Impact of Combined Chronic Obstructive Pulmonary Disease Status and Systemic Inflammation on Outcome of Advanced NSCLC: Multicenter Retrospective Cohort Study

Figures & data

Table 1 Baseline Clinical Characteristics of the Study Patients

	Overall Patients (n=277) (n,%)	Non-COPD (n=194) (n,%)	COPD (n=83) (n,%)	p-value
Sex
Female	124 (44.8)	100 (51.5)	24 (28.9)	0.001
Age (year)	64.9±11.2	61.8±10.8	72.0±8.4	<0.001
Median survival time (months)	19.6 [15.5–23.7]	21.3 [16.7–25.8]	10.7 [7.2–14.1]	0.019
Stage				0.104
IIIB	20 (7.2)	11 (5.7)	9 (10.8)
IV	257 (92.8)	183 (94.3)	74 (89.2)
BMI (kg/m^2)	23.3±3.5	23.7±3.5	22.6±3.3	0.027
EGFR mutation	92 (34.5)* 267 tested	71 (38.0)* 187 tested	21 (26.2)* 80 tested	0.065
First-line treatment				0.064
Conventional chemotherapy	166 (59.9)	113 (58.3)	53 (63.8)
Targeted therapy	68 (24.5)	53 (27.3)	15 (18.1)
Supportive care only	33 (11.9)	18 (9.3)	15 (18.1)
Smoking				<0.001
Never smoker	149 (53.8)	119 (61.7)	30 (36.1)
Ever smoker	127 (45.8)	74 (38.3)	53 (63.9)
ECOG				0.001
0–1	236 (85.5)	174 (90.2)	62 (74.7)
2–3	40 (14.5)	19 (9.8)	21 (25.3)
Pathology				0.043
Non-squamous	246 (88.8)	177 (91.2)	69 (83.1)
Squamous	31 (11.2)	17 (8.8)	14 (16.9)
FEV1 (liter)	2.0±1.5	2.0±0.7	1.9±2.5	0.845
FEV1 (% predicted)	78.8±22.4	82.7±22.3	69.9±20.0	<0.001
FVC (liter)	2.7±2.0	2.5±0.9	3.0±3.3	0.195
FVC (% predicted)	77.7±21.8	76.9±21.3	79.5±23.1	0.381
FEV1/FVC (% predicted)	74.0±11.1	79.4±6.7	61.3±8.7	<0.001
DLCO (abs)	12.4±4.6	13.1±4.7	10.8±3.9	<0.001
DLCO (%)	70.2±20.0	71.7±19.7	66.8±20.3	0.079
NLR	4.07±3.49	4.05±3.72	4.13±2.92	0.841
PLR	189.6±86.1	189.3±87.2	190.2±84.0	0.940
CRP	3.74±0.42	3.55±0.49	4.13±0.81	0.259
Hemoglobin (g/dl)	13.0 [12.0–14.0]	13.0 [12.0–14.0]	13.0 [11.7–14.3]	0.400

Note: *Only patients who are tested were considered.

Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, c-reactive protein; BMI, body mass index; EGFR, epidermal growth factor receptor; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio.

Figure 1 Survival comparison of the patients with non-small cell lung cancer according to the presence of chronic obstructive pulmonary disease.

Figure 2 (A) Survival comparison between the high and low PLR groups (P< 0.001). (B) Survival comparison between the high and low NLR groups (P= 0.001). (C) Survival comparison between the high and low CRP groups (P< 0.001).

Abbreviation: PLR, platelet–lymphocyte ratio; NLR, neutrophil–lymphocyte ratio; CRP, c-reactive protein.

Table 2 Correlation Analysis Between Inflammatory Markers and Pulmonary Function Parameters

	PLR		NLR		CRP
	r	P	r	P	r	P
FVC (absolute)	−0.149	0.015	−0.105	0.080	−0.069	0.388
FVC (%predicted)	−0.192	0.002	−0.262	<0.001	−0.236	0.003
FEV1 (absolute)	0.101	0.098	−0.203	<0.001	−0.156	0.049
FEV1 (% predicted)	−0.094	0.126	−0.217	<0.001	−0.288	<0.001
FEV1/FVC	0.101	0.098	0.045	0.460	−0.048	0.545
DLCO (absolute)	−0.271	<0.001	−0.235	<0.001	−0.112	0.179
DLCO (% predicted)	−0.139	0.032	−0.152	0.016	−0.205	0.013
PLR	–	–	0.718	<0.001	0.187	0.022
NLR	0.718	<0.001	–	–	0.427	<0.001
CRP	0.187	0.022	0.427	<0.001	–	–

Note: P-value calculated using Spearman’s rho.

Abbreviations: CRP, c-reactive protein; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio.

Figure 3 (A) Survival comparison between the 4 COPD-PLR subgroups (P= 0.001). (B) Survival comparison between the 4 COPD-NLR subgroups (P= 0.001). (C) Survival comparison between the 4 COPD-CRP subgroups (P<0.001).

Table 3 Comparison of Clinical Characteristics Between COPD-PLR Subgroups

	Non-COPD, Low PLR (n=106) (n,%)	Non-COPD, High PLR (n=83) (n,%)	COPD, Low PLR (n=44) (n,%)	COPD, High PLR (n=34) (n,%)	p-value
Sex
Female	60 (56.6)	39 (47.0)	13 (29.5)	9 (26.5)	0.002
Age (year)	60.7±10.5	63±11.3	72.3±8.6	70.6±8.1	<0.001^bcde
Mean survival time (months) (mean±SE)	37.0±3.7	20.0±2.0	26.1±4.3	12.2±2.1	<0.001
Median survival time (95% CI)	32.9 [27.0–38.8]	15.0 [6.6–23.4]	14.5 [0–34.1]	8.2 [3.7–12.6]	<0.001
Stage					0.420
IIIB	7 (6.6)	4 (4.8)	5 (11.4)	4 (11.8)
IV	99 (93.4)	79 (95.2)	39 (88.6)	30 (88.2)
BMI (kg/m^2)	24.0±3.7	23.1±3.2	23.3±2.9	22.3±3.4	0.049
EGFR mutation	(n=105) 41 (39.0)	(n=77) 30 (39.0)	(n=42) 9 (21.4)	(n=33) 11 (33.3)	0.196
First line treatment
Conventional chemotherapy	60 (56.6)	50 (60.2)	30 (68.1)	22 (64.7)	0.057
Targeted therapy	26 (24.5)	27 (32.5)	7 (15.9)	7 (20.6)
Supportive care only	11 (10.4)	3 (3.6)	7 (15.9)	4 (11.8)
Smoking					<0.001
Never smoker	65 (61.3)	53 (64.6)	17 (38.6)	9 (26.5)
Ever smoker	41 (38.7)	29 (35.4)	27 (61.4)	25 (73.5)
ECOG					0.001
0–1	93 (87.7)	77 (93.9)	34 (77.3)	23 (67.6)
2–3	13 (12.3)	5 (6.1)	10 (22.7)	11 (32.4)
Pathology					0.087
Non-squamous	95 (89.6)	77 (92.8)	39 (88.6)	26 (76.5)
Squamous	11 (10.4)	6 (7.2)	5 (11.4)	8 (23.5)
FEV1 (liter)	2.1±0.7	1.9±0.7	2.3±3.3	1.6±0.6	0.104
FEV1 (% predicted)	85.3±22.3	80.2±22.1	69.8±15.9	70.1±21.7	<0.001^bc
FVC (liter)	2.6±0.9	2.4±0.9	2.8±1.3	3.4±5.0	0.106
FVC (% predicted)	80.6±20.7	73.1±21.5	80.8±20.0	77.7±25.9	0.089
FEV1/FVC (% predicted)	78.7±6.4	80.0±6.7	60.9±9.3	63.1±6.5	<0.001^bcde
DLCO (abs)	13.9±4.6 (n=95)	12.2±4.7 (n=76)	11.5±4.1 (n=38)	10.4±3.4 (n=31)	0.001^c
DLCO (%)	73.5±18.4	69.4±21.4	67.0±21.1	67.2±20.0	0.229
NLR	2.5±1.4	5.6±3.8	2.7±1.2	5.5±2.4	<0.001^acdf
PLR	130.8±32.8	264.0±77.3	127.2±29.1	271.8±56.4	<0.001^acdf

Notes: Post-hoc pairwise comparison: ^aNon-COPD, low PLR vs Non-COPD, high PLR, ^bNon-COPD, low PLR vs COPD, low PLR, ^cNon-COPD, low PLR vs COPD, high PLR, ^dNon-COPD, high PLR vs COPD, low PLR, ^eNon-COPD, high PLR vs COPD, high PLR, ^fCOPD, low PLR vs COPD, high PLR, P-value significance cutoff=0.0125.

Abbreviations: COPD, chronic obstructive pulmonary disease; BMI, body mass index; EGFR, epidermal growth factor receptor; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio; SE, standard error.

Table 4 Associations of Clinical Variables Affecting Overall Survival of the Patients

Characteristics	Univariate	Multivariate (Model 1)			Multivariate (Model 2)
	P	P	HR	95% CI	P	HR	95% CI
Age	0.012	0.574	1.005	0.987–1.024	0.568	1.005	0.987–1.024
Male/Female	0.047	0.041	1.477	1.016–2.148	0.028	1.234	1.023–1.489
Histology (non-squamous/squamous)	0.173	-			-
EGFR mutation (mutant/wild-type)	0.001	0.001	0.501	0.338–0.740	0.001	0.518	0.353–0.761
ECOG (0–1/≥2)	0.022	0.104	1.587	0.909–2.772	0.127	1.513	0.888–2.578
First line treatment (active anticancer treatment/supportive care only)	<0.001	0.002	2.937	1.497–5.762	<0.001	4.033	2.276–7.147
Hemoglobin	0.001	0.004	0.846	0.756–0.947	0.001	0.824	0.739–0.919
BMI	0.807	-			-
COPD-PLR subtype*	<0.001	0.048
Non-COPD, PLR low			1
Non-COPD, PLR high		0.034	1.577	1.034–2.404
COPD, PLR low		0.451	1.229	0.719–2.102
COPD, PLR high		0.012	2.066	1.175–3.633
COPD-NLR subtype*	0.001				0.096
Non-COPD, NLR low						1
Non-COPD, NLR high					0.018	1.654	1.089–2.512
COPD, NLR low					0.114	1.511	0.906–2.519
COPD, NLR high					0.103	1.582	0.911–2.746

Notes: *For comparison of HR, the reference group is Non-COPD, PLR low for the COPD, PLR subtypes, and Non-COPD, NLR low for the COPD-NLR subtypes.

Abbreviations: COPD, chronic obstructive pulmonary disease; BMI, body mass index; EGFR, epidermal growth factor receptor; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide; HR, hazard ratio; CI, confidence interval; NLR, neutrophil–lymphocyte ratio; PLR, platelet–lymphocyte ratio.