Kelly Gaudian ^1* Min Jung Koh ¹ Min Ji Koh ¹ Irfan Khan ^1* Diya Kallam ² Zach Lee ^1* Ryan R. Collins ^1* Zoya Zwart ^1* Malika Danner ^1* Alan Zwart ^1* Deepak Kumar ³ Michael B. Atkins ⁴ Simeng Suy ^1* Sean P. Collins ^1*

• ¹ Department of Radiation Medicine, MedStar Georgetown University Hospital, Washington, DC, District of Columbia, United States
• ² School of Medicine and Health Sciences, George Washington University, Washington, D.C., District of Columbia, United States
• ³ The Julius L. Chambers Biomedical and Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, United States
• ⁴ Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States

Radiation-related lymphopenia (RRL) has been noted in prostate cancer patients treated with conventionally fractionated pelvic radiation therapy. The impact of hypofractionated high integral dose therapies such as stereotactic body radiation therapy (SBRT) on RRL is less well characterized. This prospective study sought to evaluate the impact of prostate SBRT +/- pelvic nodal radiation (PNI) on RRL. Between 2012 and 2023, serial serum absolute lymphocyte counts (ALCs) were measured in 226 men treated at MedStar Georgetown with SBRT using the CyberKnife® (CK) (36.25 Gy in 5 fractions) alone or CK (19.5 Gy in 3 fractions) followed by PNI using VMAT (37.5-45.0 Gy in 15-25 fractions) per an institutional protocol (IRB#: 2012-1175). Baseline ALC (k/μL) was measured 1-2 hours prior to SBRT and at follow-up appointments. Lymphopenia was graded using the CTCAEv.4. To compare two treatment groups, the Wilcoxon signed-rank test was used. A p-value of < 0.05 determined statistical significance. Of 226 patients (SBRT alone: n = 169, SBRT + PNI: n = 57), the median age was 72 and 45% of patients were non-white. Baseline lymphopenia was uncommon and of low grade. In the SBRT alone group, the baseline ALC of 1.7 k/μl decreased by 21% to 1.4 k/μL at 3 months and then stabilized. 38% of these men experienced lymphopenia, however, no patient presented with Grade 3 lymphopenia. The SBRT + PNI group had a lower baseline ALC (1.5 k/μl), and a significantly greater decrease in ALC relative to baseline, decreasing by 57% to 0.6 k/µL at 3 months and recovering to a 36% decrease from baseline (1.0 k/µL) at 24 months. Notably, 12% of these men experienced Grade 3 lymphopenia. No patient in either cohort experienced Grade 4 lymphopenia. The low incidence of high-grade lymphopenia within this elderly population further supports the safety of SBRT +/- PNI for treatment of prostate cancer. However, RRL was more severe when PNI was utilized. The effect of SBRT and PNI on lymphocytes in prostate cancer patients could act as a model for other cancers, specifically those treated with immunomodulatory agents. Future studies should focus on the clinical implications of RRL.