New Radiation Oncology Optimization Principles Based On In-Vivo Predictive Assay and Recent Developments in Molecular Radiation Biology

The recent understanding that most TP53-intact normal tissues are Low-Dose Hypersensitive (LDHS) and Low-Dose Apoptotic (LDA) implies that the well-known fractionation window at ≈ 2 Gy/Fr defines the optimal tolerance level for most organs at risk and not at all the tumor dose as still is customary today when using IMRT. This necessitates new approaches to biologically optimized radiation therapy, requiring that the maximum dose to organs at risk should be ≤2.3 Gy/Fr, and especially that it should be of low ionization density and LET . Today we know that the fractionation window is due to a low-dose initiation of full DNA repair capability in normal tissues first after ≈½ Gy, and we should use this acquired repair advantage to its full extent up to ≈2.3 Gy where the High Dose Apoptosis (HDA) may set in. Thus biologically optimized treatments should be focused on the application of a low number of high tumor-dose intensity-and/or radiation quality-modulated photon, electron or lower LET light ion beams. Doing so, reduces the integral dose delivery and the risk for secondary cancers and generates a real tumor cure without risk for caspase-3-induced accelerated tumor cell repopulation. The light ions should truly have the lowest possible LET in normal tissues to retain the fractionation window property but still have a high LET only in the gross tumor region to simultaneously maximize tumor cell inactivation. This necessitates the use of the lightest ions, from helium to ≈boron, as this fractionation advantage is practically lost for carbon and heavier ions. This unique property of the lightest ions is combined with the highest possible apoptosis and senescence in front of the Bragg peak and can best be characterized as allowing molecular radiation therapy since surrounding normal tissues are only exposed to a low dose and LET that causes easily repairable damage. Many other new associated ideas are also discussed, such as optimal use of IMRT, molecular tumor imaging with MRSI, PET-CT and phase contrast X-rays, TP53 cell survival radiation biology, biologically optimized radiation therapy: BIOART, quantum biology of curative radiation therapy, 4D-space-time radiation therapy optimization, influence of microdosimetric heterogeneity on the dose response relation, optimal time dose fractionation, accounting for tumor hypoxia, biologically optimal radiation quality, secondary cancer risks, mutant TP53 reactivation, and optimal dose delivery techniques since they are all involved directly or indirectly in these new principles for true optimization of radiation therapy.