Absolute Neutrophil Count in the Peripheral Blood Predicts Prognosis in Lung Cancer Patients Treated with Anlotinib

Figures & data

Table 1 Baseline Characteristics of Study Participants

Gender, N (%)	Male	51 (71.8)
	Female	20 (28.2)
Age at start anlotinib (years)	Average±SD	68± 9
Tobacco, N (%)	Never smoker	26 (36.6)
	Current smoker	38 (53.5)
	Former smoker	7 (9.9)
ECOG PS, N (%)	0	49 (69.0)
	1	22 (31.0)
Histologic type, N (%)	Squamous cell carcinoma	14 (57.7)
	Adenocarcinoma	49 (69.0)
	Small cell lung cancer	7 (9.9)
	Other	1 (1.4)
Metastasis sites, N (%)	Brain	8 (11.3)
	Liver	2 (2.8)
	Bone	20 (28.2)
	No	7 (9.9)
Lymphatic metastasis	Yes	61 (85.9)
	No	10 (14.1)
Number of metastatic sites, N (%)	≤ 1	59 (83.1)
	> 1	12 (16.9)
Clinical stage, N (%)	IIIA-IIIB	15 (21.1)
	IV	56 (78.9)
Gene mutation, N (%)	EGFR mutation	7 (9.9)
	Wild type	64 (90.1)
Prior lines of therapy, N (%)	≤ 3	43 (60.6)
	> 3	28 (39.4)
Previous therapy, N (%)	Chemotherapy	54 (76.0)
	Radiation therapy	18 (25.4)
	Targeted treatment	27 (38.0)
	PD–1 inhibitor	1 (1.4)
CRP, mg/L^a	Median (IQR)	12.0 (3.0–48.3)
ANC (×10^9/L)	Median (IQR)	4.6 (3.7–6.3)
ALC (×10^9/L)	Median (IQR)	1.3 (0.9–1.7)

Note: ^aData were missing in three patients.

Abbreviations: EGFR, epidermal growth factor receptor; PD-1, programmed cell death protein-1; CRP, C–reactive protein; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; SD, standard deviation; IQR, interquartile range.

Figure 1 Flowchart of the study participants.

Table 2 Univariate Cox Regression Analyses of PFS and OS

Variable	PFS			OS
	HR	95% CI	P value	HR	95% CI	P value
Age ≥ 65 (vs Age < 65 years old)	1.182	0.696–2.007	0.536	1.881	1.041–3.397	0.036*
Male (vs female)	1.264	0.708–2.256	0.428	1.312	0.694–2.482	0.403
Squamous (vs other)	1.149	0.607–2.174	0.669	1.504	0.761–2.974	0.240
Adenocarcinoma (vs other)	1.009	0.577–1.765	0.974	0.816	0.449–1.484	0.506
ECOG PS at treatment start	1.085	0.614–1.917	0.779	1.573	0.895–2.766	0.115
Tobacco use (vs none)	1.206	0.703–2.068	0.497	1.854	1.012–3.398	0.046*
Liver metastasis (vs none)	0.909	0.125–6.608	0.925	2.440	0.586–10.154	0.220
Skeletal metastasis (vs none)	1.051	0.593–1.861	0.865	0.799	0.421–1.514	0.491
Brain metastasis (vs none)	0.539	0.213–1.364	0.192	0.607	0.236–1.562	0.300
Lymphatic metastasis (vs none)	0.674	0.339–1.339	0.260	1.314	0.557–3.095	0.533
IV Stage (vs IIIA–IIIB Stage)	0.824	0.443–1.531	0.540	0.638	0.331–1.229	0.179
EGFR mutation (vs non–EGFR mutation)	1.395	0.629–3.096	0.413	0.902	0.356–2.286	0.829
No. of previous treatment lines > 3 (vs ≤ 3)	1.735	1.013–2.974	0.045*	1.112	0.634–1.950	0.710
Previous chemotherapy (vs with no previous therapy)	1.301	0.654–2.587	0.453	0.788	0.386–1.610	0.513
Previous targeted therapy (vs with no previous therapy)	1.463	0.791–2.706	0.226	1.835	0.928–3.626	0.081
Previous targeted therapy (vs with no previous therapy)	1.376	0.798–2.371	0.251	1.120	0.619–2.027	0.708
Previous PD–1 inhibitor (vs with no previous therapy)	1.581	0.216–11.583	0.652	2.658	0.357–19.77	0.340
CRP^a	1.002	0.997–1.006	0.479	1.003	0.998–1.007	0.250
ANC	1.105	1.044–1.170	0.001*	1.070	1.023–1.121	0.004*
ALC	0.841	0.567–1.249	0.391	0.862	0.553–1.346	0.515

Note: ^aData were missing in three patients. * p < 0.05.

Abbreviations: EGFR, epidermal growth factor receptor; PD-L1, programmed cell death protein ligand-1; CRP, C–reactive protein; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; HR, hazard ratio; CI, confidence interval.

Table 3 Multivariate Cox Regression Analysis of PFS and OS

Variable	PFS			OS
	HR	95% CI	P value	HR	95% CI	P value
Age ≥ 65 (vs Age < 65 years old)	0.986	0.564–1.722	0.960	1.560	0.846–2.877	0.154
Tobacco use (vs none)	1.174	0.680–2.027	0.565	1.745	0.946–3.218	0.075
No. of previous treatment lines > 3 (vs ≤ 3)	1.523	0.870–2.669	0.141	0.890	0.486–1.629	0.706
ANC	1.095	1.030–1.163	0.003*	1.057	1.003–1.113	0.037*

Notes: Cox proportional hazard models using PFS and OS as a timescale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). *p<0.05.

Table 4 ORR, PFS and OS According to Median ANC

ANC	N for CR+PR	Percentage (%)	P value
< 4.58	9	26.5
≥ 4.58	3	8.1	0.057
ANC	mPFS	95% CI	P value
< 4.58	7	4.4–9.6
≥ 4.58	5	4.4–5.7	0.024*
ANC	mOS	95% CI	P value
< 4.58	17.6	12.3–22.9
≥ 4.58	7.3	4.7–10.0	< 0.001*

Notes: The response to anlotinib between different groups were compared by Pearson χ2. The Log rank test was used for univariate analyses of PFS and OS. * p<0.05.

Figure 2 Progression-free survival (PFS) according to absolute neutrophil count (ANC). In the group with ANC ≥ 4.58, the median PFS (mPFS) is 7.0 months, and the 95% confidence interval (CI) is 4.4–9.6 months; In the group with ANC < 4.58, the mPFS is 5.0 months, and the 95% CI is 4.4–5.7 months. P value is 0.024.

Figure 3 Overall survival (OS) according to ANC. In the group with ANC ≥ 4.58, the median OS (mOS) is 17.6 months, and the 95% CI is 12.3–22.9 months; In the group with ANC < 4.58, the mOS is 7.3 months, and the 95% CI is 4.7–10.0 months. P value is less than 0.001.

Figure 4 ROC curve of the ANC for predicting 10-month survival of patients with advanced lung cancer. The area under the curve (AUC) of the ROC curve was 0.729 The sensitivity and specificity were 82.5% and 67.7%, respectively.