Abstract Body

Preclinical studies have shown that radiotherapy treatment at ultra-high dose rates (FLASH) has the potential to significantly increase the therapeutic window in radiotherapy. As a step towards introducing FLASH radiotherapy in the clinic for the treatment of human patients, we are using a 10 MeV electron beam from a clinical linear accelerator (Elekta Precise, Elekta AB, Stockholm, Sweden), which has been modified to deliver FLASH dose rates, for treatment of canine patients suffering from various spontaneous superficial solid tumors or microscopic residual disease. Our studies are performed at Skåne University Hospital (Lund, Sweden) in collaboration with veterinarians from the University of Copenhagen. Our aim is to give our canine patients the best treatment option available, in order to reduce their suffering, prolong their life and hopefully eradicate their tumors, while learning how to deliver the treatment with improved dosimetric accuracy and improve our radiobiological knowledge on how tumors and normal healthy tissue respond to FLASH radiotherapy.

Our setup consist of a short electron applicator with various Cerrobend inserts to shape the beam aperture and a 5 cm air gap between the end of the applicator and the patient, resulting in a source-to-surface distance of 70 cm. Currently, our dosimetry is reliant on radiochromic film measurement in preparation for treatment and as in vivo dosimeters during treatment, as well as a farmer-type ionization chamber positioned at a fixed position in the applicator for “live” dose measurements. However, the precision of the “live” dose measurements from the ionization chamber is severely hampered by the poor ion collection efficiency at the high dose-per-pulse values (≈2 Gy).

Our first veterinarian study was a dose escalation study aimed to evaluate the feasibility and safety of FLASH radiotherapy in a relevant clinical setting. Ten canine cancer patients were included in this initial study; seven patients with nine solid superficial tumors and three patients with microscopic disease. The treatment was administered in a single fraction, with a treatment dose starting at 15 Gy, which was then escalated in 5 Gy steps to 35 Gy. Treatments resulted in partial response, complete response or stable disease in 11 of the 13 irradiated tumors. Adverse events observed at follow-up, ranging from 3-6 months, were mild and consisted of local alopecia, leukotricia, dry desquamation, mild erythema or swelling. One patient receiving a 35 Gy dose to the nasal planum, had a grade 3 skin adverse event. From this study and subsequent treatments, we found that the maximum tolerated dose to the skin surface was 30 Gy in a single fraction which could be increased to at least 35-40 Gy at depths beyond the skin surface.

The experience from this initial study will be used as a basis for a veterinary phase II clinical trial with more specific patient inclusion selection, and subsequently for human trials. In future studies, we aim to improve our dosimetric accuracy, investigate hypofractionated treatments vs. single fraction treatments, and improved conformality of our treatments with the use of dedicated treatment planning and bolus electron conformal therapy (BECT).

Background and Aims

We have previously found that FLASH-irradiation with a pulsed electron beam (average doserate ≥600Gy/s) was less efficient to sterilize cancer cells in-vitro compared with conventional doserate irradiation (CONV, 0.2Gy/s). In the current work we aimed at investigating the effect for a malignant cell line both in vitro and in vivo.

Methods

Radiation response of melanoma cell line B16_F10 was determined in-vitro by clonogenic assays for an absorbed dose in the range 0-9 Gy comparing FLASH to CONV. In-vivo-response was studied in a syngeneic mice model (C57BL/6J) with subcutaneously injected B16_F10-tumors, irradiated to an absorbed dose of 15, 20 or 25Gy (FLASH and CONV). The tumor growth was quantified by using the relative tumor volume, normalized to unity at the time of irradiation, TV_rel.

Results

The in-vitro results showed a significantly increased survival after FLASH compared with CONV (F-test: p=0.02). Tumor growth curves in-vivo were similar for CONV and FLASH at 15 and 20Gy, but FLASH was relatively less efficient at 25Gy. Four weeks after irradiation with 25Gy, a relative tumor volume of TV_rel<1 was seen in 2/9 mice in the CONV group but in 0/8 mice in the FLASH group. A relative tumor volume of TV_rel<4 was seen in 5/9 mice in the CONV group but 0/8 mice in the FLASH group. Severe skin toxicity was observed in 5/9 vs 0/8.

Conclusions

FLASH may be less efficient than CONV to sterilize malignant cells in-vitro as well as in-vivo. Future work will address the differential response between normal tissue and tumors at higher doses.