A Novel Approach to Potentially Improving Soft-Tissue Sarcoma Survival: Prophylactic Lung Radiotherapy Inhibits Growth of Lung Metastases and Prolongs Survival in a Murine Soft-Tissue Sarcoma Model

 Circulating tumor cells and clusters (CTC) from soft-tissue sarcoma (STS) that become entrapped in the lung can form micro-metastases and lead to pulmonary metastatic disease. Many patients with localized high-risk STS later develop metastases. Radiation is effective at reducing local recurrence by eradicating microscopic infiltration and satellites in the reactive zone surrounding the primary tumor. Prophylactic lung irradiation for patients with high-risk STS is a novel concept to potentially reduce the appearance of macroscopic metastases and improve survival. A proof-of-principle study was performed based on a novel approach: prophylactic lung radiation after resection of the primary tumor to address microscopic pulmonary deposits from CTC.  Immunocompromised mice and luciferase-expressing human fibrosarcoma (HT-1080-Luc) cell lines were used. In phase 1, HT-1080-Luc cells were injected into the tail vein to simulate CTC for the development of pulmonary metastases. Whole-lung irradiation (WLI) was then performed in the treated mice prior to the appearance of macroscopic metastases. In phase 2, a flank tumor was established to simulate a primary STS, followed by a tail-vein injection of HT-1080-Luc cells. Treatment groups included surgical removal of the primary STS and hemithoracic irradiation (HTI). Body weight and bioluminescence data were obtained and the mice were euthanized on Day 31 (phase 1) and Day 15 (phase 2) or when they reached 20% weight loss.  In phase 1, prophylactic WLI increased survival and decreased pulmonary metastases. In phase 2, prophylactic HTI (left lung) decreased pulmonary metastases compared to controls. Lung histology showed dramatically decreased growth and number of established metastases with HTI. Resection of the primary tumor did not affect the growth of metastases.  Prophylactic WLI after resection of the primary tumor to inhibit the growth of pulmonary metastases from previously entrapped CTCs may be a promising approach to improve survival for patients with localized high-risk STS. Copyright © 2024, Ruditsky et al.

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