Patients’ survival outcomes in clinical stage IA lung adenocarcinoma not affected by preoperative staging brain magnetic resonance imaging

Introduction

Lung cancer represents the foremost reason for cancer-related fatalities in the United States (1). In a similar vein, lung cancer is also the top contributor to cancer-related deaths in China (2). Furthermore, more than 85% of all lung cancer cases are attributed to non-small cell lung cancer (NSCLC) patients (3). Approximately 39.1–44.1% of NSCLC patients diagnosed at stage IV, with the most common sites of distant metastasis being the brain, liver, adrenal gland, and bone (4-6). According to statistics, 25–50% of NSCLC patients will develop brain metastases during the entire disease progression process (7). Although prognosis has improved with recent advances in immunotherapy, the median survival for NSCLC patients with brain metastases remains limited, ranging from 11.8 to 19.2 months (8). The prognosis of patients is closely associated with the active management of brain metastases and primary cancer. Consequently, most staging guidelines recommend regular brain magnetic resonance imaging (MRI) examinations for patients with advanced stages of NSCLC (9).

In recent years, with the markedly increased use of low-dose computed tomography (LDCT) screening and high-resolution computed tomography (HRCT) has led to higher detection rate of early-stage lung cancer, and early-stage lung cancer is now the most common staging type of all screen-positive lung cancer patients (10,11). Selectively omitting brain MRI in patients with low-risk could avoid unnecessary scans, thereby reducing healthcare costs, conserving imaging resources, alleviating patient anxiety and potential treatment delays. However, the need to perform brain MRI for early-stage NSCLC patients remains controversial: the National Comprehensive Cancer Network guidelines and American College of Chest Physicians advise against routine brain MRI for stage IA patients, while the European Society of Medical Oncology and the Chinese Medical Association recommend brain MRI for patients preparing for treatment (12-16). It is often considered that staging brain imaging provides little value for asymptomatic patients with stage IA (clinical T1N0) NSCLC (17-19), many clinicians still use this method in staging clinical IA NSCLC patients. Based on the results of a study in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the use rate of staging brain MRI in stage IA NSCLC patients reached 25% (3,417/13,809) (17). Milligan et al. discouraged the use of staging brain MRI in clinical stage IA NSCLC patients, mainly due to low diagnostic rate (17). Based on these findings, there is currently insufficient evidence to determine the relationship between staging brain MRI and survival rate or cost-effectiveness. Understanding the effect of brain MRI on patient prognosis is the key to resolving this controversy. However, there is currently not enough evidence that brain MRI can improve the survival outcomes of this population. Therefore, it is critical to increase the focus of related research.

Among all pathological subtypes of NSCLC, lung adenocarcinoma (LUAD) is the most prevalent, and accounts for 63% of all lung cancers. In East Asia, including China, the incidence of LUAD ranks highest among both male and female patients diagnosed with NSCLC (20-22). In addition, LUAD is also a risk factor for brain metastases in NSCLC patients (19,23). These findings strongly suggest the necessity of exploring the potential survival advantage associated with performing staging brain MRI in early LUAD patients. Therefore, in this study, we recruited clinical stage IA LUAD patients to establish a single-center retrospective cohort and aimed to evaluate the survival benefit to explore whether staging brain MRI could improve survival in stage IA LUAD patients. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-331/rc).

Methods

All clinical studies were performed at the Cancer Hospital, Chinese Academy of Medical Sciences. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the Cancer Hospital, Chinese Academy of Medical Sciences (No. NCC2017B-026). The requirement for patient informed consent for this retrospective study was waived.

Patient screening and data collection

In this study, we retrospectively collected the information of patients with clinical stage IA LUAD who received curative surgery between May 2005 and December 2018. Patients were excluded if: (I) lack of a preoperative HRCT scan within 2 weeks prior to surgery; (II) clinical stage exceeded IA; (III) incomplete clinicopathologic data; (IV) prior treatments (such as radiotherapy, chemotherapy, or targeted therapy); (V) a history of previous malignancy within the last 5 years; (VI) having fewer than six lymph nodes resected; (VII) a follow-up duration of less than 6 months free from metastasis or death; or (VIII) synchronous or metachronal lung cancer. Ultimately, 593 cases were analyzed, of which 372 were utilized for the propensity score matching (PSM) (Figure 1).

Figure 1 Flowchart of study. HRCT, high-resolution computed tomography; LUAD, lung adenocarcinoma; MRI, magnetic resonance imaging.

Patient information included age, sex, tumour size, smoking history, pathological subtype, pathological stage, nodule consistency, nodule location, preoperative examination [positron emission tomography (PET)/computed tomography (CT), thoracoabdominal CT, neck ultrasound or/and abdominal ultrasound], and survival information were collected. Tumors were staged according to the Union for International Cancer Control (UICC) 8th edition tumor-node-metastasis (TNM) classification system (24).

Image acquisition and interpretation

HRCT examinations were performed on multi-detector spiral CT systems with 8-, 16-, or 64-slice configurations (LightSpeed Ultra, ProSpeed, Discovery ST, and LightSpeed VCT; GE Medical Systems, Chicago, Illinois, United States). Imaging parameters included a tube voltage of 120 kVp, tube current of 250–350 mA, and reconstruction with a standard algorithm. The reconstructed slice thickness ranged from 0.625 to 1.25 mm with 0.8–1.0 mm intervals. Brain MRI images were acquired using a 1.5 T or 3.0 T GE MRI scanner, employing axial T2WI/FLAIR sequences [repetition time (TR): 8,000 ms; echo time (TE): 130 ms; number of excitations (NEX): 1; slice thickness: 5 mm; spacing: 1 mm] and gadolinium-enhanced axial and sagittal scans (TR: 420 ms; TE: 20 ms; NEX: 1; slice thickness: 5 mm; spacing: 1 mm).

Two independent radiologists (Mengwen Liu and X.W.) evaluated the tumour for each patient and determined the nodule size, nodule consistency, nodule location, and recurrence/metastatic site(s) of the tumour on Carestream GCRIS 2.1 PACS workstation (Carestream Health, Shenzhen, China). In cases of disagreement, a third senior doctor (L.Z.) with more than 15 years of experience in chest CT interpretation gave the final result. The radiologists were blinded to all clinical and outcome information.

Follow-up strategies

Patients were followed starting from the day after surgical resection. Evaluated outcomes included 10-year overall survival (OS), 10-year recurrence-free survival (RFS), and 10-year brain metastasis-specific RFS. Follow-up data were collected through review of hospital records and structured telephone interviews performed by trained staff (Mengwen Liu and X.W.). If neither the patient nor their family could be contacted on the scheduled date, survival status was recorded at the last known follow-up. RFS was defined as the time from surgery until the first documented recurrence. Recurrence was confirmed by pathology or clinical-radiological consensus. Locoregional recurrence was defined as a new lesion at a prior surgical staple line, a new lesion in the same lobe as the original tumor, or ipsilateral enlarged mediastinal or hilar lymph nodes; distant recurrence was defined as a new pulmonary nodule in a different lobe or a new extrapulmonary lesion (25). RFS is classified into two distinct categories depending on the site of metastasis: overall RFS and brain metastases-specific RFS which specifically including brain metastasis.

Statistical analysis

Frequency distributions along with descriptive statistics were computed for each variable. Data that followed a normal distribution are reported as the mean ± standard deviation, whereas data not adhering to a normal distribution are shown as the median [interquartile range (IQR)]. The normality assumptions were evaluated utilizing the Kolmogorov-Smirnov test. Comparisons of age and tumor size between patients with and without staging brain MRI were performed using Student’s t-test for parametric data and the Wilcoxon rank-sum test for nonparametric data. For categorical variables, analyses were conducted using either the Chi-squared test or Fisher’s exact test. To balance the confounding factors, PSM was used according to the baseline characteristics of the patients (patient age, sex, tumour size, smoking history, pathological subtype and preoperative examinations including PET/CT, abdominal CT, neck ultrasound and abdominal ultrasound) in the groups with and without staging brain MRI (PSM ratio was 1:1 and caliper value was set to 0.01). All analyses of prognostic outcome were based on patient cohorts balanced for confounding factors. The Kaplan-Meier method was used to analyze OS, overall RFS and brain metastases-specific RFS. The log-rank test was used to compare with or without staging brain MRI groups of patients after PSM. Cox regression analysis to determine the hazard ratios (HRs) for metastasis or recurrence according to the assigned groups after PSM. Mengwen Liu and X.L. conducted the statistical analyses using SPSS software (version 25; IBM, Armonk, NY, USA) and R software (version 4.1.1; The R Foundation for Statistical Computing, Vienna, Austria), establishing a significance threshold at P<0.05.

Results

Clinicopathologic characteristics

A total of 593 LUAD patients (median age: 58 years, IQR, 50–64; 229 males, 364 females) with a clinical stage of T1N0M0 who underwent surgical resection from May 2005 and December 2018 were enrolled (Table 1). The median tumor size was 1.70 cm (IQR, 1.20–2.22 cm). Most patients are non-smokers [n=439 (74.0%)]. The most common pathological subtype was invasive adenocarcinoma (IAC) [n=485 (81.8%)], followed by minimally invasive adenocarcinoma (MIA) [n=53 (8.9%)], adenocarcinoma in situ (AIS) [n=49 (8.3%)] and atypical adenomatous hyperplasia (AAH) [n=6 (1.0%)]. Most patients have pathological stage I [n=393 (66.3)], 88 (14.8%) patients had stage II, 58 (9.8%) patients had stage III, and 54 (9.1%) patients had stage 0. Most lesions on CT images were part solid nodule (PSN) [n=329 (55.5%)], followed by solid nodule (SN) [n=178 (30.0%)] and ground-glass nodule (GGN) [n=86 (14.5%)]. Among 593 patients, 186 patients underwent preoperative staging brain MRI and 407 patients did not undergo preoperative staging brain MRI. Table 1 summarizes the clinical and radiological differences between patients receiving staging brain MRI and those not undergoing staging brain MRI.

After adjustment for confounding factors using PSM, a total of 372 patients (median age: 57 years, IQR, 50–64 years; 154 males, 218 females) were included (Table 2) and allocated to two groups: with-staging brain MRI group (n=186) and without-staging brain group (n=186). The median tumour size was 1.70 cm (IQR, 1.30–2.20 cm). Most patients, comprising 273 individuals (73.4%), were non-smokers. Pathological subtype for the 372 nodules was IAC in 306 (82.3%), MIA in 37 (9.9%), and AIS in 29 (7.8%). Pathological stage for the 372 nodules was stage I for 260 (69.8%), stage II for 50 (13.4%), stage III for 33 (8.9%), and stage 0 for 29 (7.8%). Nodule consistency for the 372 nodules was PSN for 218 (58.6%), SN for 101 (27.2%), and GGN for 53 (14.2%). Because PSM was performed based on patients’ baseline characteristics, no significant difference of them was observed between two groups (Table 2).

OS

During median follow-up time of 80 months (IQR, 60–103 months), a total of three (0.8%, 3/372) patients passed away. Specifically, two patients succumbed to lung cancer, while one patient died due to postoperative complications. The groups with and without staging brain MRI demonstrated 10-year OS of 98.2% and 99.4%, respectively. No significant differences were observed between the two groups (P=0.54) (Figure 2A). When stratified by tumor size, no significant difference in 10-year OS was observed between patients with and without staging brain MRI in either subgroup. Among patients with tumors <2 cm, the 10-year OS was 100% in the without-staging brain MRI group and 98.0% in the with-staging brain MRI group (P=0.26) (Figure S1A). For tumors ≥2 cm, the rates were 98.3% and 98.6%, respectively (P=0.96) (Figure S1B).

Figure 2 Evaluation of survival outcomes in patients with clinical stage IA lung adenocarcinoma. (A) OS for without versus with staging brain MRI groups. (B) Time to recurrence for without versus with staging brain MRI groups. (C) Overall RFS for without versus with staging brain MRI groups. (D) Brain metastases-specific RFS for without versus with staging brain MRI groups. MRI, magnetic resonance imaging; OS, overall survival; RFS, recurrence free survival.

RFS

Of the 372 PSM patients, a total of 56 patients (15.1%, 56/372) experienced metastasis consisting of 7 (12.5%) locoregional recurrences and 49 (87.5%) distant recurrences (Figure 2B). Most common metastatic type was brain metastasis (21.4%, 12/56), followed by non-ipsilateral lung metastasis (19.6%, 11/56), bone metastasis (16.1%, 9/56), multiple sites metastasis (14.3%, 8/56), recurrence at surgical staple line (8.9%, 5/56), contralateral mediastinal or distant lymph node metastasis (7.1%, 4/56), pleura metastasis (5.4%, 3/56), ipsilateral mediastinal lymph node metastasis (3.6%, 2/56), liver metastasis (1.8%, 1/56), and adrenal gland metastasis (1.8%, 1/56). No significant difference was detected in recurrence rate between the with-staging brain MRI group (16.1%, 30/186) and the without-staging brain MRI group (14.0%, 26/186; P=0.56) as well as recurrence pattern which expressed as distant recurrence rate (with-staging brain MRI group: 83.3%, 25/30; without-staging brain MRI group: 92.3%, 24/26; P=0.43) (Table 3). The 10-year overall RFS was 83.1% in the group that underwent staging brain MRI and 85.4% in the group that did not. No significant differences were observed between the two groups (P=0.68) (Figure 2C). Subgroup analyses by tumor size showed consistent findings. In patients with tumors <2 cm, the 10-year RFS was 86.8% in the without-staging brain MRI group and 83.6% in the with-staging brain MRI group (P=0.70) (Figure S1C). In those with tumors ≥2 cm, the corresponding rates were 74.1% and 65.6% (P=0.37) (Figure S1D).

A total of 20 patients (5.4%, 20/372) presented with brain metastases, where the brain served as the initial site of recurrence in 16 cases while it was a secondary site of metastasis in the remaining 4 cases. The 10-year brain metastases-specific RFS in the with-staging brain MRI group and the without-staging brain MRI group was 93.2% and 93.8% respectively. No significant differences were observed between the two groups (P=0.56) (Figure 2D). The incidence of brain metastases was similarly low across tumor size strata, regardless of staging brain MRI. Among patients with tumors <2 cm, the 10-year brain metastases-specific RFS was 99.1% in the without-staging brain MRI group and 91.4% in the without-staging brain MRI group (P=0.12) (Figure S1E). For tumors ≥2 cm, the rates were 82.5% and 86.5%, respectively (P=0.66) (Figure S1F).

Multivariate analysis revealed that staging brain MRI was not associated with a significant improvement in OS [HR, 2.35; 95% confidence interval (CI): 0.21–26.68; P=0.49], overall RFS (HR, 1.32; 95% CI: 0.75–2.31; P=0.33) or brain metastases-specific RFS (HR, 1.52; 95% CI: 0.60–3.84; P=0.38), when adjusted for age, sex, smoking status, nodule consistency, surgical procedure, treatment regimen, pathological type and pathological stage (Table 4).

Discussion

In this study, among clinical stage IA LUAD patients enrolled after using PSM to adjust for confounding factors, preoperative staging brain MRI did not demonstrate a correlation with neither OS, overall RFS nor brain metastases-specific RFS. In the cohort of stage IA LUAD patients who received surgical treatment, overall recurrence was observed in 15.1% (56/372) of patients, with 16.1% (30/186) in the group with staging brain MRI and 14.0% (26/186) in the group without staging brain MRI (P=0.56). What’s more, 5.9% (11/186) patients in the with staging brain MRI group and 4.8% (9/186) in the without staging brain MRI group developed brain metastases after surgery, consistent with previous evidence (26). Multivariate Cox regression analysis revealed no significant association between preoperative staging brain MRI and survival outcomes in stage IA LUAD patients, including OS (HR, 2.35; 95% CI: 0.21–26.68; P=0.49), overall RFS (HR, 1.32; 95% CI: 0.75–2.31; P=0.33) or brain metastases-specific RFS (HR, 1.52; 95% CI: 0.60–3.84; P=0.38).

The clinical application value of preoperative staging brain MRI for lung cancer has always been controversial (12-16). Consequently, researchers have consistently strived to tackle this issue. Li et al. have reported that contrast-enhanced brain MRI did not offer extra information regarding metastases in patients with multifocal GGNs (27). However, studies on the correlation between brain MRI use and the postoperative survival of clinical stage IA NSCLC patients are still relatively insufficient. LUAD is a major histological subtype of NSCLC which accounts for the highest proportion of screened lung cancer patients (20). In addition, LUAD patients also have a higher incidence of brain metastases than other types of NSCLC patients (28). Evidence has shown that LUAD is one of the risk factors for brain metastases in NSCLC patients (23). Accordingly, this study recruited patients with clinical stage IA LUAD to assess whether brain MRI confers a survival advantage in asymptomatic early-stage patients and to explore the potential association between brain MRI findings and prognosis in this cohort. Nam et al. (29) analyzed the association between brain MRI and prognosis in NSCLC patients and eventually reached the conclusion that there was no significant correlation between them. Similarly, in this study, we found that brain MRI had no significant association with prognosis in patients with clinical stage IA LUAD, which did not clearly affect the prognosis.

Evidence has shown that about 2% of asymptomatic NSCLC patients develop brain metastases (30). Nevertheless, a considerable proportion of patients still receive brain MRI for staging. A recent population-based study in the SEER database revealed that between 2004 and 2013, more than a quarter of stage IA NSCLC patients underwent brain MRI for staging (17). This excessive utilization of brain MRI may be due to insufficient clinical evidence, contributing to a sense of uncertainty among doctors. In addition, the use of brain MRI for staging may also cause treatment delay. Several studies have shown that treatment delay in early lung cancer patients is negatively correlated with prognosis (31,32). Based on the conclusions of this study, staging brain MRI of LUAD patients during the clinical IA period did not improve survival but had some potential adverse effects.

This study has several limitations. Firstly, this was a single-centre retrospective study. Due to the lack of balanced principles inherent in randomized controlled trials, this retrospective study is limited by various biases and confounding factors, thus affecting the powerful comparisons of results between the treatment and control groups. In this study, the allocation of patients for brain MRI examinations is not randomized; to be more specific, doctors may perform MRI or CT examinations for patients who are easily diagnosed with benign or malignant lesions. Under this circumstance, the survival benefit of these examinations may be overrated. To balance confounding factors, we conducted PSM, thereby enhancing comparability between the with staging brain MRI group and the without staging brain MRI group by aligning the distribution of intergroup bias and confounding factors. Therefore, the conclusions drawn in this study are relatively reliable. Secondly, a relatively low number of events, particularly deaths and brain metastases, was observed in our study, which may limit the statistical power of the survival analyses. This limitation is likely attributable to the favorable prognosis associated with clinical stage IA LUAD. Consequently, the interpretation of survival outcomes should be made with caution. Future studies with larger sample sizes and extended follow-up periods are warranted to validate these findings. Thirdly, the study excluded patients who were unable to undergo surgery because of a positive preoperative staging brain MRI, thus diminishing the importance of staging brain MRI. Therefore, further multicentre prospective research is warranted to validate our conclusions.

Conclusions

In summary, our findings suggest that staging brain MRI may not be associated with improved long-term outcomes in patients with clinically staged IA LUAD. However, the low event rates warrant cautious interpretation, and these observations require validation in larger prospective cohorts. Our ongoing research focuses on developing a standardized, risk-stratified imaging protocol to establish evidence-based criteria, helping clinicians prospectively determine the appropriate use of staging brain MRI.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-331/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-331/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-331/prf

Funding: This work was supported by the National High Level Hospital Clinical Research Funding (No. 80102022505), Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2022A22), Beijing Municipal Natural Science Foundation (No. 7184238), and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. 2021-1-I2M-012).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-331/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, and was approved by the Ethics Committee of the Cancer Hospital, Chinese Academy of Medical Sciences (No. NCC2017B-026). Individual consent for this retrospective analysis was waived.

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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