Interaction between lymphopenia, radiotherapy technique, dosimetry, and survival outcomes in lung cancer patients receiving combined immunotherapy and radiotherapy

Aim: Immune function (e.g. absolute lymphocyte count (ALC)) and modifiable predictors thereof (e.g. volume of the heart/lungs receiving low-dose radiation) impact outcomes of cancer patients, but this has not been well-studied in the immunotherapy era. This investigation of metastatic lung cancer assessed the interaction of dosimetric parameters (e.g. lung/heart V5), radiotherapy technique (e.g. stereotactic (SBRT) or traditional radiotherapy), lymphopenia, and survival outcomes. Methods: Patients were collected from three institutional phase I/II trials of combined immunotherapy and lung irradiation. SBRT referred to 50 Gy/4 fractions or 60 Gy/10 fractions, and traditional RT as 45 Gy/15 fractions. Blood collections were standardized on the first and last day of radiotherapy and each cycle of immunotherapy. Statistics included multivariable linear regression to identify variables associated with ALC decline, Kaplan-Meier analysis of overall and progression-free survival (PFS), and Cox multivariate analysis. Results: The median follow-up of the 165 patients was 21 months. The only factor independently predictive of ALC decline was traditional RT (p < 0.001). Therefore, the analysis was repeated for traditional RT and SBRT separately; lung V5 was associated with lymphopenia for traditional RT (p < 0.001) but not SBRT (p = 0.12). Pre-radiotherapy ALC was independently associated with PFS in both cohorts (p < 0.05 for both); post-RT ALC predicted for PFS in the traditional RT (p = 0.048) but not the SBRT (p = 0.90) group. Neither heart nor lung V5 was independently associated with PFS. Conclusions: When combined with immunotherapy, SBRT may better preserve lymphocytes (and hence improve outcomes) than traditional RT. When administering traditional RT, constraining the lung V5 may indirectly impact outcomes by means of ALC preservation.