Summary: Treatment status and research progress of meningeal metastasis in non-small cell lung cancer

Leptomeningal metastases (LM), also known as leptomeningal cancer (LC), are "destructive" complications that occur when tumor cells invade the meningeal space in metastatic diseases

Detecting tumor cells in the cerebrospinal fluid is the gold standard for LM diagnosis

Current treatment options include ventricular shunt placement, radiation therapy (for bulky or symptomatic disease sites), systemic or intrathecal chemotherapy, targeted therapy, immunotherapy, and more

Epidemiology and prognosis

LM occurs in about 5% of patients with malignancy, most commonly in lung, breast, and melanoma

In the past, the emergence of LM often represented a failure of metastatic disease treatment, often representing the patient's final event and almost all effective regimens exhausted (before

The incidence of LM was 3.

Patients with European Society of Neuro-Oncology (EANO) IIA (MRI with typical linear enhancement and typical neurologic symptoms, negative CSF cytology/indeterminate) have the longest OS, while patients with type I LM (CSF cytology positive) have the shortest

Researchers have developed a molecularly graded prognostic assessment model (molGPA) to estimate survival in

Treatment of LM

Radiation Therapy (RT)

LM accounts for a small part (11-20%) of central nervous system metastases

Yan et al.
analyzed 51 patients with EGFR mutation NSCLC LM and found that WBRT did not improve the objective response rate (ORR) or intracranial disease control rate (DCR
).

Li et al.
analyzed 184 patients with secondary NSCLC LM and found that patients treated with TKI had an OS benefit (10 months vs.
3.
3 months, P< 0.
001), while patients who received WBRT did not receive an extension of OS compared with patients who did not receive WBRT, and WBRT combined with TKI did not benefit
more.

An analysis of eight studies (389 patients with LM) found no conclusive evidence
for WBRT prolongation of OS.

Research data on the role of cranial spinal cord irradiation (CSI) in patients with LM are also limited
.

A recent Phase 1 clinical trial involving 24 patients who received proton cranial cord irradiation found that medians CNS PFS and OS were 7 months and 8 months
, respectively, in patients with recurrent solid tumors.

Systemic and intrathecal chemotherapy

For patients with systemic metastases with LM without drive gene mutations, systemic chemotherapy is the preferred treatment option
.

There is currently no consensus on the criteria for chemotherapy, but studies have found that bevacizumab plus pemetrexed shows promising results
.

Intrathecal chemotherapy is an effective treatment in patients with NSCLC with LM, but again, the optimal drug, dosage, and regimen have not been determined
.

Methotrexate, cytarabine, and cetepai are the most commonly used intrathecal chemotherapy agents
.

Molecularly targeted therapy

In patients with NSCLC with CNS involvement, including LM, systemic molecularly targeted therapy has shown clinical benefit
.

Several successful studies have led to the approval
of molecularly targeted drugs with increased PERMEability of the CNS.

The role of EGFR TKI in NSCLC LM

LM
occurs in approximately 9% of patients with EFGR mutation NSCLC.

A retrospective analysis of 136 patients with EGFR mutation NSCLC LM found that patients treated with TKI had a longer OS (10.
0 months vs 3.
3 months, P<0.
001) compared with patients
who did not receive TKI.

Other relevant research progress is shown in Table 1
.

Table 1 Some of the relevant research progress

Role of ALK TKI in ALK fusion-positive NSCLC LM

LM
occurs in about 10% of patients with ALK rearrangement NSCLC.

At the time of diagnosis, up to 40% of lung cancer patients with ALK fusion positive are diagnosed with CNS metastases
.

Crizotinib, serettinib, aletinib, bugotinib, and loratinib have been approved by the FDA for use in patients
with ALK-fused NSCLC.

Crizotinib is the first-generation ALK inhibitor with limited
CNS penetration.

Second/third-generation ALK inhibitors show good antitumor activity
in patients with brain metastases, including LM.

Related studies are shown in Table 2

Table 2 Some of the relevant research progress

Research advances related to other driver mutations

Other oncogenes such as ErbB2, KRAS, BRAF, PI3K, RET, PDGFR, ROS, MET exon 14-jump mutations, MEK1, and HER2 have been found to mutate, translocate, or amplify in NSCLC, and some of the relevant research advances are shown in Table 3
.

Table 3 Relevant research progress

Immunotherapy

Immune checkpoint inhibitors alter the status quo of late and even earlier NSCLCs
.

Several studies have shown that immunotherapy shows promising activity in NSCLC LM (Table 3
).

As mentioned above, the treatment landscape for NSCLC LM is rapidly changing
as diagnostic tools advance and treatment options increase.

Several prospective studies are currently exploring the use of novel diagnostic tools, monitoring methods and treatment options in patients with LM (Table 4
).

Table 4 Relevant research progress

epilogue

LM remains a fatal complication of advanced cancer, and the incidence is increasing
.

Initial diagnostic tests should include CSF cytology and intraspinal imaging
using MRI.

Novel diagnostic methods, such as cerebrospinal fluid biopsy, are expected to be used for early diagnosis and provide valuable information to guide treatment
.

Patients with NSCLC with LM require individualized therapy and multidisciplinary treatment
.

It is imperative to develop new protocols with better CNS penetration, especially for patients who drive mutations
.

For patients with systemic metastases without drive gene mutations or progressive disease, systemic or intrathecal chemotherapy
may be an option.

Several studies have shown better activity
with immune monotherapy or combination therapy.

Relevant clinical studies should focus on monitoring clinical and radiological responses, and need to expand the research data
of patients who are positive for the drive gene mutation.

Monitoring treatment responses and exploring predictors are also pressing issues
.