Respiratory motion of 20 mm nearly halves the peak-to-valley dose ratio (PVDR) that underpins proton minibeam radiotherapy's tissue-sparing effect, according to 4D Monte Carlo simulations from Institut Curie published in Physics in Medicine & Biology (10.1088/1361-6560/ae8ef8). At 5 mm depth, mean PVDR fell from 11.9 in the static 3D case to 6.7 with breathing motion — a degradation that a tenfold increase in dose rate only marginally mitigated.

The findings carry direct portfolio implications for proton therapy centres weighing pMBRT, a technique that splits the beam through a multi-slit collimator into minibeams 0.3–1 mm wide, spaced 2–6 mm apart. Because the collimator blocks most of the initial proton beam, treatment times lengthen, and with them the exposure to organ motion. Preclinical studies in small animals have shown the alternating high-dose peaks and low-dose valleys destroy tumours while sparing healthy tissue — but that spatial modulation is exactly what motion erodes.

"Given the longer irradiation times, possible patient movement could deteriorate the heterogeneous spatial dose distribution of pMBRT," senior author Ludovic De Marzi told Physics World. "This is all the more problematic because it is this heterogeneous distribution that is believed to be responsible for the technique's biological sparing effect."

Validated against phantom measurements

The team built a 4D dose calculation workflow from time-resolved Monte Carlo simulations, requiring two inputs: a 4D CT dataset capturing patient anatomy across one respiratory cycle, and a proton pencil-beam scanning (PBS) treatment plan created on a reference CT. Before applying it to pMBRT, the researchers validated the tool conventionally, irradiating a thoracic motion phantom with a standard PBS plan. Across nine phantom irradiations, the mean gamma pass rate at the 3%/3 mm criterion was 97.3% — a solid baseline for 4D dose modelling.

The thoracic simulations compared three scenarios: static 3D pMBRT; 4D pMBRT with 20 mm breathing motion; and 4D high-dose-rate pMBRT with instantaneous dose rate increased tenfold to cut beam-on time by a factor of ten. The FLASH-adjacent high-dose-rate scheme did not significantly reduce the PVDR degradation.

Motion also hit tumour coverage. Mean target dose dropped 30% and D95% — the minimum dose received by 95% of the target volume — dropped 35% for 4D pMBRT. Organs at risk shifted too: dose to the stomach decreased while mean dose to the spleen rose significantly.

"The PVDR is an index that takes into account both doses in the valleys, which are likely correlated with the biological sparing effect on healthy tissue, and the maximum delivered doses, which are likely responsible for the anti-tumour effect," De Marzi explained. "It can also be used to help optimize the 3D dose distribution of the treatment plan."

Brain treatment: tighter but achievable tolerances

For intracranial cases, the team modelled the small rigid head translations that occur despite thermoplastic masks — typically below 1 mm — as continuous 1 mm and 2 mm shifts. Target and organ-at-risk doses held up, but the peak–valley patterns did not. A 1 mm shift cut mean PVDR by 10% relative to the static case at 15 mm depth; a 2 mm shift cut it by 24%.

The study's bottom line for clinical planning: without a dedicated motion management strategy, only intracranial treatments with sub-millimetre movement proved robust to interplay effects. The same workflow, the authors argue, can estimate pMBRT's sparing effect while accounting for patient motion and guide plan adaptation.

The next route to shortening delivery may be combining pMBRT with ultrahigh-dose-rate FLASH delivery. "This idea is appealing because it could both solve the problem of reduced dose rate in pMBRT and add an additional biological effect to further spare healthy tissue," said De Marzi. "However, its feasibility remains to be demonstrated... A simple increase in dose rate — without going as far as FLASH — would already be of interest."

The group is now validating calculation and measurement procedures tailored to pMBRT — tools that are, in De Marzi's words, "fast, accurate and usable by clinicians" — as the technique moves toward first clinical application.