Abstract
Purpose or Objective Emerging evidence suggests an independent detrimental prognostic association between radiation-induced lymphopenia (RIL) and pathologic response, progression-free and overall survival in patients who undergo radiotherapy for cancer. The aim of this study was to systematically review and meta-analyze the prognostic impact of RIL on overall survival (OS) in
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patients with solid tumors. Materials and Methods PubMed/MEDLINE and Embase were systematically searched. The analysis included intervention and prognostic studies that reported on the prognostic relationship between RIL and survival in patients with solid tumors. An overall pooled adjusted hazard ratio (aHR) was calculated using a random-effects model. Subgroup analyses for different patient-, tumor-, treatment- and study-related characteristics were performed using meta-regression. Lymphopenia was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Results Twenty-one cohorts within 20 studies reporting on adjusted HRs were eligible for meta-analysis. Radiotherapy target sites included tumors of the brain, lung, pancreas, esophagus, liver, cervix, oropharynx, bone, and anal canal. Pooled analysis across the 16 cohorts reporting on grade ≥3 RIL (versus grade 0-2 RIL) demonstrated a statistically significant detrimental OS with an overall adjusted pooled HR of 1.65 (95% confidence interval [CI]: 1.43-1.90), as demonstrated in Figure 1. Moderate heterogeneity among HRs was observed (I2=49.1%), mostly attributable to overestimated HRs in 7 studies which were likely subject to model-overfitting. Subgroup analysis per tumor site showed a statistically significant association between grade ≥3 RIL and worse OS in 4 brain tumor studies (pooled aHR 1.63, 95% CI: 1.06-2.51; I2=3.6%), 4 lung cancer cohorts (pooled aHR 1.52, 95% CI: 1.01-2.29; I2=0%), and 3 pancreatic cancer studies (pooled aHR 1.92, 95% CI: 1.10-3.36; I2=0%). In addition, pooled analysis across 5 studies reporting on grade 4 RIL (versus grade 1-3 RIL) showed a statistically significant pooled aHR for detrimental OS of 1.53 (95% CI: 1.24-1.90; I2=29.1%), as demonstrated in Figure 2. Conclusion This meta-analysis of 21 cohorts demonstrated a significant detrimental prognostic association between radiation-induced lymphopenia and overall survival in patients who undergo radiotherapy for solid tumors, with an increase of 65% in the risk of death over time in patients who experience grade ≥3 lymphopenia and of 50% in patients with grade 4 lymphopenia. These HR estimates were adjusted for other prognostic factors in the individual studies. The association appears consistent for tumors of the brain, thorax and upper abdomen, and provides an imperative to further elucidate the potential survival benefit of lymphopenia mitigating strategies.
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