A total of 420 subjects diagnosed with SPSCLC after NSCLC were randomized into the training (N = 296) and validation (N = 124) cohorts. The process of population screening is presented in Supplementary Fig. 1. The median follow-up time was 10.00 months (interquartile range (IQR): 4.00, 13.63) in the overall study population, 10.00 months (IQR: 4.00, 17.00) in the training cohort, and 10.00 months (IQR: 5.00, 18.00) in the validation cohort. The baseline demographic data of the patients are reported in Table 1. The results showed that a larger proportion of the population consisted of patients who had received surgery for the first but not the second primary tumor. White was the most common ethnicity in the two cohorts. Nonetheless, no significant difference was detected between the training and validation cohorts (P > 0.05).
Table 1
Baseline clinicopathological characteristics and treatment experience of all patients and those in the training and validation cohort.
| All cohorts [cases (%)] | Training cohort [cases (%)] | Validation cohort [cases (%)] | P |
Total | 420 | 296 | 124 | |
Age, years | | | | 0.420 |
< 75 | 258 (61.4) | 186 (62.8) | 72 (58.1) | |
≥ 75 | 162 (38.6) | 110 (37.2) | 52 (41.9) | |
Marital status | | | | 0.839 |
Married | 207 (49.3) | 145 (49.0) | 62 (50.0) | |
Un-married | 192 (45.7) | 135 (45.6) | 57 (46.0) | |
Unknown | 21 (5.0) | 16 (5.4) | 5 (4.0) | |
Race | | | | 0.066 |
White | 366 (87.1) | 263 (88.9) | 103 (83.1) | |
Black | 37 (8.8) | 20 (6.8) | 17 (13.7) | |
Other | 17 (4.0) | 13 (4.4) | 4 (3.2) | |
Gender | | | | 0.839 |
Female | 239 (56.9) | 167 (56.4) | 72 (58.1) | |
Male | 181 (43.1) | 129 (43.6) | 52 (41.9) | |
Interval | | | | 0.652 |
≤ 48 months | 266 (63.3) | 190 (64.2) | 76 (61.3) | |
> 48 months | 154 (36.7) | 106 (35.8) | 48 (38.7) | |
SPSCLC stage | | | | 0.269 |
I | 89 (21.2) | 70 (23.6) | 19 (15.3) | |
II | 22 (5.2) | 16 (5.4) | 6 (4.8) | |
III | 137 (32.6) | 92 (31.1) | 45 (36.3) | |
IV | 172 (41.0) | 118 (39.9) | 54 (43.5) | |
IPLC stage | | | | 0.792 |
I | 283 (67.4) | 195 (65.9) | 88 (71.0) | |
II | 34 (8.1) | 25 (8.4) | 9 (7.3) | |
III | 77 (18.3) | 57 (19.3) | 20 (16.1) | |
IV | 26 (6.2) | 19 (6.4) | 7 (5.6) | |
SPSCLC surgery | | | | 0.898 |
No | 373 (88.8) | 262 (88.5) | 111 (89.5) | |
Yes | 47 (11.2) | 34 (11.5) | 13 (10.5) | |
IPLC surgery | | | | 0.269 |
No | 112 (26.7) | 84 (28.4) | 28 (22.6) | |
Yes | 308 (73.3) | 212 (71.6) | 96 (77.4) | |
SPSCLC laterality | | | | 0.188 |
Left | 180 (42.9) | 130 (43.9) | 50 (40.3) | |
Right | 216 (51.4) | 153 (51.7) | 63 (50.8) | |
Unknown | 24 (5.7) | 13 (4.4) | 11 (8.9) | |
IPLC laterality | | | | 0.524 |
Left | 186 (44.3) | 136 (45.9) | 50 (40.3) | |
Right | 229 (54.5) | 157 (53.0) | 72 (58.1) | |
Unknown | 5 (1.2) | 3 (1.0) | 2 (1.6) | |
SPSCLC radiotherapy | | | | 0.439 |
No | 213 (50.7) | 146 (49.3) | 67 (54.0) | |
Yes | 207 (49.3) | 150 (50.7) | 57 (46.0) | |
IPLC radiotherapy | | | | 0.535 |
No | 308 (73.3) | 214 (72.3) | 94 (75.8) | |
Yes | 112 (26.7) | 82 (27.7) | 30 (24.2) | |
SPSCLC chemotherapy | | | | 0.658 |
No | 114 (27.1) | 78 (26.4) | 36 (29.0) | |
Yes | 306 (72.9) | 218 (73.6) | 88 (71.0) | |
IPLC chemotherapy | | | | 0.924 |
No | 278 (66.2) | 195 (65.9) | 83 (66.9) | |
Yes | 142 (33.8) | 101 (34.1) | 41 (33.1) | |
IPLC histology | | | | 0.391 |
Adenocarcinoma | 157 (37.4) | 114 (38.5) | 43 (34.7) | |
SCC | 194 (46.2) | 138 (46.6) | 56 (45.2) | |
Others | 69 (16.4) | 44 (14.9) | 25 (20.2) | |
IPLC grade | | | | 1.000 |
G1/G2 | 180 (42.9) | 127 (42.9) | 53 (42.7) | |
G3/G4 | 169 (40.2) | 119 (40.2) | 50 (40.3) | |
Unknown | 71 (16.9) | 50 (16.9) | 21 (16.9) | |
Abbreviations: IPLC, initial primary lung cancer; SPSCLC, second primary small cell lung cancer; G, nuclear grade; SCC, squamous cell carcinoma. |
Univariate regression analysis indicated that age, SPSCLC stage, SPSCLC surgery, SPSCLC radiation and SPSCLC chemotherapy were significantly related to OS. However, the remaining variables had no significant association with OS (Table 2). Additionally, multivariate analysis revealed that a higher SPSCLC stage, no SPSCLC surgery, no SPSCLC radiation and no SPSCLC chemotherapy were independently adverse predictors of all-cause death (Table 2).
Table 2
Univariate and multivariate analyses of prognostic variables for overall survival in the training cohort.
Variables | Univariate Cox Regression | Multivariate Cox Regression |
HR (95% CI) | P-value | HR (95% CI) | P-value |
Marital status | | | | |
Married | Reference | Reference | - | - |
Un-married | 0.97 (0.76, 1.24) | 0.805 | - | - |
Unknown | 0.87 (0.51, 1.50) | 0.576 | - | - |
Race | | | | |
White | Reference | Reference | - | - |
Black | 1.00 (0.62, 1.62) | 0.997 | - | - |
Other | 0.79 (0.42, 1.49) | 0.469 | - | - |
Gender | | | | |
Female | Reference | Reference | - | - |
Male | 1.11 (0.87, 1.41) | 0.389 | - | - |
Age | | | | |
< 75 | Reference | Reference | Reference | Reference |
≥ 75 | 1.34 (1.05, 1.73) | 0.020 | 1.27 (0.98, 1.63) | 0.067 |
Interval | | | | |
≤ 48 months | Reference | Reference | - | - |
> 48 months | 0.99 (0.77, 1.28) | 0.971 | - | - |
SPSCLC stage | | | | |
I | Reference | Reference | Reference | Reference |
II | 1.23 (0.69, 2.18) | 0.479 | 1.48 (0.83, 2.65) | 0.185 |
III | 1.71 (1.22, 2.42) | 0.002 | 1.86 (1.28, 2.70) | 0.001 |
IV | 2.91 (2.09, 4.06) | < 0.001 | 2.61 (1.80, 3.78) | < 0.001 |
IPLC stage | | | | |
I | Reference | Reference | - | - |
II | 1.12 (0.73, 1.73) | 0.608 | - | - |
III | 1.28 (0.94, 1.73) | 0.118 | - | - |
IV | 1.00 (0.59, 1.70) | 0.994 | - | - |
SPSCLC surgery | | | | |
No | Reference | Reference | Reference | Reference |
Yes | 0.50 (0.34, 0.75) | < 0.001 | 0.51 (0.32, 0.81) | 0.004 |
IPLC surgery | | | | |
No | Reference | Reference | - | - |
Yes | 0.86 (0.66, 1.13) | 0.273 | - | - |
SPSCLC laterality | | | | |
Left | Reference | Reference | - | - |
Right | 0.89 (0.70, 1.15) | 0.386 | - | - |
Unknown | 1.47 (0.81, 2.67) | 0.207 | - | - |
IPLC laterality | | | | |
Left | Reference | Reference | - | - |
Right | 0.96 (0.75,1.22) | 0.737 | - | - |
Unknown | 1.56 (0.49, 4.93) | 0.446 | - | - |
SPSCLC radiotherapy | | | | |
No | Reference | Reference | Reference | Reference |
Yes | 0.58 (0.45, 0.74) | < 0.001 | 0.55 (0.42, 0.71) | < 0.001 |
IPLC radiotherapy | | | | |
No | Reference | Reference | - | - |
Yes | 1.14 (0.87, 1.49) | 0.335 | - | - |
SPSCLC chemotherapy | | | | |
No | Reference | Reference | Reference | Reference |
Yes | 0.62 (0.48, 0.82) | < 0.001 | 0.54 (0.40, 0.71) | < 0.001 |
IPLC chemotherapy | | | | |
No | Reference | Reference | - | - |
Yes | 0.98 (0.76, 1.26) | 0.857 | - | - |
IPLC histology | | | | |
Adenocarcinoma | Reference | Reference | - | - |
SCC | 1.17 (0.90, 1.52) | 0.251 | - | - |
Others | 1.29 (0.89, 1.86) | 0.178 | - | - |
IPLC grade | | | | |
G1/G2 | Reference | Reference | - | - |
G3/G4 | 1.23 (0.95, 1.60) | 0.123 | - | - |
Unknown | 1.06 (0.75, 1.50) | 0.751 | - | - |
Abbreviations: CI, confidence interval; HR, hazard ratio; IPLC, initial primary lung cancer; SPLC, second primary lung cancer; G, grade; SCC, Squamous cell carcinoma. |
In addition, stepwise regression analysis in the training cohort showed that age, SPSCLC stage, SPSCLC surgery, SPSCLC radiation and SPSCLC chemotherapy had minimal AIC values and they were subsequently chosen to establish the nomogram (Fig. 1). The nomogram can be used to predict the 1- and 3-year OS of an individual patient, allowing clinicians to obtain the survival probability of patients. Every independent prognostic factor corresponds to a specific point and the total risk points can be acquired by adding up the individual points. In this study, the total risk points for most patients ranged from 120 to 280.
The findings also showed that both the 1- and 3-year AUCs of the nomogram in the training and validation cohorts were more than 0.75 (Fig. 2). In addition, the 1- and 3-year calibration curves for the two cohorts indicated good linearity between the predicted and observed survival probability (Fig. 2).
The bias-corrected C-index of the nomogram in the training and validation cohorts was 0.69 and 0.75, respectively. Comparatively, the bias-corrected C-index of the AJCC 8th tumor staging in the two cohorts was 0.62 and 0.65, respectively. Besides, The IDI and NRI were carried out to compare the prognostic discriminatory power of the nomogram and the AJCC 8th tumor staging alone (Table 3). Compared to the AJCC 8th tumor staging, the nomogram had significantly higher discrimination (IDI for the 1- and 3-year OS were 0.097 (p < 0.001) and 0.052 (p = 0.02), respectively) and reclassification ability (continuous NRI for 1- and 3-year OS were 0.345 and 0.377, respectively (both p < 0.001), Table 3) in the training group. Additionally, DCA curves from the training group indicated that the nomogram model had good clinical applicability in predicting the 1- and 3-year OS as shown by the marked increase in net benefit (Fig. 3). The validation cohort obtained similar results (Table 3 and Fig. 3).
Table 3
Discrimination ability of different predictive models for primary endpoint in training cohort and validation cohort.
| Training cohort | Validation cohort |
Estimate | 95% CI | P | Estimate | 95% CI | P |
IDI (vs. the AJCC 8th tumor staging) | | | | | | |
For 1-year OS | 0.097 | 0.060–0.151 | < 0.001 | 0.152 | 0.070–0.241 | < 0.001 |
For 3-year OS | 0.052 | 0.005–0.123 | 0.020 | 0.079 | 0.002–0.181 | 0.040 |
NRI (vs. the AJCC 8th tumor staging) | | | | | | |
For 1-year OS | 0.345 | 0.220–0.457 | < 0.001 | 0.388 | 0.194–0.518 | < 0.001 |
For 3-year OS | 0.377 | 0.142–0.541 | < 0.001 | 0.186 | 0.003–0.568 | 0.020 |
Abbreviations: 95% CI, 95% confidence interval; OS, overall survival; AJCC, American Joint Committee on Cancer; NRI, net reclassification improvement; IDI, integrated discrimination improvement. Vs, versus. |
Patients were assigned into three groups based on the total risk point, namely: the low-risk group (total points ≤ 189), the middle-risk group (189 < total points ≤ 244), and the high-risk group (total points > 244). In the total population, the median OS of patients in the low-, middle-, and high-risk groups was 16 months (95% CI, 14–19), 7 months (95% CI, 6–8), and 2 months (95% CI, 1–3), respectively. The Kaplan-Meier curves suggested huge differences in prognosis among the three risk groups (Fig. 4, all Log-rank p < 0.001). Univariate Cox analysis also confirmed the Kaplan-Meier results (all p < 0.001). Compared with the low-risk group, the middle-risk and high-risk groups had a 2.75 and 8.02 times, respectively, higher risk of all-cause mortality in the total population. Similarly, results from the training and validation groups displayed that the risk of all-cause mortality was highest in the high-risk group while patients in the low-risk group had the lowest risk of mortality over time.