Exploring the Efficacy and Molecular Mechanism of Systemic Therapy-Based Split-Course Stereotactic Body Radiation Therapy for Solid Tumors.

PURPOSE/OBJECTIVE(S): Considering the therapeutic toxicity, the question of how to administer adequate chemotherapy to synchronize Stereotactic body radiation therapy (SBRT) treatment strategy for maximizing the benefits of neoadjuvant therapy to improve prognosis is a challenging and debatable issue. This study explores the feasibility and theoretical advantages of the simultaneous implementation of split-course SBRT with systemic treatment.

MATERIALS/METHODS: We evaluated the effect of three irradiation regimens (conventional radiotherapy (C-R, 15×2 Gy, (D1-5, D8-12, D15-19)), continuous SBRT (C-S, 3×7 Gy, (D1-3)), split SBRT (S-S, 3×7 Gy, (D1, D10, D19)) in combination with systemic therapy (chemotherapy (gemcitabine), PD-1 inhibitor (Anti-mouse PD-1 antibody) and angiogenesis-targeting agent (Anlotinib)) on tumor growth and survival by using the immunologically active C57BL/6 bilateral subcutaneous model with different cancer cells. At different time points after treatment, we monitored changes in the tumor microenvironment and explored the possible mechanisms.

RESULTS: In the case of radiotherapy alone, we found similar tumor control in all groups but the best survival in the S-S group. When combined with systemic therapy, the S-S group has shown advantages in tumor control and survival. And the S-S combination group induced more CD4+ and CD8+ T lymphocyte infiltration in the tumor, which had the highest number of tumor vessels and the smallest area of hypoxia. Tumor cell PD-L1 expression was increased after radiotherapy in all but the most elevated and persistent S-S combination treatment group. CD3+ T cells, CD4+ T cells and CD8+ T cells peaked at weeks 2-3 after treatment, and all remained at the highest level for 6 weeks in the S-S combination group. Meanwhile, PD-L1 expression was significantly higher in all tumors in the third week than in other groups. The most significant reduction in the hypoxic area and increase in perfusion level was observed in the S-S group in the third week. RNA sequencing analysis revealed that immune response-related pathways were upregulated on the irradiated and non-irradiated side, tumor proliferation and invasion on the non-irradiated side, and angiogenesis-related pathways were down-regulated in the fractionated SBRT combination treatment group. In both irradiated side and non-irradiated side tumor tissues where the abscopal effect was observed, immune response-related pathways were upregulated in the S-S group relative to the C-R group, and tumor proliferation and invasion and angiogenesis-related pathways were found to be downregulated in the non-irradiated side.

CONCLUSION: In preclinical models, the combination of split SBRT with systemic therapy has been shown to be more advantageous than conventional segmentation, possibly by affecting immune cell infiltration in the tumor microenvironment and reducing tumor hypoxia.