World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Original Article

Volume 14, Number 4, August 2023, pages 234-245

Impact of Liver Metastasis on First-Line Immunotherapy in Stage IV Non-Small Cell Lung Cancer

Figure 1. CONSORT diagram for case selection. De-identified cases were released from National Cancer Database.

Figure 2. Impact of liver metastasis on overall survival in stage IV non-small cell lung cancer. Kaplan-Meier curves were compared according to the liver metastasis status. Median survival months and log-rank P-values are shown.

Figure 3. Immunotherapy improves overall survival of stage IV non-small cell lung cancer regardless of liver metastasis status. Kaplan-Meier curves were compared according to the immunotherapy status. Median survival months and log-rank P-values are shown.

Figure 4. Propensity score-matched cases with liver metastasis. Matched cases among those with liver metastasis were compared for overall survival.

Figure 5. Propensity score-matched cases without liver metastasis. Matched cases among those without liver metastasis were compared for overall survival.

**Table 1.** Clinical Characteristics of Eligible Cases
Factors	Immunotherapy	P-value
CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.
Total	18,497 (22)	64,982 (78)	83,479 (100)
Institution
Academic	6,024 (23)	20,348 (77)	26,372 (100)	0.0012
Other	12,473 (22)	44,634 (78)	57,107 (100)
Age
≥ 70	7,416 (20)	30,145 (80)	37,561 (100)	< 0.00001
< 70	11,081 (24)	34,837 (76)	45,918 (100)
Sex
Male	9,655 (22)	34,482 (78)	44,137 (100)	0.0373
Female	8,842 (22)	30,500 (78)	39,342 (100)
Race
White	15,560 (23)	52,594 (77)	68,154 (100)	< 0.00001
Other	2,937 (19)	12,388 (81)	15,325 (100)
CD score
0 - 1	16,150 (23)	54,740 (77)	70,890 (100)	< 0.00001
2 - 3	2,347 (19)	10,242 (81)	12,589 (100)
Year of diagnosis
2016	6,523 (16)	35,142 (84)	41,665 (100)	< 0.00001
2017	11,974 (29)	29,840 (71)	41,814 (100)
Histology
AdNOS	13,130 (25)	40,242 (75)	53,372 (100)	< 0.00001
Other	5,367 (18)	24,740 (82)	30,107 (100)
Clinical T stage
cT3-4	8,825 (22)	31,198 (78)	40,023 (100)	0.4715
Other	9,672 (22)	33,784 (78)	43,456 (100)
Clinical N stage
cN2-3	12,169 (24)	39,097 (76)	51,266 (100)	< 0.00001
Other	6,328 (20)	25,885 (80)	32,213 (100)
Clinical M stage
cM1B	12,604 (23)	41,983 (77)	54,587 (100)	< 0.00001
Other	5,893 (20)	22,999 (80)	28,892 (100)
Surgery
Yes	407 (19)	1,719 (81)	2,126 (100)	0.0007
No	18,090 (22)	63,263 (78)	81,353 (100)
Radiation
Yes	8,911 (23)	30,389 (77)	39,300 (100)	0.0007
No	9,586 (22)	34,593 (78)	44,179 (100)
Multi-agent chemotherapy
Yes	9,807 (27)	26,418 (73)	36,225 (100)	< 0.00001
No	8,690 (18)	38,564 (82)	47,254 (100)
Bone metastasis
Yes	8,187 (23)	26,701 (77)	34,888 (100)	< 0.00001
No	10,310 (21)	38,281 (79)	48,591 (100)
Brain metastasis
Yes	5,254 (21)	20,322 (79)	25,576 (100)	< 0.00001
No	13,243 (23)	44,660 (77)	57,903 (100)
Liver metastasis
Yes	2,944 (22)	10,650 (78)	13,594 (100)	0.1242
No	15,553 (22)	54,332 (78)	69,885 (100)

Table 1. Clinical Characteristics of Eligible Cases

Factors

Immunotherapy

P-value

Yes (%)

No (%)

Total (%)

CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.

Total

18,497 (22)

64,982 (78)

83,479 (100)

Institution

Academic

6,024 (23)

20,348 (77)

26,372 (100)

0.0012

Other

12,473 (22)

44,634 (78)

57,107 (100)

Age

≥ 70

7,416 (20)

30,145 (80)

37,561 (100)

< 0.00001

< 70

11,081 (24)

34,837 (76)

45,918 (100)

Sex

Male

9,655 (22)

34,482 (78)

44,137 (100)

0.0373

Female

8,842 (22)

30,500 (78)

39,342 (100)

Race

White

15,560 (23)

52,594 (77)

68,154 (100)

< 0.00001

Other

2,937 (19)

12,388 (81)

15,325 (100)

CD score

0 - 1

16,150 (23)

54,740 (77)

70,890 (100)

< 0.00001

2 - 3

2,347 (19)

10,242 (81)

12,589 (100)

Year of diagnosis

2016

6,523 (16)

35,142 (84)

41,665 (100)

< 0.00001

2017

11,974 (29)

29,840 (71)

41,814 (100)

Histology

AdNOS

13,130 (25)

40,242 (75)

53,372 (100)

< 0.00001

Other

5,367 (18)

24,740 (82)

30,107 (100)

Clinical T stage

cT3-4

8,825 (22)

31,198 (78)

40,023 (100)

0.4715

Other

9,672 (22)

33,784 (78)

43,456 (100)

Clinical N stage

cN2-3

12,169 (24)

39,097 (76)

51,266 (100)

< 0.00001

Other

6,328 (20)

25,885 (80)

32,213 (100)

Clinical M stage

cM1B

12,604 (23)

41,983 (77)

54,587 (100)

< 0.00001

Other

5,893 (20)

22,999 (80)

28,892 (100)

Surgery

Yes

407 (19)

1,719 (81)

2,126 (100)

0.0007

18,090 (22)

63,263 (78)

81,353 (100)

Radiation

Yes

8,911 (23)

30,389 (77)

39,300 (100)

0.0007

9,586 (22)

34,593 (78)

44,179 (100)

Multi-agent chemotherapy

Yes

9,807 (27)

26,418 (73)

36,225 (100)

< 0.00001

8,690 (18)

38,564 (82)

47,254 (100)

Bone metastasis

Yes

8,187 (23)

26,701 (77)

34,888 (100)

< 0.00001

10,310 (21)

38,281 (79)

48,591 (100)

Brain metastasis

Yes

5,254 (21)

20,322 (79)

25,576 (100)

< 0.00001

13,243 (23)

44,660 (77)

57,903 (100)

Liver metastasis

Yes

2,944 (22)

10,650 (78)

13,594 (100)

0.1242

15,553 (22)

54,332 (78)

69,885 (100)

**Table 2.** Patient Characteristics: Overall Population
Factors	Liver metastasis	P-value
CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.
Total	13,594 (16)	69,885 (84)	83,479 (100)
Institution
Academic	4,174 (16)	22,198 (84)	26,372 (100)	0.0151
Other	9,420 (16)	47,687 (84)	57,107 (100)
Age
≥ 70	5,828 (16)	31,733 (84)	37,561 (100)	< 0.00001
< 70	7,766 (17)	38,152 (83)	45,918 (100)
Sex
Male	7,341 (17)	36,796 (83)	44,137 (100)	0.0039
Female	6,253 (16)	33,089 (84)	39,342 (100)
Race
White	11,251 (17)	56,903 (83)	68,154 (100)	0.0002
Other	2,343 (15)	12,982 (85)	15,325 (100)
CD score
≥ 2	2,041 (16)	10,548 (84)	12,589 (100)	0.8129
0 - 1	11,553 (16)	59,337 (84)	70,890 (100)
Year of diagnosis
2016	6,635 (16)	35,030 (84)	41,665 (100)	0.0050
2017	6,959 (17)	34,855 (83)	41,814 (100)
Histology
AdNOS	8,266 (15)	45,106 (85)	53,372 (100)	< 0.00001
Other	5,328 (18)	24,779 (82)	30,107 (100)
Clinical T stage
T3-4	6,614 (17)	33,409 (83)	40,023 (100)	0.0701
Other	6,980 (16)	36,476 (84)	43,456 (100)
Clinical N stage
N2-3	9,267 (18)	41,999 (82)	51,266 (100)	< 0.00001
Other	4,327 (13)	27,886 (87)	32,213 (100)
Clinical M stage
cM1B	11,781 (22)	42,806 (78)	54,587 (100)	< 0.00001
Other	1,813 (6)	27,079 (94)	28,892 (100)
Surgery
Yes	160 (8)	1,966 (92)	2,126 (100)	< 0.00001
No	13,434 (17)	67,919 (83)	81,353 (100)
Radiation
Yes	5,973 (15)	33,327 (85)	39,300 (100)	< 0.00001
No	7,621 (17)	36,558 (83)	44,179 (100)
Multi-agent chemotherapy
Yes	7,806 (20)	30,437 (80)	38,243 (100)	< 0.00001
No	5,788 (13)	39,448 (87)	45,236 (100)
Bone metastasis
Yes	5,550 (17)	26,844 (83)	32,394 (100)	< 0.00001
No	8,044 (16)	43,041 (84)	51,085 (100)
Brain metastasis
Yes	4,044 (16)	21,532 (84)	25,576 (100)	0.0140
No	9,550 (16)	48,353 (84)	57,903 (100)

Table 2. Patient Characteristics: Overall Population

Factors

Liver metastasis

P-value

Yes (%)

No (%)

Total (%)

CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.

Total

13,594 (16)

69,885 (84)

83,479 (100)

Institution

Academic

4,174 (16)

22,198 (84)

26,372 (100)

0.0151

Other

9,420 (16)

47,687 (84)

57,107 (100)

Age

≥ 70

5,828 (16)

31,733 (84)

37,561 (100)

< 0.00001

< 70

7,766 (17)

38,152 (83)

45,918 (100)

Sex

Male

7,341 (17)

36,796 (83)

44,137 (100)

0.0039

Female

6,253 (16)

33,089 (84)

39,342 (100)

Race

White

11,251 (17)

56,903 (83)

68,154 (100)

0.0002

Other

2,343 (15)

12,982 (85)

15,325 (100)

CD score

≥ 2

2,041 (16)

10,548 (84)

12,589 (100)

0.8129

0 - 1

11,553 (16)

59,337 (84)

70,890 (100)

Year of diagnosis

2016

6,635 (16)

35,030 (84)

41,665 (100)

0.0050

2017

6,959 (17)

34,855 (83)

41,814 (100)

Histology

AdNOS

8,266 (15)

45,106 (85)

53,372 (100)

< 0.00001

Other

5,328 (18)

24,779 (82)

30,107 (100)

Clinical T stage

T3-4

6,614 (17)

33,409 (83)

40,023 (100)

0.0701

Other

6,980 (16)

36,476 (84)

43,456 (100)

Clinical N stage

N2-3

9,267 (18)

41,999 (82)

51,266 (100)

< 0.00001

Other

4,327 (13)

27,886 (87)

32,213 (100)

Clinical M stage

cM1B

11,781 (22)

42,806 (78)

54,587 (100)

< 0.00001

Other

1,813 (6)

27,079 (94)

28,892 (100)

Surgery

Yes

160 (8)

1,966 (92)

2,126 (100)

< 0.00001

13,434 (17)

67,919 (83)

81,353 (100)

Radiation

Yes

5,973 (15)

33,327 (85)

39,300 (100)

< 0.00001

7,621 (17)

36,558 (83)

44,179 (100)

Multi-agent chemotherapy

Yes

7,806 (20)

30,437 (80)

38,243 (100)

< 0.00001

5,788 (13)

39,448 (87)

45,236 (100)

Bone metastasis

Yes

5,550 (17)

26,844 (83)

32,394 (100)

< 0.00001

8,044 (16)

43,041 (84)

51,085 (100)

Brain metastasis

Yes

4,044 (16)

21,532 (84)

25,576 (100)

0.0140

9,550 (16)

48,353 (84)

57,903 (100)

**Table 3.** Patient Characteristics With or Without Liver Metastasis
	With liver metastasis (N = 13,594)	Without liver metastasis (N = 69,885)
IO: immunotherapy; CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.
Total	2,944 (22)	10,650 (78)		15,553 (22)	54,332 (78)
Institution
Academic	934 (22)	3,240 (78)	0.1749	5,090 (23)	17,108 (77)	0.0034
Other	2,010 (21)	7,410 (79)		10,463 (22)	37,224 (78)
Age
≥ 70	1,145 (20)	4,683 (80)	< 0.00001	6,271 (20)	25,462 (80)	< 0.00001
< 70	1,799 (23)	5,967 (77)		9,282 (24)	28,870 (76)
Sex
Male	1,528 (21)	5,813 (79)	0.0098	8,127 (22)	28,669 (78)	0.2588
Female	1,416 (23)	4,837 (77)		7,426 (22)	25,663 (78)
Race
White	2,498 (22)	8,753 (78)	0.0007	13,062 (23)	43,841 (77)	< 0.00001
Other	446 (19)	1,897 (81)		2,491 (19)	10,491 (81)
CD score
≥ 2	374 (18)	1,667 (82)	0.0001	1,973 (19)	8,575 (81)	< 0.00001
0 - 1	2,570 (22)	8,983 (78)		13,580 (23)	45,757 (77)
Year of diagnosis
2016	1,011 (15)	5,624 (85)	< 0.00001	5,512 (16)	29,518 (84)	< 0.00001
2017	1,933 (28)	5,026 (72)		10,041 (29)	24,814 (81)
Histology
AdNOS	1,988 (24)	6,278 (76)	< 0.00001	11,142 (25)	33,964 (75)	< 0.00001
Other	956 (18)	4,372 (82)		4,411 (18)	20,368 (82)
Clinical T stage
T3-4	1,432 (22)	5,182 (78)	0.9878	7,393 (22)	26,016 (78)	0.4421
Other	1,512 (22)	5,468 (78)		8,160 (22)	28,316 (78)
Clinical N stage
N2-3	2,121 (23)	7,146 (77)	< 0.00001	1,951 (76)	10,048 (24)	< 0.00001
Other	823 (19)	3,504 (81)		5,505 (20)	22,381 (80)
Clinical M stage
cM1B	2,587 (22)	9,194 (78)	0.0291	10,017 (23)	32,789 (77)	< 0.00001
Other	357 (20)	1,456 (80)		5,536 (20)	21,543 (80)
Surgery
Yes	33 (21)	127 (79)	0.75	374 (19)	1,592 (81)	0.0005
No	2,911 (22)	10,523 (78)		15,179 (22)	52,740 (78)
Radiation
Yes	1,339 (22)	4,634 (78)	0.0565	7,572 (23)	25,755 (77)	0.0048
No	1,605 (21)	6,016 (79)		7,981 (22)	28,577 (78)
Multi-agent chemotherapy
Yes	1,363 (17)	6,443 (83)	< 0.00001	8,226 (27)	22,211 (73)	< 0.00001
No	1,581 (27)	4,207 (73)		7,327 (19)	32,121 (81)
Bone metastasis
Yes	1,118 (20)	4,432 (80)	0.0004	6,361 (24)	20,483 (76)	< 0.00001
No	1,826 (23)	6,218 (73)		9,192 (21)	33,849 (79)
Brain metastasis
Yes	819 (20)	3,225 (80)	0.0097	4,435 (21)	17,097 (79)	< 0.00001
No	2,125 (22)	7,425 (80)		11,118 (23)	37,235 (77)

Table 3. Patient Characteristics With or Without Liver Metastasis

With liver metastasis (N = 13,594)

Without liver metastasis (N = 69,885)

IO (%)

No IO (%)

P-value

IO (%)

No IO (%)

P-value

IO: immunotherapy; CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.

Total

2,944 (22)

10,650 (78)

15,553 (22)

54,332 (78)

Institution

Academic

934 (22)

3,240 (78)

0.1749

5,090 (23)

17,108 (77)

0.0034

Other

2,010 (21)

7,410 (79)

10,463 (22)

37,224 (78)

Age

≥ 70

1,145 (20)

4,683 (80)

< 0.00001

6,271 (20)

25,462 (80)

< 0.00001

< 70

1,799 (23)

5,967 (77)

9,282 (24)

28,870 (76)

Sex

Male

1,528 (21)

5,813 (79)

0.0098

8,127 (22)

28,669 (78)

0.2588

Female

1,416 (23)

4,837 (77)

7,426 (22)

25,663 (78)

Race

White

2,498 (22)

8,753 (78)

0.0007

13,062 (23)

43,841 (77)

< 0.00001

Other

446 (19)

1,897 (81)

2,491 (19)

10,491 (81)

CD score

≥ 2

374 (18)

1,667 (82)

0.0001

1,973 (19)

8,575 (81)

< 0.00001

0 - 1

2,570 (22)

8,983 (78)

13,580 (23)

45,757 (77)

Year of diagnosis

2016

1,011 (15)

5,624 (85)

< 0.00001

5,512 (16)

29,518 (84)

< 0.00001

2017

1,933 (28)

5,026 (72)

10,041 (29)

24,814 (81)

Histology

AdNOS

1,988 (24)

6,278 (76)

< 0.00001

11,142 (25)

33,964 (75)

< 0.00001

Other

956 (18)

4,372 (82)

4,411 (18)

20,368 (82)

Clinical T stage

T3-4

1,432 (22)

5,182 (78)

0.9878

7,393 (22)

26,016 (78)

0.4421

Other

1,512 (22)

5,468 (78)

8,160 (22)

28,316 (78)

Clinical N stage

N2-3

2,121 (23)

7,146 (77)

< 0.00001

1,951 (76)

10,048 (24)

< 0.00001

Other

823 (19)

3,504 (81)

5,505 (20)

22,381 (80)

Clinical M stage

cM1B

2,587 (22)

9,194 (78)

0.0291

10,017 (23)

32,789 (77)

< 0.00001

Other

357 (20)

1,456 (80)

5,536 (20)

21,543 (80)

Surgery

Yes

33 (21)

127 (79)

0.75

374 (19)

1,592 (81)

0.0005

2,911 (22)

10,523 (78)

15,179 (22)

52,740 (78)

Radiation

Yes

1,339 (22)

4,634 (78)

0.0565

7,572 (23)

25,755 (77)

0.0048

1,605 (21)

6,016 (79)

7,981 (22)

28,577 (78)

Multi-agent chemotherapy

Yes

1,363 (17)

6,443 (83)

< 0.00001

8,226 (27)

22,211 (73)

< 0.00001

1,581 (27)

4,207 (73)

7,327 (19)

32,121 (81)

Bone metastasis

Yes

1,118 (20)

4,432 (80)

0.0004

6,361 (24)

20,483 (76)

< 0.00001

1,826 (23)

6,218 (73)

9,192 (21)

33,849 (79)

Brain metastasis

Yes

819 (20)

3,225 (80)

0.0097

4,435 (21)

17,097 (79)

< 0.00001

2,125 (22)

7,425 (80)

11,118 (23)

37,235 (77)

**Table 4.** Univariate and Multivariable Analyses of Overall Survival in Patients With Liver Metastasis
Factors	Univariate	Multivariate
HR: hazard ratio; CI: confidence interval; Ref: reference; CD: Charlson-Deyo; NOS: not otherwise specified.
Institution
Academic	0.84 (0.81 - 0.87)	0.85 (0.81 - 0.88)
Others (Ref)	< 0.0001	< 0.0001
Age
< 70	0.85 (0.82 - 0.88)	0.90 (0.87 - 0.94)
≥ 70 (Ref)	< 0.0001	< 0.0001
Sex
Female	0.84 (0.81 - 0.87)	0.83 (0.80 - 0.86)
Male (Ref)	< 0.0001	< 0.0001
Race
Others	0.85 (0.81 - 0.89)	0.84 (0.80 - 0.88)
White (Ref)	< 0.0001	<0.0001
CD score
0 - 1	0.76 (0.73 - 0.80)	0.79 (0.75 - 0.83)
≥ 2 (Ref)	< 0.0001	< 0.0001
Year of diagnosis
2017	0.98 (0.94 - 1.01)	1.00 (0.96 - 1.04)
2016 (Ref)	0.1784	0.9889
Histology
Adenocarcinoma NOS	0.84 (0.81 - 0.88)	0.85 (0.81 - 0.88)
Others (Ref)	< 0.0001	< 0.0001
Clinical T stage
Others	0.91 (0.87 - 0.94)	0.91 (0.88 - 0.95)
T3-4 (Ref)	< 0.0001	< 0.0001
Clinical N stage
Others	0.96 (0.92 - 1.00)	0.95 (0.91 - 0.99)
N2-3 (Ref)	0.0382	0.0099
Clinical M stage
Other	0.90 (0.85 - 0.95)	0.91 (0.86 - 0.96)
M1B (Ref)	< 0.0001	0.0004
Surgery
Yes	0.81 (0.68 - 0.95)	0.82 (0.69 - 0.98)
No (Ref)	0.0137	0.0252
Radiation
No	0.94 (0.91 - 0.98)	0.98 (0.93 - 1.02)
Yes (Ref)	0.0013	0.2554
Chemotherapy
Yes	0.70 (0.68 - 0.73)	0.69 (0.67 - 0.72)
No (Ref)	< 0.0001	< 0.0001
Immunotherapy
Yes	0.62 (0.59 - 0.65)	0.62 (0.60 - 0.65)
No (Ref)	< 0.0001	< 0.0001
Bone metastasis
No	0.83 (0.80 - 0.86)	0.81 (0.78 - 0.85)
Yes (Ref)	< 0.0001	< 0.0001
Brain metastasis
No	0.93 (0.89 - 0.96)	0.94 (0.89 - 0.98)
Yes (Ref)	0.0002	0.0031

Table 4. Univariate and Multivariable Analyses of Overall Survival in Patients With Liver Metastasis

Factors

Univariate

Multivariate

HR (95% CI); P value

HR: hazard ratio; CI: confidence interval; Ref: reference; CD: Charlson-Deyo; NOS: not otherwise specified.

Institution

Academic

0.84 (0.81 - 0.87)

0.85 (0.81 - 0.88)

Others (Ref)

< 0.0001

Age

< 70

0.85 (0.82 - 0.88)

0.90 (0.87 - 0.94)

≥ 70 (Ref)

< 0.0001

Sex

Female

0.84 (0.81 - 0.87)

0.83 (0.80 - 0.86)

Male (Ref)

< 0.0001

Race

Others

0.85 (0.81 - 0.89)

0.84 (0.80 - 0.88)

White (Ref)

< 0.0001

<0.0001

CD score

0 - 1

0.76 (0.73 - 0.80)

0.79 (0.75 - 0.83)

≥ 2 (Ref)

< 0.0001

Year of diagnosis

2017

0.98 (0.94 - 1.01)

1.00 (0.96 - 1.04)

2016 (Ref)

0.1784

0.9889

Histology

Adenocarcinoma NOS

0.84 (0.81 - 0.88)

0.85 (0.81 - 0.88)

Others (Ref)

< 0.0001

Clinical T stage

Others

0.91 (0.87 - 0.94)

0.91 (0.88 - 0.95)

T3-4 (Ref)

< 0.0001

Clinical N stage

Others

0.96 (0.92 - 1.00)

0.95 (0.91 - 0.99)

N2-3 (Ref)

0.0382

0.0099

Clinical M stage

Other

0.90 (0.85 - 0.95)

0.91 (0.86 - 0.96)

M1B (Ref)

< 0.0001

0.0004

Surgery

Yes

0.81 (0.68 - 0.95)

0.82 (0.69 - 0.98)

No (Ref)

0.0137

0.0252

Radiation

0.94 (0.91 - 0.98)

0.98 (0.93 - 1.02)

Yes (Ref)

0.0013

0.2554

Chemotherapy

Yes

0.70 (0.68 - 0.73)

0.69 (0.67 - 0.72)

No (Ref)

< 0.0001

Immunotherapy

Yes

0.62 (0.59 - 0.65)

0.62 (0.60 - 0.65)

No (Ref)

< 0.0001

Bone metastasis

0.83 (0.80 - 0.86)

0.81 (0.78 - 0.85)

Yes (Ref)

< 0.0001

Brain metastasis

0.93 (0.89 - 0.96)

0.94 (0.89 - 0.98)

Yes (Ref)

0.0002

0.0031

**Table 5.** Univariate and Multivariable Analyses of Overall Survival in Patients Without Liver Metastasis
Factors	Univariate	Multivariate
HR: hazard ratio; CI: confidence interval; Ref: reference; CD: Charlson-Deyo; NOS: not otherwise specified.
Institution
Academic	0.83 (0.82 - 0.85)	0.84 (0.83 - 0.86)
Others (Ref)	< 0.0001	< 0.0001
Age
< 70	0.76 (0.75 - 0.78)	0.81 (0.79 - 0.82)
≥ 70 (Ref)	< 0.0001	< 0.0001
Sex
Female	0.82 (0.81 - 0.84)	0.83 (0.81 - 0.84)
Male (Ref)	< 0.0001	< 0.0001
Race
Others	0.87 (0.85 - 0.89)	0.86 (0.84 - 0.88)
White (Ref)	< 0.0001	< 0.0001
CD score
0 - 1	0.72 (0.71 - 0.74)	0.75 (0.73 - 0.77)
≥ 2 (Ref)	< 0.0001	< 0.0001
Year of diagnosis
2017	0.93 (0.91 - 0.94)	0.95 (0.93 - 0.97)
2016 (Ref)	< 0.0001	< 0.0001
Histology
Adenocarcinoma NOS	0.81 (0.79 - 0.82)	0.82 (0.81 - 0.84)
Others (Ref)	< 0.0001	< 0.0001
Clinical T stage
Others	0.90 (0.88 - 0.91)	0.90 (0.89 - 0.92)
T3-4 (Ref)	< 0.0001	< 0.0001
Clinical N stage
Others	0.87 (0.85 - 0.88)	0.84 (0.83 - 0.86)
N2-3 (Ref)	< 0.0001	< 0.0001
Clinical M stage
Other	0.88 (0.86 - 0.89)	0.94 (0.92 - 0.96)
M1B (Ref)	< 0.0001	< 0.0001
Surgery
Yes	0.54 (0.51 - 0.57)	0.57 (0.54 - 0.61)
No (Ref)	< 0.0001	< 0.0001
Radiation
No	0.97 (0.95 - 0.98)	1.03 (1.01 - 1.05)
Yes (Ref)	< 0.0001	0.0035
Chemotherapy
Yes	0.72 (0.70 - 0.73)	0.71 (0.70 - 0.72)
No (Ref)	< 0.0001	< 0.0001
Immunotherapy
Yes	0.64 (0.62 - 0.65)	0.64 (0.63 - 0.65)
No (Ref)	< 0.0001	< 0.0001
Bone metastasis
No	0.78 (0.77 - 0.79)	0.78 (0.76 - 0.79)
Yes (Ref)	< 0.0001	< 0.0001
Brain metastasis
No	0.95 (0.94 - 0.97)	0.87 (0.85 - 0.88)
Yes (Ref)	< 0.0001	< 0.0001

Table 5. Univariate and Multivariable Analyses of Overall Survival in Patients Without Liver Metastasis

Factors

Univariate

Multivariate

HR (95% CI); P value

HR: hazard ratio; CI: confidence interval; Ref: reference; CD: Charlson-Deyo; NOS: not otherwise specified.

Institution

Academic

0.83 (0.82 - 0.85)

0.84 (0.83 - 0.86)

Others (Ref)

< 0.0001

Age

< 70

0.76 (0.75 - 0.78)

0.81 (0.79 - 0.82)

≥ 70 (Ref)

< 0.0001

Sex

Female

0.82 (0.81 - 0.84)

0.83 (0.81 - 0.84)

Male (Ref)

< 0.0001

Race

Others

0.87 (0.85 - 0.89)

0.86 (0.84 - 0.88)

White (Ref)

< 0.0001

CD score

0 - 1

0.72 (0.71 - 0.74)

0.75 (0.73 - 0.77)

≥ 2 (Ref)

< 0.0001

Year of diagnosis

2017

0.93 (0.91 - 0.94)

0.95 (0.93 - 0.97)

2016 (Ref)

< 0.0001

Histology

Adenocarcinoma NOS

0.81 (0.79 - 0.82)

0.82 (0.81 - 0.84)

Others (Ref)

< 0.0001

Clinical T stage

Others

0.90 (0.88 - 0.91)

0.90 (0.89 - 0.92)

T3-4 (Ref)

< 0.0001

Clinical N stage

Others

0.87 (0.85 - 0.88)

0.84 (0.83 - 0.86)

N2-3 (Ref)

< 0.0001

Clinical M stage

Other

0.88 (0.86 - 0.89)

0.94 (0.92 - 0.96)

M1B (Ref)

< 0.0001

Surgery

Yes

0.54 (0.51 - 0.57)

0.57 (0.54 - 0.61)

No (Ref)

< 0.0001

Radiation

0.97 (0.95 - 0.98)

1.03 (1.01 - 1.05)

Yes (Ref)

< 0.0001

0.0035

Chemotherapy

Yes

0.72 (0.70 - 0.73)

0.71 (0.70 - 0.72)

No (Ref)

< 0.0001

Immunotherapy

Yes

0.64 (0.62 - 0.65)

0.64 (0.63 - 0.65)

No (Ref)

< 0.0001

Bone metastasis

0.78 (0.77 - 0.79)

0.78 (0.76 - 0.79)

Yes (Ref)

< 0.0001

Brain metastasis

0.95 (0.94 - 0.97)

0.87 (0.85 - 0.88)

Yes (Ref)

< 0.0001

**Table 6.** Patient Characteristics With or Without Liver Metastasis (Propensity Score-Matched Cases)
	With liver metastasis (N = 5,888)	Without liver metastasis (N = 31,106)
IO: immunotherapy; CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.
Total	2,944 (50)	2,944 (50)		15,553 (50)	15,553 (50)
Institution
Academic	934 (50)	929 (50)	0.8886	5,090 (50)	5,094 (50)	0.9615
Other	2,010 (50)	2,015 (50)		10,463 (50)	10,459 (50)
Age
≥ 70	1,145 (50)	1,141 (50)	0.9148	6,271 (50)	6,263 (50)	0.9263
< 70	1,799 (50)	1,803 (50)		9,282 (50)	9,290 (50)
Sex
Male	1,528 (50)	1,526 (50)	0.9584	8,127 (50)	8,122 (50)	0.9547
Female	1,416 (50)	1,418 (50)		7,426 (50)	7,431 (50)
Race
White	2,498 (50)	2,500 (50)	0.9420	13,062 (50)	13,074 (50)	0.8527
Other	446 (50)	444 (50)		2,491 (50)	2,479 (50)
CD score
≥ 2	374 (51)	365 (49)	0.7233	1,973 (50)	1,958 (50)	0.7980
0 - 1	2,570 (50)	2,579 (50)		13,580 (50)	13,595 (50)
Year of diagnosis
2016	1,011 (36)	1,801 (64)	< 0.00001	5,512 (36)	9,986 (64)	< 0.00001
2017	1,933 (63)	1,143 (37)		10,041 (64)	5,567 (36)
Histology
AdNOS	1,988 (50)	1,994 (50)	0.8673	11,142 (50)	11,136 (50)	0.9399
Other	956 (50)	950 (50)		4,411 (50)	4,417 (50)
Clinical T stage
T3-4	1,432 (50)	1,427 (50)	0.8963	7,393 (50)	7,390 (50)	0.9728
Other	1,512 (50)	1,517 (50)		8,160 (50)	8,163 (50)
Clinical N stage
N2-3	2,121 (48)	2,311 (52)	< 0.00001	10,048 (46)	11,757 (54)	< 0.00001
Other	823 (57)	633 (43)		5,505 (59)	3,796 (41)
Clinical M stage
cM1B	2,587 (50)	2,603 (50)	0.5189	10,017 (50)	10,017 (50)	1.0000
Other	357 (51)	341 (49)		5,536 (50)	5,536 (50)
Surgery
Yes	2,911 (50)	2,897 (50)	0.1150	374 (32)	793 (68)	< 0.00001
No	33 (41)	47 (59)		15,179 (51)	14,760 (49)
Radiation
Yes	1,339 (37)	2,322 (63)	< 0.00001	7,572 (36)	13,354 (64)	< 0.00001
No	1,605 (72)	622 (38)		7,981 (78)	2,199 (22)
Multi-agent chemotherapy
Yes	1,581 (50)	1,571 (50)	0.7939	8,226 (50)	8,225 (50)	0.9909
No	1,363 (50)	1,373 (50)		7,327 (50)	7,328 (50)
Bone metastasis
Yes	1,826 (50)	1,822 (50)	0.9145	6,361 (50)	6,357 (50)	0.9632
No	1,118 (50)	1, 122 (50)		9,192 (50)	9,196 (50)
Brain metastasis
Yes	819 (28)	2,150 (72)	< 0.00001	4,435 (42)	10,512 (58)	< 0.00001
No	2,125 (73)	794 (28)		11,118 (69)	5,041 (31)

Table 6. Patient Characteristics With or Without Liver Metastasis (Propensity Score-Matched Cases)

With liver metastasis (N = 5,888)

Without liver metastasis (N = 31,106)

IO (%)

No IO (%)

P-value

IO (%)

No IO (%)

P-value

IO: immunotherapy; CD: Charlson-Deyo; AdNOS: adenocarcinoma not otherwise specified.

Total

2,944 (50)

15,553 (50)

Institution

Academic

934 (50)

929 (50)

0.8886

5,090 (50)

5,094 (50)

0.9615

Other

2,010 (50)

2,015 (50)

10,463 (50)

10,459 (50)

Age

≥ 70

1,145 (50)

1,141 (50)

0.9148

6,271 (50)

6,263 (50)

0.9263

< 70

1,799 (50)

1,803 (50)

9,282 (50)

9,290 (50)

Sex

Male

1,528 (50)

1,526 (50)

0.9584

8,127 (50)

8,122 (50)

0.9547

Female

1,416 (50)

1,418 (50)

7,426 (50)

7,431 (50)

Race

White

2,498 (50)

2,500 (50)

0.9420

13,062 (50)

13,074 (50)

0.8527

Other

446 (50)

444 (50)

2,491 (50)

2,479 (50)

CD score

≥ 2

374 (51)

365 (49)

0.7233

1,973 (50)

1,958 (50)

0.7980

0 - 1

2,570 (50)

2,579 (50)

13,580 (50)

13,595 (50)

Year of diagnosis

2016

1,011 (36)

1,801 (64)

< 0.00001

5,512 (36)

9,986 (64)

< 0.00001

2017

1,933 (63)

1,143 (37)

10,041 (64)

5,567 (36)

Histology

AdNOS

1,988 (50)

1,994 (50)

0.8673

11,142 (50)

11,136 (50)

0.9399

Other

956 (50)

950 (50)

4,411 (50)

4,417 (50)

Clinical T stage

T3-4

1,432 (50)

1,427 (50)

0.8963

7,393 (50)

7,390 (50)

0.9728

Other

1,512 (50)

1,517 (50)

8,160 (50)

8,163 (50)

Clinical N stage

N2-3

2,121 (48)

2,311 (52)

< 0.00001

10,048 (46)

11,757 (54)

< 0.00001

Other

823 (57)

633 (43)

5,505 (59)

3,796 (41)

Clinical M stage

cM1B

2,587 (50)

2,603 (50)

0.5189

10,017 (50)

1.0000

Other

357 (51)

341 (49)

5,536 (50)

Surgery

Yes

2,911 (50)

2,897 (50)

0.1150

374 (32)

793 (68)

< 0.00001

33 (41)

47 (59)

15,179 (51)

14,760 (49)

Radiation

Yes

1,339 (37)

2,322 (63)

< 0.00001

7,572 (36)

13,354 (64)

< 0.00001

1,605 (72)

622 (38)

7,981 (78)

2,199 (22)

Multi-agent chemotherapy

Yes

1,581 (50)

1,571 (50)

0.7939

8,226 (50)

8,225 (50)

0.9909

1,363 (50)

1,373 (50)

7,327 (50)

7,328 (50)

Bone metastasis

Yes

1,826 (50)

1,822 (50)

0.9145

6,361 (50)

6,357 (50)

0.9632

1,118 (50)

1, 122 (50)

9,192 (50)

9,196 (50)

Brain metastasis

Yes

819 (28)

2,150 (72)

< 0.00001

4,435 (42)

10,512 (58)

< 0.00001

2,125 (73)

794 (28)

11,118 (69)

5,041 (31)