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


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

In This Article

Abstract and Introduction


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.


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