Author ORCID Identifier

https://orcid.org/0000-0001-6724-4913

Date of Graduation

5-2026

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Uwe Titt

Committee Member

Radhe Mohan

Committee Member

Emil Schueler

Committee Member

Susan Lynne McGovern

Committee Member

Xiaochun Wang

Committee Member

John D. Hazle

Abstract

Pediatric osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Although multi-agent chemotherapy combined with surgical resection has improved survival for localized disease, outcomes have plateaued over the past three decades, and treatment often results in substantial long-term morbidity. Radiation therapy has historically played a limited role in osteosarcoma management due to the relative radioresistance of the tumor and the risk of severe late toxicities in developing tissues. FLASH radiotherapy, which delivers radiation at ultra-high dose rates over approximately 40 Gy/s, has emerged as a promising strategy to widen the therapeutic ratio by reducing normal tissue toxicity while maintaining tumor control. However, significant technical and biological uncertainties currently limit the translation of proton FLASH radiotherapy to clinically relevant scenarios such as pediatric osteosarcoma.

The overall objective of this dissertation was to improve the current small animal proton FLASH irradiation platform, develop a clinically relevant conformal proton FLASH irradiation system, and to systematically investigate the biological robustness of proton FLASH under conditions relevant to pediatric radiotherapy. To address existing technical barriers, a synchrotron-based small-animal proton irradiation beamline was redesigned to substantially expand the achievable dose and dose-rate envelope. Through the integration of multiple beam modulation modes and discrete beam extraction configurations, the upgraded system enabled controlled delivery of doses up to 54 Gy per spill with dose rates spanning approximately 14 Gy/s to 2200 Gy/s, covering conventional, intermediate (meso), and ultra-high dose-rate regimes, which enables preclinical experiment under various dose and dose rate conditions.

To support conformal and extended-volume FLASH irradiation, a mini–spread-out Bragg peak scanning strategy was developed by integrating transverse pencil beam scanning with patient-specific ridge filters and range compensators. This approach enables three-dimensional dose conformity while preserving FLASH-compatible dose rates and represents an important step toward clinically practical conformal proton FLASH delivery.

Using the developed platforms, biological studies were conducted in juvenile murine models to investigate key translational uncertainties. Proton FLASH irradiation was found to significantly mitigate long-term radiation-induced musculoskeletal and marrow toxicity compared with conventional dose-rate irradiation, preserving trabecular bone microarchitecture, limb length, bone marrow and muscle in the long term. Furthermore, the normal tissue sparing associated with FLASH irradiation remained robust when delivered under spatially or temporally stitched delivery configurations, suggesting that clinically realistic segmented delivery strategies may preserve the FLASH effect. In contrast, irradiation delivered at a meso-dose rate (1-40 Gy/s) did not reproduce the protective effects observed under ultra-high dose-rate conditions, supporting the hypothesis that the FLASH effect may require dose rates exceeding a critical threshold.

Together, these findings address several critical technological and biological barriers to proton FLASH translation. By integrating beamline engineering, conformal delivery development, and pediatric-relevant biological validation, this work establishes a comprehensive framework for the future clinical translation of proton FLASH radiotherapy for pediatric osteosarcoma.

Keywords

proton FLASH; Pediatric Osteosarcoma; Bone Toxicity; Conformal FLASH; FLASH Beamline Design

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Available for download on Thursday, April 29, 2027

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