AbstractThis study aims to propose a novel treatment planning methodology for multi-isocenter volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) using the special feasibility dose–volume histogram (FDVH)-guided auto-planning (AP) technique. Three different multi-isocenter VMAT -CSI plans were created, including manually based plans (MUPs), conventional AP plans (CAPs) and FDVH-guided AP plans (FAPs). The CAPs and FAPs were specially designed by combining multi-isocenter VMAT and AP techniques in the Pinnacle treatment planning system. Specially, the personalized optimization parameters for FAPs were generated using the FDVH function implemented in PlanIQ software, which provides the ideal organs at risk (OARs) sparing for the specific anatomical geometry based on the valuable assumption of the dose fall-off. Compared to MUPs, CAPs and FAPs significantly reduced the dose for most of the OARs. FAPs achieved the best homogeneity index (0.092 ± 0.013) and conformity index (0.980 ± 0.011), while CAPs were slightly inferior to the FAPs but superior to the MUPs. As opposed to MUPs, FAPs delivered a lower dose to OARs, whereas the difference between FAPs and CAPs was not statistically significant except for the optic chiasm and inner ear_L. The two AP approaches had similar MUs, which were significantly lower than the MUPs. The planning time of FAPs (145.00 ± 10.25 min) was slightly lower than that of CAPs (149.83 ± 14.37 min) and was substantially lower than that of MUPs (157.92 ± 16.11 min) withP< 0.0167. Overall, introducing the multi-isocenter AP technique into VMAT-CSI yielded positive outcomes and may play an important role in clinical CSI planning in the future.