Lymphocyte Depletion Rate as a Biomarker of Radiation Dose to Circulating Lymphocytes During Fractionated Partial-Body Radiation Therapy

Abstract

Purpose: Radiation causes exponential depletion of circulating lymphocyte populations; in turn, radiation-induced lymphopenia is associated with worse survival for many solid tumors, possibly owing to attenuated antitumor immune responses. Identifying reliable and reproducible methods of calculating the radiation dose to circulating immune cells may facilitate development of techniques to reduce the risk and severity of radiation-induced toxic effects to circulating lymphocytes.

Methods and materials: Patient-specific lymphocyte loss rates were derived from a clinical data set including 684 adult patients with solid tumors. Multivariable linear regression was used to model the relationship between the lymphocyte loss rate and physical parameters of the radiation plan that determine circulating blood dose.

Results: During partial-body radiation, lymphocyte loss rates are determined by physical parameters of the radiation plan that reflect radiation exposure to circulating cells, including target volume size, dose per fraction squared, and anatomic site treated. Differences in observed versus predicted lymphocyte loss rates may be partly explained by variations in concurrent chemotherapy regimens.

Conclusions: We describe a novel method of using patient-specific lymphocyte loss kinetics to approximate the effective radiation dose to circulating lymphocytes during focal fractionated photon radiation therapy. Clinical applications of these findings include the early identification of patients at particularly high risk of severe radiation-induced lymphopenia based on physical parameters of the radiation therapy plan.

Figure 1

Scatterplot of the lymphocyte decay constant versus the product of the dose per fraction and PTV-to-blood-volume ratio. Note abdominal SBRT cases (blue circles), which have a much higher decay constant for similar dose/volume relationships compared with patients receiving conventional fractionation. Abbreviations: PTV = planning target volume; RT = radiation therapy; SBRT = stereotactic body radiation therapy.

Figure 2

Scatterplot showing the linear relationship between the lymphocyte decay constant versus the product of the dose per fraction squared and the PTV-to-blood-volume ratio. Interindividual variability in b for the same combinations of dose/fraction² and PTV:blood volume is observed. Abbreviations: CNS = central nervous system; H+N = head and neck; PTV = planning target volume; RT = radiation therapy; SBRT = stereotactic body radiation therapy.

Figure 3

Box plot correlating lnPTV with percent-per-fraction lymphocyte loss rates. The PTV size associated with a particular per-fraction lymphocyte loss rate range (displayed in increments of 5% on the x-axis) varies considerably depending on the body site irradiated and the treatment technique (SBRT vs non-SBRT). The large difference in loss rates seen with SBRT plans likely reflects the higher dose per fraction given during SBRT. Abbreviations: CNS = central nervous system; FLL = per-fraction lymphocyte loss; H+N= head and neck; PTV = planning target volume; SBRT = stereotactic body radiation therapy.

Figure 4

Scatterplot of observed versus predicted decay constants, based on the product of the planning target volume:blood volume ratio and the square of the dose per fraction, adjusted for the site treated and the chemotherapy regimen (Equation 6). Abbreviation: CNS = central nervous system.