Abstract

Background: This short paper presents the solution to an open problem in medical physics: how and when FLASH radiotherapy can have a selective anti-tumor effect. FLASH radiotherapy gives a single large dose of ionizing radiation to a cancer patient within a time span of a few milliseconds, unlike conventional radiotherapy which is divided into several dose fractions given weekly, each lasting about 10 minutes. In some animal models FLASH seems to improve tumor cell killing without damaging normal tissues. However, the mechanism of the selective anti-tumor effect remains elusive. Methods: To explore effects of tissue hypoxia in tumors, a model of relevant chemical kinetics is derived for both oxygen independent and oxygen dependent tissue damage to biomolecules, RH, from ionizing radiation. Such chemical damage is created respectively by local tissue concentrations of R• carbon centered free radicals and ROO• peroxyl radicals, each multiplied by treatment time. Peroxyl radical concentration is a function of known chemical rate constants and tissue oxygen concentration. The value of the constant of relating peroxyl radical concentration to tissue damage is derived from the familiar oxygen enhancement ratio (OER) for standard radiotherapy delivered in n fractions. A safe FLASH dose multiplier, M , is derived that produces the same radiation damage to normal tissues as in conventional, fractionated therapy. In turn, the biological treatment effect for one large single dose compared to n equal fractions is calculated for various tissue oxygen concentrations and OER values. Results: For tissue oxygen concentrations from 10 to 100 percent of normal, FLASH is 0.5 to 0.9 times less damaging than conventional therapy. However, for tissue oxygen concentrations less than 10 percent of normal FLASH is 1.1 to 1.4 times more damaging than conventional therapy. Estimated effects of vasodilator drugs such as hydralazine, which make tumors more hypoxic by diverting blood flow to normal tissues, produce further biologically meaningful improvements in selective tumor targeting. Conclusions: A compact algebraic model can synthesize concepts from several research fields to explain the mechanism of the FLASH effect (severe tumor hypoxia), the reason for mixed results (varying tumor oxygen concentrations), and the key to success in future research (selecting the most hypoxic tumors for FLASH therapy).

Keywords

angiogenesis, cancer therapy, dose fractionation, gamma radiation, hydralazine, hydroxyl radicals, kinetics, mechanism, microcirculation, OER, oxygen effect, oxygen depletion, oxygen enhancement ratio, perfusion, peroxyl radicals, pO2, tumor angiogenesis factor, vasodilator

Date of this Version

6-9-2025

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