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 http://www.wjon.org

Original Article

Volume 9, Number 1, February 2018, pages 13-20

Lymphocyte to Monocyte Ratio and Modified Glasgow Prognostic Score Predict Prognosis of Lung Adenocarcinoma Without Driver Mutation

Figure 1. Hazard ratios and cutoff values of NLR and LMR for overall survival. (a) NLR and (b) LMR. The vertical line designates the optimal cutoff values with the most significant (log-rank test) split. The plots were determined using the R software-based biostatistical tool, Cutoff Finder. LMR: lymphocyte to monocyte ratio; NLR: neutrophil to lymphocyte ratio; HR: hazard ratio; OS: overall survival.

Figure 2. Kaplan-Meier curves of overall survival according to LMR and mGPS. (a) LMR. (b) mGPS. LMR: lymphocyte to monocyte ratio; mGPS: modified Glasgow prognostic score.

Figure 3. Kaplan-Meier curves of overall survival according to combination of LMR and mGPS. LMR: lymphocyte to monocyte ratio; mGPS: modified Glasgow prognostic score.

**Table 1.** Backgrounds and Laboratory Data at the Start of First-Line Chemotherapy
	All, N = 159	LMR	mGPS
^aMean ± SD. ^bMann-Whitney test. ^cFisher’s exact test. Alb: albumin; ALP: alkaline phosphatase; BMI: body mass index; Ccr: creatinine clearance; CRP: C-reactive protein; ECOG PS: Eastern Cooperative Oncology Group performance status; Hb: hemoglobin; LDH: lactate dehydrogenase; LMR: lymphocyte to monocyte ratio; Lym: lymphocyte; Mono: monocyte; mGPS: modified Glasgow prognostic score; Neu: neutrophil; NLR: neutrophil to lymphocyte ratio; SD: standard deviation.
Background
Age (years)^a	67.2 ± 9.0	67.9 ± 9.6	67.0 ± 8.9	0.45^b	67.0 ± 9.2	67.8 ± 8.4	0.54^b
Sex (N), male/female	114/45	20/4	94/41	0.22^c	83/37	31/8	0.31^c
Stage (N), IIIB/IV	30/129	1/23	29/106	0.049^c	27/93	3/36	0.057^c
ECOG PS (N), 0 - 1/2/3	124/27/8	10/8/6	114/19/2	< 0.01^c	103/15/2	21/12/6	< 0.01^c
BMI^a	21.9 ± 3.1	20.2 ± 3.4	22.2 ± 3.0	0.01^b	22.4 ± 2.8	20.4 ± 3.5	< 0.01^b
Laboratory data^a
Neu (cells/µL)	6,004 ± 3,924	10,359 ± 7,068	5,229 ± 2,362	< 0.01^b	5,168 ± 2,398	8,575 ± 6,084	< 0.01^b
Lym (cells/µL)	1,673 ± 741	1,235 ± 1,136	1,751 ± 621	< 0.01^b	1,738 ± 654	1,473 ± 943	< 0.01^b
Mono (cells/µL)	554 ± 371	1,026 ± 714	470 ± 166	< 0.01^b	486 ± 183	764 ± 638	0.02^b
NLR	4.33 ± 4.48	10.22 ± 8.67	3.28 ± 1.85	< 0.01^b	3.38 ± 2.15	7.25 ± 7.57	< 0.01^b
LMR	3.58 ± 1.78	1.28 ± 0.48	3.99 ±1.60	< 0.01^b	3.91 ± 1.69	2.57 ± 1.69	< 0.01^b
Hb (g/dL)	12.8 ± 1.6	12.0 ± 1.7	12.9 ±1.5	< 0.01^b	13.0 ± 1.5	12.1 ± 1.6	< 0.01^b
Sodium (mEq/L)	138.7 ± 3.6	136.4 ± 5.0	139.1 ± 3.1	< 0.01^b	139.3 ± 3.1	137.1 ± 4.4	< 0.01^b
Ccr (mL/min)	60.9 ± 16.9	59.5 ± 16.1	61.1 ± 17.1	0.65	61.8 ± 16.1	58.0 ± 19.3	0.13^b
LDH (IU/L)	301 ± 456	396 ± 717	284 ± 394	0.07	257 ± 273	435 ± 779	0.10^b
ALP (IU/L)	317 ± 256	449 ± 452	293 ± 196	0.02	292 ± 257	392 ± 239	< 0.01^b
Alb (g/dL)	3.6 ± 0.5	3.0 ± 0.5	3.7 ± 0.5	< 0.01^b	3.8 ± 0.4	2.9 ± 0.4	< 0.01^b
CRP (mg/dL)	2.6 ± 4.0	6.1 ± 5.3	2.0 ± 3.4	< 0.01^b	1.6 ± 3.3	5.8 ± 4.5	< 0.01^b

Table 1. Backgrounds and Laboratory Data at the Start of First-Line Chemotherapy

All, N = 159

LMR

mGPS

< 1.97, N = 24

≥ 1.97, N = 135

0 - 1, N = 120

2, N = 39

^aMean ± SD. ^bMann-Whitney test. ^cFisher’s exact test. Alb: albumin; ALP: alkaline phosphatase; BMI: body mass index; Ccr: creatinine clearance; CRP: C-reactive protein; ECOG PS: Eastern Cooperative Oncology Group performance status; Hb: hemoglobin; LDH: lactate dehydrogenase; LMR: lymphocyte to monocyte ratio; Lym: lymphocyte; Mono: monocyte; mGPS: modified Glasgow prognostic score; Neu: neutrophil; NLR: neutrophil to lymphocyte ratio; SD: standard deviation.

Background

Age (years)^a

67.2 ± 9.0

67.9 ± 9.6

67.0 ± 8.9

0.45^b

67.0 ± 9.2

67.8 ± 8.4

0.54^b

Sex (N), male/female

114/45

20/4

94/41

0.22^c

83/37

31/8

0.31^c

Stage (N), IIIB/IV

30/129

1/23

29/106

0.049^c

27/93

3/36

0.057^c

ECOG PS (N), 0 - 1/2/3

124/27/8

10/8/6

114/19/2

< 0.01^c

103/15/2

21/12/6

< 0.01^c

BMI^a

21.9 ± 3.1

20.2 ± 3.4

22.2 ± 3.0

0.01^b

22.4 ± 2.8

20.4 ± 3.5

< 0.01^b

Laboratory data^a

Neu (cells/µL)

6,004 ± 3,924

10,359 ± 7,068

5,229 ± 2,362

< 0.01^b

5,168 ± 2,398

8,575 ± 6,084

< 0.01^b

Lym (cells/µL)

1,673 ± 741

1,235 ± 1,136

1,751 ± 621

< 0.01^b

1,738 ± 654

1,473 ± 943

< 0.01^b

Mono (cells/µL)

554 ± 371

1,026 ± 714

470 ± 166

< 0.01^b

486 ± 183

764 ± 638

0.02^b

NLR

4.33 ± 4.48

10.22 ± 8.67

3.28 ± 1.85

< 0.01^b

3.38 ± 2.15

7.25 ± 7.57

< 0.01^b

LMR

3.58 ± 1.78

1.28 ± 0.48

3.99 ±1.60

< 0.01^b

3.91 ± 1.69

2.57 ± 1.69

< 0.01^b

Hb (g/dL)

12.8 ± 1.6

12.0 ± 1.7

12.9 ±1.5

< 0.01^b

13.0 ± 1.5

12.1 ± 1.6

< 0.01^b

Sodium (mEq/L)

138.7 ± 3.6

136.4 ± 5.0

139.1 ± 3.1

< 0.01^b

139.3 ± 3.1

137.1 ± 4.4

< 0.01^b

Ccr (mL/min)

60.9 ± 16.9

59.5 ± 16.1

61.1 ± 17.1

0.65

61.8 ± 16.1

58.0 ± 19.3

0.13^b

LDH (IU/L)

301 ± 456

396 ± 717

284 ± 394

0.07

257 ± 273

435 ± 779

0.10^b

ALP (IU/L)

317 ± 256

449 ± 452

293 ± 196

0.02

292 ± 257

392 ± 239

< 0.01^b

Alb (g/dL)

3.6 ± 0.5

3.0 ± 0.5

3.7 ± 0.5

< 0.01^b

3.8 ± 0.4

2.9 ± 0.4

< 0.01^b

CRP (mg/dL)

2.6 ± 4.0

6.1 ± 5.3

2.0 ± 3.4

< 0.01^b

1.6 ± 3.3

5.8 ± 4.5

< 0.01^b

**Table 2.** Treatment and Efficacy
	All, N = 159	LMR	mGPS
^aFisher’s exact test. ^bLog-rank test. Bev: bevacizumab; CBDCA: carboplatin; CDDP: cisplatin; CI: confidence interval; DCR: disease control rate; ICI: immuno-checkpoint inhibitor; LMR: lymphocyte to monocyte ratio; mGPS: modified Glasgow prognostic score; PEM: pemetrexed; PFS: progression-free survival; RR: response rate; TRT: thoracic radiotherapy.
First-line regimen
Single or combination (N)
Single/combination	4/155	0/24	4/131	1.00^a	4/116	0/39	0.57^a
Platinum-based (N)
CDDP/CBDCA	52/103	8/16	44/87	1.00^a	43/73	9/30	0.12^a
PEM-containing (N)	77	13	64	0.66^a	59	18	0.85^a
Bev-containing (N)	32	4	28	0.79^a	23	9	0.65^a
Concurrent TRT (N)	8	0	8	0.61^a	6	2	1.00^a
First-line response
RR (%) (95% CI)	40.9 (33.2 - 48.9)	8.3 (1.0 - 27.0)	46.7 (38.0 - 55.4)	< 0.01^a	45.0 (35.9 - 54.3)	28.2 (15.0 - 44.9)	0.09^a
DCR (%) (95% CI)	69.8 (62.0 - 76.8)	33.3 (15.6 - 55.3)	76.3 (68.2 - 83.2)	< 0.01^a	76.7 (68.1 - 83.9)	48.7 (32.4 - 65.2)	< 0.01^a
PFS (months) (95% CI)	5.4 (4.6 - 6.3)	2.7 (1.0 - 3.7)	5.7 (5.3 - 6.6)	< 0.01^b	5.7 (5.2 - 6.8)	3.1 (1.6 - 5.3)	0.01^b
Second or further line (N)	96	5	91	< 0.01^a	84	12	< 0.01^a
ICI (N)	20	1	19	0.31^a	18	2	0.16^a

Table 2. Treatment and Efficacy

All, N = 159

LMR

mGPS

< 1.97, N = 24

≥ 1.97, N = 135

0 - 1, N = 120

2, N = 39

^aFisher’s exact test. ^bLog-rank test. Bev: bevacizumab; CBDCA: carboplatin; CDDP: cisplatin; CI: confidence interval; DCR: disease control rate; ICI: immuno-checkpoint inhibitor; LMR: lymphocyte to monocyte ratio; mGPS: modified Glasgow prognostic score; PEM: pemetrexed; PFS: progression-free survival; RR: response rate; TRT: thoracic radiotherapy.

First-line regimen

Single or combination (N)

Single/combination

4/155

0/24

4/131

1.00^a

4/116

0/39

0.57^a

Platinum-based (N)

CDDP/CBDCA

52/103

8/16

44/87

1.00^a

43/73

9/30

0.12^a

PEM-containing (N)

0.66^a

0.85^a

Bev-containing (N)

0.79^a

0.65^a

Concurrent TRT (N)

0.61^a

1.00^a

First-line response

RR (%) (95% CI)

40.9 (33.2 - 48.9)

8.3 (1.0 - 27.0)

46.7 (38.0 - 55.4)

< 0.01^a

45.0 (35.9 - 54.3)

28.2 (15.0 - 44.9)

0.09^a

DCR (%) (95% CI)

69.8 (62.0 - 76.8)

33.3 (15.6 - 55.3)

76.3 (68.2 - 83.2)

< 0.01^a

76.7 (68.1 - 83.9)

48.7 (32.4 - 65.2)

< 0.01^a

PFS (months) (95% CI)

5.4 (4.6 - 6.3)

2.7 (1.0 - 3.7)

5.7 (5.3 - 6.6)

< 0.01^b

5.7 (5.2 - 6.8)

3.1 (1.6 - 5.3)

0.01^b

Second or further line (N)

< 0.01^a

ICI (N)

0.31^a

0.16^a

**Table 3.** Univariate and Multivariate Cox Proportional Hazard Analysis of Factors Associated With Overall Survival
	Univariate	Multivariate
ALP: alkaline phosphatase; BMI: body mass index; CI: confidence interval; Ccr: creatinine clearance; CS: current smoker; ECOG PS: Eastern Cooperative Oncology Group performance status; Ex: ex-smoker; HR: hazard ratio; LDH: lactate dehydrogenase; mGPS: modified Glasgow prognostic score; LMR: lymphocyte to monocyte ratio; NLR: neutrophil to lymphocyte ratio; NS: non-smoker.
Age (years), < 75 vs. ≥ 75	1.47	0.97 - 2.23	0.07	1.21	0.78 - 1.89	0.39
Sex, female vs. male	1.50	0.99 - 2.26	0.054	1.13	0.73 - 1.73	0.59
Stage IIIB vs. IV	1.10	0.68 - 1.76	0.70
ECOG PS, 0 - 1 vs. 2 - 4	4.77	3.07 - 7.40	< 0.01	3.43	2.12 - 5.53	< 0.01
BMI, ≥ 18.5 vs. < 18.5	0.98	0.92 - 1.04	0.45
Smoking status, NS, Ex vs. CS	1.14	0.80 - 1.64	0.47
Hemoglobin (g/dL)	0.94	0.83 - 1.05	0.28
Ccr (mL/min) (/10)	0.92	0.82 - 1.03	0.15
Sodium (mEq/L) (/10)	0.61	0.42 - 0.90	0.01	1.28	0.78 - 2.10	0.33
LDH (IU/L) (/100)	1.03	0.99 - 1.06	0.15
ALP (IU/L) (/100)	1.06	0.99 - 1.13	0.08	1.00	0.92 - 1.09	0.99
NLR, < 4.05 vs. ≥ 4.05	2.17	1.50 - 3.13	< 0.01	1.09	0.67 - 1.78	0.72
LMR, < 1.97 vs. ≥ 1.97	0.22	0.14 - 0.36	< 0.01	0.39	0.21 - 0.72	< 0.01
mGPS, 0,1 vs. 2	2.60	1.73 - 3.90	< 0.01	1.95	1.20 - 3.16	< 0.01

Table 3. Univariate and Multivariate Cox Proportional Hazard Analysis of Factors Associated With Overall Survival

Univariate

Multivariate

95% CI

ALP: alkaline phosphatase; BMI: body mass index; CI: confidence interval; Ccr: creatinine clearance; CS: current smoker; ECOG PS: Eastern Cooperative Oncology Group performance status; Ex: ex-smoker; HR: hazard ratio; LDH: lactate dehydrogenase; mGPS: modified Glasgow prognostic score; LMR: lymphocyte to monocyte ratio; NLR: neutrophil to lymphocyte ratio; NS: non-smoker.

Age (years), < 75 vs. ≥ 75

1.47

0.97 - 2.23

0.07

1.21

0.78 - 1.89

0.39

Sex, female vs. male

1.50

0.99 - 2.26

0.054

1.13

0.73 - 1.73

0.59

Stage IIIB vs. IV

1.10

0.68 - 1.76

0.70

ECOG PS, 0 - 1 vs. 2 - 4

4.77

3.07 - 7.40

< 0.01

3.43

2.12 - 5.53

< 0.01

BMI, ≥ 18.5 vs. < 18.5

0.98

0.92 - 1.04

0.45

Smoking status, NS, Ex vs. CS

1.14

0.80 - 1.64

0.47

Hemoglobin (g/dL)

0.94

0.83 - 1.05

0.28

Ccr (mL/min) (/10)

0.92

0.82 - 1.03

0.15

Sodium (mEq/L) (/10)

0.61

0.42 - 0.90

0.01

1.28

0.78 - 2.10

0.33

LDH (IU/L) (/100)

1.03

0.99 - 1.06

0.15

ALP (IU/L) (/100)

1.06

0.99 - 1.13

0.08

1.00

0.92 - 1.09

0.99

NLR, < 4.05 vs. ≥ 4.05

2.17

1.50 - 3.13

< 0.01

1.09

0.67 - 1.78

0.72

LMR, < 1.97 vs. ≥ 1.97

0.22

0.14 - 0.36

< 0.01

0.39

0.21 - 0.72

< 0.01

mGPS, 0,1 vs. 2

2.60

1.73 - 3.90

< 0.01

1.95

1.20 - 3.16

< 0.01

**Table 4.** Cox Proportional Hazard Analysis of Overall Survival According to Combination of LMR and mGPS
	HR	95% CI	P
Adjusted for age, sex, ECOG PS, sodium, ALP and NLR. CI: confidence interval; HR: hazard ratio; mGPS: modified Glasgow prognostic score; LMR: lymphocyte to monocyte ratio.
LMR ≥ 1.97 + mGPS 0 - 1	1
LMR < 1.97 or mGPS 2	1.65	0.96 - 2.83	0.07
LMR < 1.97 + mGPS 2	5.98	2.64 - 13.5	< 0.01

Table 4. Cox Proportional Hazard Analysis of Overall Survival According to Combination of LMR and mGPS

95% CI

Adjusted for age, sex, ECOG PS, sodium, ALP and NLR. CI: confidence interval; HR: hazard ratio; mGPS: modified Glasgow prognostic score; LMR: lymphocyte to monocyte ratio.

LMR ≥ 1.97 + mGPS 0 - 1

LMR < 1.97 or mGPS 2

1.65

0.96 - 2.83

0.07

LMR < 1.97 + mGPS 2

5.98

2.64 - 13.5

< 0.01

**Table 5.** Review of Previous Studies of LMR as a Prognostic Factor for Advanced NSCLC [13, 26-28]
Author (year)	Country	N	Patient treatment	Cut-off	Multivariate analyses
Ad: adenocarcinoma; CI: confidence interval; EGFR: epidermal growth factor receptor; HR: hazard ratio; LMR: lymphocyte to monocyte ratio; mt: mutation; NA: not assessed; NSCLC: non-small cell lung cancer; PFS: progression-free survival; OS: overall survival; TKI: tyrosine kinase inhibitor.
Lin et al (2014) [13]	China	370	Stage IIIB or IV, platinum-based doublet	4.56	0.530 (0.409 - 0.687)	< 0.001	0.660 (0.512 - 0.851)	0.001
Chen et al (2015) [28]	Taiwan	253	EGFR mt (+) first-line EGFR-TKIs	3.29	2.36 (1.66 - 3.35)	< 0.001	1.71 (1.14 - 2.56)	0.009
Chang et al (2017) [27]	Taiwan	490	Stage IV	3.1	1.844 (1.212 - 1.837)	< 0.001	NA	NA
Our (2017) [26]	Japan	152	EGFR mt (+), EGFR-TKIs	5.09	0.88 (0.76 - 1.01)	0.07	1.00 (0.90 - 1.12)	0.99
Our	Japan	159	Stage IIIB or IV, Ad, platinum-based	1.97	0.39 (0.21 - 0.72)	< 0.01	NA	NA

Table 5. Review of Previous Studies of LMR as a Prognostic Factor for Advanced NSCLC [13, 26-28]

Author (year)

Country

Patient treatment

Cut-off

Multivariate analyses

PFS

HR (95% CI)

Ad: adenocarcinoma; CI: confidence interval; EGFR: epidermal growth factor receptor; HR: hazard ratio; LMR: lymphocyte to monocyte ratio; mt: mutation; NA: not assessed; NSCLC: non-small cell lung cancer; PFS: progression-free survival; OS: overall survival; TKI: tyrosine kinase inhibitor.

Lin et al (2014) [13]

China

370

Stage IIIB or IV, platinum-based doublet

4.56

0.530 (0.409 - 0.687)

< 0.001

0.660 (0.512 - 0.851)

0.001

Chen et al (2015) [28]

Taiwan

253

EGFR mt (+) first-line EGFR-TKIs

3.29

2.36 (1.66 - 3.35)

< 0.001

1.71 (1.14 - 2.56)

0.009

Chang et al (2017) [27]

Taiwan

490

Stage IV

3.1

1.844 (1.212 - 1.837)

< 0.001

Our (2017) [26]

Japan

152

EGFR mt (+), EGFR-TKIs

5.09

0.88 (0.76 - 1.01)

0.07

1.00 (0.90 - 1.12)

0.99

Our

Japan

159

Stage IIIB or IV, Ad, platinum-based

1.97

0.39 (0.21 - 0.72)

< 0.01

**Table 6.** Review of Previous Studies of GPS as a Prognostic Factor for Advanced NSCLC [16, 29-34]
Author (year)	Country	N	Patient treatment	Variables	OS	PFS
Ad: adenocarcinoma; CDDP: cisplatin; CI: confidence interval; ES-SCLC: extensive stage small cell lung cancer; GPS: Glasgow prognostic score; HR: hazard ratio; mGPS, modified Glasgow prognostic score; NA: not assessed; ND: not described; NSCLC: non-small cell lung cancer; OS: overall survival; PFS: progression-free survival.
Forrest et al (2004) [29]	UK	109	Inoperable, platinum-based chemotherapy	GPS	1.88 (1.25 - 2.84)	0.002	NA	NA
Meek et al (2010) [31]	UK	56	Inoperable	mGPS	ND	< 0.001	NA	NA
Leung et al (2012) [16]	UK	261	Inoperable	mGPS 0, 1, 2	1.67 (1.28 - 2.19)	< 0.0001	NA	NA
Simmons et al (2015) [32]	UK	390	Stage IV NSCLC (N = 288) or ES-SCLC	mGPS 0, 1, 2	1.67 (1.40 - 2.00)	< 0.001	NA	NA
Jiang et al (2015) [34]	China	138	Stage IIIB or IV CDDP-based chemotherapy	0 vs. 1 0 vs. 2	0.8 (0.4 - 0.9) 0.5 (0.2 - 0.9)	0.02	0.8 (0.5 - 0.9) 0.6 (0.2 - 0.8)	0.03
Zhu et al (2016) [33]	China	105	Inoperable stage IIIB or IV, first-line chemotherapy	mGPS 0, 1, 2	1.19 (0.81 - 1.75)	0.374	1.10 (0.79 - 1.53)	0.579
Lv et al (2017) [30]	China	266	Recurrence after resection, systemic chemotherapy	mGPS 0 - 1 vs. 2	1.47 (1.15 - 1.88)	0.002	NA	NA
Our	Japan	159	Stage IIIB or IV, Ad, platinum-based	mGPS 0 - 1 vs. 2	1.95 (1.20 - 3.16)	< 0.01	NA	NA

Table 6. Review of Previous Studies of GPS as a Prognostic Factor for Advanced NSCLC [16, 29-34]

Author (year)

Country

Patient treatment

Variables

PFS

HR (95% CI)

Ad: adenocarcinoma; CDDP: cisplatin; CI: confidence interval; ES-SCLC: extensive stage small cell lung cancer; GPS: Glasgow prognostic score; HR: hazard ratio; mGPS, modified Glasgow prognostic score; NA: not assessed; ND: not described; NSCLC: non-small cell lung cancer; OS: overall survival; PFS: progression-free survival.

Forrest et al (2004) [29]

109

Inoperable, platinum-based chemotherapy

GPS

1.88 (1.25 - 2.84)

0.002

Meek et al (2010) [31]

Inoperable

mGPS

< 0.001

Leung et al (2012) [16]

261

Inoperable

mGPS 0, 1, 2

1.67 (1.28 - 2.19)

< 0.0001

Simmons et al (2015) [32]

390

Stage IV NSCLC (N = 288) or ES-SCLC

mGPS 0, 1, 2

1.67 (1.40 - 2.00)

< 0.001

Jiang et al (2015) [34]

China

138

Stage IIIB or IV CDDP-based chemotherapy

0 vs. 1
0 vs. 2

0.8 (0.4 - 0.9)
0.5 (0.2 - 0.9)

0.02

0.8 (0.5 - 0.9)
0.6 (0.2 - 0.8)

0.03

Zhu et al (2016) [33]

China

105

Inoperable stage IIIB or IV, first-line chemotherapy

mGPS 0, 1, 2

1.19 (0.81 - 1.75)

0.374

1.10 (0.79 - 1.53)

0.579

Lv et al (2017) [30]

China

266

Recurrence after resection, systemic chemotherapy

mGPS 0 - 1 vs. 2

1.47 (1.15 - 1.88)

0.002

Our

Japan

159

Stage IIIB or IV, Ad, platinum-based

mGPS 0 - 1 vs. 2

1.95 (1.20 - 3.16)

< 0.01