Democratizing FLASH Radiotherapy

Abstract

FLASH radiotherapy (RT) is emerging as a potentially revolutionary advancement in cancer treatment, offering the potential to deliver RT at ultra-high dose rates (>40 Gy/s) while significantly reducing damage to healthy tissues. Democratizing FLASH RT by making this cutting-edge approach more accessible and affordable for healthcare systems worldwide would have a substantial impact in global health. Here, we review recent developments in FLASH RT and present perspective on further developments that could facilitate the democratizing of FLASH RT. These include upgrading and validating current technologies that can deliver and measure the FLASH radiation dose with high accuracy and precision, establishing a deeper mechanistic understanding of the FLASH effect, and optimizing dose delivery conditions and parameters for different types of tumors and normal tissues, such as the dose rate, dose fractionation, and beam quality for high efficacy. Furthermore, we examine the potential for democratizing FLASH radioimmunotherapy leveraging evidence that FLASH RT can make the tumor microenvironment more immunogenic, and parallel developments in nanomedicine or use of smart radiotherapy biomaterials for combining RT and immunotherapy. We conclude that the democratization of FLASH radiotherapy represents a major opportunity for concerted cross-disciplinary research collaborations with potential for tremendous impact in reducing radiotherapy disparities and extending the cancer moonshot globally.

Figure 1:

Technical areas for democratizing FLASH with potential for establishing one treatment approach for all cancer patients (1–4 All); SRB = smart radiotherapy biomaterials; APC = antigen presenting cells

Figure 2:

A) Currently used fiducials with single function of providing image contrast during image-guided radiotherapy; B) Design of multifunctional smart radiotherapy biomaterials (SRBs) that can provide image contrast to guide the radiotherapy, make the tumor microenvironment more immunogenic, and synergize with immunotherapy; C) Liquid SRBs designed in the form of colloid with easy administration via similar approach used for pancreatic cancer biopsy; D) Nanoparticle SRBs that can be used to target tumors with drugs; E) MRI imaging of SRBs administered in tumors show sustained image contrast and sustained presence of SRBs within the tumor microenvironment over many days as it biodegrades and releases immunotherapy; F) Injection of SRBs in cadaver demonstrates potential to provide both CT and MRI contrast as indicated by the yellow arrows.

Figure 3:

a) CT image illustrating robust regression of both treated (local) and untreated (metastatic) pancreatic tumors in mice model of pancreatic cancer when combining radiotherapy with anti-CD40 immunotherapy delivered wit smart radiotherapy biomaterials prototypes (IBM); b) tumor volume data showing significant regression of both treated (local) and untreated (metastatic) tumor for the combination treatment group; c) initial results in separate study showing that SRBs could be used to combine radiotherapy and immunotherapy. Unlike in figure 3a and 3b, which use a solid SRB, the work in figure 3c uses a liquid fiducial SRB as noted in figure 1.