Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :2580
Small font sizeDefault font sizeIncrease font size
Navigate here
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (693 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

  In this article
 »  Abstract
 » Introduction
 »  Role of Blood-Br...
 »  Clinical Present...
 »  Treatment of Lep...
 »  Role of Epiderma...
 »  Role of ALK Rear...
 »  Other Molecular ...
 » Immuno-Oncology
 »  Leptomeningeal M...
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    PDF Downloaded393    
    Comments [Add]    
    Cited by others 7    

Recommend this journal


  Table of Contents  
Year : 2019  |  Volume : 56  |  Issue : 5  |  Page : 1-9

Management of leptomeningeal metastases in non-small cell lung cancer

1 Department of Medical Oncology, Sr. Consultant Medical Oncologist, Health Care Global Enterprises Limited, Bengaluru, Karnataka, India
2 Department of Medical Oncology, Sr. Consultant Medical Oncologist, Meenakshi Mission Hospital, Madurai, Tamil Nadu, India

Date of Web Publication29-Nov-2019

Correspondence Address:
Shekar Patil
Department of Medical Oncology, Sr. Consultant Medical Oncologist, Health Care Global Enterprises Limited, Bengaluru, Karnataka
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_74_19

Rights and Permissions

 » Abstract 

In leptomeningeal metastasis (LM), malignant lung cancer cells reach the sanctuary site of the leptomeningeal space through haematogenous or lymphatic route and thrive in the leptomeninges because of restricted access of chemotherapeutic agents across the blood brain barrier. The incidence of LM is 3%–5% in non-small cell lung cancer (NSCLC) patients; the incidence is higher in patients with anaplastic lymphoma kinase (ALK) gene rearrangement or epidermal growth factor receptor (EGFR) mutations. However, the real-world burden of undiagnosed cases may be higher. LM diagnosis is based on clinical, radiological, and cytological testing. Disease management remains a challenge because of low central nervous system penetration of drugs. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment and <11 months with novel therapies. Therapy goals in this patient population are to improve or stabilize neurologic status, improve quality of life, and prolong survival while limiting the toxicity of chemotherapeutic regimens. We reviewed therapeutic options for management of LM in NSCLC patients with or without genetic mutations. Radiotherapy, systemic, or intrathecal chemotherapy, and personalized molecularly targeted therapy prolong the OS in patients with LM. Newer third generation EGFR-tyrosine kinase inhibitors have considerable brain penetration property and have been vital in increasing the OS especially in patients with EGFR mutations. Sequential or combination therapy third generation EGFR agents with radiotherapy or chemotherapy might be effective in increasing the quality of life and overall survival.

Keywords: Blood brain barrier, leptomeningeal, tyrosine kinase inhibitors

How to cite this article:
Patil S, Rathnum KK. Management of leptomeningeal metastases in non-small cell lung cancer. Indian J Cancer 2019;56, Suppl S1:1-9

How to cite this URL:
Patil S, Rathnum KK. Management of leptomeningeal metastases in non-small cell lung cancer. Indian J Cancer [serial online] 2019 [cited 2022 Jun 27];56, Suppl S1:1-9. Available from:

 » Introduction Top

Leptomeningeal metastasis (LM) is a rare but serious complication of several solid tumors.[1],[2] Non-small cell lung cancer (NSCLC) constitutes the vast majority (80%–85%) of lung cancer cases. LM affects approximately 3%–5% of patients with metastatic NSCLC, especially adenocarcinoma subtype.[3],[4],[5] However, autopsy series have illustrated a higher incidence of undiagnosed or asymptomatic LM (≥20%).[6]

Historically compared to whole brain radiotherapy (WBRT), surgery, or best supportive care, novel targeted therapies have changed the prognosis, life expectancy, and quality of life.[7] This review presents the clinical presentation, diagnostics and recent advances in the treatment modalities for LM in patients with or without genetic mutations.

 » Role of Blood-Brain Barrier (BBB) in Drug Delivery Top

With a continuous layer of endothelial cells and tight intersections surrounded by pericytes and perivascular endfeet of astrocytes, the BBB protects the CNS from toxic substances and maintains homeostasis by enabling the influx and efflux of selected substances. The influx of molecules in the brain is gated by mechanisms like adsorptive or cell-mediated transcytosis, carrier or receptor-mediated transport, and transcellular and paracellular pathways and the efflux is facilitated by P-glycoproteins, breast cancer-resistant proteins, and other mechanisms located in the luminal membrane of brain capillary endothelium. Several anticancer agents including the EGFR-TKIs are substrates for these proteins, which limits their CNS concentration due to active efflux.[8],[9] Thus the leptomeningeal space acts as a secure sanctuary for cancer cells as therapeutic agents have restricted access to the CNS.[1],[2] The physicochemical properties and CSF penetration ability determine the therapeutic efficacy of anticancer drugs in LM. Most chemotherapeutic agents have low CSF penetration because of their large molecular size (>0.5 kDa), high hydrophilicity, low lipophilicity, and protein binding in blood.[10],[11] [Table 1] shows the physicochemical properties of several drugs used for treating LM in patients with NSCLC.
Table 1: Physicochemical Properties of Newer Therapies for LM in NSCLC[9]

Click here to view

However, BM may increase the permeability of anticancer drugs in the brain. One of the proposed explanations for this increased permeability is tumor neo-angiogenesis in BM. These newer vessels may lack the stringent structural characteristics of normal BBB, and, compared with a healthy BBB, they may be more permeable to anticancer products.[12]

 » Clinical Presentation and Diagnosis of Leptomeningeal Disease Top

Malignant cells reach the leptomeningeal space by hematogenous spread (through arterial or venous circulation) or via lymphatic circulation or by direct extension of BM. There are two types of leptomeningeal tumors: diffuse type with free-floating non-adherent cancer cells and nodular type with contrast-enhanced leptomeningeal nodules.[13] Patients with LM show diverse clinical presentations [Figure 1]; however, it may remain undiagnosed in several cases with advanced NSCLC. The signs and symptoms of LM are due to involvement of cerebral, cranial, and spinal nerves.[9],[14] Since several CNS conditions can mimic the clinical signs and symptoms of LM, it is important to have a differential diagnosis in patients with an advanced stage of NSCLC.
Figure 1: Clinical Presentation of Leptomeningeal Metastasis. Source: Figure recreated from Pavlidis N. Ann Oncol 2004;15 (Suppl 4):iv285-91 and Brower JV, et al. J Clin Neurosci 2016;27:130-7

Click here to view

Improved diagnostic techniques have played an important role in increasing the reported events of LM.[15] The diagnosis of LM is usually challenging and relies on three assessments: clinical symptoms, radiological imaging, and CSF cytology, with the latter being the gold standard. The clinical symptoms of LM may be subtle or diverse; hence, a definitive diagnosis solely on basis of clinical symptoms is not possible. The sensitivity of initial lumbar puncture is 50%, which increases to 75%–80% with a repeat puncture. Though approximately 20% of patients never have a positive cytometry, false-positives are rare.[16] The classic features of CSF cytology indicative of LM are low glucose concentration, high protein concentration, lymphocytic pleocytosis, and positive cytology for malignant cells. Sometimes there is increased CSF pressure, raised white blood cell count, and xanthochromia.[17],[18] The presence of infectious meningitis is another important factor that can be excluded.[19] Rarely meningeal biopsy might be required for confirming diagnosis.[3]

Brain and spinal imaging are crucial for the diagnosis of LM, especially in case of negative cytology. Neuroimaging may help establish the location of metastasis—the leptomeningeal space as opposed to the brain, skull, or dura. A gadolium-enhanced magnetic resonance imaging (MRI) has sensitivity and specificity of about 75%; hence, it is the best imaging technique for evaluating LM.[20] In a retrospective analysis involving 519 lung cancer patients, of the 334 suspected cases of LM, 35% were diagnosed by MRI, 22% by CSF cytology, and 42% by inclusion of both techniques.[7] Computed tomography (CT) can be performed in patients unable to undergo MRI, but CT has a low sensitivity compared with MRI.[19]

Newer methods of diagnosis

Of the newer methods being studied, tumor marker immunostaining fluorescence in situ hybridization (TM-iFish) technology demonstrated a higher sensitivity in detecting LM originating from lung cancers.[21] Another method of direct sequencing and evaluating CSF-circulating tumor deoxyribonucleic acid (DNA) allowed the identification of EGFR-sensitizing and -resistant mutations in LM, which is beneficial in deciding the course of therapy for targeted agents.[22]

For epithelial tumors like NSCLC, the techniques for identifying circulating tumor cells (CTCs) in blood can be modified for testing CSF samples for a highly specific and sensitive analysis. In a study on 51 patients with solid tumors, CTCs were detected in all 15 patients with LM and in one additional patient with negative cytology for LM. This patient developed classical symptoms of LM 6 months later.[6],[23],[24],[25] In another study, sensitivity and specificity were 93% and 95%, respectively, with more than one CTC evaluation.[26] In the BLOOM study, LM was confirmed by CSF cytometry and EGFR mutation DNA testing in the CSF. EGFR-sensitizing mutations were detected in six patients, and T790M mutation was detected in two patients. The clinical progress during the treatment was also confirmed by decrease in the number of EGFR-mutated DNA copies in these patients.[27],[28] Thus, liquid biopsy seems to be a promising tool in LM diagnosis, mutation detection, and deciding treatment course.

 » Treatment of Leptomeningeal Metastases Top

LM is a serious and usually fatal complication of advanced cancers. Patients with LM have very poor prognosis with median overall survival (OS) of <3 months with contemporary treatments and 3–11 months with novel therapies.[3],[29],[30] The goals of therapy in LM are to improve or stabilize neurologic status, improve quality of life, and prolong survival while limiting toxicity. Treatment modalities depend on histology characterization of NSCLC, molecular expression, time of appearance of metastases, and patient's performance status. Though there is no standard treatment for the disease, the United States National Comprehensive Cancer Network (NCCN) has categorized patients in two strata on the basis of risk stratification [Figure 2]. For patients with good risk, systemic and contemporary therapy is recommended, while for patients with poor risk, supportive care is recommended.[3],[9],[31]
Figure 2: Risk Group Stratification for Leptomeningeal Metastases Patients[3].Source: Recreated from Remon J, et al. Cancer Treat Rev 2017;53:128-137

Click here to view

The response to therapy should be evaluated by using a standardized neurological examination, CSF cytology or flow cytometry, and radiologic evaluation. In addition, OS remains the most important indicator of response. Several studies have been conducted to evaluate the efficacy of different treatment modalities in NSCLC patients with LM and/or BM [Table 2].[27],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48] [Figure 3] shows a flow chart on treatment of LM in NSCLC.
Table 2: Selected Trials Published for Treatment Modalities for Leptomeningeal Metastases and/or Brain Metastases in NSCLC Patients

Click here to view
Figure 3: Treatment Algorithm in NSCLC with LM. Source: Figure Recreated from Remon J, et al. Cancer Treat Rev 2017;53:128-137 and Cheng H, et al. Lancet Oncol 2018;19:e43-55

Click here to view


The main role of radiotherapy (RT) in the treatment of LM is to reduce the bulk of nodular disease, correct the CSF flow to reduce intracranial pressure, and alleviate symptom burden.[49] The WBRT is majorly used in patients with concurrent BM. The standard radiotherapeutic regimens are 20 Gy in five fractions of 4 Gy and 30 Gy in ten fractions of 3Gy. The survival benefit of WBRT alone has not been established in clinical studies. In a retrospective study, patients (n = 212) receiving WBRT had a longer median OS (10.9 months) compared with patients receiving no treatment (2.4 months; P = 0.002).[50] In another retrospective analysis, (n = 125), the median OS was not significantly different in RT and no treatment groups.[49] Other studies on RT in NSCLC patients with LM are summarized in [Table 2].

Several studies have been conducted to identify patients who are likely to benefit the most from WBRT. The prognostic factors that positively affected the OS were Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1, time to LM after NSCLC diagnosis, Karnofsky Performance Status ≥70, lack of parenchymal BM, and adenocarcinoma histology.[15],[51] The use of RT is usually limited because of toxicity associated with increasing doses. The adverse events associated with RT include myelosuppression, mucositis, esophagitis, and leukoencephalopathy, and other delayed effects.[20] Although WBRT is usually preferred, focal RT in fractionated regimens, such as involved-field RT (IFRT) or stereotactic RT can be used to treat patients with no gross disease in the sulci (nodular disease) and symptomatic cerebral or spinal sites. The NCCN 2017 guidelines recommend IFRT in combination with intrathecal chemotherapy (ITC) in patients with good prognosis; patients not meeting criteria for good prognosis are advised to undergo IFRT alone to symptomatic sites or best supportive care.[52] A study to determine the combined effect of IFRT with concurrent intrathecal methotrexate or intrathecal cytabarine is ongoing (NCT03082144).

RT may play a role in boosting the immune system through multiple mechanisms like increasing tumor-activated antigen availability, T cell stimulation, and enhancing dendritic cell infiltration. However, limited evidence is available to show the effect of RT on immunomodulation in LM. In one study (n = 18 patients), the combination of RT with pembrolizumab (a programmed cell death protein 1 [PD-1] inhibitor) provided a positive BM response in six patients, and the response was durable in five of them.[53]

Intrathecal chemotherapy

The BBB restricts the penetration of chemotherapeutic agents in the brain. CSF exposure of chemotherapeutic agents is <5%.[6] ITC is the most common method for delivering chemotherapeutic agents to non-nodular and non-bulky LM. Systemic chemotherapy combined with ITC is the standard treatment in lung cancer patients with LM and a good risk profile, but its superiority compared with systemic chemotherapy has not been established.[35] A standardized regimen is not defined for ITC[3]; however, the most commonly used intrathecal agents are methotrexate, cytarabine, and thiotepa. In a pooled analysis of four prospective and five retrospective studies, 37 NSCLC patients with LM received ITC alone and 552 patients received a combination of ITC, TKIs, WBRT, or systemic chemotherapy. The cytological response was 55% and radiologic response was 64% in patients receiving ITC alone. The median OS was higher (7.5 months) in the ITC alone group compared with 3 to 5 months in the multiple intervention group.[54]

Systemic chemotherapy

The role of systemic chemotherapy in NSCLC patients with LM is not well-studied; however, the therapy may prolong survival as most patients have an active lung cancer at the time of LM diagnosis. The median OS with systemic chemotherapy is approximately 11.5 months in NSCLC patients with good risk.[55] Though a standardized treatment regimen is unavailable, a platinum based-chemotherapy with or without RT is recommended at diagnosis of LM without oncogenic driver mutations or programmed death-ligand 1 (PD-L1) tumor proportion score values ≥50%. Pemetrexed in combination with platinum is also approved in first-line setting against BM from NSCLC with an intracranial response rate of 30.8%−41.9% and an overall clinical benefit of 63%.[56],[57]

Targeted therapies

Approximately 20%–25% of patients with NSCLC have oncogene driver mutations—the most common ones are EGFR (10%–15%) and Anaplastic Lymphoma Kinase (ALK) rearrangements (3%–5%).[58],[59] Other less commonly observed mutations are KRAS, MET, ROS, BRAF, and HER2. Targeted therapies against these mutations have demonstrated survival benefits in NSCLC; however, their effect on LM is unknown.

 » Role of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors Top

Two retrospective studies reported that NSCLC patients with EGFR mutations were more likely to develop BM and LM than patients with wild-type EGFR. The incidence of LM in EGFR-mutated NSCLC patients is approximately 9%, higher than that in the non-mutated population, with a median OS of 3.1 months. The median OS improved in patients with a good performance score (<2) and TKI therapy (10 months).[30],[51],[60],[61]

First- and second-generation EGFR-TKIs have poor CNS penetration. Erlotinib has the highest penetration compared with gefitinib and afatinib.[62],[63] Clinical studies on the efficacy of different treatment modalities in NSCLC patients with LM or BM are summarized in [Table 2].

Osimertinib, a third generation EGFR-TKI, CNS active EFGR-TKI that potently and selectively inhibits both EGFR sensitizing and EGFR T790M resistance mutations. In a preclinical study on osimertinib, the CNS penetration of osimertinib was higher than erlotinib, gefitinib, and afatinib.[63] In a study on 13 patients with EGFR mutations and progression on first- or second-generation EGFR-TKIs, five patients had definitive diagnosis of LM and the remaining eight had probable LM. Osimertinib showed CNS improvement in six of eight (75%) possible cases and two of five (40%) definitive cases, and extracranial improvement in all eight possible cases and four of five (80%) definitive cases. The median progression-free survival (PFS) was 7.2 months.[44]

The efficacy of osimertinib was evaluated in a subset of 46 patients with measurable BM in AURA3 clinical study without any specific data on LM. As a second-line therapy, osimertinib provided longer PFS of 8.5 months in patients with BM compared with 4.2 months with a standard chemotherapeutic regimen. The CNS response rate was 70% (21/30) in the osimertinib group compared with 31% (5/16) in the chemotherapy group (odds ratio, 5.13; 95% confidence interval [CI]: 1.44-20.64; P = 0.015) and the PFS was 8.9 months compared with 5.7 months.[64] In a first-line setting (FLAURA study), osimertinib demonstrated encouraging CNS activity. A higher proportion of patients in the osimertinib group (n = 61) than in the control group (n = 67) achieved a CNS objective response (66% vs. 43%, respectively, odds ratio = 2.5), while the incidence of CNS progression was lower (20% vs. 39%) as was the rate of CNS progression due to new lesions (12% vs. 30%).[65] In a post hoc competing risk analysis of this study, after adjusting the non-CNS progression and death to estimate, osimertinib-treated patients had a 5% probability of experiencing a CNS event at 6 months and an 8% probability at 12 months compared with 18% and 24% in patients treated with EGFR standard of care (gefitinib or erlotinib).[66]

In a phase I trial (BLOOM, NCT02228369) specifically designed for treatment-naive patients with EGFR-mutated advanced NSCLC and LM, osimertinib was administered at 160 mg/day. Out of 32 patients with LM, 23 had 12-week brain image assessment, of which 10 had radiological improvement, and 13 had stable disease. At 12-week neurological assessment, seven patients showed improvement (two with confirmed cytology and five neurologically), one had stable disease, two worsened, and 13 remained asymptomatic. The geometric mean decrease in EGFR-mutant DNA copy was 57% (95% CI: 30-74) in 22 patients. The safety profile of osimertinib was manageable.[27],[28]

The efficacy and tolerability of osimertinib in NSCLC patients with LM were evaluated in a retrospective study on 20 patients. Clinical response was obtained in 17 of 20 patients and radiologic response was obtained in 9 of 11 radiologically assessable patients. The median OS and PFS after initiation of osimertinib were 18.0 and 17.2 months, respectively.[67]

AZD3759 is a new EGFR-TKI with CNS penetration of nearly 100% and no known efflux mechanism. The efficacy of AZD3759 was evaluated in a treatment arm in the phase I BLOOM study on 18 NSCLC patients with LM who were progressed on other EGFR-TKIs. AZD3579 at 200 or 300 mg twice daily was well-tolerated with no dose-limiting toxicities. Nine (53%) patients responded to the treatment and had stable disease or improvement on MRI imaging. Most commonly reported adverse events with AZD3579 were diarrhea and rash.[47],[48]

 » Role of ALK Rearrangements Top

ALK rearrangements are seen in approximately 5% of NSCLC patients with LM. The median time from diagnosis of NSCLC to LM is approximately 9 months, similar to other mutations. Several ALK inhibitors have been approved for use in NSCLC, but their efficacy in treating LM is not evaluated. Crizotinib is a first-generation ALK, ROS, and MET inhibitor, and is approved for first-line treatment in NSCLC patients with ALK rearrangements.[68],[69] Though crizotinib has low CNS penetration (CNS to plasma ratio of 0.026), retrospective evaluation of two randomized clinical studies has shown a good disease control rate (intracranial disease control rate of approximately 55–65% over 12–24 weeks) in patients with BM.[70],[71] Three case reports have presented efficacy of the crizotinib-methotrexate combination in treatment of LM in NSCLC patients (progression free survival of 6–10 months).[72],[73]

Ceritinib, a second-generation ALK inhibitor with 20 times higher potency than crizotinib, has been evaluated in NSCLC patients with BM.[74] Pulse dosing of crizotinib and ceritinib has also been effective in controlling BM in patients who have progressed on crizotinib alone.[75] Alectinib is another second-generation ALK inhibitor with CNS to plasma ratios of 0.63-0.94; these high values show that alectinib is not a substrate for efflux through P-glycoprotein channels.[76] The efficacy of alectinib in patients with BM was proven in a randomized trial.[77] Gainor et al. (2015) showed that three of four patients with ALK-positive tumor and LM or BM (who had progressed on crizotnib, ceritinib, chemotherapy, and WBRT) had radiological and neurological improvements in LM after treatment with alectinib, while the remaining patient had stable CNS disease. Furthermore, an increased dose of alectinib from 600 mg to 900 mg twice daily led to sustained radiological and neurological improvements for 3.5–6 months in two patients.[76] Brigatinib and lorlatinib are other ALK inhibitors approved for NSCLC, but their efficacy in patients with LM is not evaluated.

 » Other Molecular Alterations Top

HER2 and BRAF mutations are observed in about 1%–2% and 3%–4% of lung cancer patients. Trastuzumab is an anti-HER2 monoclonal antibody with efficacy in HER2-postive NSCLC patients[78]; however, its efficacy in LM is not known. Vemurafenib, an oral selective inhibitor of BRAF kinase, showed radiologic and neurologic improvement with OS of 10 months in a patient with BRAF-positive NSCLC and LM.[79]

 » Immuno-Oncology Top

Immunotherapeutic agents, especially PD-1 and PDL-1, in NSCLC have improved the survival outcomes for patients. Nevertheless, the efficacy of PD-1/PDL-1 drugs (pembrolizumab, nivolumab, and atezolizumab) in LM and BM is being evaluated. These agents cannot penetrate the BBB because of their very high molecular weight (>140,000 Da), but they affect stimulation of immunomodulatory agents in systemic circulation. Immune cells like lymphocytes might be able to cross the BBB after its disruption in advanced LM. Increased PDL-1 expression in the brain might occur in some cases.[9],[80],[81]

Four randomized studies have shown the efficacy of PD-1 and PDL-1 inhibitors in patients with advanced NSCLC including patients with pre-treated BM.[82],[83],[84],[85] In an Italian real-world effectiveness of nivolumab expanded access program of 1,588 NSCLC patients, 409 had BM. After nivolumab therapy for a median of 6.1 months, the disease control rate in patients with BM was 40%, and the overall safety profile of nivolumab was comparable to that of other standard therapies.[86] Several case reports have described the efficacy of nivolumab and pembrolizumab in patients with BM and LM.[87],[88],[89] In two case reports in patients with EGFR mutated NSCLC, neurological and radiological improvement in LM was observed on combination of erlotinib and bevacizumab after failure of erlotinib monotherapy.[90] Several other immunomodulatory agents are being studied for their efficacy in patients with LM from NSCLC and other solid tumors.[91],[92]

 » Leptomeningeal Metastases—The Way Forward Top

The leptomeningeal space remains a sanctuary site for metastasis of NSCLC because of the BBB. Though the incidence of LM is <5% in NSCLC, the real-world burden of undiagnosed cases seems higher and management remains a challenge because of low CNS penetration of drugs. Recent advances have been made in the diagnostics and treatment with the advent of molecularly targeted therapies. Third generation EGFR-TKIs with higher CNS penetration have shown survival benefits compared with standard therapies including RT and chemotherapy. Combination or sequential use of third generation EGFR agents along with RT and chemotherapy may provide further benefits regarding increased OS and improved quality of life.


The authors thank AstraZeneca Pharma India Ltd for providing medical writing assistance in the development of this manuscript, in collaboration with Sciformix Technologies Pvt. Ltd, Mumbai.

Financial support and sponsorship

Financial support to authors - Nil.

The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.

 » References Top

Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol 2006;5:443-52.  Back to cited text no. 1
Chamberlain MC. Leptomeningeal metastasis. Curr Opin Oncol 2010;22:627-35.  Back to cited text no. 2
Remon J, Le Rhun E, Besse B. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era. Cancer Treat Rev 2017;53:128-137.  Back to cited text no. 3
Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002;94:2698-705.  Back to cited text no. 4
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22:2865-72.  Back to cited text no. 5
Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surgical Neurology International 2013;4(Suppl 4):S265-88.  Back to cited text no. 6
Le Rhun E, Galanis E. Leptomeningeal metastases of solid cancer. Curr Opin Neurol 2016;29:797-805.  Back to cited text no. 7
Patel MM, Patel BM. Crossing the blood-brain barrier: Recent advances in drug delivery to the brain. CNS Drugs 2017;31:109-33.  Back to cited text no. 8
Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol 2018;19:e43-55.  Back to cited text no. 9
Weidle UH, Niewöhner J, Tiefenthaler G. The blood-brain barrier challenge for the treat of brain cancer, secondary brain metastasis, and neurological diseases. Cancer Genomics Proteomics 2015;12:167-77.  Back to cited text no. 10
Inno A, Di Noia V, D'Argento E, Modena A, Gori S. State of the art of chemotherapy for the treatment of central nervous system metastases from non-small cell lung cancer. Transl Lung Cancer Res 2016;5:599-609.  Back to cited text no. 11
Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284:1994-8.  Back to cited text no. 12
Pavlidis N. The diagnostic and therapeutic management of leptomeningeal carcinomatosis. Ann Oncol 2004;15(Suppl 4):iv285-91.  Back to cited text no. 13
Brower JV, Saha S, Rosenberg SA, Hullett CR, Ian Robins H. Management of leptomeningeal metastases: Prognostic factors and associated outcomes. J Clin Neurosci 2016;27:130-7.  Back to cited text no. 14
Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin 2003;21:25-66.  Back to cited text no. 15
Chamberlain M, Soffietti R, Raizer J, Rud R, Brandsma D, Boogerd W, et al. Leptomeningeal metastasis: A response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials. Neuro Oncol 2014;16:1176-85.  Back to cited text no. 16
Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, et al. Cerebrospinal fluid cytology in patients with cancer: Minimizing falsenegative results. Cancer 1998;82:733-9.  Back to cited text no. 17
Chamberlain MC, Kormanik PA, Glantz MJ. A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases. Neuro Oncol 2001;3:42-5.  Back to cited text no. 18
Demopoulos A. Clinical features and diagnosis of leptomeningeal metastases from solid tumors. Up to Date. 2018. Available from: [Last accessed on 2019 Mar 12].  Back to cited text no. 19
Demopoulos A, Brown P. Treatment of leptomeningeal metastases (carcinomatous meningitis) Up to Date. 2018. Available from: [Last accessed on 2019 Mar 12].  Back to cited text no. 20
Ma C, Lv Y, Jiang R, Li J, Wang B, Sun L. Novel method for the detection and quantification of malignant cells in the CSF of patients with leptomeningeal metastasis of lung cancer. Oncol Lett 2016;11:619-23.  Back to cited text no. 21
Sasaki S, Yoshioka Y, Ko R, Katsura Y, Namba Y, Shukuya T, et al. Diagnostic significance of cerebrospinal fluid EGFR mutation analysis for leptomeningeal metastasis in non-small-cell lung cancer patients harboring an active EGFR mutation following gefitinib therapy failure. Respir Investig 2016;54:14-9.  Back to cited text no. 22
Le Rhun E, Massin F, Tu Q, Bonneterre J, De Carvalho Bittencourt M, Faure GC. Development of a new method for identification and quantification in cerebrospinal fluid of malignant cells from breast carcinoma leptomeningeal metastasis. BMC Clin Pathol 2012;12:21.  Back to cited text no. 23
Patel AS, Allen JE, Dicker DT, Peters KL, Sheehan JM, Glantz MJ, et al. Identification and enumeration of circulating tumor cells in the cerebrospinal fluid of breast cancer patients with central nervous system metastases. Oncotarget 2011;2:752-60.  Back to cited text no. 24
Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 2013;80:1598-605.  Back to cited text no. 25
Lin X, Fleisher M, Rosenblum M, Lin O, Boire A, Briggs S, et al. Cerebrospinal fluid circulating tumor cells: A novel tool to diagnose leptomeningeal metastases from epithelial tumors. Neuro Oncol 2017;19:1248-54.  Back to cited text no. 26
Yang JC, Cho BC, Kim D, Kim SW, Lee JS, Su WC, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study. Proc Am Soc Clin Oncol 2017;35(Suppl 1):2020 (abstr).  Back to cited text no. 27
Yang JC, Kim D, Kim S, Cho BC, Lee JS, Ye X, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study. Proc Am Soc Clin Oncol 2016;34(Suppl 1):9002 (abstr).  Back to cited text no. 28
Li YS, Jiang BY, Yang JJ, Tu HY, Zhou Q, Guo WB, et al. Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thorac Oncol 2016;11:1962-9.  Back to cited text no. 29
Hyun JW, Jeong IH, Joung A, Cho HJ, Kim SH, Kim HJ. Leptomeningeal metastasis: Clinical experience of 519 cases. Eur J Cancer 2016;56:107-14.  Back to cited text no. 30
Turkaj A, Morelli AM, Vavalà T, Novello S. Management of leptomeningeal metastases in non-oncogene addicted non-small cell lung cancer. Front Oncol 2018;8:278.  Back to cited text no. 31
Wolf A, Donahue B, Silverman JS, Chachoua A, Lee JK, Kondziolka D. Stereotactic radiosurgery for focal leptomeningeal disease in patients with brain metastases. J Neurooncol 2017;134:139-43.  Back to cited text no. 32
Pan Z, Yang G, He H, Zhao G, Yuan T, Li Y, et al. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single-arm study. Int J Cancer 2016;139:1864-1872.  Back to cited text no. 33
Ozdemir Y, Yildirim BA, Topkan E. Whole brain radiotherapy in management of non-small-cell lung carcinoma associated leptomeningeal carcinomatosis: Evaluation of prognostic factors. J Neurooncol 2016;129:329-35.  Back to cited text no. 34
Gani C, Müller AC, Eckert F, Schroeder C, Bender B, Pantazis G, et al. Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors. Strahlenther Onkol 2012;188:148-53.  Back to cited text no. 35
Hermann B, Hültenschmidt B, Sautter-Bihl ML. Radiotherapy of the neuroaxis for palliative treatment of leptomeningeal carcinomatosis. Strahlenther Onkol 2001;177:195-9.  Back to cited text no. 36
Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, non-small-cell lung carcinoma, or malignant melanoma: A prospective study. Cancer 1999;85:1599-605.  Back to cited text no. 37
Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-69.  Back to cited text no. 38
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. 39
Yang H, Yang X, Zhang Y, Liu X, Deng Q, Zhao M, et al. Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib failure. Target Oncol 2015;10:135-40.  Back to cited text no. 40
Kawamura T, Hata A, Takeshita J, Fujita S, Hayashi M, Tomii K, et al. High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs. Cancer Chemother Pharmacol 2015;75:1261-66.  Back to cited text no. 41
Jackman DM, Cioffredi LA, Jacobs L, Sharmeen F, Morse LK, Lucca J, et al. A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer. Oncotarget 2015;6:4527-36.  Back to cited text no. 42
Liao BC, Lee JH, Lin CC, Chen YF, Chang CH, Ho CC, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis. J Thorac Oncol 2015;10:1754-61.  Back to cited text no. 43
Nanjo S, Hata A, Okuda C, Kaji R, Okada H, Tamura D, et al. Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer. Br J Cancer 2018;118:32-7.  Back to cited text no. 44
Ota K, Shiraishi Y, Harada T. Phase II study of erlotinib in advanced non-small cell lung cancer patients with leptomeningeal metastasis (LOGIK1101). J Thorac Oncol 2017;12:S271-2.  Back to cited text no. 45
Tamiya A, Tamiya M, Nishihara T, Shiroyama T, Nakao K, Tsuji T, et al. Efficacy and cerebrospinal fluid concentration of afatinib in NSCLC patients with EGFR mutation developing leptomeningeal carcinomatosis. J Thorac Oncol 2017;12:S273.  Back to cited text no. 46
Ahn M, Kim D, Kim TM, Lin CC, Ratnayake J, Carlie DJ, et al. Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningealmetastasis (LM). Proc Am Soc Clin Oncol 2016;34:9003.  Back to cited text no. 47
Cho BC, Ahn M, Lee J, Kim DW, Kim SW, John T, et al. Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anticancer therapy. Proc Am Soc Clin Oncol 2017;35:2069.  Back to cited text no. 48
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. 49
Harada H, Asakura H, Ogawa H, Mori K, Takahashi T, Nakasu Y, et al. Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy. J Cancer Res Ther 2016;12:267-70.  Back to cited text no. 50
Le Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, et al. EANO Executive Board and ESMO Guidelines Committee. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol 2017;28(Suppl 4):iv84-99.  Back to cited text no. 51
Central Nervous System Cancers: Leptomeningeal Metastases: National Comprehensive Cancer Network's Clinical Practice Guidelines in Oncology (2017). v. 1.2017: Available from: [Last accessed on 2018 Oct 22].  Back to cited text no. 52
Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: Early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016;17:976-83.  Back to cited text no. 53
Wu YL, Zhou L, Lu Y. Intrathecal chemotherapy as a treatment for leptomeningeal metastasis of non-small cell lung cancer: A pooled analysis. Oncol Lett 2016;12:1301-14.  Back to cited text no. 54
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. 55
Barlesi F, Gervais R, Lena H, Hureaux J, Berard H, Paillotin D, et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: A multicenter phase II trial (GFPC 07-01). Ann Oncol 2011;22:2466-70.  Back to cited text no. 56
Bailon O, Chouahnia K, Augier A, Bouillet T, Billot S, Coman I, et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol 2012;14:491-5.  Back to cited text no. 57
Matsumoto S, Takahashi K, Iwakawa R, Matsuno Y, Nakanishi Y, Kohno T, et al. Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int J Cancer 2006;119:1491-4.  Back to cited text no. 58
Iuchi T, Shingyoji M, Itakura M, Yokoi S, Moriya Y, Tamura H, et al. Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol 2015;20:674-9.  Back to cited text no. 59
Kuiper JL, Hendriks LE, van der Wekken AJ, de Langen AJ, Bahce I, Thunnissen E, et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis. Lung Cancer 2015;89:255-61.  Back to cited text no. 60
Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama lung cancer study group. Lung Cancer 2012;77:134-9.  Back to cited text no. 61
Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 2012;70:399-405.  Back to cited text no. 62
Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-Mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016;22:5130-40.  Back to cited text no. 63
Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, et al. cns efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: Data from a randomized phase III trial (AURA3). J Clin Oncol 2018;36:2702-9.  Back to cited text no. 64
Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated egfr-mutated advanced non-small-cell lung cancer. J Clin Oncol 2018:JCO2018783118. doi: 10.1200/JCO.2018.78.3118.  Back to cited text no. 65
Medwire News. FLAURA findings add to evidence for CNS efficacy of osimertinib in advanced NSCLC. 2018. Available from: [Last accessed on 2019 Mar 12].  Back to cited text no. 66
Saboundji K, Auliac JB, Pérol M, François G, Janicot H, Marcq M, et al. Efficacy of osimertinib in EGFR-mutated non-small cell lung cancer with leptomeningeal metastases pretreated with EGFR-tyrosine kinase inhibitors. Target Oncol 2018;13:501-7.  Back to cited text no. 67
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. Investigators, first-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77.  Back to cited text no. 68
Shaw AT, Janne PA, Besse B, Solomon BJ, Blackhall FH, Camidge DR, et al. Crizotinib vs chemotherapy in ALK+advanced non-small cell lung cancer (NSCLC): Final survival results from PROFILE 1007. ASCO Meeting Abst 2016;34:9066.  Back to cited text no. 69
Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged nonsmall- cell lung cancer and brain metastases. J Clin Oncol 2015;33:1881-8.  Back to cited text no. 70
Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: Results from PROFILE 1014. J Clin Oncol 2016;34:2858-65.  Back to cited text no. 71
Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443-5.  Back to cited text no. 72
Ahn HK, Han B, Lee SJ, Lim T, Sun JM, Ahn JS, et al. ALK inhibitor crizotinib combined with intrathecal methotrexate treatment for non-small cell lung cancer with leptomeningeal carcinomatosis. Lung Cancer 2012;76:253-4.  Back to cited text no. 73
Crinò L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: Results from ASCEND-2. J Clin Oncol 2016;34:2866-73.  Back to cited text no. 74
Dudnik E, Siegal T, Zach L, Allen AM, Flex D, Yust-Katz S, et al. Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy. J Clin Neurosci 2016;26:46-9.  Back to cited text no. 75
Gainor JF, Sherman CA, Willoughby K, Logan J, Kennedy E, Brastianos PK, et al. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol 2015;10:232-6.  Back to cited text no. 76
Nokihara H, Hida T, Kondo M, Kim YH, Azuma K, Seto T, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+NSCLC): Primary results from the J-ALEX study. ASCO Meeting Abst 2016;34:9008.  Back to cited text no. 77
Mazières J, Barlesi F, Filleron T, Besse B, Monnet I, Beau-Faller M, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2- targeted drugs: Results from the European EUHER2 cohort. Ann Oncol 2016;27:281-6.  Back to cited text no. 78
Fernandes MG, Costa J, Reis J, Jacob M, Moura C, Machado J, et al. BRAF-V600E advanced lung adenocarcinoma with leptomeningeal (lm) disease treated with vemurafenib. J Thorac Oncol 2017;12:S274-5.  Back to cited text no. 79
O'Kane GM, Leighl NB. Are immune checkpoint blockade monoclonal antibodies active against CNS metastases from NSCLC?—Current evidence and future perspectives. Transl Lung Cancer Res 2016;5:628-36.  Back to cited text no. 80
Berghoff AS, Inan C, Ricken G, Rajky O, Widhalm G, Dieckmann K, et al. Tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in non-small cell lung cancer brain metastases (BM) and matched primary tumors (PT). Ann Oncol 2014;25(Suppl 4):iv426-70.  Back to cited text no. 81
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.  Back to cited text no. 82
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.  Back to cited text no. 83
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016;387:1540-50.  Back to cited text no. 84
Barlesi F, Keunchil P, Ciardiello F, von Pawel J, Gadgeel S, Hida T, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in advanced NSCLC. ESMO 2016;LBA44-PR. (n.d.).  Back to cited text no. 85
Crinò L, Bidoli P, Roila F, Cortesi E, Garassino M, Cappuzzo F, et al. 1315P Efficacy and safety data from patients with advanced non-squamous NSCLC and brain metastases from the nivolumab expanded access programme (EAP) in Italy. Ann Oncol 2017;28:mdx380.018.  Back to cited text no. 86
Dudnik E, Yust-Katz S, Nechushtan H, Goldstein DA, Zer A, Flex D, et al. Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Lung Cancer 2016;98:114-7.  Back to cited text no. 87
Pluchart H, Pinsolle J, Cohen J, Ferretti GR, Bedouch P, Giaj Levra M, et al. Partial response of pulmonary adenocarcinoma with symptomatic brain metastasis to nivolumab plus high-dose oral corticosteroid: A case report. J Med Case Rep 2017;11:183.  Back to cited text no. 88
Gion M, Remon J, Caramella C, Soria JC, Besse B. Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non-small cell lung cancer patient. Lung Cancer 2017;108:72-4.  Back to cited text no. 89
Ariyasu R, Horiike A, Koyama J, Saiki M, Sonoda T, Kawashima Y, et al. Efficacy of bevacizumab and erlotinib combination for leptomeningeal carcinomatosis after failure of erlotinib. Anticancer Drugs 2017;28:565-7.  Back to cited text no. 90
Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and CDK inhibitors in human cancer. Adv Cancer Res 1996;68:67-108.  Back to cited text no. 91
Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016;6:740-53.  Back to cited text no. 92


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]

This article has been cited by
1 Advances in Diagnosis and Treatment for Leptomeningeal Disease in Melanoma
Yolanda Piña, Sirisha Yadugiri, Debra N. Yeboa, Sherise D. Ferguson, Peter A. Forsyth, Isabella C. Glitza Oliva
Current Oncology Reports. 2022;
[Pubmed] | [DOI]
2 Next-generation Tumor-homing Induced Neural Stem Cells as an Adjuvant to Radiation for the Treatment of Metastatic Lung Cancer
Alison R. Mercer-Smith, Andrew Buckley, Alain Valdivia, Wulin Jiang, Morrent Thang, Noah Bell, Rashmi J. Kumar, Hunter N. Bomba, Alex S. Woodell, Jie Luo, Scott R. Floyd, Shawn D. Hingtgen
Stem Cell Reviews and Reports. 2022;
[Pubmed] | [DOI]
3 The microRNA-520a-3p inhibits invasion and metastasis by targeting NF-kappaB signaling pathway in non-small cell lung cancer
Xiang Fang, Huiying Shi, Fang Sun
Clinical and Translational Oncology. 2022;
[Pubmed] | [DOI]
4 Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis
Musen Wang, Fuxin Zhu, Ningning Luo, Mengmeng Li, Yingxue Qi, Mingbo Wang
Medicine. 2021; 100(44): e27727
[Pubmed] | [DOI]
5 Next Generation Sequencing in the Management of Leptomeningeal Metastases of Non-Small Cell Lung Cancer: A Case Report and Literature Review
Shuo Li, Linping Ke, Xue Meng, Haiyan Zhou, Xiqin Zhang, Huaguo Wu, Jinming Yu, Hui Zhang
Recent Patents on Anti-Cancer Drug Discovery. 2021; 16(1): 108
[Pubmed] | [DOI]
6 Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer
Bin Wang, Hanfei Guo, Haiyang Xu, Hongquan Yu, Yong Chen, Gang Zhao
Cells. 2021; 10(10): 2620
[Pubmed] | [DOI]
7 Evaluation of osimertinib for advanced non-small cell lung cancer with leptomeningeal metastases: a cost-effectiveness and budget impact analysis
Shaohong Luo, Xiuhua Weng, Shen Lin, Xiaoting Huang, Lingning Huang, Wei Zhou, Xianzhong Guo, Xiongwei Xu
International Journal of Clinical Pharmacy. 2021;
[Pubmed] | [DOI]


Print this article  Email this article


  Site Map | What's new | Copyright and Disclaimer | Privacy Notice
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow