oDigital pathology biomarkers for guiding radiotherapy-based treatment concepts in prostate cancer - a systematic review and expert consensus

Constantinos Zamboglou¹, William De Doncker², Andreas Thomas Christoforou³, Stefano Arcangeli⁴, Alejandro Berlin⁵, Pierre Blanchard⁶, Glenn Bauman⁷, Riccardo Campi⁸, Elena Castro⁹, Ananya Choudhury¹⁰, Alan Dal Pra¹¹, Cédric Draulans¹², Neil Desai¹¹, Konstantinos Ferentinos¹, Giulio Francolini¹³, Silke Gillessen¹⁴, Anca-Ligia Grosu¹⁵, Juan Gómez Rivas¹⁶, Tobias Hoelscher¹⁷, George Hruby¹⁸, Barbara Alicja Jereczek-Fossa¹⁹, Sophia Kamran²⁰, Veeru Kasivisvanathan²¹, Amar U Kishan²², Valentinos Kounnis²³, Andrew Loblaw²⁴, Jarad Martin²⁵, Federico Mastroleo²⁶, Axel S Merseburger²⁷, Marcin Miszczyk²⁸, Osama Mohamad²⁹, Piet Ost³⁰, Athanasios Papatsoris³¹, Jan C Peeken³², Francesco Sanguedolce³³, Paul Sargos³⁴, Nina Schmidt-Hegemann³⁵, Tyler M Seibert³⁶, Mohamed Shelan³⁷, Shankar Siva³⁸, Timo F W Soeterik³⁹, Daniel E Spratt⁴⁰, Arnulf Stenzl⁴¹, Iosif Strouthos⁴², Philip Sutera⁴³, Stephane Supiot⁴⁴, Derya Tilki⁴⁵, Phuoc T Tran⁴⁶, Alison C Tree⁴⁷, Jonathan Tward⁴⁸, Yüksel Ürün⁴⁹, Neha Vapiwala⁵⁰, Mark R Waddle⁵¹, Eric Wegener²⁵, Thomas Zilli⁵², Vedang Murthy⁵³, Alexander Henry Thieme⁵⁴, Simon Spohn⁵⁵

Affiliations

¹ Department of Radiation Oncology, German Medical Institute, Limassol, Cyprus.
² AI Department, German Medical Institute, Limassol, Cyprus. Electronic address: William.dedoncker@gooc.com.cy.
³ Department of Research and Innovation, German Medical Institute, Limassol, Cyprus.
⁴ Department of Radiation Oncology, University of Milan Bicocca, Milan, Italy.
⁵ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Radiation Oncology, Gustave Roussy, Villejuif, France.
⁷ Department of Oncology, Division of Radiation Oncology, London Health Sciences Centre and Western University, London, ON, Canada.
⁸ Unit of Urology and Renal Transplantation, Oncology Department, Careggi University Hospital, Florence, Italy.
⁹ Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹⁰ Division of Cancer Sciences, The University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, UK.
¹¹ Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.
¹² Department of Oncology, KU Leuven, Leuven, Belgium; Department of Radiation Oncology, AZ Sint-Maarten, Mechelen, Belgium.
¹³ Radiation Oncology Unit, Oncology Department, Careggi University Hospital, Florence, Italy.
¹⁴ Department of Oncology, Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland.
¹⁵ Department of Radiation Oncology, University Hospital of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁶ Department of Urology, Hopital Clinico San Carlos, Madrid, Spain.
¹⁷ Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁸ Department of Radiation Oncology Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
¹⁹ Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy; Department of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
²⁰ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK; The Alan Turing Institute, London, UK.
²² Department of Radiation Oncology, University of California, Los Angeles, USA.
²³ Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
²⁴ Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Department of Health Policy, Measurement and Evaluation, University of Toronto, Toronto, Ontario, Canada.
²⁵ GenesisCare, Newcastle, New South Wales, Australia.
²⁶ Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy; Department of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy; Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany.
²⁸ Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Collegium Medicum - Faculty of Medicine, WSB University, Dąbrowa Górnicza, Poland.
²⁹ Department of Genito-Urinary Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA.
³⁰ Department of Radiation Oncology, Iridium Network, Wilrijk (Antwerp), Belgium.
³¹ Department of Urology, National & Kapodistrian University, Sismanoglio General Hospital, Athens, Greece.
³² Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Digitalization and Artificial Intelligence Working Group, German Society for Radiation Oncology, Berlin, Germany; Partner Site Munich, German Consortium for Translational Cancer Research (DKTK), Munich, Germany; Institute of Radiation Medicine (IRM), Helmholtz Zentrum München (HMGU), Munich, Germany.
³³ Department of Urology, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain.
³⁴ Department of Radiotherapy, Institut Bergonié, Bordeaux, France; Amethyst Radiotherapy Group, Paris, France.
³⁵ Department of Radiation Oncology, LMU University Hospital, LMU Munich, Munich, Germany.
³⁶ Departments of Radiation Medicine & Applied Sciences, Radiology, Urology, Bioengineering, University of California San Diego, La Jolla, CA, USA.
³⁷ Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
³⁸ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
³⁹ Department of Value-Based Healthcare, Santeon Group, Utrecht, the Netherlands; Department of Urology, St. Antonius Hospital, Nieuwegein/Utrecht, the Netherlands.
⁴⁰ Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, USA.
⁴¹ Department of Urology, Eberhard-Karls-University, Tübingen, Germany.
⁴² Department of Radiation Oncology, German Medical Institute, University Clinic of European University Cyprus, Limassol, Cyprus.
⁴³ Department of Radiation Oncology, University of Rochester Medical Center, Rochester, MN, USA.
⁴⁴ Department of Radiotherapy, ICO René Gauducheau, Saint-Herblain, France; Nantes University, Nantes, France.
⁴⁵ Stanford Center for Biomedical Informatics Research (BMIR), Department of Medicine, Stanford University, Stanford, CA, USA; Martini-Klinik Prostate Cancer Center, University Hospital Hamburg Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Radiation Oncology, University of Maryland, Baltimore, MD, USA.
⁴⁷ Department of Radiotherapy, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, UK.
⁴⁸ Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
⁴⁹ Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey; Ankara University Cancer Research Institute, Ankara, Turkey.
⁵⁰ Department of Radiation Oncology, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, USA.
⁵¹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
⁵² Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Department of Radiation Oncology, Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland; Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁵³ Radiation Oncology Tata Memorial Centre Homi Bhabha National Institute Mumbai, India.
⁵⁴ Stanford Center for Biomedical Informatics Research (BMIR), Department of Medicine, Stanford University, Stanford, CA, USA.
⁵⁵ German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center, Freiburg, Germany; Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

PMID: 40645505
DOI: 10.1016/j.radonc.2025.111039

Review

oDigital pathology biomarkers for guiding radiotherapy-based treatment concepts in prostate cancer - a systematic review and expert consensus

Constantinos Zamboglou et al. Radiother Oncol. 2025 Sep.

. 2025 Sep:210:111039.

doi: 10.1016/j.radonc.2025.111039. Epub 2025 Jul 9.

Authors

Affiliations

¹ Department of Radiation Oncology, German Medical Institute, Limassol, Cyprus.
² AI Department, German Medical Institute, Limassol, Cyprus. Electronic address: William.dedoncker@gooc.com.cy.
³ Department of Research and Innovation, German Medical Institute, Limassol, Cyprus.
⁴ Department of Radiation Oncology, University of Milan Bicocca, Milan, Italy.
⁵ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Radiation Oncology, Gustave Roussy, Villejuif, France.
⁷ Department of Oncology, Division of Radiation Oncology, London Health Sciences Centre and Western University, London, ON, Canada.
⁸ Unit of Urology and Renal Transplantation, Oncology Department, Careggi University Hospital, Florence, Italy.
⁹ Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹⁰ Division of Cancer Sciences, The University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, UK.
¹¹ Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.
¹² Department of Oncology, KU Leuven, Leuven, Belgium; Department of Radiation Oncology, AZ Sint-Maarten, Mechelen, Belgium.
¹³ Radiation Oncology Unit, Oncology Department, Careggi University Hospital, Florence, Italy.
¹⁴ Department of Oncology, Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland.
¹⁵ Department of Radiation Oncology, University Hospital of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁶ Department of Urology, Hopital Clinico San Carlos, Madrid, Spain.
¹⁷ Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁸ Department of Radiation Oncology Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
¹⁹ Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy; Department of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
²⁰ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK; The Alan Turing Institute, London, UK.
²² Department of Radiation Oncology, University of California, Los Angeles, USA.
²³ Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
²⁴ Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Department of Health Policy, Measurement and Evaluation, University of Toronto, Toronto, Ontario, Canada.
²⁵ GenesisCare, Newcastle, New South Wales, Australia.
²⁶ Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy; Department of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy; Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany.
²⁸ Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Collegium Medicum - Faculty of Medicine, WSB University, Dąbrowa Górnicza, Poland.
²⁹ Department of Genito-Urinary Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA.
³⁰ Department of Radiation Oncology, Iridium Network, Wilrijk (Antwerp), Belgium.
³¹ Department of Urology, National & Kapodistrian University, Sismanoglio General Hospital, Athens, Greece.
³² Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Digitalization and Artificial Intelligence Working Group, German Society for Radiation Oncology, Berlin, Germany; Partner Site Munich, German Consortium for Translational Cancer Research (DKTK), Munich, Germany; Institute of Radiation Medicine (IRM), Helmholtz Zentrum München (HMGU), Munich, Germany.
³³ Department of Urology, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain.
³⁴ Department of Radiotherapy, Institut Bergonié, Bordeaux, France; Amethyst Radiotherapy Group, Paris, France.
³⁵ Department of Radiation Oncology, LMU University Hospital, LMU Munich, Munich, Germany.
³⁶ Departments of Radiation Medicine & Applied Sciences, Radiology, Urology, Bioengineering, University of California San Diego, La Jolla, CA, USA.
³⁷ Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
³⁸ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
³⁹ Department of Value-Based Healthcare, Santeon Group, Utrecht, the Netherlands; Department of Urology, St. Antonius Hospital, Nieuwegein/Utrecht, the Netherlands.
⁴⁰ Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, USA.
⁴¹ Department of Urology, Eberhard-Karls-University, Tübingen, Germany.
⁴² Department of Radiation Oncology, German Medical Institute, University Clinic of European University Cyprus, Limassol, Cyprus.
⁴³ Department of Radiation Oncology, University of Rochester Medical Center, Rochester, MN, USA.
⁴⁴ Department of Radiotherapy, ICO René Gauducheau, Saint-Herblain, France; Nantes University, Nantes, France.
⁴⁵ Stanford Center for Biomedical Informatics Research (BMIR), Department of Medicine, Stanford University, Stanford, CA, USA; Martini-Klinik Prostate Cancer Center, University Hospital Hamburg Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Radiation Oncology, University of Maryland, Baltimore, MD, USA.
⁴⁷ Department of Radiotherapy, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, UK.
⁴⁸ Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
⁴⁹ Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey; Ankara University Cancer Research Institute, Ankara, Turkey.
⁵⁰ Department of Radiation Oncology, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, USA.
⁵¹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
⁵² Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland; Department of Radiation Oncology, Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland; Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁵³ Radiation Oncology Tata Memorial Centre Homi Bhabha National Institute Mumbai, India.
⁵⁴ Stanford Center for Biomedical Informatics Research (BMIR), Department of Medicine, Stanford University, Stanford, CA, USA.
⁵⁵ German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center, Freiburg, Germany; Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

PMID: 40645505
DOI: 10.1016/j.radonc.2025.111039

Abstract

Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity, and digital pathology (DP) combined with artificial intelligence (AI) tools (DP-AI) may offer a solution to this challenge. The aim of this work is to summarize the role of DP-AI for PCa patients treated with radiotherapy (RT), and to point out future areas of research. We conducted (1) a systematic review on the evidence of DP-AI for patients treated with RT and (2) a survey of experts using a modified Delphi method, addressing the current role of DP-AI in clinical and research practice to identify relevant fields of future development. Eleven studies investigated DP-AI in PCa RT, with most using the multimodal AI (MMAI) classifier and four ongoing studies are currently prospectively testing the DP-AI performance. DP-AI showed strong prognostic and predictive performance for endpoints like distant metastasis free survival and overall survival, outperforming traditional risk models and assisting treatment decisions such as androgen deprivation therapy (ADT) duration. Fifty-one and 35 experts responded to round 1 and round 2 of the survey respectively. Questions with ≥75 % agreement were considered relevant and included in the qualitative analysis. Survey results confirmed growing adoption of DP scanners, although regional differences in re-imbursement mechanisms and availability persist, with experts endorsing DP-AI's potential across localized, postoperative, and metastatic settings, though further prospective validation is needed. DP-AI tools show strong prognostic and predictive potential in various PCa by guiding patient stratification and optimising ADT duration in primary RT. Prospective studies and validation in cohorts using modern diagnostic and treatment methods are needed before broad clinical adoption.

Keywords: Androgen deprivation therapy; Artificial intelligence; Biomarkers; Digital pathology; Personalized medicine; Prostate cancer; Radiotherapy; Risk stratification; Treatment selection.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alison Tree is supported by a Cancer Research UK Radiation Research Centre of Excellence at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust (grant ref: A28724 and RRCOER-Jun24/100006) and a Cancer Research UK Programme Grant (ref: C33589/A28284). Alison Tree acknowledges NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. She declares research funding from Elekta, Varian, Accuray and Artera. Alison Tree declares honoraria or travel assistance from Elekta, Accuray and Janssen. Marcin Miszczyk was supported by the European Urological Scholarship Programme (EUSP) Scholarship of the European Association of Urology (EAU). Tyler Seibert reports honoraria from Varian Medical Systems, WebMD, MJH Life Sciences, GE Healthcare, Blue Earth Diagnostics, and Janssen; he has an equity interest in CorTechs Labs, Inc. and serves on its Scientific Advisory Board; he receives research funding from GE Healthcare and Blue Earth Diagnostics, as well as in-kind research support from Quibim, Inc., both through the University of California San Diego. These companies might potentially benefit from the research results. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. Silke Gillessen reports personal honoraria for invited speaker for ESMO, Schweizerische Gesellschaft für Medizinische Onkologie (SGMO)/Meister ConCept GmbH; other honoraria from University of Applied Sciences and Arts of Southern Switzerland (SUPSI). Travel grants from Bayer, Gilead, Intellisphere LLC, Johnson & Johnson. Institutional honoraria advisory boards or in Independent Data Monitoring-/Steering Committees from Amgen, Astellas, AstraZeneca, Avalere Health, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Innomedica, Ipsen, LinkinVax, Macrogenics, Merck, MDS Merck Sharp & Dohme, Novartis, Pfizer; invited speaker for AdMeTech Foundation, EPG Health, ESMO, Intellisphere LLC, Medtoday Switzerland, Orikata, PeerVoice, Pfizer, Schweizerische Gesellschaft für Medizinische Onkologie (SGMO)/Meister ConCept GmbH, Silvio Grasso Consulting, Swiss group for Clinical Cancer Research (SAKK), UroPratica Group. Patent for a research method for biomarker WO2009138392. Elena Castro acts as a consultant or advisory role for AstraZeneca, Bayer, Full Life, Johnson & Johnson, Lilly, Medscape, Merck, MSD Oncology, Novartis and Pfizer; travel/accommodation support from AstraZeneca, Bayer, Janssen and Pfizer; honoraria from Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, Medscape, Peerview, Pfizer and Telix; and research funding from Bayer, Johnson & Johnson and Pfizer. Constantinos Zamboglou and Iosif Strouthos receive study support from Artera for the HypoPro and HypoElect trials. Constantinos Zamboglou acts as a consultant for Teleflex. All remaining authors have declared no conflicts of interest.

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oDigital pathology biomarkers for guiding radiotherapy-based treatment concepts in prostate cancer - a systematic review and expert consensus

Affiliations

oDigital pathology biomarkers for guiding radiotherapy-based treatment concepts in prostate cancer - a systematic review and expert consensus

Authors

Affiliations

Abstract

Conflict of interest statement

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Medical