Abstract
Objective
To investigate the clinical efficacy of thermal ablation in the treatment of pulmonary carcinoid (PC) tumor.
Methods
Data of patients with inoperable PC diagnosed from 2000 to 2019 were obtained from the SEER database and analyzed according to different therapeutic modality: thermal ablation vs non-ablation. Propensity score matching (PSM) was used to reduce intergroup differences. Kaplan–Meier curves and the log-rank test were used to compare intergroup differences of overall survival (OS) and lung cancer-specific survival (LCSS). Cox proportional risk models were used to reveal prognostic factors.
Results
After PSM, the thermal ablation group had better OS (p < .001) and LCSS (p < .001) than the non-ablation group. Subgroup analysis stratified by age, sex, histologic type and lymph node status subgroups showed similar survival profile. In the subgroup analysis stratified by tumor size, the thermal ablation group showed better OS and LCSS than those of the non-ablation group for tumors ≤3.0 cm, not statistically significant for tumors >3.0 cm. Subgroup analysis by M stage showed that thermal ablation was superior to non-ablation in OS and LCSS for patients with M0 stage, but no significant difference was found in subgroups with distant metastatic disease. Multivariate analysis showed that thermal ablation was an independent prognostic factor for OS (HR: 0.34, 95% CI: 0.25–0.46, p < .001) and LCSS (HR: 0.23, 95%CI: 0.12–0.43, p < .001).
Conclusion
For patients with inoperable PC, thermal ablation might be a potential treatment option, especially in M0-stage with tumor size ≤3 cm.
Introduction
Pulmonary neuroendocrine tumors include large-cell neuroendocrine carcinoma (LCNEC), small-cell lung cancer (SCLC), and pulmonary carcinoid (PC) [Citation1,Citation2]. PC tumors originate from the neuroendocrine cells of the bronchial mucosa and, based on mitotic count and necrosis, can be subdivided into typical carcinoid (TC) and atypical carcinoid (AC) tumors [Citation3–5]. PC constitutes 20–25% of all neuroendocrine tumors and 1–2% of lung tumors [Citation3–8], albeit with an increasing prevalence owing to the higher detection rates with improvements in diagnostic technology and preventive health [Citation6–9]. However, PC is refractory to radiation and chemotherapy, and evidence-based immunotherapy in PC is lacking; thus, resection [Citation7,Citation10–13] to ensure complete tumor removal with maximal preservation of lung function [Citation4,Citation7,Citation13] is the main treatment option for PC. For patients who cannot undergo resection due to various factors, such as greater age, serious cardiovascular or cerebrovascular diseases, contraindications to anesthesia, and refusal to undergo surgery [Citation14,Citation15], an effective alternative treatment with trauma minimization is urgently required.
The rapid development of thermal ablation technology, which enables precise, minimally invasive, localized treatment, has, in recent years, increasingly become irreplaceable in the treatment of various cancers, including liver, kidney, and lung tumors [Citation16–20]. Thermal ablation for lung cancer has been used for approximately 20 years, mainly for stage I non–small cell lung cancer (NSCLC), especially in patients with high-risk features for whom surgery is unsuitable [Citation21–23]. More recently, thermal ablation has been used successfully in stage II–III NSCLC [Citation15] and, when combined with chemotherapy, conferred a survival benefit in stage IV NSCLC [Citation19]. Despite its confirmed clinical efficacy in NSCLC, it is unclear whether thermal ablation confers a survival benefit in PC patients. Therefore, in this study, the clinical efficacy of thermal ablation was investigated in patients with inoperable PC.
Patients and methods
Study population
Data in the Surveillance, Epidemiology, and End Results (SEER) database – an open-access cancer dataset derived from 18 cancer registries – comprises information on approximately 35% of the U.S. population [Citation6,Citation7]. SEER*Stat 8.4.0 (reference number 10466-Nov2021), published in 2022, was used to screen for PC patients, with pathological diagnosis (histological codes: 8240 and 8249) registered from 2000 to 2019, who were treated with or without thermal ablation (including fulguration, electrocautery, cryotherapy, and laser ablation). Patients with PC who received surgical treatment besides thermal ablation and those with missing data on survival and stage were excluded from this analysis (Figure S1). Demographic characteristics, including age, sex, race and marital status, were extracted. Tumor characteristics were extracted, including primary tumor site, laterality, grade, histologic type, tumor size, N stage and M stage. Information on treatment characteristics, including radiotherapy, chemotherapy and thermal ablation, was obtained. Based on whether thermal ablation administered, the participants were divided into two groups: thermal ablation vs non-ablation. All participants were restaged according to the revised criteria specified in the TNM staging manual, 8th edition.
Outcomes
The primary endpoints were overall survival (OS) and lung cancer-specific survival (LCSS), The OS was defined as the interval from the diagnosis of PC to death from any cause; patients were censored at the last follow-up (31 December 2019). The LCSS was defined as the time to death from PC, and patients who were alive at the last follow-up or those who died from any cause besides PC were censored.
Ethics statement
The SEER database contains publicly available, deidentified data that poses no risk of identification of individual participants. Accordingly, the ethics committee of our hospital exempted this study from the requirement of ethics approval or the need for written informed consent from the participants.
Statistical analysis
Categorical variables were expressed as frequency and percentages. To decrease the treatment selection bias, propensity score matching (PSM) with a caliper of 0.05 was performed using 1:3 nearest-neighbor matching. Propensity scores were calculated in a logistic regression model that included age, laterality, race, grade, primary tumor site, marital status, sex, histologic type, tumor size, N stage, and M stage. Balances in characteristics before and after PSM were evaluated using McNemar’s test, for categorical variables, and the non-parametric Wilcoxon signed rank test or paired t-test, for continuous variables. Unadjusted OS and LCSS curves were estimated using the Kaplan–Meier method, and the intergroup comparisons were undertaken using the log-rank test. Subgroup analyses in all possible subgroups were performed with the Cox proportional hazard model, and forest plots were drawn. Variables with p < .05 in the univariable analysis were entered into the multivariable analysis. Cox proportional hazards models were used to identify factors that were associated with OS or LCSS. p < .05 was considered statistically significant. All statistical analyses were performed using SPSS version 26 (IBM Corp, Armonk, NY) and R version 3.5.0 (http://www.R-project.org).
Results
Baseline characteristics
From 2000 to 2019, a total of 13,671 patients were diagnosed with PC, of whom 498 participants received thermal ablation. Based on the inclusion and exclusion criteria, a total of 1965 eligible PC patients were enrolled in this study; among them, 272 participants received thermal ablation. The basic characteristics of this cohort comprising 1002 (50.99%) patients aged ≤70 years are shown in . More than half of the cohort were white (86.51%) and female (67.94%). During a median follow-up time of 47 months, 783 deaths were recorded, of which 431 were due to PC.
Table 1. Baseline characteristics before and after propensity score matching, n (%).
The distributions in age (p < .001), sex (p = .004), race (p = .002), marital status (p < .001), primary tumor site (p < .001), grade (p < .001), histologic type (p < .001), tumor size (p < .001), N stage (p < .001), and M stage (p < .001) differed significantly between the thermal ablation and non-ablation groups. After 1:3 PSM, 191 and 481 cases were included in the thermal ablation and non-ablation groups, respectively, and all matched variables were well-balanced between the groups.
Survival analysis after PSM
After PSM, the thermal ablation group had better OS and LCSS than the non-ablation group. The 5- and 10-year OS of the thermal ablation and non-ablation groups was 82.67% vs. 62.66% and 67.95% vs. 44.06% (p < .001, ), whereas the 5- and 10-year LCSS was 93.44% vs. 81.73% and 90.61% vs. 73.61%, respectively (p < .001, ). A similar survival trend was found in the subgroup analyses stratified by age, sex, and histologic type ().
Figure 1. Kaplan–Meier curves of PC. (A) thermal ablation versus non-ablation for OS after PSM; (B) thermal ablation versus non-ablation for LCSS after PSM. PC: pulmonary carcinoid; OS: overall survival; LCSS: lung cancer-specific survival; PSM: propensity score matching.
Figure 2. Kaplan–Meier curves of PC. (A) thermal ablation versus non-ablation for OS of patients aged ≤70 years after PSM; (B) thermal ablation versus non-ablation for LCSS of patients aged ≤70 years after PSM; (C) thermal ablation versus non-ablation for OS of patients aged >70 years after PSM; (D) thermal ablation versus non-ablation for LCSS of patients aged >70 years after PSM. PC: pulmonary carcinoid; OS: overall survival; LCSS: lung cancer-specific survival; PSM: propensity score matching.
Figure 3. Kaplan–Meier curves of PC. (A) thermal ablation versus non-ablation for OS of female patients after PSM; (B) thermal ablation versus non-ablation for LCSS of female patients after PSM; (C) thermal ablation versus non-ablation for OS of male patients after PSM; (D) thermal ablation versus non-ablation for LCSS of male patients after PSM. PC: pulmonary carcinoid; OS: overall survival; LCSS: lung cancer-specific survival; PSM: propensity score matching.
Figure 4. Kaplan–Meier curves of PC. (A) thermal ablation versus non-ablation for OS of TC patients after PSM; (B) thermal ablation versus non-ablation for LCSS of TC patients after PSM; (C) thermal ablation versus non-ablation for OS of AC patients after PSM; (D) thermal ablation versus non-ablation for LCSS of AC patients after PSM. PC: pulmonary carcinoid; TC: Typical carcinoid; AC: atypical carcinoid; OS: overall survival; LCSS: lung cancer-specific survival; PSM: propensity score matching.
Subgroup analysis
To ascertain the potential survival benefit from thermal ablation for the OS and LCSS among different subgroups, subgroup analyses were performed (). The results showed that thermal ablation improved survival amongst nearly all subgroups. In the subgroup analysis stratified by tumor size, patients with tumors ≤3.0 cm who received thermal ablation showed better OS and LCSS than those who did not; however, statistically significant differences in survival benefits for patients with tumors >3.0 cm were not detected. Subgroup analysis by M stage showed that thermal ablation was superior to non-ablation in terms of survival benefits (OS and LCSS) for patients with M0 stage, though no significant difference was found in subgroups with distant metastatic disease.
Figure 5. Subgroup analysis for OS (A) and LCSS (B) in the matched population. OS: overall survival; LCSS: lung cancer-specific survival.
Univariable and multivariable analyses
and present the results of univariable analysis. Factors that were considered meaningful in the univariable analysis were evaluated in the multivariable analysis, and the results established that age, sex, grade, histological type, tumor size, N stage, M stage, and therapeutic modality were independent prognostic factors for OS and LCSS in patients with PC. Thermal ablation decreased the mortality risk by 64% () and the risk of PC-related death by 77% ().
Table 2. Univariable and multivariable analysis for overall survival in the whole cohort.
Table 3. Univariable and multivariable analysis for lung cancer-specific survival in the whole cohort.
Discussion
In this study of the clinical efficacy of thermal ablation in patients with inoperable PC, the results confirmed that thermal ablation can significantly improve survival amongst all of the study subgroups.
Current treatment for PC mainly comprises tumor resection because PC is insensitive to radiation and chemotherapy [Citation7,Citation13]. However, surgery is unfeasible in some patients owing to advanced age, poor cardiopulmonary function, and intolerance to surgery. Therefore, an effective alternative treatment that involves minimal trauma is important to mitigate the clinical burden of PC and to improve patient survival. Recently, thermal ablation, including microwave ablation (MWA), radiofrequency ablation (RFA), and cryoablation, have increasingly gained popularity as treatments for malignant tumors in various organs, such as the lungs, kidneys, and liver [Citation20]. The key principle of thermal ablation involves the application of heat to induce irreversible damage or coagulation necrosis of tumor cells and to thereby achieve an anti-tumor effect [Citation19]. A multicenter long-follow-up study of 105 patients with stage I NSCLC who were treated with MWA identified median, 3-year, and 5-year OS of 64.2%, 75.6%, and 54.1%, respectively, with mostly mild or moderate complications. The most common complication was perioperative or postoperative pain, followed by pneumothorax. The authors concluded that MWA was effective, safe, technically effective, and well tolerated for all patients with inoperable early-stage NSCLC [Citation14]. Yang et al. [Citation15] analyzed data from the SEER database and concluded that thermal ablation could constitute a safe alternative for inoperable stage II–III NSCLC patients, especially those aged ≥70 years and with a tumor size ≤3.0 cm. Thus, the efficacy and safety of thermal ablation have been confirmed in NSCLC. However, reports of the clinical efficacy of thermal ablation in patients with PC are scarce. Therefore, this study investigated the clinical efficacy of thermal ablation in patients with inoperable PC and found that, both before and after PSM, the thermal ablation group had better OS and LCSS than the non-ablation group. Furthermore, similar survival differences were found in the subgroup analyses stratified by age, sex, and pathological type. As early as 1997, laparoscopic thermal ablation was reported to not only effectively inhibit tumor growth and reduce symptoms of excessive hormone secretion but also to accelerate recovery and shorten the hospital stay in patients with neuroendocrine tumors that had metastasized to the liver [Citation24]. Thus, thermal ablation is a minimally invasive, novel treatment method for neuroendocrine tumors. A case report by Corsello et al. [Citation25] in 2014 reported the outcome of RFA for hypercortisolism induced by corticotrophin secretion from an 8-mm pulmonary nodule in a 43-year-old woman with extremely high risk for surgery owing to severe, rapid deterioration of her clinical condition. RFA not only rapidly controlled hypercortisolism but also improved the patient’s survival. Therefore, in patients with PC who cannot be treated with surgery because of various potential limitations, thermal ablation that confers less trauma can be an effective alternative to surgery.
To further determine the population for whom thermal ablation would be more appropriate, we performed subgroup analyses. In patients with tumors ≤3.0 cm, the OS and LCSS in the thermal ablation group were better than those in the non-ablation group, whereas no significant intergroup difference in the treatments was detected in patients with tumors >3.0 cm. This requires a reconsideration of the principle of thermal ablation: regardless of whether the electromagnetic wave is used to obtain energy that is converted into heat or an alternating current is used to generate heat flow, both mechanisms induce tumoral and peritumoral necrosis. The range of the ablation depends on the unique characteristics of the tissue. In the lung parenchyma, both blood flow and airflow around the target tissue should be taken into account, because lung tissue contains a high percentage of air and therefore has lower thermal conductivity than other organs; therefore, it is difficult to generate enough energy for ablation, and blood circulation and airflow dispels heat away from the target tissue, which thus limits tissue damage [Citation26]. In our previous study, in patients with advanced NSCLC with a tumor size of 0–3 cm, the 1-year and 2-year OS and LCSS of the thermal ablation plus chemotherapy group were better than those of the chemotherapy-only group; however, the difference was not significant in the subgroups with tumor size >3 cm [Citation19]. In the subgroup analysis stratified for M stage, the OS and LCSS in thermal ablation group were superior to those in the non-ablation group for patients with M0; however, the difference was not significant in the M1 subgroup. In patients with M1, namely distant metastasis, thermal ablation is administered as a palliative localized treatment and only acts on the tumor cells at the treatment site; however, as the tumor cells that have been disseminated to other sites will continue to proliferate, this treatment may not confer therapeutic benefits in these patients.
Multiple studies have shown that lymph node (LN) staging is a strong predictor of prognosis [Citation27,Citation28]. LN metastases are mostly seen in AC, which often suggests a poor prognosis; however, a small number of LN metastases are also seen in TC. Lisa et al. [Citation29] analyzed data from 1,495 patients with stage T1aN0M0 typical carcinoid and found that, regardless of the type of surgery, LN evaluation was important for prognosis. The authors thus found that LN staging was an independent predictor of OS. For patients with LN metastasis, no survival benefit was found after postoperative adjuvant chemotherapy [Citation30]; therefore, to our knowledge, there is a lack of effective postoperative adjuvant therapy. Our study showed that, for patients without LN metastasis, both OS and LCSS in the thermal ablation group were better than those of patients in the non-ablation group, though the difference was very close to statistical significance in patients with LN metastasis (p = .074 and p = .052). Therefore, as a localized treatment method, thermal ablation may be more suitable for patients without LN metastasis, and for patients with LN metastasis, the clinical efficacy needs to be further studied.
The nomogram constructed by He et al. [Citation31] for predicting cancer-specific survival of PC showed that age, grade, histological type, N stage, M stage, primary site surgery, primary site radiotherapy, and tumor size were all independent prognostic factors. Similar to their results, in our study, multivariate Cox analysis showed that age, sex, grade, histological type, tumor size, N stage, M stage, and therapeutic modality were independent prognostic factors for OS and LCSS. In addition, thermal ablation could reduce the risk of death by 64% and the risk of PC-related death by 77% compared with the non-ablation group. Some patients with PC can develop carcinoid syndrome due to abnormal secretion of hormones. As the condition continues to deteriorate, it may lead to a carcinoid crisis, with a high mortality risk [Citation32–34]. When there is no other effective treatment for these patients, clinicians may consider thermal ablation to reduce tumor load and improve prognosis. Moreover, when evaluating the prognosis of patients in clinical work, we need to consider these influencing factors comprehensively, so as to choose individualized treatment to improve the survival time and quality of life of patients.
There are some limitations of our study. Firstly, this study has inherent biases due to the retrospective design, such as selection bias and information bias. Secondly, as mentioned above, thermal ablation includes RFA, MWA, cryoablation and other specific therapy forms. Different ablation methods may have different impacts on survival. However, the SEER database lacks detailed information on RFA, MWA and cryoablation and we could not therefore conduct a subgroup analysis based on the type of thermal ablation modality. Thirdly, thermal ablation is often selected as a treatment for small tumors in clinical practice, which could constitute a major selection bias. Fourthly, it is very important to know the lesion location (central versus peripheral) and ablation. The location and ablation may have important implications for prognosis and treatment, and thereby influence survival. However, due to the limitations with regard to the data available in the SEER database, we could not ascertain the specific lesion location (central vs peripheral). Fifth, though the SEER database provides information on radiotherapy and chemotherapy, information on chemotherapeutic drugs, radiotherapy dose, treatment course, endocrine therapy, targeted therapy, neoadjuvant therapy, and immune therapy was unavailable, which could also introduce selection bias. Due to the insensitivity of PC to radiation and chemotherapy, few patients had received radiation and chemotherapy. Therefore, we did not include radiation and chemotherapy as confounders in the analyses. Finally, the SEER database lacks data on some aspects, such as smoking status, family history of cancer, co-existing diseases and performance scores that may affect survival. Therefore, a large number of prospective studies are needed to further confirm the clinical efficacy of thermal ablation in inoperable PC patients.
Conclusion
Thermal ablation constitutes a potential treatment option for patients with inoperable PC, especially in patients with M0 stage and tumor size ≤3 cm.
Ethical approval
As the data used were from SEER dataset, which is publicly available, ethics approval and consent to participate is not applicable.
Author contributions
H. Yang, L. Luo, and M. Li contributed to the study design. H. Yang, M. Li, and T. Liu preformed the data analysis. H. Yang wrote the manuscript. L. Luo and M. Li critically revised and edited the manuscript. All authors reviewed and approved the final manuscript.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Supplemental Material
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Not applicable.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All SEER data and information are publicly available at https://seer.cancer.gov/.
Additional information
Funding
References
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