Survival advantage of radiotherapy and nomogram for patients with pulmonary neuroendocrine neoplasms: a propensity score-matched Surveillance, Epidemiology, and End Results database study

Introduction

Pulmonary neuroendocrine neoplasms (pNENs), a common type of neuroendocrine neoplasm (NEN) and originate from pulmonary neuroendocrine cells (1). They account for approximately 25% of all primary lung tumors and for 20–25% of primary NENs (2,3). According to the World Health Organization (2015), pulmonary NENs are mainly classified into four categories: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC) (4). Moreover, carcinomas with both neuroendocrine carcinoma (NEC) and non-small cell carcinoma components have also been detected (4). Typical and atypical carcinoids are well differentiated and low-grade and intermediate-grade lesions, respectively. They are classified as carcinoid tumors, accounting for 2% of primary lung tumors (with typical-to-atypical ratio of 10:1). In contrast, LCNECs and SCLCs are high-grade and poorly differentiated tumors associated with poor prognosis and classified as NECs (4). However, an intermediate classification between neuroendocrine tumors (NETs) and NECs has recently been reported (5). Overall, SCLCs and LCNECs account for approximately 15%, and 3% of cases, respectively (6). In the United States, the incidence and prevalence of NENs continue to rise in a linear pattern due to the improvements in detection methods and diagnostic protocols (7).

The treatment of pNEN remains controversial and is generally determined according to the histologic type and stage. Typical carcinoids are usually slow-growing, and their treatment consists mainly of surgery in the early stage and somatostatin analogs (SSA) and everolimus for advanced disease (8,9). Unlike SCLC, for which there are established treatment options, atypical carcinoid tumors and LCNECs are managed with a variety therapeutic strategy due to the lack of large-scale clinical studies (10,11). Surgical resection is the mainstay of therapy for patients with localized pNENs (10-12). Systemic treatment options for metastatic pNENs include chemotherapy, targeted therapy, immunotherapy, SSA, and peptide receptor radionuclide therapy, among others (13,14). At present, there is a lack of consensus among the treatment guidelines regarding the appropriate treatment for locally advanced disease. Radiotherapy (RT) is a core treatment option for tumors; however, the role of RT in the treatment of pNENs remains unclear. A few prospective trials and meta-analyses involving patients with limited-stage SCLC have indicated that RT is effective against poorly differentiated tumors and useful as a radical therapy for local or advanced tumors (15,16). Yet, small-scale studies have yielded conflicting results regarding the optimal RT option for the other stages of SCLC, atypical carcinoid tumors, LCNECs, and combined carcinomas (10,17,18). In this study, we conducted a matched-pair analysis using data derived from the Surveillance, Epidemiology and End Results (SEER) database to evaluate the survival benefit of RT for patients with pNENs, particularly atypical carcinoid tumors and NECs, according to updated pathological classifications and modern radiological staging. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2233/rc).

Methods

Patients

Data of patients diagnosed with pNENs between 2000 and 2019 were extracted from the SEER database (https://seer.cancer.gov/). The inclusion criteria were as follows: (I) pathological diagnosis of atypical carcinoid tumors and NECs (International Classification of Disease for Oncology, third edition, code 8013/3, 8244/3, 8246/3, 8249/3, and 8574/3); (II) availability of key clinicopathological data, including sex, race, age, marital status, and year of diagnosis; (III) availability of clinical and pathological information, including disease stage and treatment specifics; and (IV) absence of metastasis. Ultimately a cohort of 7,470 patients was included, among which patients with atypical carcinoid tumors was 739, and 2123 patients were LCNECs. And among them, 2,394 patients received RT. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Covariates

The following variables were evaluated to identify the risk factors associated with atypical carcinoid tumors and NECs: age, sex, race, year of diagnosis, stage extension, marital status, surgery, chemotherapy, RT, and follow-up information. The prognostic factors for patients were determined through survival analyses. Overall survival (OS) was the primary endpoint, and cancer-specific survival (CSS) was the secondary endpoint. OS was defined as the period of time from diagnosis to death due to any reason. CSS was defined as the interval between the day of diagnosis and the day of death caused by atypical carcinoid tumors and NECs.

Propensity score matching (PSM)

PSM involves the conditional probability of assignment to a particular treatment given a vector of observed covariates (19). In this study, PSM was used to reduce the selection bias between the RT and no-RT groups of each subgroup. A logistic regression model was used to estimate propensity scores for all patients, including covariates that might have led to independent correlations between variables and RT status. The propensity score, ranging from 0 to 1, was determined using SPSS 26 (IBM Corp., Armonk, NY, USA). PSM was performed using 1:1 nearest-neighbor matching in the RT and no-RT groups to compare survival outcomes.

Statistical analyses

SPSS 26 (IBM Corp.) and R software version 4.2.3 (The R Foundation for Statistical Computing) were used for statistical analyses. A P value <0.05 indicated a statistically significant difference. The Kaplan-Meier method was used to estimate the survival rates of patients, and log-rank tests were used to assess differences between groups. Univariate and multivariate Cox proportional hazards regression analyses were used to examine the potential risk factors. Variables with a P value <0.05 or previously identified as prognostic factors were included in the multivariate analysis conducted via SPSS 26. In addition, a novel diagnostic nomogram was constructed using R software version 4.2.3 based on the independent risk factors.

Results

Patient characteristics before and after PSM

A total of 7,470 cases with complete information were enrolled in this study. Patients were further divided into RT (n=2,394) and no-RT (n=5,076) groups. After 1:1 PSM, each group comprised 1,429 patients (Figure 1). Table 1 shows that PSM helped to balance the covariates and minimize the potential confounders, thus enhancing the comparability of the study groups.

Figure 1 Flowchart depicting the patient selection process. pNEN, pulmonary neuroendocrine neoplasm; RT, radiotherapy.

Prognostic factors for survival after PSM

Univariate analysis of patients for both OS and CSS was conducted with baseline characteristics and with selected variables. The results of Cox regression analysis identified six related variables: age, sex, marital status, disease extension, surgery, and RT (Table 2). Kaplan-Meier curves of OS indicated that the younger patients or those with early-stage disease had better survival than did the older patients or those with late-stage disease. Moreover, married patients and female patients had better OS than did those with other marital statuses or male patients. Furthermore, patients who received RT or who underwent surgery received greater survival benefit than those who did not (Figure 2). Additionally, the Kaplan-Meier curves for CSS yielded similar results; however, the survival benefits were reduced in patients with regional disease after surviving for 75 months (all P values <0.05) (Figure 3).

Figure 2 Kaplan-Meier OS estimates for patients grouped by (A) age, (B) marital status, (C) sex, (D) RT, (E) surgery, and (F) disease extension. OS, overall survival; RT, radiotherapy.

Figure 3 Kaplan-Meier CSS estimates grouped by (A) age, (B) marital status, (C) sex, (D) RT, (E) surgery, and (F) disease extension. CSS, cancer-specific survival; RT, radiotherapy.

In the multivariate analysis, all six variables were associated with survival. Moreover, RT was the intervention associated with better survival (OS: hazard ratio =0.793, 95% confidence interval: 0.733–0.857, P<0.001; CSS: hazard ratio =0.797, 95% confidence interval: 0.731–0.870, P<0.001) after PSM (all P values <0.05) (Figure 4).

Figure 4 Forest plot of subgroup analysis for OS (A) and CSS (B) after 1:1 PSM. CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival; PSM, propensity score matching.

Additionally, we used Cox proportional hazards models to create nomograms that incorporated six key variables for OS and CSS. These nomograms were used to predict the 6-, 12-, and 24-month OS rates (Figure 5). The concordance index was applied to assess the discriminative ability of the models. The concordance index for the prediction of OS and CSS was 0.667 and 0.675, respectively. The nomograms demonstrated value for prognostic prediction in clinical practice, suggesting that RT is an important predictor of OS and CSS in patients with pNENs.

Figure 5 Nomogram for estimating the risk of overall survival (A) and cancer-specific survival (B) in patients with pulmonary neuroendocrine neoplasms. RT, radiotherapy.

Subgroup analysis for OS and CSS after PSM

We further investigated the survival benefits of RT with or without surgery. Subgroup analyses of OS and CSS indicated that the patients who underwent surgery combined with RT had slightly greater survival benefits than did those without RT, both in terms of OS (OS: 32 vs. 27 months; P=0.22) and CSS (38 vs. 35 months; P=0.72). In patients without surgery, RT was associated with greater survival benefit as compared to no RT, both in terms of OS (15 vs. 11 months; P<0.001) and CSS (17 vs. 12 months; P<0.001) (Figures 6,7).

Figure 6 Kaplan-Meier (A) overall survival and (B) cancer-specific survival estimates for patients with and without RT who underwent surgery. RT, radiotherapy.

Figure 7 Kaplan-Meier (A) overall survival and (B) cancer-specific survival estimates for patients with RT and without RT who did not undergo surgery. RT, radiotherapy.

Discussion

pNENs are a family of heterogeneous pulmonary neoplasms showing neuroendocrine morphology and immunophenotype, and there is limited evidence or accumulated knowledge regarding their management. RT is a common treatment option for tumors, but its role in pNENs has not been thoroughly investigated. Retrospective studies involving small samples with different classifications have reported contradictory findings (20,21). Moreover, there is no consistency across the different guidelines or an expert consensus regarding pNENs, except in SCLC. To the best of our knowledge, this is the first study that investigated the role of RT in pNENs in atypical carcinoid tumors and NECs using PSM. The findings demonstrated that RT offers significant benefits for patients with atypical carcinoid tumors and NECs, particularly for those who did not undergo surgery.

For resectable pulmonary atypical carcinoids, surgery is the only curative option recommended by the relevant guidelines and consensus statement. The European Neuroendocrine Tumor Society (ENETS) suggests using adjuvant RT or chemotherapy in patients with atypical carcinoids and positive lymph node status (22). However, The North American Neuroendocrine Tumor Society guidelines do not support the implementation of adjuvant RT or chemotherapy owing to a lack of evidence (22,23). A similar situation exists or pulmonary LCNECs, and the role of RT in patients with resected or regional LCNEC remains undefined (24,25). Lo et al. reported comparable survival outcomes of survival with surgery or stereotactic body RT in patients with early-stage pulmonary LCNEC. In their study, among patients who meet the surgical criteria, patients who underwent surgery had better survival than those who received stereotactic body RT (26). Findings based on the data obtained from SEER database suggest that RT may provide a survival benefit in patients with pulmonary LCNEC but not in those after surgery (27,28). In-depth analysis has been conducted on the genetic susceptibility and molecular pathology of SCLC (29), and prospective research studies and consensus statements have been established for its treatment. RT is critical to the treatment of local disease (2). In this study, we examined the role of RT in atypical carcinoid tumors and NECs. We found that RT was significantly associated with improved survival, particularly in patients who did not undergo surgery. Besides, we also constructed a nomogram to predict the OS of patients, which showed that in the same situation, patients who have undergone surgery, radiation therapy, chemotherapy, or combination therapy will have a longer survival time, while patients who have undergone surgery or radiation therapy will have a longer tumor related survival time.

However, there were certain limitations to our study that should be noted. First, despite the use of the PSM method, bias was inevitable due to the observational nature of the study design. Second, we did not independently analyze the outcomes for different pathological types due to an imbalance in the number of cases. Finally, the details of RT implementation (e.g., times and fractional doses) and updated radiation techniques were not available in the database. Thus, further investigation in larger prospective studies is warranted to validate our findings.

Conclusions

Our cohort study indicated that RT may provide survival benefit in patients with atypical carcinoid tumors and NECs, particularly in those who do not undergo surgery.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2233/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2233/prf

Funding: This study was funded by the grants from the Zhejiang Province Medical and Health Project (No. 2022KY296), the Ningbo Natural Science Foundation (No. 2023J225), the Ningbo Youth Science and Technology Innovation Leading Talents Program (No. 2023QL054), and the Ningbo Health Technology Project (No. 2022Y53).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2233/coif). R.A.R. has received consulting fees paid to him from ITM Radiopharma, Regeneron, TerSera Therapeutics, Exelixis, Novartis and Lantheus; has served on a speaker’s bureau for AstraZeneca; is an unpaid Board of Directors member for the North American Neuroendocrine Tumor Society. The other 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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