Risk and impact of radiation related lymphopenia in lung cancer: A systematic review and meta-analysis

Background: Despite the modern advances in treatment techniques, the survival of locally advanced lung cancer patients continues to remain poor. Circulating lymphocytes have an important role to play in local immune response to RT as well as immune checkpoint inhibitors, and radiation related lymphopenia has been associated with inferior survival in various tumors. Methods: We undertook this systematic review and meta-analysis to evaluate the literature on risk and impact of lymphopenia in thoracic tumors. A systematic methodology search of the PubMed, Embase and Cochrane library was performed and eligible studies selected based on pre-defined inclusion and exclusion criteria. Review Manager Version 5.4.1 was used for the meta-analysis. Results: Fourteen studies were included in the final systematic review and 10 in the quantitative analysis. Overall mean incidence of severe lymphopenia (absolute lymphocyte count < 500) was 64.24%. The patients with severe lymphopenia were at increased risk of death with a pooled HR of 1.59 (95% CI: 1.40, 1.81, I² = 17%, P < 0.001) and progression with a pooled HR of 2.1 (95% CI: 1.57, 2.81, I² = 59%, P < 0.001) compared to patients with no severe lymphopenia. Dosimetric parameters including gross tumor volume, lung V5 and heart V5 were predictive of lymphopenia, while advanced age, lower baseline lymphocyte counts, higher stage and large tumor size were other risk factors. Models predicting estimated radiation dose to lymphocytes were a good surrogate for treatment outcomes. Conclusion: Radiation related lymphopenia is associated with increased hazard of progression and death in lung cancer. Minimizing the lung and heart dose, especially in patients with concurrent other risk factors can reduce lymphopenia and potentially improve treatment outcomes in these patients.