Pencil Beam Scanning Carbon Ion Radiotherapy for Hepatocellular Carcinoma

Figures & data

Table 1 OAR Constraints for 10- and 15-Fraction Regimens

Structure	10-Fraction Regimens	15-Fraction Regimens
Liver minus GTV	Dmean <20 Gy	Dmean <24 Gy
Stomach	D2cm3 <43 Gy	D2cm3 <50 Gy
	D6cm3 <28 Gy	D6cm3 <32 Gy
Duodenum	D2cm3 <43 Gy	D2cm3 <50 Gy
	D6cm3 <28 Gy	D6cm3 <32 Gy
Bowel	D2cm3 <43 Gy	D2cm3 < 50 Gy
	D6cm3 <28 Gy	D6cm3 < 32 Gy
Kidney (right and left)	Dmean <12 Gy, V14 <30%	Dmean <13 Gy, V15 <30%
Spinal cord	Dmax <30 Gy	Dmax <34 Gy

Abbreviations: OAR, organ at risk; GTV, gross tumor volume; D_mean, mean RBE-weighted dose; Gy, gray; D_2cm3, maximum RBE-weighted dose that covers 2 cm³ of the organs; D_6cm3, maximum RBE-weighted dose that covers 6 cm³ of the organs; V₁₄, percentage of volume receiving more than 14 Gy; V₁₅, percentage of volume receiving more than 15 Gy; D_max, maximum RBE-weighted dose.

Figure 1 Two representative cases of hepatocellular carcinoma treated with CIRT using different fractionation regimens. The first case: (A) T2-weighted and hepatic arterial phase T1-weighted MRI before CIRT. (B) Dose distribution of the CIRT plan with a prescription relative biological effectiveness-weighted dose of 67.5 Gy in 15 fractions. (C) Follow-up MRI at 45 months after CIRT demonstrated disappearance of the intrahepatic mass. The second case: (D) Baseline MRI before CIRT. (E) Dose distribution with a prescription of 55 Gy in 10 fractions. (F) The MRI taken 51 months after CIRT showing a clinically complete response.

Table 2 Patient and Treatment Characteristics

Characteristics	No. of Patients	%
Age, median (range), years	58.5 (28–87)
Gender
Male	76	84.4
Female	14	15.6
Treatment status
Initial	68	75.6
Recurrent	22	24.4
ECOG performance status
0	61	67.8
1	29	32.2
AFP, median (range), ng/mL	31.3 (1.3–21,852.0)
> 20	52	57.8
≤ 20	38	42.2
AJCC stage (8th edition)
Ia	4	4.4
Ib	31	34.5
II	14	15.6
IIIa	10	11.1
IIIb	28	31.1
IVa	3	3.3
BCLC stage
0	2	2.2
A	6	6.6
B	41	45.6
C	41	45.6
Tumor size, median (range), cm	4.6 (1.6–15.5)
Vascular tumor thrombosis
Yes	30	33.3
No	60	66.7
Portal vein hypertension
Yes	33	36.7
No	57	63.3
Unresectable/inoperable
Yes	78	86.7
No	12	13.3
Liver disease
HBV	70	77.8
HCV	5	5.6
HBV and Schistosoma	2	2.2
Schistosoma	1	1.1
None	12	13.3
Child–Pugh score before CIRT
5	83	92.2
6	6	6.7
7	1	1.1
Number of lesions treated
Solitary	67	74.4
Multiple	23	25.6
TACE before/after CIRT
Yes	72	80.0
No	18	20.0
Motion mitigation approaches
Respiratory gating	72	80.0
ABC	16	17.8
Abdominal compression	2	2.2
DRBE, Gy/fractions (BED10, Gy)
50/10 (75)	2	2.2
55/10 (85)	9	10.0
60/10 (96)	17	18.9
65/10 (107)	26	28.9
70/10 (119)	4	4.4
60/15 (84)	5	5.6
63.75/15 (91)	3	3.3
67.5/15 (98)	24	26.7

Abbreviations: ECOG, Eastern Cooperative Oncology Group; AFP, alpha fetoprotein; AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus; CIRT, carbon ion radiotherapy; TACE, transcatheter arterial chemoembolization; ABC, active breath coordinator; D_RBE, RBE-weighted dose; Gy, gray; BED, biological equivalent dose.

Figure 2 Kaplan–Meier curves for overall survival (OS), local control (LC), elsewhere liver recurrences-free survival (ELRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS).

Note: ^#Number.

Table 3 Two-Year Clinical Outcomes of Prognostic Factors

Variables	No. of Patients	2-yr OS (%)	p value	2-yr LC (%)	p value	2-yr ELRFS (%)	p value	2-yr DMFS (%)	p value	2-yr PFS (%)	p value
ECOG performance status			0.012		0.511		0.472		0.791		0.562
0	61	88.9		96.5		76.3		77.9		62.4
1	29	71.9		96.3		69.2		73.2		55.1
AFP before CIRT (ng/mL)			0.614		0.510		0.470		0.011		0.122
> 20	52	82.4		95.8		70.6		66.5		52.1
≤ 20	38	84.5		97.2		78.5		91.3		71.5
Tumor size (cm)			0.956		0.901		0.278		0.033		0.020
> 5	38	85.0		97.3		69.1		67.1		46.8
≤ 5	52	82.0		95.7		77.5		84.5		70.8
T stage (AJCC, 8th edition)			0.007		0.724		0.062		0.048		0.008
1a-1b	36	91.3		94.1		85.2		87.6		76.6
2–4	54	77.1		98.0		64.3		68.4		47.9
BCLC stage			0.005		0.848		0.096		0.171		0.111
0-B	49	91.3		95.7		82.9		82.2		69.3
C	41	72.5		97.4		63.2		67.4		48.1
Vascular tumor thrombosis			0.010		0.820		0.169		0.245		0.080
Yes	30	70.2		96.4		56.4		64.2		38.0
No	60	88.9		96.4		80.8		81.4		69.6
Portal vein hypertension			0.664		0.679		0.640		0.086		0.267
Yes	33	73.3		93.9		73.3		87.4		66.1
No	57	89.8		98.0		73.1		70.0		55.4
Child–Pugh score before CIRT			0.967		0.531		0.798		0.229		0.947
5	83	83.3		96.2		73.8		76.9		58.7
6–7	7	83.3		100		71.4		71.4		71.4
Number of lesions treated			0.114		0.205		0.030		0.096		0.007
Solitary	67	88.3		95.2		79.1		79.3		66.5
Multiple	23	71.6		100		55.8		68.5		41.6
TACE before/after CIRT			0.252		0.004		0.694		0.993		0.700
Yes	72	85.1		100		74.2		77.0		59.8
No	18	76.7		82.4		73.3		74.7		60.6
BED10 (Gy)			0.747		0.688		0.172		0.819		0.819
≥ 100	30	86.7		93.3		80.4		76.2		63.0
< 100	60	81.4		98.1		70.6		75.4		57.8

Abbreviations: 2-yr, 2-year; OS, overall survival; LC, local control; ELRFS, elsewhere liver recurrence-free survival; DMFS, distant metastasis-free survival; PFS, progression-free survival; ECOG, Eastern Cooperative Oncology Group; AFP, alpha fetoprotein; CIRT, carbon ion radiotherapy; AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; TACE, transcatheter arterial chemoembolization; BED, biological equivalent dose.

Table 4 Acute and Late Toxicities

Toxicities	Grade 1–2		Grade 3–4		Grade 5
	n	%	n	%	n	%
Acute
Hematological abnormalities
Leucopenia	35	38.9	6	6.7	0	0
Thrombocytopenia	23	25.6	3	3.3	0	0
Liver function impairment
Hyperbilirubinemia	2	2.2	0	0	0	0
Hypoalbuminemia	9	10.0	0	0	0	0
γ-glutamyltransferase increase	2	2.2	0	0	0	0
Alkaline phosphatase increase	6	6.7	0	0	0	0
Dysphagia	2	2.2	0	0	0	0
Dermatitis radiation	32	35.6	0	0	0	0
Abdominal pain	18	20.0	0	0	0	0
Late
Stomach bleeding	0	0	3	3.3	1	1.1
Bile duct stenosis	0	0	1	1.1	1	1.1
Rib fracture	1	1.1	0	0	0	0