Defining the optimal radiation-induced lymphopenia metric to discern its survival impact in esophageal cancer

Pim J J Damen; Max Peters; Brian Hobbs; Yiqing Chen; Uwe Titt; Remi Nout; Radhe Mohan; Steven H Lin; Peter S N van Rossum

doi:10.1016/j.ijrobp.2024.12.014

Defining the optimal radiation-induced lymphopenia metric to discern its survival impact in esophageal cancer

Int J Radiat Oncol Biol Phys. 2025 Jan 2:S0360-3016(24)03770-2. doi: 10.1016/j.ijrobp.2024.12.014. Online ahead of print.

Authors

Pim J J Damen¹, Max Peters², Brian Hobbs³, Yiqing Chen⁴, Uwe Titt⁵, Remi Nout⁶, Radhe Mohan⁵, Steven H Lin⁷, Peter S N van Rossum⁸

Affiliations

¹ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, United States of America; Department of Radiation Oncology, Amsterdam UMC, Amsterdam, The Netherlands; Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: p.damen@erasmusmc.nl.
² Department of Radiotherapy, Radiotherapiegroep, Deventer, The Netherlands.
³ Department of Population Health, Dell Medical School, The University of Texas at Austin, Austin TX, United States of America.
⁴ Department of Biostatistics and Data Science, University of Texas Health Science Center, Houston TX, United States of America.
⁵ Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston TX, United States of America.
⁶ Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, United States of America.
⁸ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, United States of America; Department of Radiation Oncology, Amsterdam UMC, Amsterdam, The Netherlands.

PMID: 39755214
DOI: 10.1016/j.ijrobp.2024.12.014

Abstract

Background: A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in esophageal cancer patients has been established. However, an optimal metric for RIL remains undefined, but is important for application of this knowledge in clinical decision-making and trial designs. The aim of this study was to find the optimal RIL metric discerning survival.

Methods: Esophageal cancer patients treated with concurrent chemoradiotherapy (CRT; 2004-2022) were selected. Studied metrics included absolute lymphocyte counts (ALCs) and neutrophil counts -and calculated derivatives- at baseline and during CRT. Multivariable Cox regression models for progression-free survival (PFS) and overall survival (OS) were developed for each RIL metric. The optimal RIL metric was defined as the one in the model with the highest c-statistic.

Results: Among 1,339 included patients, 68% received photon-based and 32% proton-based CRT (median follow-up 24.9 months). In multivariable analysis, the best performing models included "ALC in week 3 of CRT" (corrected c-statistic 0.683 for PFS, and 0.662 for OS). At an optimal threshold of <0.5 × 10³/μL (i.e. grade ≥3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio [aHR] 1.64; 95% confidence interval [CI] 1.27-2.13) and OS (aHR 1.56; 95%CI 1.15-2.08), with 5-year PFS of 29% vs. 40% and OS of 38% vs. 51%, respectively.

Conclusions: Reaching grade ≥3 RIL in week 3 of CRT for esophageal cancer is the strongest RIL metric to distinguish survival outcomes. We suggest that this metric should be the target for lymphopenia-mitigating strategies, and propose this metric to be included in future trials.

Keywords: chemoradiotherapy; esophageal cancer; immune cells; lymphopenia; survival.