Patient Characteristics
We selected 1811 eligible stage I SCLC patients (Figure 1). The distribution of the patients’ demographics and clinical characteristics is presented in Table 1. Of these, 342 (18.9%) patients were aged <60 years, 981 (54.2%) were aged 60–74 years, and 488 (26.9%) were aged more than 75 years. The number of female patients was 949 (52.4%) and that of the Caucasians was 1578 (87.1%). The most common site was the upper lobe (56.6%), followed by the lower lobe (27.9%) and the other areas (15.56%). The number of patients with a right-sided primary tumor was 1018 (56.2%). The distribution of the tumor size was 53.4%, 28.9%, and 17.7% for <3 cm, 3–5 cm, and >5 cm. As for the tumor extension, the local and the regional ones accounted for 84.3% and 15.7%, respectively. In all, 457 (25.2%) patients were treated with surgery, 929 (51.3%) patients were treated with radiotherapy, and 1217 (67.2%) patients were treated with chemotherapy.
The median follow-up for these patients was 16 months (range: 7 to 33 months). During the follow-up period, 1221 patients died: 986 died of specific causes, and 235 died of other causes. The top three other causes of death were heart disease (27.2%), chronic obstructive pulmonary disease (COPD) and allied conditions (20.9%), and cerebrovascular diseases (4.7%).
Table 1. One-, three-, and five-year cumulative incidence of mortality in stage I SCLC patients
Characteristics
|
N
|
%
|
Event
|
%
|
Cancer-specific death
|
|
Death from other causes
|
1-year (%)
|
3-year (%)
|
5-year (%)
|
P
|
|
1-year (%)
|
3-year (%)
|
5-year (%)
|
P
|
Total
|
1811
|
|
1221
|
|
28.7
|
56.5
|
61.5
|
|
|
5.8
|
11.1
|
13.6
|
|
Age at diagnosis
|
|
|
|
|
|
|
|
<0.001
|
|
|
|
|
0.001
|
<60 years
|
342
|
18.9
|
192
|
15.7
|
18.6
|
49.8
|
53.1
|
|
|
5.2
|
7.7
|
8.2
|
|
60–75 years
|
981
|
54.2
|
640
|
52.4
|
26.1
|
53.5
|
59.5
|
|
|
5.5
|
10.7
|
14.3
|
|
>75 years
|
488
|
26.9
|
389
|
31.9
|
40.9
|
67.1
|
71.4
|
|
|
6.9
|
14.2
|
15.9
|
|
Gender
|
|
|
|
|
|
|
|
0.574
|
|
|
|
|
0.016
|
Female
|
949
|
52.4
|
619
|
50.7
|
27.3
|
56.3
|
60.5
|
|
|
5.1
|
9.1
|
11.3
|
|
Male
|
862
|
47.6
|
602
|
49.3
|
30.1
|
56.7
|
62.6
|
|
|
6.5
|
13.3
|
16.0
|
|
Race
|
|
|
|
|
|
|
|
0.690
|
|
|
|
|
0.183
|
White
|
1578
|
87.1
|
1064
|
87.1
|
28.9
|
56.1
|
60.8
|
|
|
5.9
|
11.3
|
13.8
|
|
Black
|
167
|
9.2
|
111
|
9.1
|
26.4
|
57.9
|
66.0
|
|
|
5.7
|
7.8
|
9.9
|
|
Others
|
66
|
3.7
|
46
|
3.8
|
27.7
|
64.3
|
66.6
|
|
|
3.3
|
15.1
|
17.4
|
|
Anatomic sites
|
|
|
|
|
|
|
|
<0.001
|
|
|
|
|
0.048
|
Upper
|
1025
|
56.6
|
685
|
56.1
|
26.5
|
55.9
|
60.6
|
|
|
5.6
|
11.8
|
14.5
|
|
Middle
|
115
|
6.4
|
76
|
6.2
|
22.7
|
51.6
|
55.1
|
|
|
12.5
|
19.8
|
19.8
|
|
Lower
|
505
|
27.9
|
336
|
27.5
|
29.4
|
55.7
|
61.8
|
|
|
5.1
|
8.0
|
11.1
|
|
Bronchus/others
|
166
|
9.2
|
124
|
10.2
|
43.6
|
66.0
|
70.5
|
|
|
4.5
|
9.9
|
10.8
|
|
Primary tumor location
|
|
|
|
|
|
|
|
0.221
|
|
|
|
|
0.682
|
Left-sided
|
793
|
43.8
|
522
|
42.8
|
28.1
|
55.3
|
59.8
|
|
|
6.2
|
12.0
|
14.1
|
|
Right-sided
|
1018
|
56.2
|
699
|
57.2
|
29.1
|
57.4
|
62.8
|
|
|
5.5
|
10.4
|
13.1
|
|
Tumor size
|
|
|
|
|
|
|
|
<0.001
|
|
|
|
|
0.030
|
≤3 cm
|
967
|
53.4
|
602
|
49.3
|
23.7
|
50.6
|
55.0
|
|
|
5.7
|
12.1
|
15.7
|
|
3–5 cm
|
523
|
28.9
|
379
|
31.0
|
30.5
|
59.6
|
66.1
|
|
|
7.1
|
10.9
|
12.1
|
|
>5 cm
|
321
|
17.7
|
240
|
19.7
|
40.5
|
68.8
|
73.3
|
|
|
3.9
|
8.5
|
9.5
|
|
Tumor extension
|
|
|
|
|
|
|
|
<0.001
|
|
|
|
|
0.005
|
Local
|
1526
|
84.3
|
1020
|
83.5
|
27.9
|
55.4
|
59.7
|
|
|
6.3
|
11.8
|
14.6
|
|
Regional
|
285
|
15.7
|
201
|
16.5
|
32.5
|
62.2
|
71.3
|
|
|
3.3
|
7.3
|
8.0
|
|
Grading
|
|
|
|
|
|
|
|
0.038
|
|
|
|
|
0.375
|
Good or moderate
|
34
|
1.9
|
18
|
1.5
|
16.3
|
36.6
|
41.3
|
|
|
3.1
|
6.8
|
16.7
|
|
Poor
|
343
|
18.9
|
207
|
17.0
|
26.3
|
51.3
|
54.1
|
|
|
4.9
|
11.8
|
13.3
|
|
Undifferentiated
|
439
|
24.2
|
318
|
26.0
|
26.5
|
58.0
|
65.0
|
|
|
5.6
|
8.4
|
11.6
|
|
NOS
|
995
|
54.9
|
678
|
55.5
|
30.8
|
58.1
|
62.9
|
|
|
6.3
|
12.3
|
14.5
|
|
Surgery
|
|
|
|
|
|
|
|
<0.001
|
|
|
|
|
0.593
|
Yes
|
457
|
25.2
|
214
|
17.5
|
11.2
|
35.6
|
40.4
|
|
|
4.6
|
9.5
|
12.0
|
|
No
|
1354
|
74.8
|
1007
|
82.5
|
34.5
|
63.4
|
68.5
|
|
|
6.2
|
11.6
|
14.1
|
|
Chemotherapy
|
|
|
|
|
|
|
|
<0.001
|
|
|
|
|
<0.001
|
Yes
|
1217
|
67.2
|
783
|
64.1
|
23.8
|
54.0
|
60.0
|
|
|
3.6
|
8.6
|
11.2
|
|
No
|
594
|
32.8
|
438
|
35.9
|
38.7
|
61.8
|
64.6
|
|
|
10.4
|
16.3
|
18.6
|
|
Radiotherapy
|
|
|
|
|
|
|
|
<0.001
|
|
|
|
|
0.773
|
Yes
|
929
|
51.3
|
595
|
48.7
|
21.7
|
52.1
|
58.8
|
|
|
4.1
|
10.3
|
13.3
|
|
No
|
882
|
48.7
|
626
|
51.3
|
36.0
|
61.2
|
64.4
|
|
|
7.6
|
12.0
|
13.8
|
|
Probability of Death
The cumulative incidence function curves are plotted in Figure 2. The one-, three-, and five-year estimates of the cumulative incidence of mortality according to the age at diagnosis, gender, race, anatomic sites, laterality, tumor size, tumor extension, grading, and treatment are summarized in Table 1. The five-year cumulative incidence of mortalities resulting from specific causes and other causes was 61.5% and 13.6%, respectively. Patients with the characteristics of big tumor size, regional tumor extension, older age, and no surgery, chemotherapy, and radiotherapy were associated with high cause-specific death probabilities. Patients aged more than 75 years had the highest probability of death resulting from specific causes (71.4%). The cumulative incidence of cause-specific death for patients who did not undergo surgery was as low as 40.4%. As for the patients who did not receive chemotherapy and radiotherapy, their cumulative incidence of cause-specific death was 64.6% and 64.4%, respectively.
As the results of competing risk model displayed on Table 2, tumor size, extent of tumor, laterality of tumor, surgery, and radiotherapy could strongly predict cancer-specific death. Patients who underwent surgery or radiotherapy had a lower cause-specific mortality, with a subdistribution hazard ratios (sdHR) of 0.370 (95%CI 0.304-0.450) and 0.553 (95%CI 0.477-0.641), respectively. Patients with regional tumor extension were more likely to die of their disease, with an sdHR of 1.434 (95%CI 1.216-1.693), when compared with local extension. Additionally, right-sided and larger tumor size were also associated with worse cancer-specific outcomes. For those patients who died from other causes, age, male, local extension, and patients without chemotherapy had a more aggressive impact, with a higher sdHR
Table 2. Proportional Subdistribution Hazard Models of Probabilities of Cancer-Specific Death and Death from Other Causes for Patients with Stage I SCLC.
Characteristics
|
Cancer-Specific Death
|
|
Death from Other Causes
|
Coefficient
|
sdHR (95%CI)
|
P
|
|
Coefficient
|
sdHR (95%CI)
|
P
|
Age
|
0.011
|
1.010 (0.997-1.024)
|
0.130
|
|
0.056
|
1.057 (1.010-1.105)
|
0.015
|
Age'
|
0.015
|
1.015 (0.999-1.031)
|
0.065
|
|
-0.050
|
0.951 (0.911-0.993)
|
0.024
|
Tumor size
|
0.118
|
1.125 (1.013-1.249)
|
0.027
|
|
-0.106
|
0.899 (0.746-1.083)
|
0.260
|
Tumor size'
|
-0.071
|
0.931 (0.806-1.076)
|
0.340
|
|
0.044
|
1.045 (0.780-1.399)
|
0.770
|
Male
|
-0.024
|
0.976 (0.858-1.110)
|
0.720
|
|
0.332
|
1.393 (1.071-1.811)
|
0.013
|
Race
|
|
|
|
|
|
|
|
Black
|
-0.022
|
0.978 (0.805-1.187)
|
0.830
|
|
-0.454
|
0.634 (0.368-1.094)
|
0.100
|
Others
|
-0.159
|
0.853 (0.591-1.231)
|
0.400
|
|
-0.028
|
0.972 (0.490-1.929)
|
0.940
|
Anatomic sites
|
|
|
|
|
|
|
|
Middle
|
-0.248
|
0.780 (0.580-1.050)
|
0.100
|
|
0.424
|
1.528 (0.937-2.492)
|
0.089
|
Lower
|
0.011
|
1.010 (0.874-1.168)
|
0.880
|
|
-0.256
|
0.774 (0.564-1.060)
|
0.110
|
Bronchus/Other
|
0.256
|
1.291 (1.018-1.636)
|
0.034
|
|
-0.192
|
0.825 (0.492-1.382)
|
0.470
|
Right-sided
|
0.149
|
1.160 (1.015-1.324)
|
0.028
|
|
-0.132
|
0.876 (0.669-1.147)
|
0.340
|
Regional
|
0.361
|
1.434 (1.216-1.693)
|
<0.001
|
|
-0.516
|
0.597 (0.381-0.934)
|
0.024
|
Grading
|
|
|
|
|
|
|
|
Poorly
|
0.171
|
1.186 (0.701-2.006)
|
0.520
|
|
-0.213
|
0.807 (0.317-2.053)
|
0.650
|
Undifferentiated
|
0.229
|
1.257 (0.748-2.111)
|
0.390
|
|
-0.353
|
0.702 (0.277-1.779)
|
0.460
|
NOS
|
0.156
|
1.168 (0.698-1.955)
|
0.550
|
|
-0.108
|
0.897 (0.356-2.259)
|
0.820
|
Surgery
|
-0.992
|
0.370 (0.304-0.450)
|
<0.001
|
|
-0.162
|
0.850 (0.590-1.223)
|
0.380
|
Chemotherapy
|
-0.064
|
0.937 (0.801-1.096)
|
0.420
|
|
-0.582
|
0.558 (0.411-0.758)
|
<0.001
|
Radiotherapy
|
-0.592
|
0.553 (0.477-0.641)
|
<0.001
|
|
0.182
|
1.199 (0.885-1.625)
|
0.240
|
Note: Age’ and Tumor size’ are constructed spline variables (when k=3).
Nomogram
The nomogram built on the basis of Fine and Gray’s model is shown in Figure 3. The nomogram was used to find the corresponding score on the points row above the graph for each variable included in the model. All the assigned scores of the variables were added to obtain the total score, and then, a straight line was drawn to the bottom of the graph to estimate the probability of death.
Model Performance
The Harrell C index [5] was applied to indicate the discrimination, and a calibration plot obtained using the method provided by Gray [2], which was adopted to evaluate calibration. Discrimination, as measured by the 1000 resample bootstrap-corrected C index, was 0.696 (95% CI: 0.688–0.705) for the cancer-specific death and 0.672 (95% CI: 0.650–0.694) for other causes resulting in death. The calibration plot (Figure 4) showed a high consistency between the predicted and the observed events.