Table 2.

Dosimetric studies assessing Conformity Index, Homogeneity Index, and Dmean and/or Dmax for OARs.

Authors (year)	Tumor histology	Patient number	Dosimetric study assessment	Mean total target dose (Gy/RBE/CGE) (dose/fraction)	Evaluation of at least one target parameter: CI (or CN), HI	Dmean/Dmax for OARs (Gy or %) with mean and SD	Conclusions
Stoker et al. (2018) [14]	Primary brain tumors requiring hippocampal-avoidance- (HA-) WBRT	10/20	Dosimetric comparison between VMAT and IMPT for HA-WBRT	36 Gy (1.8 Gy/die) HA-WBRT	HI	Dmax and Dmean reported for the normal brain, hippocampi, cochlea, and lens and Dmean for the brainstem	HA-IMPT can match or improve dosimetric benefits obtained with VMAT.
Freund et al. (2015) [12]	Glioma Ependymoma	8 5	Dosimetric comparison between VMAT, PSPT, and IMPT and risk of cerebral radionecrosis assessment	54 Gy (RBE) (1.8 Gy/die)	CI, HI	Dmax and Dmean evaluated and reported for the normal brain	Both PSPT and IMPT plans significantly improved the maximum dose to the brain. A significant lower risk of brain radionecrosis was observed with PBT.
Howell et al. (2012) [13]	Medulloblastoma	18	Comparison of dose distributions and DVHs between photon and proton CSI	23.4 Gy (1.8 Gy/fr)	CI, HI	Dmean and/or Dmax not reported for the analyzed OARs	Both photon and proton plans provided good target coverage; PBT dose distributions were more homogeneous. Proton CSI improved normal tissue sparing.
Correia et al. (2019) [11]	Intracranial germ-cell tumor	11	Comparison of dose distributions and DVHs between WV-RT/TB IMRT, VMAT, and PBS-PT	24 Gy (RBE) WV-RT plus boost up to 40 Gy (1.6 Gy/fr)	HI and inhomogeneity coefficient	Dmean and Dmax reported (%) for the brainstem, chiasm, normal brain, pituitary gland, circle of Willis, bilateral cochlea, hippocampus, lens, and lacrimal gland	PBS-PT was superior to photons in conformality and OAR sparing.
Boehling et al. (2012) [10]	Craniopharyngioma	10	Comparison of dose distributions and DVHs between IMRT, 3D-PRT, and IMPT	50.4 Gy (CGE) (1.8 Gy/fr)	CN, HI	Dmean and Dmax reported for the vascular OARs, brainstem, and normal brain	PBT was able to avoid excess integral dose to a variety of normal structures at all dose levels while maintaining equal target coverage.
Takizawa et al. (2017) [31]	Ependymoma Germinoma	6 6	Comparison of dose distributions and DVHs between PBT, 3D-CRT, and IMRT	Median of 52.2 Gy for ependymoma and median of 30.6 Gy for germinoma	Not reported	Normal brain dose reported for each patient and as a percentage of the prescription dose (visual inspection of raw data)	PBT reduces the average dose to normal brain tissue as compared to 3D-CRT and IMRT.
MacDonald et al. (2008) [26]	Ependymoma	2/17	Comparison of dose distributions and DVHs between IMPT, 3D-PBT, and IMRT	55.8 Gy	Not reported	Dmean for the brain, brainstem, pituitary gland, optic chiasm, and cochlea evaluated and reported for each patient (Gy)	Dose distributions for PBT were compared favourably with IMRT plans. IMPT allows further sparing of some critical structures.
Beltran et al. (2012) [16]	Craniopharyngioma	14	Dosimetric comparison between IMRT, double-scatter (DS) PT, and IMPT	54 Gy (1.8 Gy/die)	CI	Not reported (other dosimetric parameters are reported)	PBT significantly reduced the dose to the whole brain. IMPT was the most conformal treatment that improved OAR dose sparing, but it was highly sensitive to target changes.
Dennis et al. (2013) [17]	Low-grade glioma	11	Dosimetric (DVH) comparison between IMRT and PBT. SMN risk assessment	54 Gy (1.8 Gy/die)	Not reported	Dmean for the brainstem, pituitary gland, optic chiasm, and lacrimal gland evaluated and reported for each patient (Gy)	PBT improved the reduction of doses to normal tissues, especially when tumors were in close proximity to critical structures. IMRT had a twofold higher risk of SMNs as compared to PBT.
Mu et al. (2005) [18]	Medulloblastoma	5	Dosimetric comparison between conventional photons, IMRT, electrons, and PBT. SMN risk assessment	23.4 Gy (1.8 Gy/die)	Not reported	Dmean evaluated and reported for the thyroid, esophagus, heart, lungs, and liver	IMPT significantly reduced mean doses to OARs, except for the lungs (not significantly). IMPT reduced SMN risk.
Zhang et al. (2014) [19]	Medulloblastoma	17	Dosimetric comparison between PSPT CSI and field-in-field photon CSI. SMN risk assessment	23.4 Gy (1.8 Gy/die)	Not reported	Dmean evaluated and reported for the thyroid, heart, lungs, and liver	PSPT CSI provided lower doses to OARs, superior predicted outcomes, and lower predicted risks of SMNs and cardiac mortality than field-in-field photon CSI.
Yoon et al. (2011) [15]	Various CNS tumors	10	Comparison of dose distributions, DVHs, and SMN risk between CSI with 3D-CRT, TOMO, and PBT. SMN risk assessment	36 Gy (1.8 Gy/fr) to the spine; total target dose ranged between 54 and 60.6 Gy	CI, HI	Dmean evaluated and reported for the lens, thyroid, esophagus, lungs, liver, and kidneys	PBT provided the best HI and a superior CI than 3D-CRT (no significant difference compared to TOMO). OAR doses with PBT were lower than those obtained with 3D-CRT or TOMO. Lower SMN risk was reported with PBT.

CI: Conformity Index; HI: Homogeneity Index; CGE: cobalt Gy equivalents; RBE: relative biological effectiveness; SD: standard deviation; CSI: craniospinal irradiation; TOMO: tomotherapy; PBS-PT: pencil beam scanning-proton therapy; PSPT: passively scattered PT; VMAT: volumetric modulated arc therapy; IMRT/IMPT: intensity-modulated radiotherapy or PT; SMNs: secondary malignant neoplasms; WBRT: whole-brain RT; WV-RT/TB: whole-ventricular RT followed by a boost to the tumor bed.