Study of linear energy transfer effect on rib fracture in breast cancer patients receiving pencil-beam-scanning proton therapy

Background: In breast cancer patients treated with pencil-beam scanning proton therapy (PBS), the increased linear energy transfer (LET) near the end of the proton range can affect nearby ribs. This may associate with a higher risk of rib fractures. Purpose: To study the effect of LET on rib fracture in breast cancer patients treated with PBS using a novel tool of dose-LET volume histogram (DLVH). Methods: From a prospective registry of patients treated with post-mastectomy proton therapy to the chest wall and regional lymph nodes for breast cancer between 2015 and 2020, we retrospectively identified rib fracture cases detected after completing treatment. Contemporaneously treated control patients who did not develop rib fracture were matched to patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year. The DLVH index, V(d, l), defined as volume(V) of the structure with at least dose(d) and dose-averaged LET (l) (LETd), was calculated. DLVH plots between the fracture and control group were compared. Conditional logistic regression (CLR) model was used to establish the relation of V(d, l) and the observed fracture at each combination of d and l. The p-value derived from CLR model shows the statistical difference between fracture patients and the matched control group. Using the 2D p-value map derived from CLR model, the DLVH features associated with the patient outcomes were extracted. Results: Seven rib fracture patients were identified, and fourteen matched patients were selected for the control group. The median time from the completion of proton therapy to rib fracture diagnosis was 12 months (range 5-14 months). Two patients had grade 2 symptomatic rib fracture while the remaining 5 were grade 1 incidentally detected on imaging. The derived p-value map demonstrated larger V(0-36 Gy[RBE], 4.0-5.0 keV/mu m) in patients experiencing fracture (p < 0.1). For example, the p-value for V(30 Gy[RBE], 4.0 keV/um) was 0.069. Conclusion: In breast cancer patients receiving PBS, a larger volume of chest wall receiving moderate dose and high LETd may result in an increased risk of rib fracture.