Combining IMPT and spot-scanning hadron arc to efficiently boost dose and LET in hypoxic target volumes

Background: Hypoxia significantly affects radiotherapy by increasing tumor radioresistance. High linear energy transfer radiation, such as carbon ion therapy, can help mitigate this issue. Carbon ion arc therapy offers the potential to increase LET in hypoxic tumor regions, offering a promising approach to improve treatment outcomes, but lacks robustness. Purpose: We introduced and quantitatively evaluated a new heavy ion therapy treatment strategy named LET bOost by heavy Particle Arc RaDiation (LEOPARD), which combines intensity-modulated particle therapy (IMPT) with spot-scanning hadron arc (SHArc) strategy. LEOPARD aims to increase dose and the dose-averaged linear energy transfer (LETd) within the hypoxic target volume (HTV) while maintaining plan quality and robustness. IMPT and SHArcBoost are used as reference strategies for comparison. Methods: A proof of concept for LEOPARD was realized on 15 head & neck cancer patients with an artificially contoured HTV generated from isotropic shrinking of the clinical target volume (CTV). The LEOPARD plans integrate a full arc field (0(degrees) to 358(degrees), step = 2(degrees), 180 fields) delivering a boost dose to the HTV with additional IMPT fields(10(degrees) and 170(degrees)) that simultaneously provide the prescribed dose to the CTV, combining both approaches in a unified treatment plan. To evaluate the potential of LEOPARD, we compared it to intensity modulated particle therapy dose boost plans (IMPTBoost) which included 2 IMPT fields (10(degrees) and 170(degrees)) for CTV, with 2 identical fields added to boost dose in HTV, and SHArc-only boost plans (SHArcBoost) which used same arc fields as LEOPARD aimed at both CTV and HTV but without IMPT fields. Plans were evaluated for dosimetric accuracy, robustness, LETd, and cell survival fraction considering the oxygen-enhancement ratio. Treatment delivery times were calculated using an in-house dynamic carbon ion arc therapy delivery simulator. Results: LEOPARD combined treatment demonstrated a capacity to balance plan quality by mitigating the robustness issues inherent in SHArc plans while improving the LET distribution compared to IMPTBoost plans. Compared with SHArcBoost, LEOPARD showed higher mean D95 in the HTV (96.1% vs. 95.4%; p<0.001), lower mean D2 (113.2% vs. 117.0%; p<0.001) and HI (18.3% vs. 22.6%; p<0.001). Compared with IMPTBoost, mean LET(d)50 in the HTV increased by 16.9% (p<0.001), and mean SF50 in the HTV reduced by 3.8% (p<0.001). Conclusion: We developed a new treatment strategy-LEOPARD, which can generate higher LETd in the HTV than IMPTBoost, while achieving better dose distribution and plan robustness compared to SHArcBoost. This work therefore indicates promising potential of LEOPARD for the treatment of hypoxic tumors.