Dose and Fractionation Effects on Lymphocyte-Sparing after Stereotactic Body Radiation Therapy in Patients with Pancreatic Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Radiation-induced lymphopenia (RIL) is caused by exposing the blood pool to radiation therapy and is associated with inferior survival in patients with pancreatic cancer (PC). Dose escalation with stereotactic body radiation therapy (SBRT) is associated with decreased severity of RIL and improved survival compared to conventional chemoradiation, however, there is also increasing appreciation for the need for larger field sizes to treat occult microscopic disease. We retrospectively analyzed patients undergoing SBRT for PC to explore if the number of fractions, BED10 dose, and PTV volume correlated with lymphopenia. <h3>Materials/Methods</h3> Total lymphocyte counts (TLCs) were compared before and up to 2 months after SBRT for 139 patients treated with SBRT for PC at two institutions. Univariate and multivariate analyses (MVA) were used to identify associations between TLC and G2+ lymphopenia (<800/mm^3), number of fractions, total BED10, and PTV. Baseline TLC were compared using Kruskal-Wallis test. PTV threshold for G2+ RIL was determined with receiver operating characteristic analysis. <h3>Results</h3> Median BED10 was 54.8Gy (48-100) (Table 1). Median baseline and post-SBRT ALC were 1.6/uL (0.59-6.09) and 0.85/uL (0.18-1.99), respectively. All groups had similar median baseline TLCs (p=0.567). G2+ lymphopenia was seen in 49/139 (35%) patients after SBRT. Median planning target volume (PTV) and tumor diameter was 85.5 (11.5-381.6) cm³ and 2.5 (0.3-7.8) cm³. On MVA, only PTV volume was associated with decrease in ALC (95% CI 0.24 - 0.95; P=0.001) and with G2+ lymphopenia (95% CI 1.2-12.9; p=0.019). G2+ lymphopenia was more common with PTV ≥ 178 cm^3 (P<0.01). There was no association between ALC or G2+ lymphopenia and age, gender, tumor diameter, tumor location, BED10, treatment with 5 vs 3 fractions, or treatment with 50 Gy in 5 fractions versus 36-39 Gy in 3 fractions. <h3>Conclusion</h3> While previous studies have shown that SBRT has improved RIL compared to conventional CRT, this effect appears to be independent of SBRT fractionation and total BED, but dependent on PTV size, a surrogate for the volume of lymphocytes exposed to RT. Given the association of severe RIL with survival in LAPC, our study suggests that PTV volume may drive development of lymphopenia and survival. Therefore, we demonstrate the need to balance the lymphopenia effect by limiting PTV size with SBRT with expansion of PTVs to include elective nodes at risk of harboring microscopic disease.