Prognosis
Based on the literature and clinical expertise, the working group advises using the following classification for the prognosis of patients with leptomeningeal metastases without brain metastases.
| Category |
Characteristics |
Prognosis |
| 1 |
KPS >70, no serious encephalopathy or neurological deficit, non-threatening extra-CNS disease, tumour is not resistant to chemotherapy or hormone therapy |
Not unfavourable |
| 2 |
Other |
Unfavourable |
| 3 |
KPS <70, progressive non-treatable extra-CNS disease |
Very unfavourable |
KPS = Karnofsky Performance Score, CNS = central nervous system
Diagnosis
Diagnostic Imaging
The working group is of the opinion that, if leptomeningeal metastases are suspected in a patient known to have a malignancy:
- Magnetic resonance imaging (MRI) assessment is the preferred choice over cerebrospinal fluid (CSF) assessment. If MRI is not available or contraindicated, a computed tomography (CT) evaluation of the intracranial region can be performed.
- If the MRI (or CT) results are positive, no further assessment is necessary to make the diagnosis of leptomeningeal metastases. If the MRI (or CT) results are inconclusive or negative, CSF assessment should be conducted.
- If leptomeningeal metastases are found in the spinal canal and the intention is to treat the patient, consideration should be given to performing a brain MRI at the same time to rule out subclinical brain metastases, which could be relevant to later treatment protocols. For the performance of the MRI evaluation (see appendix 22 in the original guideline document).
CSF Diagnosis
If leptomeningeal metastases are suspected and the first cytological analysis of the CSF is negative, performing a second lumbar puncture is advisable.
If possible, 10 mL of fluid should be collected for cytological analysis. Depending on the intended line of inquiry, 5 mL of liquid should be collected for clinical chemistry analysis.
The amount of fluid required can differ for each clinical chemistry laboratory; the clinical chemist involved should advise on this matter.
Both cytological and clinical-chemical processing of the fluid should occur as soon as possible following puncture. Clinical-chemical markers and immunocytochemical/cytogenetic CSF analysis are adjuvant to cytology and have only limited additional value. Standard CSF analysis should include cell count and concentrations of lactate dehydrogenase (LDH), protein and glucose. Abnormalities in these factors can lend support to clinical suspicions of leptomeningeal metastases if the CSF cytology is negative.
Organisation of Care
The working group is of the opinion that specific procedures regarding the organisation of care for patients with leptomeningeal metastases are not strictly necessary. However, if it is decided to employ intraventricular chemotherapy, the insertion of the ventricular reservoir should take place in a neurosurgical centre with experience in this area. Treatment institutions should have adequate access to radiation therapy. In case of rare complications, it is advisable that physicians consult with a referral centre by telephone. For patients with leptomeningeal metastases of primitive neuroectodermal tumours (PNETs), consideration can also be given to consultation with paediatric oncology centres for their experience. Given the severity of the stage of disease in which leptomeningeal metastases occur, providing adequate care as close as possible to the patient's home is more important than the centralisation of care and treatment.
Treatment
LM of Extracranial Solid Tumors
Systemic Therapy
In patients with leptomeningeal metastases of a metastasised solid tumour, systemic drug therapy should be considered as first choice for treatment. The choice of drug is determined by the sensitivity of the tumour type in question.
If leptomeningeal metastases are the only manifestation of tumour activity, potentially effective systemic therapy is recommended as the treatment of choice. Endocrine therapy can be effective against leptomeningeal metastases of hormone-sensitive breast carcinoma.
Radiation Therapy
In patients with leptomeningeal metastases of solid tumours, radiation therapy is recommended as a treatment modality to reduce symptoms or, when combined with intrathecal chemotherapy, to reduce CSF flow disturbances. Radiation therapy is applied locally to sites of bulky disease. A dose of 20 to 30 Gy in 5 to 10 fractions is recommended. If brain metastases are also present, treatment should consist of brain irradiation, followed by systemic therapy if possible.
Intrathecal Chemotherapy
In the context of meaningful palliation (i.e., a self-sufficient existence for at least several months without disabling symptoms), systemic chemotherapy with radiation therapy to clinically relevant sites as need is preferred over intrathecal chemotherapy for patients with leptomeningeal metastases of solid tumours. If potentially effective systemic treatment is not possible, leptomeningeal metastases are the only relevant tumour activity and the primary tumour is potentially sensitive to intrathecal methotrexate, cytarabine or thiotepa, then intrathecal chemotherapy in combination with radiation therapy to clinically relevant sites and macroscopic tumour locations is recommended. The combination of intrathecal methotrexate and whole brain radiation therapy (WBRT) should be avoided if possible.
In patients with leptomeningeal metastases, the intrathecal treatment of choice is intraventricular methotrexate 10 mg given twice weekly. Treatment should stop as soon as the cytology is negative. Intrathecal treatment beyond six weeks has no further beneficial effect and can therefore be discontinued. A comparable alternative is depot cytarabine 50 mg given once every two weeks by lumbar puncture. In patients with leptomeningeal metastases and a Karnofsky Performance Score > 70 who experience disease progression or recurrence following a clinically meaningful stabilisation or response, re-challenge with or switch to systemic therapy or intrathecal chemotherapy can be considered. If brain metastases are present in addition to leptomeningeal metastases, treatment should consist of brain irradiation followed by systemic therapy if possible.
The neurological response to treatment is preferred over the CSF cytological response as a measure for determining further actions. The working group is of the opinion that, for patients without realistic prospects for neurological/clinical improvement and tumour control, such as those who are care-dependent due to encephalopathy, have severe motor loss or progressive, non-treatable tumour activity, treatment should consist of symptom management with psychosocial support.
Complications of Intrathecal Treatment
A cumulative dose of intraventricular methotrexate treatment > 150 mg is strongly advised against for patients with leptomeningeal metastases. Combination with whole brain radiation therapy is also advised against due to the high risk of late progressive leukoencephalopathy (ataxia, dementia, incontinence). During treatment with intrathecal chemotherapy, use of oral dexamethasone on days 1 to 5 is recommended to reduce the risk of chemotherapy meningitis.
Neurosurgery
Insertion of a Ventricular Reservoir and Antibiotic Prophylaxis
For patients with leptomeningeal metastases in whom a ventricular reservoir will be inserted, administering flucloxacillin 1 g intravenously immediately before the operation is preferred as antibiotic prophylaxis to prevent wound infections and ventriculitis.
To reduce the risk of infection, it is recommended that the insertion of a ventricular reservoir is performed in an operating room and not as a bed-side procedure in a ward or in intensive care. The working group is of the opinion that puncturing the reservoir should be carried out using a 25-gauge needle (possibly 23-gauge) under strict sterile conditions.
Infection during Intrathecal Therapy Using a Ventricular Reservoir
In patients with leptomeningeal metastases and infectious meningitis, which is often caused by Staphylococcus epidermidis or aureus, treatment with antibiotics should begin while waiting for the results of CSF cultures. The Ommaya reservoir can remain in situ as long as intraventricular treatment is needed. For optimal treatment of infectious meningitis, the reservoir should be removed as soon as possible.
Hydrocephalus
In patients with leptomeningeal metastases with symptomatic hydrocephalus, a ventriculoperitoneal drain can be considered to ameliorate symptoms. For tumours that are sensitive to radiation therapy, local irradiation may be an option in some rare cases.
Asymptomatic hydrocephalus does not require treatment.
Intracranial Haemorrhage Caused by a Ventricular Reservoir
The working group is of the opinion that, if there are signs of a sudden increase in intracranial pressure, intracranial haemorrhage should be considered and a CT or MRI scan should be performed. Intracranial haemorrhage should be treated according to standard procedures (conservative/surgical).
Symptomatic Treatment
The working group is of the opinion that patients with a poor prognosis should forgo tumour-directed treatment and undergo therapy aimed at symptom management instead.
The Role of Dexamethasone
The working group is of the opinion that a short course of dexamethasone can be considered if signs of irritation are present. The dose should be lower than that used in the management of oedema caused by brain metastases: 3 mg twice daily appears to be sufficient. If there is no response, dexamethasone should be discontinued; increasing the dose is not advisable.
Headache and Vomiting
The working group is of the opinion that headache and vomiting should be handled with standard approaches. For severe headache, CSF drainage by means of lumbar puncture, or possibly a ventriculoperitoneal drain, may be considered. For excessive vomiting, radiation therapy at the posterior fossa may be considered.
Confusion
Haloperidol is the treatment of choice for most cases of delirium for patients with somatic disease. For older patients and those with more severe somatic disease, a starting dose of 1 to 2 mg daily and maximum dose of 0.5 to 5.0 mg is recommended given orally (tablets or liquid), subcutaneously or intramuscularly. Intravenous administration is not recommended because of the risk of QT prolongation and sudden death.
In case of inadequate sedation, lorazepam can also be given orally, intramuscularly or intravenously at a dose of 0.5 to 2 mg daily. For delirious patients who require opiates for pain, it should be considered whether pain medication is appropriate and treatment with haloperidol might be necessary.
Psychosocial Support
Clinicians who treat patients with leptomeningeal metastases should acquire specific communication skills. Good communication with patients and their family members is important given the stage of disease, its severity and the threatening nature of the disorder. In all cases, it should be clear to the patient and family members who is the treating physician and/or treatment coordinator.
Active inquiry into the possible need for psychosocial support should be a part of the management strategy for patients with leptomeningeal metastases during diagnosis and planning for further treatment. It should made be clear at each institution which care provider is responsible for the patient with leptomeningeal metastases and which disciplines the patient and/or family members can call on for support. If psychosocial support is indicated, then it should also be available, regardless of the location of the patient. Good transferrals with attention to the psychosocial aspects of care are therefore required.
Organisation of Care
The working group is of the opinion that specific procedures regarding the organisation of care for patients with leptomeningeal metastases are not strictly necessary. However, if it is decided to employ intraventricular chemotherapy, the insertion of the ventricular reservoir should take place in a neurosurgical centre with experience in this area. Treatment institutions should have adequate access to radiation therapy. In case of rare complications, it is advisable that physicians consult with a referral centre by telephone. For patients with leptomeningeal metastases of PNETs, consideration can also be given to consultation with paediatric oncology centres for their experience. Given the severity of the stage of disease in which leptomeningeal metastases occur, providing adequate care as close as possible to the patient's home is more important than the centralisation of care and treatment.
LM of Primary Tumours of the CNS
Medical Technical
Consultation with a referral centre is recommended for the treatment of leptomeningeal metastases of medulloblastomas, ependymomas and germ cell tumours. The treatment of synchronous leptomeningeal metastases of these tumours is curative.
For PNET/medulloblastomas with leptomeningeal metastases, a combination of chemotherapy and radiation therapy should be administered. Various regimens with vincristine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), etoposide, methotrexate, cis/carboplatin and cyclophosphamide can be used. A radiation dose or 35 Gy in 20 to 22 fractions is given to the craniospinal axis with a boost of 15 to 20 Gy in 8 to 12 fractions to the posterior fossa and other macroscopic tumour locations if applicable.
Of the germ cell tumours, the germinomas are highly sensitive to chemotherapy and radiation therapy; the chance of cure of leptomeningeal metastases in this setting is probably high.
Symptomatic Treatment
The working group is of the opinion that patients with a poor prognosis should forgo tumour-directed treatment and undergo therapy aimed at symptom management instead.
The Role of Dexamethasone
The working group is of the opinion that a short course of dexamethasone can be considered if signs of irritation are present. The dose should be lower than that used in the management of oedema caused by brain metastases: 3 mg twice daily appears to be sufficient. If there is no response, dexamethasone should be discontinued; increasing the dose is not advisable.
Headache and Vomiting
The working group is of the opinion that headache and vomiting should be handled with standard approaches.
For severe headache, CSF drainage by means of lumbar puncture, or possibly a ventriculoperitoneal drain, may be considered. For excessive vomiting, radiation therapy at the posterior fossa may be considered.
Confusion
Haloperidol is the treatment of choice for most cases of delirium for patients with somatic disease. For older patients and those with more severe somatic disease, a starting dose of 1 to 2 mg daily and maximum dose of 0.5 to 5.0 mg is recommended given orally (tablets or liquid), subcutaneously or intramuscularly. Intravenous administration is not recommended because of the risk of QT prolongation and sudden death.
In case of inadequate sedation, lorazepam can also be given orally, intramuscularly or intravenously at a dose of 0.5 to 2 mg daily. For delirious patients who require opiates for pain, it should be considered whether pain medication is appropriate and treatment with haloperidol might be necessary.
Psychosocial Support
Clinicians who treat patients with leptomeningeal metastases should acquire specific communication skills. Good communication with patients and their family members is important given the stage of disease, its severity and the threatening nature of the disorder. In all cases, it should be clear to the patient and family members who is the treating physician and/or treatment coordinator.
Active inquiry into the possible need for psychosocial support should be a part of the management strategy for patients with leptomeningeal metastases during diagnosis and planning for further treatment. It should made be clear at each institution which care provider is responsible for the patient with leptomeningeal metastases and which disciplines the patient and/or family members can call on for support.
If psychosocial support is indicated, then it should also be available, regardless of the location of the patient. Good transferrals with attention to the psychosocial aspects of care are therefore required.
Organisation of Care
The working group is of the opinion that specific procedures regarding the organisation of care for patients with leptomeningeal metastases are not strictly necessary. However, if it is decided to employ intraventricular chemotherapy, the insertion of the ventricular reservoir should take place in a neurosurgical centre with experience in this area. Treatment institutions should have adequate access to radiation therapy. In case of rare complications, it is advisable that physicians consult with a referral centre by telephone. For patients with leptomeningeal metastases of PNETs, consideration can also be given to consultation with paediatric oncology centres for their experience. Given the severity of the stage of disease in which leptomeningeal metastases occur, providing adequate care as close as possible to the patient's home is more important than the centralisation of care and treatment.
