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1. EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort

Author

Antoine G. van der Heijden, Konstantinos Dimitropoulos, Joost L. Boormans, Bogdan Geavlete, Iris Brummelhuis, Andrew K. Williams, Christoph R. Müller, Susanne Vahr Lauridsen, Arturo Chiti, Manish I. Patel, Jonathan E. Rosenberg, Baris Turkbey, Carl Salembier, Thomas Wiegel, Anja Lorch, Valérie Fonteyne, Willem de Blok, Evanguelos Xylinas, Antti Salminen, Ann Henry, Karin Plass, Amir Sherif, Hugh Mostafid, Peter Wiklund, Erik Veskimäe, Hein Van Poppel, Max Bürger, Juan Palou, J. Domínguez-Escrig, Karel Decaestecker, Morgan Rouprêt, Helle Pappot, Paul Sargos, Berardino De Bari, Riccardo Valdagni, Luís Pacheco-Figueiredo, Jorge Huguet, Silke Gillessen, Olivier Rouvière, Maria J. Ribal, Yann Neuzillet, Richard Cathomas, Shaista Hafeez, Robert Jan Smeenk, Mark Frydenberg, Marek Babjuk, Antoni Vilaseca, Maria De Santis, Jonathan Richenberg, Annemarie Leliveld, Tom J.H. Arends, Shomik Sengupta, Vibeke Løgager, Harry W. Herr, Wim J.G. Oyen, Ananya Choudhury, Nicholas D. James, Susanne Osanto, Shahrokh F. Shariat, Vincent Khoo, A. Müller, Neeraj Agarwal, Pieter De Visschere, Bradley R. Pieters, Alberto Briganti, Robert Jones, Peter C. Black, Alberto Bossi, H. Maxim Bruins, Richard P. Meijer, Bertrand Tombal, Ken Herrmann, Donna E. Hansel, M. Carmen Mir, Stéphane Culine, J. Alfred Witjes, Virginia Hernández, Joaquim Bellmunt, Arnulf Stenzl, Eva Compérat, Alan Horwich, Alison Birtle, Jorg R. Oddens, Bernhard Grubmüller, Margitta Retz, Sylvain Ladoire, Marco Moschini, Aristotle Bamias, Simon J. Crabb, Michel Bolla, Theo H. van der Kwast, Steven MacLennan, Michael Rink, Anita Smits, Yohann Loriot, Estefania Linares-Espinós, James N'Dow, Theo M. de Reijke, Thomas Powles, Jurgen J. Fütterer, Arndt Hartmann, Daniel Castellano, Mesut Remzi, Paolo Gontero, Dickon Hayne, Anne E. Kiltie, Richard Zigeuner, Georgios Gakis, Franklin A. Vives Rivera, Stefano Fanti, Susanne Krege, Pedro C. Lara, Mihai Dorin Vartolomei, Ashish M. Kamat, Jan Oldenburg, Peter Hoskin, Andrea Necchi, Barbara Alicja Jereczek-Fossa, George N. Thalmann, Bernard H. Bochner, Florian Roghmann, Horwich, A, Babjuk, M, Bellmunt, J, Bruins, Hm, De Reijke, Tm, De Santis, M, Gillessen, S, James, N, Maclennan, S, Palou, J, Powles, T, Ribal, Mj, Shariat, Sf, Van der Kwast, T, Xylinas, E, Agarwal, N, Arends, T, Bamias, A, Birtle, A, Black, Pc, Bochner, Bh, Bolla, M, Boormans, Jl, Bossi, A, Briganti, A, Brummelhuis, I, Burger, M, Castellano, D, Cathomas, R, Chiti, A, Choudhury, A, Comperat, E, Crabb, S, Culine, S, De Bari, B, De Blok, W, De Visschere, Pjl, Decaestecker, K, Dimitropoulos, K, Dominguez-Escrig, Jl, Fanti, S, Fonteyne, V, Frydenberg, M, Futterer, Jj, Gakis, G, Geavlete, B, Gontero, P, Grubmuller, B, Hafeez, S, Hansel, De, Hartmann, A, Hayne, D, Henry, Am, Hernandez, V, Herr, H, Herrmann, K, Hoskin, P, Huguet, J, Jereczek-Fossa, Ba, Jones, R, Kamat, Am, Khoo, V, Kiltie, Ae, Krege, S, Ladoire, S, Lara, Pc, Leliveld, A, Linares-Espinos, E, Logager, V, Lorch, A, Loriot, Y, Meijer, R, Mir, Mc, Moschini, M, Mostafid, H, Muller, Ac, Muller, Cr, N'Dow, J, Necchi, A, Neuzillet, Y, Oddens, Jr, Oldenburg, J, Osanto, S, Oyen, Wjg, Pacheco-Figueiredo, L, Pappot, H, Patel, Mi, Pieters, Br, Plass, K, Remzi, M, Retz, M, Richenberg, J, Rink, M, Roghmann, F, Rosenberg, Je, Roupret, M, Rouviere, O, Salembier, C, Salminen, A, Sargos, P, Sengupta, S, Sherif, A, Smeenk, Rj, Smits, A, Stenzl, A, Thalmann, Gn, Tombal, B, Turkbey, B, Lauridsen, Sv, Valdagni, R, Van der Heijden, Ag, Van Poppel, H, Vartolomei, Md, Veskimae, E, Vilaseca, A, Rivera, Fav, Wiegel, T, Wiklund, P, Williams, A, Zigeuner, R, Witjes, Ja, Radiation Oncology, Horwich A, Babjuk M, Bellmunt J, Bruins HM, De Reijke TM, De Santis M, Gillessen S, James N, Maclennan S, Palou J, Powles T, Ribal MJ, Shariat SF, Van Der Kwast T, Xylinas E, Agarwal N, Arends T, Bamias A, Birtle A, Black PC, Bochner BH, Bolla M, Boormans JL, Bossi A, Briganti A, Brummelhuis I, Burger M, Castellano D, Cathomas R, Chiti A, Choudhury A, Compérat E, Crabb S, Culine S, De Bari B, DeBlok W, De Visschere PJL, Decaestecker K, Dimitropoulos K, Dominguez-Escrig JL, Fanti S, Fonteyne V, Frydenberg M, Futterer JJ, Gakis G, Geavlete B, Gontero P, Grubmüller B, Hafeez S, Hansel DE, Hartmann A, Hayne D, Henry AM, Hernandez V, Herr H, Herrmann K, Hoskin P, Huguet J, Jereczek-Fossa BA, Jones R, Kamat AM, Khoo V, Kiltie AE, Krege S, Ladoire S, Lara PC, Leliveld A, Linares-Espinós E, Løgager V, Lorch A, Loriot Y, Meijer R, Carmen Mir M, Moschini M, Mostafid H, Müller AC, Müller CR, N'Dow J, Necchi A, Neuzillet Y, Oddens JR, Oldenburg J, Osanto S, Oyen WJG, Pacheco-Figueiredo L, Pappot H, Patel MI, Pieters BR, Plass K, Remzi M, Retz M, Richenberg J, Rink M, Roghmann F, Rosenberg JE, Rouprêt M, Rouvière O, Salembier C, Salminen A, Sargos P, Sengupta S, Sherif A, Smeenk RJ, Smits A, Stenzl A, Thalmann GN, Tombal B, Turkbey B, Vahr Lauridsen S, Valdagni R, Van Der Heijden AG, Van Poppel H, Vartolomei MD, Veskimäe E, Vilaseca A, Vives Rivera FA, Wiegel T, Wiklund P, Williams A, Zigeuner R, Witjes JA., Universidade do Minho, APH - Personalized Medicine, APH - Quality of Care, CCA - Cancer Treatment and Quality of Life, Urology, Radiotherapy, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - (SLuc) Service d'urologie, and Pathology

Subjects
0301 basic medicine, Delphi Technique, diagnosis, International Cooperation, Medicina Básica [Ciências Médicas], Delphi method, Medizin, CISPLATIN-INELIGIBLE PATIENTS, Medical Oncology, Delphi, 0302 clinical medicine, PROGNOSTIC-FACTORS, Multidisciplinary approach, Surveys and Questionnaires, consensu, follow-up, SINGLE-ARM, Medicine, Statistical analysis, Multi stakeholder, TRANSITIONAL-CELL CARCINOMA, Societies, Medical, computer.programming_language, treatment, Consensus conference, Hematology, 3. Good health, Europe, diagnosi, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Ciências Médicas::Medicina Básica, Practice Guidelines as Topic, TUMOR RESPONSE, Special article, bladder cancer, RADICAL CYSTECTOMY, LYMPHOCYTE RATIO, medicine.medical_specialty, METASTATIC UROTHELIAL CARCINOMA, Urology, Urinary Bladder, education, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], LONG-TERM-SURVIVAL, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Stakeholder Participation, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Journal Article, Humans, Oligometastatic disease, Neoplasm Staging, Science & Technology, Bladder cancer, business.industry, medicine.disease, 030104 developmental biology, Urinary Bladder Neoplasms, consensus, Family medicine, business, computer
Abstract

Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as 70% agreement and 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.

Published
2019

2. Incidence, Patterns, and Outcomes with Adjuvant Chemotherapy for Residual Disease After Neoadjuvant Chemotherapy in Muscle-invasive Urinary Tract Cancers

Author

Sumanta K. Pal, Lauren C. Harshman, Thomas Powles, Simon J. Crabb, Matthew I. Milowsky, Lillian Werner, Ajjai Alva, Jonathan E. Rosenberg, Sylvain Ladoire, Nieves Martinez Chanza, Joaquim Bellmunt, Matthew D. Galsky, Syed A. Hussain, Dominik Berthold, Cora N. Sternberg, Ulka N. Vaishampayan, Andrea Necchi, Jack Baniel, Neeraj Agarwal, Elizabeth R. Plimack, Evan Y. Yu, Martinez Chanza, N., Werner, L., Plimack, E., Yu, E. Y., Alva, A. S., Crabb, S. J., Powles, T., Rosenberg, J. E., Baniel, J., Vaishampayan, U. N., Berthold, D. R., Ladoire, S., Hussain, S. A., Milowsky, M. I., Agarwal, N., Necchi, A., Pal, S. K., Sternberg, C. N., Bellmunt, J., Galsky, M. D., and Harshman, L. C.

Subjects
Oncology, Male, medicine.medical_specialty, Urologic Neoplasms, Neoplasm, Residual, Urology, medicine.medical_treatment, Population, 030232 urology & nephrology, Neoadjuvant chemotherapy, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, Humans, Radiology, Nuclear Medicine and imaging, Neoplasm Invasiveness, Risk of relapse, Stage (cooking), education, Aged, Retrospective Studies, Chemotherapy, education.field_of_study, Proportional hazards model, business.industry, Incidence (epidemiology), Cancer, Middle Aged, Residual disease, medicine.disease, Time to recurrence, Neoadjuvant Therapy, Adjuvant chemotherapy, Regimen, Treatment Outcome, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Surgery, Female, Neoplasm Recurrence, Local, business, Muscle-invasive bladder cancer, Muscle-invasive urinary tract cancer
Abstract

BACKGROUND: Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence.OBJECTIVE: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC.DESIGN, SETTING, AND PARTICIPANTS: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN+).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses.RESULTS AND LIMITATIONS: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: CONCLUSIONS: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials.PATIENT SUMMARY: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system.

Published
2020

3. Corrigendum to ‘EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer—An International Collaborative Multistakeholder Effort Under the Auspices of the EAU-ESMO Guidelines Committees’ [European Urology 77 (2020) 223–250](S0302283819307638)(10.1016/j.eururo.2019.09.035)

Author

Bogdan Geavlete, Stefano Fanti, Susanne Krege, Alberto Briganti, Harry W. Herr, Shaista Hafeez, Mark Frydenberg, Marek Babjuk, Willem de Blok, Antti Salminen, Maria De Santis, Yann Neuzillet, Arnulf Stenzl, Joost L. Boormans, Hein Van Poppel, Karel Decaestecker, Vibeke Løgager, Jorg R. Oddens, Silke Gillessen, Pedro C. Lara, Berardino De Bari, Baris Turkbey, Andrew K. Williams, Thomas Wiegel, Mihai Dorin Vartolomei, Robert Jones, Riccardo Valdagni, Vincent Khoo, Ashish M. Kamat, Christoph R. Müller, Georgios Gakis, Neeraj Agarwal, Annemarie Leliveld, Franklin A. Vives Rivera, Robert Jan Smeenk, Luís Pacheco-Figueiredo, H. Maxim Bruins, Juan Palou, Jorge Huguet, Konstantinos Dimitropoulos, Jonathan E. Rosenberg, Carl Salembier, Ken Herrmann, Iris Brummelhuis, Morgan Rouprêt, Helle Pappot, Susanne Osanto, Shahrokh F. Shariat, Anita Smits, Susanne Vahr Lauridsen, Manish I. Patel, Theo H. van der Kwast, Paul Sargos, Michel Bolla, Karin Plass, Jurgen J. Fütterer, Hugh Mostafid, Olivier Rouvière, Valérie Fonteyne, Erik Veskimäe, Bradley R. Pieters, Richard P. Meijer, Anne E. Kiltie, Tom J.H. Arends, Arndt Hartmann, Amir Sherif, Antoni Vilaseca, Stéphane Culine, Wim J.G. Oyen, Evanguelos Xylinas, Daniel Castellano, Shomik Sengupta, James N'Dow, Maria J. Ribal, Mesut Remzi, Richard Zigeuner, A. Müller, Richard Cathomas, Joaquim Bellmunt, Nicholas D. James, Paolo Gontero, Pieter De Visschere, Eva Compérat, Alison Birtle, Margitta Retz, Dickon Hayne, Michael Rink, Virginia Hernández, J. Alfred Witjes, Marco Moschini, J. Domínguez-Escrig, Yohann Loriot, Estefania Linares-Espinós, Peter C. Black, Alberto Bossi, Bertrand Tombal, Sylvain Ladoire, Aristotle Bamias, Ananya Choudhury, Simon J. Crabb, Steven MacLennan, Peter Wiklund, Antoine G. van der Heijden, Arturo Chiti, Bernhard Grubmüller, Barbara Alicja Jereczek-Fossa, Alan Horwich, George N. Thalmann, Bernard H. Bochner, Florian Roghmann, Max Bürger, Jan Oldenburg, Peter Hoskin, Andrea Necchi, Jonathan Richenberg, Anja Lorch, Peter Paul M. Willemse, Donna E. Hansel, M. Carmen Mir, Thomas Powles, Theo M. de Reijke, Ann Henry, Witjes, J. A., Babjuk, M., Bellmunt, J., Bruins, H. M., De Reijke, T. M., De Santis, M., Gillessen, S., James, N., Maclennan, S., Palou, J., Powles, T., Ribal, M. J., Shariat, S. F., Van Der Kwast, T., Xylinas, E., Agarwal, N., Arends, T., Bamias, A., Birtle, A., Black, P. C., Bochner, B. H., Bolla, M., Boormans, J. L., Bossi, A., Briganti, A., Brummelhuis, I., Burger, M., Castellano, D., Cathomas, R., Chiti, A., Choudhury, A., Comperat, E., Crabb, S., Culine, S., De Bari, B., De Blok, W., De Visschere, P. J. L., Decaestecker, K., Dimitropoulos, K., Dominguez-Escrig, J. L., Fanti, S., Fonteyne, V., Frydenberg, M., Futterer, J. J., Gakis, G., Geavlete, B., Gontero, P., Grubmuller, B., Hafeez, S., Hansel, D. E., Hartmann, A., Hayne, D., Henry, A. M., Hernandez, V., Herr, H., Herrmann, K., Hoskin, P., Huguet, J., Jereczek-Fossa, B. A., Jones, R., Kamat, A. M., Khoo, V., Kiltie, A. E., Krege, S., Ladoire, S., Lara, P. C., Leliveld, A., Linares-Espinos, E., Logager, V., Lorch, A., Loriot, Y., Meijer, R., Mir, M. C., Moschini, M., Mostafid, H., Muller, A. -C., Muller, C. R., N'Dow, J., Necchi, A., Neuzillet, Y., Oddens, J. R., Oldenburg, J., Osanto, S., Oyen, W. J. G., Pacheco-Figueiredo, L., Pappot, H., Patel, M. I., Pieters, B. R., Plass, K., Remzi, M., Retz, M., Richenberg, J., Rink, M., Roghmann, F., Rosenberg, J. E., Roupret, M., Rouviere, O., Salembier, C., Salminen, A., Sargos, P., Sengupta, S., Sherif, A., Smeenk, R. J., Smits, A., Stenzl, A., Thalmann, G. N., Tombal, B., Turkbey, B., Lauridsen, S. V., Valdagni, R., Van Der Heijden, A. G., Van Poppel, H., Vartolomei, M. D., Veskimae, E., Vilaseca, A., Rivera, F. A. V., Wiegel, T., Wiklund, P., Willemse, P. -P. M., Williams, A., Zigeuner, R., Horwich, A., Urology, APH - Personalized Medicine, APH - Quality of Care, CCA - Cancer Treatment and Quality of Life, Radiotherapy, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service d'urologie

Subjects
medicine.medical_specialty, Bladder cancer, business.industry, Urology, 030232 urology & nephrology, MEDLINE, Cancer, Regret, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Urologia, University medical, Bufeta -- Càncer, Protocols clínics, business
Abstract

The authors regret that a co-author was mistakenly missed from the authorship. The following co-author should have been included in the authorship: Peter-Paul M. Willemse Department of Oncological Urology, University Medical Center, Utrecht Cancer Center, Utrecht, The Netherlands

Published
2020

4. Treatment of Metastatic Urothelial Carcinoma After Previous Cisplatin-based Chemotherapy for Localized Disease: A Retrospective Comparison of Different Chemotherapy Regimens

Author

Olivia A. Do, Tanya B. Dorff, Joaquim Bellmunt, Evan Y. Yu, Aristotelis Bamias, Ulka N. Vaishampayan, Sandy Srinivas, Jorge Ramos, Andrea Necchi, Lorin A. Ferris, Sarah K. Holt, Elizabeth R. Plimack, Jack Baniel, Lauren C. Harshman, Ugo De Giorgi, Sumanta K. Pal, Simon J. Crabb, Sylvain Ladoire, Matthew D. Galsky, Do, O. A., Ferris, L. A., Holt, S. K., Ramos, J. D., Harshman, L. C., Plimack, E. R., Crabb, S. J., Pal, S. K., De Giorgi, U., Ladoire, S., Baniel, J., Necchi, A., Vaishampayan, U. N., Bamias, A., Bellmunt, J., Srinivas, S., Dorff, T. B., Galsky, M. D., and Yu, E. Y.

Subjects
Oncology, medicine.medical_specialty, Metastatic Urothelial Carcinoma, Survival, Urology, medicine.medical_treatment, 030232 urology & nephrology, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Retrospective Studies, Platinum, Carcinoma, Transitional Cell, Chemotherapy, Bladder cancer, business.industry, Proportional hazards model, Hazard ratio, First-line, Perioperative, medicine.disease, Treatment Outcome, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Localized disease, Cisplatin, Neoadjuvant, business
Abstract

Background: Optimal chemotherapy for patients who received cisplatin for localized urothelial carcinoma (UC) and develop metastatic disease is unclear. We compared the efficacy of platinum-based (PBC) versus non–platinum-based (NPBC) first-line chemotherapy for metastasis. Patients and Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3024 patients from 28 international academic centers from 2005 to 2012. Patient inclusion criteria included: (1) predominant UC; (2) any primary tumor site; (3) cT2-4, cN0-N2, cM0; (4) prior receipt of perioperative/radiation cisplatin-containing chemotherapy; and (5) receipt of cytotoxic chemotherapy in the first-line metastatic setting. Multivariate Cox proportional hazards models were used to show progression-free survival (PFS) and overall survival (OS) from the first day of chemotherapy for metastatic disease to date of censor. Results: Eligibility criteria was met by 132 patients (n = 74 PBC; n = 58 NPBC). The median OS was 8.13 months (interquartile range, 4.87-16.64 months) and 8.77 months (interquartile range, 4.01-13.49 months) for PBC and NPBC, respectively. Neither OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.64-1.69; P =. 87) nor PFS (HR, 0.86; 95% CI, 0.56-1.31; P =. 48) differed for PBC versus NPBC. However, for patients who received chemotherapy more than a year after perioperative/radiation chemotherapy, OS was superior for PBC over NPBC (HR, 0.31; 95% CI, 0.10-0.92; P = .03). Conclusions: There is no significant outcome difference between PBC and NPBC in patients with metastatic UC who previously received cisplatin-based chemotherapy for localized disease. However, if over a year has elapsed, return to PBC is associated with superior OS. The optimal chemotherapy regimen for metastatic urothelial carcinoma following previous cisplatin-based chemotherapy, administered for localized disease, remains unclear. We found benefit of platinum-based over non–platinum-based first-line chemotherapy for patients with metastatic disease treated at least 1 year from completion of prior perioperative and/or peri-radiation cisplatin-based chemotherapy. These findings support return to platinum chemotherapy in this clinical scenario.

Published
2020

5. Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis

Author

Vadim S. Koshkin, Joaquim Bellmunt, Matthew D. Galsky, Sylvain Ladoire, B.J. Eigl, Bas W.G. van Rhijn, Andrea Necchi, Johnathan E. Rosenberg, Guenter Niegisch, Kees Hendricksen, Salvatore Lo Vullo, Daniel W. Bowles, Sandy Srinivas, Aristotelis Bamias, Ali Reza Golshayan, Evan Y. Yu, Florian Roghmann, Michael Woods, Matthew I. Milowsky, Jakub Dobruch, Petros Grivas, Evanguelos Xylinas, Dominik D. Berthold, Yu-Ning Wong, Neeraj Agarwal, Srikala S. Sridhar, Jack Baniel, Lucia Nappi, Federica Recine, Ulka N. Vaishampayan, Lauren C. Harshman, Ugo De Giorgi, Simon J. Crabb, Luigi Mariani, Carsten Ohlmann, Ajjaj Alva, Sumanta K. Pal, Thomas Powles, Christine Theodore, Cora N. Sternberg, Necchi, A, Mariani, L, Lo Vullo, S, Yu, Ey, Woods, Me, Wong, Yn, Harshman, Lc, Alva, A, Sternberg, Cn, Bamias, A, Grivas, P, Koshkin, V, Roghmann, F, Dobruch, J, Eigl, Bj, Nappi, L, Milowsky, Mi, Niegisch, G, Pal, Sk, De Giorgi, U, Recine, F, Vaishampayan, U, Berthold, Dd, Bowles, Dw, Baniel, J, Theodore, C, Ladoire, S, Srinivas, S, Agarwal, N, Crabb, S, Sridhar, S, Golshayan, Ar, Ohlmann, C, Xylinas, E, Powles, T, Rosenberg, Je, Bellmunt, J, van Rhijn, B, Galsky, Md, and Hendricksen, K

Subjects
medicine.medical_specialty, Urology, medicine.medical_treatment, Retroperitoneal Lymph Node, 030232 urology & nephrology, Cystectomy, Article, Pelvis, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Retroperitoneal Space, Propensity Score, Lymph node, Aged, Neoplasm Staging, Retrospective Studies, Carcinoma, Transitional Cell, Bladder cancer, business.industry, Hazard ratio, Middle Aged, medicine.disease, Primary tumor, Progression-Free Survival, 3. Good health, Surgery, Treatment Outcome, medicine.anatomical_structure, Urinary Bladder Neoplasms, Chemotherapy, Adjuvant, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Propensity score matching, Lymph Node Excision, Lymphadenectomy, Lymph Nodes, business
Abstract

Background: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. Objective: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. Design, setting, and participants: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic. ±. RP) only, first-line platinum-based chemotherapy given. Intervention: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. Outcome measures and statistical analysis: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. Results and limitations: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p = 0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p = 0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. Conclusions: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. Patient summary: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies. In contemporary cohorts of patients with metastatic pelvic or retroperitoneal lymph nodes from bladder cancer, we found no survival benefit from postchemotherapy surgery versus observation in a retrospective study. Performing postchemotherapy lymphadenectomy remains investigational in patients with metastatic bladder cancer.

Published
2019

6. The Impact of Cisplatin- or Non-Cisplatin-Containing Chemotherapy on Long-Term and Conditional Survival of Patients with Advanced Urinary Tract Cancer

Author

Sumanta K. Pal, Thomas Powles, Lauren C. Harshman, Ugo De Giorgi, Christine Theodore, Aristotelis Bamias, Simon J. Crabb, Elizabeth R. Plimack, Christina Bamia, Ulka N. Vaishampayan, Joaquim Bellmunt, Guenter Niegisch, Cora N. Sternberg, Andrea Necchi, Sandy Srinivas, Jonathan E. Rosenberg, Matthew D. Galsky, Michalis Liontos, Kimon Tzannis, Evan Y. Yu, Neeraj Agarwal, Sylvain Ladoire, Bamias, A, Tzannis, K, Bamia, C, Harshman, Lc, Crabb, S, Plimack, Er, Pal, S, De Giorgi, U, Ladoire, S, Theodore, C, Agarwal, N, Yu, Ey, Niegisch, G, Sternberg, Cn, Srinivas, S, Vaishampayan, U, Necchi, A, Liontos, M, Rosenberg, Je, Powles, T, Bellmunt, J, and Galsky, Md

Subjects
Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Urologic Neoplasms, medicine.medical_treatment, Urinary system, Genitourinary Cancer, 03 medical and health sciences, 0302 clinical medicine, Conditional survival, Internal medicine, medicine, Humans, In patient, 030212 general & internal medicine, Aged, Retrospective Studies, Cisplatin, Aged, 80 and over, Chemotherapy, business.industry, Combination chemotherapy, Middle Aged, medicine.disease, Survival Analysis, Confidence interval, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, business, medicine.drug
Abstract

Background The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC. Materials and Methods A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy. Results Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1–38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7–93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8–17.6) and 49.3% (95% CI: 28.2–67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation. Conclusion Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients. Implications for Practice Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.

Published
2019

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

Author

Lauren C. Harshman, Ugo De Giorgi, Kevin Chan, Simon J. Crabb, Ulka N. Vaishampayan, Evan Y. Yu, Guru Sonpavde, Günter Niegisch, Cora N. Sternberg, Joaquim Bellmunt, Ali Reza Golshayan, Yu-Ning Wong, Sylvain Ladoire, Rafael Morales-Barrera, Syed A. Hussain, Ajjai Alva, Jonathan E. Rosenberg, Andrea Necchi, Simon Chowdhury, Matthew I. Milowsky, Gregory R. Pond, Daniel W. Bowles, Aristotelis Bamias, Jack Baniel, Matthew D. Galsky, Srikala S. Sridhar, Marc C. Smaldone, Sandy Srinivas, Dominik Berthold, Neeraj Agarwal, Sumanta K. Pal, Thomas Powles, Christine Theodore, Linda Cerbone, Rosalia Viterbo, Fondazione IRCCS Istituto Nazionale dei Tumori, McMaster University [Hamilton, Ontario], Fox Chase Cancer Center, City of Hope Comprehensive Cancer Center [Duarte], UAB Comprehensive Cancer Center UAB Comprehensive Cancer Center [Birmingham, AL, USA], University of Alabama at Birmingham [ Birmingham] (UAB), Dana-Farber Cancer Institute [Boston], University of Southampton, University of Michigan [Ann Arbor], University of Michigan System, Guy's and St Thomas' Hospital [London], Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Utah School of Medicine [Salt Lake City], National and Kapodistrian University of Athens (NKUA), Rabin Medical Center - Beilinson and Hasharon Hospitals [Petach-Tikva, Israel], Medical University of South Carolina [Charleston] (MUSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, San Camillo Forlanini Hospital [Rome], University of Washington [Seattle], Karmanos Cancer Institute, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Liverpool, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Hôpital Foch [Suresnes], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Toronto, Princess Margaret Hospital, Barts & The London School of Medicine, Memorial Sloane Kettering Cancer Center [New York], Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Necchi, A, Pond, Gr, Smaldone, Mc, Pal, Sk, Chan, K, Wong, Yn, Viterbo, R, Sonpavde, G, Harshman, Lc, Crabb, S, Alva, A, Chowdhury, S, De Giorgi, U, Srinivas, S, Agarwal, N, Bamias, A, Baniel, J, Golshayan, Ar, Ladoire, S, Sternberg, Cn, Cerbone, L, Yu, Ey, Bellmunt, J, Vaishampayan, U, Niegisch, G, Hussain, S, Bowles, Dw, Morales-Barrera, R, Milowsky, Mi, Theodore, C, Berthold, Dr, Sridhar, S, Powles, T, Rosenberg, Je, and Galsky, Md

Subjects
Male, medicine.medical_treatment, 030232 urology & nephrology, Urinary Diversion, 0302 clinical medicine, Robotic Surgical Procedures, Interquartile range, Perioperative chemotherapy, Oncologists, Muscle invasive, Margins of Excision, Middle Aged, Prognosis, Neoadjuvant Therapy, 3. Good health, Survival Rate, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Urothelial carcinoma, medicine.medical_specialty, Urology, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cystectomy, Article, Disease-Free Survival, 03 medical and health sciences, medicine, Humans, Robot-assisted surgery, Neoplasm Invasiveness, Aged, Proportional Hazards Models, Retrospective Studies, Carcinoma, Transitional Cell, Chemotherapy, Bladder cancer, business.industry, Proportional hazards model, Muscle, Smooth, Retrospective cohort study, medicine.disease, Surgery, Logistic Models, Urinary Bladder Neoplasms, Multivariate Analysis, Lymph Node Excision, Muscle-invasive disease, Lymph Nodes, business
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, χ2 tests, and Wilcoxon rank-sum tests were used to compare the RARC and ORC groups. Logistic and Cox regression analyses were performed to evaluate potential prognostic factors. 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. In contemporary cohorts of patients who have received perioperative chemotherapy for muscle-invasive bladder cancer, no substantial differences were found between robot-assited radical cystectomy (RARC) and open radical cystectomy, and the number of lymph nodes removed was higher with RARC.

Published
2018

8. Impact of timing of adjuvant chemotherapy following radical cystectomy for bladder cancer on patient survival

Author

Evan Y. Yu, Ulka N. Vaishampayan, Jack Baniel, Lauren C. Harshman, Alina Henn, Ugo De Giorgi, Camilla Marisa Grunewald, Simon J. Crabb, Matthew D. Galsky, Guenter Niegisch, Thomas Powles, Elizabeth R. Plimack, Sylvain Ladoire, Joaquim Bellmunt, Neeraj Agarwal, Ajjai Alva, Andrea Necchi, Aristotelis Bamias, Sumanta K. Pal, Cora N. Sternberg, Grunewald, C. M., Henn, A., Galsky, M. D., Plimack, E. R., Harshman, L. C., Yu, E. Y., Crabb, S. J., Pal, S. K., Alva, A. S., Powles, T., De Giorgi, U., Agarwal, N., Bamias, A., Ladoire, S., Necchi, A., Vaishampayan, U. N., Sternberg, C. N., Bellmunt, J., Baniel, J., and Niegisch, G.

Subjects
Male, Oncology, Cancer Research, medicine.medical_specialty, Time Factors, Adjuvant chemotherapy, RISC data base, Urology, medicine.medical_treatment, 030232 urology & nephrology, Locally advanced bladder cancer, Cystectomy, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, Muscle invasive bladder cancer, Adjuvant therapy, Humans, Medicine, Survival analysis, Aged, Retrospective Studies, Chemotherapy, Univariate analysis, Bladder cancer, business.industry, Proportional hazards model, Hazard ratio, Patient survival, Middle Aged, medicine.disease, Survival Rate, Treatment Outcome, Urinary Bladder Neoplasms, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, business
Abstract

BACKGROUND: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start within 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome.METHODS: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Univariate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed using Kruskal-Wallis testing and Fisher's exact test. Analysis of progression-free (PFS) and overall survival (OS) (follow-up time beginning with the start date of adjuvant chemotherapy) was analyzed in relation to S-AC-interval (continuous and dichotomous with a cut-off at 90 days) using Kaplan-Meier method and COX regression analysis.RESULTS: We identified 238 eligible patients (83.5% male, mean age: 63.4 years, 76.1% T3/T4, 66.4% pN+, 14.7% R+, 70.6% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). The majority of patients (n = 207, 87%) started chemotherapy within 90 days after surgery. Median S-AC-interval was 57 days (interquartile range 32.8). S-AC-interval did not have consistent association with any patient/tumor characteristics or surgery related factors (type of surgery, urinary diversion). Survival analysis using continuous S-AC-interval revealed a trend toward an impact of S-AC-interval on OS (hazard ratio 1.004, 95% confidence ratio 0.9997-1.0084, P = 0.071). With regards to PFS, that impact was shown to be statistically significant (hazard ratio 1.004, 95% confidence ratio 1.0003-1.0075, P = 0.032). In multivariate analysis, however, S-AC-interval was negated by tumor and patient related factors (pathological T-stage, N-stage, ECOG performance status). Accounting for eligibility criteria defined in some clinical trials, we extended our analysis dividing S-AC-interval in ≤90 and >90 days. Although we could confirm the trend toward better outcome in patients with a shorter S-AC interval in dichotomous analysis, neither differences in OS nor in PFS reached statistical significance (P = 0.438 and P = 0.056).CONCLUSIONS: In a large multi-institutional experience, 87% of patients who received adjuvant chemotherapy received it within the guideline recommended window of 90 days. While it was not possible to determine whether this is the optimal cut-off, early start of adjuvant chemotherapy seems to be reasonable. Regarding prognosis, tumor-related pathological factors abrogated the importance of the S-AC-interval in our analysis.

Published
2020

9. Neoadjuvant vs. Adjuvant Chemotherapy in Muscle Invasive Bladder Cancer (MIBC): Analysis From the RISC Database

Author

Aristotelis Bamias, Evan Y. Yu, Andrea Necchi, Joaquim Bellmunt, Gabriella Del Bene, Cora N. Sternberg, Diana Giannarelli, Sumanta K. Pal, Thomas Powles, Günter Niegisch, Elizabeth R. Plimack, Jack Baniel, Sylvain Ladoire, Ajjai Alva, Fabio Calabrò, Matthew D. Galsky, Neeraj Agarwal, Ulka N. Vaishampayan, Lauren C. Harshman, Ugo De Giorgi, Simon J. Crabb, San Camillo Forlanini Hospital [Rome], National Cancer Institute Regina Elena [Rome, Italy], Fox Chase Cancer Center, Dana-Farber Cancer Institute [Boston], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), University of Southampton, City of Hope Comprehensive Cancer Center [Duarte], University of Michigan [Ann Arbor], University of Michigan System, St Bartholomew's Hospital (London), IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (Meldola), University of Utah School of Medicine [Salt Lake City], Huntsman Cancer Institute, National and Kapodistrian University of Athens (NKUA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Karmanos Cancer Institute, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Rabin Medical Center (Petah Tikva), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Del Bene, G, Calabro, F, Giannarelli, D, Plimack, Er, Harshman, Lc, Yu, Ey, Crabb, Sj, Pal, Sk, Alva, A, Powles, T, De Giorgi, U, Agarwal, N, Bamias, A, Ladoire, S, Necchi, A, Vaishampayan, Un, Niegisch, G, Bellmunt, J, Baniel, J, Galsky, Md, and Sternberg, Cn

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Adjuvant chemotherapy, medicine.medical_treatment, RISC data base, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, muscle invasive bladder cancer, Cancer specific survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Adjuvant therapy, Overall survival, Medicine, Original Research, Chemotherapy, Bladder cancer, business.industry, Muscle invasive, Perioperative, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, adjuvant chemotherapy, locally advanced bladder cancer, 030104 developmental biology, 030220 oncology & carcinogenesis, business, neoadjuvant chemotherapy
Abstract

Background: MIBC is an aggressive disease, with 5-year survival rates ranging from 36% to 48% for p T3/p T4/p N+tumors. Perioperative treatment can improve overall survival, with more robust evidence in favor of neoadjuvant chemotherapy. Few randomized studies have compared neoadjuvant and adjuvant therapy in bladder cancer. Consequently, it has been difficult to establish the benefit of adjuvant chemotherapy(AC) in MIBC. Methods: data from patients with muscle invasive bladder cancer (>pT2) collected from 2005 to 2012 within the RISC data base (Retrospective International Study of Cancers of the Urothelial Tract) were evaluated. Overall survival(OS), cancer specific survival (CSS) and disease-free survival (DFS) between NC and AC generated using the Kaplan-Meier methodwere compared for MIBC by log-rank test. All patients in this analysis received either NC or AC. Results: A total of 656 patients with MIBC (325 treated with AC and 331 with NC) were analyzed. The median disease-free survival (DFS) was 37.6 months (95% CI:24.7-50.5) for NC vs 24.3 months (95% CI: 19.3- 29.3) with AC, with a reduction in the risk of disease progression of 21% in favor of NC (HR: 0.79, 95% CI: 0.63-0.99, p: 0.04). There were no significant differences in terms of CSS (HR: 1.21, IC 95%: 0.90-1.63, p: 0.21), and OS (HR: 1.22, 95% CI: 0.95-1.58, P=0.12). Conclusions: within the limits of this retrospective study, this analysis suggests that NC is the best treatment for MIBC in terms of DFS. Nonetheless, CSS and OS were similar with both NC and AC strategies.

Published
2018

10. Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: a Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

Author

Ajjai Alva, Jonathan E. Rosenberg, Matthew D. Galsky, Andrea Necchi, U. De Giorgi, Thomas Powles, Joaquim Bellmunt, Michalis Liontos, L. Cerbone, Yu-Ning Wong, Aristotelis Bamias, Kimon Tzannis, Evan Y. Yu, Neeraj Agarwal, S. Kumar Pal, Lauren C. Harshman, Simon J. Crabb, Ulka N. Vaishampayan, Cora N. Sternberg, Günter Niegisch, Sylvain Ladoire, S. Srinivas, Department of Clinical Therapeutics (School of Medicine, National and Kapodistrian University of Athens), National and Kapodistrian University of Athens (NKUA), Dana-Farber Cancer Institute [Boston], University of Southampton, Fox Chase Cancer Center, City of Hope Comprehensive Cancer Center [Duarte], IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (Meldola), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, University of Utah School of Medicine [Salt Lake City], University of Washington [Seattle], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Fondazione IRCCS Istituto Nazionale dei Tumori, San Camillo Forlanini Hospital [Rome], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Michigan [Ann Arbor], University of Michigan System, Karmanos Cancer Institute (Detroit), Memorial Sloane Kettering Cancer Center [New York], Barts and the London School of Medicine and Dentistry [London, UK], Queen Mary University of London (QMUL), Mount Sinai School of Medicine, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Bamias, A, Tzannis, K, Harshman, Lc, Crabb, Sj, Wong, Yn, Pal, Sk, De Giorgi, U, Ladoire, S, Agarwal, N, Yu, Ey, Niegisch, G, Necchi, A, Sternberg, Cn, Srinivas, S, Alva, A, Vaishampayan, U, Cerbone, L, Liontos, M, Rosenberg, J, Powles, T, Bellmunt, J, and Galsky, Md

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Urologic Neoplasms, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, 030304 developmental biology, Retrospective Studies, Cisplatin, 0303 health sciences, Chemotherapy, business.industry, Standard treatment, Hazard ratio, Retrospective cohort study, Combination chemotherapy, Hematology, Urogenital tumor, Chemotherapy regimen, Corrigenda, Carboplatin, 3. Good health, 030104 developmental biology, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

BackgroundCisplatin-based combination chemotherapy is the standard treatment for advanced urinary tract cancer (aUTC) but 50% of patients are ineligible for cisplatin according to recently published criteria. We used a multinational database to study patterns of chemotherapy utilization in patients with aUTC and determine their impact on survival.Patients and MethodsThis was a retrospective study of patients with: UTC (bladder, renal pelvis, ureter or urethra); advanced disease (stages T4b and/or N+ and/or M+); urothelial, squamous or adenocarcinoma histology. Primary objective was overall survival (OS). Eligibility-for-cisplatin was defined by: Eastern Cooperative Oncology group (ECOG) performance status (PS)≤1, creatinine clearance (CrCl)≥60 ml/min, no hearing loss, no neuropathy, no heart failure. Cox regression multivariate analyses were used to establish independent associations of cisplatin vs. non-cisplatin-based chemotherapy on OS.ResultsAbout 1794 patients treated between 2000 and 2013 at 29 centers were analyzed. Median follow-up was 29.1 months. 1333 patients (74%) received 1st-line chemotherapy: Use of 1st-line chemotherapy was associated with longer OS: (Hazard ratio [HR]: 1.91, 95% confidence interval [CI]: 1.67-2.20). Type of 1st-line chemotherapy received was: cisplatin-based 669 (50%), carboplatin-based 399 (30%), other 265 (20%). Cisplatin use was an independent favorable prognostic factor (HR: 1.54, 95% CI: 1.35-1.77). This benefit was independent of baseline characteristics or co-morbidities but was associated with eligibility-for-cisplatin: eligible patients treated with cisplatin lived longer than those who were not (HR: 1.74, 95% CI: 1.36-2.21), while such benefit was not observed among ineligible patients. 26% of patients who did not receive cisplatin were eligible for this agent. Median OS of ineligible patients was poor irrespective of the chemotherapy used.ConclusionsThe importance of applying published criteria of eligibility-for-cisplatin was confirmed in a multinational, real-world setting in aUTC. The reasons for deviations from these criteria set targets to improve adherence. Effective therapies for cisplatin-ineligible patients are needed.

Published
2018

11. Bone Metastases as the Only Metastatic Site in Patients With Urothelial Carcinoma: Focus on a Special Patient Population

Author

Aristotelis Bamias, Günter Niegisch, Jonathan E. Rosenberg, Sylvain Ladoire, Dominik Berthold, Neeraj Agarwal, Joaquim Bellmunt, Daniel W. Bowles, Andrea Necchi, Sandy Srinivas, Lauren C. Harshman, Jack Baniel, Simon J. Crabb, Elizabeth R. Plimack, Gregory R. Pond, Evan Y. Yu, Matthew D. Galsky, Sumanta K. Pal, Thomas Powles, Fondazione IRCCS Istituto Nazionale dei Tumori, McMaster University [Hamilton, Ontario], City of Hope Comprehensive Cancer Center [Duarte], University of Utah School of Medicine [Salt Lake City], University of Washington [Seattle], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Rabin Medical Center - Beilinson and Hasharon Hospitals [Petach-Tikva, Israel], University of Southampton [Southampton], Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Stanford University School of Medicine [Stanford], Stanford University [Stanford], Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Memorial Sloane Kettering Cancer Center [New York], Barts & The London School of Medicine, National and Kapodistrian University of Athens, Dana-Farber Cancer Institute [Boston], IMIM-Hospital del Mar, Generalitat de Catalunya, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai [New York], Necchi, A, Pond, Gr, Pal, Sk, Agarwal, N, Bowles, Dw, Plimack, Er, Yu, Ey, Ladoire, S, Baniel, J, Crabb, S, Niegisch, G, Srinivas, S, Berthold, Dr, Rosenberg, Je, Powles, T, Bamias, A, Harshman, Lc, Bellmunt, J, Galsky, Md, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, University of Southampton, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), National and Kapodistrian University of Athens (NKUA), and Icahn School of Medicine at Mount Sinai [New York] (MSSM)

Subjects
Oncology, Male, medicine.medical_specialty, Urologic Neoplasms, Urology, medicine.medical_treatment, 030232 urology & nephrology, Antineoplastic Agents, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Systemic therapy, Disease-Free Survival, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Outcomes of bone-only metastatic urothelial carcinoma, medicine, Humans, In patient, Urothelial carcinoma, Aged, Platinum, Retrospective Studies, Chemotherapy, Carcinoma, Transitional Cell, Bladder cancer, business.industry, Bone metastases, Retrospective cohort study, Middle Aged, medicine.disease, Prognosis, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, Female, business, Outcomes of chemotherapy
Abstract

Worldwide, patients with urothelial carcinoma characterized by a bone-exclusive metastatic spread usually present with poor performance status, have limited access to active therapy, and have a poor outcome. Consequently, treatments offered and outcomes should be improved in this rare subgroup. BACKGROUND: Patients with exclusive bone metastatic spread from urothelial carcinoma (UC) throughout their disease course represent a rare subgroup with unique clinical features. These patients deserved special consideration in a retrospective multicenter study. PATIENTS AND METHODS: Analyses were made from a pool of 1911 patients with a diagnosis of metastatic UC, from 23 centers. Baseline characteristics, access to treatment, and outcomes were analyzed according to metastatic spread. Univariable and multivariable Cox analyses were performed. RESULTS: A total of 128 evaluable patients (6.7%), diagnosed between February 1997 and April 2013, were identified. Eastern Cooperative Oncology Group performance status (PS) was ≥ 2 in 33.3% versus 17.7% of the remaining patients. Seventy-three (57%) received first-line chemotherapy, that was platinum-based in 50 patients (69%). Twenty-eight (21.9%) received second-line chemotherapy (vs. 75.9% and 32.2%, respectively, of the remaining patients). In multivariable analyses, no clinical factor was significantly associated with overall survival (OS). Among platinum chemotherapy-treated patients (total evaluable n = 972), significantly different relapse-free survival (RFS) and OS were observed according to bone metastases status (no bone metastases vs. bone metastases only vs. bone and other sites, P < .001). In these groups, 2-year RFS was 37.4%, 28.8%, and 25.9%, respectively. Two-year OS was 35.5%, 15.8%, and 23%, respectively. CONCLUSION: Patients with metastatic UC and bone-only metastases are less likely to receive systemic therapy than those with other metastases, likely because of their lower PS. The prognostic effect of having exclusive bone metastases or additional sites seems to be equally poor. These patients deserve new effective and tolerable agents, and improvements in the knowledge of their disease.

Published
2017

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

Author

Yu-Ning Wong, Risc Investigators, Aristotelis Bamias, Ajjai Alva, Jonathan E. Rosenberg, Sylvain Ladoire, Lauren C. Harshman, Ugo De Giorgi, Martin F. Casey, Evan Y. Yu, Sumanta K. Pal, Matthew D. Galsky, Thomas Powles, Joaquim Bellmunt, Neeraj Agarwal, Guenter Niegisch, Simon J. Crabb, Andrea Necchi, Federica Recine, Ulka N. Vaishampayan, Jorge Ramos, University of Washington [Seattle], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Southampton, National and Kapodistrian University of Athens (NKUA), Dana-Farber Cancer Institute [Boston], Fox Chase Cancer Center, IMIM-Hospital del Mar, Generalitat de Catalunya, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Barts & The London School of Medicine, City of Hope, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Michigan [Ann Arbor], University of Michigan System, University of Utah School of Medicine [Salt Lake City], Fondazione IRCCS Istituto Nazionale dei Tumori, Karmanos Cancer Institute, Memorial Sloane Kettering Cancer Center [New York], Ramos, Jd, Casey, Mf, Crabb, Sj, Bamias, A, Harshman, Lc, Wong, Yn, Bellmunt, J, De Giorgi, U, Ladoire, S, Powles, T, Pal, Sk, Niegisch, G, Recine, F, Alva, A, Agarwal, N, Necchi, A, Vaishampayan, Un, Rosenberg, Je, Galsky, Md, and Yu, Ey

Subjects
Male, Oncology, Cancer Research, medicine.medical_treatment, Disease, 030204 cardiovascular system & hematology, Deoxycytidine, 0302 clinical medicine, Neoplasm Metastasis, Original Research, Incidence, Incidence (epidemiology), Middle Aged, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, chemotherapy survival, bladder cancer, Female, Bufeta -- Càncer, medicine.drug, Adult, medicine.medical_specialty, Metastatic Urothelial Carcinoma, venous thromboembolism, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, Urothelial, medicine, Humans, Radiology, Nuclear Medicine and imaging, cardiovascular diseases, Aged, Retrospective Studies, Trombosi -- Tractament, Gynecology, Cisplatin, Carcinoma, Transitional Cell, Chemotherapy, Bladder cancer, business.industry, Clinical Cancer Research, Cancer, medicine.disease, equipment and supplies, Survival Analysis, Gemcitabine, Urinary Bladder Neoplasms, business
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 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

Published
2017

13. Nomogram-based prediction of overall survival in patients with metastatic urothelial carcinoma receiving first-line platinum-based chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

Author

Salvatore Lo Vullo, Günter Niegisch, Yu-Ning Wong, Jack Baniel, Sylvain Ladoire, Luigi Mariani, Lauren C. Harshman, Ugo De Giorgi, Daniel W. Bowles, Simon J. Crabb, Sumanta K. Pal, Rafael Morales-Barrera, Guru Sonpavde, Thomas Powles, Andrea Necchi, Christine Theodore, Ajjai Alva, Jonathan E. Rosenberg, Joaquim Bellmunt, Linda Cerbone, Simon Chowdhury, Ulka N. Vaishampayan, Cora N. Sternberg, Evan Y. Yu, Neeraj Agarwal, Aristotelis Bamias, Dominik Berthold, Matthew D. Galsky, Gedske Daugaard, Daniele Giardiello, Ali Reza Golshayan, Matthew I. Milowsky, Sandy Srinivas, Srikala S. Sridhar, Necchi, A, Sonpavde, G, Lo Vullo, S, Giardiello, D, Bamias, A, Crabb, Sj, Harshman, Lc, Bellmunt, J, De Giorgi, U, Sternberg, Cn, Cerbone, L, Ladoire, S, Wong, Yn, Yu, Ey, Chowdhury, S, Niegisch, G, Srinivas, S, Vaishampayan, Un, Pal, Sk, Agarwal, N, Alva, A, Baniel, J, Golshayan, Ar, Morales-Barrera, R, Bowles, Dw, Milowsky, Mi, Theodore, C, Berthold, Dr, Daugaard, G, Sridhar, S, Powles, T, Rosenberg, Je, Galsky, Md, Mariani, L, Fondazione IRCCS Istituto Nazionale dei Tumori, UAB Comprehensive Cancer Center UAB Comprehensive Cancer Center [Birmingham, AL, USA], University of Alabama at Birmingham [ Birmingham] (UAB), National and Kapodistrian University of Athens (NKUA), University of Southampton, Dana-Farber Cancer Institute [Boston], Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), San Camillo Forlanini Hospital [Rome], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Fox Chase Cancer Center, University of Washington [Seattle], Guy's and St Thomas' Hospital [London], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Karmanos Cancer Institute, City of Hope Comprehensive Cancer Center [Duarte], University of Utah School of Medicine [Salt Lake City], University of Michigan [Ann Arbor], University of Michigan System, Rabin Medical Center - Beilinson and Hasharon Hospitals [Petach-Tikva, Israel], Medical University of South Carolina [Charleston] (MUSC), Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Service d'Oncologie Médicale, Service d'Oncologie Médicale, Hôpital Foch, Suresnes, Dept of Oncology, Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Barts & The London School of Medicine, Memorial Sloane Kettering Cancer Center [New York], and Icahn School of Medicine at Mount Sinai [New York] (MSSM)

Subjects
Oncology, Male, medicine.medical_specialty, Urologic Neoplasms, Metastatic Urothelial Carcinoma, Internationality, Urology, Population, 030232 urology & nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Nomogram, Article, Carboplatin, 03 medical and health sciences, chemistry.chemical_compound, Random Allocation, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, Overall survival, education, Survival analysis, Aged, Retrospective Studies, 2. Zero hunger, education.field_of_study, Carcinoma, Transitional Cell, Performance status, business.industry, Proportional hazards model, Combination chemotherapy, Middle Aged, Prognosis, Survival Analysis, 3. Good health, Platinum chemotherapy, Nomograms, chemistry, 030220 oncology & carcinogenesis, Urothelial carcinoma, Female, Cisplatin, business
Abstract

IF 16.265; International audience; BACKGROUND:The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients.OBJECTIVE:To develop a new model based on real-world patients.DESIGN, SETTING, AND PARTICIPANTS:Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011.INTERVENTION:First-line, platinum-based, combination chemotherapy.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms.RESULTS AND LIMITATIONS:A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p

Published
2016

14. An Immunosurveillance Mechanism Controls Cancer Cell Ploidy

Author

Guillermo Mariño, Frank Madeo, Lorenzo Galluzzi, Shensi Shen, Isabelle Martins, Alexander Valent, Bastien Job, Mark J. Smyth, Maria Castedo, Gian Maria Fimia, Mickaël Michaud, Francesco Berardinelli, Claire Pailleret, Alfredo Criollo, Vladimir Lazar, Santiago Rello-Varona, Guillaume Pourcher, Mauro Piacentini, Antonella Sistigu, Vichnou Poirier-Colame, Laura Senovilla, Sylvain Ladoire, Ming Li, Sandy Adjemian, Clara Locher, Ilio Vitale, Takahiro Yamazaki, Christoph Ruckenstuhl, Josef M. Penninger, Monique Talbot, Nicole L Messina, Antonio Antoccia, François Ghiringhelli, Verena Sigl, Fabiola Ciccosanti, Guido Kroemer, Mireia Niso-Santano, Maximilien Tailler, Oliver Kepp, Laurence Zitvogel, Alice Boilève, Carlos López-Otín, Didac Carmona-Gutierrez, Christopher J. Chan, Antonio Fueyo, Senovilla, L, Vitale, I, Martins, I, Tailler, M, Pailleret, C, Michaud, M, Galluzzi, L, Adjemian, S, Kepp, O, NISO SANTANO, M, Shen, S, Mariño, G, Criollo, A, Boilève, A, Job, B, Ladoire, S, Ghiringhelli, F, Sistigu, A, Yamazaki, T, RELLO VARONA, S, Locher, C, POIRIER COLAME, V, Talbot, M, Valent, A, Berardinelli, Francesco, Antoccia, Antonio, Ciccosanti, F, Fimia, Gm, Piacentini, M, Fueyo, A, Messina, Nl, Li, M, Chan, Cj, Sigl, V, Pourcher, G, Ruckenstuhl, C, CARMONA GUTIERREZ, D, Lazar, V, Penninger, Jm, Madeo, F, LÓPEZ OTÍN, C, Smyth, Mj, Zitvogel, L, Castedo, M, Kroemer, G., Senovilla, Laura, Vitale, Ilio, Martins, Isabelle, Tailler, Maximilien, Pailleret, Claire, Michaud, Mickaël, Galluzzi, Lorenzo, Adjemian, Sandy, Kepp, Oliver, Niso Santano, Mireia, Shen, Shensi, Mariño, Guillermo, Criollo, Alfredo, Boilève, Alice, Job, Bastien, Ladoire, Sylvain, Ghiringhelli, Françoi, Sistigu, Antonella, Yamazaki, Takahiro, Rello Varona, Santiago, Locher, Clara, Poirier Colame, Vichnou, Talbot, Monique, Valent, Alexander, Ciccosanti, Fabiola, Fimia, Gian Maria, Piacentini, Mauro, Fueyo, Antonio, Messina, Nicole L, Li, Ming, Chan, Christopher J, Sigl, Verena, Pourcher, Guillaume, Ruckenstuhl, Christoph, Carmona Gutierrez, Didac, Lazar, Vladimir, Penninger, Josef M, Madeo, Frank, López Otín, Carlo, Smyth, Mark J, Zitvogel, Laurence, Castedo, Maria, and Kroemer, Guido

Subjects
Settore BIO/06, Eukaryotic Initiation Factor-2, medicine.disease_cause, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Epigenetics, Phosphorylation, Endoplasmic Reticulum Stre, Immunologic Surveillance, Inbred BALB C, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, Tumor, Ploidies, Multidisciplinary, biology, Animal, Endoplasmic reticulum, Cancer, DNA, Neoplasm, DNA, Endoplasmic Reticulum Stress, medicine.disease, 3. Good health, Immunosurveillance, Common Variable Immunodeficiency, Cell culture, 030220 oncology & carcinogenesis, Cancer cell, Immunology, biology.protein, Cancer research, Neoplasm, Calreticulin, Carcinogenesis, Immunocompetence, Human
Abstract

Keeping Cancer Cells At Bay Cancer cells are often aneuploid; that is, they have an abnormal number of chromosomes. But to what extent this contributes to the tumorigenic phenotype is not clear. Senovilla et al. (p. 1678 ; see the Perspective by Zanetti and Mahadevan ) found that tetraploidization of cancer cells can cause them to become immunogenic and thus aid in their clearance from the body by the immune system. Cells with excess chromosomes put stress on the endoplasmic reticulum, which leads to movement of the protein calreticulin to the cell surface. Calreticulin exposure in turn caused recognition of cancer cells in mice by the host immune system. Thus, the immune system appears to serve a protective role in eliminating hyperploid cells that must be overcome to allow unrestricted growth of cancer cells.

Published
2012

15. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Author

Aicha Goubar, Julien Adam, Joanna Cyrta, Kariman Chaba, Mireia Niso-Santano, Valentina La Sorsa, Laurence Zitvogel, Christina Pfirschke, Guido Kroemer, Gilles Uzé, Oliver Kepp, Magali Lacroix-Triki, Francesca Urbani, Antonella Sistigu, Elisa E. Baracco, Suzette Delaloge, Sylvain Ladoire, David Enot, Camilla Engblom, Marco Bianchi, Laurent Arnould, Virginie Quidville, Mauro Delorenzi, Enrico Proietti, Melvyn T. Chow, Laetitia Aymeric, Fabrice Andre, Giovanna Ziccheddu, Joachim L. Schultze, Alexander M.M. Eggermont, Thomas Tüting, Laetitia Fend, Mark J. Smyth, Catarina Remédios, Takahiro Yamazaki, Robert D. Schreiber, Laura Bracci, Erika Vacchelli, Rosa Conforti, Ilio Vitale, Paola Sestili, Mikael J. Pittet, Marie Charlotte Dessoliers, Filippo Belardelli, Vichnou Poirier-Colame, Frédérique Penault-Llorca, Jean Philippe Spano, Lajos Pusztai, Xavier Préville, Dalil Hannani, Yuting Ma, National Cancer Institute Regina Elena [Rome, Italy], Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Département de biologie et pathologie médicales [Gustave Roussy], Apoptose, cancer et immunité (U848), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Life and Medical Sciences Institute for Genomics and Immunoregulation, Universität Bonn = University of Bonn, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], UNICANCER-UNICANCER, Harvard Medical School [Boston] (HMS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology and Neurosciences, Université Paris-Sud - Paris 11 (UP11), Sistigu, A, Yamazaki, T, Vacchelli, E, Chaba, K, Enot, Dp, Adam, J, Vitale, I, Goubar, A, Baracco, Ee, Remédios, C, Fend, L, Hannani, D, Aymeric, L, Ma, Y, Niso Santano, M, Kepp, O, Schultze, Jl, Tüting, T, Belardelli, F, Bracci, L, La Sorsa, V, Ziccheddu, G, Sestili, P, Urbani, F, Delorenzi, M, Lacroix Triki, M, Quidville, V, Conforti, R, Spano, Jp, Pusztai, L, Poirier Colame, V, Delaloge, S, Penault Llorca, F, Ladoire, S, Arnould, L, Cyrta, J, Dessoliers, Mc, Eggermont, A, Bianchi, MARCO EMILIO, Pittet, M, Engblom, C, Pfirschke, C, Préville, X, Uzè, G, Schreiber, Rd, Chow, Mt, Smyth, Mj, Proietti, E, André, F, Kroemer, G, Zitvogel, L., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), University of Bonn, Istituto Superiore di Sanità, Service d'Oncologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Superiore di Sanita', and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Myxovirus Resistance Proteins, Messenger, Receptor, Interferon alpha-beta, Inbred C57BL, chemotherapy, Interferon alpha-beta, Mice, Interferon, Receptors, Anthracyclines, Neoplasm Metastasis, RIG-I, Pattern recognition receptor, Adaptor Proteins, General Medicine, Neoadjuvant Therapy, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Receptors, Pattern Recognition, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunocompetence, medicine.drug, Receptor, Signal Transduction, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pattern Recognition, Settore BIO/09, General Biochemistry, Genetics and Molecular Biology, Paracrine signalling, Immune system, medicine, CXCL10, Animals, Humans, cancer, RNA, Messenger, Autocrine signalling, Neoplastic, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Toll-Like Receptor 3, Mice, Inbred C57BL, Vesicular Transport, Chemokine CXCL10, Adaptor Proteins, Vesicular Transport, Gene Expression Regulation, Doxorubicin, Immunology, TLR3, RNA
Abstract

International audience; The immune system is routinely confronted with cell death resulting from the physiological turnover of renewable tissues, as well as from pathological insults of several types. We hypothesize the existence of a mechanism that allows the immune system to discriminate between physiological and pathological instances of cell death, but the factors that determine whether cellular demise is perceived as a neutral, tolerogenic or immunogenic event remain unclear 1. Infectious insults are accompanied by so-called microbe-associated molecular patterns (MAMPs), i.e., viral or bacterial products that activate immune cells through a panel of pattern-recognition receptors (PRRs) 2. Moreover, intracellular pathogens generally trigger adaptive mechanisms aimed toward the re-establishment of homeosta-sis, including the unfolded protein response (UPR) and autophagy 3,4. In mammals, MAMPs coupled to the activation of stress responses Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN- and IFN- receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy. npg

Published
2014

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