Abstract
Simple SummaryDose and efficacy of radiation therapy are limited by the toxicity to normal tissue adjacent to the treated tumor region. Recently, ultra-high dose rate radiotherapy (FLASH radiotherapy) has shown beneficial reduction of normal tissue damage while preserving similar tumor efficacy with electron, photon and scattered proton beam irradiation in preclinical models. Proton therapy is increasingly delivered by pencil beam scanning (PBS) technology, and we therefore set out to test PBS FLASH radiotherapy on normal tissue toxicity and tumor control in vivo in mouse using a clinical proton delivery system. This validation of the FLASH normal tissue-sparing hypothesis with a clinical delivery system provides supporting data for PBS FLASH radiotherapy and its potential role in improving radiotherapy outcomes. Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.
Highlights
Conventional X-ray radiation therapy (XRT) remains one of the major therapies for cancer, and half of all cancer patients receive XRT treatments
We demonstrate the existence of a beneficial FLASH effect on skin and soft tissue using proton pencil beam scanning (PBS), and show that FLASH PBS is equivalent to conventional dose rate for the control of indolent and aggressive squamous cell carcinoma
35 Gy and 15 Gy in a single fraction at an average dose rate of 1.0 Gy/s (Conv), 57.4 Gy/s (Flash60) and a maximum achievable dose rate of 115.1 Gy/s (Flash115) with a variation of dose rate ranging from 0.9% to 1.9% (Figure 1C)
Summary
Conventional X-ray radiation therapy (XRT) remains one of the major therapies for cancer, and half of all cancer patients receive XRT treatments. FLASH dose delivery using electron, X-ray and more recently scattered protons to animal models was reported to improve toxicity of a range of normal tissues including skin, while retaining similar tumor control [6,14,15,16,17,18]. In the Bragg Peak FLASH radiotherapy case, validating the FLASH effect on the entrance region is still valuable as, for most deep-seated tumors, skin, soft tissue and other organs may be in the beam path and irradiated For this purpose, we used a classical radiation-induced mouse leg contracture assay to define toxicity of FLASH versus conventional PBS on skin and soft tissue for the first time. We demonstrate the existence of a beneficial FLASH effect on skin and soft tissue using proton PBS, and show that FLASH PBS is equivalent to conventional dose rate for the control of indolent and aggressive squamous cell carcinoma
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