Surgery versus radiotherapy in octogenarians with stage Ⅰa non‑small cell lung cancer: Propensity score‑matching analysis of SEER database

Abstract

Purpose

To compare the overall survival (OS) and cancer-specific survival (CSS) of surgery with radiotherapy in octogenarians with stage Ⅰa non–small cell lung cancer (NSCLC).

Methods

Patients aged ≥ 80 years with clinical stage Ⅰa (T1N0M0) NSCLC from 2012 to 2017 were identified from the population-based Surveillance, Epidemiology, and End Results (SEER) database. Included patients were divided into surgery and radiotherapy group. Multivariate Cox regression was used to identify factors associated with survival. Propensity score‑matching (PSM) analysis was used to adjust treatment groups. OS and CSS were compared among groups by the Kaplan–Meier analysis.

Results

A total of 1641 patients were identified, with 46.0% received surgery and 54.0% radiotherapy. Compared with surgery, patients treated with radiotherapy were older, later diagnosed, and had more squamous cell carcinoma, unknown grade and increased tumor size. Radiotherapy was associated with a significantly worse OS as compared with surgery (hazard ratio 2.426; 95% CI, 2.003 to 2.939; P < .001). After PSM, the OS (P < 0.001) and CSS (P < 0.001) was higher in the surgery group. The 1-, 3-, and 5-year OS rates of surgery and radiotherapy group were 90.0%, 76.9%, 59.9%, and 86.0%, 54.3%, 28.0%, respectively. The 1-, 3-, and 5-year CSS rates of surgery and radiotherapy group were 94.5%, 86.1%, 78.0% and 90.7%, 74.5%, 61.0%, respectively. No differences in the OS (P = 0.146) and CSS (P = 0.675) were found between the matched surgery without lymph node examination (LNE) and radiotherapy group.

Conclusions

Surgery with lymph node dissection offers better OS and CSS than radiotherapy in octogenarians with stage Ⅰa NSCLC.

Introduction

Lung cancer remains a serious health issue (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths) (Sung, et al. 2021). With the lung cancer screening recommendations and aging of the general population, early-stage non-small cell lung cancer (NSCLC) is projected to increase in the elderly. Elderly is often associated with multiple comorbidities, poor cardiopulmonary function, frailty, and higher operative risk, which makes the treatment of lung cancer more sophisticated (Clérigo et al. 2020). It is necessary to explore the best treatment strategy for the octogenarians with early stage NSCLC.

The optimal treatment is unclear for octogenarians and older patients diagnosed with early-stage NSCLC. Surgery combined with lymph node dissection is the standard treatment for early-stage NSCLC (Ettinger et al. 2021). However, surgery is often precluded in elderly patients aged ≥ 80 years owing to comorbidities. Radiotherapy (RT), especially stereotactic ablative radiotherapy (SABR), is the first-line recommendation for inoperable early-stage NSCLC (Ettinger et al. 2021). Over the last decade SABR has gained increasing popularity, particularly for older patients. RT had replaced surgery as the most commonly used modality in early-stage NSCLC in patient ≥ 80 years in the United States and European countries (de Ruiter et al.2020; Bei et al 2021; Damhuis et al.2021). However, with respect to the clinical outcome, the role of SABR versus surgery for such patients should continue to be debated. It is difficult to perform randomized clinical trials in octogenarians. In this study, The SEER database was used to compare survival differences among octogenarians and older receiving surgery versus those who received radiotherapy as the sole treatment for stage Ⅰa NSCLC.

Materials And Methods

Data sources

We analyzed the SEER database via SEER Stat (version 8.3.9; http:// www. seer. cancer. gov) in March 2022 with the identifier 15362-Nov2020. This study was conducted in accordance with the Declaration of Helsinki (as revised in Tokyo 2004). No personal identifying information was used in the retrospective and anonymous study. So patient consent and Institutional Review Board approval were not required. SEER 18 Regs Research Plus Data (with additional treatment fields) was chosen to select patients. Its’ follow-up ended by December 31, 2018.

Study population

Patients aged ≥ 80 years with histological diagnosis of NSCLC in early stage and treated with surgery or radiation alone from January 2012 to December 2017 were included. The early stage was defined as clinical T1N0M0 (T ≤ 3 cm), classified as stage Ⅰa according to the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual. Patients who had multiple cancers or a second diagnosis of lung cancer, diagnosed by autopsy/death certificate, without sufficient survival data and receiving chemotherapy were excluded.

The following information was obtained for each patient: patient ID, age at diagnosis, sex, race, year of diagnosis, anatomical tumor location, size, tumor histology, grade, type of treatment, number of regional lymph node examined (LNE) in patients who underwent surgery, reasons of no cancer-directed surgery in patients who underwent radiotherapy, and cause of death in the SEER database. Type of treatment categories included (1) surgery alone, (2) RT alone. 

Statistical Analysis   

All analyses were performed using SPSS 26.0 (IBM Corp, Armonk, NY). Patients were grouped into surgery or radiotherapy. Demographic and clinical characteristics were compared between groups using the χ² test or Student t test. The influence of patient characteristics and treatment on OS was evaluated using Cox’s regression analysis. The multivariate Cox regression analysis was performed with factors identified as significant in univariate analysis (P<0.05). Propensity score–matched (PSM) analysis based on factors significant on Cox regression analysis for OS was performed. Success of propensity score matching was assessed by t-test and χ² test. Survival time was measured from the time of diagnosis to the time of death or last follow-up. The overall survival (OS) and cancer-specific survival (CSS) before and after PSM were analyzed using the Kaplan–Meier (KM) methods, and evaluated by log-rank test. All the data tests were 2-sided, with a threshold of P ≤ 0.05 for significant differences.

Results

Patient characteristics

A total of 1641 patients with stage Ⅰa NSCLC were included, including 755 (46%) who received surgery and 886 (54%) radiotherapy. The median age of the entire cohort was 83 years, and the median follow-up was 42 months. Baseline demographics and clinical characteristics for the surgery and radiotherapy groups are described in detail in Table 1. Most patients who underwent surgery received either lobectomy (63.4%) or wedge resection (27.5%). Regional LNE was conducted in 611(80.9%) patients in the surgery cohort. Of the 886 patients who received radiotherapy, reasons of no cancer-directed surgery in 808 (91.2%) were “not recommended”, and only 78 (8.8%) patients “recommended but not performed, patient refused”. Compared with surgery, patients treated with radiotherapy were older, later diagnosed, and had more squamous cell carcinoma, unknown grade and increased tumor size.

Table 1 Baseline demographics and clinical characteristics

Survival Analysis 

Unadjusted Kaplan–Meier survival curves for the unmatched groups are shown in Fig. 1. The median OS time for the entire cohort was 56.0 months (95% confidence interval [CI], 51.7-60.3 months). The OS (P<0.001) and CSS (P<0.001) of the surgery group was higher than that of the radiotherapy group. The median OS time was not reached in surgery group and 41.0 months (95% CI, 36.7-45.3 months) in radiotherapy group. The 1-, 3-, and 5-year OS rates were 91.4%, 78.6%, and 63.6% for the surgery group, 87.2%, 54.4%, and 30.4% for the radiotherapy group, respectively. The 1-, 3-, and 5-year cancer-specific survival rates were 95.9%, 89.4%, and 81.4% for surgery group, and 92.9%, 74.8%, and 62.6% for radiotherapy group, respectively. 

Univariate and multivariate analyses of the predictors for OS are shown in Table 2. The age of diagnosis, sex, years of diagnosis, tumor size, histology, grade, and treatment pattern were significantly associated with survival in univariate analysis. On multivariate Cox regression analysis, patients who underwent radiotherapy had significantly worse survival as compared with patients who had surgery (hazard ratio 2.426; 95% CI, 2.003 to 2.939; P<.001). Younger age, female sex, later year of diagnosis, adenocarcinoma histology, well or moderately differentiation, and smaller tumor size were independent prognostic factors for better OS.

Table 2 Cox regression analyses of overall survival in patients treated with surgery or radiotherapy

Propensity score matching(PSM) based on age, sex, race, year of diagnosis, tumor size, histology, and pathologic grade resulted in 372 patients in both surgery and radiotherapy groups (1:1 ratio). The demographics and clinical variables were well balanced as shown in Tables 3. After PSM, the OS (P<0.001) and CSS (P<0.001) of the surgery group were still higher than that of the radiotherapy group. Median survival time were 79.0 and 41.0 months in the surgery and radiotherapy groups, respectively. The 1-, 3-, and 5-year OS rates were 90.0%, 76.9%, and 59.9% in the surgery group, and 86.0%, 54.3%, and 28.0% in the radiotherapy group. The 1-, 3-, and 5-year cancer-specific survival rates were 94.5%, 86.1%, and 78.0% in surgery group, and 90.7%, 74.5%, and 61.0% in radiotherapy group. (Fig. 2).

Table 3 Characteristics of patients in the surgery and radiotherapy groups after propensity score matching

Survival was also compared in matched subgroups of surgery without LNE versus radiotherapy. The demographics and clinical variables were well matched after propensity matching (Online Resource 1). Kaplan–Meier survival curves for the matched groups are displayed in Fig.3. No differences in the OS (P =0.146) and CSS (P =0.675) were found between the surgery without LNE and radiotherapy group.

Discussion

The present study showed that compared with surgery, octogenarians patients treated with radiotherapy were older, later diagnosed, and had more squamous cell carcinoma, unknown grade and increased tumor size. Surgery with regional LNE offers better survival than radiotherapy in octogenarians with clinical stage Ⅰa NSCLC after PSM. The 1-, 3-, and 5-year OS rates of surgery and radiotherapy group were 90.0%, 76.9%, 59.9%, and 86.0%, 54.3%, 28.0%, respectively. The 1-, 3-, and 5-year CSS rates of surgery and radiotherapy group were 94.5%, 86.1%, 78.0% and 90.7%, 74.5%, 61.0%, respectively.

The results of our study are consistent with those of most studies and meta-analyses comparing the clinical outcomes of surgery versus radiotherapy in elderly or non-elderly patients (Cao et al. 2019; Wu et al. 2020; Ganti et al, 2016; Ijsseldijk et al. 2021). Although the popularity of radiotherapy in elderly patients with NSCLC and the great progress of radiotherapy in the last 10 years, surgery should still be the first choice for patients with stage Ⅰa NSCLC, in view of the better OS and lung CSS, even for the elderly over 80 years old. Yet it is worth mentioning that there were no survival advantage when surgery without LNE compared with radiotherapy in the subgroup analysis after PSM. An analysis of the National Cancer Database (NCDB) also showed that no survival differences were observed between the lobectomy with 0 LN and SABR among healthy patients with clinical stage I NSCLC (RaZi et al. 2021). There are two inspirations from these results. First, for the surgeons, it is crucial to choose appropriate patient who can tolerate the operation and perform regional LNE to ensure the best survival benefits; Secondly, the disadvantage of radiotherapy compared with surgery is the impossibility of regional lymph node dissection, which may leave out occult lymph node involvement and affect the overall prognosis (Chi et al. 2019). Larger tumors are known to be associated with higher rates of occult nodal involvement (Verma, et al. 2017; Haque et al. 2022). In order to reduce the influence of occult lymph node metastasis as much as possible, patients with a tumor size more than 3 cm were excluded in our study. However, the rate of occult lymph node involvement was 12.9% even in less than 3 cm NSCLC (Haque et al. 2022). For radiologists, it is important to perform accurate clinical staging before radiotherapy. Conventional imaging examination such as enhanced computed tomography (CT) or ¹⁸F-fluorodeoxyglucose positron emission tomography (PET-CT) (Schmidt-Hansen et al. 2015; Wu et al. 2013; Gao et al. 2017) may not be able to judge the nature of lymph nodes completely accurately. Use of endobronchial ultrasound bronchoscopy (EBUS) with hilar and mediastinal nodal fine-needle aspiration sampling may provide more information on lymph node staging (Crombag et al. 2019; Hegde et al. 2020). Recently, the revised STARS study, in which pathological nodal sampling using EBUS was performed in > 90% patients, showed that the 3-year OS rate of SABR and surgical group (video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection, VATS L-MLND) is 91%, the 5-year OS rate of SABR group is 87%, and 84% for surgical group. Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage Ia NSCLC (Chang et al. 2021). One may be able to expect better survival outcomes of radiotherapy in early stage NSCLC by accurate lymph node staging.

The findings of this study should not be interpreted as a comparative analysis of surgery and radiotherapy yet, since it may magnify the survival difference between radiotherapy and surgery. Although the outcomes were significantly lower in patients undergoing radiotherapy, these patients were vast majority (91.2%) nonsurgical candidates, that is, these patients are generally with poor physical status, and might have a shorter life expectancy. Bei et al. (Bei et al. 2020) demonstrated that pretreatment physical state was significantly associated with OS in patients > 80 years old patients with early-stage NSCLC receiving SABR. Watanabe et al. also revealed that inoperability was the predictors of poor overall survival after SABR in elderly patients (Watanabe et al. 2021). Although we have done the PSM to adjust the two groups as much as possible, the lack of data about patient’s performance status and comorbid conditions in SEER database makes it impossible to match completely. The revised STARS study selected the operable Ia NSCLC and showed that survival of SABR was non-inferior than that of VATS L-MLND (Chang et al. 2021). A propensity score‑matching analysis from Tomita et al., which matched performance status, forced expiratory volume and Charlson comorbidity index between groups, also demonstrated that survivals were not significantly different between surgery and SBRT in patients with c-stage I NSCLC (Tomita et al. 2021). One may infer that survival difference between surgery and radiotherapy may not be as great as in our study among operable patients or patients with good performance status. Therefore, larger RCT studies are needed to further clarify which treatment strategy is better for the octogenarians with early stage NSCLC.

There are several limitations in this study. First, given the retrospective nature of the data collection from the SEER database, inherent selection bias was inevitable. Second, prognostic factors of NSCLC, such as the performance status, comorbid conditions and specific details regarding radiotherapy regimens were not provided by the SEER database. Although propensity score matching analysis was performed, biases cannot be excluded. Prospective trials are required to confirm the findings reported here.

In summary, our study demonstrates that surgery with lymph node dissection is associated with better OS and CSS than radiotherapy for octogenarians and older with stage Ⅰa NSCLC. It is reasonable for operable octogenarians with stage Ⅰa NSCLC to choose surgery other than radiotherapy.

Declarations

Funding This study was supported by Healthcare Research Project of the Central Health Committee (Grant 2020YB32).

Competing Interests The authors have no relevant financial or non-financial interests to disclose.

Author Contributions All authors contributed to the study conception and design. Lianfang Ni and Xinmin Liu contributed to the conception of the study and drafting of the manuscript. Dan Sun and Zhonghui Liu contributed to the data extraction. Gang Lin and Zhigang Zhang contributed to the statistical analysis. The first draft of the manuscript was written by Lianfang Ni, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval No personal identifying information was used in the study. Hence, we did not require Institutional Review Board approval or patient informed consent.

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