Modelling the immunosuppressive effect of liver SBRT by simulating the dose to circulating lymphocytes: an in-silico planning study

Abstract

Background: Tumor immune-evasion and associated failure of immunotherapy can potentially be overcome by radiotherapy, which however also has detrimental effects on tumor-infiltrating and circulating lymphocytes (CL). We therefore established a model to simulate the radiation-dose delivered to CL.

Methods: A MATLAB-model was established to quantify the CL-dose during SBRT of liver metastases by considering the factors: hepatic blood-flow, -velocity and transition-time of individual hepatic segments, as well as probability-based recirculation. The effects of intra-hepatic tumor-location and size, fractionation and treatment planning parameters (VMAT, 3DCRT, photon-energy, dose-rate and beam-on-time) were analyzed. A threshold dose ≥0.5Gy was considered inactivating CL and CL0.5 (%) is the proportion of inactivated CL.

Results: Mean liver dose was mostly influenced by treatment-modality, whereas CL0.5 was mostly influenced by beam-on-time. 3DCRT and VMAT (10MV-FFF) resulted in lowest CL0.5 values of 16 and 19%. Metastasis location influenced CL0.5, with a mean of 19% for both apical and basal and 31% for the central location. PTV-volume significantly increased CL0.5 from 27 to 67% (10MV-FFF) and from 31 to 98% (6MV-FFF) for PTV-volumes ranging from 14cm³ to 268cm³.

Conclusion: A simulation-model was established, quantifying the strong effects of treatment-technique, tumor-location and tumor-volume on dose to CL with potential implications for immune-optimized treatment-planning in the future.

Keywords: Abscopal effect; Immunotherapy; Modelling; Stereotactic body radiotherapy (SBRT); Treatment planning.

Fig. 1

Intrahepatic locations of the three virtual liver metastasis

Fig. 2

Mean liver dose (MLD, a) and proportion of circulating lymphocytes receiving ≥0.5Gy (CL0.5) by treatment modality as mean values with SD for all intrahepatic locations (b)

Fig. 3

Effect of either 3 × 15 Gy, 10 × 4.5 Gy or 20 × 2.25 Gy fractionation on CLs (a) with VMAT 10MV FFF as treatment modality. 3DCRT did not show a relevant fractionation effect (see Additional file 4). b. PTV volume dependent CL0.5 by treatment modality, based on either 14 cm³, 65 cm³, 114 cm³ or 268 cm³ PTV sizes in the central tumor metastasis

Fig. 4

CL0.0 to CL5.0 for VMAT 10MV FFF and 6MV FF in the central tumor location and either 14 cm³ or 268 cm³ PTV volume