A systematic review on the clinical implementation of 4D particle therapy

Intrafractional motion in the thoracic and abdominal regions remains a major challenge in particle therapy representing one of the key anatomical changes during radiotherapy. Interfractional changes further contribute to cumulative uncertainties and may require adaptive strategies over the course of treatment. The high dose conformality and steep dose fall-off of particle beams, combined with motion-induced range variations, make dose delivery highly sensitive to temporal and anatomical changes. This systematic review provides an overview of clinically implemented 4D treatment approaches addressing intrafractional motion for thoracic and abdominal indications, aiming to support harmonisation of clinical practices across centres and vendors. Systematic searches in PubMed and Web of Science identified relevant publications from January 2020 to December 2025 covering the full 4D workflow in particle therapy. The focus was on clinical implementation for lung, pancreas, liver, lymphoma, oesophagus, and breast, complemented by phantom studies and ongoing research activities. Publications were screened by eight experts using predefined inclusion and exclusion criteria. Writing and synthesis were conducted by a multidisciplinary panel of eighteen experts. A total of 751 publications were identified, of which 231 were included and categorised into six key subtopics: motion management, imaging, treatment planning optimisation and evaluation, clinical indications, phantom studies, and future perspectives. The results confirm that intrafractional motion remains a major source of uncertainty across the workflow. Despite numerous proposed 4D techniques, clinical implementation varies widely. A key limitation is the lack of standardised methods for 4D dose evaluation and interplay assessment, particularly relevant for hypofractionated treatments and advanced delivery techniques. Increasing clinical experience demonstrates that motion-related challenges can be effectively managed using appropriate 4D-aware workflows. This review represents an important step towards establishing consensus and developing guidelines for treating moving targets in particle therapy.