CNS metastasis incidence and patient’s characteristics

Of 3283 patients diagnosed with GEC, a total of 120 (3.65%) patients were identified in our database with CNS metastases (Fig. 2). Of these, 100 (3.04%) patients were diagnosed with BrM and 20 (0.61%) were found with LMC (Fig. 2). Some patients in the database may have had only 1 or 2 initial consultations and were not followed up. Their eventual development of brain metastases may not be recorded. To address a possible more accurate incidence, we selected in our cohort patients who were actively followed until death or achieved a disease-free survival of at least 5 years. Within this refined cohort (2230 patients), the frequency of BrM and LMC was determined to be 4.48% and 0.89%, respectively (Fig. 1).

Fig. 1

Study flow chart. presents two distinct study flow cohorts of the same population, elucidating the prevalence of CNS metastases among patients diagnosed with GEC. The initial cohort encompasses all 3,283 patients, where 100 (3.04%) were found with BrM and 20 (0.61%) with LMC, regardless of if they were treated or followed up in our institution or not. It’s noteworthy that patients decided to received treatment in other centers, potentially impacting the accuracy of reported CNS metastasis frequencies. In the second cohort, comprising 2,230 patients actively monitored until death or achieving a disease-free survival of at least 5 years, the recalculated frequencies for BrM and LMC are 4.48% and 0.89%, respectively. This recalibration providing a more accurate representation of incidence within this specific patient group

Among the patients with BrM, the median age was 64.4 years. Most patients were non-asian (n = 93, 93%), and 63 patients (63%) were either current or former smokers. In terms of the initial gastroesophageal staging, 65% received a de novo stage IV diagnosis, while 35% initially had stage I-III diagnoses, subsequently experiencing recurrence, and progressing to metastatic disease. Concerning the presentation of CNS metastasis, 28% presented with de novo brain metastasis, and 72% developed brain metastasis during their disease course. Adenocarcinoma histology was observed in 86 patients (86%), while 14 patients (14%) had squamous cell carcinoma (SCC). Additionally, only 19 patients (20%) had an ECOG PS score of 2 or higher at the time of BrM diagnosis (Table 1).

Table 1 Baseline characteristics of patients with CSN metastases from gastroesophageal carcinoma (N = 120)

In the population diagnosed with LMC, the median age was 53.6 years. Out of the total, 17 individuals (85%) were non-asian, and 12 individuals (60%) were either smokers or former smokers. Additionally, 16 individuals (80%) were diagnosed with stage IV disease at the time of GEC diagnosis. Notably, there were no patients with de novo leptomeningeal carcinomatosis; all cases of leptomeningeal carcinomatosis developed at some point in their course. All 20 individuals (100%) had adenocarcinoma histology, and 3 individuals (15%) had an ECOG Performance Status of 2 or higher at the time of the diagnosis of LMC as shown in Table 1.

Diagnostic methods

Among those with leptomeningeal carcinomatosis in our study, 16 patients (80%) received a diagnosis solely through brain MRI without requiring further confirmation through a lumbar puncture. However, for the remaining 4 patients (20%), the diagnosis was established through a lumbar puncture. None of these patients were treated with intrathecal chemotherapy.

Symptoms at CNS presentation

All patients in this study presented neurological symptoms at the time of CNS involvement. Patients could have experienced more than one symptom at the time of CNS presentation. Among patients with brain metastasis, the most prevalent symptoms were sensory, or motor neurological deficits (24 patients) followed by headaches (16 patients), as described in Fig. 2. Sensory or motor neurological deficits (13 patients), headaches (10 patients) and visual loss (10 patients) were the primary symptoms observed in patients with leptomeningeal carcinomatosis. (Fig. 3).

Fig. 2

Symptoms experienced by the patients at the time at brain metastases diagnosis

Fig. 3

Symptoms experienced by the patients at the time of leptomeningeal carcinomatosis diagnosis

Histological and molecular characteristic

The molecular and histological characteristics were derived from the primary tumor. It’s important to note that not all patients who underwent lumbar puncture or brain metastasis resection had their tumors retested for molecular characteristics, therefore, histological, and molecular features were not compared between the primary and corresponding metastatic tissue sample.

HER2-positive disease was defined as a score of 3 on immunohistochemical (IHC) analysis or a score of 2 + on IHC analysis with a positive result from subsequent fluorescent in situ hybridization testing. In patients where the HER2 status were known (41 patients), 61% (25 patients) were found to be HER2-positive. In the leptomeningeal carcinomatosis population with known HER2 status (13 patients), only 2 (15%) patients were HER2-positive (p-value 0.009) (Table 2). In terms of histology classification based on the Lauren system [19], among LMC patients, 12 (86%) had the diffuse type and 16% had the Intestinal type and no SCC were found in this population (p-value < 0.001) (Table 2).

Table 2 Histology characteristics*Treatment modalities

In relation to treatment approaches, a total of 25 (25%) patients with brain metastases underwent a combination of surgery followed by radiation therapy. Among the BrM patients, 63 (63%) received radiation therapy alone, which could either be stereotactic radiosurgery (SRS) (13 patients) or whole brain radiation therapy (WBRT) (45 patients).

Five patients (8%) underwent radiation treatment outside our institution, and there is no record documenting the specific modality of radiation treatment administered. Additionally, 12 (12%) BrM patients did not undergo any CNS or systemic treatment (best support of care).

For patients diagnosed with leptomeningeal carcinomatosis, 12 (65%) individuals received WBRT as their treatment modality. On the other hand, 7 (35%) patients had no specific treatment modality (Table 1).

The only two patients with HER2 + disease with leptomeningeal carcinomatosis were treated with trastuzumab before or during the LMC diagnosis. Among the 26 patients with brain metastasis and HER2 + disease, five did not receive any treatment (three declined systemic treatment, and two died before initiating any treatment). Of the remaining 21 patients, 16 received trastuzumab either before or after the diagnosis of brain metastasis, while five had an unknown systemic treatment history as they sought treatment at our center specifically for brain radiation.

Time to develop brain metastasis

The median time to develop CNS metastases, calculated from the primary cancer diagnosis to CNS metastasis, was different between patients with BrM HER2 positive, BrM HER2 negative and leptomeningeal carcinomatosis. Patients with BrM and HER2-positive disease developed BrM late into their cancer course, with a median of 12 months (95% CI, 9.7–19.1 months). Alternatively, patients with BrM and HER2-negative disease and patient with leptomeningeal carcinomatoses, developed CNS metastasis with a median of 6.7 (95%, CI 3.4,13.8) and 4.9 months, respectively (Table 3).

Table 3 Time to develop brain metastases and leptomeningeal carcinomatosis*Number and distribution of CNS metastases and survival

Most GEC patients with CNS metastases [100 (82%)] were brain metastases, while only [20 (16,6%)] had leptomeningeal carcinomatosis. Among those with brain metastases, multilobe disease was prevalent in 32% of cases. The most common locations for BrM were the cerebellum (27 [22%]), followed by the frontal lobe (14 [12%]) (Fig. 4).

Fig. 4

Baseline distribution of CNS metastasis location

Survival analysis

The median OS for patients with one single metastasis was 6.7 months (95% CI, 4.1-8.0) and those with 2–3 metastases had a median OS of 6.8 (95% CI, 3.1–8.8), months. In contrast, patients with more than three metastases had a significantly lower median OS of 1.1 months (95% CI, 0.4–2.3), (p-value < 0.001) (Fig. 5).

In the group of patients with brain metastases, the median survival varied depending on the treatment approach. Those who received best supportive care had a median survival of 0.7 months (95% CI, 0.2–4.2), while patients treated with radiation alone had a longer median survival of 3.8 (95% CI, 2.2–6.6) months. Notably, patients who underwent surgery followed by radiation had the most extended median survival of 7.7 (95% CI, 5.7–16.5) months (p < 0.001) as illustrated in Fig. 6.

Fig. 5

OS in patients with 1; 2–3 and > 3 Brain metastases

Fig. 6

OS and treatment modalities in patients with Brain metastasis

The overall survival rates in the group of patients with brain metastasis treated with radiation was 3.8 months. The difference in survival was calculated between the two radiation modalities (SRS and WBRT). The median survival time was 9.53 months (95% CI: 4.0–16.5.) in the SRS group and 3.13 months (95% CI: 1.9–4.4) in the WBRT with a statistically significant difference in OS between the two groups (p = 0.008) as seen in Fig. 7. Patients treated with SRS had a higher functional status (100% had ECOG 0 or 1) and out of the patient cohort, 6 out of 13 individuals had HER2 positive disease and underwent systemic treatment either right before or after receiving brain radiation. The patients who received SRS generally had a lower count of brain metastases, as 100% (13/13) of them presented with only 1 to 3 brain metastases (Table 4).

Fig. 7

OS in WBRT and SRS group in patients with metastasis

Table 4 Patients with brain metastasis treated with radiation

The multivariate analysis showed a higher probability of death in brain metastasis patients with ECOG performance status ≥ 2 (HR, 2.6; 95% CI, 1.4, 4.8; p 0.002), number of BrM ≥ 4 (HR, 2.8; 95% CI, 1.5, 5.1; p < 0.001), number of metastatic sites (HR, 1.2; 95% CI, 1.1, 1.5, p 0.009) and predicted superior survival in patients who received surgery followed by radiation (HR,0.4; 95% CI, 0.1, 0.9; p 0.03). (Table 5.)

Table 5 Multivariable Cox Model (only patients with brain metastasis)

In patients with leptomeningeal carcinomatosis, the median survival also differed based on the treatment received. Patients who received BSC had a median survival of 0.7 months (7 out of 20 patients), whereas those who underwent WBRT had a significantly longer median survival of 2.8 months (12 out of 20 patients) (p = 0.015) shown in Fig. 8.

Fig. 8

OS and treatment modalities in patients with Leptomeningeal Carcinomatosis