The role of external beam radiotherapy for hepatocellular carcinoma patients with lymph node metastasis: a meta-analysis of observational studies

Figures & data

Figure 1 The study inclusion process.

Table 1 Characteristics of the included studies

Study	Country	Year	N	NOS score	Male (%)	CPC A (%)	Age (median, range)	Other distant metastasis (%)	Primary controlled	Intra- abdominal LNs (%)	Concomitant or post-RT chemotherapy
Chen et al^Citation11	People’s Republic of China	2013	191	6	86.4	94.2	52 (25–83)	22.0	38.2	83.2
Lee et al^Citation13	Korea	2015	65	6	89.2	78.5	59 (37–79)	43.1	64.6	89.2	Sorafenib 36.9%, CTx 15.4% (post-RT)
Wee et al^Citation15	Korea	2016	105	5	86.7	71.4	59 (30–81)	39.1	38.1	73.4
Park et al^Citation14	Korea	2006	45	5	82.2	82.2	55 (39–68)	24.4	77.8	100.0
Yamashita et al^Citation16	Japan	2006	21	5	81	57.1				71.4
Jang et al^Citation12	Korea	2009	20	6							HAIC and 5FU as indicated after RT
Yoon et al^Citation17	Korea	2004	51	6	78		63% in 50s–60s		27.0	94.1
Toya et al^Citation10	Japan	2009	23	5	91.3	69.6	68 (44–76)	13	60.9	56.5

Abbreviations: NOS, Newcastle–Ottawa Scale; CPC, Child–Pugh Class; LN, lymph node; RT, radiotherapy; CTx, chemotherapy; HAIC, hepatic arterial infusion chemotherapy; 5FU, 5-fluorouracil.

Table 2 Treatment profiles and clinical outcomes

Study	Modality	Median dose (BED, Gy) ^Citation10	Fraction size (Gy)	Overall			Responder	Nonresponder	Responder vs nonresponder	Response criteria	ORR (%)	LD	HD	Borderline of low/high dose (BED, Gy10)	Grade ≥3 toxicity (%)	Criteria
				MOS (months)	1-year OS (%)	2-year OS (%)	MOS, months (1-year OS %)	MOS, months (1-year OS %)				RR (%)	RR (%)
Chen et al^Citation11	2D/3D	60	2	8	39.3	18.9	10.4	6.7 (SD), 3 (PD)	<0.001	WHO	79.1	54.8	85.9	60	Grade 3 thrombocytopenia in 9.9%	RTOG
Lee et al^Citation13	3D/IMRT	65.5	1.8–3	8.1		19.6	14.5	3.7	<0.001	RECIST	61.5	38.9	70.2	54	1 (1.5%) case of late GI ulcer grade 3	CTCAE
Wee et al^Citation15	3D/IMRT	58.5	1.8–3	5.8			13.8	4	<0.001	RECIST	56.7	40.0	75.6	60	3 cases (2.9%) of late grade 3 GI bleeding in BED >60 Gy10	RTOG
Park et al^Citation14	3DCRT	50	1.8–3	7	35.2	21.7	10 (48.5%)	6 (0%)	<0.01	RECIST	86.7	64.7	90.9	50	4 (8.9%) patients with grade 3 GI bleeding, all were >50 Gy10	CTCAE
Yamashita et al^Citation16	3DCRT	60	2	13	53	33	13 (55.1%)	11 (50%)	0.857	WHO	81.0				14.3% G3 thrombocytopenia	RTOG
Jang et al^Citation12	IMRT	75	10							RECIST	60.0					RTOG
Yoon et al^Citation17	3DCRT	58.5	2–3	7	31.3	15.7	(34%)	(0%)	0.008	WHO	76.0	56.5	93.0	55	3 (5.9%) cases of grade ≥3 GI bleeding, 1 underwent subtotal gastrectomy and 1 expired	CTCAE
Toya et al^Citation10	3DCRT	58.5	1.8–4	19	60					RECIST	83.0	56.0	100.0	58	No grade ≥3 toxicity	RTOG

Abbreviations: BED, biologically equivalent dose; LD, low-dose group; HD, high-dose group; MOS, median overall survival; ORR, overall response rate; OS, overall survival; RR, response rate; 2DRT, 2-dimensional radiotherapy; 3DCRT, 3-dimensional conformal radiotherapy; LN, lymph node; SD, stable disease; PD, progressive disease; RTOG, Radiation Therapy Oncology Group; IMRT, intensity-modulated radiation therapy; CTCAE, Common Terminology Criteria for Adverse Event; GI, gastrointestinal.

Table 3 Pooled rates of main clinical outcomes

	Study (n)	Patients (n)	P-value, He	I^2 (%)	Egger’s test, P-value	Events (95% CI)
RR
Overall	8	521	<0.001	75.2	0.49	73.1 (63.6–80.9)
High dose	6	313	0.035	58.2	0.324	82.2 (74.4–88.1)
Low dose	6	161	0.362	8.5	0.551	51.1 (40.3–61.7)
High dose vs low dose P=0.001
OS
1-year OS	5	331	0.129	43.9	0.464	41.0 (32.9–49.6)
2-year OS	5	373	0.566	0	0.408	19.9 (16.1–24.3)
Median OS in months 8 (5.8–19)

Abbreviations: CI, confidence interval; OS, overall survival; RR, response rate.

Figure 2 (A) Forest plots of the RRs and 1-year OS rates. The P-values from the Cochran Q test²¹ and I² statistics are described below the figures. Significant heterogeneity among the studies was found in regard to RRs, but not in 1-year OS rates. (B) Forest plots of RRs comparing high- and low-dose groups. The P-value was derived from a Q-test, based on an analysis of the variance and a random-effects model, where P (total between) <0.001 suggests a significant difference of RRs between high-dose and low-dose subgroups.

Abbreviations: OS, overall survival; RR, response rate.

Figure 3 (A) Forest plot of GI toxicities of grade 3 or higher, (B) forest plot of thrombocytopenia of grade 3 or higher.

Abbreviations: CI, confidence interval; GI, gastrointestinal.

Figure 4 Funnel plots assessing RRs and OS rates.

Abbreviations: OS, overall survival; RR, response rate.

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