![]() Moreover, the mechanisms by which FLASH RT spares normal tissues is not known. While these findings indicate an increased therapeutic index for FLASH across multiple tissues and species, whether this holds for highly proliferative and radiosensitive tissues such as the intestine is not known. Meanwhile, in preclinical models of lung cancer FLASH achieves similar tumor control as CONV RT 7. FLASH mediated sparing of the skin from radiation-induced necrosis has been demonstrated in both minipigs and cats 10. In mice, FLASH produces less radiation-induced lung fibrosis and radiation-induced neurocognitive impairment after lung and brain irradiation, respectively 7– 9. In contrast to clinically used conventional dose rates of about 2-20 Gy/minute (CONV), FLASH has been variably defined as having average dose rates of >40 Gy/second (more than 2 orders of magnitude higher) 7. Ultra-high dose rate FLASH irradiation is emerging as a new strategy to reduce radiation-induced normal tissue toxicity and enhance the therapeutic index of radiation therapy. Therefore, new strategies are needed to enhance the therapeutic index of RT for the treatment of abdominal and pelvic tumors. However, amifostine can cause severe nausea and hypotension limiting the clinical use of this agent 6. Amifostine is currently the only FDA-approved radioprotector for normal tissues. In addition to reducing patient quality of life, radiation-induced bowel toxicity limits the radiation dose and curative potential of the therapy for many patients with abdominal and pelvic tumors including women with ovarian cancer 3– 5. Moreover, patients can develop delayed radiation enteropathy, which is a chronic and progressive disease associated with significant long-term morbidity. Approximately 60-80% of patients who receive pelvic or abdominal RT experience acute bowel toxicity symptoms including nausea, abdominal pain, diarrhea, and fatigue 2. For example, intestinal injury is the primary dose-limiting factor in RT for patients with abdominal and pelvic tumors. However, radiotherapy is still limited by toxicities to nearby normal tissues. Radiation therapy (RT) is the most effective cytotoxic cancer therapy available for the treatment of localized tumors it is used to treat 60% of patients with cancer in the United States 1. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of abdominal and pelvic tumor disease. Importantly, FLASH and CONV irradiation have similar efficacy in the reduction of ovarian cancer peritoneal metastases. A reduced number of γ-H2AX foci in crypt cells indicates less DNA damage and/or increased DNA repair after FLASH compared to CONV irradiation. ![]() Using FLASH for total abdominal irradiation of mice, we observed lower mortality from gastrointestinal syndrome, preserved gut function and epithelial integrity, and decreased cell death in crypt base columnar cells. Here we report that ultrahigh dose rate FLASH irradiation causes significantly less radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to conventional dose rate (CONV) irradiation. In particular, the highly radiosensitive intestine greatly limits the use of radiation for patients with intra-abdominal tumor diseases. However, radiation-induced toxicity to normal tissues limits the radiation dose and therefore the curative potential of radiotherapy. ![]() Radiation therapy is the most effective treatment of localized tumors.
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