Patient Characteristics
Between 2015 and 2023, 97 patients with lung cancer and LM were identified, of whom 77 with NSCLC-LM were included. Follow-up was completed for all 77 patients by May 20, 2023. The median follow-up time from diagnosis of NSCLC to the end of this study was 19.5 months (range: 1.8–83.3 months). Seventy (90.9%) patients died and 7 (9.1%) were still alive by the end of the study. All 77 patients were treated, some before progression to LM, some after progression to LM, and some both before and after the development of LM (Fig. 1).
The clinical characteristics of the cohort are presented in Tables 1 and 2. Sex, age, smoking, disease history, family history of cancer, brain parenchymal metastasis, and extracranial disease status did not differ among the four treatment groups. The ethnic minority percentage of patients with NSCLC treated before progression to LM was significantly different among groups (80.0% vs. 45.5% vs. 10.5% vs. 10.0%, P = 0.004).
Table 1
Clinical characteristics of patients with NSCLC treated before progression to LM(n = 45)
Characteristic | Chemo n = 5 | Chemo + A n = 11 | EGFR-TKI n = 19 | EGFR-TKI + A n = 10 | P-value |
Female, n (%) | 1(20.0) | 5(45.5) | 8(42.1) | 7(70) | 0.336 |
Age in years, Median(P25, P75) | 55.0 (49.5,68.0) | 50.0 (43.0,54.0) | 56.0 (49.0,69.0) | 52.5 (45.0,66.5) | 0.329 |
Ethnic Minorities, n (%) | 4(80.0) | 5(45.5) | 2(10.5) | 1(10.0) | 0.004 |
Smokers, n (%) | 1(20.0) | 3(27.3) | 9(47.4) | 3(30.0) | 0.591 |
Disease history, n (%) | 0(0.0) | 3(27.3) | 5(26.3) | 3(30.0) | 0.739 |
Family history of cancer, n (%) | 0(0.0) | 2(18.2) | 3(15.8) | 4(40.0) | 0.304 |
Adenocarcinoma(%) | 4(80.0) | 11(100.0) | 19(100.0) | 10(100.0) | 0.111 |
>3 sites Metastasis count,n (%) | 1(20.0) | 3(30.0) | 4(21.1) | 1(11.1) | 0.903 |
Brain parenchymal metastasis, n (%) | 5(100.0) | 5(45.5) | 6(31.6) | 4(40.0) | 0.055 |
Liver metastasis, n (%) | 1(20.0) | 2(18.2) | 6(31.6) | 2(20.0) | 0.882 |
Chemo platinum-based chemotherapy, chemo + A platinum-based chemotherapy plus anti-angiogenic, EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI + A epidermal growth factor receptor tyrosine kinase inhibitor plus anti-angiogenic
Table 2
Clinical characteristics of patients with NSCLC treated after LM diagnosis(n = 73)
Characteristic | Chemo n = 11 | Chemo + A n = 15 | EGFR-TKI n = 36 | EGFR-TKI + A n = 11 | P-value |
Female, n (%) | 3(27.3) | 7(46.7) | 21(58.3) | 7(63.6) | 0.263 |
Age in years, Median(P25, P75) | 57.0 (50.0,65.0) | 50.0 (39.0,57.0) | 55.5 (49.0,68.8) | 57.0 (50.0,64.0) | 0.127 |
Ethnic Minorities, n (%) | 3(27.3) | 6(40.0) | 5(13.9) | 3(27.3) | 0.204 |
Smokers ,n (%) | 5(45.5) | 4(26.7) | 12(33.3) | 2(18.2) | 0.575 |
Disease history, n (%) | 3(27.3) | 5(33.3) | 9(25.0) | 3(27.3) | 0.978 |
Family history of cancer, n (%) | 1(9.1) | 1(6.7) | 5(13.9) | 1(9.1) | 0.944 |
Adenocarcinoma(%) | 10(90.9) | 14(93.3) | 35(97.2) | 11(100.0) | 0.510 |
>3 sites Metastasis count, n (%) | 4(40.0) | 4(26.7) | 6(17.6) | 4(36.4) | 0.353 |
Brain parenchymal metastasis, n (%) | 5(45.5) | 11(73.3) | 14(38.9) | 7(63.6) | 0.115 |
Liver metastasis, n (%) | 2(18.2) | 4(26.7) | 7(19.4) | 5(45.5) | 0.374 |
Chemo platinum-based chemotherapy, chemo + A platinum-based chemotherapy plus anti-angiogenic, EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI + A epidermal growth factor receptor tyrosine kinase inhibitor plus anti-angiogenic
LM-free survival
The median LFS (mLFS) was 5.0 (95%CI, 2.2–7.8) months; the 1-year LFS rate was 33% (95%CI, 24–45%) and the 2-year LFS rate was 12% (95%CI, 6–22%). The mLFS was not significantly different between the chemo and chemo + A groups (Fig. 2a). The mLFS was longer with EGFR-TKI + A than with EGFR-TKI alone (Fig. 2b). The 1- and 2-year LFS rates were higher with combination therapy than with chemotherapy or EGFR-TKI monotherapy (Table 3).
Table 3
LFS treated with chemotherapy, EGFR-TKI and combined with anti-angiogenic therapy.
Therapy | Median LFS(Months,95% CI) | P-Value HR(95%CI) | 1–Year LFS(95% CI) | 2–Year LFS(95% CI) |
Chemo | 6.0(1.7–10.3) | 0.430 0.66(0.21–2.01) | 0(NA–NA) | 0(NA–NA) |
Chemo + A | 6.0(3.3–8.7) | 27%(10–72%) | 9%(1–6%) |
EGFR-TKI | 14.0(9.7–18.3) | 0.035 0.42(0.18–0.98) | 58%(40–85%) | 16%(6–45%) |
EGFR-TKI + A | 19.0(11.4–26.6) | 90%(73–100%) | 40%(19–86%) |
NA Not Available, Chemo platinum-based chemotherapy, chemo + A platinum-based chemotherapy plus anti-angiogenic, EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI + A epidermal growth factor receptor tyrosine kinase inhibitor plus anti-angiogenic
LM Overall Survival
After LM diagnosis, the median LM OS (mOS) was 8.9 (95%CI, 7.4–10.4) months; the 1-year mOS rate was 39% (95%CI, 29–52%) and the 2-year mOS rate was 12% (95%CI, 6–22%). After progression to LM, the mOS with EGFR-TKI plus anti-angiogenic drugs was significantly longer than that with EGFR-TKI monotherapy. The mOS were also longer in patients who received platinum-based chemotherapy with anti-angiogenic therapy than in those who did not receive anti-angiogenic therapy, although not significantly so. One- and two-year OS rates were higher with combination therapy than with chemotherapy or EGFR-TKI monotherapy (Table 4). The Kaplan–Meier curves for OS are shown in Fig. 3.
Table 4
OS of NSCLC patients after diagnosis of LM treated with chemotherapy, EGFR-TKI and combined with anti-angiogenic therapy.
Therapy | Median OS (Months,95% CI) | P-Value HR(95%CI) | 1–Year OS (95% CI) | 2–Year OS (95% CI) |
Chemo | 8.5(5.7–11.3) | 0.170 0.55(0.23–1.32) | 27%(10–72%) | NA |
Chemo + A | 10.1(7.4–12.8) | 36%(18–73%) | 7%(1–5%) |
EGFR-TKI | 8.3(5.6–11.0) | 0.038 0.47(0.22–0.97) | 35%(22–55%) | 10%(4–30%) |
EGFR-TKI + A | 21.9(12.4–31.4) | 82%(62–100%) | 36%(17–80%) |
NA Not Available, Chemo platinum-based chemotherapy, chemo + A platinum-based chemotherapy plus anti-angiogenic, EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI + A epidermal growth factor receptor tyrosine kinase inhibitor plus anti-angiogenic
LFS Prognostic Factors
The results of the univariate and multifactorial analyses of LFS are listed in Table 5. Age (HR 1.74; 95%CI, 1.05–2.88; P = 0.032), family history of cancer (HR 0.46; 95%CI, 0.22–0.97; P = 0.041), metastasis counts (HR 2.47; 95%CI, 1.39–4.38; P = 0.002), brain parenchymal metastasis (HR 2.33; 95%CI, 1.41–3.86; P = 0.001), EGFR mutation (HR 0.50; 95%CI, 0.30–0.83; P = 0.007), and EGFR-TKI + A (HR 0.41; 95%CI, 0.18–0.96; P = 0.040) were included in multivariate analysis.
Multivariate analysis indicated that metastatic counts and EGFR-TKI + A levels correlated significantly with LFS. In multivariate analysis, metastasis counts > 3 sites were associated with worse LFS (HR 4.02; 95%CI, 1.00–16.08; P = 0.049). LFS also differed significantly between the cohorts receiving EGFR-TKI with or without anti-angiogenic therapy, with adjustment for metastasis counts (HR 0.37; 95%CI, 0.14–0.95; P = 0.039) (Table 5).
Table 5 Univariate and multivariate analyses of factors associated with LFS
|
Univariate analysis
|
Multivariate analysis
|
|
HR (95% CI)
|
P-value
|
HR (95% CI)
|
P-value
|
Gender
|
|
0.613
|
|
|
Male
|
Ref
|
|
|
|
Female
|
0.89(0.57-1.40)
|
|
|
|
Age (years)
|
|
0.032
|
|
0.355
|
<50
|
Ref
|
|
Ref
|
|
≥50
|
1.74 (1.05-2.88)
|
|
1.56(0.61-3.98)
|
|
Nationality
|
|
0.086
|
|
|
Han
|
Ref
|
|
|
|
Minority
|
1.60 (0.93-2.75)
|
|
|
|
Smoking
|
|
0.855
|
|
|
No
|
Ref
|
|
|
|
Yes
|
0.96 (0.59-1.54)
|
|
|
|
Disease history
|
|
0.513
|
|
|
No
|
Ref
|
|
|
|
Yes
|
0.84 (0.5-1.41)
|
|
|
|
Family history of cancer
|
|
0.041
|
|
0.553
|
No
|
Ref
|
|
Ref
|
|
Yes
|
0.46 (0.22-0.97)
|
|
1.43(0.44-4.66)
|
|
Pathology
|
|
0.142
|
|
|
Adenocarcinoma
|
Ref
|
|
|
|
Others
|
2.41 (0.75-7.77)
|
|
|
|
Metastasis counts
|
|
0.002
|
|
0.049
|
≤3 sites
|
Ref
|
|
Ref
|
|
>3 sites
|
2.47 (1.39-4.38)
|
|
4.02(1.00-16.08)
|
|
Brain parenchymal metastasis
|
|
0.001
|
|
0.166
|
No
|
Ref
|
|
Ref
|
|
Yes
|
2.33 (1.41-3.86)
|
|
2.18(0.72-6.59)
|
|
Liver metastasis
|
|
0.256
|
|
|
No
|
Ref
|
|
|
|
Yes
|
1.37 (0.8-2.34)
|
|
|
|
EGFR mutation
|
|
0.007
|
NA
|
NA
|
No
|
Ref
|
|
|
|
Yes
|
0.50 (0.30-0.83)
|
|
|
|
Resistance T790M-
|
Ref
|
0.064
|
|
|
Resistance T790M+
|
0.57(0.31-1.03)
|
|
|
|
PD-L1(%)
|
|
0.195
|
|
|
≤5
|
Ref
|
|
|
|
>5
|
1.83 (0.73-4.54)
|
|
|
|
Anti-angiogenesis therapy(A)
|
|
|
|
|
Chemo
|
Ref
|
0.414
|
|
|
Chemo+A
|
0.62(0.20-1.93)
|
|
|
|
EGFR-TKI
|
Ref
|
0.040
|
Ref
|
0.039
|
EGFR-TKI+A
|
0.41(0.18-0.96)
|
|
0.37(0.14-0.95)
|
|
LM OS Prognostic factors
The results of the univariate and multifactorial analyses of OS are listed in Table 6. Liver metastasis (HR 1.65; 95%CI, 0.96–2.81; P = 0.069) and EGFR-TKI + A (HR 0.46, 95%CI, 0.22–0.97; P = 0.041) were included in multifactorial regression analysis.
Multivariate analysis indicated that liver metastasis and EGFR-TKI+A levels correlated significantly with OS. Liver metastasis was a poor prognostic factor for OS (HR 2.31; 95%CI, 1.28–4.19; P = 0.017). The OS differed significantly between the groups treated with EGFR-TKI with or without anti-angiogenic therapy, with adjustment for liver metastasis (HR 0.37; 95%CI, 0.17–0.81; P = 0.012) (Table 6).
Table6 Univariate and multivariate analyses of factors associated with OS
|
Univariate analysis
|
Multivariate analysis
|
|
HR (95% CI)
|
P-value
|
HR (95% CI)
|
P-value
|
Gender
|
|
0.291
|
|
|
Male
|
Ref
|
|
|
|
Female
|
0.78 (0.48-1.24)
|
|
|
|
Age (years)
|
|
0.151
|
|
|
<55
|
Ref
|
|
|
|
≥55
|
0.71 (0.44-1.13)
|
|
|
|
Nationality
|
|
0.489
|
|
|
Han
|
Ref
|
|
|
|
Minority
|
0.82 (0.47-1.43)
|
|
|
|
Smoking
|
|
0.482
|
|
|
No
|
Ref
|
|
|
|
Yes
|
1.19 (0.73-1.95)
|
|
|
|
Diseaase history
|
|
0.677
|
|
|
No
|
Ref
|
|
|
|
Yes
|
0.89 (0.51-1.54)
|
|
|
|
Family history of cancer
|
|
0.839
|
|
|
No
|
Ref
|
|
|
|
Yes
|
0.92 (0.42-2.02)
|
|
|
|
Pathology
|
|
0.879
|
|
|
Adenocarcinoma
|
Ref
|
|
|
|
Others
|
1.09 (0.34-3.51)
|
|
|
|
Metastasis count
|
|
0.850
|
|
|
≤3 sites
|
Ref
|
|
|
|
>3 sites
|
1.05 (0.62-1.79)
|
|
|
|
Brain parenchymal metastasis
|
|
0.781
|
|
|
No
|
Ref
|
|
|
|
Yes
|
0.94 (0.58-1.5)
|
|
|
|
Liver metastasis
|
|
0.069
|
|
0.017
|
No
|
Ref
|
|
Ref
|
|
Yes
|
1.65 (0.96-2.81)
|
|
2.31 (1.28-4.19)
|
|
EGFR mutation
|
|
0.131
|
|
|
No
|
Ref
|
|
|
|
Yes
|
0.67 (0.40-1.13)
|
|
|
|
Resistance T790M-
|
Ref
|
0.150
|
|
|
Resistance T790M+
|
0.63 (0.33-1.18)
|
|
|
|
PD-L1(%)
|
|
0.077
|
|
|
<20
|
Ref
|
|
|
|
≥20
|
0.32 (0.09-1.13)
|
|
|
|
Anti-angiogenesis therapy(A)
|
|
|
|
|
Chemo
|
Ref
|
|
|
|
Chemo+A
|
0.55 (0.23-1.31)
|
0.179
|
|
|
EGFR-TKI
|
Ref
|
|
Ref
|
|
EGFR-TKI+A
|
0.46 (0.22-0.97)
|
0.041
|
0.37 (0.17-0.81)
|
0.012
|