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

Management of leptomeningeal metastases in non-small cell lung cancer

Shekar Patil1, Krishna Kumar Rathnum2,  
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

Correspondence Address:
Shekar Patil
Department of Medical Oncology, Sr. Consultant Medical Oncologist, Health Care Global Enterprises Limited, Bengaluru, Karnataka
India

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.



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


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 2019 Dec 12 ];56:1-9
Available from: http://www.indianjcancer.com/text.asp?2019/56/5/1/272016


Full Text



 Introduction



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



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}

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



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}

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



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}

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}{Figure 3}

Radiotherapy

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



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



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



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



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



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.

Acknowledgements

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.

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