Jake Pensavalle ^1* Fabio Di Martino ^1,2,3 Andrea Cavalieri ⁴ Mariagrazia Celentano ^1,3 Angelica De Gregorio ^5,6 Massimo Di Francesco ⁷ Gaia Franciosini ^6,8 Lorenzo Galluzzo ⁷ Luigi Masturzo ^1,3 Giuliana Milluzzo ⁹ Pierre Montay-Gruel ^10,11 Fabiola Paiar ^12,2,4 Maurizio Pantaleoni ¹³ Vincenzo Patera ^6,8 Steafano Pioli ¹⁴ Philip Poortmans ^15,16 Francesco Romano ^17,9 Alessio Sarti ^6,8 Anna Subiel ^18,19 Alessandro Vannozzi ¹⁴ Giuseppe Felici ^7*

• ¹ Azienda Ospedaliero Universitaria Pisa (AOUP), Fisica Sanitaria, Pisa, Italy, PISA, Italy
• ² Centro Pisano Multidisciplinare Sulla Ricerca e Implementazione Clinica Della Flash Radiotherapy (CPFR@CISUP), Pisa, Italy, PISA, Italy
• ³ National Institute of Nuclear Physics of Pisa, Pisa, Tuscany, Italy
• ⁴ Center for Instrument Sharing University of Pisa (CISUP), University of Pisa, Pisa, Italy, PISA, Italy
• ⁵ Dipartimento di Fisica, Sapienza Università di Roma, Roma, Italy, Rome, Italy
• ⁶ INFN Sezione di Roma I, Roma, Italy, Rome, Italy
• ⁷ Sordina IORT Technologies S.p.A., Aprilia, Italy
• ⁸ Dipartimento di Scienze di Base e Applicate per l’Ingegneria, Sapienza Università di Roma, Roma, Italy, Rome, Italy
• ⁹ Istituto Nazionale di Fisica Nucleare, Sezione di Catania, Catania, Italy, Catania, Italy
• ¹⁰ Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium, Antwerp, Belgium
• ¹¹ Iridium Netwerk, Radiation Oncology, Antwerp, Belgium, Antwerp, Belgium
• ¹² Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Tuscany, Italy
• ¹³ Maytal International Ltd – Global Med Dev Expertise, London, UK, London, United Kingdom
• ¹⁴ LNF-INFN, Via E. Fermi 40, 00044 Frascati (Rome), Italy, Rome, Italy
• ¹⁵ Department of Radiation Oncology, Iridium Netwerk, Wilrijk-Antwerp, Belgium, Antwerp, Belgium
• ¹⁶ University of Antwerp, Faculty of Medicine and Health Sciences, Wilrijk-Antwerp, Belgium, Antwerp, Belgium
• ¹⁷ Particle Therapy Research Center (PARTREC), Department of Radiation Oncology, University Medical Center Gro-Ningen, University of Groningen, Groningen, Netherlands, Groningen, Netherlands
• ¹⁸ University College London, Gower Street, London, WC1E 6BT, UK, London, United Kingdom
• ¹⁹ National Physical Laboratory, Hampton Road, Teddington, TW11 0LW, UK, London, United Kingdom

Very High-Energy Electrons (VHEE) present a promising innovation in radiation therapy (RT), particularly for the treatment of deep-seated tumors using Ultra High Dose Rate (UHDR) within the framework of FLASH-RT. VHEE offers significant advantages, such as improved tumor targeting, reduced treatment times, and potential utilization of the FLASH effect, which may minimize normal tissue toxicity. However, the lack of an international technical standard for VHEE systems, especially for UHDR applications, remains a critical challenge.Current standards for radiation therapy equipment, such as IEC 60601-2-1 and IEC 60601-2-64, do not encompass VHEE technology. This regulatory gap underscores the need for developing a structured international standard to ensure the basic safety and essential performance of VHEE medical devices. Addressing this challenge requires overcoming complex dose delivery issues, such as the interaction of multiple fields and beam conformality and incorporating novel techniques like broad beam or pencil beam scanning.Establishing comprehensive regulatory standards is essential to ensure patient safety, consistent treatment practices, and the successful clinical integration of VHEE systems. These standards must encompass design guidelines, radiation protection protocols, and integration with existing oncology practices. Collaborative research and development efforts are crucial to formulating evidence-based guidelines, fostering the safe and effective use of VHEE in clinical settings. By addressing these challenges, VHEE technology has the potential to revolutionize cancer therapy, particularly for deep-seated tumors, while enhancing therapeutic outcomes for patients.