Prognostic implications of circulating Epstein–Barr virus DNA for extranodal natural killer/T-cell lymphoma, nasal type: a meta-analysis

Figures & data

Figure 1 Selection of studies.

Note: Flow diagram showing the selection process for the enrolled studies.

Table 1 Baseline characteristics of the enrolled studies

References	Country	No of patients	Type of study	Clinical stage	Primarysite	Detection of EBV DNA					Outcomes
						Time	Sample type	Positive rate, No (%)	Median (range) (copies/mL)	Cut-off value (copies/mL)
Lei et al 2003^Citation22	HK	15	Retrospective	I–IV/recurrent	All sites	Pre/intra	Plasma	25 (96.2%)	1.67×10^3 (307−2.25×10^5)	600	OS
Ishii et al 2007^Citation24	Japan	20	Retrospective	I–IV	UNKTL	Pre/intra/post	Serum	20/19 (100%/95%)	349.9 (74.4−1.12×10^5)/55.57 (<4−310)	700/40	OS, DFS
Suzuki et al 2011^Citation25	Japan	32	Prospective	I–IV	All sites	Pre/intra/post	Plasma/MNC	14 (43.75%)/6 (18.75%)	1.23×10^5 (50−7.1×10^5)/0.2 (0.02−0.78)	0	OS
Wang et al 2012^Citation26	China	69	Retrospective	I–II	UNKTL	Pre/post	Plasma	58 (84.1%)	491 (0−4.53125×10^5)	500	OS, PFS
Ito et al 2012^Citation27	Japan	26	Prospective	I–IV/recurrent	ENKTL	Pre/intra/post	Plasma/whole blood	15 (59%)/22 (85%)	870 (0−1.3×10^7)/3.7×10^3 (0−1.1×10^7)	10^4/10^5	OS
Kwong et al 2014^Citation28	HK	56	Retrospective	I–IV	All sites	Pre/intra/post	Plasma	41 (73.2%)	1.9×10^2 (0−1.4×10^7)	0	OS, DFS
Kim et al 2015^Citation29	Korea	27	Prospective	IV	ENKTL	Pre	Whole blood	17 (63%)	60 (2−4183)	60	OS
Wang et al 2015^Citation30	China	68	Prospective	I, II	All sites	Pre/post	Plasma	43 (63.2%)/15 (22.1%)	NA	0	OS, PFS
Kim et al 2015^Citation31	Korea	102	Retrospective	I–IV	ENKTL	Pre/post	Whole blood	48 (47%)/30 (29.4%)	60 (19.3−165.5)	0	OS, PFS
Liang et al 2016^Citation32	China	120	Retrospective	I–IV	ENKTL	Pre	Plasma	5 (4.2%)	NR	0	OS, DFS
Lim et al 2016^Citation33	Korea	27	Retrospective	I–IV	ENKTL	Pre	Whole blood	12 (44.4%)	NR	0	OS, PFS

Abbreviations: DFS, disease-free survival; EBV, Epstein–Barr virus; ENKTL, extranodal NK/T-cell lymphoma; HK, Hongkong; Intra, Intra-treatment; MNC, mononuclear cells; No, number; NR, not reported; OS, overall survival; PFS, progression-free survival; post, post-treatment; pre, pre-treatment; UNKTL, upper aerodigestive tract NK/T cell lymphoma.

Table 2 Assessment of study quality using the Newcastle–Ottawa scale

References	Selection (0–4)				Comparability (0–2)		Outcome (0–3)			Total
	REC	SNEC	AE	DO	SC	AF	AO	FU	AFU
Lei et al 2002^Citation23	1	1	1	1	0	0	1	0	0	5
Ishii et al 2007^Citation24	0	1	1	1	0	0	1	1	1	6
Suzuki et al 2011^Citation25	1	1	1	1	0	0	1	1	1	7
Wang et al 2012^Citation26	0	1	1	1	0	0	1	1	0	5
Ito et al 2012^Citation27	0	1	1	1	0	0	1	1	0	5
Kwong et al 2014^Citation28	1	1	1	1	0	0	1	1	0	6
Kim et al 2015^Citation29	0	1	1	1	0	0	1	1	1	6
Wang et al 2015^Citation30	0	1	1	1	0	0	1	1	1	6
Kim et al 2015^Citation31	0	1	1	1	0	0	1	1	1	6
Liang et al 2016^Citation32	0	1	1	1	0	0	1	1	1	6
Lim et al 2016^Citation33	0	1	1	1	0	0	1	1	1	6

Notes: “1” means that the study satisfied the item, and “0” means the opposite situation.

Abbreviations: AE, ascertainment of exposure; AF, study controls for any additional factors (chemoradiotherapy, curative resection); AFU, adequacy of follow-up of cohorts; AO, assessment of outcome; DO, demonstration that outcome of interest was not present at start of study; FU, follow-up long enough for outcomes to occur; REC, representativeness of the exposed cohort; SC, study controls for age, sex; SNEC, selection of the non-exposed cohort.

Figure 2 Estimated hazard ratios for OS and PFS/DFS in pre-treatment group.

Notes: (A) Forest plot of OS in pre-treatment group. (B) Forest plot of PFS/DFS in pre-treatment group.

Abbreviations: DFS, disease-free survival; EBV, Epstein–Barr virus; OS, overall survival; PFS, progression-free survival.

Figure 3 Estimated hazard ratios for OS and PFS/DFS in post-treatment group.

Notes: (A) Forest plot of OS in post-treatment group. (B) Forest plot of PFS/DFS in post-treatment group.

Abbreviations: DFS, disease-free survival; EBV, Epstein-Barr virus; OS, overall survival; PFS, progression-free survival.

Table 3 Results of subgroup analysis on OS

Variables	Pre-treatment				Post-treatment
	HR (95% CI)	n	I^2 (%)	P-value	HR (95% CI)	n	I^2 (%)	P-value
Sample types
Plasma/serum	5.30 (3.01–9.33)	8	1	0.42	8.25 (4.43–15.36)	5	49	0.10
Whole blood/MNC	5.30 (1.68–16.75)	4	58	0.07	2.75 (1.09–6.98)	1	–	–
Tumor sites
UNKTL	7.24 (1.24–42.10)	3	38	0.20	4.68 (1.66–13.19)	2	0	0.61
Others	4.15 (2.40–7.17)	3	8	0.37	7.29 (2.13–24.91)	4	73	0.01
Type of study
Prospective	3.05 (1.52–6.11)	6	15	0.32	46.24 (7.50–284.93)	1	–	–
Retrospective	7.53 (3.60–15.78)	4	0	0.88	4.90 (2.86–8.40)	5	35	0.19
Sample sizes
N>30	4.81 (2.15–10.79)	4	0	0.76	7.75 (2.54–23.61)	4	71	0.02
N<30	4.43 (1.96–10.06)	6	44	0.12	3.92 (1.20–12.86)	2	0	0.38

Note: “–” = no results.

Abbreviations: HR, hazard ratio; MNC, mononuclear cells; OS, overall survival; UNKTL, upper aerodigestive tract NK/T cell lymphoma.

Figure 4 Funnel plots of the enrolled studies.

Notes: (A) OS in pre-treatment group. (B) OS in post-treatment group.

Abbreviation: OS, overall survival.

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