Chemotherapy in neoplastic meningitis
Introduction
Neoplastic meningitis (NM) is the result of the diffuse or multifocal localization of cancer cells in the cerebral spinal fluid (CSF). NM is often a late complication of solid tumour or lymphoproliferative malignancies.
The clinical diagnosis of NM is documented in 4–7% of all cancer patients and develops in more than 20% of patients affected by metastastic melanoma, 9–25% of those affected by lung cancer, 5–34% by breast cancer, 4–14% by gastrointestinal cancer and 1–2% by brain tumors [1], [2]. Up to 7% of NM originates from unknown primary cancer. Leptomeningeal dissemination in patients with leukemia and lymphoma is not uncommon and occurs in 5–15% cases [3]. The clinical incidence of NM is probably underestimated considering that autoptic series reveal a frequency of 20% [4]. There are several possible mechanisms by which a primary tumour can spread to the leptomeninges: hematogenous diffusion is the most common, either via the arteries or the veins. Other routes are: direct extension, diffusion along nerves, subependymal metastases or iatrogenic after surgical removal of posterior brain fossa metastases. Pathological evidences suggest that in most cases of breast or lung cancer the meningeal carcinomatosis derives from vertebral or paravertebral metastases [5].
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Clinical presentation
Symptoms and signs at presentation reflect the altered flow of the cerebral spinal fluid, the involvement of the brain and cranial nerves and spine. Multifocal signs are present in 70% of patients and spinal symptoms affect more than 50% [6]. Headache and mental changes are the most common symptoms at onset; cranial nerve involvement includes ophtalmoplegia due to abducens, oculomotor or troclear palsy and trigeminal and cochlear neuropathy; spinal symptoms develop from nerve root, cauda equina
Treatment
At present, the goal of therapeutic strategies is palliative and the evaluation of high or low risk is important to identify patients who may benefit from aggressive treatment such as radiation therapy and chemotherapy [12]. Early intrathecal chemotherapy can be curative for patients with leukemic or lymphoblastic meningitis but most of patients with NM from solid tumor have a very poor prognosis and die for progressive neurologic deterioration.
The role of surgery is limited to the treatment of
Systemic chemotherapy
The major theoretical limitation of systemic chemotherapy is the poor CSF penetration of most anticancer agents. However, the blood–brain barrier may be disrupted in NM and some authors suggest that high- or standard-doses of intravenous chemotherapy may be as effective as intrathecal chemotherapy, particularly in breast cancer patients [17]. Continuous intravenous infusion of methorexate, cytarabine or thiotepa permits to maintain a cytotoxic drug concentration for prolonged period but the
New agents and new modalities in neoplastic meningitis chemotherapy
New drugs and novel therapeutical approaches are currently under investigation.
Mafosfamide, a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxycyclophosphamide, is a preactivated cyclophosphamide derivative that does not require hepatic activation and, therefore, may potentially be utilized for regional chemotherapy. This drug has shown in vitro significant activity against transplantable murine tumors, including P388 and L1210 leukemia, B16 melanoma and cyclophosphamide-resistant
Toxicity
Complications from intrathecal chemotherapy are not infrequent and can influence the quality of life of patients. Surgical complications may be due to misplaced intraventricular catheter, intracranial or intraventricular hemorrage or infection from skin flora contamination of Ommaya reservoir resulting in bacterial meningitis.
However, the most common complications of intrathecal chemotherapy are related to the toxicity of the drugs administered. Aseptic chemical meningitis occurs in 20–40% of
Response evaluation
In the evaluation of tumor response to treatment, the gold standard still remains sequential CSF cytology. Prospective studies on NM from different histologies report a large range of cytological improvement (0–30%). However, there is a poor correlation between cytology and clinical course during treatment and in many cases patients show clinical deterioration while cytology results are negative. Several studies have reported that clinical response and survival are independent of cytologic
Conclusions
Therapeutic options for patients with NM have not significantly improved survival. Most patients die from progression of meningeal carcinomatosis with a median survival of 2–3 months despite aggressive treatment. Given the palliative role of treatment strategies, it is important to assess what subset of patients will benefit from aggressive treatment.
Therefore, careful evaluation and treatment planning is warranted to avoid treatment-associated toxicities and to maximize the impact of the
Reviewers
Prof. Jean-Louis MISSET, Medical Oncology Unit, Hôpital Saint-Louis, 1, Av. Claude Vellefaux, FR-75475 Paris, Cedex 10, France.
Dr. M.J. Van Den Bent, Department of Neuro-Oncology, Daniel den Hoed Cancer Center, NL-3008 AE Rotterdam, Netherlands.
Dr. Riccardo Soffietti, Department of Neurology, University of Turin, Via Cherasco 15, IT-10126 Turin, Italy.
Andrea Pace M.D., is consultant in Neurology at Regina Elena National Cancer Institute in Rome (Italy) and head of Palliative Home Care Unit for Brain Tumor Patients.
His clinical and research interests in neurooncology are in the fields of chemotherapy of malignant brain tumors, palliative care in neurooncology and peripheral neurotoxicity of anticancer agents.
References (57)
- et al.
The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study
Eur J Cancer
(2004) Neoplastic meningitis
Semin Neurol
(2004)The pathogenesis of neoplastic meningitis
Curr Oncol Rep
(2003)Neoplastic meningitis
J Clin Oncol
(2005)The diagnostic and therapeutic management of leptomeningeal carcinomatosis
Ann Oncol
(2004)- et al.
Neoplastic meningitis
Curr Treat Options Oncol
(2001) - et al.
Leptomeningeal metastases: current concepts and management guidelines
J Natl Compr Cancer Netw
(2005) - et al.
Leptomeningeal carcinomatosis
Arch Neurol
(1996) - et al.
Current options for the treatment of neoplastic meningitis
J Neurooncol
(2002) - et al.
The contribution of MRI to the diagnosis of diffuse meningeal lesions
Neuroradiology
(2004)
Neoplastic meningitis-related encephalopathy. Prognostic significance
Neurology
Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment
Cancer
Defining patients at risk for neoplastic meningitis: what parameters can be used to determine who should be treated?
Expert Rev Neurother
Systemic chemotherapy, intrathecal chemotherapy, and symptom management in the treatment of leptomeningeal metastasis
Curr Oncol Rep
Methotrexate distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injection
New Engl J Med
An open label trial of sustained-release cytarabine (DepoCyt) for the intrathecal treatment of solid tumor neoplastic meningitis
J Neurooncol
Quality-of-life-adjusted survival comparison of sustained-release cytosine arabinoside versus intrathecal methotrexate for treatment of solid tumor neoplastic meningitis
Cancer
Leptomeningeal metastases: rationale for systemic chemotherapy or what is the role of intra-CSF-chemotherapy
J Neurooncol
Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy
Neurology
Leptomeningeal metastases from solid tumors: a comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy
Cancer
High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?
J Clin Oncol
Durable remission of leptomeningeal metastasis of breast cancer with letrozole: a case report and implications of biomarkers on treatment selection
Jpn J Clin Oncol
Response of leptomeningeal metastases from breast cancer to hormonal therapy
Neurology
Antineoplastic activity of ASTA Z 7557 (NSC-34582, INN mafosfamide) on transplantable murine tumors
Invest New Drugs
Phase-I study of mafosfamide-cyclohexylamine (ASTA-Z-7557, NSC 345 842) and limited phase-I data on mafosfamide-lysine
Invest New Drugs
Phase I study of cyclohexylamine and lysine salt of mafosfamide
Cancer Chemother Pharm
Intrathecal mafosfamide: a preclinical pharmacology and phase I trial
J Clin Oncol
Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone
Cancer Res
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2012, Hematology/Oncology Clinics of North AmericaCitation Excerpt :Clinical syndromes that suggest NM include cauda equina syndrome (ie, asymmetric lower extremity weakness and dermatomal sensory disturbance), communicating hydrocephalus presenting with symptoms of raised intracranial pressure, and cranial neuropathies, most often involving oculomotor function and presenting with diplopia.1–5 Establishing a diagnosis of NM requires careful consideration of clinical findings such that any patient with cancer and a neurologic disturbance should be considered as potentially having NM (Fig. 1).1–5 Neuroradiographic imaging (ie, MRI of brain or relevant spine) may suggest NM based on focal or diffuse leptomeningeal enhancement, subarachnoid or ventricular tumor nodules, and the frequent (30%–40%) coexistence of brain parenchymal metastases in instances of nonhematologic cancers (see Fig. 1).6,7
Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours
2010, The Lancet OncologyCitation Excerpt :Incidence of leukoencephalopathy (20%) is probably underestimated and is higher in patients surviving more than 4 months after treatment.21,22 Methotrexate is a folate antimetabolite, and an S-phase specific cytotoxic drug with a CSF half-life of 4·5–8·0 h5 (table 1). One common dosage regimen19 specifies that intrathecal induction treatment consist of two injections per week for 4 weeks, a consolidation treatment of one injection per week for 4 weeks, and a maintenance treatment of one injection per month until disease progression.
Andrea Pace M.D., is consultant in Neurology at Regina Elena National Cancer Institute in Rome (Italy) and head of Palliative Home Care Unit for Brain Tumor Patients.
His clinical and research interests in neurooncology are in the fields of chemotherapy of malignant brain tumors, palliative care in neurooncology and peripheral neurotoxicity of anticancer agents.
Alessandra Fabi M.D., is oncologist in the Division of Medical Oncology at Regina Elena National Cancer Institute, Rome (Italy). The principal clinical and research area is breast and brain cancer and supportive care. She conduced phase I, II and III clinical trials in oncology.