Hypofractionated particle beam therapy for hepatocellular carcinoma–a brief review of clinical effectiveness

Table 1 Clinical patient characteristics of the selected studies

Ref.	Study, Patient	Source/ Energy (MeV)	Liver function	Vascular invasion	Tumor size
Bush et al[40]	Phase II, 76	Proton	CPC score	4 patients	5.5 cm (mean)
			5-6 22
			7-9 36
			10-15 18
Hong et al[41]	Phase II, 44	Proton (230-250)	CPC	15 patients	5.0 cm (median,1.9-12.0)
			A 32
			B 9
			C 3
Chiba et al[42]	Retro, 162	Proton (250)	CPC	10 patients	3.8 cm (median, 1.5–14.5)
			A 82
			B 62
			C 10
Nakayama et al[37]	Retro, 47	Proton (155 to 250)	CPC	7 patients	N/A
			A 35
			B 9
			C 3
Kawashima et al[43]	Phase II, 30	Proton (235)	CPC	12 patients	45 cm (median,25-82)
			A 20
			B 10
Kim et al[44]	Phase I, 27	Proton (250)	CPC	N/A	2.3-3.2 cm (median, 1.3-7)
			A 24
			B 3
Kato et al[45]	Phase I/II, 24	Carbon‐ion (290-400)	CPC	3 patients	5.0 cm (median,2.1-8.5)
			A 16
			B 8
Mizumoto et al[34]	Retro, 266	Proton	CPC	N/A	< 3 cm 100
			A 203		3.0–4.9 cm 96
			B 60		50–99 cm 62
			C 3		> 100 cm 8
Komatsu et al[39]	Retro, 343	Proton, Carbon‐ion	CPC	92 patients	< 50 277 50-100
			A 262		80
			B 75		> 100 22
			C 6
Kim et al[46]	Retro, 71	Proton (230)	CPC	0	1.5 (median,1.0–8.5)
			A 68
			B 3
Shibuya et al[38]	Retro, 174	Carbon‐ion	CPC	0	3.0 (median,0.8‐10.3)
			A 153
			B 20

CPC: Child-pugh classification; Retro: Retrospective study; N/A: Non-analyses. CPC: Child-pugh classification; Retro: Retrospective study; N/A: Non-analyses.

Table 2 Main clinical results of the selected studies

Ref.	Dose fractionation (GyE/fractions)	Treatment planning	Local control	Survival outcome	Late severe adverseevents (number or %)
Bush et al[40]	63 /15	PTV = GTV + 10-20 mm	80%	median PFS: 36 mo	G2 toxicities: 5/76
Hong et al[41]	58.05–67.5 /15	PTV = CTV +5-10 mm	94.8% (2 yr)	Median PFS: 13.9 mo	G3 toxicities: 4
				PFS: 39.9% (2 yr)
				OS: 63.2% (2 yr)
Chiba et al[42]	72 /16, 78 /20, 84 /28, 50 /10	CTV = GTV + 5–10 mm	86.9% (5 yr)	OS: 23.5% (5 yr)	Infection biloma: 1.1% Biliary duct stenosis: 0.5% GI bleeding:1.1%
Nakayama et al[37]	72.6/22, 77/ 35	PTV1 = CTV+ 5-10 mm PTV2 = PTV1 with alimentary tract avoiding	88% (3 yr)	OS: 50% (3 yr)
Kawashima et al[43]	76 /20	CTV= GTV+5 mm, PTV = CTV+3 mm	96% (2 yr)	OS: 62% (3 yr)	Hepatic insufficiencies : 8
Kim et al[44]	60/20 –72/24	PTV = ITV + 5-10 mm	71.4%–83.3% (3y)	OS: 42.3% (5 yr)	G2 toxicity: 0
Kato et al[45]	49.5–79.5/15	PTV= GTV+10 mm	81% (3 yr)	OS: 25% (5 yr)	No severe liver injury No > 2 points increase in CP score at any time
Mizmoto et al[34]	66/10, 72.6/22, 77/35	CTV= GTV+ 5-10 mm	81% (5 yr)	OS: 45 (5 yr)	G 2/3 GI toxicity: 6
Komatsu et al[39]	52.8–84.0 /4-38 (proton) 52.8–76.0 /4-20 (carbon ion)	CTV = GTV + 5 mm PTV = CTV + 5 mm	90.8% (5 yr)	OS: 38.2%	G 3: 12 RIHD: 4
Kim et al[36]	66/10	PTV = ITV + 0.5-0.7 cm	89.9% (3 yr)	PFS: 26.8% (3 yr) OS: 74.4% (3 yr)	no late GI toxicities or liver failure
Shibuya et al[38]	52.8/4, 60.0/4, 48/2,	CTV = GTV + 0.5 cm PTV = CTV+ 5‐15 mm	87.7% (3 yr)	73.3% (3 yr)	G 3-4: 5.7% (10) RIHD: 1.7% (3)

PFS: Progression-free survival; OS: Overall survival; PTV: Planned target volume; GTV: Gross tumor volume; CTV: Clinical target volume; G: Grade; RILD: Radiation-induced hepatic dysfunction; GI: Gastrointestinal.