Patients’ physical and clinical characteristics
A summary of physical and clinical characteristics of the 137 patients included in this study is shown in Table 1. Briefly, all patients’ ECOG scores ranged from 0–3, and none of them had received treatment to either increase or decrease their blood lipid levels. The group’s median age was 62 years old, while clinicopathological diagnosis revealed that all patients presented more than 4 stages. Squamous and non-squamous cell carcinoma accounted for 51.8 and 48.2%, respectively, and the median line of treatment using anlotinib was 3. The other three items alongside their median values are also listed in Table 1.
Table 1
Physical and clinicopathological characteristics of the 137 patients included in the present study
Patient characteristics
|
N = patients (%)
|
All
|
137
|
Age (years)
|
|
< 65
|
83 (60.5%)
|
≥ 65
|
54 (39.5%)
|
Gender
|
|
Male
|
99 (72.3%)
|
Female
|
38 (27.7%)
|
Histology
|
|
squamous
|
71 (51.8%)
|
non-squamous
|
66 (48.2%)
|
PS (ECOG)
|
|
0–1
|
95 (69.3%)
|
2–3
|
42 (30.7%)
|
Driver gene
|
|
wild
|
108 (78.8%)
|
mutation
|
29 (21.2%)
|
Metastasis sites
|
|
≤ 3
|
73 53.3%)
|
> 3
|
64 (46.7%)
|
Line(s) of treatment
|
|
3
|
78 (56.9%)
|
> 3
|
59 (43.1%)
|
Optimal cut-off values for lipids
We generated ROC curves to determine the optimal cut-off values for the aforementioned blood lipids in all patients under this study. For TG, the optimal cut-off value for TG was 1.82 with an area under the curve (AUC) of 0.639 (95% CI: 0.527–0.751), that for TC was 4.77 with an AUC of 0.700 (95% CI: 0.606–0.795), whereas those for LDL and HDL were 2.965 (95% CI: 0.592–0.797) and 1.095 (95% CI: 0.431–0.654), respectively, with corresponding AUC values of 0.695 0.543. A summary of ROC curves is presented in Fig. 1.
Curative effect analysis
No patient from the analyzed cohort achieved CR (0%), thus the ORR (4%) was thought to be equal to the PR value (4%). SD took a majority of the response. We calculated the curative effect among different lipids groups layered based on their respective optimal cut-off values, and these are listed in Table 2. For TG, a total of 100 patients reached DCR, with the low group (TG < 1.82) comprising a significantly higher proportion (59.1%) relative to the high group (13.9%, P = 0.000). Conversely, the high group exhibited the highest proportion of PD (13.9%), which was significant different from those obtained in PR and SD (P = 0.002). Results from LDL corroborated those of TG and TC (Table 2). However, we observed no significant differences in the curative effect in the HDL group.
Table 2
Associations among the four lipids with treatment response
Response
|
n
|
%
|
TG
|
TC
|
LDL
|
HDL
|
< 1.82
|
≥ 1.82
|
P value
|
< 4.77
|
≥ 4.77
|
P value
|
< 2.965
|
≥ 2.965
|
P value
|
< 1.095
|
≥ 1.095
|
P value
|
CR
|
0
|
0
|
|
|
|
|
|
|
|
|
|
|
|
|
PR
|
6
|
4
|
5
(3.6%)
|
1
(0.7%)
|
0.002
|
4
(2.9%)
|
2
(1.4%)
|
0.000
|
5
(3.6%)
|
1
(0.7%)
|
0.000
|
2
(1.4%)
|
4
(2.9%)
|
0.218
|
SD
|
94
|
68.6
|
76
(55.5%)
|
18
(13.1%)
|
|
67
(48.9%)
|
27
(19.7%)
|
|
73
(53.3%)
|
21
(15.3%)
|
|
52
(38%)
|
42
(30.1%)
|
|
PD
|
37
|
27
|
19
(13.9%)
|
18
(13.1%)
|
|
8
(5.8%)
|
29
(21.2%)
|
|
12
(8.8%)
|
25
(18.2%)
|
|
15
(10.9%)
|
22
(16.1%)
|
|
ORR
|
6
|
4
|
|
|
|
|
|
|
|
|
|
|
|
|
DCR
|
100
|
72.6
|
81
(59.1%)
|
19
(13.9%)
|
0.000
|
71
(51.8%)
|
29
(21.2%)
|
0.000
|
78
(56.9%)
|
22
(16.1%)
|
0.000
|
54
(39.4%)
|
46
(33.6%)
|
0.162
|
Identification of prognostic factors of layered baseline lipids in the overall population
The study population had a median follow-up time of 16.3 months, and all patients exhibited recurrence. On the other hand, the entire population recorded median PFS and OS of 4 (95% CI 3.142–4.858) and 8.3 (95% CI 6.843–9.757) months, respectively. Results from univariate analyses revealed that TG and TC and LDL were all significant risk factors for PFS, while TC and LDL were risk factors for OS (Table 3). Incorporating the significant risk factors into multivariate analysis demonstrated that high TC and high LDL was independently associated with poor PFS (Table 4). For the results of TC in Fig. 2B and Fig. 3B, moreover, the high TC group showed shorter median PFS and OS rates, at 2 and 6 months, respectively, compared to those in the low group, namely 5.9 and 9.9 months, respectively (PPFS = 0.000, POS = 0.003). Similarly, the high LDL group exhibited significantly shorter median PFS (Fig. 2C) and OS (Fig. 3C) compared with the low group (1.75 months vs 5 months, PPFS = 0.000; 5.8 months vs 9.7 months, POS = 0.029). The high TG group exhibited significantly shorter median PFS (Fig. 2A) compared with the low group (2.0 months vs 5.0 months, P = 0.004) while there was no significant difference in OS between the high and low TG groups (Fig. 3A). Notably, we found no statistically significant differences in neither PFS (Fig. 2D) nor OS (Fig. 3D) between the high and low HDL groups (Table 4).
Table 3
Results of univariate analysis of factors associated with progression-free and overall survival rates
Variable (N = 137)
|
PFS
|
OS
|
HR
|
95%CI
|
Univariate (P value)
|
HR
|
95%CI
|
Univariate (P value)
|
Age (years)
|
1.057
|
0.756–1.505
|
0.713
|
0.897
|
0.508–1.324
|
0.564
|
< 65
|
|
|
|
|
|
|
≥ 65
|
|
|
|
|
|
|
Gender
|
1.162
|
0.797–1.694
|
0.435
|
1.067
|
0.697–1.634
|
0.764
|
Male
|
|
|
|
|
|
|
Female
|
|
|
|
|
|
|
Histology
|
1.198
|
0.855–1.679
|
0.294
|
1.165
|
0.799-1.700
|
0.428
|
squamous
|
|
|
|
|
|
|
non-squamous
|
|
|
|
|
|
|
PS (ECOG)
|
1.168
|
0.810–1.584
|
0.405
|
1.453
|
0.975–2.165
|
0.066
|
0–1
|
|
|
|
|
|
|
2–3
|
|
|
|
|
|
|
Driver gene
|
1.002
|
0.663–1.515
|
0.993
|
1.147
|
0.726–1.811
|
0.557
|
wild
|
|
|
|
|
|
|
mutation
|
|
|
|
|
|
|
Metastasis sites
|
0.932
|
0.667–1.316
|
0.707
|
0.997
|
0.685–1.453
|
0.989
|
≤ 3
|
|
|
|
|
|
|
> 3
|
|
|
|
|
|
|
Line(s) of treatment
|
1.063
|
0.758–1.494
|
0.725
|
0.768
|
0.523–1.127
|
0.178
|
3
|
|
|
|
|
|
|
≥ 3
|
|
|
|
|
|
|
TG
|
1.689
|
1.152–2.475
|
0.007
|
1.431
|
0.949–2.159
|
0.088
|
< 1.82
|
|
|
|
|
|
|
≥ 1.82
|
|
|
|
|
|
|
TC
|
2.647
|
1.655–3.777
|
0.000
|
1.773
|
1.213–2.592
|
0.003
|
< 4.77
|
|
|
|
|
|
|
≥ 4.77
|
|
|
|
|
|
|
LDL
|
3.056
|
2.091–4.495
|
0.000
|
1.532
|
1.040–2.257
|
0.031
|
< 2.965
|
|
|
|
|
|
|
≥ 2.965
|
|
|
|
|
|
|
HDL
|
1.085
|
0.773–1.522
|
0.637
|
0.910
|
0.623–1.328
|
0.624
|
< 1.095
|
|
|
|
|
|
|
≥ 1.095
|
|
|
|
|
|
|
Table 4
Results of multivariate analysis of significant factors associated with progression-free survival
Variable (N = 137)
|
PFS
|
HR
|
95%CI
|
Multivariate (P value)
|
TC
|
1.841
|
1.187–2.857
|
0.006
|
< 4.77
|
|
|
|
≥ 4.77
|
|
|
|
LDL
|
2.133
|
1.336–3.406
|
0.002
|
< 2.965
|
|
|
|
≥ 2.965
|
|
|
|
The prediction model by TC and LDL value
We incorporated the significant factors, namely baseline TC and LDL values, into multivariate analysis to identify independent prognostic factors using. The high value was equivalent to a risk factor, and for the presence of each a risk factor, the patients’ risk score was raised by 1. Based on this, we found that patient’s scores ranged from 0 (extremely favorable) to 2 score (extremely unfavorable). Results indicated that scores of 0, 1 and 2 were significantly associated with PFS (P = 0.000, 95%CI 3.142–4.858) and OS (P = 0.017, 95%CI 6.843–9.757). Specifically, 0 score was associated with superior survival rates while relative to 1 and 2 (Table 5). However, the survival rates showed a cross connection among the three group (Fig. 4A, 4B). Additionally, in grouped comparison, 0 score exhibited no significant differences with score 1 in mPFS (P = 0.198). Therefore, we combined scores 1 and 2 groups into a high score group (≥ 1 score), then re-calculated the survival between 0 score and ≥ 1 score group. Results revealed significant differences in PFS and OS between the two groups as well as the survival curve (Fig. 4C and D).
Table 5
Median progression-free survival (mPFS) and median overall survival (mOS) for different scores in patients stratified according to presence of different independent prognostic factors obtained from multivariate analysis (TC and LDL)
Prognosis
|
Score
|
95%CI
|
P value
|
0(n = 75)
|
1(n = 19)
|
2(n = 43)
|
mPFS (months)
|
5.8
|
4.8
|
1.5
|
3.142–4.858
|
0.000
|
mOS (months)
|
9.9
|
7.9
|
5.6
|
6.843–9.757
|
0.017
|
Note: The unit of measurement for lipids is mmol/L. A score of 0 represents low TC (< 4.77) and low LDL (< 2.965) at baseline; a score of 1 denotes low TC (< 4.77) and high LDL (≥ 2.965) or low LDL (< 2.965) and high TC (≥ 4.77) at baseline; whereas 2 represents high TC (≥ 4.77) and high LDL (≥ 2.965) at baseline. |