TP53 and the Ultimate Biological Optimization Steps of Curative Radiation Oncology

SIMPLE SUMMARY: This review of several recent developments and findings in molecular and radiation biology and medical physics was put together to improve the treatment of cancer. An improved understanding of the effect of radiation on tumors and normal tissue responses makes it possible to treat tumors more effectively and with less damage to normal tissues. This paper is based on a new, improved understanding of the cellular damage and repair processes and the associated internal cellular program to eliminate itself when critically damaged (apoptosis) to avoid severe mutations of the hereditary material of the individual. An improved radiation dose–time fractionation method is proposed to more effectively cure cancer without damaging the surrounding normal tissues. Furthermore, the best possible radiation beams of intensity-modulated electrons, photons, and the lightest ions from lithium to boron are proposed to obtain the best possible treatment results, increasing the tumor cure probability by about 20%. ABSTRACT: The new biological interaction cross-section-based repairable–homologically repairable (RHR) damage formulation for radiation-induced cellular inactivation, repair, misrepair, and apoptosis was applied to optimize radiation therapy. This new formulation implies renewed thinking about biologically optimized radiation therapy, suggesting that most TP53 intact normal tissues are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA). This generates a fractionation window in LDHS normal tissues, indicating that the maximum dose to organs at risk should be ≤2.3 Gy/Fr, preferably of low LET. This calls for biologically optimized treatments using a few high tumor dose-intensity-modulated light ion beams, thereby avoiding secondary cancer risks and generating a real tumor cure without a caspase-3-induced accelerated tumor cell repopulation. Light ions with the lowest possible LET in normal tissues and high LET only in the tumor imply the use of the lightest ions, from lithium to boron. The high microscopic heterogeneity in the tumor will cause local microscopic cold spots; thus, in the last week of curative ion therapy, when there are few remaining viable tumor clonogens randomly spread in the target volume, the patient should preferably receive the last 10 GyE via low LET, ensuring perfect tumor coverage, a high cure probability, and a reduced risk for adverse normal tissue reactions. Interestingly, such an approach would also ensure a steeper rise in tumor cure probability and a higher complication-free cure, as the few remaining clonogens are often fairly well oxygenated, eliminating a shallower tumor response due to inherent ion beam heterogeneity. With the improved fractionation proposal, these approaches may improve the complication-free cure probability by about 10–25% or even more.