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 » Introduction
 » Epidemiology
 » Pathology
 »  References

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  Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 410-413
 

Leptomeningeal metastasis in solid tumors with a special focus on lung cancer


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Feb-2016

Correspondence Address:
V Noronha
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175351

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 » Abstract 

Leptomeningeal metastasis is a common problem in advanced solid tumor malignancies. A significant number of patients have underlying lung cancer. With the advent of better therapies, the management of leptomeningeal metastasis is gained more importance to improve survival and quality of live. This review article focuses on the epidemiology, clinical features, diagnostics and the recent management strategies directed towards leotomeningela metastasis from solid tumor, esp lung cancer.


Keywords: Leptomeningeal, lung cancer, solid tumors


How to cite this article:
Joshi A, Ghosh J, Noronha V, Parikh P M, Prabhash K. Leptomeningeal metastasis in solid tumors with a special focus on lung cancer. Indian J Cancer 2014;51:410-3

How to cite this URL:
Joshi A, Ghosh J, Noronha V, Parikh P M, Prabhash K. Leptomeningeal metastasis in solid tumors with a special focus on lung cancer. Indian J Cancer [serial online] 2014 [cited 2019 Aug 24];51:410-3. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/410/175351



 » Introduction Top


The frequency of neoplastic meningitis (NM) is increasing because of heightened clinical suspicion, improved neuroimaging techniques and longer survival in patients with extraneural cancer. Longer survival allows residual tumor cells within central nervous system (CNS) sanctuary sites time to become symptomatic. There has been a significant leap in the management of systemic disease control across solid tumors, but the progress in leptomeningeal metastasis (LM) treatment has been disappointing, mostly because of the poor penetrance to the cerebrospinal fluid (CSF) of the majority of drugs. Entire neuraxis magnetic resonance imaging (MRI) is required for diagnosis, but the identification of neoplastic cell by CSF cytological study is a key feature determining LM. The specificity and the sensitivity of MRI and CSF analyses remain poor. Newer modalities are experimental but may prove beneficial in the future. Various studies have addressed the prognostic markers that affect the outcome. The survival is dismal in most of the situation and is limited to few weeks to few months. Specific treatment of LM typically combines systemic and intrathecal (IT) chemotherapy and site-specific radiotherapy. New agents are now under evaluation. This review focuses on LM originating from solid tumors.


 » Epidemiology Top


Leptomeningeal metastasis is seen in around 5% of patients in solid tumors and around 10% in hemotolymphoid cases. However, in some autopsy series, the asymptomatic incidence may be up to 20%. Adenocarcinoma is most frequently found cytology, and the relative contributions are breast cancer (12–35%), lung cancer (10–26%), melanoma (5–25%), gastrointestinal cancer (4–14%), and cancers of unknown primary (1–7%). Small cell carcinoma of lung and melanoma has the highest incidence of spread to meninges (11% and 20%, respectively).

Pathophysiology

A study by Kokkoris et al. showed that in most cases of breast or lung cancer, pure leptomeningeal carcinomatosis is the result of cancer propagation from vertebral or paravertebral metastases; in most cases of primary gastrointestinal cancer metastasis to the leptomeninges takes place via perineural spaces; and in cases where deep CNS parenchymal metastases are present leptomeningeal carcinomatosis follows cancer metastasis through the arterial route. Direct spread of the primary cancer in proximity to the CNS accounts for a small proportion of cases of cancerous invasion of the pia-arachnoid. It is not certain if metastasis can take place via the choroid plexus or meningeal arteries.


 » Pathology Top


Characteristically there is diffuse or multifocal infiltration of arachnoid membranes by cancer cells, often filling the subarachnoid and Virchow–Robin spaces, and sometimes invading the underlying neuraxis, vessels, and nerve surfaces. Cranial and spinal nerve demyelination and axonal degeneration are occasionally observed without any tumor infiltration. A pure encephalitic variant is characterized by massive invasion of the Virchow–Robin spaces, without infiltration of the sub-arachnoid spaces of the brain surface.

Clinical manifestations

Neoplastic meningitis classically presents with pleomorphic clinical manifestations encompassing symptoms and signs in three domains of neurological function: (a) The cerebral hemispheres (15% of all patients), (b) the cranial nerves (35%), and (c) the spinal cord and roots (60%). Signs on examination generally exceed the symptoms reported by the patient. The most common manifestations of cerebral hemisphere dysfunction are headache and mental status changes. Other signs include confusion, cognitive impairment, seizures, and hemiparesis. Diplopia is the most common symptom of cranial nerve dysfunction, with cranial nerve VI being the most frequently affected, followed by cranial nerves III and IV. Trigeminal sensory or motor loss, cochlear dysfunction, and optic neuropathy are also common findings. Nuchal rigidity is only present in 15% of cases. There should be a high index of suspicion for the diagnosis. Any new neurological sign or symptoms should be investigated, especially the ones with multifocal neurological not explained by any other etiology like infective/paraneoplastic.

Diagnosis

Imaging

The main modality of radiological diagnosis remains MRI of the craniospinal axis. Contrast-enhanced computed tomography brain has been shown to have very poor sensitivity. The standard examination should include at the cerebral level, axial T1-weighted images without contrast, fluid attenuation inversion recovery (FLAIR) sequences and three-dimensional axial T1-weighted sequences with contrast. The spine is best evaluated with sagittal T1-weighted sequences with and without contrast and sagittal fat suppression T2-weighted sequences combined with axial T1-weighted images with contrast of regions of interest. Contrast-enhanced T1-weighted and FLAIR sequences are the most sensitive to detect LM.[1] The most frequent brain MRI findings are subarachnoid nodules (35–50%) and the pial enhancement (15–50%). Spine involvement is present in 15–25% of the patients. The most frequent MRI findings are subarachnoid and parenchymal enhancing nodules (10–35%), diffuse or focal pial enhancement (10–20%). Brain parenchymal metastases may be associated with LM in 21–82%.[2] Radionuclide studies with 111Indium-diethylene-triamine pentaacetic or 99Tc macro-aggregated albumin represent the techniques of assessment of CSF flow blocks, which are amenable to focused RT. however, resolution of flow blocks have not shown to improve OS in some series, but it leads to neurological improvement.

Cerebrospinal fluid studies

Various tumor markers have been studied in CSF, but none had any impact on clinical applicability. Nonspecific tumor markers such as creatine-kinase BB isoenzyme, tissue polypeptide antigen, beta 2-microglobulin, beta-glucoronidase, lactate dehydrogenase isoenzyme-5, and more recently vascular endothelial growth factor can be strong indirect indicators of NM, but none is sensitive enough to improve the cytological diagnosis.

In rare cases, meningeal biopsy might be necessary to confirm the diagnosis in patients with presumed NM and localized radiological lesions but without positive CSF cytology.

Prognosis

The median survival time of untreated patients with NM is 4–6 weeks, and death generally occurs because of progressive neurological dysfunction. Of the solid tumors, breast cancer responds best, with median survival times of 6 months and 11–25% 1-year survival rates. In most studies, it has been shown that poor performance status, multiple fixed neurologic deficits, bulky CNS disease, coexistent carcinomatous encephalopathy, and CSF flow abnormalities demonstrated by radionuclide ventriculography. In general, patients with widely metastatic aggressive cancers that do not respond well to systemic chemotherapies are also less likely to benefit from intensive therapy. In a study by Lee et al. in Korea, results showed that in univariate analysis, encephalopathy, Eastern Cooperative Oncology Group (ECOG) performance status, low initial CSF glucose, high initial CSF protein, high initial CSF white blood cell count, treatment with intra thecal chemotherapy (ITC), systemic therapy with epidermal growth factor receptor tyrosine kinase inhibitors or cytotoxic chemotherapy, whole-brain radiotherapy (WBRT), ventriculo-peritoneal (VP) shunt operations, and negative cytologic conversion after IT chemotherapy were identified as variables that had prognostic influence on survival. In multivariate analysis, poor ECOG performance status (P = 0.026), high protein level of CSF (P = 0.027), and high initial CSF WBC count (P = 0.015) remained significant predictors of poor prognosis for survival, whereas ITC (P < 0.001), epidermal growth factor receptor/tyrosine-kinase inhibitor (EGFR-TKI) use (P = 0.018), WBRT (P = 0.009), and VP shunt operation (P = 0.013) remained significant predictors of favorable prognosis for survival. These results suggest that more active treatment strategies, including ITC, WBRT, and EGFR-TKI use might improve clinical outcomes in NSCLC patients with LC and good performance status, low initial CSF protein and low WBC counts in CSF.

Treatment options

Surgery

Two modalities are commonly used. First is the placement of A VP shunt. It works by decompression of the supratentorial pressure. If the patient is not able to tolerate the 'off' phase of an on/off valve, the utility of a VPS goes down, as the drug gets rapidly cleared form the intraventricular sites.[2] Drugs can be instilled into the subarachnoid space by lumbar puncture or via an intraventricular reservoir system, the ommaya reservoir. The latter is the preferred approach because it is simpler, more comfortable for the patient, and safer than repeated lumbar punctures. It also results in a more uniform distribution of the drug in the CSF space and produces the most consistent CSF levels. In up to 10% of lumbar punctures, the drug is delivered to the epidural space, even if there is CSF return after placement of the needle, and drug distribution has been shown to be better after drug delivery through a reservoir.

Radiotherapy

It can be given in the involved areas, to relieve CSF blocks, reduce bulky meningeal disease and sites of cranial nerve compression. WBRT is usually indicated in the setting of the concomitant brain parenchymal metastasis as the IT chemotherapy does not reach more than 3–4 mm into the parenchyma. Whole neuraxis irradiation is not indicated in adult patients due to poor tolerance, significant toxicity and neurocognitive side effects.

Chemotherapy

Chemotherapy remains the mainstay for the treatment of LM disease. It offers selective compartmental therapy with minimal systemic toxicity. Intraventricular application is advantageous pharmacokinetically because this method ensures neuraxis cytotoxic drug delivery even for chemotherapeutics with a short half-life. However, it is less clear whether intraventricular drug administration has a better survival advantage than lumbar administration.

Agents used

Methotrexate (MTX), a folate anti-metabolite, is given either twice a week by IT or intraventricular bolus injection or by multiple low daily doses (concentration × time approach). It has a CSF half-life of 4.5–8 h. Use of folinic acid concomitantly is preferred for reduction of systemic toxicity. Usually, MTX is initially administered on a twice-weekly schedule for 4 weeks, followed by a decrease in frequency over a total treatment time of 3–6 months. The exact duration of treatment has not been established, but some patients may benefit from prolonged treatment. A dose intense regimen of MTX (15 mg/day, 5/7 days, 1 week on 1 week off) has been explored retrospectively in breast cancer patients with a reported median survival of 4.5–5 months.[3],[4] Intra-CSF MTX converts tumor positive CSF to negative in 20–61% of patients with LM.[5],[6] Achieving a cytological response within the 1st month of IT MTX treatment may be predictive of a better median additional survival (6 vs. 2 months). Renal insufficiency resulting in delayed excretion of MTX or the presence of pleural or peritoneal effusions that create a "third space effect" and thereby accumulation of MTX, can increase systemic MTX toxicity resulting in myelosuppression or mucositis.

Ara-C is initially administered at a dosage of 25–100 mg twice weekly and used in a similar manner to that of MTX with a 4-week induction, followed by 4 weeks of consolidation and subsequent maintenance. The half-life of ara-C is much longer in the CSF than MTX. Depot preparation of ara-C, depocyte has even more longer half-life of around 140 h, and is thus preferable over conventional cytarabine. In solid tumor-related LM, a randomized trial comparing intra-CSF liposomal ara-C to MTX found that liposomal ara-C increased median time to neurologic progression (58 vs. 30 days, P = 0.0068) but did not affect median survival (105 vs. 78 days, not significant). The improvement in neurologic PFS with DepoCyt administration was associated with a slight increase in toxicity and decreased patient visits to the hospital (75% reduction). The liposomal ara-C regimen provided greater quality-adjusted survival regardless of the quality-of-life valuations placed on time with toxicity and time following disease progression (range, 44–79 days).[7] The main side-effect of liposomal ara-C was arachnoiditis (i.e. a sterile chemical meningitis) whose incidence was reduced by concomitant administration of oral dexamethasone (4 mg twice daily during 5 days, initiating therapy 1 day before liposomal ara-C injection).[7],[8]

Thiotepa, the only alkylating agent (that by definition has a cell cycle nonspecific mechanism of action) used for intra-CSF chemotherapy, has the shortest half-life (approximately 20 min) of all agents used for intra-CSF chemotherapy and shows complete CSF clearance within 4 h the efficacy and toxicity of intra-CSF thiotepa has been prospectively compared with intra-CSF MTX in a randomized trial of adults with LM and demonstrated statistically significant differences in median survival (14 weeks with intra-CSF thiotepa vs. 16 weeks with intra-CSF MTX), a CSF cytological clearance rate of 30% and patients on the thiotepa arm experienced fewer neurological toxicities [9] There is no evidence that has demonstrated using an intra-CSF drug combination in LM from solid tumors that shows any superiority to that of a single agent regimen. In addition, increased toxicity and decreased tolerance to treatment has been demonstrated with multi-agent intra-CSF chemotherapy. In the single randomized trial testing this hypothesis, intra-CSF MTX was compared with intra-CSF MTX + ara-C + hydrocortisone in 55 patients. The combination provided a higher rate of cytological response (38% vs. 14%) and a longer median survival (19 vs. 10 weeks), but a selection bias (better risk patients receiving combination) cannot be excluded.

Newer modalities of treatment

Newer agents: Considerable effort has been invested in evaluating new intra-CSF chemotherapeutic drugs such as diaziquone (AZQ), mafosfamide, nimustine hydrochloride (ACNU), 4-hydroperoxycyclophosphamide, 6-mercaptopurine (6-MP), dacarbazine and gemcitabine. Unfortunately, none of these agents has shown clear evidence of activity in LM.

Monoclonal agents

Trastuzumab: In LM, a high level of concordance in the tumor human epidermal growth factor receptor-2/neu (HER-2) status has been reported between primary tumors and malignant cells in the CSF unlike the situation in parenchymal brain metastasis. Intra-CSF trastuzumab has been administered at varying doses (5–100 mg) with clinical and cytological success reported in case studies of patients with LM and HER-2/neu positive breast cancer. In addition, occasional prolonged survival have been reported (>72 months). These results are encouraging but the intra-CSF use of trastuzumab remains investigational, as more data and experience are necessary before this regimen can be considered standard.

Systemic agents

Breast

Capecitabine has shown promise with durable responses in breast cancer patients, but larger trials are lacking.

Lung

Recently, Park et al. reported that administration of systemic chemotherapy after diagnosis of LM in NSCLC patients was a significant prognostic factor.[2] In their retrospective series, 22 patients (44%) underwent systemic chemotherapy (cytotoxic chemotherapy or EGFR inhibitor) after being diagnosed with LM. Patients treated with combined therapy had a prolonged survival (11.5 vs. 1.4 months, P < 0.001) such that the authors concluded that a proportion of NSCLC patients with LM may benefit from further systemic chemotherapy. Several studies have suggested that a subset of patients with LM secondary to NSCLC may benefit with long lasting remission (11–12 months) from erlotinib and gefitinib at normal or higher dose if an EGFR mutation is present. Two recent and a large retrospective series have demonstrated particularly encouraging results with the use of these agents. In the US series, the median survival of the nine patients with LM and known EGFR mutations (all of whom received TKI at some point) was 14 months (range, 1–28 months).[10] In a Korean series, median survival was 19 months. EGFR TKI may be a valuable option in patients with LM particularly in patients with activating EGFR mutations or favorable clinical factors for EGFR TKI responsiveness.[2] In a study by Lee et al., erlotinib was found to be better than gefitinib for LM carcinomatosis from lung cancer –64% versus 9% clearance.[11]

Bevacizumab: VEGF levels in CSF have been found to be associated with poor prognosis. Retrospective data suggests that bevacizumab is safe in CNS metastases and not associated with an increased risk of intratumoral or intracranial hemorrhage particularly when intracranial lesions are asymptomatic and are of comparatively small volume. Intra-CSF bevacizumab is currently being evaluated in LM. A pilot study (n = 15) showed that bevacizumab significantly decreases CSF VEGF levels over time and resulted in clinical, imaging and CSF responses or stable disease in 54–73% of LM patients.[12]

Complications of intrathecal therapy

  • Aseptic meningitis Several hours after injection. Any IT agent Mimics bacterial meningitis CSF: Pleocytosis,↑protein. Oral antipyretics, Antiemetics and steroids Reversible within 1–3 days Further treatment possible Usually totally reversible
  • Acute encephalopathy
  • Myelopathy: Poor prognosis with residual neurodeficit
  • Acute cerebellar syndrome: Usually reversible
  • Acute/subacute encephalopathy: Usually reversible
  • Posterior reversible encephalopathy syndrome: Headache, change in mental status and seizures. MR: Reversible cortical and subcortical changes consisting of high-intensity lesions on T2-WI and FLAIR sequences with postGd ↑, ↓signal intensity on diffusion-WI and ↑apparent diffusion coefficient. Usually total resolution within days
  • Delayed leukoencephalopathy: Usually irreversible.


 
 » References Top

1.
Singh SK, Leeds NE, Ginsberg LE. MR imaging of leptomeningeal metastases: Comparison of three sequences. AJNR Am J Neuroradiol 2002;23:817-21.  Back to cited text no. 1
    
2.
Park JH, Kim YJ, Lee JO, Lee KW, Kim JH, Bang SM, et al. Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era. Lung Cancer 2012;76:387-92.  Back to cited text no. 2
    
3.
Fizazi K, Asselain B, Vincent-Salomon A, Jouve M, Dieras V, Palangie T, et al. Meningeal carcinomatosis in patients with breast carcinoma. Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer 1996;77:1315-23.  Back to cited text no. 3
    
4.
Gauthier H, Guilhaume MN, Bidard FC, Pierga JY, Girre V, Cottu PH, et al. Survival of breast cancer patients with meningeal carcinomatosis. Ann Oncol 2010;21:2183-7.  Back to cited text no. 4
    
5.
Glantz MJ, Cole BF, Recht L, Akerley W, Mills P, Saris S, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: Is intrathecal chemotherapy necessary? J Clin Oncol 1998;16:1561-7.  Back to cited text no. 5
    
6.
Siegal T, Lossos A, Pfeffer MR. Leptomeningeal metastases: Analysis of 31 patients with sustained off-therapy response following combined-modality therapy. Neurology 1994;44:1463-9.  Back to cited text no. 6
    
7.
Glantz MJ, LaFollette S, Jaeckle KA, Shapiro W, Swinnen L, Rozental JR, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999;17:3110-6.  Back to cited text no. 7
    
8.
Esteva FJ, Soh LT, Holmes FA, Plunkett W, Meyers CA, Forman AD, et al. Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer. Cancer Chemother Pharmacol 2000;46:382-6.  Back to cited text no. 8
    
9.
Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol 1993;11:561-9.  Back to cited text no. 9
    
10.
Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, et al. Leptomeningeal metastasis from non-small cell lung cancer: Survival and the impact of whole brain radiotherapy. J Thorac Oncol 2012;7:382-5.  Back to cited text no. 10
    
11.
Lee E, Keam B, Kim DW, Kim TM, Lee SH, Chung DH, et al. Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer. J Thorac Oncol 2013;8:1069-74.  Back to cited text no. 11
    
12.
Groves MD, DeGroot J, Tremont I, Forman A, Kang S, Pei BL, et al. A pilot study of systemically administered bevacizumab with neoplastic meningitis NM: Imaging, clinical, CSF and biomarker outcomes. Neurooncol (OT-02) 2011;13:Iii85-91.  Back to cited text no. 12
    




 

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