What Is Leptomeningeal Metastasis? How Effective Is Immunotherapy in This Setting?

Pembrolizumab -based immunotherapy, according to a phase-2 clinical trial, shows promise in patients with leptomeningeal metastases.

What is leptomeningeal metastasis?

Leptomeningeal metastases (LM) occur in some cancers, such as breast cancer, lung cancer, and melanoma: cancer cells reach the meninges (membranes around the brain), cerebrospinal fluid (CSF), or both by spreading from their original site.

• The leptomeninges are membranes that cover and protect the brain and spinal cord. They are sometimes described as a jacket or envelope.
• Cerebrospinal fluid (CSF) is produced inside the brain and is located between these membranes. It helps protect the brain and spinal cord from trauma like an airbag. It circulates nutrients and chemicals around the brain and spinal cord.

Leptomeningeal metastases may also be called carcinomatous meningitis, leptomeningeal disease, leptomeningeal carcinomatosis, or neoplastic meningitis.

Cancer cells can travel to the leptomeninges from other parts of the body through blood vessels (hematogenous spread), spread directly from the bones of the spine, or travel along neural pathways. After entering the CSF, they settle and grow at a site in the brain and/or spinal cord.

CSF is continuously produced in cavities in the brain called ventricles. It is made from blood and travels from the center to the back of the brain, down the spinal cord, and then back up. From there, CSF passes over the brain’s surface and returns to the bloodstream. Our body completely renews CSF several times a day. If tumor cells enter the CSF and survive, they may spread throughout the central nervous system and cause neurological problems.

What are the symptoms of leptomeningeal metastases?

The most common symptoms of leptomeningeal metastases are:

• confusion,
• headache,
• nausea,
• vomiting,
• double vision,
• weakness,
• loss of bladder control, and
• difficulty walking.

However, leptomeningeal disease can cause almost any neurological problem, depending on where the cancer cells are located.

An example of leptomeningeal metastatic disease

Above is a contrast-enhanced T1-weighted magnetic resonance image from a patient with a history of breast cancer. The arrows indicate leptomeningeal metastases.

Consider leptomeningeal metastases in advanced cancer with neurological symptoms!

Leptomeningeal metastases in stage 4 cancer are diagnosed in 1-15% of patients; however, autopsy studies reveal a higher incidence, with leptomeningeal metastases found in up to 20% of cancer patients suffering from neurological symptoms.

In cancer, the development of systemic treatments (chemotherapy, immunotherapy, targeted drugs) used in advanced disease has increased the incidence of leptomeningeal metastases over the past decade by providing a longer time frame for this late-stage complication to emerge. Nevertheless, the outlook is generally poor when cancer cells spread into the CSF, with a median survival of 2-6 months.

Treatment of leptomeningeal metastases and related research

There is no established standard treatment for leptomeningeal metastases because we still do not clearly know which treatments penetrate cerebrospinal fluid (CSF) well and produce good outcomes.

Treatment for patients with leptomeningeal metastases generally aims to control cancer growth and relieve symptoms.

Treatment in this setting depends on where the primary cancer began (for example, the breast or lung). Treatments usually include chemotherapy, targeted cancer drugs, or radiotherapy.

Research into treating leptomeningeal metastases focuses on:

• chemotherapy combinations
• new-generation targeted cancer drugs
• medications that help the immune system fight cancer cells (immunotherapy).

Results from the study of the immunotherapy drug pembrolizumab were reported at the Society for Immunotherapy of Cancer (SITC) 35th Anniversary Annual Meeting.

Treating leptomeningeal metastases with pembrolizumab

The study’s lead author, Dr. Jarushka Naidoo, an assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University in Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin, commented, "Unfortunately, patients generally have a poor prognosis when they present with leptomeningeal disease. Their median survival is 6-24 weeks."

Naidoo added, "Although there are some standard approaches to how we treat leptomeningeal disease, there are no international standard treatments that are effective across solid tumor types."

With this in mind, Naidoo and colleagues tested pembrolizumab in a study of patients with leptomeningeal metastases from solid tumors.

The study enrolled patients with 5 breast cancers, 3 high-grade gliomas, 3 non-small cell lung cancers, 1 cutaneous squamous cell carcinoma (skin cancer), and 1 head and neck squamous cell cancer, for a total of 13 patients. Nine patients (69%) had received at least two previous lines of systemic therapy.

Response, side effects, and biomarkers

Naidoo reported that 13 patients included 5 (38%) responders, magnetic resonance imaging showing a radiological response, a response involving a reduction in cancer cells in cerebrospinal fluid (CSF), and/or a clinical response with reduced neurological symptoms.

Two patients had a complete central nervous system response: a patient with skin cancer who remains alive after 3 years, and a patient with non-small cell lung cancer who survived 9 months but experienced cancer progression with metastases elsewhere.

For the entire group, median central nervous system progression-free survival was 2.9 months, and median overall survival was 4.9 months.

Naidoo said, "This is consistent with published prospective studies of systemic agents for leptomeningeal disease. Remarkably, although the numbers are small, we see a tail phenomenon in both survival curves, consistent with prospective studies of immune checkpoint blockade." (patients with long response durations whom we would not normally expect to see)

The rate of serious (grade 3 or higher) treatment-related side effects was 15.4%, and there were no grade 3 or higher immune-related side effects.

Both patients who achieved a complete clinical response developed immune-related side effects.

The study’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA was good at detecting leptomeningeal metastases: compared with a sensitivity of only 53.8% for CSF cytopathology (the current preferred method), the aneuploidy assay had a sensitivity of 84.6%.

A multiplex analysis of CSF cytokines identified similar baseline profiles in patients with ongoing responses, and similar changes in the profiles of the two complete responders (particularly a reduction in proinflammatory cytokines).

A major unmet need in treating leptomeningeal metastases

"Given the trial’s 38% CSF response rate, pembrolizumab needs to be studied in larger patient groups to confirm this finding, but it may be used as a potential treatment option for patients with leptomeningeal disease from solid tumors. Reassuringly, pembrolizumab was well tolerated, which is extremely important in this characteristically very frail patient group, in whom other standard treatments (such as high-dose methotrexate or intrathecal chemotherapy, injected directly into the spinal fluid) are associated with much higher rates of side effects." Naidoo concluded.

This study is noteworthy for achieving activity with systemically administered immunotherapy alone rather than chemotherapy delivered into cerebrospinal fluid, and for providing information about various biomarkers.

For subsequent studies in this setting, combining two immunotherapies rather than using a single agent may be a better idea, because dual immunotherapy — the best-known example being nivolumab + ipilimumab— is known to be more effective against brain metastases.