Implications of surgical intervention in patients with metastatic pulmonary carcinoid tumors: a SEER-based population study and propensity score matching comparative analysis

Introduction

Lung neuroendocrine tumors encompass large-cell neuroendocrine carcinoma (LCNEC), small-cell lung cancer (SCLC), and pulmonary carcinoid tumors (PC) (1,2). The development of PC is linked to neuroendocrine cells in the bronchial mucosa. Individuals diagnosed with carcinoid tumors are generally younger, have a more positive prognosis, and are less associated with smoking, unlike those with SCLC and LCNEC (3). Mitotic activity and necrosis are used to differentiate between typical carcinoid (TC) and atypical carcinoid (AC) tumors in PC (4-6). While TC has a low rate of cell division (<2 mitoses per high-power field) and no necrosis, AC has a higher mitotic rate, regardless of the presence of necrosis (7). Approximately 20–25% of neuroendocrine tumors and 1–2% of lung tumors are identified as PC (4-6,8-10). Advancements in diagnostic methods and enhancements in preventive healthcare are leading to a rise in their detection rate (8-11). It is estimated that roughly half of individuals with carcinoid tumors are without symptoms at initial diagnosis (12). Patients with symptoms often show signs like difficulty breathing, coughing up blood, coughing, and pneumonia that blocks airways. Carcinoid tumors are commonly linked to paraneoplastic syndromes such as carcinoid syndrome and Cushing’s syndrome (13). The main signs of carcinoid syndrome are redness of the skin and diarrhea (14). Carcinoid syndrome was present in 229 (7.6%) of the 3,002 patients with PC in a large-scale study (15).

Surgical removal is the primary method of treatment for carcinoid tumors, as shown in past research (16). The prognosis for TC patients is generally good, with few fatalities directly attributed to the tumor. The preferred course of action for central tumors is usually lobectomy. Segmental lung resection is a possible consideration for tumors found in the outer regions of the lungs. TC patients have excellent survival rates even with lymph node metastases (17). The 5-year survival rate is notably lower for individuals with AC, ranging from 61% to 88%, in comparison to those with TC (18-20).

Despite being labeled as low and moderately malignant neuroendocrine tumors, TC and AC can still metastasize to regional lymph nodes and distant sites (21). TC exhibits a lower prevalence of lymph node metastases, with rates varying from 4% to 14%, while AC has a much higher range of 35% to 64%. Stage IV TC has a 10-year overall survival (OS) rate of 47%, while AC only has 18% (21,22). Since PC is relatively resistant to chemotherapy and radiotherapy, surgery may be a treatment for metastatic conditions (23). However, the current literature is unclear about the efficacy of surgical treatment for metastatic PC. The available treatment options are limited, primarily based on reviewing past data, trials with only one group, and analyzing subsets of phase II/III trials for metastatic neuroendocrine tumors, and inferences drawn from the data obtained during the Gastroenteropancreatic Neuroendocrine Tumors Phase III Trial. Therefore, this study explored the implications of patients with metastatic PC receiving surgical treatment using the Surveillance, Epidemiology, and End Results (SEER) database. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1935/rc).

Methods

Database

The study was performed using the SEER public database, which includes 18 SEER registries and is currently updated to the SEER*Stat 8.4.3 dataset.

Study population

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. SEER*Stat software (version 8.4.3) was utilized to obtain all details regarding patients with metastatic PC from the SEER database. Inclusion criteria: (I) patients with a primary cancer diagnosis of PC in the SEER database from 2000 to 2020 (International Classification of Diseases code 8240 for TC and 8249 for AC); (II) those with definitive pathological confirmation of PC; (III) those with distant metastasis; (IV) those with detailed surgical data. Exclusion criteria: (I) no complete survival data (including year of diagnosis, cause of death, survival time, and current survival status); (II) unknown Tumor-Node-Metastasis (TNM) staging; (III) pathologic confirmation by autopsy/death certificate; (IV) under 18 years of age; (V) unknown metastatic site (bone, brain, liver, lung, or lymph node); (VI) unspecified radiotherapy information. Information on individuals who fit the specific criteria was gathered, such as age, ethnicity, sex, marital status, year of diagnosis, location of the main tumor, histological grade, TNM staging, treatment modalities, where distant metastases occurred, and OS duration in months. Ultimately, the study included a total of 472 suitable participants (refer to Figure 1 for a flowchart illustrating the study cohort selection process).

Figure 1 Flowchart of the study cohort screening process. LN, lymph node; SEER, Surveillance, Epidemiology, and End Results.

Data preprocessing

For further statistical analysis, we classified age groups as follows: <60, 60–79, and ≥80 years; tumor size groups: <3 and ≥3 cm. The restaging of all subjects was conducted in accordance with the updated criteria provided in the TNM Staging Manual (9th Edition) (24).

Research results

The results of this research involved OS and cancer-specific survival (CSS), with OS being determined from the time of diagnosis to the time of death for any reason. From the moment of diagnosis to the time of death due to PC, CSS was assessed, regardless of the direct or indirect cause.

Statistical analysis

The baseline characteristics and clinical features of patients in the surgical and non-surgical groups were compared through the use of a Pearson Chi-squared test and Student’s t-test. The effectiveness of surgery in patients with advanced PC was assessed using the Kaplan-Meier (K-M) method and log-rank test. A 1:1 propensity score matching (PSM) was conducted using the “MatchIt” R package to ensure balance in the variables between the surgical and non-surgical cohorts. The logistical model incorporated variables such as patient race, gender, tumor site, age group, year of diagnosis, histological grade, T stage, N stage, tumor size, radiotherapy, lymph node dissection, and site of metastasis to calculate propensity scores, using a caliper of 0.01. In R software (version 4.1.2), statistical tests were conducted with a significance level of P<0.05.

Results

Baseline characteristics

This study involved 472 patients from the SEER cohort in the U.S. who met the specified criteria, including 118 patients who received surgical treatment before PSM and 354 patients who did not receive surgical treatment. The baseline characteristics are provided in Table 1. The surgical group had a greater proportion of patients under the age of 60 (50.0% vs. 24.0%, P<0.001); their histological grading was mostly grade I/II (55.1% vs. 38.7%, P=0.004); a greater proportion of patients had a tumor size of less than 3 cm (67.8% vs. 42.7%, P<0.001). Those with metastatic PC who did not undergo surgery had a median survival of 28.44 months, whereas those receiving surgery had a median survival of 57.01 months. A 1:1 PSM was conducted on the patient cohort, considering the substantial discrepancies in demographics and medical factors between the two groups, including sex, site of primary tumor, year of diagnosis, age, histological grade, T stage, N stage, tumor size, lymph nodes, and metastatic site. There were 82 patients each in the surgical and non-surgical groups after PSM. All covariates had P values above 0.05 post-matching, suggesting that PSM effectively reduced potential selection bias. The baseline data of patients after PSM are shown in Table 2.

Analysis of OS and CSS using Cox regression (univariate and multivariate) before PSM in patients

Tables 3,4 illustrate the results of Cox regression analyses (univariate and multivariate) for OS and CSS in patients with metastatic PC before PSM. The multivariate Cox regression model included only variables with P values below 0.05 in univariate analysis. Surgery was identified as an independent prognostic determinant for OS (P=0.003) and CSS (P=0.007) in metastatic PC patients, as indicated by the results of multivariate Cox regression analysis. In addition, age exceeding 80 years, histologic grade 3 or 4, N2 stage, brain metastasis, and bone metastasis were all identified as independent factors affecting OS and CSS. Being between 60 and 79 years old was identified as a significant predictor of OS (P=0.03) but did not show the same impact on CSS (P=0.09). Tumor sizes ≥3 cm (P=0.02) and N1 (P=0.02) were identified as predictors of CSS but did not show the same impact on OS (P=0.06, P=0.050). Race, sex, primary tumor site, year of diagnosis, T stage, lymph node dissection, and postoperative adjuvant therapy were not associated with patient prognosis.

Survival outcomes and CSS before PSM

The K-M survival curves for OS and CSS in patients before PSM are shown in Figure 2 and Figure 3, respectively, with significant differences in P values (P<0.001, P<0.001). Patients who underwent surgery had notably improved OS and CSS compared to those who did not receive surgery.

Figure 2 Overall survival of patients with metastatic pulmonary carcinoid tumors before propensity score matching.

Figure 3 Cancer-specific survival of patients with metastatic pulmonary carcinoid tumors before propensity score matching.

Analysis of OS and CSS using Cox regression (univariate and multivariate) after PSM in patients

Tables 5,6 illustrate the results of Cox regression analyses (univariate and multivariate) for OS and CSS in patients with metastatic PC after PSM. The multivariate Cox regression model included only variables that demonstrated statistical significance with a P value less than 0.05 in univariate analyses. N2 was identified as an independent predictor for OS and CSS (P=0.001, P<0.001) in patients with metastatic PC based on the outcome analysis using multivariate Cox regression. Surgery (P=0.02) was an independent predictor for OS, while it did not show significance for CSS (P=0.11). T2 (P=0.01), T3 (P=0.02), T4 (P<0.001), N3 (P=0.02), chemotherapy (P=0.01), and bone metastasis (P=0.02) were independent predictors for CSS but not for OS. Race, sex, primary tumor site, age, year of diagnosis, histological grade, tumor size, T stage, lymph node dissection, and postoperative adjuvant therapy were not associated with patient prognosis.

Survival outcomes and CSS after PSM

Figures 4,5 illustrate the K-M survival curves of OS and CSS in patients after PSM, and P values exhibited significant differences (P=0.02, P=0.02). Patients who received surgery showed significantly enhanced OS and CSS in contrast to those who did not undergo surgery.

Figure 4 Overall survival of patients with metastatic pulmonary carcinoid tumors after propensity score matching.

Figure 5 Cancer-specific survival of patients with metastatic pulmonary carcinoid tumors after propensity score matching.

Discussion

The incidence of TC in the U.S. is 0.77 per 100,000 individuals, while the incidence of AC is 0.22 per 100,000 individuals (8). Over the last thirty years, there has been a significant rise of 6% each year in the number of PC cases, as reported by the SEER database (25). The behavior of PC, a neuroendocrine tumor, is relatively passive when compared to lung adenocarcinoma or squamous cell carcinoma (26). The primary approach for treating early-stage PC involves complete surgical removal while saving as much healthy lung tissue as possible. A study has demonstrated high five-year survival rates of 94% and 67% for TC and AC, respectively (27).

Upon diagnosis, 24% of individuals with metastatic disease present with pulmonary symptoms such as cough, hemoptysis, pain, atelectasis, or lung infection (28). In North American registries, the 5-year survival rate for patients with metastatic pancreatic cancer stands at 27% (10), and the optimal approach to managing the tumor site for many other neuroendocrine tumors, including the role of surgical resection of the primary tumor, is a subject of debate. This is connected to the gradual development of PC and its ability to secrete substances, potentially impacting QoL through conditions like sepsis or cardiac carcinoid syndrome. Retrospective research has explored the effectiveness of removing the primary tumor in cases of small bowel (29) or pancreatic neuroendocrine tumors. Yet, based on our understanding, there is a scarcity of research on surgery for the primary tumor in metastatic PC.

No curative treatment is available for metastatic PC, and adjuvant therapy has no clear effect on patients with advanced PC. There is a lack of extensive prospective studies demonstrating advantages in contrast to non-small cell lung cancer (NSCLC). There are conflicting suggestions in guidelines about the use of adjuvant therapy for N2-positive AC, with some noting the lack of data (30). Insufficient information leads other recommendations to advise against the application of adjuvant therapy for all stages (31). The current research findings align with the idea that radiotherapy and chemotherapy did not independently impact patient survival rates in the study, as indicated by multifactorial Cox regression analysis after PSM (P=0.80 for radiotherapy and P=0.12 for chemotherapy). The main objectives in late-stage illness are to manage both tumor progression and symptoms. Treatment approaches are commonly shaped by past encounters with neuroendocrine tumors in the gastrointestinal or pancreatic areas (32). Octreotide or lanreotide is frequently advised for severe cases due to the common occurrence of somatostatin receptors (SSTRs) in PC (5,30,31).

Therefore, it is important to assess how well surgical procedures work for this group of patients. The study investigated the survival prospects of patients with metastatic PC who had surgery as opposed to those receiving no surgery, utilizing data from the SEER database. In our study, 79.45% of patients who underwent surgical intervention had a tumor T-stage of ≥T2, and 47.2% had an N-stage of ≥N1. Prior research has indicated that approximately 30% of patients are asymptomatic at presentation (33). This can be attributed to the fact that symptoms in patients with PC often manifest at more advanced stages. Our multifactorial Cox regression analysis demonstrated that OS was comparable across different T-stages, corroborating the findings of Yaldız et al. that the size of the tumor was not a strong indicator of prognosis (34,35). Regarding the N-stage, the hazard ratio (HR) increased with higher N-stages in the Cox regression analysis. Aydin et al. and Yaldız et al. also highlighted the importance of considering lymph node involvement as a key factor that influences long-term survival outcomes (34,36). Furthermore, we discovered that in this cohort, bone metastasis became a significant predictor of CSS following PSM, while metastasis from other sites did not demonstrate the same significance—a result in alignment with a previous study (35). Interestingly, while in certain reviews of NSCLC cases, it was noted that those with liver metastases had the least favorable prognosis, and our findings revealed that, following PSM, patients with bone metastases exhibited worse CSS compared to those with liver metastases. This conclusion aligns with the findings of Zhang et al. (35), suggesting that liver metastases in patients with PC may be more amenable to complete surgical resection compared to bone metastases.

Moreover, study results suggest that undergoing surgery following PSM independently influences OS in these individuals. OS and CSS were enhanced in patients receiving surgery compared to those who did not, both pre- and post-PSM. Surgery notably relieved lung symptoms and was more efficacious in the management of carcinoid syndrome in patients with PC compared to no surgery. The removal of the primary tumor may lead to the resolution of the obstruction in the bronchial tubes, which in turn could alleviate symptoms like cough, infection, collapsed lung, and coughing up blood. It might also help in reducing the tumor burden that circulates in the body, thereby lowering the chances of carcinoid syndrome. The results hold substantial clinical significance for patients with PC, as many individuals can achieve prolonged survival even in the metastatic stage (37). These findings further demonstrate the value of primary tumor resection in patients with metastatic PC.

This study has several limitations that warrant consideration. Firstly, due to its retrospective design, the study is subject to inherent biases, including selection bias and information bias. Our team is working on conducting prospective studies to further validate the conclusions presented herein. However, the rarity of PC poses a significant challenge and necessitates a longer preparation period. Secondly, the SEER database, which primarily collects data on cancer incidence and survival in the United States, includes only a small proportion of the Asian population. This introduces heterogeneity within the patient cohort, and it remains unclear whether the findings of this study are fully generalizable to domestic populations in China. Thirdly, the inherent limitations of the SEER database may have prevented us from comprehensively accounting for certain confounding factors or biases. Lastly, while this study highlights the survival benefit of primary tumor resection in patients with metastatic PC, it does not explore the impact of specific surgical techniques or chemotherapy on patient outcomes. The low incidence of PC and the even rarer occurrence of metastatic cases limit the sample size available for analysis. After PSM, each of the surgical and non-surgical groups comprised 82 patients, which is insufficient to support further subgroup or categorical analyses.

Conclusions

The prognostic importance of surgical intervention in PC patients was clarified through the PSM study using SEER database data. Surgical resection at the primary site has been shown to significantly enhance the OS and CSS in this population. Therefore, aggressive surgical management should be considered for individuals with metastatic PC. In any case, more randomized controlled trials are essential to analyze the efficacy and proper indications for surgery in these specific patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1935/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1935/prf

Funding: The study was supported by General Program of National Natural Science Foundation of China (No. 82273325).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1935/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 and its subsequent amendments.

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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