Risk Factors Associated with Lymphocyte Reduction during Radiotherapy in Patients with Limited Stage Small Cell Lung Cancer

Abstract

We have recently demonstrated that lymphocyte reduction, i.e. lymphopenia, is common during radiation therapy (RT) and is associated with survival in patients with small cell lung cancer (SCLC). This report examines the risk factors contributing to the severity of the treatment induced lymphopenia. We hypothesize that radiation doses to the major normal tissues particularly circulating lymphocytes, play an important role on lymphopenia. This is a retrospective analysis of 582 LS-SCLC patients treated from one single institution during 2013 to 2017.All patients received definitive chemoradiation and had at least three time points of a complete blood count test including a baseline test. The dosimetry parameters for the Planning Target Volume (PTV), RT timing, dose fractionation, RT technique in terms of 3D conformal radiation therapy (3DCRT) versus intensity modulated radiation therapy (IMRT) and important Organs At Risk (OARs) like heart, lung and the total body were analyzed. Effective dose to immune cells (EDIC) was estimated based on these dosimetry parameters. The primary end point was lymphocyte reduction, which was represented by the absolute count of the lymphocyte nadir, percentage of nadir over baseline, and the timing of the lymphocyte nadir. Linear regression was used to examine the significance of the clinical and dosimetry factors on lymphocyte nadir. A total of 582 patients met the study inclusion criteria. The mean absolute lymphocyte counts (ALC’s) were 1.65K (95% CI 0.97-2.30K), 0.94K (95% CI 0.56-1.32K), 0.67K (95% CI 0.38-0.98K) and 0.61K (95% CI 0.33-0.89K) at baseline, 2, 4 and 6 weeks from the start of treatments, respectively. Radiation induced lymphopenia occurred in 414 (66.5%) patients and reached a nadir at median of 4 (95% CI 2.4-5.5) weeks from radiation start. Univariate analysis revealed the clinical stage, body mass index (BMI), use of concurrent chemotherapy, number of chemotherapy cycles before radiotherapy, baseline ALC, RT treatment time, RT technique (3DCRT vs. IMRT), RT fractionation, the total dose of RT and mean dose of lung, heart and total body, and EDIC were all significantly associated with the lymphocyte nadir (all p-values<0.05). Multiple linear regressions showed that clinical stage, baseline ALC, RT technique (CRT vs. IMRT), use of concurrent chemoradiation, the number of chemotherapy cycles before RT, the mean lung dose, the integral total body dose, and EDIC were significant for the lymphocyte nadir. This study of 582 patients demonstrated that many independent risk factors are associated with lymphopenia during RT, as outlined above. These include several treatment related factors that can be modified for improvement.