The flow chart of patient enrollment was shown in Figure 1. Between January 2012 and June 2018, Among the 229 consecutive patients with EGFR-mutated advanced NSCLC, three patients were excluded due to short EGFR-TKI treatment (< 1 month), and 69 patients were excluded due to synchronous BM. A total of 157 patients without BM at initial diagnosis were included: 30 patients (19.1%) developed metachronous BM during EGFR-TKIs treatment and 127 patients (80.9%) didn’t. The clinical and treatment characteristics of these patients grouped by BM status are shown in Table 1. The median age of the patients without BM and patients developing metachronous BM was 60 and 54 years, respectively. Patients who would develop metachronous BM were more likely to have a more favorable Karnofsky Performance Status (KPS score ≥ 80: 100% patients developing metachronous BM vs. 90.5% patients without BM). There was no difference between the two groups with respect to gender, histology, BMI, smoking status, tumor markers level, clinical stages, and extracranial metastatic location.
The incidence of metachronous BM and survival
The median duration of follow-up was 24.1 months (95% CI: 19.6-28.6 months). Thirty patients (19.1%) developed metachronous BM during EGFR-TKIs treatment. Among them, patients with symptomatic and asymptomatic BM were 18 (60%) and 12 (40%) respectively. Fourteen patients (46.7%) received WBRT and 8 patients (26.7%) received stereotactic radiosurgery (SRS) plus continuous EGFR-TKIs treatment, other 2 patients (6.7%) received continuous EGFR-TKIs plus supportive care, and 6 patients (20%) switched to chemotherapy. In addition, 9 patients (9/30, 30%) receiving chemotherapy as the first-line treatment developed metachronous BM during subsequent EGFR-TKIs therapy. The 1-, 2- and 3-year risks of BM were 11.6%, 22.6% and 29.4% respectively (Figure 2).
The median OS of these 157 patients was 37.5 months (95% CI: 27.6-47.4 months). The 1-, 2- and 3-year OS rates were 86.9%, 69.8% and 55.9% respectively (Figure 2). For PFS, 105 patients (66.9%) progressed during follow-up time. Median PFS was 13.6 months (95% CI:11.2-15.9 months). The 1-, 2- and 3-year PFS rates were 57.8%, 29.4% and 21.3% respectively (Figure 2). Our median OS and PFS were longer than those of the clinical trials for patients with EGFR-mutated advanced NSCLC .
The overall response rates were partial for 76.4%, stable for 23.0%, and progressive for 0.6% of EGFR-TKIs treatment at the first follow-up examination.
Overall survival of patients grouped by BM status
To evaluate the impact of BM status on OS, the 157 patients were grouped by with metachronous BM and without BM during EGFR-TKIs treatment. Compared with patients without BM, patients developing metachronous BM during the course of EGFR-TKIs treatment were at a higher risk on OS (HR=1.86, 95%CI:1.07-3.26). Our findings confirmed that patients developing metachronous BM during EGFR-TKIs treatment had poorer outcomes (median OS: 28.6 months) than patients without BM (median OS: 44.8 months, Figure 3).
Risk factors of developing metachronous BM
Several clinical factors were associated with metachronous BM in both univariate and multivariate analyses (Table 2). In univariate analyses, BM was associated with age, the first-line treatment regimens, types of EGFR mutations, numbers of extracranial metastases, and malignant pleural effusion. Other factors such as gender, KPS score, smoking status, tumor marker levels before treatment, clinical stages, types of EGFR-TKIs, and metastatic locations were not associated with metachronous BM.
The factors showing associations (P < 0.100) in the univariable Cox regression analyses, as well as other factors that were reported to be associated with BM in previous studies [27,31] were further examined by multivariable Cox regression analysis. Results of multivariate analysis indicated that age ≤ 49 years (P = 0.035), numbers of extracranial metastases (P = 0.013), and documented malignant pleural effusion (P = 0.002) were independent high-risk factors of developing metachronous BM, while the first-line treatment regimens and types of EGFR mutations were not associated with metachronous BM in multivariate Cox regression analysis.
Furthermore, the 1-year actuarial incidence of developing metachronous BM in patients with no risk factor (n =101), 1 risk factor (n =46), and 2 risk factors (n =10) were 7.01%, 14.61%, and 43.75%, respectively (P < 0.001, Figure 4). Meanwhile, we performed an internal validation by randomly selecting 52 cases from our patient cohort. The 1-year actuarial incidence of developing metachronous BM in these 52 patients with no risk factor (n = 37), 1 risk factor (n = 11), and 2 risk factors (n = 4) were 5.65%, 22.2%, and 50.0%, respectively (P = 0.004, Figure S1). These results were consistent with the whole cohort, indicating the credibility of the result to some extent. Therefore, patients with more risk factors had a higher risk of developing metachronous BM. Our studies suggested that the patients with ≥ 1 risk factors were more likely to benefit from PCI or the first-line Osimertinib treatment.