Exploratory Investigation of Dose-Linear Energy Transfer (LET) Volume Histogram (DLVH) for Adverse Events Study in Intensity-Modulated Proton Therapy (IMPT)

Abstract

We proposed a novel tool of dose-linear-energy-transfer (LET) volume histogram (DLVH) and performed an exploratory study to investigate rectal bleeding in prostate cancer treated by intensity-modulated proton therapy (IMPT).DLVH was constructed with dose and LET as two axes, while the normalized volume of the structure was contoured in the dose-LET plane as iso-volume lines. We defined DLVH index, DLv% (d,l), i.e., v% of the structure have a dose of d ≥ Gy and an LET of l ≥ keV/µm similar to dose-volume histogram index Dv%. Nine prostate cancer patients with rectal bleeding (CTCAE grade ≥2) were included as the adverse event group, while 48 patients with no complication were considered as the control group. P-value map was constructed by comparison of the DLVH indices of all patients between the two groups using the Mann-Whitney U test. Dose-LET volume constraints (DLVCs) were derived based on the P-value map with a manual selection procedure facilitated by Spearman's correlation tests. The obtained DLVCs were further cross-validated using a multivariate support-vector-machine (SVM)-based normal tissue complication probability (NTCP) model with an independent testing dataset composed of 8 AE and 13 control patients.We extracted two DLVC constraints. One DLVC was obtained: V (dose/LET boundary: 2.5keV/μm at 75 Gy to 3.2keV/μm at 8.65 Gy) < 1.27% (DLVC1), revealing high LET volume effect. The second DLVC was observed: V(72.2 Gy,0keV/μm) < 2.23% (DVLC2), revealing high dose volume effect. The SVM-based NTCP model with two DLVCs provided slightly superior performance on training, validation, and testing compared to the model using generalized equivalent uniform dose (gEUD) alone (Table 1). The corresponding area-under-the-curves (AUCs) of the receiver operating characteristic (ROC) curve were 0.785 vs. 0.762, 0.720 vs. 0.704, and 0.798 vs. 0.779 for the training, validation, and testing dataset, respectively. Sensitivity of 0.67 and specificity of 0.69 were achieved at the NTCP cutoff value of 0.5 in validation.Our results demonstrated the importance of rectal "hot spots" in both high LET (DLVC1) and high dose (DLVC2) in inducing rectal bleeding. The SVM-based NTCP model confirmed the derived DLVCs as good predictors for rectal bleeding. The established NTCP model based on these two DLVCs has been used routinely at our proton center during the plan evaluation to minimize the possible incidence of rectal bleeding in prostate cancer patients treated by IMPT. Table 1 Performances of the NTCP models.