Milowsky, Matthew I / Ladoire, Sylvain / Créhange, Gilles / Anonymous1711261. ·a Department of Radiation Oncology , University Hospital of Besançon , Besançon , France. · b Department of Biostatistics , Georges François Leclerc Center, University of Burgundy , Dijon , France. · c Icahn School of Medicine at Mount Sinai , New York , NY , USA. · d Memorial Sloan Kettering Cancer Center , New York , NY , USA. · e Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA. · f Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London , London , UK. · g Medical Oncology Department , Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS , Meldola , Italy. · h Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA. · i Guy's and St. Thomas' Hospital , London , UK. · j Heinrich-Heine-University , Düsseldorf , Germany. · k Fred Hutchinson Cancer Research Center , Seattle , WA , USA. · l City of Hope Comprehensive Cancer Center , Duarte , CA , USA. · m Department of Medical Oncology , Southampton General Hospital , Southampton , UK. · n Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , Chapel Hill , NC , USA. · o Department of Medical Oncology , Georges François Leclerc Cancer Center, University of Burgundy , Dijon , France. · p Department of Radiation Oncology , Georges François Leclerc Cancer Center, University of Burgundy , Dijon , France. ·Acta Oncol · Pubmed #28853615.

ABSTRACT: BACKGROUND: Radical cystectomy (RC) and radiochemotherapy (RCT) are curative options for muscle-invasive bladder cancer (MIBC). Optimal treatment strategy remains unclear in elderly patients. MATERIAL AND METHODS: Patients aged 80 years old and above with T2-T4aN0-2M0-Mx MIBC were identified in the Retrospective International Study of Cancers of the Urothelial Tract (RISC) database. Patients treated with RC were compared with those treated with RCT. The impact of surgery on overall survival (OS) was assessed using a Cox proportional hazard model. Progression included locoregional and metastatic relapse and was considered a time-dependent variable. RESULTS: Between 1988 and 2015, 92 patients underwent RC and 72 patients had RCT. Median age was 82.5 years (range 80-100) and median follow-up was 2.90 years (range 0.04-11.10). Median OS was 1.99 years (95%CI 1.17-2.76) after RC and 1.97 years (95%CI 1.35-2.64) after RCT (p = .73). Median progression-free survival (PFS) after RC and RCT were 1.25 years (95%CI 0.80-1.75) and 1.52 years (95%CI 1.01-2.04), respectively (p = .54). In multivariate analyses, only disease progression was significantly associated with worse OS (HR = 10.27 (95%CI 6.63-15.91), p < .0001). Treatment modality was not a prognostic factor. CONCLUSIONS: RCT offers survival rates comparable to those observed with RC for patients aged ≥80 years.

15 Article Robot-assisted Versus Open Radical Cystectomy in Patients Receiving Perioperative Chemotherapy for Muscle-invasive Bladder Cancer: The Oncologist's Perspective from a Multicentre Study. 2018

Necchi, Andrea / Pond, Gregory R / Smaldone, Marc C / Pal, Sumanta K / Chan, Kevin / Wong, Yu-Ning / Viterbo, Rosalia / Sonpavde, Guru / Harshman, Lauren C / Crabb, Simon / Alva, Ajjai / Chowdhury, Simon / De Giorgi, Ugo / Srinivas, Sandy / Agarwal, Neeraj / Bamias, Aristotelis / Baniel, Jack / Golshayan, Ali-Reza / Ladoire, Sylvain / Sternberg, Cora N / Cerbone, Linda / Yu, Evan Y / Bellmunt, Joaquim / Vaishampayan, Ulka / Niegisch, Gunter / Hussain, Syed / Bowles, Daniel W / Morales-Barrera, Rafael / Milowsky, Matthew I / Theodore, Christine / Berthold, Dominik R / Sridhar, Srikala S / Powles, Thomas / Rosenberg, Jonathan E / Galsky, Matthew D / Anonymous1221193. ·Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: andrea.necchi@istitutotumori.mi.it. · McMaster University, Hamilton, Ontario, Canada. · Fox Chase Cancer Center, Philadelphia, PA, USA. · City of Hope Comprehensive Cancer Center, Duarte, CA, USA. · UAB Comprehensive Cancer Center, Birmingham, AL, USA. · Dana Farber Cancer Institute, Boston, MA, USA. · University of Southampton, Southampton, UK. · University of Michigan, Ann Arbor, MI, USA. · Guy's and St. Thomas' Hospital, London, UK. · IRCCS Istituto Scientifico Romagnolo per lo studio e la Cura dei Tumori, Meldola, Italy. · Stanford University School of Medicine, Stanford, CA, USA. · University of Utah, Salt Lake City, UT, USA. · University of Athens, Athens, Greece. · Rabin Medical Center, Petach Tikva, Israel. · Medical University of South Carolina, Charleston, SC, USA. · Centre Georges-François Leclerc, Dijon, France. · San Camillo Forlanini Hospital, Rome, Italy. · University of Washington, Seattle, WA, USA. · Karmanos Cancer Institute, Detroit, MI, USA. · Heinrich-Heine-University, Düsseldorf, Germany. · University of Liverpool, Liverpool, UK. · Denver Veterans Affairs Medical Center, Eastern Colorado Health Care System, Denver, CO, USA. · Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain. · University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, NC, USA. · Hopital Foch, Suresnes, France. · Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · Princess Margaret Hospital, University Health Network, Toronto, Canada. · Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, UK. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY, USA. ·Eur Urol Focus · Pubmed #28753879.

ABSTRACT: BACKGROUND: Little is known about the outcomes of robot-assisted radical cystectomy (RARC) compared to open radical cystectomy (ORC) combined with perioperative chemotherapy for muscle-invasive urothelial bladder cancer (UBC). OBJECTIVE: To evaluate surgical and oncological outcomes for RARC and ORC in multimodal treatment. DESIGN, SETTING, AND PARTICIPANTS: Data from 28 centres were collected for cystectomies performed between January 2000 and July 2013. INTERVENTION: RARC or ORC combined with perioperative chemotherapy for UBC. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Fisher's exact tests, χ RESULTS AND LIMITATIONS: A total of 688 patients (n=603 ORC and n=85 RARC) were analysed; 60.6% received neoadjuvant chemotherapy, and 45.1% adjuvant chemotherapy. No significant differences in baseline characteristics were found between the groups. The median time from surgery to adjuvant chemotherapy was 1.9 mo for both RARC and ORC groups. The median number of lymph nodes removed was 21 (interquartile range [IQR] 14-35) for RARC and 13 (IQR 8-21) for ORC (p<0.001); the results were confirmed in subgroup analyses. Multivariable analyses revealed no difference in the rate of positive surgical margins (p=0.54 and p=0.78), rate of neobladder diversion (p=0.33 and p=0.51), relapse-free survival (p=0.31 and p=0.23), and overall survival (p=0.63 and p=0.69). The retrospective nature of the data is the major limitation. CONCLUSIONS: In this study, no differences in efficacy outcomes or ability to deliver adjuvant chemotherapy were observed between RARC and ORC. The increasing use of RARC is justifiable from an oncological viewpoint. PATIENT SUMMARY: In a retrospective study of patients who received perioperative chemotherapy for urothelial bladder cancer, we found no difference in key outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy. Performing RARC seems to be justifiable in the multidisciplinary setting.

16 Article Venous thromboembolism in metastatic urothelial carcinoma or variant histologies: incidence, associative factors, and effect on survival. 2017

Ramos, Jorge D / Casey, Martin F / Crabb, Simon J / Bamias, Aristotelis / Harshman, Lauren C / Wong, Yu-Ning / Bellmunt, Joaquim / De Giorgi, Ugo / Ladoire, Sylvain / Powles, Thomas / Pal, Sumanta K / Niegisch, Guenter / Recine, Federica / Alva, Ajjai / Agarwal, Neeraj / Necchi, Andrea / Vaishampayan, Ulka N / Rosenberg, Jonathan E / Galsky, Matthew D / Yu, Evan Y / Anonymous2881008. ·University of Washington, Seattle, Washington. · Icahn School of Medicine at Mount Sinai, New York, New York. · University of Southampton, Southampton, England. · National and Kapodistrian University of Athens, Athens, Greece. · Dana Farber Cancer Institute, Boston, Massachusetts. · Fox Chase Cancer Center, Philadelphia, Pennsylvania. · Hospital del Mar, Barcelona, Spain. · Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Georges François Leclerc Center, Dijon, France. · Université de Bourgogne, Dijon, France. · Barts and the London School of Medicine, London, England. · City of Hope, Duarte, California. · Heinrich-Heine-University, Düsseldorf, Germany. · University of Michigan, Ann Arbor, Michigan. · University of Utah, Salt Lake City, Utah. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Karmanos Cancer Institute, Detroit, Michigan. · Memorial Sloan Kettering Cancer Center, New York, New York. ·Cancer Med · Pubmed #28000388.

ABSTRACT: Venous thromboembolism (VTE) is common in cancer patients. However, little is known about VTE risk in metastatic urothelial carcinoma or variant histologies (UC/VH). We sought to characterize the incidence, associative factors, including whether various chemotherapy regimens portend different risk, and impact of VTE on survival in metastatic UC/VH patients. Patients diagnosed with metastatic UC/VH from 2000 to 2013 were included in this multicenter retrospective, international study from 29 academic institutions. Cumulative and 6-month VTE incidence rates were determined. The association of first-line chemotherapy (divided into six groups) and other baseline characteristics on VTE were analyzed. Each chemotherapy treatment group and statistically significant baseline clinical characteristics were assessed in a multivariate, competing-risk regression model. VTE patients were matched to non-VTE patients to determine the impact of VTE on overall survival. In all, 1762 patients were eligible for analysis. There were 144 (8.2%) and 90 (5.1%) events cumulative and within the first 6 months, respectively. VTE rates based on chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator. Non-urotheilal histology (SHR: 2.67; 95% CI: 1.72-4.16, P < 0.001), moderate to severe renal dysfunction (SHR: 2.12; 95% CI: 1.26-3.59, P = 0.005), and cardiovascular disease (CVD) or CVD risk factors (SHR: 2.27; 95% CI: 1.49-3.45, P = 0.001) were associated with increased VTE rates. Overall survival was worse in patients with VTE (median 6.0 m vs. 10.2 m, P < 0.001). Thus, in metastatic UC/VH patients, VTE is common and has a negative impact on survival. We identified multiple associated potential risk factors, although different chemotherapy regimens did not alter risk.

17 Article Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. 2015

Galsky, Matthew D / Pal, Sumanta K / Chowdhury, Simon / Harshman, Lauren C / Crabb, Simon J / Wong, Yu-Ning / Yu, Evan Y / Powles, Thomas / Moshier, Erin L / Ladoire, Sylvain / Hussain, Syed A / Agarwal, Neeraj / Vaishampayan, Ulka N / Recine, Federica / Berthold, Dominik / Necchi, Andrea / Theodore, Christine / Milowsky, Matthew I / Bellmunt, Joaquim / Rosenberg, Jonathan E / Anonymous7310826. ·Department of Hematology and Medical Oncology, Mount Sinai Medical Center, New York, New York. · Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California. · Department of Urology, Guy's and St. Thomas' Hospital, London, United Kingdom. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, Southampton General Hospital, Southampton, United Kingdom. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. · Division of Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington. · Department of Medical Oncology, Barts Cancer Institute, London, United Kingdom. · Division of Biostatistics, Department of Preventative Medicine, Mount Sinai Medical Center, New York, New York. · Department of Medical Oncology, Georges François Leclerc Center, Dijon, France. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. · Department of Hematology and Oncology, Barbara Ann Karmanos Cancer Center, Detroit, Michigan. · Department of Medical Oncology, Samuel and Barbara Sternberg Cancer Research Foundation, Rome, Italy. · Department of Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland. · Department of Medical Oncology, Foundation IRCCS National Cancer Institute, Milan, Italy. · Department of Oncology, Hospital Foch, Suresnes, France. · Division of Hematology and Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina. · Division of Genitourinary Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. ·Cancer · Pubmed #25872978.

ABSTRACT: BACKGROUND: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC. RESULTS: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48). CONCLUSIONS: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice.

18 Article Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder. 2012

Blick, Christopher / Hall, Peter / Pwint, Thinn / Al-Terkait, Faisal / Crew, Jeremy / Powles, Thomas / Macaulay, Valentine / Munro, Nicholas / Douglas, David / Kilbey, Neviana / Protheroe, Andrew / Chester, John D. ·Department of Urology, Oxford Cancer Centre, The Churchill Hospital, Oxford, UK. ·Cancer · Pubmed #22614698.

ABSTRACT: BACKGROUND: Meta-analysis data demonstrate a 5% absolute survival benefit for neoadjuvant chemotherapy (NAC) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer (MIBC). However, there are no randomized, controlled trial data on the optimum regimen. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) is a dose-intense regimen that has the potential to minimize delays to definitive, potentially curative therapy. A retrospective analysis is presented of the efficacy and toxicity of AMVAC as NAC in patients with MIBC and its impact on the patient pathway. METHODS: Eighty consecutive patients with MIBC were treated with AMVAC as NAC by 2 UK multidisciplinary uro-oncology teams. Three or 4 cycles of AMVAC (methotrexate 30 mg/m(2) , vinblastine 3 mg/m(2) , doxorubicin 30 mg/m(2) , and cisplatin 70 mg/m(2) ) were given at 2-week intervals, with granulocyte colony-stimulating factor support, prior to either radical surgery or radical radiotherapy. RESULTS: All planned cycles of chemotherapy were completed, without dose reduction or delay in 84% of patients. All 80 patients subsequently received their planned definitive therapy. Grade 3/4 toxicities were seen in 26% of the 42% of patients for whom toxicity data are available, including 12% grade 3/4 neutropenia. Pathological complete response to AMVAC was seen in 43% of 60 surgical patients. Objective radiological local response was seen in 83% of 57 evaluable patients. Two-year disease-free and overall survival were 65% and 77%, respectively. CONCLUSIONS: AMVAC is safe and appears to be a well-tolerated and effective NAC regimen for MIBC. It minimizes delays to definitive treatment and produces excellent pathological and radiological response rates. It is an appropriate comparator for future randomized trials.

19 Minor Reply to Pontus Eriksson, Gottfrid Sjödahl, and Fredrik Liedberg's Letter to the Editor re: Thomas Powles, Robert A. Huddart, Tony Elliott, et al. Phase III, Double-blind, Randomized Trial that Compared Maintenance Lapatinib versus Placebo after First-line Chemotherapy in Patients with Human Epidermal Growth Factor Receptor 1/2-positive Metastatic Bladder Cancer. J Clin Oncol 2017;35:48-55. Knowing HER2 Status is Not Enough: A Molecular Subtype Approach to Bladder Cancer is Also Needed: Protein Expression to Predict Outcome to Targeted Therapy in Bladder Cancer: Too Little, Too Late? 2017

Powles, Thomas / Gómez de Liaño, Alfonso / Ackerman, Charlotte. ·Department of Oncology, Barts Cancer Institute, London, UK. Electronic address: thomas.powles@bartshealth.nhs.uk. · Department of Oncology, Barts Cancer Institute, London, UK. ·Eur Urol · Pubmed #28606457.

ABSTRACT: -- No abstract --

20 Minor Immunotherapy: The development of immunotherapy in urothelial bladder cancer. 2015

Powles, Tom. ·Barts Cancer Institute, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London EC1A 7BE, UK. ·Nat Rev Clin Oncol · Pubmed #25781573.

ABSTRACT: -- No abstract --