Prognostic factors and treatment strategies of limited-stage primary esophageal small-cell carcinoma—a SEER database analysis

Introduction

Primary esophageal small-cell carcinoma (PESC) is one of the poorly differentiated esophageal neuroendocrine carcinoma (1), first discovered and reported by McKeown in 1952 (2); the incidence rate of PESC is low, accounting for 0.05–4% of esophageal carcinoma (3,4), so there is still no prospective randomized controlled study. Its malignant degree is high, treatment effect is poor. Of the 515 cases with PESC reported by Li et al. (5), the 1-, 2-, and 5-year survival rates were only 31.5%, 14.7%, and 6.0%, respectively, with a median survival of 7.0 months. A single-centre study by Miao et al. included 113 patients and showed that the 1-year and 3-year survival rates were 45% and 12%, respectively (4). The 1-, 3-, and 5-year survival rates of 100 PESC patients reported by Xiayimaierdan et al. (6) were 57.0%, 18.0%, and 11.0%, respectively, with a median survival of 13.8 months. Most patients metastasize and die within 1 year; even limited-stage patients have a poor prognosis. Verma et al. reported 323 cases of non-metastatic PESC, with a median overall survival (mOS) of 21 months in the surgery group, 18 months in the chemoradiotherapy (CR) group, and 10 months in the chemotherapy alone group (7). Its treatment mode has not yet been established. Treatments are mostly based on small cell lung cancer, but that is not necessarily scientific. Recent studies have found that its genetic background is very different (8,9). In recent years, it has been reported that the survival time of the combined treatment group mainly based on surgery is longer than that of the CR group, but it is not known whether it is due to insufficient cases or other reasons, showing no statistical difference (5,7). This is also different from small cell lung cancer. Therefore, there is an urgent need to explore treatment modalities for PESC, particularly for patients with limited-stage PESC, where timely and correct treatment may be more likely to prolong survival. The Surveillance, Epidemiology, and End Results (SEER) database is a public database established by the National Cancer Institute of the United States. Its data represents about 50 percent of the U.S. population. The data are large and reliable. This paper intends to search and analyze the basic characteristics, treatment approaches, and prognosis of patients with limited-stage PESC in the SEER database, explore and summarize prognostic factors and more appropriate treatment approaches for such patients, and provide certain references for clinical use. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-311/rc).

Methods

Data source and participants

This is a retrospective population cohort study performed using data obtained from the SEER database. Case identification and data collection for the SEER program began in 1973 with diagnoses in several geographic areas of the United States and its possessions. Over the past 50 years, the geographic areas and population coverage have expanded and now represent nearly 50% of the United States (https://seer.cancer.gov/). We selected three datasets [Incidence-SEER Research Plus data, 8 Registries (1975–2019), Incidence-SEER Research Plus data, 12 Registries (1992–2019), Incidence-SEER Research Plus data, 17 Registries (2000–2019)] published by the SEER database to cover nearly all tumor patients in this database. SEER*Stat software (SEER*Stat, v8.4.0.1) was used to retrieve our study population by tumor site and pathology type between 1975 and 2019. Selection statement: site recode ICD-0-3 = esophagus, histologic type ICD-0-3 =8041/8042/8043/8044/8045. The basic information, clinical information, treatment information and prognosis information of these patients were also exported. Specifically as follows: patient ID, age at diagnosis, race, sex, year of diagnosis, median household income, primary site, biopsy pathology, postoperative pathology, TNM stage (AJCC 7th ed), SEER stage, treatment methods (including surgery, chemotherapy, and radiotherapy) and sequence, survival months, vital status and so on. Each of the three databases was retrieved and the data exported, after which duplicates were removed using Excel software based on patient ID. The information was then collated, code interpreted, screened, checked and analysed. After collation, staging was performed using Veterans Administration Lung Study Group (VALSG) staging system. Limited-stage refers to the tumor being confined to the local anatomical range, irrespective of lymph node metastasis (10). Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Inclusion criteria: (I) PESC is confirmed by pathology. (II) Limited-stage, no distant transfer. (III) There is a clear survival period (OS). (IV) There are definite treatments. Figure 1 shows the case screening process. This process was carried out independently by two Masters, respectively, after which a PhD was responsible for review and verification. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Figure 1 Process of case screen. PESC, primary esophageal small-cell carcinoma; SEER, Surveillance, Epidemiology, and End Results.

Statistical analysis

The survival curves were plotted using the Kaplan-Meier method to calculate the survival rate, and the Log-rank was used to test the differences between the survival curves. Prognostic factors were explored through univariate and multivariate Cox regression survival analyses. A Cox regression survival analysis was also performed to analyze the risk of death among the treatment groups and to compare the survival differences between each treatment group. The non-single treatment (ST) group was defined as the comprehensive treatment (CT) group and was compared to the ST group. SPSS 21. 0 (IBM, USA) was used for statistical analysis. Follow-up period was 230 months (median: 11.5 months). Test level was set as α =0.05 (two-sided test).

Results

Overall study object

From 1975 to 2019, 94,239 cases of esophageal carcinoma were screened from the SEER database, of which 564 (0.60%) were PESC. A total of 186 limited-stage PESC cases were included in the study, excluding four patients with no survival information, 304 patients with distant metastases, and 70 patients with unknown stage. Among them, 32 patients underwent surgery (1 to 4 regional lymph nodes removed), including six cases of partial esophagectomy, 13 cases of esophagectomy with partial gastrectomy, one case of esophagectomy with laryngectomy, seven cases of esophagectomy and five cases of esophagectomy with gastrectomy. Four patients received neoadjuvant radiotherapy. Seven patients received neoadjuvant radiotherapy and chemotherapy. The method of radiotherapy was beam radiation. The mOS of all the 186 patients was 12.0 months [95% confidence interval (CI): 9.827–14.173]. The 6-, 12- and 24-month OS rates were 72.8%, 47.5% and 27.8%, respectively. Only 12.8 percent of patients survived beyond 5 years.

Analysis of prognostic factors

The demographics and characteristics of the cohort was presented in Table 1. And univariate analysis was performed between the different groups. Kaplan-Meier analysis (Figure 2) showed that there were statistical differences in survival time among each group with different ages, years, median household income and N stages (P<0.001, P=0.041, P=0.002, P=0.001). The mOS of the operation group (19 months) was longer than that of the non-operation group (11 months) (P=0.01). The mOS (16 months) in the chemotherapy group was longer than that in the non-chemotherapy group (4 months) (P<0.001). The mOS (16 months) in radiotherapy group was longer than that in the non-radiotherapy group (8 months) (P<0.001).

Figure 2 Survival curves. CT, comprehensive treatment; ST, single treatment.

The results of the univariate and multivariate analyses to identify risk factors for OS are shown in Figures 3,4. Univariate analysis showed that age ≥80 years (P=0.006), year of diagnosis (1997–2007) (P=0.01), year of diagnosis (2008–2019) (P=0.01), N2 (P=0.003), surgery (P=0.02), radiotherapy (P<0.001), and chemotherapy (P<0.001) were prognostic factors affecting OS in limited-stage PESC patients.

Figure 3 Univariate Cox regression survival analysis. HR, hazard ratio; CI, confidence interval; SEER, Surveillance, Epidemiology, and End Results.

Figure 4 Multivariate Cox regression survival analysis. HR, hazard ratio; CI, confidence interval; SEER, Surveillance, Epidemiology, and End Results.

Multivariate analysis showed that SEER stage (P=0.02), age at diagnosis (P=0.007), radiotherapy (P<0.001), surgery (P=0.006), and chemotherapy (P<0.001) were independent prognostic factors affecting OS in patients of limited-stage PESC.

Treatment strategy

Surgery combined with chemoradiotherapy (SCR), surgery combined with chemotherapy (SC) as well as CR could decrease risk of death for patients with limited-stage PESC by 90.3%, 92.9%, 86.2%, respectively (Table 2).

A pairwise comparison between the SCR, SC and CR groups showed no statistical difference.

We defined the SCR, SC and CR groups as CT groups, and the single surgery, single radiotherapy and single chemotherapy groups as ST groups. The difference between the two groups was statistically significant (P<0.001, mOS: 19 vs. 9 months, survival curve as shown in the Figure 2).

It was also interesting to note that mOS was significantly better in each CT group than in each ST group, as shown in Table 3.

Discussion

PESC is a neuroendocrine tumor with a low incidence, high malignancy and poor therapeutic response. Due to its low incidence, there have been no prospective randomized controlled studies and no standardized and validated treatment modalities. Of the 515 patients with PESC reported by Li et al. (5), 259 had distant metastases, excluding 95 cases with unknown staging, representing 61.66% of patients with distant metastases at the time of detection. Despite the tireless efforts of physicians and researchers, the currently reported mOS varies from 8 to 12.5 months (11). So, there is an urgent need to explore its effective treatment options, especially for patients without metastases, as they are likely to receive the most benefit.

Currently, the treatment of PESC is mostly taking reference to that of the treatment of small cell lung cancer, but it is still inconclusive whether this is appropriate. The transcriptomic landscape of PESC is very similar to that of small cell lung cancer (12), but the treatment of PESC remains controversial. Some researchers believe that SC may be effective in certain patients. Gu et al. studied 69 limited-stage PESC patients treated with curative esophagectomy, and support that surgery alone appears to be adequate for disease control in the surgery response disease group, whereas multimodality therapy was associated with improved survival in the surgery nonresponse disease group (13). Verma et al. searched 323 nonmetastatic PESC, and found that despite no OS differences between the surgery-based (median OS: 21 months) and CR arms (18 months), both were superior to chemotherapy alone (10 months) (P<0.001) (7). Jeene et al. studied 58 nonmetastatic PESC, and in multivariable analyses, only the number of chemotherapy cycles was associated with better survival [hazard ratio (HR) =0.78; P=0.006] (14). Zhu et al. conducted a multicentre retrospective study that including 458 patients with limited-stage PESC, and the analysis showed that compared with CR treatment, patients with tumor length >5 cm (HR =0.52; 95% CI: 0.3–0.9; P=0.02) or tumor location in the lower 1/3 (HR =0.59; 95% CI: 0.37–0.93; P=0.03) could achieve significant OS benefit with SC treatment. Patients with tumor length ≤5 cm (HR =1.49; 95% CI: 1.02–2.17; P=0.04) or tumor location in the middle 1/3 (HR =1.55; 95% CI: 1.03–2.36; P=0.04) favored CR treatment (15). Other investigators believe that better outcomes can be achieved with CR. A Japanese study (16) of seven cases of resectable PESC treated with definitive CR showed a median survival of 32 months, and a median survival of 56 months in four patients without recurrence. They therefore concluded that definitive CR is a viable treatment for patients with resectable PESC, and that some patients may have a long survival. Other researchers believe that the sequence of treatments is equally important and emphasise the role of chemotherapy. A multicentre study by Cai et al., which included 280 cases of limited-stage PESC, found that mOS (26.0 vs. 19.5 months, respectively; HR =0.69; 95% CI: 0.51 to 0.92; P=0.01) and progression-free survival (16.0 vs. 13.0 months, respectively; HR =0.75; 95% CI: 0.57 to 0.99; P=0.03) were longer in the preoperative chemotherapy group than in the direct surgery group (10). Li et al. (17) found from 162 patients with PESC who underwent radiotherapy in the SEER database that combination chemotherapy could improve the survival rate of such patients at all stages. Zhao et al. (18) reported a single-centre study of 129 cases of limited-stage PESC and found that patients who received concurrent CR had better OS and recurrence-free survival (RFS) than those who received sequential CR (P=0.006).

In this study, in the univariate analysis, age, year, median household income, N stage, whether surgery, radiotherapy, chemotherapy were prognostic factors. Basically, the younger the age, the longer the survival time. As the number of years increases, the survival time of patients also lengthens, which may be related to improved medical technology and living conditions. Supposedly, the higher the income, the better the ability to resist disease, but in this study, median survival increased with household income, but not significantly. The difference in median survival time varies for different N stages, roughly following the rule that higher stages lead to shorter survival times. Compared with surgery, radiation and chemotherapy, the median survival of the treated group was longer than that of the untreated group. In multivariate analysis, only SEER stage, age of diagnosis, surgery, radiotherapy and chemotherapy were independent prognostic factors. And what is the optimal combination of treatments? In terms of reduced risk of death, SCR, SC, and CR decreased by 90.3%, 92.9%, and 86.2%, respectively, with median survival times of 23, 50, and 16 months. It appeared that the SC group had the best survival advantage, but unfortunately no statistical difference was shown when the three groups were compared head-to-head. This may be because the numbers are so small that large randomized controlled studies are urgently needed.

This article has certain limitations. Firstly, due to the rarity of the disease itself, it is difficult for us to conduct prospective randomized controlled studies. Furthermore, we were unable to further reveal the reasons behind these conclusions.

Conclusions

In summary, this study explored limited-stage PESC in the SEER database and found age, year, median household income, stage N, surgery, radiation, chemotherapy to be prognostic factors. SEER stage, age, surgery, radiotherapy and chemotherapy were independent prognostic factors. Among the treatment methods, any type of CT group outperformed the ST, and the CT group even outperformed the ST group. The SC group had the highest reduced risk of death and the longest mOS. Unfortunately, no statistical difference was shown between the three groups.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-311/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-311/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-311/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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