Brain metastases in non-small cell lung cancer: Prevalence, high-risk factors, and overall survival prognosis

Brain metastases (BM) in non-small cell lung cancer (NSCLC) at the time of diagnosis are quite common, occurring in about 10%–20% of cases^[1,2]. Risk factors associated with the frequency of BM in NSCLC include non-squamous carcinoma, elevated serum carcinoembryonic antigen (CEA) levels, lymph node metastases (especially metastasis to multiple mediastinal lymph nodes), and EGFR/ALK gene mutations^[3]. Chinese authors have also observed that lesion diameter, calcium concentration, and CEA level are independent risk factors for brain metastasis^[4]. Increased lymph node size is also linked to asymptomatic BM^[5].

The primary treatments for NSCLC with BM used to be surgery, radiosurgery, and whole-brain radiotherapy. Chemotherapy had limited effectiveness due to the presence of the blood–brain barrier. However, now there are numerous treatment options, and the effectiveness has greatly improved with the emergence of targeted drugs^[6].

Although immunotherapy is an emerging option for increasing treatment options in NSCLC, its benefits in BM are unclear and require further study^[7,8]. The median overall survival time for patients with BM is approximately 12 months^[9]. Factors such as performance status, gene mutation status, and histopathology play an important role in predicting the survival time of NSCLC with BM^[9,10].

Overall assessment of BM in NSCLC will assist clinicians in gaining an overview, thereby contributing to diagnosis and treatment strategies. In Vietnam, no comprehensive studies have evaluated this situation thoroughly. Our study aimed to determine the incidence of brain metastasis, evaluate overall survival time, and assess factors influencing these outcomes in the NSCLC population in Vietnam.

Table 1 presents the characteristics of the study participants. The median age of the study participants was 63 ± 13 years, The majority of patients were male, with non-squamous carcinoma, older than 60 years, and with PS ECOG 0–1. Approximately one-third of cases had positive EGFR/ALK gene mutations.

Table 2 shows a brain metastasis prevalence of 13.1%. It is high in non-squamous carcinoma subgroups, lymph node stage N3, short axis of mediastinal node ≥1.5 cm, and CEA ≥5 ng/ml.

Table 3 shows the association of BM in NSCLC with several factors: BM are associated with non-squamous carcinoma (OR = 2.04, 95% CI: 1.01–4.14), lymph node stage N3 (OR = 1.77, 95% CI: 1.15–2.72), and CEA status ≥5 ng/ml (OR = 1.81, 95% CI: 1.05–3.13).

Figure 1 shows the overall survival time for NSCLC patients with and without BM. The median overall survival time of patients with BM was lower than that of patients without BM (15.3 vs. 18.3 months, p = 0.005). The 1-year and 2-year overall survival rates for patients with NSCLC and BM are 55.0% and 27.6%, respectively.

Figure 1:

Overall survival time for non-small cell lung cancer patients with and without brain metastases: Kaplan–Meier analysis.

Table 4 presents a multivariable Cox regression analysis of the association between overall survival time in patients with brain metastatic NSCLC and various factors. Overall survival time is associated with positive EGFR/ALK gene mutation status (HR = 0.38, 95% CI: 0.20–0.70) and the number of 1–3 BM lesions (HR = 0.56, 95% CI: 0.33–0.96).

Figure 2 shows that the median overall survival time is higher in the group with 1–3 BM (19.5 vs. 9.3 months, p = 0.004) (Figure 2A) and in the EGFR/ALK gene mutation positive group (20.3 vs. 8.7 months, p = 0.001) (Figure 2B).

Figure 2:

Overall survival time of patients with NSCLC with brain metastases in subgroups: Kaplan–Meier analysis, log-rank test.

In Vietnam, this is the first study to evaluate BM in NSCLC. We observed a high prevalence of BM at the time of diagnosis, and it was closely linked to several factors. In addition, BM limit the overall survival time of patients with NSCLC. We also found some prognostic factors for overall survival in this group of patients. Our findings will assist clinicians in gaining a comprehensive perspective on patients with brain metastatic NSCLC during diagnosis and treatment.

The presence of BM was typically detected using CT scan or MRI of the brain at the time of diagnosis. We observed that the prevalence of BM at the time of diagnosis was 13.1%, consistent with findings from other studies^[1,15], but lower than in India, where the prevalence was 21%^[2]. Our study was conducted with a large sample size at the largest oncology center in central Vietnam. Therefore, this result can be considered representative of the NSCLC population in central Vietnam.

In this study, when analyzing univariate and multivariate logistic regression, we found that BM are closely associated with non-squamous carcinoma, lymph node stage N3, and serum CEA status ≥5 ng/ml. In an analysis from the US National Cancer database, factors such as younger age, glandular and large cell histology, histological grade >II, tumor size >3 cm, and lymph node positivity were associated with BM in NSCLC^[1]. In addition, distant metastases to the liver/bone/lymph nodes, tumor stage, and higher node stage also showed a higher likelihood of BM^[16]. Lesion diameter >5.505 cm, calcium concentration >2.295 mmol/l, and CEA >11.160 ng/ml are also prognostic factors for this condition^[4]. In Mexico, age, serum CEA, and genetic mutation status are recognized as high-risk factors for BM^[17]. Previous studies indicate a high incidence of BM in patients with positive EGFR/ALK gene mutations^[18,19]. However, we did not find an association of BM with EGFR/ALK gene mutations in multivariate analysis. Perhaps due to limited economic resources, a certain proportion of patients do not have access to diagnostic testing for EGFR/ALK gene mutations, which thus affects these results when analyzed.

BM are a factor that affects the quality of life as well as the overall survival of patients with NSCLC. Our study found that the median overall survival time in the group of patients with BM was lower than in those without BM (15.3 vs. 18.3 months, p = 0.005). A previous study found that the median overall survival in patients with NSCLC with BM was approximately 12 months^[9]. Real-life data of patients with BM in Japan showed a median overall survival of 14.3 months^[10]. In the present circumstances, the overall survival time for this group of patients has significantly improved due to the use of new local and systemic treatments. A study in the USA revealed that the median overall survival for patients with BM from NSCLC was 17.0 months^[20]. The results of our study are quite similar to those of other studies around the world. With the combination of multimodality treatment, in particular, the effectiveness of targeted treatment drugs on patients with NSCLC with BM has improved and significantly prolonged the overall survival time.

When analyzing multivariable Cox regression, we noted a benefit in overall survival time in patients with BM with EGFR/ALK gene mutations compared to patients with EGFR/ALK-negative/unknown (HR = 0.38, 95% CI: 0.20–0.70, p = 0.002), thereby proving the clear benefits of targeted drugs on patients with BM. This observation is completely consistent with previous reports^[21,22]. In our study, we observed a survival benefit among patients with 1–3 BM (HR = 0.56, 95% CI: 0.33–0.96, p = 0.036). Previously reported prognostic factors include PDL1 status, EGFR/ALK gene mutation, performance status, age, number of BM, and extracranial metastases^[23]. For patients with BM, brain radiotherapy is one of the recommended local treatment methods. In cases of limited metastases, radiosurgery (SRS) is recommended as an alternative to surgery or as an adjunct after brain tumor surgery^[24,25]. In cases of multiple BM, whole-brain radiotherapy is indicated^[26]. Currently, due to limited local resources, the main treatment at our center is steroid or whole-brain radiation therapy. In some cases, the ability of EGFR/ALK tyrosine kinase inhibitor drugs to penetrate the brain supports the decision to delay brain radiotherapy in selected patients without negatively impacting treatment outcomes^[27]. Whole-brain radiotherapy is performed at our unit for BM that are symptomatic and do not benefit from targeted drugs. In our analysis, whole-brain radiotherapy did not improve survival benefits for patients with NSCLC with BM (HR = 0.98, 95% CI: 0.55–1.81, p = 0.970). This result is also consistent with previous reports^[28].

The limitations of this study include its retrospective design and the fact that it was conducted at a single center. The collection of data, particularly regarding the smoking variable, was somewhat affected. Limited resources may have resulted in some patients lacking access to new treatment options, such as targeted therapies and immunotherapy, which could influence the results. Nevertheless, this study provides valuable information on the treatment of NSCLC in Vietnam. Future research should aim to evaluate the effectiveness of new medications, like targeted therapies and immunotherapy, specifically for patients with NSCLC who have BM.

Our study indicates a high prevalence of BM in NSCLC in Vietnam. The application of new treatment methods has improved treatment effectiveness.

This study offers an overview of BM in NSCLC, aiming to enhance diagnostic and treatment effectiveness in real-life settings in Vietnam.