Characteristics & treatments of the patients
This study enrolled a total of 111 patients, who received thoracic radiotherapy from September 2008 to April 2019. The majority of the patients were females (71, 63.96%) and non-smokers (90, 81.08%). Among the 111 patients, 80 patients (72.07%) died and 31 patients (27.93%) survived. Their median age was 53 (ranged: 32–82). There were 32 people (28.83%) over the age of 60 (including 60). For the EGFR mutation type analysis, mutations in exon 21 and 19 accounted for 45.05% and 44.14%, respectively. The duration from the diagnosis of lung cancer to the last date of follow-up, the number of patients, received radiotherapy at 1, 2, 3, 4, 5, and 6 sites were 28 (25.23%), 52 (46.85%), 24 (21.62%), 3 (2.70%), 3 (2.70%), and 1 (0.90%), respectively. The sites of the patients targeted with radiotherapy mainly included thorax (111, 100%), brain (60, 54.05%), and bone (47, 42.34%). There were 69 cases (62.16%) of grade 1 radiation pneumonia, 10 cases (9.01%) of grade 2 pneumonia, and 4 (3.60%) cases of grade 3 pneumonia, respectively. Of the 111 patients, who received thoracic radiotherapy, 25 patients (22.52%) received less than 50 Gy, 35 patients (31.53%) received 50–60 Gy (including 50 Gy) and 51 patients (45.95%) received 60 Gy or more. A total of 19 patients (17.12%) were treated with targeted combined radiotherapy concurrently. The clinicopathological characteristics of the patients are summarized in Table 1.
Table 1 Characteristics of 111 advanced lung adenocarcinoma patients
Characteristic
|
Total (N = 111)
|
%
|
Gender
|
|
|
Male
|
40
|
36.04%
|
Female
|
71
|
63.96%
|
Age, n (%)
|
|
|
Median age, y (range)53
|
|
|
≥60
|
32
|
28.83%
|
<60
|
79
|
71.17%
|
Tobacco smoking, n (%)
|
|
|
yes
|
21
|
18.92%
|
no
|
90
|
81.08%
|
EGFR mutation, n (%)
|
|
|
19
|
49
|
44.14%
|
21
|
50
|
45.05%
|
other
|
12
|
10.81%
|
Dose,Gy
|
|
|
<50
|
25
|
22.52%
|
≥50,<60
|
35
|
31.53%
|
≥60
|
51
|
45.95%
|
Number of radiotherapy sites
|
|
|
1
|
28
|
25.23%
|
2
|
52
|
46.85%
|
3
|
24
|
21.62%
|
4
|
3
|
2.70%
|
5
|
3
|
2.70%
|
6
|
1
|
0.90%
|
The Site of Radiotherapy
|
|
|
Thoracic
|
111
|
100.00%
|
Brain
|
60
|
54.05%
|
Bone
|
47
|
42.34%
|
radiation pneumonitis
|
|
|
G1
|
69
|
62.16%
|
G2
|
10
|
9.01%
|
G3
|
4
|
3.60%
|
Radiotherapy targeting synchronization
|
|
|
yes
|
19
|
17.12%
|
no
|
92
|
82.88%
|
Abbreviations: EGFR, epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors.
Survival status of the entire study cohort
The OS of the patients was defined as the duration from the beginning of therapy to death from any cause or the last follow-up. The patients, who were lost to follow-up or survived until the end of this study observation time were defined as censored. After the follow-up duration, there were 80 patients (72.07%) in the entire cohort. The median overall survival (mOS) of the patients was 41.6 months (Fig.1A). The rates of 1-, 3-, and 5-year OS rates among the entire cohort were 91.89%, 54.36%, and 28.25%, respectively. There were no significant differences in OS rates between the 90 non-smokers and 21 smokers (hazard ratio(HR) =0.651; 95% CI 0.358 to 1.186; log-rank P = 0.104; Fig.1B).The mOS rates of the patients with exons 19 and 21 mutations were 41.7 months and 37.1 months, respectively (HR = 0.695; 95% CI 0.434 to 1.113; log-rank P = 0.130; Fig.1C). There was no significant difference in the OS rate of the 60 patients who received brain radiotherapy and those who did not receive brain radiotherapy (HR = 0.778; 95% CI 0.494 to 1.225; log-rank P = 0.279; Fig.2A). Among the 79 patients with bone metastases, there was no significant difference in the OS rates between 47 patients who received bone radiotherapy and those who did not receive bone radiotherapy (HR = 0.751; 95% CI 0.479 to 1.175; log-rank P = 0.199; Fig.2B). The difference in the OS of the 19 patients, receiving targeted immunotherapy combined with radiotherapy synchronously and those, receiving radiotherapy combined with targeted immunotherapy asynchronously was not statistically significant (HR = 0.743; 95% CI 0.439 to 1.259; log-rank P = 0.308; Fig.2C).
Effect of different thoracic radiotherapy doses on the patients’ OS and incidence of radiation pneumonia.
The effects of different lung radiotherapy doses on the patients’ OS were analyzed. The patients were divided into three groups based on the different doses. This difference was statistically significant in the OS of the patients, who received a radiotherapy dose scheme of less than 50 Gy, and those, who received a radiotherapy dose scheme of more than 50 Gy (including 50 Gy)(HR = 0.457; 95% CI 0.253 to 0.826; log-rank P = 0.009; Fig.3A). The difference in the OS of patients, receiving less than 60 Gy and those, receiving more than 60 Gy (including 60 Gy) was not statistically significant (HR = 0.628; 95% CI 0.399 to 0.987; log-rank P = 0.011; Fig.3B). The mOS rates of the patients, who received radiotherapy dose scheme of less than 50 Gy, 50-60 Gy (including 50 Gy), and 60 Gy or more were 29.1 months, 34.4 months, and 51.0 months, respectively (log-rank P = 0.011). The patients, who received a radiotherapy dose scheme of 60 Gy or more had a longer mOS rate as compared to the other two groups (HR = 0.628; 95% CI 0.399 to 0.987; log-rank P = 0.011; Fig.3C).
The subgroup analysis revealed that this difference was not statistically significant in the OS of the patients, who received a radiotherapy dose scheme of 50-60 Gy (including 50 Gy), and those, who received a radiotherapy dose scheme of less than 50 Gy(mOS: 34.4 months vs. 29.1 months; HR = 0.684; 95% CI 0.383 to 1.223; log-rank P = 0.172; Fig.4A). The mOS of patients, who received a radiotherapy dose scheme of 60 Gy or more was longer than that of the patients, who received a radiotherapy dose scheme of less than 50 Gy (mOS: 51.0 months vs. 29.1 months, HR = 0.444; 95% CI 0.236 to 0.835; P = 0.003; Fig.4B). This difference inclined to statistically insignificant in the OS rates of 56 patients, who received radiotherapy dose scheme of 60 Gy or more, as compared to those, who received radiotherapy dose scheme of 50-60Gy (including 50 Gy) (mOS: 51.0 months vs. 34.4 months, HR = 0.672; 95% CI 0.396 to 1.141; P = 0.119; Fig.4C).
The results showed that the incidence of grade 1 and 2 radiation pneumonia was 21.52% in the patients, receiving radiotherapy dose scheme of less than 50 Gy, 30.38% in the patients, receiving radiotherapy dose scheme of 50 to 60 Gy (including 50 Gy), 48.10% in the patients, receiving radiotherapy dose scheme of 60 Gy or more. There was no grade 3 radiation pneumonia in the patients, receiving a radiotherapy dose scheme of less than 50 Gy. Two patients in those, receiving radiotherapy dose schemes of less than 50 Gy and 60 Gy or more developed radiation pneumonia. Most importantly, the patients with different levels of radiation pneumonia did not differ in the three different radiotherapy dose scheme groups (χ2 = 1.331; P = 0.514; Table2). The severity of radiation pneumonia was not related to the synchronization of targeted immunotherapy and radiotherapy (χ2 = 0.152; P = 0.697; Table3).
Table 2 Characteristics of patients in the three groups and with the X2 test for categorical variables
Characteristic
|
<50Gy
|
≥50Gy,
<60Gy
|
≥60Gy
|
P
|
|
|
|
|
|
|
Gender
|
|
|
|
|
|
Male
|
40 (36.04%)
|
13
|
11
|
16
|
0.168
|
Female
|
71 (63.96%)
|
12
|
24
|
35
|
|
Age, n (%)
|
|
|
|
|
|
Median age, y (range)53
|
|
|
|
|
|
≥60
|
32 (28.83%)
|
10
|
8
|
14
|
0.337
|
<60
|
79 (71.17%)
|
15
|
27
|
37
|
|
Tobacco smoking, n (%)
|
|
|
|
|
|
yes
|
21 (18.92%)
|
9
|
5
|
7
|
0.032
|
no
|
90 (81.08%)
|
15
|
30
|
45
|
|
EGFR mutation, n (%)
|
|
|
|
|
|
19
|
49 (44.14%)
|
5
|
19
|
25
|
0.065
|
21
|
50 (45.05%)
|
15
|
14
|
21
|
|
Number of radiotherapy sites
|
|
|
|
|
|
1、2、3
|
104(93.70%)
|
23
|
31
|
50
|
0.192
|
4、5、6
|
7 (6.30%)
|
2
|
4
|
1
|
|
Radiation pneumonitis
|
|
|
|
|
|
1、2
|
79 (71.18%)
|
17
|
24
|
38
|
0.514
|
3
|
4(3.60%)
|
0
|
2
|
2
|
|
Radiotherapy targeting synchronization
|
|
|
|
|
|
yes
|
19 (17.12%)
|
4
|
9
|
6
|
0.237
|
no
|
92 (82.88%)
|
21
|
26
|
45
|
|
Table 3 Characteristics of patients in the two groups and with the X2 test for categorical variables
|
Radiotherapy targeting synchronization
|
|
|
yes
|
no
|
P
|
grade1 or 2
|
19
|
90
|
0.697
|
grade 3
|
1
|
3
|
|
Univariate and multivariate analysis of independent predictors of overall survival
In order to exclude the influence of other clinicopathological factors on the OS of patients, χ2-test was used to analyze the differences in clinicopathological factors among the different dose groups. The non-smoking patients were more common among those, who received ≥60Gy (16, <50Gy; 31 ≥50, and 49 ≥60 Gy; P = 0.032;). There were no differences among the three groups for age, sex, EGFR mutation type, radiation pneumonia, treatment sequence of targeted immunotherapy and radiotherapy, or many radiotherapy sites (Table2).
The univariate and multivariate analyses of OS were performed using the COX regression model. The factors considered for these analyses included age, gender, smoking status, lung radiotherapy dose schemes, type of mutations in EGFR gene, sites of radiotherapy, number of radiotherapy sites, and treatment sequence of targeted immunotherapy and radiotherapy. The multivariate analysis showed that, after adjusting for the significant covariates, including thoracic radiotherapy doses, type of EGFR mutations, number of radiotherapy sites, sites of radiotherapy, and treatment sequence of targeted and radiotherapy, the thoracic radiotherapy dose schemes were independently associated with the improved OS of patients (adjusted hazard ratio [HR], 0.606; 95% CI, 0.382 to 0.961; P = 0.033; Table4).
Table 4 Univariable and Multivariable analyses of covariable associated with OS
Variable
|
Univariate analysis
|
Multivariate analysis
|
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
Gender
|
|
|
|
|
Male VS Female
|
0.875 (0.559 to 1.371)
|
0.563
|
|
|
Age
|
|
|
|
|
≥60 VS <60
|
1.086 (0.678 to 1.739)
|
0.733
|
|
|
Tobacco smoking
|
|
|
|
|
yes VS no
|
0.651 (0.358 to 1.186)
|
0.104
|
0.785 (0.494 to 1.247)
|
0.305
|
EGFR mutation, n (%)
|
|
|
|
|
19 VS 21
|
0.695 (0.434 to 1.113)
|
0.130
|
0.721 (0.421 to 1.233)
|
0.232
|
Number of radiotherapy sites
|
|
|
|
|
1 VS 2-6
|
0.617 (0.377 to 1.010)
|
0.086
|
0.743 (0.413 to 1.335)
|
0.321
|
The Site of radiotherapy
|
|
|
|
|
Brain yes VS no
|
0.778 (0.494 to 1.225)
|
0.279
|
|
|
Bone yes VS no
|
0.751 (0.479 to 1.175)
|
0.199
|
|
|
Dose,Gy
|
|
0.011
|
|
|
<50
|
0.457 (0.253 to 0.826)
|
0.009
|
|
|
≥50,<60
|
1.247 (0.788 to 1.974)
|
0.528
|
|
|
≥60
|
0.628 (0.399 to 0.987)
|
0.011
|
0.606 (0.382 to 0.961)
|
0.033
|
Radiotherapy targeting synchronization
|
|
|
|
|
yes VS no
|
0.743 (0.439 to 1.259)
|
0.308
|
0.758 (0.423 to 1.357)
|
0.351
|
Abbreviations: OS, overall survival