The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients

Abstract

Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called "FLASH-RT" and irradiation delivered at a conventional dose rate called "Conv-RT." A clinical, phase I, single-dose escalation trial (25-41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%.C Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients.

FLASH radiotherapy: Newsflash or flash in the pan?

“…When interpreting this literature, we should scientifically assess the FLASH results. For example, one of the articles referenced includes the claim that FLASH sparing has been demonstrated in cat and mini‐pig species, the studies closest to human applications . We find that for the cat treatments, this was a single arm study, demonstrating only that radiation therapy works.…”

“…The phenomenon of the increased therapeutic index of FLASH compared to conventional dose rate irradiation, or the “FLASH effect,” has now been reported in multiple preclinical models. Normal tissue sparing by FLASH of multiple organ systems including lung, brain, intestinal tract, and skin has been demonstrated in multiple mouse strains and even additional species (cat and mini‐pig), while demonstrating an equivalent (and in some cases superior) tumoricidal effect relative to conventional dose‐rate delivery in multiple in vivo tumor models . Given the nascent state of the field, a large portion of experimental observations to date remain preliminary and unpublished, and many questions remain unanswered particularly with respect to mechanism.…”

On the capabilities of conventional x‐ray tubes to deliver ultra‐high (FLASH) dose rates

“…In both subjects, the target normal tissues (pig skin and cat nasal planum) exhibited improved tolerance when irradiated to high doses with only mild superficial side effects observed (i.e. depilation) for the range of doses considered in the escalation studies . These outcomes point to the opportunity for further dose escalation in FLASH therapy, which could foster improved tumor control or allow for application to cases concerned with radiosensitive organs at risk.…”

“…While the concept of high‐dose rate therapy is not altogether new, interest has been rekindled in light of the reduction in normal tissue toxicity that has been observed following treatment . FLASH therapy is currently characterized by the use of dose rates exceeding 30–40 Gy/s and is notable for its apparent capacity to improve the therapeutic ratio of RT by fostering a differential response between normal and tumoral tissue …”

“…While the concept of high-dose rate therapy is not altogether new, [6][7][8][9] interest has been rekindled in light of the reduction in normal tissue toxicity that has been observed following treatment. [10][11][12][13] FLASH therapy is currently characterized by the use of dose rates exceeding 30-40 Gy/s and is notable for its apparent capacity to improve the therapeutic ratio of RT by fostering a differential response between normal and tumoral tissue. 13 Recent preclinical studies have showcased remarkable improvements in treatment outcome following FLASH therapy, owed in large part to the increased normal tissue tolerance (FLASH effect) and maintenance of tumor-control efficacy for a given prescription.…”