Dose-Linear Energy Transfer Interactions Predict Capsular Contracture After Proton Postmastectomy Radiation Therapy

Pencil beam scanning proton therapy enables highly conformal dose distributions and is increasingly used for postmastectomy radiation therapy (PMRT) to reduce cardiopulmonary exposure. However, implant-based reconstruction (IBR) in the setting of PMRT remains susceptible to capsular contracture, and the potential contribution of elevated linear energy transfer (LET) in pencil beam scanning has not been well characterized. This study aimed to investigate the combined effects of dose-LET and dose-averaged LET on capsular contracture after proton PMRT and to derive preliminary, exploratory volume cutoff values of dose-LET volume constraints (DLVCs).

We conducted a retrospective case-control study of patients with consecutive breast cancer who underwent mastectomy followed by IBR and conventionally fractionated proton PMRT (50 Gy in 25 fractions) between 2015 and 2021. Patients who developed Baker grades III to IV capsular contracture were identified and matched 1:2 with controls using nearest-neighbor matching based on clinical and pathologic variables. Dose-LET volume histograms (DLVHs) were calculated for peri-implant tissue (5-mm shell around the implant). Generalized linear mixed-effects regression was used to identify DLVH indices significantly associated with capsular contracture. Redundant indices were removed using Spearman correlation analysis. DLVCs were derived from receiver operating characteristic curve analysis and evaluated using a support vector machine-based normal tissue complication probability model with leave-one-out cross-validation.

Among 145 consecutive patients, 8 developed capsular contracture and were matched to 16 controls. Three independent DLVH indices were significantly associated with capsular contracture (P < .01): V (55.8 Gy [relative biological effectiveness {RBE} value = 1.1], 2.2 keV/μm), V (50.3 Gy [RBE value = 1.1], 5.4 keV/μm), and V (32.8 Gy [RBE value = 1.1], 0.9 keV/μm). After Benjamini-Hochberg false discovery rate correction across all 4096 DLVH indices, all 3 remained significant (q_Benjamini-Hochberg = 0.052). The corresponding DLVCs were V (55.8 Gy [RBE value = 1.1], 2.2 keV/μm) < 0.0017%, V (50.3 Gy [RBE value = 1.1], 5.4 keV/μm) < 0.0033%, and V (32.8 Gy [RBE value = 1.1], 0.9 keV/μm) > 96.98%. The support vector machine-based normal tissue complication probability model achieved an area under the receiver operating characteristic curve value of 0.867, with an accuracy of 91.7%, a sensitivity of 87.5%, and a specificity of 93.8%.

Capsular contracture following proton PMRT is significantly associated with the combined effects of dose-LET and dose-averaged LET in peri-implant tissue. The derived DLVCs represent exploratory candidate dosimetric constraints that warrant further investigation and prospective validation in patients with breast cancer undergoing proton PMRT with IBR.