Table 2.

Proposed SBRT dose schedule approaches with or without harmonized combination therapies matching the tumor profile of the vascular-immuno-phenotypic (VIP) model.

SBRT Dose Schedule/Strategy	Tumor Profile Targeting vis-a-vis Normal Tissue Effects
Single or high dose multiple (>12 Gy per fraction)	Vascular disruption with subsequently increased hypoxia; even higher dose may not be adequate to kill resistant cells; a one-time flood of antigen generation and presentation; dose modification not possible for concurrent side effects; DRT or similar differential sensitization of cancer cells sparing the ECs—preclinical trials required
Intermediate dose, multiple (<10 Gy/fraction)	One of the fundamental five R’s of RT “reoxygenation” is accounted for to an extent resulting in increased levels of hypoxic cells lysis; vascular and ECM integrity maintained; multiple time, scalable neoantigenic presentation; leeway for optimization of total tolerable dose of SBRT based on concurrent side effects; DRT or similar differential sensitization; preclinical trials required to identify optimum dose between 6 and 10 Gy.
Intermediate dose, multiple (<10 Gy/fraction), boost—concomitant or delayed	Targets proliferating resistant cells and stem cells; vascular and ECM integrity maintained with better oxygenation and drug delivery; continued scalable neoantigen presentation; optimization of volume and total tolerable dose of SBRT based on response with limitable “titratable” acute side effects; preclinical trials required.
Cyclical” SBRT <10 Gy/fraction, multiple fractions before each immunotherapy dose and/or cyclical antiangiogenics	SBRT as sensitizer secondary to primary therapy, i.e., chemo-immunotherapy; optimum reoxygenation; repeated scalable neoantigenic presentation; vascular and ECM integrity maintained; optimization of total tolerable dose of SBRT with limitable and titratable acute side effects; preclinical trials required.