Over the years, the global focus on lung-related diseases has increased significantly due to the outbreak and spread of COVID-19. Consequently, there has been a rise in the detection of lung nodules and malignant tumors. Lung cancer has emerged as the most prevalent tumor worldwide, and significant advancements have been made in its treatment and control, particularly for non-small cell lung cancer (NSCLC). However, despite improvements in lung cancer prognosis, effectively managing brain metastases remains a challenge. The deterioration of neurocognitive function, along with the subsequent distress and anxiety following brain metastases, significantly reduces the feasibility of life-saving treatments and escalates medical and economic burdens17–21.
The occurrence of brain metastases after the diagnosis of lung cancer can vary depending on factors such as patient age, histological features, and the treatment modality employed for lung cancer. Notably, brain metastases within 23 months after the initial lung cancer diagnosis have shown relatively poor prognoses following brain metastasis surgery.
Several prognostic indicators impact survival after NSCLC brain metastasis surgery. These include age, histopathological type of NSCLC, advanced NSCLC, higher T stage at the time of NSCLC diagnosis, NSCLC chemotherapy, and the presence of EGFR and ALK mutations22–33. However, it remains uncertain whether the time interval (TI) between brain metastasis and NSCLC diagnosis affects the prognosis of brain metastasis surgery. Previous studies have suggested that a longer TI is beneficial for prognosis. Systemic treatment of NSCLC and the presence of EGFR and ALK mutations have also been significantly associated with longer interval times16,34,35.
Our study conducted a univariate analysis, which revealed that gender, adjuvant chemotherapy for NSCLC, hemoglobin status before brain metastasis surgery, and adjuvant targeted therapy after brain metastasis were associated with the TI. Among NSCLC-related features, only adjuvant chemotherapy was independently associated with a shorter TI (< 23 months). Among brain metastasis-related features, the lack of postoperative adjuvant targeted therapy was associated with a shorter TI. In conclusion, adjuvant chemotherapy and adjuvant targeted therapy may be crucial factors affecting the survival and prognosis of the TI following NSCLC brain metastasis surgery.
In our study cohort, the median TI from the diagnosis of NSCLC to the diagnosis of brain metastasis was 19 months. Earlier historical estimates indicated a median TI of 9–13 months22–24, 28,29,36, while later multicenter retrospective studies reported a median TI of approximately 16 months for NSCLC brain metastasis, which aligns with our findings16,37,38. Consistent with previous research reports, our study also confirmed the significant association between the presence of EGFR and ALK mutations and the progression and prognosis of NSCLC brain metastasis. Further research is needed to unravel the complex mechanisms underlying the timing and prognosis of brain metastasis in NSCLC patients.
Historically, survival estimates for patients with NSCLC brain metastases ranged from 3 to 6 months, whereas our study observed a median survival of 16 months. This is consistent with the findings of Deborah and colleagues16, as well as an earlier multicenter retrospective study by Sperduto and colleagues, which reported a median survival of approximately 12 months39. While the overall prognosis of lung cancer brain metastases remains debatable, some researchers have found that these metastases have an adverse impact on prognosis40, while others have shown that a longer TI between lung cancer brain metastases is associated with a reduced risk of death16. This finding aligns with our results, highlighting the significance of studying late incidences and related risk factors of TI (≥ 36 months) in NSCLC brain metastases.
Within our study cohort, 15 cases (20.3%) had advanced brain metastases (TI ≥ 36 months). We identified the age at lung cancer diagnosis, NSCLC histological type, adjuvant chemotherapy, and targeted therapy as significant predictors for TI ≥ 36 months. Intriguingly, all 15 patients had EGFR or ALK mutations, which prompted the administration of targeted therapy. This result further corroborates the association between systemic NSCLC treatment, the presence of EGFR and ALK mutations, and a longer TI16,34,35. The age at lung cancer diagnosis has been widely recognized as a prognostic and survival predictor, as supported by numerous studies22,23,25,26,41. The histological type of NSCLC has also gained consensus as a predictive factor26–32, 41. Lung adenocarcinoma accounts for approximately 50% of all lung cancers, and EGFR and ALK mutations are the primary gene mutation types that serve as survival predictors. These findings align with a retrospective multicenter study by Sperduto and colleagues, which revealed a significant association between EGFR and ALK mutations and prolonged TI to brain metastases.
Although.our study has provided valuable insights, it is important to consider several limitations. Firstly, being a retrospective single-center study, there are inherent limitations and potential selection biases that may influence the derived conclusions and subsequent clinical practice. Although we hope that our results contribute to the overall assessment of prognosis after NSCLC brain metastasis surgery in the future, it is essential to acknowledge the inherent errors and limitations in our assessment due to the small sample size of our experimental cohort, which restricts the generalizability of our research findings. Furthermore, the follow-up data for our patients may have some incompleteness, leading to deviations from the actual situation, which is a common limitation in retrospective research. Additionally, our analysis focused on patients who underwent surgery for brain metastasis, representing a specific subgroup, and not all lung cancer patients with brain metastasis received surgical treatment. Consequently, the generalizability of our findings to patients with lung cancer brain metastasis who did not undergo surgical treatment is limited.
Despite these limitations, our study provides significant insights for understanding the disease progression and clinical prognosis assessment of NSCLC brain metastasis.