Biologically optimized 3D range modulators for fast conformal carbon ion therapy: in vitro validation, treatment planning, and robustness analysis

OBJECTIVE: Patient-specific 3D range modulators (RMs) allow rapid and conformal particle therapy with monoenergetic beams and may support motion management and ultra-high dose rate (UHDR) studies. For carbon ions, however, relative biological effectiveness (RBE) varies strongly with depth, so RM geometry should be optimized for biological effect rather than physical dose alone. This work presents a translational pathway for biologically optimized 3D RMs (bio-RMs) for carbon ion therapy, evaluated through dosimetric verification, radiobiological validation, and patient-specific planning. Approach. A fast Monte Carlo-based RM platform was extended to perform RBE-weighted optimization using the modified microdosimetric kinetic model (mMKM) and local effect model 1 (LEM1). Cell line-specific mMKM parameters were determined for a non-small cell lung cancer cell line. Bio-RMs were designed for 4 and 8 Gy(RBE) biological spread-out Bragg peaks (SOBPs), 3D printed, and evaluated with clonogenic assays. Clinical feasibility was assessed through comparative treatment planning for vertebral metastasis and lung tumor cases. Main results. Measured survival fractions agreed with mMKM predictions within 5% on average across the biological SOBP, and physical dose measurements agreed with Monte Carlo calculations within 1.2%. Secondary fragment analysis showed that the bio-RMs increased the relative contribution of light and intermediate fragments. In the retrospective clinical cases, bio-RM plans achieved target coverage and OAR metrics comparable to reference intensity modulated particle therapy (IMPT), with slightly reduced target homogeneity. Estimated delivery times were reduced from minutes to seconds by eliminating energy switching. Robustness analyses showed acceptable stability under the evaluated manufacturing, setup, and range uncertainties. Significance. Bio-RMs enable fast, biologically conformal carbon ion therapy with plan quality approaching IMPT in the two cases studied. The framework links biological modeling to patient-specific implementation and provides a basis for future motion-management and UHDR studies in synchrotron-based facilities. .