Pulmonary LCNEC is a rare primary malignant tumor with a poor prognosis[15, 16]. The clinical and biological characteristics of pulmonary LCNEC were similar to small cell lung carcinoma, but standard treatment management has not yet been established. Recent reports showed that surgery remains a reliable option for patients with pulmonary LCNEC[17-21]. We used competing risks model to analyze the survival of pulmonary LCNEC patients after surgery in the SEER database. Our results indicated that age, T stage, M stage, RNP, radiotherapy, and chemotherapy were independent prognostic factors for patients with pulmonary LCNEC after surgery. In addition, the competing risks model showed more accurate results compared to traditional survival analysis. In our study, 93 patients died due to other causes, accounting for 26% of deaths. In the traditional survival analysis, these 93 competing events will be used as censored data, which may lead to incorrect and biased results.
We found that age was an independent factor that influences the prognosis in the multivariate analysis based on Fine-Gray model. However, the Cox model showed that age was not an independent prognostic factor for patients with pulmonary LCNEC after surgery. This suggested that ignoring the competing risk between outcome events may lead to bias in results. Age has been identified as a prognostic factor for patients with pulmonary LCNEC, but the division of age is still controversial. Kujtan et al. concluded that patients older than 70 years have a worse prognosis, while Cao et al. report that patients 65 years or older have worse survival outcomes than younger patients. For patients with pulmonary LCNEC after surgery, our results showed that patients over 75 years of age had a higher risk of LCSD. Due to the differences in the populations included in these studies and the limited number of current studies, multicenter studies were needed for validation.
The TNM stage were the important and stable indicators to predict the survival time of patients with lung cancer. The prognosis of patients differed significantly between different clinical stages. Our results indicated that T stage and M stage were an independent prognostic factor for patients with pulmonary LCNEC after surgery. However, no correlation between N stage and LCNEC-specific death was observed in the Fine-Gray model and Cox model. Cattoni et al. analyzed 101 patients with pulmonary LCNEC who underwent lung resection, and the results showed that the higher the T stage, the worse the prognosis, and there was no statistical significance between N stage and survival rate. A recent study analyzed the metastasis pattern of pulmonary LCNEC and found that lymph node metastasis and distant metastasis were adverse factors for survival. Our results also showed a similar phenomenon. Patients with distant metastases had a worse prognosis than patients without metastases, and the greater the number of positive regional lymph nodes, the worse the prognosis. Positive lymph nodes had a predictive role in the prognosis of lung cancer. Previous study had reported that patients with lymph node positive non-small cell lung cancer had a higher risk of recurrence. In addition, the positive-to-resected lymph node ratio predicted survival in many cancers[27, 28]. Therefore, positive lymph node assessment may be a way to predict survival outcomes in patients with pulmonary LCNEC.
Given that we know very little about the clinicopathological and biological characteristics of pulmonary LCNEC, there is currently no uniform treatment available for reference. Previous studies have shown that surgery is very important for patients with early-stage pulmonary LCNEC[19-21]. However, the use of radiotherapy and chemotherapy remains controversial. Our study showed that radiotherapy and chemotherapy were an independent prognostic factor for patients with pulmonary LCNEC after surgery. Iyoda et al. analyzed 79 patients with pulmonary LCNEC and showed that platinum-based adjuvant chemotherapy after surgery may reduce tumor recurrence. Tang et al. reported that cisplatin combined with pemetrexed is effective and safe in patients with pulmonary LCNEC. Furthermore, a retrospective study included 139 patients undergoing curative-intent surgery for LCNEC, of which 50 patients received adjuvant chemotherapy, radiotherapy, or concurrent chemoradiotherapy after surgery. The results of long-term follow-up showed that the 5-year overall survival rate was 53% and the disease-free survival rate was 39%. In summary, current evidence suggests that patients with pulmonary LCNEC after surgery may benefit from adjuvant therapy.
This study still had some limitations. First, since the study had a retrospective design, inherent selection bias might have been present. Second, the SEER database did not contain all clinical factors, so some factors that may affected the survival of patients were not included, such as smoking status, comorbidities, and weight. Third, although the SEER database is a source of high-quality data that can be used for population-based studies, it still has limitations, such as lack of detailed information on chemotherapy, surgery, and combination therapy. Fourth, small sample size of patients in some subgroups may reduce accuracy of results.