Longitudinally Heterogeneous Tumor Dose Optimizes Proton Broadbeam, Interlaced Minibeam, and FLASH Therapy

SIMPLE SUMMARY: The aim of any kind of external radiation therapy is to control a tumor with the highest possible probability of the lowest possible side effects. Here, we study further opportunities of reducing the side effects of proton therapy by applying longitudinally heterogeneous dose distributions in the tumor respecting the delivery of a minimum prescribed dose. In our simulations, the longitudinally heterogeneous dose distributions show a reduced dose in the healthy tissue already in the case of proton broadbeam irradiations, but a much higher (calculated) mean cell survival in the case of proton minibeam irradiation. This demonstrates its potential to substantially reduce side effects at a simultaneously higher tumor control probability, opening new opportunities of easier application when striving for high dose-rate applications of proton beams (>~10 Gy/s), in order to additionally profit from the so-called FLASH effects. ABSTRACT: The prerequisite of any radiation therapy modality (X-ray, electron, proton, and heavy ion) is meant to meet at least a minimum prescribed dose at any location in the tumor for the best tumor control. In addition, there is also an upper dose limit within the tumor according to the International Commission on Radiation Units (ICRU) recommendations in order to spare healthy tissue as well as possible. However, healthy tissue may profit from the lower side effects when waving this upper dose limit and allowing a larger heterogeneous dose deposition in the tumor, but maintaining the prescribed minimum dose level, particularly in proton minibeam therapy. Methods: Three different longitudinally heterogeneous proton irradiation modes and a standard spread-out Bragg peak (SOBP) irradiation mode are simulated for their depth-dose curves under the constraint of maintaining a minimum prescribed dose anywhere in the tumor region. Symmetric dose distributions of two opposing directions are overlaid in a 25 cm-thick water phantom containing a 5 cm-thick tumor region. Interlaced planar minibeam dose distributions are compared to those of a broadbeam using the same longitudinal dose profiles. Results and Conclusion: All longitudinally heterogeneous proton irradiation modes show a dose reduction in the healthy tissue compared to the common SOBP mode in the case of broad proton beams. The proton minibeam cases show eventually a much larger mean cell survival and thus a further reduced equivalent uniform dose (EUD) in the healthy tissue than any broadbeam case. In fact, the irradiation mode using only one proton energy from each side shows better sparing capabilities in the healthy tissue than the common spread-out Bragg peak irradiation mode with the option of a better dose fall-off at the tumor edges and an easier technical realization, particularly in view of proton minibeam irradiation at ultra-high dose rates larger than ~10 Gy/s (so-called FLASH irradiation modes).