Association between lymphopenia and the survival of patients with colorectal cancer: A meta-analysis

Table 1 Characteristics of the included studies

Ref.	Country	Design	Diagnosis	Number of patients	Mean age (years)	Men (%)	Cancer stage	Main treatment	Definition of lymphopenia	Number of patients with lymphopenia	Median follow-up duration (months)	Outcomes reported	Variables adjusted
Cézé et al[11]	France	RC	CRC	260	64.8	60.8	II-IV	Chemotherapy	Pretreatment ALC < 1000/μL	49	18.5	PFS and OS	Age, sex, WHO PS, tumor site, number of metastatic sites, chemotherapy regimen, and ALP level
Chu-Yuan et al[12]	China	RC	CRC	243	59	55.1	II-III	Chemotherapy	Chemotherapy-associated ALC < 660/μL	42	31	PFS and OS	Age, sex, cancer differentiation, stage, location, pretreatment albumin, and pretreatment CEA level
Liang et al[13]	China	RC	CRC	1332	60	61.6	II	Curative tumor resection and adjuvant chemotherapy	Pretreatment ALC < 1300/μL	373	26.8	PFS and OS	Age, T stage, vessel invasion, perineural invasion, LN sampling, and CEA level
Iseki et al[14]	Japan	RC	CRC	362	67	53.9	II-III	Curative tumor resection and neoadjuvant chemotherapyor neoadjuvant CRT	Pretreatment ALC < 1700/μL for PFS and ALC < 1100/μL for OS	205	63.4	PFS and OS	Age, sex, BMI, tumor location, size, T stage, LVI, LN metastasis, preoperative CEA level, adjuvant chemotherapy, and tumor histology
Oh et al[15]	Korea	RC	Rectal adenocarcinoma	139	56	77	I-III	Preoperative CRT and surgical resection	Pretreatment ALC < 1993/μL	69	49.6	PFS and OS	Age, sex, tumor stage, histology grade, and surgery type
Yamamoto et al[17]	Japan	RC	CRC	379	NR (> 70)	55.4	I-IV	Surgical resection	Pretreatment ALC < 1280/μL	145	30	OS	None
Xu et al[16]	China	RC	Locally advanced rectal cancer	34	59	73.5	II-III	Neoadjuvant CRT, surgical resection, and adjuvant chemotherapy	Pretreatment ALC < 500/μL	10	32	PFS	Age, sex, tumor stage, and pretreatment CEA level
Shibutani et al[18]	Japan	RC	CRC	115	65	46.1	II-III	Surgical resection, and adjuvant chemotherapy	Chemotherapy-associated ALC < 1000/μL	17	32.9	PFS and OS	Age, sex, tumor location, depth, histology type, LN metastasis, pretreatment CEA level, CA-199 level, albumin level, and chemotherapy regimen
Li et al[19]	China	RC	Locally advanced rectal cancer	36	60.5	63.9	II-III	Surgical resection and CRT	CRT-associated ALC < 500/μL	20	34	PFS	Age, sex, LN metastasis, pretreatment CEA level, and pretreatment ALC
Baik et al[20]	Korea	RC	Rectal adenocarcinoma	147	65	63.3	I-III	Preoperative CRT and surgical resection	CRT-associated ALC < 500/μL	21	60.7	PFS and OS	Age, BMI, DM, hypertension, tumor stage, LVI, and perineural invasion
Koukourakis et al[21]	Greece	RC	Rectal adenocarcinoma	33	72	69.7	I-III	CRT	CRT associated ALC < 518/μL	18	32	PFS	None
Soyfer et al[22]	Israel	RC	Rectal cancer	110	61	60	I-III	Radiotherapy and surgical resection	Radiotherapy-associated ALC < 500/μL	9	62.5	PFS and OS	Age, sex, tumor stage, pretreatment CEA level, tumor location, and comorbidities
Kim et al[23]	United States	RC	Rectal adenocarcinoma	193	58	62	II-III	Neoadjuvant CRT, surgical resection	CRT-associated ALC < 500/μL	110	68	PFS and OS	Age, sex, race, ECOG PS, smoking, tumor stage, baseline albumin level, TB level, CEA level, and surgery type

NR: Not reported; RC: Retrospective cohort; CRC: Colorectal cancer; ALC: Absolute lymphocyte count; PFS: Progression-free survival; OS: Overall survival; WHO PS: World Health Organization performance status; ALP: Alkaline phosphatase; CEA: Carcinoembryonic antigen; LN: Lymph node; BMI: Body mass index; CRT: Chemoradiotherapy; LVI: Lymphovascular invasion; CA-199: Carbohydrate antigen 19-9; DM: Diabetes mellitus; ECOG PS: Eastern Cooperative Oncology Group performance status; TB: Total bilirubin.

Table 2 Study quality evaluation via the Newcastle-Ottawa Scale

Ref.	Representativeness of the exposed cohort	Selection of the non- exposed cohort	Ascertainment of exposure	Outcome not present at baseline	Control for age	Control for other confounding factors	Assessment of outcome	Sufficiently long follow-up duration	Adequacy of follow-up of cohorts	Total
Cézé et al[11]	0	1	1	1	1	1	1	0	1	7
Chu-Yuan et al[12]	0	1	1	1	1	1	1	1	1	8
Liang et al[13]	1	1	1	1	1	1	1	1	1	9
Iseki et al[14]	0	1	1	1	1	1	1	1	1	8
Oh et al[15]	0	1	1	1	1	1	1	1	1	8
Yamamoto et al[17]	1	1	1	1	0	0	1	1	1	7
Xu et al[16]	0	1	1	1	1	1	1	1	1	8
Shibutani et al[18]	0	1	1	1	1	1	1	1	1	8
Li et al[19]	0	1	1	1	1	1	1	1	1	8
Baik et al[20]	0	1	1	1	1	1	1	1	1	8
Koukourakis et al[21]	0	1	1	1	0	0	1	1	1	6
Soyfer et al[22]	0	1	1	1	1	1	1	1	1	8
Kim et al[23]	0	1	1	1	1	1	1	1	1	8

Table 3 Results of univariate meta-regression analysis of the influence of absolute lymphocyte count cutoffs on the outcomes

Outcomes	Influence of the ALC cutoffs
	Coefficient	95%CI	P value	Adjusted R2
HR for the association between lymphopenia and PFS	0.00055	-0.00025 to 0.00136	0.17	37.9%
HR for the association between lymphopenia and OS	0.00024	-0.00052 to 0.00099	0.49	7.5%

ALC: Absolute lymphocyte count; PFS: Progression-free survival; OS: Overall survival; HR: Hazard ratio; CI: Confidence interval.