Meta-analysis and Critical Review: Association Between Radio-induced Lymphopenia and Overall Survival in Solid Cancers

Abstract

Purpose: Immune system modulation, with the use of immune checkpoint inhibitors, has drastically changed the field of oncology. Strong preclinical data indicate that radiation therapy (RT) may enhance the response rate to such drugs via in situ vaccination, although these data do not consider immune radiotoxicity. This meta-analysis investigates whether radio-induced lymphopenia (RIL) is associated with overall survival (OS). Methods and Materials: A systematic literature search and quantitative analysis were planned, conducted, and reported per the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Quality of Reporting of Meta-analyses checklists. The literature from January 1990 to March 2021 was searched to identify clinical studies with OS data in patients treated with RT and presenting with lymphopenia. A random-effect model was employed for the meta-analysis. Heterogeneity was assessed using the I2 statistic. Publication bias was estimated using a P-curve analysis. Results: A total of 56 studies with 13 223 patients and 11 types of cancers were selected. The mean follow-up time was 35.9 months. Over a third of patients had RIL (37.25%). After removing outlying studies (n = 14), the between-study heterogeneity variance was estimated at t2 = 0.018 (P = .01) with an I2 value of 36.0% (95% confidence interval, 6%-56%). The results showed that RIL was significantly associated with worse OS (hazard ratio: 1.70; 95% confidence interval, 1.55-1.86; P < .01; 95% prediction interval, 1.27-2.26). A subgroup analysis was performed based on the type of primary tumor, and a difference between the subgroups was found (P < .01). Based on the P-curve analysis, a significant evidential value was found, and no significant publication bias was identified among the studies. Conclusions: RIL is a significant prognostic factor for mortality in virtually all solid cancers. Pooled-effect estimates indicate a significantly reduced risk of death in patients without RIL. Tailoring RT regimens to spare the immune system and updating dosimetric constraints for new organs at risk, such as major blood vessels, organs with rich blood supplies, bones, and all lymph node areas, may improve prognoses.