Patient characteristics
As a result, 210 patients with BM who underwent CRT between January 2019 and December 2020 were reviewed in the present study. According to the therapeutic modality, 26.7% (56/210) of patients used chemotherapy, 44.3% (93/210) used TKIs and 29.0% (61/210) used ICIs during treatment. There were 56 patients in the CRT + ICIs group and 154 patients in the CRT + non-ICIs group.
The median follow-up time was 27.4 months (range, 1.0-50.4 months), and the median imaging follow-up time was 12.6 months (range, 1.0-43.2 months). The baseline characteristics of the patients in the two groups are summarized in Table 2. Except for gender and pathology, the baseline characteristics of patients with BM who did and did not receive ICIs were generally well balanced. In the two groups, the median age of all patients was 57 years, ranging from 32 to 78 years. There were 52.9% (111/210) males and 47.1% (99/210) females in our study. A total of 91.0% (191/210) of patients had a Karnofsky performance status (KPS) score greater than 70 (KPS > 70), and 83.3% of the patients had no history of hypertension. There were 51.4% (108/210) of patients with 1–3 BMs and 48.6% (102/210) patients with more than three BMs (> 3). In addition, 146 (69.5%) patients had adenocarcinoma. Only 11 patients had leptomeningeal metastases. Among all patients, the proportion of patients with symptomatic BM was 58.6% (123/210). CRT modes include WBRT, PBRT and WBRT-SIB. The choice of mode is related to the number and size of BMs, pathological types, general conditions and so on. In the CRT + ICIs group, the ratio of the three radiotherapy modes was 26.8% vs. 35.7% vs. 37.5%. In addition, WBRT-SIB was the main treatment mode in the CRT + non-ICIs group, and the ratio of the three radiotherapy modes was 29.2% vs. 28.6% vs. 42.2%. During the whole course of treatment, twenty (9.5%) patients received re-radiotherapy.
Table 2
Baseline characteristics of patients
Characteristics
|
Total (n = 210)
|
No. (%)
|
|
|
CRT + ICIs
(n = 56)
|
CRT + non-ICIs
(n = 154 )
|
P Valuea
|
Gender
Male
Female
|
111
99
|
42 (75.0)
14 (25.0)
|
69 (44.8)
85 (55.2)
|
0.000
|
Age (median, range) (y)
< 65
≥ 65
|
57 (32–78)
161
49
|
59 (32–78)
14 (25.0)
42 (75.0)
|
57 (32–77)
35 (22.7)
119 (77.3)
|
0.731
|
Hypertension history
No
Yes
|
175
35
|
47 (83.9)
9(16.1)
|
128 (83.1)
26 (16.9)
|
0.889
|
KPS score
≤ 70
> 70
|
19
191
|
5 (8.9)
51 (91.1)
|
14 (9.1)
140 (90.9)
|
0.971
|
Pathology
Squamous cell carcinoma
Adenocarcinoma
Small cell lung cancer
Other
|
14
146
43
7
|
6 (10.7)
30 (53.6)
17 (30.4)
3 (5.4)
|
8 (5.2)
116 (75.3)
26 (16.9)
4 (2.6)
|
0.030
|
Basic cerebral ischemic lesion
Yes
No
|
87
124
|
28 (50.0)
28 (50.0)
|
57 (37.0)
97 (63.0)
|
0.090
|
Symptomatic brain metastases
Yes
No
|
123
88
|
31 (55.4)
25 (44.6)
|
91 (59.1)
63 (40.9)
|
0.628
|
Maximum diameter of lesion (median, range) (cm)
|
1.7 (0.2–6.4)
|
1.8 (0.5–6.4)
|
1.7 (0.2-5.0)
|
|
Number of brain metastases
≤ 3
> 3
|
108
102
|
33 (58.9)
23 (41.1)
|
75 (48.7)
79 (51.3)
|
0.190
|
Leptomeningeal metastases
No
Yes
|
199
11
|
54 (96.4)
2 (3.6)
|
145 (94.2)
9 (5.8)
|
0.513
|
Radiotherapy mode
WBRT
PBRT
WBRT-SIB
|
60
64
86
|
15 (26.8)
20 (35.7)
21 (37.5)
|
45 (29.2)
44 (28.6)
65 (42.2)
|
0.608
|
Re-radiotherapy
Yes
No
|
20
190
|
5(8.9)
51 (91.1)
|
15 (9.7)
139 (90.3)
|
0.859
|
Abbreviations: CRT:cranial radiotherapy, ICIs: immune checkpoint inhibitors, WBRT: whole brain radiotherapy, PBRT: partial brain radiotherapy, WBRT-SIB: WBRT with simultaneous integrated boost. |
Incidence Of Rbi
Overall, we first analyzed the follow-up MRI of 210 patients and found that 17 (8.1%) patients developed RN and 142 (67.6%) patients developed WML after CRT.
1. RN
The median time of development of RN was 13.3 months (range 0.53–34.8 months). The typical imaging images from patients with RN are shown in Fig. 1. All RNs occurred at the location of the BM, which has no location correlation with the white matter area of WML occurrence. Among 17 patients with RN in the two groups, 12 (70.6%) patients received PBRT, four (23.5%) patients received WBRT-SIB, and only one (5.9%) patient received WBRT. A total of 76.5% (13/17) of patients with RN received secondary CRT, and 70.6% (12/17) of patients with RN developed WML at different times during treatment. Moreover, the median cumulative radiation dose of patients with RN was 50 Gy (range 40–110 Gy).
As a result, eight patients developed RN in the CRT + ICIs group, and nine patients developed RN in the CRT + non-ICIs group. The rate of RN was relatively higher in the CRT + ICIs group than that in CRT + non-ICIs group (14.3% vs. 5.8%, p = 0.090), but the difference was not significant. However, if ICIs were used within three months of CRT, the incidence of RN in the CRT + ICIs group was significantly higher than that in the CRT + non-ICIs group (18.5% vs. 5.4%, p = 0.045). Therefore, in this study, when ICIs were applied within three months before and after CRT, the incidence of RN was 3.43 times that of the CRT group. Then, we took three months before and after CRT as the cut-off time and divided the patients who used ICIs in the whole treatment process into two groups: the group using ICIs in combination within three months and the group using ICIs in combination beyond three months. By analyzing the incidence of RN, we found that the difference was not statistically significant (p > 0.05).
According to CTCAE V5.0, among 17 patients with RN, five patients were grade 1, which were observed only during the imaging follow-up; 1 patient was grade 2, and the patient had mild symptoms of dizziness and headache, and no special treatment was needed; 10 patients were grade 3, and clinicians generally used bevacizumab or a combination of mannitol and dexamethasone for symptomatic treatment, and the symptoms of patients were relieved after treatment; 1 patient was grade 4, and the patient had severe headache and limited movement of one side of the limb, so surgery had been considered to alleviate the symptoms after consultation with neurosurgery experts; and no patients died because of RN.
2. WML
The typical imaging images from patients with WML are shown in Table 1. WML mainly occurred in periventricular white matter (PVWM) and deep white matter (DWM), and the location of WML was not related to RN. Among 142 patients with WML, the numbers of patients receiving WBRT, PBRT and WBRT-SIB were 44, 33 and 65, respectively. A total of 11.3% (16/142) of patients had received re-radiotherapy. The median time of WML occurrence was 5.87 (range 0.5–30.1). According to the Fazekas scale, there were 23 (16.2%) patients with grade 1 WML, 50 (35.2%) patients with grade 2 WML and 69 (48.6%) patients with grade 3 WML.
Among 142 patients with WML, the rate of any grade WML was 62.5% (35/56) in the CRT + ICIs group and 69.5% (107/154) in the CRT + non-ICIs group. The incidence of WML between the two groups was not significantly different (p = 0.339). If ICIs were used within three months of CRT, the incidence of WML between the CRT + ICIs group and the CRT group was 51.9% vs. 69.8% (p = 0.068).
We compared brain MRI of patients before and after CRT. There were 65 patients with ischemic spots on MRI imaging before CRT, and they were assessed as grade 1 WML. Among them, 80.0% (52/65) of patients developed grade 2–3 WML after CRT. Then, we analyzed the natural risk of WML in patients before CRT and found that there was no statistical correlation between age and WML (OR 1.53; 95% CI 0.81–2.92, p = 0.193).
Effects Of Rn And Wml On Survival
The median OS (mOS) for the 210 patients was 28.2 months (95% CI 26.5–31.2 months). For 17 patients with RN, the mOS was significantly longer than for those without RN. The mOS for patients in the non-RN group was 26.1 months (95% CI 22.4–30.0 months), while the mOS of patients in the RN group was not reached (p = 0.016). In addition, there was no significant difference in mOS between the non-WML group and the WML group, which were 24.4 months and 29.1 months, respectively (p = 0.329). (Fig. 2)
Risk Factors For Rbi
As shown in Table 3, we first conducted a univariate analysis on the factors that may be related to the occurrence of RN and WML, and then in consideration of the collinearity of some variables, the statistically significant factors in the univariate analysis were further included in the multivariate analysis. The factors include categorical variables and continuous variables. The optimal cut-off values of statistically significant continuous variables were obtained by ROC curve analysis.
Table 3
univariate and multivariate analysis of risk of developing RN and WML
|
Univariate analyses
|
Multivariate analyses
|
Risk Factors
|
OR (95%CI) p-value
|
OR (95%CI) p-value
|
Brain necrosis
|
|
|
|
|
Gender (Female)
|
0.98(0.36–2.64)
|
0.962
|
NA
|
—
|
Age (≥ 65)
|
0.19(0.02–1.46)
|
0.110
|
NA
|
—
|
KPS score (> 70)
|
0.72(0.15–3.44)
|
0.685
|
NA
|
—
|
BM after progression
|
3.50 (1.24–9.89)
|
0.018
|
2.96 (0.82–10.74)
|
0.098
|
Number of BM (> 3)
|
0.20 (0.06–0.73)
|
0.015
|
0.38 (0.09–1.59)
|
0.184
|
Maximum diameter(> 3.3cm)
|
1.51(1.04–2.19)
|
0.030
|
1.67 (1.08–2.60)
|
0.023
|
Asymptomatic BM
|
0.74(0.26–2.08)
|
0.566
|
NA
|
—
|
Radiotherapy mode (PBRT)
|
6.51(2.19–19.37)
|
0.001
|
2.01 (0.25–16.09)
|
0.512
|
Cumulative radiation dose of the whole brain (Gy)
|
0.97 (0.95–0.99)
|
0.040
|
1.00 (0.95–1.06)
|
0.982
|
Cumulative radiation dose of metastatic lesions(> 75.7Gy)
|
1.05 (1.02–1.08)
|
0.001
|
1.05(1.01–1.09)
|
0.018
|
Re-radiotherapy
|
3.40(0.99–11.67)
|
0.051
|
NA
|
—
|
WML
|
1.16(0.39–3.45)
|
0.785
|
NA
|
—
|
White matter lesions
|
|
|
|
|
Gender (Female)
|
1.13(0.63–2.01)
|
0.684
|
NA
|
—
|
Age (≥ 65)
|
1.64(0.80–3.40)
|
0.180
|
NA
|
—
|
KPS score (> 70)
|
1.24(0.47–3.31)
|
0.663
|
NA
|
—
|
Number of BM (> 3)
|
2.04 (1.13–3.69)
|
0.019
|
1.63(0.80–3.31)
|
0.180
|
Basic cerebral ischemic lesion
|
1.89 (1.03–3.48)
|
0.041
|
3.26(1.57–6.75)
|
0.002
|
Maximum diameter
|
0.95(0.75–1.20)
|
0.671
|
NA
|
—
|
Pathology (squamous cell carcinoma)
|
0.33(0.11-1.00)
|
0.049
|
0.31(0.09–1.03)
|
0.057
|
Radiotherapy mode (PBRT)
|
0.36(0.20–0.67)
|
0.001
|
0.51(0.17–2.24)
|
0.373
|
The dose per fraction of the whole brain
|
1.70 (1.32–2.19)
|
0.000
|
1.39(0.83–2.33)
|
0.210
|
Cumulative radiation dose of the whole brain
|
1.04 (1.02–1.06)
|
0.000
|
1.04(1.00-1.08)
|
0.084
|
Cumulative radiation dose of metastatic lesions (Gy)
|
1.02(0.99–1.04)
|
0.149
|
NA
|
—
|
Re-radiotherapy
|
2.03(0.65–6.33)
|
0.221
|
NA
|
—
|
Abbreviations: WML: white matter lesion |
In univariate analysis, the results showed that the number and size of BMs were significantly correlated with the occurrence of RN. More than three metastatic lesions are a protective factor for the development of RN (OR 0.20; 95% CI 0.06–0.73, p = 0.015), and the maximum diameter of BM is a risk factor (OR 1.51; 95% CI 1.04–2.19, p = 0.030); in other words, the larger the maximum diameter of metastatic lesions is, the higher the risk of RN. Then, the ROC curve analysis results showed that the cut-off value of the maximum diameter of BM was 3.3 cm. Compared to patients initially diagnosed with BM, BM after progression (OR 3.50; 95% CI 1.24–9.89, p = 0.018) was a risk factor for the occurrence of RN. In addition, PBRT as a radiotherapy mode (OR 6.51; 95% CI 2.19–19.37, p = 0.001), total cumulative radiation dose of metastatic lesions (OR 1.05; 95% CI 1.02–1.08, p = 0.001) and total cumulative radiation dose of the whole brain (OR 0.97; 95% CI 0.95–0.99, p = 0.040) were significantly correlated with the occurrence of RN. The cut-off value of the cumulative radiation dose of metastatic lesions was 75.7 Gy. In consideration of the collinearity of some variables, we then included all variables identified as statistically significant in the multivariate analysis. The results showed that the maximum diameter of BM (> 3.3 cm, OR 1.67; 95% CI 1.08–2.60, p = 0.023) and the cumulative radiation dose of brain metastases (> 75.7 Gy, OR 1.05; 95% CI 1.01–1.09, p = 0.018) were significantly correlated with the occurrence of RN. Moreover, among the risk factors, re-radiotherapy (OR 3.40; 95% CI 0.99–11.67, p = 0.051) was also a trend factor in the development of RN, although the data in this study did not reach statistical significance.
On the other hand, univariate analysis showed that the number of BMs (> 3), the basic cerebral ischemic lesion, the dose per fraction of the whole brain and the total cumulative radiation dose of the whole brain were statistically significant risk factors for WML. The pathological type of squamous cell carcinoma (OR 0.33; 95% CI 0.11-1.00, p = 0.049) and CRT mode of PBRT (OR 0.36; 95% CI 0.20–0.67, p = 0.001) were protective factors for WML. However, we further conducted multivariate analysis and found that only basic cerebral ischemic lesions (OR 3.26; 95% CI 1.57–6.75, p = 0.002) were a statistically significant risk factor for the development of WML.