Reirradiation With Proton Therapy Using Hypofractionated Schedules: A Systematic Review of the Literature

International Journal of Particle Therapy, vol. 22, pp. 101963

Abstract

Aim: Re-irradiation (re-RT) with hypofractionated proton therapy (PT) may be a treatment option in selected cases. Aim is to provide a critical overview of the state of the art. Methods: PRISMA-compliant systematic review was performed on 2nd October 2025. All tumor sites were considered, provided that re-RT was performed with dose/fraction>2Gy(RBE) in adults. Oncological and toxicity outcomes were retrieved. Results: = 123). Median sample size was 32 (interquartile range: 26-46, range: 14-83). Moderate hypofractionation (< 5 Gy(RBE)/fraction) was the most frequent schedule. All included studies had a radical intent. Overall, 2 year overall survival ranged from 8.4% (head & neck) to 87.5% (liver). The rate of severe side effects remained relevant. Of note, clinical outcomes and toxicity profiles were highly heterogeneous among the different tumor sites. Therefore, in the setting of re-RT with PT, conclusive data on the efficacy and toxicity profile of hypofractionated schedules could not be provided yet. Re-RT remains a personalized approach in almost all settings of tumor recurrence. Conclusion: Evidence supporting the use of hypofractionated PT re-RT remains limited but encouraging. Identifying predictors of toxicity and treatment response is essential to guide future research and to establish this approach as a viable option for selected patients.

Authors 17

1. Daniela Alterio

   European Institute of Oncology

   Affiliation as printed

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

2. Vanessa Eleonora Pierini

   University of Milan · European Institute of Oncology

   Affiliation as printed

   Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

3. Stefania Volpe

   University of Milan · European Institute of Oncology

   Affiliation as printed

   Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

4. Maria Giulia Vincini

   European Institute of Oncology

   Affiliation as printed

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

5. Mattia Zaffaroni

   European Institute of Oncology

   Affiliation as printed

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

6. Annamaria Ferrari

   European Institute of Oncology

   Affiliation as printed

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

7. Marvaso Giulia

   University of Milan · European Institute of Oncology

   Affiliation as printed

   Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

8. Federico Mastroleo

   European Institute of Oncology

   Affiliation as printed

   Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy

9. Nicolaus H. Andratschke

   University of Zurich · University Hospital Zurich

   Affiliation as printed

   Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

10. Matthias Guckenberger

    University of Zurich · University Hospital Zurich

    Affiliation as printed

    Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

11. Jiří Kubeš

    Proton Therapy Centre

    Affiliation as printed

    Proton Therapy Center Czech, Prague, Czech Republic

12. Icro Meattini

    Azienda Ospedaliero-Universitaria Careggi · University of Florence

    Affiliation as printed

    Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Florence, Italy

    Radiation Oncology & Breast Unit - Oncology Department, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy

13. Carsten Nieder

    Nordland Hospital Trust · UiT The Arctic University of Norway

    Affiliation as printed

    Department of Clinical Medicine, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway

    Department of Oncology and Palliative Medicine, Nordland Hospital Trust, Bodø, Norway

14. Yvette van der Linden Aachen Centre of Expertise in Palliative Care Department of Radiotherapy, Leiden University Medical Centre

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Centre of Expertise in Palliative Care, Leiden University Medical Centre, Leiden, The Netherlands

    Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands

15. Giuseppe Petralia

    European Institute of Oncology

    Affiliation as printed

    Division of Radiology, IEO European Institute of Oncology IRCCS, Milan, Italy

16. Roberto Orecchia

    European Institute of Oncology

    Affiliation as printed

    Scientific directorate, IEO European Institute of Oncology IRCCS, Milan, Italy

17. Barbara Alicja Jereczek-Fossa

    University of Milan · European Institute of Oncology

    Affiliation as printed

    Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Division of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy