Strategies to tackle the challenges of external beam radiotherapy for liver tumors

Table 1 Summary of hepatocellular carcinoma radiotherapy studies

Ref.	No. of patients	Percent of Child-Pugh B patients	Median tumor diameter (range), cm	Dose (range)/No. of fractions	Median follow-up interval, mo	1-yr OS	2-yr LC	Toxicity
Scorsetti et al[68], 2015	43	36%	≤ 6 cm	48-75 Gy/3 (51%) and 36-60 Gy/6 (49%)	8	77.9%	64.4%	≥ gr3: 0
Yamashita et al[69], 2015	79	11%	2.7 cm	48 Gy (40-60)/4-10	21	53% at 2 yr	40%	gr3-4: 4.6% gr2: 2.3%
Huertas et al[70], 2015	77	14.3%	2.4 cm	45 Gy/3	12	81.8	99%	14.9%
Zhong et al[71], 2014	72	26%	13.1 cm	35.6 Gy/12	18	56%	NR	gr1-2: 5.6% liver
								gr1-2: 9.8%
								gastrointestinal
Lo et al[72], 2014	53	NR	4.3 cm	40 Gy/4-5	13.1	70.1%		RILD 9.4%
Van de Voorde et al[73], 2014	5	NR	NR	93.6 Gy (62.5-150 )/3-10	21	85.4%	NR	0
Sanuki et al[74], 2014	63	16%	2.6 cm	35-40 Gy/5	31.1	100%	95%	gr3:
								early: 16%
								late: 21%
								gr4-5: 0%
Park et al[75], 2013	26	27%	2.8 cm	40-50 Gy; 4-5 Gy per fraction	20.2	88.5%	87.6%	gr3: 4%
								gr4-5: 0%
Bujold et al[30], 2013	102	0%	9.9 cm	24-54 Gy (36)/6	31.4	75%	74%	gr3: 21% gr4: 2.9% gr5: 6.9%
Yoon et al[76], 2013	93	26%	2 cm	45 Gy (30-60)/3-4	25.6	86.0%	94.8%1 (2 yr)	gr3: 4.3%
								gr4: 1.0%
								gr5: 1.0%
Jang et al[65], 2013	108	10%	3.0 cm	51 Gy (33-60 )/3	30	83%1	87%	gr3: 6.5%
								gr4: 1.9%
								gr5: 0%
Jung et al[77], 2013	92	26%	Vol: 8.6 cc	45 Gy (30-60 )/3-4	25.7	86.9%	92.1% (3 yr)	gr ≥ 3: 7%
Bibault et al[78], 2013	75	11%	3.7 cm	40-45 Gy/3	10	78.5%	89.8%	gr3: 4%
								gr4: 1.3%
								gr5: 0%
Honda et al[79], 2013	30	23%	16 cm	48 Gy/4	12.3	100%	95%1	gr3: 10%
								gr4-5: 0%
Yuan et al[80], 2013	22	45%	4.3 cm	45 Gy (39-54)/3-8	53.4	73%	92.9%	gr2: 31.8%
Sanuki et al[81], 2013	185	15%	CP-A: 27 cm	CP-A: 40 Gy/5	24	95%	93% (2 yr)	gr5: 1.1%
			CP-B: 24 cm	CP-B: 35 Gy/5
Xi et al[18], 2013	41	0%	Mean GTV vol: 65.4 cc (SD: 47.9)	30-48 Gy (36)	10	50.3%	NR	gr3: 2.4%
								gr4-5: 0%
Huang et al[82], 2012	36	NR	1.1-12.3 cm	37 Gy (25-48)/4-5	14	64% at 2 yr	98%	gr2: 3%
Kang et al[83], 2012	47	13%	2.9 cm	42-60 Gy/3	17	83%1	94.6%	gr3: 6.4%
								gr4: 4.3%
								gr5: 0%
Ibarra et al[84], 2012	21	NR	GTV vol: 334.2 cc	30 Gy (18-50 )/1-10	12.9	87%	57%1 (2 yr)	gr3: 4.8%
								gr4: 4.8%
								gr5: 0%
Price et al[85], 2012	26	46%	Median GTV vol: 33.9 cc	42 Gy (24-48 )/3-5	13	77%	NR	NR
Andolino et al[86], 2011	60	40%	3.1 cm	CP-A: 30-48 Gy/3	27	82%1	90% (2 yr)	gr3: 35%
				CP-B: 24-48 Gy/5				gr4: 1.7%
								gr5: 0%
Chan et al[87], 2011	11	25%	3 cm	45 Gy/10	24	62%	NR	gr ≥ 3 22%
Louis et al[88], 2010	25	12%	4.5 cm	45 Gy/3	12.7	79%	95%	gr3:
								early 8%
								late 4%
Kwon et al[89], 2010	42	10%	Vol: 15.4 cc	30-39 Gy/3	28.7	92.9%	67.5%	gr3: 0%
								gr4: 2%
								gr5: 0%
Cárdenes et al[66], 2010	17	65%	≤ 6 cm	CP-A: 48 Gy/3 CP-B: 42 Gy/3 then 40/5	24	75%	100%	gr3: 13 instances
								gr4: 11.8%
								gr5: 0%
Son et al[90], 2010	47	8%	18.3 cm	36 Gy (30-39)/3	NR	NR	NR	gr2: 33%
Goyal et al[91], 2010	6	NR	9.3 cm	34 (24-45 Gy)/1-3	10	83%	100% at 9 mo	0%
Seo et al[92], 2010	38	11%	Vol: 40.5 cc	33-57 Gy/3-4	15	68.4%	66.4% (local PFS)	gr3: 3%
								gr4-5: 0%
Choi et al[21], 2008	22	14%	Vol: 23.5 cc	36 Gy (30-39 )/3	11.5	88.1%	NR	gr3: 4.5%
								gr4-5: 0%
Tse et al[61], 2008	31	0%	173 cc	36 Gy (24-54 )/6	17.6	48%	NR	gr3: 29% gr4-5: 0%
Méndez Romero et al[93], 2006	8	25%	3.2 cm	< 4 cm: 37.5 Gy/3 ≥ 4 cm: 25 Gy/5 or 30 Gy/3	12.9	75%	75% (22 mo)	gr5: 12.5% RILD

¹Estimated from survival curve. CP-A: Child-Pugh class A; CP-B: Child-Pugh class B; gr: Grade; GTV: Gross tumor volume; LC: Local control; OS: Overall survival; NR: Not reported; PFS: Progression-free survival; RILD: Radiation induced liver disease; vol: Volume.

Table 2 Prospective metastatic liver stereotactic body radiotherapy studies

Ref.	No. of patients	Dose (Gy/fraction)	Median follow-up (mo)	2-yr local control (%)
Herfarth et al[94], 2001	37	14-26 Gy/1	5.7	812
Hoyer et al[95], 2006	44	45 Gy/3	51.6	79
Kavanagh et al[96], 2006	36	60 Gy/3	19	93
Ambrosino et al[97], 2009	27	Median 36 (25-60) Gy/3	13	74 crude2
Rusthoven et al[62], 2009	47	36-60, 60 Gy/3	16	92
Lee et al[98], 2009	68	Median 41.8 Gy/6	10.8	712
Méndez Romero et al[93], 2006	171	30-37.5 Gy/2		86
Stintzing et al[99], 2010	361	24 Gy/l	21.3	872
Goodman et al[100], 2010	261	18-30 Gy/l	17	772
Rule et al[63], 2011	27	30 Gy/5	20	56
		50 Gy/5		89
		60 Gy/5		100
Janoray et al[101], 2014	56	45 Gy/3-60 Gy/3	12.5	642

¹Included hepatocellular patients;

²12-18 mo local control percentage.

Table 3 Summary of dose constraints by number of fractions

Organ at risk	3 fraction (RAS trial[102])	5 fraction (RTOG 1112[103])	QUANTEC (1.8-2 Gy per fraction)[104]	Toxicity
Liver excluding CTV	700 mL < 15 Gy	V 10 < 70%	D mean < 30 Gy	Radiation induced liver dysfunction
Esophagus	D 1 mL < 21 Gy	D 0.5 mL < 32 Gy	V 35 < 50%	Esophagitis
Stomach	D 1 mL < 21 Gy	D 0.5 mL < 30 Gy	D 100 < 35 Gy	Ulceration
Kidney	D 35% < 15 Gy	D mean < 10 Gy	D mean < 28 Gy (1.8-2 Gy per fraction)	Renal dysfunction
Bowel and duodenum	D 1 mL < 21 Gy	D 0.5 mL < 30 Gy	D 45 < 195 cc	Enteritis/fistula
Spinal cord	Dmax < 18 Gy	D 0.5 mL < 25 Gy	Dmax = 45	Myelopathy
Heart	D 1 mL, 30 Gy	D 30 mL < 30 Gy	V 25 < 10%	Pericarditis

CTV: Clinical target volume.