Towards FLASH Radiotherapy in Lung Cancer: A Review on Preclinical Evidence and Technical Feasibility.

Background/Objectives: Alongside surgery and systemic treatments, radiotherapy plays a crucial role in the treatment of lung cancer but can affect healthy tissue and cause serious side effects. Compared to photon therapy, proton therapy can lower toxicity because protons deposit most of their energy within the tumor (the Bragg peak), sparing healthy tissue. FLASH radiotherapy (FLASH-RT), which is characterized by using ultra-high dose rates (UHDR), may further enhance healthy tissue sparing. Preclinical studies using electrons, protons, or photons have shown that FLASH-RT may reduce toxicity, while tumor response is maintained, known as the FLASH-effect. FLASH-RT with protons (FLASH-PT) is a promising treatment for lung cancer, integrating the biological advantages of FLASH with the physical advantages of proton beams. Methods: A literature search was performed on preclinical evidence of the FLASH-effect on lung-related endpoints, the proposed mechanisms, and treatment planning and delivery strategies for FLASH-PT in lung cancer. Results: Preclinical studies have shown reduced pulmonary fibrosis, inflammation, vascular damage, and oxidative stress with FLASH-RT. Current evidence suggests that the FLASH-effect likely arises from multiple radiochemical and biological processes, can vary between tissues, and depends on dose, beam and/or delivery characteristics. Despite growing evidence, the exact dose delivery conditions and technological factors required to obtain a FLASH-effect remain unclear. Treatment planning studies achieved clinically acceptable thoracic FLASH-PT plans for lung cancer, with similar or improved organ-at-risk sparing compared with conventional radiotherapy, while meeting (fraction) dose and dose rate criteria for the FLASH-effect. However, clinically feasible technologies for conformal dose delivery under UHDR conditions with respiratory motion mitigation are still under development. Conclusions: FLASH-PT holds the potential to reduce radiation-induced pulmonary side effects and expand the therapeutic window of radiotherapy. Still, key (pre)clinical and technological challenges must be addressed before clinical implementation for patients with lung cancer.