01.12.2011 | Research | Ausgabe 1/2011 Open Access

Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease
- Zeitschrift:
- Respiratory Research > Ausgabe 1/2011
Electronic supplementary material
Competing interests
Authors' contributions
Background
Methods
Study subjects
Diagnosis of preexisting pulmonary disorder and EGFR-TKIs induced ILD
Subclassification of EGFR-TKIs induced ILD
EGFR mutation status
Electrochemiluminescence immunoassay (ECLIA) to determine circulating levels of KL-6
Statistical analysis
Results
Characteristics of patients
Characteristics
|
No. of patients
|
% patients
|
---|---|---|
Total
|
341
|
100
|
Age (years)
|
||
Mean (± SEM)
|
65.2(± 0.6)
|
|
< 60
|
102
|
29.9
|
≥ 60
|
239
|
70.1
|
Sex
|
||
Female
|
167
|
49.0
|
Male
|
174
|
51.0
|
Histologic type
|
||
Adenocarcinoma
|
296
|
86.8
|
Squamous cell carcinoma
|
34
|
10.0
|
Others
|
11
|
3.2
|
Smoking history
|
||
Current
|
60
|
17.6
|
Former
|
110
|
32.3
|
Never
|
171
|
50.1
|
Disease stage
|
||
IV
|
206
|
60.4
|
IIIB
|
54
|
15.8
|
I-IIIA
|
18
|
5.3
|
Recurrence after surgery
|
63
|
18.5
|
Performance status
|
||
≥ 2
|
141
|
41.3
|
0-1
|
200
|
58.7
|
No. of prior chemotherapy regimens
|
||
≥ 2
|
118
|
34.6
|
0-1
|
223
|
65.4
|
Prior thoracic radiotherapy
|
||
Yes
|
47
|
13.8
|
No
|
294
|
86.2
|
Preexisting pulmonary fibrosis
|
||
Yes
|
48
|
14.1
|
No
|
293
|
85.9
|
Preexisting pulmonary emphysema
|
||
Yes
|
82
|
24.0
|
No
|
259
|
76.0
|
EGFR mutation status
|
||
Wild type
|
57
|
16.7
|
Mutant
|
91
|
26.4
|
Not evaluated
|
193
|
56.9
|
Types of EGFR-TKI
|
||
Gefitinib
|
302
|
88.6
|
Erlotinib
|
39
|
11.4
|
Characteristics
|
Total
|
EGFR-TKIs induced ILD (+)
|
EGFR-TKIs induced ILD (-)
|
p-value
|
---|---|---|---|---|
Total
|
48
|
8
|
40
|
|
Age (years)
|
||||
Mean (± SEM)
|
67.5(± 3.6)
|
66.2(± 1.8)
|
||
< 60
|
12
|
2
|
10
|
1.000
|
≥ 60
|
36
|
6
|
30
|
|
Sex
|
||||
Female
|
11
|
3
|
8
|
0.361
|
Male
|
37
|
5
|
32
|
|
Histologic type
|
||||
Adenocarcinoma
|
37
|
5
|
32
|
0.361
|
Squamous cell carcinoma/Others
|
11
|
3
|
8
|
|
Smoking history
|
||||
Current/Former
|
40
|
5
|
35
|
0.116
|
Never
|
8
|
3
|
5
|
|
Disease stage
|
||||
IV
|
24
|
3
|
21
|
0.701
|
I-IIIB/Recurrence after surgery
|
11
|
5
|
19
|
|
Performance status
|
||||
≥ 2
|
26
|
5
|
21
|
0.710
|
0-1
|
22
|
3
|
19
|
|
No. of prior chemotherapy regimens
|
||||
≥ 2
|
20
|
1
|
19
|
0.116
|
0-1
|
28
|
7
|
21
|
|
Prior thoracic radiotherapy
|
||||
Yes
|
10
|
0
|
10
|
0.177
|
No
|
38
|
8
|
30
|
|
Pattern of preexisting pulmonary fibrosis
|
||||
IPF pattern
|
3
|
1
|
2
|
0.429
|
Non-IPF pattern
|
45
|
7
|
38
|
|
Preexisting pulmonary emphysema
|
||||
Yes
|
24
|
3
|
21
|
0.701
|
No
|
24
|
5
|
19
|
|
EGFR mutation status
|
||||
Wild type
|
9
|
5
|
4
|
0.0498*
|
Mutant
|
11
|
1
|
10
|
|
(Not evaluated)
|
(28)
|
(2)
|
(26)
|
|
Types of EGFR-TKI
|
||||
Gefitinib
|
40
|
5
|
35
|
0.116
|
Erlotinib
|
8
|
3
|
5
|
Incidence and characteristics of patients with EGFR-TKIs induced ILD
No
|
Age
|
Sex
|
Histological type
|
Smoking history
|
Stage
|
PS
|
Prior CT
|
Prior RT
|
Preexisting fibrosis
|
Preexisting emphysema
|
EGFRmutation
|
Type of EGFR-TKI
|
Length of EGFR-TKI
|
CT findings
|
Prognosis
|
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1
|
68
|
M
|
SCC
|
Ex
|
IIIB
|
1
|
1
|
No
|
No
|
Yes
|
N.E.
|
Gefitinib
|
11
|
COP/EP
|
Alive
|
2
|
80
|
M
|
SCC
|
Never
|
Rec
|
2
|
1
|
No
|
Yes
|
Yes
|
Wild
|
Gefitinib
|
17
|
COP/EP
|
Alive
|
3
|
70
|
F
|
SCC
|
Never
|
IIIA
|
1
|
1
|
Yes
|
No
|
No
|
N.E.
|
Gefitinib
|
24
|
HP
|
Alive
|
4
|
60
|
M
|
ADC
|
Never
|
IIIB
|
1
|
1
|
No
|
No
|
No
|
N.E.
|
Gefitinib
|
35
|
COP/EP
|
Alive
|
5
|
68
|
F
|
ADC
|
Ex
|
Rec
|
1
|
2
|
No
|
No
|
No
|
Wild
|
Gefitinib
|
16
|
AIP
|
Dead
|
6
|
60
|
M
|
ADC
|
Current
|
IIIB
|
1
|
2
|
No
|
No
|
Yes
|
N.E.
|
Gefitinib
|
26
|
COP/EP
|
Alive
|
7
|
57
|
M
|
ADC
|
Never
|
Rec
|
0
|
3
|
No
|
No
|
No
|
L858R
|
Gefitinib
|
51
|
COP/EP
|
Alive
|
8
|
73
|
M
|
ADC
|
Current
|
IV
|
4
|
0
|
No
|
Yes
|
Yes
|
N.E.
|
Gefitinib
|
13
|
AIP
|
Dead
|
9
|
65
|
F
|
ADC
|
Never
|
IV
|
2
|
3
|
No
|
No
|
No
|
N.E.
|
Gefitinib
|
38
|
HP
|
Dead
|
10
|
69
|
F
|
ADC
|
Never
|
IIIB
|
2
|
1
|
No
|
Yes
|
No
|
N.E.
|
Gefitinib
|
14
|
AIP
|
Dead
|
11
|
84
|
F
|
ADC
|
Ex
|
IIIB
|
4
|
0
|
No
|
Yes
|
No
|
Wild
|
Gefitinib
|
16
|
AIP
|
Dead
|
12
|
63
|
F
|
SCC
|
Never
|
IV
|
1
|
1
|
No
|
Yes
|
No
|
N.E.
|
Gefitinib
|
50
|
COP/EP
|
Dead
|
13
|
67
|
F
|
ADC
|
Never
|
Rec
|
0
|
1
|
No
|
No
|
No
|
Deletion
|
Gefitinib
|
48
|
HP
|
Alive
|
14
|
60
|
M
|
ADC
|
Current
|
IV
|
4
|
0
|
No
|
Yes
|
Yes
|
L858R
|
Gefitinib
|
17
|
HP
|
Dead
|
15
|
55
|
M
|
ADC
|
Ex
|
IV
|
3
|
4
|
No
|
No
|
No
|
L858R
|
Gefitinib
|
47
|
COP/EP
|
Dead
|
16
|
69
|
M
|
ADC
|
Current
|
IV
|
3
|
1
|
No
|
Yes
|
No
|
Wild
|
Erlotinib
|
14
|
AIP
|
Dead
|
17
|
56
|
M
|
SCC
|
Current
|
Rec
|
0
|
1
|
No
|
Yes
|
Yes
|
Wild
|
Erlotinib
|
21
|
COP/EP
|
Alive
|
18
|
59
|
M
|
ADC
|
Ex
|
Rec
|
1
|
2
|
No
|
Yes
|
No
|
Wild
|
Erlotinib
|
5
|
HP
|
Alive
|
19
|
66
|
M
|
ADC
|
Current
|
IIIB
|
0
|
0
|
No
|
No
|
No
|
L858R
|
Gefitinib
|
17
|
COP/EP
|
Alive
|
20
|
64
|
F
|
ADC
|
Never
|
Rec
|
1
|
1
|
No
|
No
|
No
|
L858R
|
Erlotinib
|
31
|
HP
|
Alive
|
Risk factors for developing EGFR-TKIs induced ILD
Variables
|
Odds ratio
|
95% CI
|
P-value
|
|
---|---|---|---|---|
Univariate analysis
|
||||
Age (years)
|
≥ 60/< 60
|
1.758
|
0.626-6.256
|
0.301
|
Gender
|
Male/Female
|
1.472
|
0.593-3.848
|
0.406
|
Histological type
|
Non-ADC/ADC
|
2.342
|
0.730-6.420
|
0.142
|
Smoking history
|
Never/Smoker
|
1.006
|
0.402-2.516
|
0.989
|
Performance status
|
≥ 2/0-1
|
0.942
|
0.360-2.341
|
0.899
|
No. of prior chemotherapy regimens
|
≥ 2/0-1
|
0.800
|
0.277-2.053
|
0.652
|
Prior thoracic radiotherapy
|
Yes/No
|
0.315
|
0.017-1.575
|
0.187
|
Preexisting pulmonary fibrosis
|
Yes/No
|
4.683
|
1.741-12.042
|
0.003*
|
Preexisting pulmonary emphysema
|
Yes/No
|
1.382
|
0.476-3.574
|
0.531
|
EGFR mutation
|
Wild type/
EGFR mutant
|
1.667
|
0.497-5.594
|
0.400
|
Types of EGFR-TKI
|
Gefitinib/Erlotinib
|
2.043
|
0.562-5.948
|
0.253
|
Serum KL-6 level at baseline (U/ml)
|
≥ 500/< 500
|
2.096
|
0.679-7.116
|
0.199
|