A Risk Prediction Model for Severe Radiation Induced Lymphopenia in Patients with Pancreatic Cancer Treated with Concurrent Chemoradiotherapy

Abstract

In pancreatic cancer, radiation induced lymphopenia (RIL) is associated with a poor prognosis. However, normal tissue complication probability (NTCP) models predicting RIL in pancreatic cancer treated with concurrent chemoradiotherapy (CCRT) have yet to be developed. This study aims to develop a least absolute shrinkage and selection operator (LASSO)-based multivariate NTCP model to predict severe RIL in patients with pancreatic cancer during CCRT and to validate the model internally. We retrospectively reviewed patients with localized pancreatic cancer who underwent CCRT using three-dimensional conformal radiation therapy from 2013 to 2021. The exclusion criteria were patients with distant metastasis; patients who did not complete RT due to tumor progression; patients who did not have absolute lymphocyte count (ALC) data available before or during RT. An ALC of < 0.5 K/μL during CCRT was defined as severe RIL. A NTCP model of severe RIL was developed by LASSO-based multivariate analysis. We used age, sex, Karnofsky performance status, maximum tumor size, carbohydrate antigen 19-9 level before RT, ALC before RT, volume of planning target volume (PTV), and dosimetric parameters for surrounding organs (including spleen, vertebrae, liver, bilateral kidneys, gastrointestinal tracts) as variables for LASSO. In addition, internal validation was performed by the bootstrap method. The predictive performance of the model was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve and scaled Brier score. Of the 131 patients included in the study, the median age was 68 years (range, 42-84), and 55% were male. The median ALC before RT was 1.37 K/µL (0.52-3.50). The median PTV volume was 315.4 ml (86.3-1079.3). The median dose of radiotherapy was 50.4 Gy (16.2-50.4), with 1.8 Gy per fraction. Combination chemotherapy was S-1 in 99 cases (75.6%) and gemcitabine in 32 cases (24.4%). Induction chemotherapy before CCRT was performed in 39 patients (29.8%). Severe RIL was observed in 84 (63.6%) patients. The LASSO showed that low baseline ALC (p = 0.0002), large PTV volume (p < 0.0001), and a large kidney V5 defined as the percentage of bilateral kidneys receiving 5 Gy or more (p = 0.0338) were selected as parameters of the prediction model for severe RIL (AUC = 0.917) and scaled Brier score was 0.511. As a result of internal validation by the bootstrap method, the average AUC was 0.918 (95% confidence interval, 0.849-0.954). Severe RIL occurred frequently during CCRT for pancreatic cancer, and a NTCP model for severe RIL developed and validated internally in this study showed good predictive performance. External validation is needed before this NTCP model can be used as a benchmark for treatment planning to reduce the risk of severe RIL and for considering future treatment approaches.