Effect of perioperative branched chain amino acids supplementation in liver cancer patients undergoing surgical intervention: A systematic review

Table 1 Risk of bias assessment of non-randomised studies, using Cochrane ROBINS-1 tool

Ref.	Confounding factor bias	Selection bias	Bias in classification of interventions	Bias due to deviations from intended intervention	Bias due to missing data	Bias in measurement of outcomes	Bias in selection of the reported result	Overall bias
Ardito et al[45]	Low	Low	Low	Low	Low	Low	Low	Low
Kobayashi et al[36]	Low	Moderate	Low	Low	Low	Low	Moderate	Moderate
Okabayashi et al[33]	Low	Low	Low	Low	Low	Low	Low	Low
Shirabe et al[37]	Low	Low	Low	Low	Low	Low	Low	Low

Table 2 Baseline participant information of included randomised control trials, observational studies and non-randomised trials

Ref.	Country/year	Study design	Sample size			Gender (M/F)		Male (%)		Age (yr)		Pathology
			Intervention	Control	Total	Intervention	Control	Intervention	Control	Intervention	Control		Intervention	Control
Beppu et al[38]	Japan, 2015	RCT	13	15	28	9/4	10/5	69.2	66.7	64.7 (30.0)	68.4 (18.0)	Metastasis	1	2
												HCC	11	10
												Cholangiocarcinoma	1	3
												Others	0	0
Fan et al[43]	Hong Kong, 1994	RCT	64	60	124	56/9	53/7	87.5	88.3	51 (33.4)	53 (35)	Metastasis	0	0
												HCC	64	60
												Cholangiocarcinoma	0	0
												Others	0	0
Hachiya et al[39]	Japan, 2020	RCT	74	80	154	59/15	66/14	79.7	82.5	NR	NR	Metastasis	0	0
												HCC	74	80
												Cholangiocarcinoma	0	0
												Others	0	0
Ichikawa et al[40]	Japan, 2013	RCT	26	30	56	20/6	18/12	76.9	60	64.5 (11.4)	64.7 (9.8)	Metastasis	0	0
												HCC	26	30
												Cholangiocarcinoma	0	0
												Others	0	0
Ishikawa et al[30]	Japan, 2010	RCT	10	10	20	NR	NR	NR	NR	NR	NR	Metastasis	2	1
												HCC	7	7
												Cholangiocarcinoma	1	2
												Others1	1	3
Kikuchi et al[41]	Japan, 2016	RCT	39	38	77	31/8	29/9	79.5	76.3	69.4 (7.5)	71.9 (7.4)	Metastasis	0	0
												HCC	39	38
												Cholangiocarcinoma	0	0
												Others	0	0
Krapf et al[44]	Austria, 2021	RCT	12	9	21	NR	NR	NR	NR	NR	NR	Metastasis	NR	NR
												HCC	NR	NR
												Cholangiocarcinoma	NR	NR
												Others	NR	NR
Meng et al[31]	Hong Kong, 1999	RCT	21	23	44	19/2	18/5	90.5	78.3	51.5 (10.8)	53.3 (12.8)	Metastasis	0	0
												HCC	21	23
												Cholangiocarcinoma	0	0
												Others	0	0
Nagasue et al[32]	Japan, 1997	RCT	67	65	132	54/13	55/10	80.6	84.6	NR	NR	Metastasis	NR	NR
												HCC	NR	NR
												Cholangiocarcinoma	NR	NR
												Others	NR	NR
Okabayashi et al[33]	Japan, 2010	RCT	13	13	26	9/4	8/5	69.2	61.5	68.2 (11.0)	63.5 (5.7)	Metastasis	0	0
												HCC	8	7
												Adenocarcinoma	5	6
												Cholangiocarcinoma	0	0
												Others	0	0
Okabayashi et al[34]	Japan, 2011	RCT	40	36	76	29/11	24/12	72.5	66.7	68.7 (7.6)	65.1 (11.3)	Metastasis	0	0
												HCC	32	26
												Cholangiocarcinoma	8	10
												Others	0	0
Togo et al[42]	Japan, 2005	RCT	21	22	43	17/5	17/6	81	77.3	66.5 (4.5)	64.3 (9.1)	Metastasis	NR	NR
												HCC	NR	NR
												Cholangiocarcinoma	NR	NR
												Others	NR	NR
Ardito et al[45]	Japan, 2020	Retrospective	107	205	312	NR	NR	NA	NA	NR	NR	Metastasis	83	163
		Cohort										HCC	18	36
												Cholangiocarcinoma	6	6
												Others2	6	48
Okabayashi et al[35]	Japan, 2008	Retrospective	40	72	112	29/11	55/17	72.5	76.4	65.7 (8.6)	68.3 (8.1)	Metastasis	0	0
		Cohort										HCC	40	72
												Cholangiocarcinoma	0	0
												Others	0	0
Shirabe et al[37]	Japan, 2011	Retrospective	72	56	128	NR	NR	NR	NR	NR	NR	Metastasis	NR	NR
		Cohort										HCC	72	56
												Cholangiocarcinoma	NR	NR
												Others	NR	NR
Kobayashi et al[36]	Japan, 2019	Non- randomised trial	26	10	36	21/5	5/5	80.8	50	69.2 (29.0)	64.8 (26.7)	Metastasis	4	2
												HCC	22	8
												Cholangiocarcinoma	0	0
												Others	0	0

¹Benign.

²Benign, intra-hepatic stones, others.

RCT: Randomised controlled trial; HCC: Hepatocellular carcinoma; NR: Not reported.

Table 3 Relevant surgical details of included studies

Ref.	Surgical method		Intervention	Control	Blood loss/mL1
					Intervention	Control
Ardito et al[45], 2020	Hepatectomy	Minimally invasive liver surgery	33	74	NR	NR
		Major hepatic resection	16	62
		Multiple resections	43	44
		Total	92	180
Beppu et al[38], 2015	Hepatectomy	Right hemihepatectomy	8	7	NR	NR
		Left hemihepatectomy	0	1
		Sectionectomy	1	3
		Left hemihepatectomy + sectionectomy	0	1
		Total	9	12
Fan et al[43], 1994	Hepatectomy	Major hepatic resection	47	42	2600 (300-20000)	1900 (400-10500)
		Minor hepatic resection	17	18
		Total	64	60
Hachiya et al[39], 2020	Hepatectomy	Non-anatomical resections	19	25	348 (5-3400)	359 (5-3741)
		Anatomical resections	55	55
		Total	74	80
Ichikawa et al[40], 2013	Hepatectomy	Major hepatic resection	10	14	716 +/- 704	492 +/- 329
		Limited resection of the liver	16	16
		Total	26	30
Ishikawa et al[30], 2010	Hepatectomy	Major hepatic resection	7	5	802.7 +/- 350.6	838.8 +/- 597.6
		Minor hepatic resection	6	8
		Total	13	13
Kikuchi et al[41], 2016	Hepatectomy	Partial hepatectomy	13	12	665.7 +/- 528.9	578.5 +/- 492.1
		Segmentectomy	0	6
		Bisgmentectomy/sectionectomy	13	10
		Bisectionectomy or more	13	10
		Total	39	38
Kobayashi et al[36], 2019	Hepatectomy	Major hepatic resection	4	0	454 (140-5103)	365 (35-3650)
		Minor hepatic resection	22	10
		Total	26	10
Krapf et al[44], 2021	Liver transplant- Hepatectomy	Major hepatic resection	24	12	NR	NR
		Hepatic resection	9	12
		Total	33	24
Meng et al[31], 1999	Hepatectomy	Major hepatic resection	13	18	NR	NR
		Minor hepatic resection	8	5
		Total	21	23
Nagasue et al[32], 1997	Hepatectomy	Major hepatic resection	19	26	NR	NR
		Minor hepatic resection	48	39
		Total	67	65
Okabayashi et al[35], 2008	Hepatectomy	Major hepatic resection	10	19	516 +/- 354	821 +/- 552
		Minor hepatic resection	30	53
		Total	40	72
Okabayashi et al[33], 2010	Hepatectomy	Major hepatic resection	5	7	1252 +/- 1205	669 +/- 575
		Minor hepatic resection	8	6
		Total	13	13
Okabayashi et al[34], 2011	Hepatectomy	Hemihepatectomy	4	4	945 +/- 827	676 +/- 695
		Segmentectomy	12	10
		Limited hepatic resection	24	22
		Total	40	36
Shirabe et al[37], 2011	Liver transplant	Total	129	107	7388 +/- 9031	6448 +/- 6547
Togo et al[42], 2005	Hepatectomy	Partial hepatectomy	8	8	1163 +/- 853	1209 +/- 872
		Segmentectomy	7	8
		Sectionectomy	4	3
		Hemihepatectomy	2	3
		Total	21	22

¹Data is expressed as n or mean +/- SD (median, range).

NR: Not reported.

Table 4 Presence and severity of liver diseases in patients of included studies

Ref.	Hepatitis		Cirrhosis		Child-Pugh Score
	Intervention	Control	Intervention	Control		Intervention	Control
Ardito et al[45], 2020	NR	NR	NR	NR	A	NR	NR
					B	NR	NR
					C	NR	NR
Beppu et al[38], 20151	9	8	NR	NR	A	NR	NR
					B	NR	NR
					C	NR	NR
Fan et al[43], 1994	18	12	39	33	A	NR	NR
					B	NR	NR
					C	NR	NR
Hachiya et al[39], 2020	74	80	NR	NR	A	61	64
					B	13	16
					C	0	0
Ichikawa et al[40], 2013	10	7	16	23	A	21	25
					B	5	5
					C	0	0
Ishikawa et al[30], 20101	4	2	5	5	A	10	12
					B	1	1
					C	0	0
Kikuchi et al[41], 2016	39	38	NR	NR	A	39	38
					B	0	0
					C	0	0
Kobayashi et al[36], 20191	20	6	12	8	A	NR	NR
					B	NR	NR
					C	NR	NR
Krapf et al[44], 2021	NR	NR	NR	NR	A	NR	NR
					B	NR	NR
					C	NR	NR
Meng et al[31], 1999	18	19	15	15	A	17	20
					B	4	3
					C	0	0
Nagasue et al[32], 1997	21	10	46	53	A	53	50
					B	13	14
					C	1	1
Okabayashi et al[35], 2008	33	54	NR	NR	A	33	62
					B	7	10
					C	0	0
Okabayashi et al[33], 2010	8	7	NR	NR	A	10	11
					B	3	2
					C	0	0
Okabayashi et al[34], 20111	22	16	NR	NR	A	28	25
					B	12	10
					C	0	0
Shirabe et al[37], 2011	NR	NR	26	18	A	3	18
					B	36	39
					C	90	50
Togo et al[42], 2005	21	22	21	22	A	15	17
					B	7	5
					C	0	0

¹All participants, including non-hepatocellular carcinoma patients were included.

NR: Not reported.

Table 5 Intervention and control protocol for all included studies

Ref.	Intervention type	Intervention protocol1						Control protocol	Follow up period2
		Pre-operative regime	Total BCAA received (g)/d	Duration	Post-operative regime	Total BCAA received (g)/d	Duration		Intervention		Control
									Mean	Range	Mean	Range
Ardito et al[45], 2020	Preoperative, postoperative	BCAA 500 mg 2 tablets TDS with personalised diet (ERAS)	3	2/52	BCAA 500 mg 2 tablets TDS (ERAS)	3	1/12	Normal usual diet (ERAS)	NR	NR	NR	NR
Beppu et al[38], 2015	Preoperative, postoperative	Livact 4.15 g BD	8	6/12	NIL	NIL	NIL	Normal usual diet	NR	NR	NR	NR
Fan et al[43], 1994	Preoperative, postoperative	BCAA 1.5 g/kg	Weight dependent	1/52	BCAA 1.5 g/kg	Weight dependent	1/52	Normal usual diet	NR	NR	NR	NR
Hachiya et al[39], 2020	Postoperative	NIL	NIL	NIL	Livact 4 g TDS	12	4 yr	Normal usual diet	21.8	1.2-48	NR	NR
Ichikawa et al[40], 2013	Preoperative, postoperative	Livact 4.74 g TDS	12	2/52	Livact 4.74 g TDS	12	≥ 6/12	Normal usual diet	39.5 mo	7-48 mo	36.0 mo	6-50 mo
Ishikawa et al[30], 2010	Preoperative, postoperative	Aminoleban EN 50 g BD	11.123	2/52	Aminoleban EN 50 g BD	11.123	1/52	Normal usual diet	NR	NR	NR	NR
Kikuchi et al[41], 2016	Preoperative, postoperative	Livact 4.74 g TDS	12	1/12	Livact 4.74 g TDS	12	1 yr	Normal usual diet (35-40 kcal/kg/d) + 4.74 g Livact TDS × 1 yr post-operatively	NR	NR	NR	NR
Kobayashi et al[36], 2019	Preoperative, postoperative	Aminoleban EN 50 g ON	5.5615	2/52	Aminoleban EN ON	5.5615	12/52	Normal usual diet	NR	NR	NR	NR
Krapf et al[44], 2021	Postoperative	NIL	NIL	NIL	High BCAA diet	NA	2/52	Normal usual diet (standard isocaloric meal plan)	NR	NR	NR	NR
Meng et al[31], 1999	Postoperative	NIL	NIL	NIL	Aminoleban EN TDS with 40 g protein/d + 6300 kJ/d	NA	12/52	Normal usual diet (80 g protein/d + 6300 kJ/d)	511.6d	6-982 d	512.7d	48-983 d
Nagasue et al[32], 1997	Postoperative	NIL	NIL	2/52	Aminoleban EN 50 g BD	11.123	≥ 1 yr	Normal usual diet	35.8 mo (17.9)	NR	36.0 mo (17.7)	NR
Okabayashi et al[35], 2008	Preoperative	Aminoleban EN 50 g BD	11.123	2/52	NIL	NIL	NIL	Normal usual diet	16.3 mo	2-47 mo	23.3 mo	2-84 mo
Okabayashi et al[33], 2010	Preoperative	Aminoleban EN 50 g BD	11.123	2/52	NIL	NIL	NIL	Normal usual diet	NR	NR	NR	NR
Okabayashi et al[34], 2011	Preoperative, postoperative	Aminoleban EN 50 g BD	11.123	2/52	Aminoleban EN 50 g BD	11.123	≥ 6/12	Normal usual diet	NR	NR	NR	NR
Shirabe et al[37], 2011	Preoperative	Regime 1: Livact 3 packets OD Regime 2: Aminoleban EN 50 g 1 to 3 packets	Regime 1: 12Regime 2: 5.5615-16.6845	> 1/12	NIL	NIL	NIL	Normal usual diet	NR	NR	NR	NR
Togo et al[42], 2005	Post-operative	NIL	NIL	NIL	Livact 4.74 g TDS	12	1 yr	Normal usual diet	NR	NR	NR	NR

¹Composition of livact and Aminoleban described in supplementary table 4.

²Data is expressed as n or mean +/- SD (median, range).

Participants on branched chain amino acid supplementation were also taking normal usual diet. BCAA: Branched chain amino acid; ERAS: Enhanced recovery after surgery; TDS: Ter die sumendum ; NR: Not reported; NIL: Nothing.