Low Dose-Averaged Linear Energy Transfer Contributes to Local Recurrence of Pancreatic Cancer Treated With Carbon Ion Radiation Therapy

This retrospective study examined the relationship between dose-averaged linear energy transfer (LETd) and local recurrence (LR) in patients with inoperable pancreatic cancer treated with carbon ion radiation therapy (CIRT) at Gunma University. Data from 106 patients treated between 2013 and 2021 with a prescribed dose of 55.2 Gy (RBE) in 12 fractions were analyzed. Using an in-house LETd calculation algorithm, researchers correlated LETd profiles with clinical outcomes. The two-year local recurrence rate was 20.2%, and analysis revealed that a lower minimum LETd within the clinical target volume (CTV Lmin) significantly increased the likelihood of LR. Patients with CTV Lmin below 42.2 keV/μm had a 32.4% recurrence rate compared to 12.7% for those above this threshold (p = 0.03). Larger CTVs were associated with lower LETd values, indicating that insufficient LETd coverage in tumor centers may limit CIRT effectiveness.

The findings demonstrate that low LETd regions correspond to poor tumor control, suggesting that current dose prescriptions based solely on relative biological effectiveness (RBE) may overestimate the therapeutic impact of low-LET carbon ions, particularly in hypoxic tumor regions. The study supports incorporating LETd optimization (“LET painting”) into treatment planning to ensure minimum values of 42–45 keV/μm are delivered throughout the tumor volume.

In conclusion, this is the largest study to date linking LETd heterogeneity to pancreatic tumor recurrence after CIRT. Ensuring adequate LETd coverage could enhance local control, supporting future clinical trials of LET-modulated carbon ion therapy for radioresistant tumors such as pancreatic cancer.

International Journal of Radiation Oncology, Biology, Physics – Accepted 6 July 2025, Available online 16 July 2025, Version of Record 14 October 2025. https://doi.org/10.1016/j.ijrobp.2025.07.1406