Neoplastic Meningitis Due to Lung, Breast, and Melanoma Metastases

Emilie Le Rhun, MD; Sophie Taillibert, MD; Marc C. Chamberlain, MD

Disclosures

Cancer Control. 2017;24(1):22-32. 

In This Article

Treatment

Combined treatment utilizing systemic chemotherapy (or targeted therapy), the intra-CSF administration of chemotherapy, and site-specific radiotherapy may improve rates of survival in patients otherwise determined to be good candidates for neoplastic meningitis– directed treatment. A number of randomized trials have been conducted in solid tumor–related neoplastic meningitis (Table 3).[65,69–72] Most of these trials included multiple tumor types, thereby limiting the applicability of the study results with respect to specific cancer-related neoplastic meningitis.[65,69–72] In addition, these trials varied with respect to methodology and the absence of any standardized criteria by which to evaluate response to treatment;[65,69–72] thus, the results cannot be generalized to specific groups of patients with neoplastic meningitis.

Because the progression of systemic disease is the primary cause of death in patients with neoplastic meningitis, treatment of systemic disease should not be neglected.[73] In general, patients with neoplastic meningitis who have a good performance status are treated with site-specific radiotherapy and disease-specific systemic therapy (chemotherapy or targeted therapy) that may treat both neoplastic meningitis and the systemic disease. The role of the intra-CSF administration in solid tumor–related neoplastic meningitis is not clearly defined. No prospective trial has established the superiority of the intra-CSF administration of chemotherapy relative to systemic therapy. Thus, treatment of neoplastic meningitis should be individualized to the general and neurological status of the patient, the available therapeutic options for systemic disease, and the manner of neurological presentation.

Symptomatic Treatment

Symptomatic treatment is indicated for all patients with neoplastic meningitis. Pain is treated using opioid analgesics, tricyclic antidepressants, or antiepileptic drugs when present. Corticosteroids may improve radicular pain. The contribution of corticosteroids is limited in neoplastic meningitis because, unlike in brain metastases, neoplastic meningitis does not result in vasogenic edema. However, steroids are useful for the treatment of associated brain metastasis or epidural spinal compression.[4] Focal radiotherapy of symptomatic sites may also provide pain relief. Prophylactic antiepileptic drugs are not indicated, except in patients with seizures and, if used, non–enzyme-inducing drugs are preferred to mitigate pharmacodynamic interaction with systemic therapies. Symptomatic hydrocephalus can be treated by a ventriculoperitoneal shunt or, in some instances, whole-brain/skull-base radiotherapy.[4,7]

Surgery

The main surgical indications in neoplastic meningitis include placement of a ventriculoperitoneal shunt for symptomatic hydrocephalus and implantation of ventricular-access devices (eg, Ommaya reservoir) to facilitate the intra-CSF administration of therapy. In 1 report, diverting CSF improved survival in patients with neoplastic meningitis.[74] Complications of a ventriculoperitoneal shunt include possible peritoneal dissemination; however, data from studies of medulloblastoma indicate the absence of peritoneal metastases, nor do any data in the medical literature on neoplastic meningitis suggest a similar seeding pattern.[75]

Ventricular-access devices offer several advantages for the intra-CSF administration of chemotherapy. After lumbar puncture, the intra-CSF administration of a drug may unknowingly be placed into the epidural or subdural space in up to 12% of patients.[76] Furthermore, following intralumbar drug administration, the drug distribution may be not uniform with the variable drug concentration observed in the intracranial compartment.[4,7] These pharmacodynamic aspects of intralumbar drug delivery may partly explain the benefit seen in progression-free survival after the intraventricular administration of select agents.[76] Placing a ventricular-access device is a relatively pain-free procedure.

Ventricular-access devices may also be used in the setting of thrombocytopenia, a relative contraindication for intralumbar drug administration.[7] In a cohort of 112 patients (a median of 9 injections per study patient), of whom 72% were treated with both systemic and intraventricular chemotherapy, 11 cases of complications were observed, including 7 infections related to the ventricular-access device.[77] These results confirmed the safety of ventricular-access devices in patients with neoplastic meningitis. Rarely, intracranial hemorrhage, symptomatic leukoencephalopathy, or malposition or obstruction of the catheter can be observed with ventricular-access devices in patients with neoplastic meningitis.[4,77]

Radiotherapy

Radiotherapy is indicated for the treatment of symptomatic sites of disease, bulky disease defined by MRI, or to correct CSF flow blocks demonstrated by radioisotope CSF flow dynamics.[1,4,78] Radiotherapy is indicated for cauda equina or skull-base syndromes, even in the absence of correlated radiographical signs.[4] Radiotherapy often provides pain relief and may help stabilize but does not typically improve neoplastic meningitis– related neurological disease.[4]

Bulky radiographical disease is another indication for radiotherapy because the intra-CSF administration of chemotherapy has limited diffusion (< 3 mm) into tumor nodules and is limited in its effectiveness.[4]

Correction of CSF flow obstruction is yet another indication for radiotherapy in neoplastic meningitis, and, if normalized, outcomes are similar to those seen in patients with normal CSF flow dynamics.[42]

Stereotactic radiosurgery and fractionated stereotactic radiotherapy have little utility in managing neoplastic meningitis except in co-existent brain metastasis.[1,78] In general, CNS site-specific radiotherapy is well tolerated, but use of more extensive radiation treatment fields, such as craniospinal irradiation, have not improved outcomes in solid tumor–related neoplastic meningitis and may result in serious adverse events (eg, myelosuppression, gastrointestinal toxicity).[1,4,6,7]

Whole-brain radiotherapy may ameliorate neoplastic meningitis–related communicating hydrocephalus secondary to the interruption of CSF flow over the convexity of the brain. Whole-brain radiotherapy can be used to treat co-existent brain metastasis. In a retrospective cohort of patients with NSCLC and neoplastic meningitis, whole-brain radiotherapy did not prolong survival when used as a single-modality therapy for neoplastic meningitis.[38]

Systemic Therapy

The selection of systemic chemotherapy to treat neoplastic meningitis is based on the chemosensitivity profile of the primary tumor and the ability of the therapeutic agent to cross the blood–CSF barrier. Temozolomide, an alkylator chemotherapeutic agent known to cross the blood–CSF barrier, failed in a phase 2, nonrandomized study of patients with neoplastic meningitis related to either breast cancer or NSCLC.[79] It is likely that it failed due to the inactivity of temozolomide in these cancers.[79] Cytotoxic concentrations can also be achieved in the CSF with intravenous high-dose methotrexate or cytarabine, but these regimens have limited effectiveness, except in breast cancer, and often result in significant rates of toxicity.[7]

Breast Cancer. Capecitabine, a fluoropyrimidine that can penetrate the CNS, has shown durable responses in small case series of breast cancer–related neoplastic meningitis.[80,81] Taxane-based chemotherapies (paclitaxel and docetaxel, which are common agents used to treat breast cancer), do not cross the blood–CSF barrier and have no efficacy in treating neoplastic meningitis.[82] Responses in patients with neoplastic meningitis after endocrine therapy (tamoxifen, letrozole, anastrozole, megestrol) have occasionally been reported, but most often at the initial presentation of neoplastic meningitis.[7] Breast cancer has acquired resistance to these therapies.[7]

Anti-erb-b2 receptor tyrosine kinase 2 (ERBB2) therapies (eg, trastuzumab, pertuzumab, lapatinib) are approved for use in metastatic ERBB2-positive breast cancer. However, no systemic anti-ERBB2 agent has been evaluated in neoplastic meningitis, except for responses observed in brain metastases.[83,84] Several authors have reported a potential role of bevacizumab alone or in combination with chemotherapy for certain patients with neoplastic meningitis, and the results from several prospective studies evaluating bevacizumab in breast cancer–related neoplastic meningitis are forthcoming (NCT00924820, NCT01281696).[85–89]

Lung Cancer. The impact of systemic chemotherapy in the treatment of lung cancer–related neoplastic meningitis is unclear, but anecdotal responses have been observed following platinum-couplet chemotherapy.[90] Some data suggest that patients treated with select systemic therapies containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor have improved overall survival in select patients, but the effectiveness of these therapies in patients with neoplastic meningitis is not certain.[17] Nonetheless, responses to pemetrexed and bevacizumab have been observed in small case reports of NSCLC-related neoplastic meningitis.[16,91] Results from a prospective study of bevacizumab for the treatment of neoplastic meningitis that enrolled patients with lung cancer and neoplastic meningitis are forthcoming (NCT00924820).

Activity of the EGFR–tyrosine kinase inhibitors erlotinib and gefitinib at normal and higher doses was observed in patients with activating mutations of EGFR and NSCLC-related neoplastic meningitis.[16,32,38] However, whether standard-dose or pulsatile, high-dose regimens of EGFR inhibitors are of utility has not yet been defined.[92] Erlotinib may achieve higher CSF concentrations than gefitinib, and this drug has potential in neoplastic meningitis.[16] CNS responses with erlotinib after prior progression on gefitinib and vice versa have been reported.[93] Second-generation EGFR inhibitors such as afatinib (combined with cetuximab) also have activity in lung cancer–related neoplastic meningitis.[94] Thirdgeneration EGFR inhibitors exist that have both improved CNS penetration and activity against the T790M mutation that commonly results in resistance to EGFR inhibition, and these investigational drugs may prove to be effective for both brain metastases and neoplastic meningitis.[95] In a single case series, response to an anaplastic lymphoma kinase inhibitor was observed in the setting of neoplastic meningitis and NSCLC.[96]

Melanoma. Standard systemic chemotherapy for the management of melanoma includes temozolomide, dacarbazine, and fotemustine. However, systemic chemotherapy has limited activity in CNS metastases. Immunotherapy with anti-CTLA-4 (ipilimumab) alone or in combination with fotemustine has demonstrated efficacy in patients with minimal symptomatic brain metastasis.[97,98] Similar responses have been observed in brain metastasis treated with vemurafenib and dabrafenib.[99,100] In patients with both systemic and CNS metastases, similar response rates (78% and 90%) were observed when they were treated with dabrafenib.[101]

Cases of melanoma-related neoplastic meningitis responding to ipilimumab or dabrafenib have been reported, but whether targeted therapies can substitute for standard treatment has not yet been determined.[102]

Intracerebrospinal Fluid Administration of Chemotherapy

The intra-CSF administration of chemotherapy is a type of regional or intracavitary administration associated with minimal rates of systemic toxicity; it also produces high levels of the drug in the CSF compartment.[103] Although it is frequently used for the treatment of neoplastic meningitis, no prospective trials have demonstrated any benefit of intra-CSF administration of chemotherapy in patients with solid tumor–related neoplastic meningitis. Four drugs are commonly used in routine practice for intra-CSF administration and include methotrexate, cytarabine and its liposomal form, and thiotepa (Table 4). The length of treatment following the successful induction has not yet been defined for neoplastic meningitis, wherein patients have converted from positive to negative findings on CSF cytology and are otherwise clinically stable. Intra-CSF administration of chemotherapy was identified as a significant prognostic factor in the treatment of patients with NSCLC and neoplastic meningitis.[38] Several trials in adults with neoplastic meningitis have not demonstrated any superiority with respect to either response or survival when comparing combination therapy with single-agent therapy.[7,65,69,104] Common to all chemotherapy administered into the CSF, and, in par ticular, the long half-life agent liposomal cytarabine, is treatment-related, transient, aseptic chemical meningitis that can be mitigated by the concomitant oral administration of dexamethasone. A challenge with the current intra-CSF administration of chemotherapy is the limited efficacy of these agents in solid tumors.[1]

Another limitation of intra-CSF chemotherapy when used for the treatment of neoplastic meningitis is its limited penetration (1–3 mm) into tumor nodules, such that the intra-CSF administration of chemotherapy is relatively ineffective in MRI-defined bulky leptomeningeal disease. In patients with CSF flow blocks defined by radioisotope studies, the intra-CSF administration of chemotherapy can be associated with an increased risk of neurotoxicity.

Although these agents are rarely used, the intra-CSF administration of alternative agents (etoposide, topotecan, diaziquone, mafosfamide, nimustine, hydroperoxycyclophosphamide, mercaptopurine, dacarbazine, gemcitabine, interferon α) have either failed or shown similar activity to standard agents used in neoplastic meningitis.[7] The continuous ventricular infusion of methotrexate may represent an alternative, pharmacologically rational approach to treating neoplastic meningitis, because few CTCs are present in the active cell cycle.[57] Intra-CSF administration of targeted therapies (trastuzumab in breast cancer, interleukin 2 in melanoma, and panitumumab in NSCLC) has been used in neoplastic meningitis, but it has been described in case reports alone.[7,105,106] Two phase 1/2 studies are researching ERBB2-positive breast cancer and neoplastic meningitis to define the safety and efficacy of the intra-CSF administration of trastuzumab (NCT01325207, NCT01373710).

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