Leptomeningeal Metastases Treatment & Management

Treatment of leptomeningeal metastases (LM) is individualized based on factors including histology, prognosis, presence of bulky CNS disease, and the state of systemic disease. ^[16]  Treatment modalities may include systemic chemotherapy, radiation therapy, use of targeted agents, intrathecal therapy, and immunotherapy.

Treatment goals for patients with LM include improvement or stabilization of the patient's neurologic status, prolongation of survival, and palliation. Maintaining quality of life (QOL) is a major consideration (as well as a distinct challenge) for patients with this disease. Decisions are made on a case-by-case basis. Some clinicians are hesitant to treat LM, given the previously reported short duration of survival and risk of neurotoxicity. In some cases, a high index of suspicion (ie, early diagnosis) and prompt treatment can prevent or delay neurologic damage and act to prolong QOL. Given the lack of large randomized controlled trials, the choices for treatment are usually options rather than according to established guidelines. Multimodality treatment is often pursued.

Assessing the response to treatment in LM is difficult for a variety of reasons, and therefore utilizes three elements: standardized neurologic examination, CSF cytology or flow cytometry, and radiographic evaluation. Progressive disease is defined by worsening neurologic examination as a result of LM or worsening neuroradiographic assessment. ^[24]

The intensity of treatment for leptomeningeal metastases (LM) is based on the presence of a systemic cancer that is responsive to treatment and preexisting neurologic damage and relatively preserved functionality.

Treat the systemic cancer, as the patient is likely to die from systemic disease.

For patients with lung cancer, systemic therapy with modern chemotherapeutic agents prolongs survival. In a study from Stanford University, a systemic regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor was associated with mean survival of six months and a statistically significant decreased hazard of death (hazard ratio [HR], 0.24; P = .007). ^[25]

Treat the entire neuraxis, as tumor cells are disseminated widely by CSF flow. The standard therapies are (1) radiation therapy to symptomatic sites and regions where imaging has demonstrated bulk disease and (2) intrathecal chemotherapy.

Radiation palliates local symptoms, relieves CSF flow obstruction, and treats areas such as nerve-root sleeves, Virchow-Robin spaces, and the interior of bulky lesions that chemotherapy does not reach. Even without evidence of bulky disease, patients may benefit from radiation. Radiation therapy typically consists of 2400 rads given in 8 doses over 10–14 days. Radiation is directed to the site of major clinical involvement and planned so that myelosuppression is acceptable and does not compromise efforts to eliminate malignant cells from the CSF. Dosages can range from 20 Gy in 1 week to 30 Gy over 3–4 weeks. The dosage for lymphomatous and leukemic meningitis is usually 30 Gy given over 10 doses.

Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, preventing further seeding. ^[8]

Three agents are routinely given; methotrexate (MTX), cytarabine (Ara-C), and thiotepa.

Cytararabine is the first-choice agent (in its liposomal form only); it is not effective for solid tumors but is useful in leukemic and lymphomatous meningitis. It has been available in liposome-encapsulated form (DepoCyt) that can be administered every 2 weeks rather than 2–3 times a week and results in a longer time to disease progression and higher quality of life than therapy with MTX.

Thiotepa, the second-line agent after MTX and cytarabine, is cleared from CSF within minutes and has survival curves similar to those of MTX with less neurologic toxicity than MTX.

The superiority of combination intrathecal therapies over single agents is controversial. Six randomized trials have shown no difference between single-agent methotrexate and combined therapy, and combination treatments may be more neurotoxic than single agents.

For patients who respond well to treatment, start treatment with radiation to bulky tumors and symptomatic sites, and place a ventricular catheter if possible. Scan CSF flow, and follow this with intrathecal chemotherapy if CSF flow is not obstructed. Also, optimally manage any systemic cancers.

Additional chemotherapeutic regimens have been associated with prolonged survival in systemic cancers and are discussed below.

For patients with a fair response to treatment, local radiation therapy and intrathecal chemotherapy delivered by means of LP may be appropriate.

For patients who are classified as poor risk, offer radiation therapy to symptomatic sites or supportive measures only (eg, analgesics, anticonvulsants, and steroids). Treatment is difficult and primarily palliative, and results are generally poor because of the presence of many metastases.

Therapies in development

A number of other therapies are under development or experimental.

• Mafosfamide is a form of cyclophosphamide that is active intrathecally and has little neurotoxicity aside from headaches, but only phase II trials have been conducted.

• Trastuzumab has been given intrathecally to treat LM from breast cancer. ^{[26, 27, 28, 29]}

• Diaziquone is effective in hematologic tumors. Adverse effects include headaches and immunosuppression. It can be given at a dosage of 2 mg twice weekly.

• Temozolomide, in combination with Ara-C, has completed Phase I/II trials.

• Another drug, 4-hydroperoxycyclophosphamide (4-HC) is in phase I trials and is apparently effective in treating medulloblastoma.

• Topotecan, a topoisomerase I inhibitor, has completed phase II trials.

• A drug available for high-dose systemic administration, 6-mercaptopurine (6-MP), has shown efficacy in some patients.

• There are case reports of LM from non-small cell lung cancer (NSCLC) or breast cancer responding to intrathecal gemcitabine, trastuzumab, letrozole, and tamoxifen.

• Epidermal growth factor receptor inhibitors (EGRG) as monotherapy or in combnation may be beneficial in treatment of LM due to non-small cell lung cancer. Example of these agents include afatinib, cetuximab, erlotinib, afatinib, pemetrexed, bevacizumab,  and orbevacizumab.

• Bevacizumab has also demonstrated activity in CNS choroidal metastases and is used to treat radiation necrosis of the brain and glioblastoma multiforme.

• Tyrosine kinase inhibitiors such as crizotinib, erlotinib, or gefitinib may also be helpful in patients with LM in the context of NSLC.

• The survival benefit for NSLC patients with LM was also greater for patients treated with pemetrexed, an inhibitor of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are involved in purine and pyrimidine synthesis necessary for formation of new DNA and RNA.

• One patient with LM from prostate cancer responded to hormonal manipulation.

• Intrathecal busulfan, currently in phase I trials, may be active against cyclophosphamide-resistant neoplasms and other tumors.

• Another drug, 3-(4-amino-2-methyl-5-pyrimidinyl) methyl-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) is modestly effective in animal studies; however, it is neurotoxic and not yet available for use in humans.

• Immunotoxins, such as monoclonal antibodies coupled with a protein toxin or radioisotope, seem effective and are being studied.

• Gene therapy based on the herpes simplex virus thymidine kinase gene combined with ganciclovir is under study but not yet available.

Supportive care: Offer analgesia with opioids, anticonvulsants for seizures, antidepressants, and anxiolytics to all patients as needed. Treat attention problems and somnolence from whole-brain radiation with psychostimulants or modafinil.

Placement of an intraventricular or subgaleal catheter is necessary for the administration of cytotoxic drugs.

In patients with symptomatic increased intracranial pressure (ICP) (ie, severe intractable headache, papilledema, stupor, and repetitive plateau waves on EEG), placement of a ventriculoperitoneal (VP) shunt may be necessary if the increased ICP is not ameliorated by steroids. This should be done even with the risk of peritoneal seeding as the presence of LC in the context of systemic cancer implies that diffuse spread of the cancer has already occurred. Placment of a VP shunt is typically a palliative procedure however, because the presence of hydrocephalus portends poor survival.

In patients with leptomeningeal metastases (LM) and hydrocephalus, Lin et al found that placement of a combined reservoir-on/off valve-ventriculoperitoneal shunt system was safe, resulted in symptomatic improvement in most patients, and could effectively administer intrathecal chemotherapy. ^[30]

Administer intrathecal chemotherapy by means of LP rather than an Ommaya device if a shunt is present to ensure that the medication reaches the basal cisterns and spinal leptomeninges.

Intrathecal (IT) administrations may be preferable to lumbar puncture (LP) for short half-life drugs such as methotrexate; for drugs with longer half-lives, route of administration (IT or LP) may be less critical. ^[31]

Resect parenchymal brain metastases, if present.

As has been pointed out, management goals for patients with leptomeningeal metastases (LM) include improving or stabilizing neurologic function, prolonging survival, and preserving quality of life whenever possible. ^[16]  Hospice care is often eventually required, either as an outpatient or on an inpatient basis.

Once intrathecal chemotherapy has been initiated, CSF cytology is typically checked every 4 weeks (ie, with each additional intrathecal dose). ^{[32, 2]}

If CSF cytology result is negative, chemotherapy is continued at the same rate of twice a week for 2 more weeks, then decreased to twice a week for 1 week per month, followed by further CSF monitoring every two months.

If CSF cytology results remain positive, chemotherapy is continued at the same rate, the chemotherapeutic agent is changed, or the patient is reclassified as having a poor prognosis with the administration of palliative care.

Supportive care also may include anticonvulsants for seizure control, analgesia with opioids, antiemetics, and antidepressants and anxiolytics as needed. Corticosteroids may help vasogenic edema associated with metastases, although they may have limited effect on the neurologic symptoms associated with LM. Psychostimulants may help with inattention and somnolence secondary to whole-brain radiation.

In addition to hematology–oncology care, consultations to radiation therapy, neurology and neurosurgery may be extremely helpful in cases of leptomeningeal metastases (LM).

No special diet has been known to be useful in the treatment of leptomeningeal metastases (LM), but nutritional support is always useful in the treatment of cancer patients.

There are currently no known preventative measures for stopping spread to the leptomeninges, other than preventing or treating the primary cancer. Early treatment of leptomeningeal metastases (LM) would seem to be advantageous. ^[4]