Author Of 2 Presentations
FLASH PROTON RADIOTHERAPY IS EQUIPOTENT TO STANDARD RADIATION IN TREATMENT OF MURINE SARCOMAS WHILE REDUCING TOXICITIES TO NORMAL SKIN, MUSCLE AND BONE
Abstract
Background and Aims
Compared to Standard dose rates, the high dose rates of FLASH radiation can reduce radiotherapy toxicities to normal tissues. We examined the potential of FLASH-proton radiotherapy (F-PRT) to treat murine sarcomas and protect normal epithelial and mesenchymal tissues relative to the effects of standard-proton radiotherapy (S-PRT).
Methods
Mice received 30 or 45 Gy of F-PRT (69-124 Gy/sec) or S-PRT (0.39–0.65 Gy/sec) to their hind legs. Skin, muscle and bone injuries were recorded as acute through chronic macroscopic and/or microscopic observations of radiation-induced damage. Murine skin and bone RNAseq analyses were performed to delineate involved mechanisms. Skin stem cell depletion, inflammatory reaction and TGF-β levels were evaluated, and antitumor efficacy of F-PRT was compared to S-PRT in two murine models of sarcoma.
Results
Fewer severe morbidities were induced by F-PRT, with RNAseq revealing S-PRT to upregulate pathways involved in apoptosis signaling and keratinocyte differentiation in skin, and osteoclast differentiation and chondrocyte development in bone. Accordingly, F-PRT reduced skin injury, stem cell depletion and inflammation; mitigated lymphedema; and decreased myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. Equipotent control of sarcoma growth was achieved by the radiation modalities. Finally, S-PRT produced higher levels of TGF-β1 in murine skin than did F-PRT, and this finding was corroborated in the skin samples of dogs treated on a F-PRT clinical trial.
Conclusions
F-PRT can alleviate radiation-induced damage to both epithelial and mesenchymal tissues without compromise to sarcoma response; continuing investigation will further F-PRT translation to the clinic.
A RANDOMIZED DOSE ESCALATION STUDY OF FLASH VS STANDARD DOSE RATE PROTON RADIOTHERAPY FOR CANINE OSTEOSARCOMA
Abstract
Background and Aims
To examine the impact of ultra-high dose rate, “FLASH,” proton RT (F-PRT) vs standard dose rate PRT (S-PRT), we have performed a randomized dose escalation study of F-PRT vs S-PRT for dogs with osteosarcoma (OSA). Standard of care treatment typically involves complete or partial amputation, allowing for pathological and molecular examination of tumor vs normal tissue PRT effects.
Methods
Following owner signing informed consent, dogs were randomly assigned to F-PRT vs S-PRT at escalating doses from 4-24 Gy. Under fluoroscopic guidance, fields were designed to treat segments of tumor vs normal metaphyseal bone. Five days after PRT, dogs underwent limb amputation and samples of tumor, normal bone, skin and subcutaneous soft tissues were collected from irradiated and unirradiated sites.
Results
To date 27 dogs have completed treatment, with 4 remaining dogs to be treated in the 24 Gy cohort. Acute toxicity following PRT has been observed in 2 dogs, with one dog having a pathologic fracture and one dog experiencing intertumoral hemorrhage following treatment with 12 Gy S-PRT and F-PRT, respectively. Preliminary histologic analyses suggest no difference in tumor necrosis between F-PRT and S-PRT and molecular analysis demonstrates F-PRT dramatically reduces induction of TGF-beta signaling in normal tissues as compared to S-PRT. More detailed molecular studies using RNAseq are ongoing to help define mechanisms of F-PRT effects.
Conclusions
We have performed the first study of F-PRT in dogs with spontaneous OSA demonstrating both the clinical feasibility and potential utility of this novel modality in a genetically heterogeneous model system.