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

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

^*Corresponding author for this work

Radiotherapy

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Purpose:

A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the 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 and Materials:

Patients with esophageal cancer treated with concurrent chemoradiation therapy (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 1339 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 (ie, grade ≥3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio, 1.64; 95% CI, 1.27-2.13) and OS (adjusted hazard ratio, 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.

Original language	English
Pages (from-to)	31-42
Number of pages	12
Journal	International Journal of Radiation Oncology Biology Physics
Volume	122
Issue number	1
DOIs	https://doi.org/10.1016/j.ijrobp.2024.12.014
Publication status	E-pub ahead of print - Jan 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

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Damen, P. J. J., Peters, M., Hobbs, B., Chen, Y., Titt, U., Nout, R., Mohan, R., Lin, S. H., & van Rossum, P. S. N. (2025). Defining the Optimal Radiation-induced Lymphopenia Metric to Discern Its Survival Impact in Esophageal Cancer. International Journal of Radiation Oncology Biology Physics, 122(1), 31-42. Advance online publication. https://doi.org/10.1016/j.ijrobp.2024.12.014

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title = "Defining the Optimal Radiation-induced Lymphopenia Metric to Discern Its Survival Impact in Esophageal Cancer",

abstract = "Purpose: A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the 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 and Materials: Patients with esophageal cancer treated with concurrent chemoradiation therapy (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 1339 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 (ie, grade ≥3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio, 1.64; 95\% CI, 1.27-2.13) and OS (adjusted hazard ratio, 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.",

author = "Damen, \{Pim J.J.\} and Max Peters and Brian Hobbs and Yiqing Chen and Uwe Titt and Remi Nout and Radhe Mohan and Lin, \{Steven H.\} and \{van Rossum\}, \{Peter S.N.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = jan,

doi = "10.1016/j.ijrobp.2024.12.014",

language = "English",

volume = "122",

pages = "31--42",

journal = "International Journal of Radiation Oncology Biology Physics",

issn = "0360-3016",

publisher = "Elsevier Inc.",

number = "1",

}

TY - JOUR

T1 - Defining the Optimal Radiation-induced Lymphopenia Metric to Discern Its Survival Impact in Esophageal Cancer

AU - Damen, Pim J.J.

AU - Peters, Max

AU - Hobbs, Brian

AU - Chen, Yiqing

AU - Titt, Uwe

AU - Nout, Remi

AU - Mohan, Radhe

AU - Lin, Steven H.

AU - van Rossum, Peter S.N.

PY - 2025/1

Y1 - 2025/1

N2 - Purpose: A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the 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 and Materials: Patients with esophageal cancer treated with concurrent chemoradiation therapy (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 1339 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 (ie, grade ≥3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio, 1.64; 95% CI, 1.27-2.13) and OS (adjusted hazard ratio, 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.

AB - Purpose: A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the 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 and Materials: Patients with esophageal cancer treated with concurrent chemoradiation therapy (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 1339 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 (ie, grade ≥3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio, 1.64; 95% CI, 1.27-2.13) and OS (adjusted hazard ratio, 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.

UR - https://www.scopus.com/pages/publications/85215599485

U2 - 10.1016/j.ijrobp.2024.12.014

DO - 10.1016/j.ijrobp.2024.12.014

M3 - Article

C2 - 39755214

AN - SCOPUS:85215599485

SN - 0360-3016

VL - 122

SP - 31

EP - 42

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

IS - 1

ER -

Defining the Optimal Radiation-induced Lymphopenia Metric to Discern Its Survival Impact in Esophageal Cancer

Abstract

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