2023 - Treatment-Associated Lymphopenia from Hypofractionated vs. Conventional Chemoradiation in Locally Advanced Non-Small Cell Lung Cancer

K. Chen¹, B. Kalaghchi¹, D. Caruthers¹, C. G. Robinson¹, S. Waqar², D. Morgensztern², R. Govindan², Y. Huang¹, C. Bergom¹, P. Samson¹, and G. R. Vlacich¹; ¹Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, ²Washington University School of Medicine, Department of Medicine, Division of Oncology, St. Louis, MO

Purpose/Objective(s): Radiation-induced lymphopenia can mitigate the effect of immunotherapy and negatively impact survival for locally advanced non-small cell lung cancer (LA-NSCLC). Irradiation volume, use of protons, and dose fractionation independently affect lymphopenia. We hypothesize that photon-based hypofractionation in particular reduces lymphopenia relative to conventional fractionation when treating LA-NSCLC. Materials/

Methods: A retrospective comparison was performed among patients with LA-NSCLC receiving either conventional (60 Gy/30 fractions) or hypofractionated (60 Gy/15 fractions) IMRT with concurrent carboplatin/paclitaxel. The hypofractionated group is derived from a prospective institutional phase II trial, while the conventional group consists of a contemporary retrospective cohort. All patients completed their full course of treatment between 2017 and 2023. Weekly complete blood count was obtained at chemotherapy infusion. Degree of lymphopenia was measured by absolute lymphocyte count (ALC) in units of K/mm³ at its lowest level during chemoradiation (ALC nadir) and 2-4 weeks after completing chemoradiation (post-treatment ALC), and by CTCAE lymphopenia grade. Non-parametric statistics were used to analyze these endpoints. Multivariate logistic regression was used to control for confounding bias.
Results: Eighty-seven patients were analyzed, 26 of whom received hypofractionation. The cohorts were well matched except for larger PTV (p = 0.003) and more T4 tumors (p = 0.04) in the conventional group. GTV, N stage, and pre-treatment ALC were not significantly different. ALC nadir during chemoradiation was higher in the hypofractionated group (mean 0.35 vs 0.20, p = 0.003). With each increasing lymphopenia grade, the proportion of patients receiving conventional fractionation also increased in a stepwise manner (p < 0.001). Grade 3 or 4 lymphopenia was specifically seen in 73% of the hypofractionated group versus 93% of the conventional group (p = 0.008). Post-treatment ALC was also improved in the hypofractionated group (mean 0.77 vs 0.47, p < 0.001), again with an increasing proportion of conventional fractionation as post-treatment lymphopenia grade increased (p < 0.001). Ultimately, hypofractionation was an independent predictor of high-grade lymphopenia (OR 0.23, 95% CI 0.05-0.96, p = 0.04) controlling for PTV (p = 0.3) and T4 staging (p = 0.7).
Conclusion: Photon-based hypofractionation in LA-NSCLC results in less severe lymphopenia during and after chemoradiation when compared to conventional fractionation. With subsequent confirmation of the clinical significance of this difference, hypofractionation may provide an improved platform to combine chemoradiation with immunotherapy where this has previously failed to demonstrate a benefit with conventional fractionation. (NCT03916419)