Clinical Features and Prognostic Factors of Combined Small Cell Lung Cancer

Development and Validation of a Nomogram Based on the SEER Database

Lan Yang; Yuwen Zhou; Gang Wang; Dan Liu; Bojiang Chen; Dan Pu; Pierpaolo Correale; Dirk Rades; Yusuke Tomita; Alessandro Inno; Mariacarmela Santarpia; Yalun Li; Weimin Li

Disclosures

Transl Lung Cancer Res. 2021;10(11):4250-4265.

Abstract and Introduction

Abstract

Background: Combined small-cell lung cancer (CSCLC) refers to the simultaneous presence of small cell lung cancer (SCLC) and any subtype of the non-small cell lung cancer (NSCLC). This study aimed to explore the prognosis of CSCLC, NSCLC, and pure SCLC patients, and to develop a nomogram to estimate the overall survival (OS) for CSCLC patients.

Methods: Patients diagnosed with NSCLC, CSCLC, and pure SCLC between 2004 and 2015 were identified from the Surveillance Epidemiology and End Results (SEER) database. Survival analyses were performed by using the Kaplan Meier curves and Cox proportional hazards regression. All CSCLC patients were randomly split 7:3 into training and validation sets. A nomogram was developed by integrating all independent predictors for OS. The performance of the nomogram was determined by discrimination, calibration ability, clinical usefulness, and risk stratification ability.

Results: A total of 326,695 lung cancer patients, including 871 with CSCLC, 280,391 with NSCLC, and 45,433 with pure SCLC were enrolled. CSCLC was associated with worse survival compared with NSCLC both in the unmatched and matched cohorts. However, compared to pure SCLC, CSCLC was associated with significantly better survival in the unmatched cohorts only, while showed marginally non-significantly better survival after propensity score matching (PSM). For CSCLC, a nomogram was constructed for the 6-month, 1-year, and 3-year OS prediction by combining the independent risk factors, including age, gender, tumor, node, and metastasis stage, surgery, and chemotherapy. The nomogram showed good discrimination and calibration both in the training and validation sets, and better performance than the tumor–node–metastasis staging system. Risk stratification analysis indicated that the nomogram scores efficiently divided CSCLC patients into low-, intermediate-, and high-risk groups (P<0.001).

Conclusions: CSCLC patients presented a significantly worse prognosis than patients with NSCLC, but comparable prognosis when compared with pure SCLC patients in the matched cohorts. In addition, we developed and validated a nomogram for predicting the 6-month, 1-year, and 3-year OS in CSCLC patients.

Introduction

Small cell lung cancer (SCLC) represents a well-defined class of lung tissue-derivative malignancies showing a neuroendocrine pattern associated to a rapid growth, disposition to early metastasization and mortality.^[1,2] The World Health Organization (WHO) histology classification divides SCLC into SCLC and combined SCLC (CSCLC), with the latter accounting for approximately 5–20% of total SCLC cases.^[3,4] As a relatively infrequent subtype of SCLC, CSCLC refers to the simultaneous presence of SCLC histology and any subtype of the non-small cell lung cancer (NSCLC) histology. Except for the minimum requirement of 10% for large-cell neuroendocrine carcinoma components, CSCLC presents no restrictions on the amount of any other NSCLC components.^[5]

In this context, the prognosis and treatment of patients with CSCLC subset has seldom been investigated.^[6–10] Previous studies have reported that CSCLC and SCLC do not present any significant differences in term of clinical and pathologic features.^[6,7] The latest European Society for Medical Oncology (ESMO) Clinical Practice Guideline does not significantly distinguish between the treatment of CSCLC and pure SCLC.^[5] For what concerns the prognosis of these patients, conflicting results have been reported by different studies. Some studies in fact detected a worse overall survival (OS) in patients with CSCLC compared with those diagnosed with a pure SCLC,^[8,9] while some studies have reported that CSCLC patients have better OS.^[11] A further population-based analysis reported better OS in CSCLC over pure SCLC patients only if diagnosed in the early stage of disease, while any difference in survival was lost for the advanced disease.^[7]

On the OS for patients with CSCLC, there is still a lack of prediction models for what concerns prognosis and risk stratification. Accurate estimation of prognosis at individual level is critical for either decision-making or engagement on an aggressive treatment guidance. We believe that the use of nomogram, a graphic depiction of model which integrate multiple variables, could provide reliable numerical predictions able to individualize the specific risk based on both patient and disease features.^[12] Therefore, we attempted to develop a nomogram based on prognostic model for CSCLC patients using the population-based Surveillance, Epidemiology, and End Results (SEER) database. We present the following article in accordance with the TRIPOD reporting checklist (available at https://dx.doi.org/10.21037/tlcr-21-804).

1 2 3 4 5

Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Demographics and clinicopathologic characteristics of patients with CSCLC, NSCLC, and pure SCLC
Characteristics	CSCLC (n=871)		NSCLC (n=280,391)		P₁ value	Pure SCLC (n=45,433)		P₂ value
Characteristics	Number	%	Number	%	P₁ value	Number	%	P₂ value
Age (years)					0.066			0.298
≤60	229	26.3	71,494	25.5		12,775	28.1
60–70	305	35.0	89,909	32.1		16,162	35.6
>70	337	38.7	118,988	42.4		16,496	36.3
Gender					0.099			<0.001
Female	378	43.4	129,512	46.2		22,700	50.0
Male	493	56.6	150,879	53.8		22,733	50.0
Race					<0.001			0.003
White	727	83.5	224,921	80.2		39,384	86.7
Black	109	12.5	34,226	12.2		4,157	9.1
Other	35	4.0	21,244	7.6		1,892	4.2
Primary site					<0.001			<0.001
Left upper lobe	217	24.9	66,680	23.8		9,921	21.8
Left lower lobe	100	11.5	33,018	11.8		4,159	9.2
Right upper lobe	270	31.0	86,587	30.9		11,949	26.3
Right middle lobe	32	3.7	12,179	4.3		1,860	4.1
Right lower lobe	100	11.5	42,316	15.1		4,952	10.9
Main bronchus	66	7.6	11,450	4.1		5,539	12.2
Unspecific	86	9.9	28,161	10.0		7,053	15.5
T					0.014			<0.001
T1	184	21.1	61,292	21.9		5,276	11.6
T2	291	33.4	92,440	33.0		11,830	26.0
T3	36	4.1	18,775	6.7		2,098	4.6
T4	360	41.3	107,884	38.5		26,229	57.7
N					<0.001			<0.001
N0	285	32.7	119,329	42.6		7,029	15.5
N1	83	9.5	26,116	9.3		3,325	7.3
N2	375	43.1	100,578	35.9		26,110	57.5
N3	128	14.7	34,368	12.3		8,969	19.7
M					0.006			<0.001
M0	460	52.8	161,104	57.5		17,051	37.5
M1	411	47.2	119,287	42.5		28,382	62.5
Surgery					0.537			<0.001
None	626	71.9	198,855	70.9		44,275	97.5
Yes	245	28.1	81,536	29.1		1,158	2.5
Radiation					0.009			0.196
None	473	54.3	164,501	58.7		23,669	52.1
Yes	398	45.7	115,890	41.3		21,764	47.9
Chemotherapy					<0.001			<0.001
None	306	35.1	152,260	54.3		12,780	28.1
Yes	565	64.9	128,131	45.7		32,653	71.9

CSCLC, combined small cell lung cancer; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

Table 2. Univariate and multivariate Cox analyses of OS for NSCLC and CSCLC patients in unmatched and matched cohorts
Characteristics	CSCLC (n=871) and NSCLC (n=280,391)						1:4 match of CSCLC (n=871) and NSCLC (n=3,484)
	Univariable			Multivariable			Univariable			Multivariable
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Age (years)
≤60	1			1			1			1
60–70	1.02	1.01–1.03	<0.001	1.11	1.10–1.12	<0.0.001	1.14	1.04–1.24	0.003	1.16	1.06–1.27	0.001
>70	1.28	1.27–1.30	<0.001	1.30	1.28–1.31	<0.001	1.34	1.23–1.45	<0.001	1.32	1.21–1.44	<0.001
Gender
Female	1			1			1			1
Male	1.29	1.27–1.30	<0.001	1.24	1.23–1.25	<0.001	1.30	1.22–1.39	<0.001	1.30	1.21–1.39	<0.001
Race
White	1			1			1			1
Black	1.13	1.11–1.14	<0.001	0.99	0.98–1.00	0.144	1.13	1.02–1.24	0.016	0.97	0.88–1.07	0.516
Other	0.89	0.87–0.90	<0.001	0.75	0.74–0.76	<0.001	0.94	0.79–1.11	0.444	0.69	0.58–0.81	<0.001
Primary site
Left upper lobe	1			1			1			1
Left lower lobe	1.00	0.98–1.01	0.598	1.03	1.02–1.05	<0.001	1.00	0.89–1.12	0.983	1.00	0.89–1.13	0.945
Right upper lobe	0.99	0.99–1.00	0.059	0.98	0.97–0.99	0.001	0.99	0.90–1.08	0.989	0.92	0.84–1.00	0.055
Right middle lobe	0.96	0.94–0.98	<0.001	0.98	0.96–1.01	0.144	1.14	0.95–1.35	0.150	1.14	0.96–1.36	0.128
Right lower lobe	1.04	1.02–1.05	<0.001	1.05	1.04–1.07	<0.001	1.13	1.00–1.27	0.053	1.13	1.00–1.27	0.051
Main bronchus	1.77	1.74–1.81	<0.001	1.21	1.18–1.23	<0.001	1.61	1.41–1.84	<0.001	1.21	1.05–1.38	0.007
Unspecific	1.90	1.87–1.93	<0.001	1.20	1.18–1.22	<0.001	1.84	1.63–2.08	<0.001	1.26	1.11–1.42	<0.001
T
T1	1			1			1			1
T2	1.69	1.67–1.72	<0.001	1.47	1.45–1.49	<0.001	1.50	1.36–1.65	<0.001	1.45	1.31–1.60	<0.001
T3	2.37	2.33–2.42	<0.001	1.88	1.84–1.92	<0.001	1.99	1.68–2.37	<0.001	1.70	1.42–2.02	<0.001
T4	3.39	3.35–3.43	<0.001	1.90	1.87–1.93	<0.001	2.61	2.37–2.86	<0.001	1.77	1.60–1.97	<0.001
N
N0	1			1			1			1
N1	1.46	1.44–1.48	<0.001	1.41	1.39–1.43	<0.001	1.24	1.09–1.40	0.001	1.33	1.17–1.51	<0.001
N2	2.35	2.33–2.38	<0.001	1.54	1.52–1.56	<0.001	2.18	2.01–2.36	<0.001	1.62	1.48–1.77	<0.001
N3	2.71	2.68–2.75	<0.001	1.55	1.52–1.57	<0.001	2.46	2.22–2.73	<0.001	1.53	1.36–1.72	<0.001
M
M0	1			1			1			1
M1	2.97	2.94–2.99	<0.001	1.80	1.78–1.82	<0.001	2.78	2.59–2.97	<0.001	1.86	1.72–2.01	<0.001
Histology
CSCLC	1			1			1			1
NSCLC	0.82	0.77–0.88	<0.001	0.77	0.72–0.83	<0.001	0.84	0.77–0.91	<0.001	0.77	0.71–0.83	<0.001
Surgery
None	1			1			1			1
Yes	0.22	0.22–0.23	<0.001	0.31	0.30–.0.31	<0.001	0.26	0.24–0.29	<0.001	0.36	0.33–0.40	<0.001
Radiation
None	1			1			1			1
Yes	1.34	1.33–1.35	<0.001	0.90	0.89–0.91	<0.001	1.189	1.11–1.27	<0.001	0.92	0.85–0.98	0.015
Chemotherapy
None	1			1			1			1
Yes	1.02	1.01–1.03	<0.001	0.51	0.51–0.52	<0.001	0.97	0.90–1.04	0.335	0.48	0.45–0.52	<0.001

OS, overall survival; CSCLC, combined small cell lung cancer; NSCLC, non-small cell lung cancer; HR, hazard ratio; CI, confidence interval.

Table 3. Univariate and multivariate Cox analyses of OS for NSCLC and pure SCLC patients in unmatched and matched cohorts
Characteristics	CSCLC (n=871) and pure SCLC (n=45,433)						1:4 match of CSCLC (n=871) and pure SCLC (n=3,366)
	Univariable			Multivariable			Univariable			Multivariable
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Age (years)
≤60	1			1			1			1
60–70	1.17	1.14–1.20	<0.001	1.14	1.11–1.17	<0.001	1.17	1.08–1.27	<0.001	1.19	1.10–1.30	<0.001
>70	1.60	1.56–1.64	<0.001	1.41	1.37–1.44	<0.001	1.55	1.43–1.68	<0.001	1.52	1.40–1.66	<0.001
Gender
Female	1			1			1			1
Male	1.18	1.16–1.20	<0.001	1.16	1.14–1.18	<0.001	1.38	1.29–1.47	<0.001	1.31	1.23–1.40	<0.001
Race
White	1			1			1			1
Black	0.93	0.90–0.97	<0.001	0.94	0.91–0.97	<0.001	1.11	1.01–1.23	0.032	1.02	0.93–1.13	0.646
Other	0.96	0.91–1.00	0.061	0.91	0.87–0.95	<0.001	1.00	0.85–1.18	0.985	0.73	0.62–0.86	<0.001
Primary site
Left upper lobe	1			1			1			1
Left lower lobe	1.06	1.02–1.10	0.004	1.03	0.99–1.07	0.112	0.95	0.85–1.07	0.411	1.03	0.92–1.16	0.590
Right upper lobe	0.98	0.96–1.01	0.231	1.00	0.97–1.03	0.881	0.94	0.86–1.03	0.183	0.93	0.85–1.02	0.130
Right middle lobe	0.99	0.94–1.04	0.638	0.99	0.94–1.04	0.639	0.87	0.73–1.04	0.137	0.82	0.69–0.98	0.031
Right lower lobe	1.08	1.04–1.12	<0.001	1.04	1.01–1.08	0.026	1.00	0.89–1.12	0.983	1.07	0.95–1.21	0.241
Main bronchus	1.12	1.08–1.16	<0.001	1.05	1.01–1.09	0.006	1.38	1.21–1.57	<0.001	1.11	0.97–1.26	0.144
Unspecific	1.32	1.28–1.36	<0.001	1.08	1.05–1.11	<0.001	1.63	1.46–1.83	<0.001	1.10	0.98–1.23	0.122
T
T1	1			1			1			1
T2	1.31	1.26–1.35	<0.001	1.23	1.19–1.27	<0.001	1.62	1.47–1.78	<0.001	1.27	1.15–1.40	<0.001
T3	1.47	1.40–1.55	<0.001	1.36	1.29–1.43	<0.001	2.15	1.82–2.54	<0.001	1.54	1.29–1.83	<0.001
T4	1.70	1.65–1.76	<0.001	1.43	1.39–1.48	<0.001	2.64	2.41–2.90	<0.001	1.62	1.46–1.79	<0.001
N
N0	1			1			1			1
N1	1.10	1.05–1.14	<0.001	1.14	1.09–1.19	<0.001	1.33	1.17–1.51	<0.001	1.38	1.22–1.57	<0.001
N2	1.39	1.35–1.43	<0.001	1.31	1.27–1.35	<0.001	2.07	1.91–2.24	<0.001	1.52	1.39–1.66	<0.001
N3	1.47	1.42–1.52	<0.001	1.34	1.29–1.38	<0.001	2.20	1.99–2.44	<0.001	1.36	1.22–1.53	<0.001
M
M0	1			1			1			1
M1	2.13	2.08–2.17	<0.001	1.78	1.74–1.82	<0.001	2.94	2.74–3.15	<0.001	2.02	1.88–2.18	<0.001
Histology
CSCLC	1			1			1
Pure SCLC	1.40	1.30–1.50	<0.001	1.10	1.02–1.19	0.012	1.06	0.97–1.14	0.185
Surgery
None	1			1			1			1
Yes	0.38	0.36–0.41	<0.001	0.44	0.42–0.48	<0.001	0.36	0.33–0.39	<0.001	0.51	0.46–0.56	<0.001
Radiation
None	1			1			1			1
Yes	0.49	0.48–0.50	<0.001	0.67	0.42–0.69	<0.001	0.72	0.67–0.76	<0.001	0.77	0.71–0.82	<0.001
Chemotherapy
None	1			1			1			1
Yes	0.36	0.36–0.37	<0.001	0.39	0.38–0.40	<0.001	0.58	0.54–0.62	<0.001	0.51	0.47–0.55	<0.001

OS, overall survival; CSCLC, combined small cell lung cancer; SCLC, small cell lung cancer; HR, hazard ratio; CI, confidence interval.

Table 4. Univariate and multivariate Cox analyses in CSCLC patients
Characteristics	Univariable			Multivariable
Characteristics	HR	95% CI	P	HR	95% CI	P
Age (years)
≤60	1			1
60–70	1.22	0.98–1.52	0.083	1.30	1.04–1.64	0.023
>70	1.55	1.25–1.92	<0.001	1.59	1.27–1.99	<0.001
Gender
Female	1			1
Male	1.33	1.12–1.58	0.001	1.24	1.03–1.48	0.022
Race
White	1
Black	1.01	0.78–1.31	0.935
Other	1.23	0.75–2.03	0.411
Primary site
Left upper lobe	1			1
Left lower lobe	1.21	0.89–1.64	0.216	1.19	0.87–1.62	0.274
Right upper lobe	0.92	0.73–1.16	0.463	0.87	0.68–1.10	0.230
Right middle lobe	1.12	0.69–1.81	0.642	1.36	0.83–2.22	0.222
Right lower lobe	1.08	0.80–1.46	0.613	1.16	0.85–1.57	0.361
Main bronchus	1.75	1.23–2.50	0.002	1.25	0.86–1.81	0.249
Unspecific	1.63	1.19–2.23	0.002	1.03	0.74–1.43	0.871
T
T1	1			1
T2	1.27	0.99–1.64	0.057	1.22	0.94–1.58	0.129
T3	1.98	1.17–3.17	0.012	1.44	0.82–2.51	0.204
T4	2.36	1.86–2.99	<0.001	1.46	1.12–1.91	0.006
N
N0	1			1
N1	1.17	0.85–1.61	0.333	1.26	0.90–1.75	0.180
N2	2.40	1.95–2.96	<0.001	1.76	1.39–2.25	<0.001
N3	2.94	2.22–3.89	<0.001	1.95	1.42–2.67	<0.001
M
M0	1			1
M1	2.68	2.24–3.21	<0.001	1.82	1.49–2.23	<0.001
Surgery
None	1			1
Yes	0.35	0.28–0.43	<0.001	0.46	0.36–0.58	<0.001
Radiation
None	1
Yes	0.85	0.72–1.01	0.068
Chemotherapy
None	1			1
Yes	0.64	0.54–0.77	<0.001	0.41	0.33–0.50	<0.001

CSCLC, combined small cell lung cancer; HR, hazard ratio; CI, confidence interval.

Table S1. Demographics and clinicopathological characteristics of all patients after PSM
Characteristics	CSCLC (n=871)		NSCLC (n=3,484)		P₁ value	CSCLC (n=871)		Pure SCLC (n=3,366)		P₂ value
Characteristics	Number	%	Number	%	P₁ value	Number	%	Number	%	P₂ value
Age (years)					0.793					0.935
≤60	229	26.3	956	27.4		229	26.3	903	26.8
60–70	305	35.0	1,201	34.5		305	35.0	1,180	35.1
>70	337	38.7	1,327	38.1		337	38.7	1,283	38.1
Gender					0.830					0.965
Female	378	43.4	1,498	43.0		378	43.4	1,458	43.3
Male	493	56.6	1,986	57.0		493	56.6	1,908	56.7
Race					0.974					0.970
White	727	83.5	2,904	83.4		727	83.5	2,818	83.7
Black	109	12.5	434	12.5		109	12.5	411	12.2
Other	35	4.0	146	4.2		35	4.0	137	4.1
Site					0.970					0.973
Left upper lobe	217	24.9	832	23.9		217	24.9	830	24.7
Left lower lobe	100	11.5	427	12.3		100	11.5	390	11.6
Right upper lobe	270	31.0	1,092	31.3		270	31.0	1,011	30.0
Right middle lobe	32	3.7	145	4.2		32	3.7	133	4.0
Right lower lobe	100	11.5	379	10.9		100	11.5	388	11.5
Main bronchus	66	7.6	261	7.5		66	7.6	244	7.2
Unspecific	86	9.9	348	10.0		86	9.9	370	11.0
T					0.994					0.870
T1	184	21.1	740	21.2		184	21.1	690	20.5
T2	291	33.4	1,168	33.5		291	33.4	1,097	32.6
T3	36	4.1	150	4.3		36	4.1	153	4.5
T4	360	41.3	1,426	40.9		360	41.3	1,426	42.4
N					0.867					0.457
N0	285	32.7	1,115	32.0		285	32.7	1,025	30.5
N1	83	9.5	358	10.3		83	9.5	302	9.0
N2	375	43.1	1,520	43.6		375	43.1	1,544	45.9
N3	128	14.7	491	14.1		128	14.7	495	14.7
M					0.220					0.243
M0	460	52.8	1,759	50.5		460	52.8	1,703	50.6
M1	411	47.2	1,725	49.5		411	47.2	1,663	49.4
Surgery					0.384					0.141
None	626	71.9	2,555	73.3		626	71.9	2,502	74.3
Yes	245	28.1	929	26.7		245	28.1	864	25.7
Radiation					0.457					0.791
None	473	54.3	1,843	52.9		473	54.3	1,811	53.8
Yes	398	45.7	1,641	47.1		398	45.7	1,555	46.2
Chemotherapy					0.775					0.325
None	306	35.1	1,206	34.6		306	35.1	1,123	33.4
Yes	565	64.9	2,278	65.4		565	64.9	2,243	66.6

PSM, propensity score matching; CSCLC, combined small cell lung cancer; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

Table S2. Univariate and multivariate Cox analyses of LCSS for NSCLC and CSCLC patients in unmatched and matched cohorts
Characteristics	CSCLC (n=871) and NSCLC (n=280,391)						1:4 match of CSCLC (n=871) and NSCLC (n=3,484)
	Univariable			Multivariable			Univariable			Multivariable
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Age (years)
≤60	1			1			1			1
60–70	0.97	0.96–0.98	<0.001	1.07	1.06–1.08	<0.001	1.10	1.01–1.21	0.031	1.14	1.04–1.25	0.005
>70	1.15	1.14–1.17	<0.001	1.20	1.19–1.22	<0.001	1.23	1.13–1.35	<0.001	1.24	1.13–1.36	<0.001
Gender
Female	1			1			1			1
Male	1.27	1.26–1.28	<0.001	1.21	1.20–1.22	<0.001	1.30	1.21–1.39	<0.001	1.28	1.19–1.37	<0.001
Race
White	1			1			1			1
Black	1.14	1.12–1.15	<0.001	0.98	0.96–0.99	0.001	1.16	1.05–1.29	0.005	0.97	0.88–1.08	0.626
Other	0.90	0.89–0.92	<0.001	0.75	0.73–0.76	<0.001	0.92	0.77–1.10	0.363	0.66	0.55–0.80	<0.001
Primary site
Left upper lobe	1			1			1			1
Left lower lobe	1.00	0.98–1.01	0.597	1.04	1.02–1.06	<0.001	1.03	0.91–1.16	0.683	1.04	0.91–1.17	0.586
Right upper lobe	1.00	0.99–1.01	0.647	0.98	0.97–1.00	0.013	1.01	0.92–1.11	0.882	0.92	0.84–1.01	0.092
Right middle lobe	0.97	0.94–0.99	0.005	0.99	0.97–1.02	0.437	1.19	0.99–1.43	0.060	1.19	0.99–1.43	0.061
Right lower lobe	1.04	1.03–1.06	<0.001	1.06	1.04–1.08	<0.001	1.09	0.96–1.24	0.186	1.09	0.95–1.24	0.211
Main bronchus	1.87	1.83–1.91	<0.001	1.22	1.19–1.25	<0.001	1.68	1.46–1.93	<0.001	1.21	1.05–1.39	0.009
Unspecific	1.99	1.96–2.02	<0.001	1.21	1.19–1.23	<0.001	1.88	1.66–2.14	<0.001	1.23	1.08–1.40	0.002
T
T1	1			1			1			1
T2	1.92	1.90–1.95	<0.001	1.60	1.57–1.62	<0.001	1.70	1.52–1.89	<0.001	1.59	1.42–1.78	<0.001
T3	2.81	2.75–2.86	<0.001	2.08	2.03–2.12	<0.001	2.34	1.95–2.81	<0.001	1.90	1.57–2.29	<0.001
T4	4.06	4.01–4.12	<0.001	2.09	2.05–1.12	<0.001	3.02	2,73–3.35	<0.001	1.93	1.73–2.16	<0.001
N
N0	1			1			1			1
N1	1.62	1.60–1.65	<0.001	1.49	1.47–1.52	<0.001	1.34	1.17–1.53	<0.001	1.38	1.20–1.58	<0.001
N2	2.70	2.67–2.73	<0.001	1.63	1.61–1.65	<0.001	2.46	2.52–2.68	<0.001	1.72	1.56–1.90	<0.001
N3	3.14	3.09–3.18	<0.001	1.63	1.60–1.65	<0.001	2.80	2.50–3.12	<0.001	1.61	1.42–1.82	<0.001
M
M0	1			1			1			1
M1	3.37	3.34–3.40	<0.001	1.92	1.90–1.94	<0.001	3.10	2.88–3.34	<0.001	2	1.84–2.17	<0.001
Histology
CSCLC	1			1			1			1
NSCLC	0.77	0.72–0.83	<0.001	0.74	0.69–0.80	<0.001	0.80	0.73–0.87	<0.001	0.73	0.67–0.79	<0.001
Surgery
None	1			1			1			1
Yes	0.18	0.18–0.19	0.280	0.27	0.27–0.28	<0.001	0.23	0.21–0.26	<0.001	0.35	0.31–0.39	<0.001
Radiation
None	1			1			1			1
Yes	1.39	1.38–1.40	<0.001	0.91	0.90–0.92	<0.001	1.24	1.16–1.33	<0.001	0.93	0.86–1.00	0.050
Chemotherapy
None	1			1			1			1
Yes	1.12	1.11–1.13	<0.001	0.52	0.52–0.53	<0.001	1.06	0.98–1.14	0.151	0.49	0.45–0.54	<0.001

LCSS, lung cancer-specific survival; CSCLC, combined small cell lung cancer; NSCLC, non-small cell lung cancer; HR, hazard ratio; CI, confidence interval.

Table S3. Univariate and multivariate Cox analyses of LCSS for NSCLC and pure SCLC patients in unmatched and matched cohorts
Characteristics	CSCLC (n=871) and pure SCLC (n=45,433)						1:4 match of CSCLC (n=793) and pure SCLC (n=3,366)
	Univariable			Multivariable			Univariable			Multivariable
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Age (years)
≤60	1			1			1			1
60–70	1.14	1.12–1.17	<0.001	1.12	1.09–1.44	<0.001	1.12	1.03–1.23	0.011	1.14	1.04–1.24	0.005
>70	1.53	1.49–1.57	<0.001	1.36	1.32–1.39	<0.001	1.47	1.35–1.60	<0.001	1.43	1.31–1.56	<0.001
Gender
Female	1			1			1			1
Male	1.17	1.15–1.20	<0.001	1.15	1.13–1.17	<0.001	1.38	1.29–1.48	<0.001	1.29	1.21–1.39	<0.001
Race
White	1			1			1
Black	0.92	0.89–0.95	<0.001	0.93	0.89–0.96	<0.001	1.11	1.00–1.23	0.057
Other	0.92	0.87–0.97	0.001	0.88	0.83–0.92	<0.001	1.00	0.84–1.19	0.985
Primary site
Left upper lobe	1			1			1			1
Left lower lobe	1.06	1.02–1.10	0.006	1.03	0.99–1.07	0.115	0.95	0.84–1.08	0.452	1.04	0.92–1.17	0.570
Right upper lobe	0.99	0.96–1.02	0.332	1.00	0.97–1.03	0.992	0.94	0.86–1.04	0.221	0.94	0.85–1.03	0.182
Right middle lobe	0.98	0.93–1.04	0.560	0.99	0.94–1.04	0.623	0.90	0.75–1.08	0.255	0.84	0.70–1.02	0.075
Right lower lobe	1.07	1.04–1.11	<0.001	1.04	1.00–1.07	0.067	0.98	0.86–1.10	0.686	1.04	0.92–1.18	0.516
Main bronchus	1.13	1.10–1.18	<0.001	1.05	1.02–1.09	0.005	1.35	1.17–1.55	<0.001	1.06	0.92–1.22	0.443
Unspecific	1.32	1.28–1.37	<0.001	1.07	1.04–1.11	0.000	1.61	1.43–1.82	<0.001	1.07	0.95–1.21	0.274
T
T1	1			1			1			1
T2	1.35	1.30–1.40	<0.001	1.26	1.21–1.31	<0.001	1.74	1.57–1.93	<0.001	1.33	1.20–1.48	<0.001
T3	1.53	1.45–1.62	<0.001	1.40	1.32–1.48	<0.001	2.35	1.97–2.81	<0.001	1.57	1.31–1.89	<0.001
T4	1.77	1.72–1.83	<0.001	1.47	1.42–1.52	<0.001	2.85	2.57–3.15	<0.001	1.66	1.48–1.85	<0.001
N
N0	1			1			1			1
N1	1.11	1.06–1.16	<0.001	1.14	1.09–1.19	<0.001	1.37	1.20–1.57	<0.001	1.40	1.22–1.60	<0.001
N2	1.44	1.40–1.48	<0.001	1.34	1.30–1.38	<0.001	2.24	2.05–2.43	<0.001	1.57	1.43–1.73	<0.001
N3	1.52	1.47–1.58	<0.001	1.36	1.31–1.41	<0.001	2.36	2.11–2.63	<0.001	1.39	1.23–1.57	<0.001
M
M0	1			1			1			1
M1	2.25	2.21–2.30	<0.001	1.88	1.84–1.92	<0.001	3.18	2.96–3.42	<0.001	2.14	1.98–2.32	<0.001
Histology
CSCLC	1			1			1
Pure SCLC	1.38	1.28–1.49	<0.001	1.06	0.98–1.15	0.134	1.02	0.94–1.11	0.669
Surgery
None	1			1			1			1
Yes	0.36	0.33–0.38	<0.001	0.43	0.40–0.46	<0.001	0.33	0.30–0.36	<0.001	0.49	0.44–0.55	<0.001
Radiation
None	1			1			1			1
Yes	0.49	0.48–0.50	<0.001	0.68	0.40–0.46	<0.001	0.73	0.68–0.78	<0.001	0.77	0.72–0.83	<0.001
Chemotherapy
None	1			1			1			1
Yes	0.37	0.36–0.37	<0.001	0.39	0.38–0.39	<0.001	0.59	0.55–0.64	<0.001	0.51	0.47–0.56	<0.001

LCSS, lung cancer-specific survival; CSCLC, combined small cell lung cancer; SCLC, small cell lung cancer; HR, hazard ratio; CI, confidence interval.

Table S4. Demographics and clinicopathologic characteristics of the training and validation data sets
Characteristics	All patients (n=871)		Training data set (N=602)		Validation data set (N=269)		P value
Characteristics	Number	%	Number	%	Number	%	P value
Age (years)							0.009
≤60	229	26.3	174	28.9	55	20.4
60–70	305	35.0	194	32.2	111	41.3
>70	337	38.7	234	38.9	103	38.3
Gender							0.396
Female	378	43.4	267	44.4	111	41.3
Male	493	56.6	335	55.6	158	58.7
Race							0.269
White	727	83.5	508	84.4	219	81.4
Black	109	12.5	74	12.3	35	13.0
Other	35	4.0	20	3.3	15	5.6
Site							0.902
Left upper lobe	217	24.9	154	25.6	63	23.4
Left lower lobe	100	11.5	70	11.6	30	11.2
Right upper lobe	270	31.0	184	30.6	86	32.0
Right middle lobe	32	3.7	22	3.7	10	3.7
Right lower lobe	100	11.5	70	11.6	30	11.2
Main bronchus	66	7.6	41	6.8	25	9.3
Unspecific	86	9.9	61	10.1	25	9.3
T							0.032
T1	184	21.1	125	20.8	59	21.9
T2	291	33.4	197	32.7	94	34.9
T3	36	4.1	18	3.0	18	6.7
T4	360	41.3	262	43.5	98	36.4
N							0.614
N0	285	32.7	194	32.2	91	33.8
N1	83	9.5	61	10.1	22	8.2
N2	375	43.1	263	43.7	112	41.6
N3	128	14.7	84	14.0	44	16.4
M							0.891
M0	460	52.8	317	52.7	143	53.2
M1	411	47.2	285	47.3	126	46.8
Surgery							0.447
None	626	71.9	428	71.1	198	73.6
Yes	245	28.1	174	28.9	71	26.4
Radiation							0.564
None	473	54.3	323	53.7	150	55.8
Yes	398	45.7	279	46.3	119	44.2
Chemotherapy							0.077
None	306	35.1	200	33.2	106	39.4
Yes	565	64.9	402	66.8	163	60.6

Authors and Disclosures

Lan Yang^{1#^}, Yuwen Zhou^{2#^}, Gang Wang^{3^}, Dan Liu^{1^}, Bojiang Chen¹, Dan Pu^{1^}, Pierpaolo Correale^{4^}, Dirk Rades⁵, Yusuke Tomita⁶, Alessandro Inno⁷, Mariacarmela Santarpia⁸, Yalun Li^9* and Weimin Li^{1,10*^}

¹Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China; ²Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; ³Department of Respiratory and Critical Care Medicine, Clinical Research Centre for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, China; ⁴Medical Oncology Unit, Grand Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy; ⁵Department of Radiation Oncology, University of Lübeck, Lübeck, Germany; ⁶Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; ⁷Medical Oncology, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar di Valpolicella (VR), Italy; ⁸Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy; ⁹Department of Respiratory and Critical Care Medicine, Lung Cancer Treatment Center, West China Hospital, Sichuan University, Chengdu, China; ¹⁰Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China

Correspondence to
Yalun Li. Department of Respiratory and Critical Care Medicine, Lung Cancer Treatment Center, West China Hospital, Sichuan University, Chengdu, China. Email: lunlunhx@qq.com; Weimin Li. Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China. Email: weimin003@163.com.

Contributions
(I) Conception and design: L Yang, Y Zhou, G Wang, Y Li, W Li; (II) Administrative support: Y Li, W Li; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: G Wang, D Liu, B Chen, D Pu; (V) Data analysis and interpretation: L Yang, Y Zhou, G Wang, D Liu, B Chen, D Pu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

^#These authors contributed equally to this work.

*These authors contributed equally to this work.

^ORCID: Lan Yang, 0000-0001-9112-4137; Yuwen Zhou, 0000-0002-3625-2854; Gang Wang, 0000-0002-5048-6606; Dan Liu, 0000- 0001-6791-1704; Dan Pu, 0000-0001-7333-478X; Pierpaolo Correale, 0000-0003-2154-6734; Weimin Li, 0000-0003-0985-0311.

Conflicts of Interest
All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-804). The authors have no conflicts of interest to declare.