In 2014, Favaudon et al invigorated new research into ultra-high dose rate (UHDR) irradiations and its potential for normal tissue sparring [1]. In the radiation oncology community, the interest in exploring the use of FLASH radiotherapy (FRT) has substantially increased, with the goal of enhancing the therapeutic window through improving normal tissue sparring while preserving tumor control efficacy. In the past several years, UHDR irradiations and FRT have been the focus of much basic, pre-clinical, and translational science and engineering research. Based on this work, FRT clinical trials are open or in preparation across the world, using various modalities of FLASH irradiation. At Cincinnati Children’s Hospital and the University of Cincinnati Proton Therapy Center, in October 2020, the first FRT clinical trial, Feasibility Study of FLASH Radiotherapy for Treatment of Symptomatic Bone Metastases (FAST-01) [2], began accruing patients and, by November 2021, met enrollment.
Preparations for FRT clinical trials involve many aspects, notably but not exclusively (1) absolute dose and dose rate, (2) safety and shielding, (3) treatment planning, (4) quality assurance and (5) clinical readiness and treatment. In this presentation, the work in support of a proton therapy, transmission beam, pencil beam scanning FRT clinical trial (FAST-01) is discussed, with attempts to draw analogies to other potential FRT modalities and clinical trials. In support of FAST-01, the absolute dose, as defined by a standard cross-calibrated ion chamber formulism, was studied and validated against other dosimeters, notably calorimetry, a dose rate independent metrology system. The dose rate definition, as establish in Folkerts et al [3], had been used in pre-clinical data and then translated into the clinical trial design. Despite the fact that the FLASH-enabled treatment room vault was not designed with a priori knowledge of FRT, it was validated for FRT conditions and deemed safe. The FAST-01 treatment planning workflow relied on a pre-defined, pre-commissioned library of rectangular FRT fields suited for extremity bone metastases. Both a machine and patient quality assurance program was developed and instituted, with added quality checks related to dose rate, using beam monitor log file analysis. Finally, the end-to-end workflow was validated during a clinical readiness period.
These technical preparations, combined with a safety-first clinical trial design, led to the successful execution and enrollment of the first FRT clinical trial. Current and future FLASH radiotherapy sites may find this experience generalizable to other modalities, setting, and clinical trial plans.
[1] Favaudon V, Caplier L, Monceau V, Pouzoulet F, Sayarath M, Fouillade C, Poupon MF, Brito I, Hupé P, Bourhis J, Hall J, Fontaine JJ, Vozenin MC. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med. 2014 Jul 16;6(245):245ra93. doi: 10.1126/scitranslmed.3008973. Erratum in: Sci Transl Med. 2019 Dec 18;11(523): PMID: 25031268.
[2] Breneman J. Feasibility Study of FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases (FAST-01). Oct 2020 – Nov 2021. NCT04592887. https://clinicaltrials.gov/ct2/show/NCT04592887
[3] Folkerts MM, Abel E, Busold S, Perez JR, Krishnamurthi V, Ling CC. A framework for defining FLASH dose rate for pencil beam scanning. Med Phys. 2020 Dec;47(12):6396-6404. doi: 10.1002/mp.14456. Epub 2020 Nov 15. PMID: 32910460; PMCID: PMC7894358.