Purpose: The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results we designed a randomized phase III trial to investigate the FLASH effect in cat-patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-RT was studied on mini-pigs using large field irradiation. Experimental Design: Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to 2 arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10x4.8 Gy (90% isodose), arm 2 used 1x30 Gy (90% isodose) FLASH. Mini-pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH Results: In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis which occurred 9-15 months after RT in 3/7 cats treated with FLASH-RT (43%), as compared to 0/9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded but severe late skin necrosis occurred in a volume-dependent manner (7-9 months) which later resolved. Conclusions: The reported outcomes point to the caveats of translating single-high-dose FLASH-RT and emphasizes the need for caution and further investigations.