While radiation serves as an important pillar in oncology treatment, radiation therapy often comes with significant side effects. Patients treated with conventionally fractionated radiation for tumors located in the brain, spleen, lung, breast, pancreas, and head and neck show decreases in lymphocyte counts following therapy (1-7). Importantly, this phenomenon, termed radiation-induced lymphopenia (RIL), directly correlates with decreased overall survival (OS) for patients with non-small cell lung cancer (NSCLC), pancreatic adenocarcinoma, and gliomas (1, 2, 8). While it was initially theorized that RIL resulted from radiation exposure to sites of lymphocyte production or maturation, newer studies indicate that radiotoxic doses to the circulating lymphocytes themselves may be responsible (9). Post-radiation lymphopenia shows surprising persistence after the radiation event, taking up to two years for counts to normalize (5).
Modeling dose received by lymphocytes circulating throughout the body, traveling in and out of the radiation field, creates numerous difficulties. One model developed to measure radiation received during a standard 30 fraction glioma treatment estimates a mean dose of >2 Gy to circulating lymphocytes (10). Experimental studies done extracorporeally indicate that a 2 Gy dose is sufficient to kill 60% of the lymphocyte population (11). In mice, whole body exposures of as low as 0.3 Gy produce significant RIL while exposures of 0.5 Gy produce marked RIL (12). Increasing the number of radiation fractions greatly increases the proportion of lymphocytes exposed to large doses of radiation as it increases the opportunities for the circulating blood pool to flow into the treatment field. Ergo, the model further suggests that hypofractionation may help mitigate decreases in lymphocyte count (10). Research into stereotactic body radiation therapy (SBRT) for pancreatic cancer supports this hypothesis. While conventionally fractionated radiation induces treatment associated lymphopenia, SBRT therapies cause no significant decrease in lymphocyte counts (7, 13).
NSCLC represents an interesting study for RIL. As highly vascular organs, the lungs receive a large portion of blood flow at any given time. Prior studies demonstrate RIL with chemotherapy combined with conventionally fractionated (60 Gy in 30 fractions) radiation in stage III NSCLC. RIL occurs in 50% of the patients studied with an average reduction of 67%. RIL below 500 cells/mm3 corresponds with a non-significant decrease in median survival time from 27.3 to 21.8 months (p = 0.38) (2).
While historically treated with conventional fractionation, inoperable early stage NSCLC is increasingly treated definitively with SBRT, providing outcomes comparable to lobectomy (14). Compared with conventional fractionation, SBRT delivers a higher dose per fraction in fewer fractions. Modern SBRT techniques compensate for respiratory motion, further reducing the volume of lung (and therefore volume of circulating blood pool) exposed to large doses of radiation. However, it is noteworthy that patients treated with SBRT may suffer from a large volume of low-dose spillage in healthy lung which receives a large proportion of the circulating blood pool. This spillage could theoretically expose a large fraction of blood to meaningful radiation doses.
This paper seeks to explore whether patients treated with SBRT for NSCLC experience lymphopenia similar to those treated with conventionally fractionated radiation using incidentally collected total lymphocyte counts before and after SBRT.