What is LMD in cancer?

Leptomeningeal Disease (LMD) in Cancer

LMD is a rare but serious complication of cancer where malignant cells spread to the layers of the leptomeninges (pia and arachnoid maters) and subarachnoid space, occurring in approximately 3-5% of cancer patients and carrying a poor prognosis with significant neurologic morbidity and mortality. 1

Diagnosis and Classification

• Diagnosis of LMD is based on clinical evaluation, cerebrospinal magnetic resonance imaging (MRI) with contrast enhancement, and cerebrospinal fluid (CSF) analysis 2
• The European Association of Neuro-Oncology (EANO) and ESMO propose classifying LMD using two major criteria: presence (type I) or not (type II) of positive CSF and neuroimaging findings 2
• A high index of suspicion should be maintained for leptomeningeal involvement, especially in patients with druggable oncogenic drivers receiving TKI treatment 2
• CSF sampling with cytological assessment is diagnostic of LMD with high specificity but limited sensitivity 2

Prognosis

• LMD carries a poor prognosis, with median overall survival (OS) of approximately 4 weeks without treatment, which can be prolonged to a few months with aggressive multimodal treatment 2
• In HER2-positive breast cancer, LMD has a poorer prognosis than brain metastases without LMD, with retrospective analyses showing OS ranging from 4.4-20.0 months in LMD compared to approximately 24 months in those with brain metastases without LMD 2
• Recent treatment advances have improved survival outcomes in specific cancer types, particularly HER2-positive breast cancer 2

Treatment Approaches

General Treatment Considerations

• There is no accepted standard of care for cancer LMD, and recommendations are essentially expert opinion-based 2
• Treatment decisions should always involve multidisciplinary discussion and consider the patient's life expectancy 2
• The therapeutic plan should be based on the presentation of the disease: nodular (A), linear (B), or mixed (C) meningeal involvement, presence of positive CSF cytology, and presence of extracerebral disease 2

Radiotherapy Options

• Focal radiotherapy (RT) is recommended for circumscribed, notably symptomatic lesions 2
• Whole-brain radiotherapy (WBRT) is recommended for extensive nodular or symptomatic linear LMD 2
• Craniospinal irradiation is generally avoided due to its toxicity profile but may be considered in carefully selected patients 3

Intrathecal Therapy

• The use of intrathecal therapy is controversial 2
• It is recommended in cases where tumor cells are present in the CSF; it is optional in cases of linear metastatic meningeal disease 2
• Intrathecal therapy is not recommended in patients with obstructive hydrocephalus or in patients with nodular meningeal metastases only 2
• Three agents commonly used for intrathecal treatment are methotrexate, cytarabine (including liposomal cytarabine), and thiotepa 2
• Neurotoxicity is increased with the combined use of methotrexate and RT, and this combination is not recommended 2
• Addition of intrathecal to systemic therapy has shown no overall survival or quality of life advantage in two prospective trials 2

Systemic Therapy

• Systemic pharmacotherapy is generally preferred for patients with HER2-positive disease and LMD 2
• For patients with druggable oncogenic drivers and LMD, CNS-penetrant next-generation TKIs can be used 2
• In HER2-positive breast cancer with LMD:
  • The tucatinib, trastuzumab, and capecitabine combination has shown promising results with median OS of 11.9 months in the phase 2 TBCRC049 study 2
  • T-DXd (trastuzumab deruxtecan) has shown potential with median OS of 13.3 months in the phase 2 DEBBRAH study 2
  • In a Japanese retrospective review, median OS was not reached with T-DXd at a median follow-up of 12 months in patients with HER2-positive breast cancer and LMD 2

Special Considerations

• Patients with LMD may present with non-specific neurological symptoms (headaches, nausea, vomiting) or discrete signs related to the CNS area involved (gait difficulties, cranial nerve palsies) 2
• The incidence of LMD is increasing due to longer survival of cancer patients and the use of newer large-molecule therapies with poor central nervous system penetration 4
• Early diagnosis and treatment are crucial for improving outcomes, as lower disease burden may respond better to treatment 4
• Caution should be exercised when considering combining radiotherapy and antibody-drug conjugates (ADCs), as recent evidence suggests an increased risk of radionecrosis 2