The Incidence and Risk Analysis of Lung Cancer Development in Patients with Chronic Obstructive Pulmonary Disease: Possible Effectiveness of Annual CT-Screening

Figures & data

Figure 1 Study outline. We enrolled 253 stable COPD patients. Of the enrolled patients, eight were excluded from the analysis due to missing blood data, while two were excluded due to missing Asthma-COPD overlap (ACO) data. Eight patients were excluded because of a short follow-up period (less than six months). Additionally, nine patients were excluded because they had a history of lung cancer, and two patients were excluded because they had lung cancer at enrollment. Therefore, we analyzed 224 patients with stable COPD.

Table 1 Patient Characteristics

	Mean, Number, or Median (Interquartile Range)		Mean, Number, or Median (Interquartile Range)
Age (yr)	70.4 ± 8.4	TP (g/dl)	7.1 ± 0.5
Male/Female	214/10	T. Bil (mg/dl)	0.74 ± 0.31
BMI (kg/m^2)	22.7 ± 3.4	AST (U/l)	23.0 ± 8.3
Follow-up period (yr)	4.58 (2.91–6.25)	ALT (U/l)	21.6 ± 11.2
Lung cancer onset (%/yr)	1.85	LDH (U/l)	197.4 ± 40.3
Pack-years	50.7 ± 31.6	BUN (mg/dl)	16.9 ± 5.2
Current smoker (%)	12.9	Cr (mg/dl)	0.83 ± 0.24
Death (%)	8.0	eGFR (mL/min/1.73 m^2)	74.7 ± 19.7
Survival period (days)	1671 (1062 −2282)	UA (mg/dl)	5.9 ± 1.4
CAT (score)	9.6 ± 7.3	Na (mEq/l)	141.3 ± 2.3
LAA (score)	5.2 ± 4.1	K (mEq/l)	4.3 ± 0.4
Change in LAA (score)	0.0 (0.0–0.5)	Cl (mEq/l)	104.7 ± 2.6
Exacerbations (/yr)	0.00 (0.00–0.16)	WBC (/μL)	6384.4 ± 1960.7
GOLD I/II/III/IV	73/108/33/10	Neut (/μL)	3830.1 ± 1470.1
GOLD A/B/C/D	124/87/5/8	Lymph (/μL)	1816.9 ± 685.3
FVC (L)	3.25 ± 0.77	Mono (/μL)	392.8 ± 142.1
FEV1 (L)	1.88 ± 0.64	Eos (/μL)	170.0 (100.0–260.0)
%FEV1 (%)	68.4 ± 20.4	Baso (/μL)	41.7 ± 23.4
Changes in FEV1 (mL/yr)	−14.0 (−52.0–15.0)	RBC (10^6/μL)	4.57 ± 0.53
Changes in %FEV1 (%/yr)	0.112 (−1.177–1.375)	Hb (g/dl)	14.0 ± 1.6
Bronchodilator reversibility (%)	15.8	Ht (%)	42.9 ± 4.3
FeNO (ppb)	32.4 ± 24.2	Plt (104/μL)	22.2 ± 6.9
Use of LAMA (%)	23.2	IgE (IU/mL)	70.0 (23.8–236.0)
Use of LABA (%)	20.1	Fe (μg/dl)	93.9 ± 38.7
Use of ICS at enrollment (%)	11.2	Fer (ng/mL)	94.0 (44.0–169.8)
Use of ICS during follow-up period (%)	29.9	hsCRP (mg/dl)	0.09 (0.04–0.21)
ACO (%)	13.8	D-dimer (μg/dl)	0.83 (0.54–1.39)
Interstitial pneumonia (%)	7.6	Fib (mg/dl)	329.0 ± 77.5
CPFE (%)	5.8	5-HIAA (ng/mL)	5.8 (4.6–8.5)
		ACE (U/L)	12.8 (10.0–15.5)
		TARC (pg/mL)	384.9 ± 226.5
		Hcy (nmol/mL)	11.4 ± 5.1
		PRA (ng/mL/hr)	1.2 (0.7–2.1)

Note: Data are presented as mean ± SD, median (with ranges in parentheses, 25th–75th percentile) or n.

Abbreviations: BMI, body mass index; CAT, COPD assessment score; LAA, low attenuation area on CT scan; FeNO, fractional exhaled nitric oxide; LAMA, long-acting muscarinic antagonist; LABA, long-acting β2 agonist; ICS, inhaled corticosteroid; ACO, asthma-COPD overlap; CPFE, combined pulmonary fibrosis and emphysema; IgE, immunoglobulin E; Fer, ferritin; hsCRP, high-sensitivity C-reactive protein; Fib, fibrinogen; 5-HIAA, 5-hydroxyindoleacetic acid; TARC, thymus and activation-regulated chemokine; Hcy, homocysteine; PRA, plasma renin activity.

Table 2 Comparison of the Characteristics of Patients Who Developed Lung Cancer with Those Who Did Not

	Developed Lung Cancer (n = 19)	Did Not Develop Lung Cancer (n = 205)	P value
Age (yr)	72.4 ± 7.1	70.2 ± 8.5	0.2903
Male/Female	19/0	195/10	0.3246
BMI (kg/m^2)	21.9 ± 2.5	22.7 ± 3.5	0.3509
Follow-up period (yr)	4.39 (3.10–5.73)	4.61 (2.71–6.26)	0.7708
Pack-years	62.7 ± 31.0	49.6 ± 31.5	0.0836
Current smoker (%)	31.6	11.2	0.0226
Death (%)	36.8	5.4	<0.001
Survival period (days)	1602 (1133–2091)	1682 (991–2282)	0.7708
CAT (score)	10.4 ± 6.3	9.5 ± 7.3	0.6113
LAA (score)	7.4 ± 4.4	5.1 ± 4.1	0.0437
Change in LAA (score)	0.0 (−0.3–0.5)	0.0 (0.0–0.5)	0.7312
Exacerbations (/yr)	0.00 (0.00–0.25)	0.00 (0.00–0.16)	0.7128
GOLD I/II/III/IV	7/7/1/4	66/101/32/6	0.0021
GOLD A/B/C/D	7/11/0/1	117/76/5/7	0.2774
FVC (L)	3.27 ± 0.68	3.24 ± 0.78	0.8808
FEV1 (L)	1.78 ± 0.81	1.89 ± 0.62	0.4724
%FEV1 (%)	63.8 ± 26.9	68.8 ± 19.7	0.3116
Changes in FEV1 (mL/yr)	−21.0 (−50.5–8.8)	−10.5 (−52.3–25.8)	0.4773
Changes in %FEV1 (%/yr)	−0.323 (−1.132–1.407)	0.220 (−1.129–1.661)	0.6677
Bronchodilator reversibility (%)	7.1	16.4	0.7028
FeNO (ppb)	25.5 ± 11.7	33.0 ± 24.8	0.2814
Use of LAMA (%)	5.3	24.9	0.0835
Use of LABA (%)	10.5	21.0	0.3780
Use of ICS at enrollment (%)	5.3	11.7	0.7031
Use of ICS during follow-up period (%)	15.8	31.2	0.1599
ACO (%)	5.3	14.6	0.4843
Interstitial pneumonia (%)	15.8	6.8	0.1583
TP (g/dl)	7.1 ± 0.5	7.1 ± 0.5	0.7975
T. Bil (mg/dl)	0.74 ± 0.41	0.74 ± 0.30	0.9821
AST (U/l)	22.2 ± 12.5	23.1 ± 7.8	0.6260
ALT (U/l)	19.7 ± 16.0	21.8 ± 10.7	0.4446
LDH (U/l)	182.0 ± 27.7	198.9 ± 41.0	0.0809
BUN (mg/dl)	16.8 ± 5.0	16.9 ± 5.2	0.9465
Crea (mg/dl)	0.74 ± 0.12	0.84 ± 0.25	0.0995
eGFR (mL/min/1.73m^2)	80.5 ± 12.5	74.1 ± 20.1	0.1764
UA (mg/dl)	5.7 ± 1.7	5.9 ± 1.4	0.5096
Na (mEq/l)	140.7 ± 3.2	141.4 ± 2.2	0.2507
K (mEq/l)	4.3 ± 0.4	4.3 ± 0.4	0.6641
Cl (mEq/l)	103.5 ± 3.7	104.8 ± 2.5	0.9776
WBC (/μL)	6336.3 ± 1306.0	6388.9 ± 2013.2	0.9112
Neut (/μL)	4170.0 ± 982.2	3804.3 ± 1499.4	0.3543
Lymph (/μL)	1595.3 ± 770.5	1833.8 ± 677.6	0.1947
Mono (/μL)	390.7 ± 122.5	393.0 ± 143.8	0.9514
Eos (/μL)	80.0 (60.0–250.0)	170.0 (100.0–260.0)	0.0554
Baso (/μL)	28.0 ± 15.7	42.8 ± 23.5	0.0016
RBC (10^6/μL)	4.52 ± 0.42	4.58 ± 0.54	0.6126
Hb (g/dl)	14.0 ± 1.2	14.0 ± 1.6	0.8423
Ht (%)	42.5 ± 3.6	42.9 ± 4.3	0.7000
Plt (104/μL)	20.9 ± 5.6	22.4 ± 6.2	0.3176
IgE (IU/mL)	89.3 (30.9–221.0)	69.6 (23.4–242.0)	0.7387
Fe (μg/dl)	96.2 ± 31.8	93.7 ± 39.3	0.7947
Fer (ng/mL)	111.7 (61.0–149.5)	90.6 (43.5–173.5)	0.6470
hsCRP (mg/dl)	0.10 (0.04–0.34)	0.09 (0.04–0.21)	0.8805
D-dimer (μg/dl)	0.86 (0.53–1.59)	0.79 (0.54–1.36)	0.5744
Fib (mg/dl)	329.1 ± 49.6	329.0 ± 79.3	0.9946
5-HIAA (ng/mL)	5.3 (4.0–9.4)	6.0 (4.7–8.5)	0.3681
ACE (U/l)	11.2 (9.0–15.0)	12.8 (10.4–15.8)	0.2570
TARC (pg/mL)	397.9 ± 197.3	384.0 ± 228.8	0.8310
Hcy (nmol/mL)	10.8 ± 2.7	11.5 ± 5.3	0.5686
PRA (ng/mL/hr)	1.3 (0.6–1.4)	1.2 (0.7–2.3)	0.3651

Note: Data are presented as mean ± SD, median (with ranges in parentheses, 25th–75th percentile) or n.

Abbreviations: BMI, body mass index; CAT, COPD assessment score; LAA, low attenuation area on CT scan; FeNO, fractional exhaled nitric oxide; LAMA, long-acting muscarinic antagonist; LABA, long-acting β2 agonist; ICS, inhaled corticosteroid; ACO, asthma-COPD overlap; IgE, immunoglobulin E; Fer, ferritin; hsCRP, high-sensitivity C-reactive protein; Fib, fibrinogen; 5-HIAA, 5-hydroxyindoleacetic acid; TARC, thymus and activation-regulated chemokine; Hcy, homocysteine; PRA, plasma renin activity.

Figure 2 Survival curves. A survival curve analysis according to the Kaplan–Meier method showed that mortality was significantly increased in the lung cancer development group compared with the group that did not develop lung cancer.

Table 3 Characteristics of Patients Who Developed Lung Cancer

	Histology	Days Before Onset	Stage	Therapy	Outcome	Supplement
1. 61-yr M	Ad	41	pT1aN0M0 IA1	Ope	Survival
2. 66-yr M	Ad	1042	pT1bN0M0 IA2	Ope	Survival
3. 78-yr M	Ad	931	cT1aN0M0 IA1	RT	Survival
4. 65-yr M	Ad	247	cT3N2M0 IIIB	Chemo	Survival
5. 66-yr M	Ad	1133	cT1bN0M0 IA2	RT	Survival
6. 74-yr M	Ad	1918	cT1bN0M0 IA2	Ope	Survival	Complication of interstitial pneumonia
7. 76-yr M	Sq	181	pT1aN0M0 IA1	Ope	Survival
8. 67-yr M	Sq	392	pT1bN0M0 IA2	Ope	Survival	Complication of interstitial pneumonia
9. 67-yr M	Sq	929	pT1bN0M0 IA2	Ope	Survival
10. 78-yr M	Non-small	95	pT1bN0M0 IA2	Ope	Survival
11. 70-yr M	Small	317	cT3N2M0 IIIB	Chemo	Death (Lung cancer)
12. 68-yr M	Small	1019	cT3N2M0 шB	BSC	Death (Interstitial pneumonia)	Complication of interstitial pneumonia
13. 80-yr M	Clinical	941	cT1aN0M0 IA1	RT	Death (Unknown)
14. 77-yr M	Clinical	968	cT1aN0M0 IA1	RT	Death (Unknown)
15. 78-yr M	Clinical	217	cT2aN0M1a IVA	BSC	Death (Senility)	Due to poor pulmonary function, treatment could not be performed
16. 79-yr M	Clinical	643	cT2aN0M0 IB	BSC	Death (Lung cancer)	The patient did not want to be examined and treated
17. 86-yr M	Clinical	817	cT1aN0M0 IA1	BSC	Survival	The patient did not want to be examined and treated
18. 61-yr M	Clinical	1444	cT3N0M0 IIIB	BSC	Survival	Due to poor pulmonary function, treatment could not be administered
19. 77-yr M	Clinical	1500	cT1aN0M0 IA1	BSC	Death (Pancreatic cancer)	The patient did not want to be examined and treated

Abbreviations: Ad, adenocarcinoma; Sq, squamous cell carcinoma; Small, small cell carcinoma; Ope, operation; RT, radiation therapy; Chemo, chemotherapy; BSC, best supportive care.

Table 4 Univariate and Multivariate Logistic Regression Analyses for Discriminating the Subjects Who Developed Lung Cancer

Univariate Analysis	OR	95% CI	P
Age (increasing 1-age)	1.03	0.98–1.10	0.2717
LAA (increasing 1-score)	1.14	1.00–1.29	0.0493
Current smoker (vs non-smoker)	3.65	1.27–10.54	0.0253
GOLD II (vs I)	1.53	0.51–4.56	0.4453
GOLD III (vs I)	3.39	0.40–28.77	0.2625
GOLD IV (vs I)	0.16	0.04–0.70	0.0153
Multivariate Analysis	OR	95% CI	P
Age (increasing 1-age)	1.07	0.97–1.18	0.1097
LAA (increasing 1-score)	1.17	1.01–1.37	0.0399
Current smoker (vs non-smoker)	4.8	1.15–20.46	0.0416
GOLD II (vs I)	2.74	0.71–10.63	0.1435
GOLD III (vs I)	-	-	0.9986
GOLD IV (vs I)	0.38	0.05–2.66	0.3273

Abbreviation: LAA, low attenuation area on CT scan.