Emerging Therapies are Showing Promise for Leptomeningeal Disease

Leptomeningeal disease (LMD) is a devastating complication of metastatic cancer, characterized by the spread of malignant cells to the cerebrospinal fluid (CSF) and the leptomeninges. While historically associated with poor prognosis, advancements in diagnostics and therapeutic strategies are improving patient outcomes. Below, we address key questions providers may encounter when diagnosing and managing LMD.

Understanding LMD: Pathophysiology and Presentation

Which cancers most commonly lead to LMD?

LMD is most frequently seen in solid tumors and blood cancer, particularly:

• Breast cancer (HER2-positive and triple-negative subtypes have a higher risk)
• Lung cancer (especially small-cell lung cancer and EGFR-mutated adenocarcinomas)
• Melanoma (due to its neurotropic properties)
• Gastrointestinal cancers (less common but increasingly recognized)
• Hematologic malignancies (such as lymphoma and leukemia)

We're excited about the dendritic cell vaccine, which is taken from the patients and exposes them to the protein on the triple negative or HER-2 breast cancer tumor cell that allows the immune response.

Peter Forsyth, MD

Chair, Neuro-Oncology Program

What are the hallmark clinical symptoms of LMD?

LMD symptoms are highly variable, depending on the location of tumor involvement within the CNS. Common presentations include:

• Cranial nerve dysfunction (e.g., vision loss, hearing impairment, facial weakness)
• Cognitive changes (confusion, memory deficits, personality alterations)
• Headaches and nausea (often due to increased intracranial pressure)
• Radiculopathy (weakness, numbness, or pain in the extremities)
• Gait instability and ataxia (due to spinal cord involvement)

Diagnosis: Enhancing Detection and Accuracy

When should providers suspect LMD in oncology patients?

LMD should be considered in any cancer patient presenting with new, unexplained neurological symptoms, especially in those with known CNS involvement or progressive disease despite systemic therapy.

Timely treatment of leptomeningeal disease is key to living longer and experiencing the best possible quality of life. Our multidisciplinary experts at Moffitt are sub-specialty trained in neuro-oncology. We focus exclusively on complex neurological cancers like leptomeningeal disease. We are honored to partner with you to provide the highest level of treatment and supportive care for these patients.  

Treatment Strategies: Current Approaches and Innovations

What are the primary treatment options for LMD?

Treatment should be individualized based on tumor type, patient performance status, and overall disease burden. The main options include:

1. Intrathecal (IT) Chemotherapy:
• Delivered via lumbar puncture or an Ommaya reservoir.
• Common agents: Methotrexate, Cytarabine, and Topotecan.
• Indicated primarily for hematologic malignancies and selected solid tumors.
2. Systemic Therapy:
• Essential for patients with widespread disease or those with tumors known to cross the blood-CSF barrier.
• Targeted therapies (e.g., osimertinib for EGFR-mutant lung cancer, tucatinib for HER2+ breast cancer) have shown promising CNS penetration.
• Immunotherapy (e.g., checkpoint inhibitors) is under investigation.
3. Radiation Therapy (RT):
• Focal RT can palliate symptoms caused by bulky leptomeningeal deposits.
• Whole-brain RT (WBRT) may be considered.
• Cranial spinal radiotherapy with IMRT or protons may be superior to WBRT.
4. Supportive and Palliative Care:
• Dexamethasone for symptom relief in cases of elevated intracranial pressure.
• Pain management, rehabilitation, and psychosocial support are critical.

What clinical trials and emerging therapies are showing promise for LMD?

Moffitt has three clinical trials currently open for patient accrual, including:

MCC 21262 A first in human dose escalation of Dendritic Cell Vaccine (DCV) administered Intrathecally (IT) primed against HER2/HER3 in Patients with Leptomeningeal Disease (LMD) from Triple-Negative Breast Cancer (TNBC) or HER2+ Breast Cancer (HER2+BC)

MCC 20487 Phase I/II Study of Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab in the Management of HER2+ Breast Leptomeningeal Disease. The purpose of this study is to find out if radiation therapy followed by intrathecal trastuzumab and Pertuzumab is safe and will result in improved survival in HER2-positive breast cancer that has metastasized to the leptomeninges.

Other recent advancements include drug delivery, including nanoparticle-based therapies and convection-enhanced delivery (CED) are being explored in clinical trials. Additionally, CSF liquid biopsies are being developed to improve real-time treatment monitoring.

MCC 23481 A first in human Dendritic Cell Vaccine (DCV) administered intrathecally (IT) with IT Nivolumab or IT Trastuzumab in HR2 + or HR2- BC LMD patients (expected to open November 2025).

The purpose of this study is to learn about the effects of the treatment, Dendritic Cell Vaccine (DCV), in combination with other drugs, to find the highest dose of the study treatment that can be given safely to patients with HER2 + Breast Cancer (HER2-BC). 

Other trials in development include Tumor Infiltrating Lymphocytes (TILs), CAR-T therapies, and drugs to target LMD metabolism.

We have several novel clinical trials that have shown promising results for patients. Using combination approaches to treatment and bringing novel laboratory findings to the clinic will ultimately help improve outcomes for this devastating disease.

Kamran Ahmed, MD

Prognosis and Patient Counseling

What is the typical prognosis for LMD patients?

Prognosis varies based on primary tumor type and response to therapy:

• Without treatment: Median survival is 4–6 weeks.
• With aggressive treatment, median survival can extend to 3–12 months, with outliers achieving longer-term disease control.
• Breast cancer LMD has a slightly better prognosis compared to lung cancer or melanoma LMD, particularly in HER2+ cases where targeted therapies are available.

How should providers counsel patients and families about LMD?

Be honest, but compassionate communication is key. Discussions should include:

• Treatment goals: Balancing life extension with quality-of-life considerations.
• Clinical trial options: Encouraging participation in research for novel therapies.
• Palliative care involvement: Addressing symptoms and optimizing comfort early in the disease course.
• Referral: To a cancer center that has expertise in LMD

LMD remains a challenging diagnosis, but ongoing research and evolving therapeutic strategies are offering new hope. At Moffitt, our Neuro-Oncology Program is comprised of a multidisciplinary team involving neuro-oncology, radiation oncology, medical oncology and palliative care to deliver personalized care, all in a single location. This is essential for optimizing patient outcomes. Providers should maintain a high index of suspicion for LMD in at-risk populations and stay updated on emerging treatment options.

Considerations for Clinical Practice

• Patient Selection: Careful assessment of patient eligibility for clinical trials is crucial, considering factors such as performance status, extent of systemic disease, and prior treatments.
• Multidisciplinary Collaboration: Engagement with neuro-oncology, radiation oncology, medical oncology, and palliative care teams ensures comprehensive management of LMD patients.
• Informed Consent: Thorough discussions with patients and families about the potential risks and benefits of participation in clinical trials are essential for shared decision-making.

Staying informed about ongoing research and emerging therapies enables providers to offer leading-edge care and potential clinical trial opportunities to patients facing leptomeningeal disease.

To refer a patient to Moffitt, complete our online form or contact a physician liaison at Physician.Relations@Moffitt.org. Online referrals are responded to within 24 - 48 hours.