KEY POINTS
- This structured narrative review screened 214 records and included 20 preclinical studies examining lung-related biological endpoints and 16 studies addressing proton FLASH planning or delivery. The technological analysis focused on cyclotron-based proton systems.
- Across electron, photon, and proton models, FLASH irradiation frequently reduced pulmonary fibrosis, inflammation, vascular injury, oxidative stress, cellular senescence, and functional impairment while generally maintaining tumor response. Human lung-cell and ex vivo tissue experiments also reported reduced DNA damage and fibrosis-associated changes.
- The findings were not uniform. Some models showed no meaningful FLASH advantage, including a 20 Gy whole-thorax study and chronic obstructive pulmonary disease-derived organoids, in which FLASH slightly worsened organoid-forming capacity. The commonly used threshold of 40 Gy/s is therefore a convention rather than a validated biological cut-off.
- Reported normal-tissue protection depended on dose, dose rate, fractionation, beam characteristics, tissue type, and endpoint. Proposed mechanisms include oxygen depletion, mitochondrial protection, immune modulation, and reduced cellular senescence, but no single mechanism adequately explains the observed effect.
- Current cyclotron systems usually achieve ultra-high dose rates only at their highest energy, approximately 230–250 MeV, favouring transmission beams. Transmission delivery is relatively simple and robust to range uncertainty but deposits dose beyond the target and may increase integral dose.
- Ultra-high-dose-rate Bragg-peak delivery can reduce distal and integral dose but generally requires patient-specific range modulators, range shifters, or apertures. Planning studies achieved acceptable dose distributions, although Bragg-peak approaches were often less conformal than conventional intensity-modulated proton therapy.
- Delivery-pattern optimization increased healthy-tissue FLASH coverage above 40 Gy/s from 6.9% to 29% in one lung planning study. In another comparison, transmission-beam FLASH produced an integral dose 33% higher than conventional intensity-modulated proton therapy despite comparable target and organ-at-risk doses.
- Millisecond delivery may partially freeze respiratory motion and reduce interplay, but this benefit remains primarily theoretical. Residual movement, target verification, gating accuracy, breath-hold reproducibility, and the possible effect of supplemental oxygen on the FLASH response remain unresolved.
CLINICAL TAKEAWAY
FLASH proton therapy has a credible preclinical rationale for reducing pulmonary injury, and technically acceptable lung plans can already be generated in selected scenarios. It is not ready for clinical lung cancer treatment: the required biological conditions remain undefined, respiratory-motion solutions are unvalidated, and no patient-level efficacy or toxicity evidence exists.