Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era

doi:10.1016/j.ctrv.2016.12.006

Cancer Treatment Reviews

Volume 53, February 2017, Pages 128-137

https://doi.org/10.1016/j.ctrv.2016.12.006 Get rights and content

Highlights

•
Incidence of LM is 3.8% in the overall NSCLC population, and 9% in EGFR-mutant NSCLC patients.
•
Prognosis remains poor, even with the use of personalized treatments.
•
Systemic treatment and intrathecal chemotherapy is an appropriate strategy for treating LM.
•
In molecularly-selected patients the best strategy remains unknown.

Abstract

Leptomeningeal metastasis is a fatal manifestation seen in advanced cancer patients. Its incidence is increasing, reaching 3.8% in molecularly unselected non-small cell lung cancer patients and up to 5% and 9% in ALK-rearranged and EGFR-mutant lung cancer patients, respectively. The prognosis remains poor despite systemic treatment, intrathecal chemotherapy, radiation therapy and personalized treatments in molecularly selected patients. However, new therapies with improved cerebral-spinal fluid penetration have been developed for subgroups of molecular selected patients indicating they could be promising therapeutic options for managing leptomeningeal disease. Systemic chemotherapy, which may be combined with intrathecal chemotherapy, remains standard treatment for lung cancer patients with leptomeningeal disease and a good-risk profile. We summarize evidence reported in the literature for managing this complication in lung cancer patients. Based on this, we have selected potential therapeutic strategies that could be used in daily clinical practice.

Introduction

Leptomeningeal metastases (LM) are the multifocal seeding of the leptomeninges by malignant carcinomatous cells [1]. Malignant cells can reach the meninges by several different pathways: haematogenous spread via arterial or venous circulation, perivascular lymphatic spread, endoneural and perineural spread, direct spread from metastases located in the brain or bone in proximity to the subarachnoid or ventricular spaces, and spread from choroid plexus and subependymal metastases. Two types of leptomeningeal tumor spread can be distinguished: the first with free-floating non-adherent cancer cells (diffuse type); and the second characterized by contrast-enhanced leptomeningeal nodules (nodular type). LM are found in approximately 5% of patients with malignant tumours [1], and most arise from lung, breast carcinoma and melanoma [2]. In autopsy series, LM incidence may be 20% or more for many solid tumours [3], suggesting that they are clinically underdiagnosed and likely occur at a late stage of the disease. Clinical features vary according to the CNS region involved. Classically, three domains of neurological functions are used to characterize the clinical features: the cerebral hemisphere, cranial nerve, and spinal cord and exiting nerve roots [4].

LM are becoming increasingly common due to availability of improved treatments, leading ultimately to prolonged patient survival, and as neuroimaging methods improve. However, prognosis of LM remain poor, with patient performance status (PS) being the main prognostic factor [2]. Up to one-third of patients are treated with best supportive care alone [5]. Despite the lack of standard treatment, active treatment has been associated independently with longer overall survival (OS) [5] .

Among non-small cell lung cancer (NSCLC) patients, the incidence of LM is 3.8%, being more frequent in adenocarcinoma subtype. One-third of patients have concomitant brain metastases [6]. Median OS of NSCLC patients with LM ranges from 3.6 to 11 months [6], [7], mostly as a consequence of using modern systemic therapies, which decrease the risk of death (hazard ratio [HR], 0.24; P = 0.007) [8]. In the modern treatment era, LM is a devastating complication for oncologic patients, including molecularly selected patients, and the optimal therapeutic approach remains a challenge. This review explores the present cutting edge options for diagnosis, systemic treatment and immunotherapy for LM among NSCLC patients, examining the efficacy of personalized treatments in molecularly-selected lung cancer patients with LM. Based on our literature review we have selected some therapeutic recommendations, which could be used in daily clinical practice (Table 1).

Section snippets

Diagnostic

Diagnosis of LM is based on three assessments types: clinical, imaging and cerebral-spinal fluid (CSF) cytological examinations. Initial clinical manifestations can be subtle and may include cauda equine symptoms or signs, cranial nerve deficits, headaches and back pain, visual disturbances, diplopia, hearing loss and neurocognitive syndromes. In advanced stages, symptoms related to elevated intracranial pressure could occur [9], [10]. In current trials, it is based on the identification of

Treatment

Treatment objectives for LM are to improve neurologic symptoms, quality of life, and survival, while maintaining marginal toxicity. Standard treatment is yet to be established due to the lack of randomized clinical trials with definitive conclusions. This situation is explained by low incidence rates, the rapidly progressing nature of the disease, and the heterogeneous LM population. As such, most treatment recommendations are based on clinical experience or patient cohorts and experts’

Molecularly-selected lung cancer patients

Approximately 20–25% of advanced NSCLC tumours, especially the adenocarcinoma subtype, have an actionable oncogenic driver mutations [36] allowing personalized treatment. In Caucasian patients, the most frequent genetic alterations in advanced NSCLC are the KRAS mutation in ∼29% of patients, the EGFR mutations in ∼11%, ALK rearrangements in ∼5% [37], and MET mutations (exon 14) in 4% [38]. Other less frequent mutations include BRAF and PIK3CA mutations in ∼2%, each, HER2 mutations in 1% of

Immunotherapy

Four randomized phase III, two with nivolumab [110], [111], one trial with pembrolizumab [112] (both anti-PD-1 agents); and one trial with atezolizumab [113] reported that immunotherapy significantly improved survival compared to docetaxel in previously-treated patients advanced NSCLC patients, even among the subpopulation of patients with pre-treated brain metastases. The efficacy of immunotherapy among patients with symptomatic or untreated brain metastases is unknown. In a recent phase II

Conclusions

LM is an increasing complication among cancer patients. Incidence of LM is 3.8% in the overall NSCLC population, and can increase to 9% in EGFR-mutant NSCLC patients. Prognosis remains poor, even with the use of personalized treatments, principally due to low penetration into the CSF of currently used TKI and cytotoxic agents. However, third generation EGFR and ALK TKIs have been developed with better brain-barrier penetration, which may have an impact as therapeutic strategies among

Conflicts of interests

The authors declare don’t have any conflict of interest.

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Cited by (145)

A Retrospective Real-World Study of Prognostic Factors Associated With EGFR Mutated Lung Cancer With Leptomeningeal Metastasis
2024, Clinical Lung Cancer
To analyze the factors associated with EGFR-mutated lung cancer with leptomeningeal metastasis (LM) in the real world that affects the prognosis of patients.
The clinical data of 123 patients with advanced EGFR mutated lung cancer combined with LM treated at Henan Cancer Hospital and confirmed by histology between January 2016 and December 2020 were retrospectively collected, and all patients were followed up until September 2021. Analyze the median overall survival (mOS) time of patients with clinical characteristics and treatment factors to explore the factors influencing the prognosis of lung cancer patients with LM.
A total of 123 patients with EGFR-mutated lung cancer and LM were included in this study. Overall, patients with exon 19 deletion (19del) in the classical mutation of the EGFR gene had a prolonged mOS compared to patients with exon 21 L858R mutation (21L858R) (30.1 months vs. 26.0 months); patients with primary LM (mOS 21.2 months) had a significantly shorter mOS than those with secondary LM (mOS 28.3 months); mOS was also significantly shorter in patients with combined brain metastases (mOS of 25.4 months) than in patients without combined brain metastases (mOS of 33.4 months); Patients treated with tyrosine kinase inhibitors (TKI) combined with antiangiogenic therapy (bevacizumab) experienced delayed onset of LM (mOS1: 19.4 months vs. 13.9 months), and prolonged survival after LM compared with those treated with EGFR-TKI alone (mOS2: 14.5 months vs. 10.0 months); There is no survival benefit to the patients treated with EGFR-TKI combined with chemotherapy compared to the patients treated with EGFR-TKI alone.
Among NSCLC-LM patients with EGFR mutation, receiving EGFR-TKI combined with antiangiogenic therapy may result in a better survival benefit. The factors of primary LM, combined brain metastasis may be prognostic factors for poor OS.
Therapeutic role of EGFR - Tyrosine kinase inhibitors in non-small cell lung cancer with leptomeningeal metastasis
2024, Translational Oncology
Leptomeningeal metastasis (LM) is a significant complication that advances fast and has a poor prognosis for patients with advanced non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Current therapies for LM are inconsistent and ineffective, and established techniques such as radiation, chemotherapy, and surgery continue to fall short of potential outcomes. Nonetheless, EGFR tyrosine kinase inhibitors (TKIs) exhibit potent anti-tumor activity and hold considerable promise for NSCLC patients with EGFR mutations. Thus, assessing EGFR-TKIs effectiveness in treating these central nervous system (CNS) problems is crucial. This review integrates current literature on the intracranial efficacy of EGFR-TKIs to explore the varying impacts of approved EGFR-TKIs in LM patients and the therapeutic possibilities presented by other EGFR-TKIs in development. To delineate the optimal clinical treatment strategy, further exploration is needed regarding the optimal sequencing of EGFR-TKIs and the selection of alternative therapy options following initial treatment failure with EGFR-TKIs.
A phase II study of concurrent involved-field radiotherapy and intrathecal chemotherapy for leptomeningeal metastasis from solid tumors
2023, Radiotherapy and Oncology
The role of involved-field radiation therapy (IFRT) and intrathecal chemotherapy (IC) in leptomeningeal metastasis (LM) from solid tumors was gradually underestimated in the era of targeted therapy. This study was aimed to investigate the safety and effectiveness of concurrent IFRT and intrathecal methotrexate (MTX)/cytarabine (Ara-C) for LM, particularly for those who developed LM while receiving targeted therapy.
Enrolled patients were given induction IC first and then concurrent treatment, which consisted of IFRT (40 Gy total; 2 Gy/f) and IC (MTX 15 mg or Ara-C 50 mg, once per week). Primary endpoint was clinical response rate (RR). Secondary endpoints were safety and overall survival (OS).
Fifty-three patients received induction intrathecal MTX (n = 27) or Ara-C (n = 26). Forty-two patients completed concurrent therapy. Total RR was 34% (18/53). The improvement rate of neurological symptoms and KPS scores were 72% (38/53) and 66% (35/53) respectively. Adverse events (AEs) rate was 28% (15/53). Eight patients (15%, 8/53) showed grade 3–4 AEs, including myelosuppression (n = 4) and radiculitis (n = 5). Median OS was 6.5 months (95% CI, 5.3–7.7 months). Median survival for 18 patients who had clinical response was 7.9 months (95% CI, 4.4–11.4 months), and 0.8 months (95% CI, 0.08–1.5 months) for 6 patients who had LM progression. The median survival in 22 patients who received prior targeted therapy was 6.3 months (95% CI, 4.5–8.1 months).
Concurrent IFRT and intrathecal MTX or Ara-C was proved to be a feasible treatment option with an acceptable safety profile for LM from a common tumor entity.
Pretreated EGFR<sup>del19</sup>/BRAF<sup>V600E</sup> Lung Adenocarcinoma With Leptomeningeal Disease Achieving Long-Lasting Disease Control on Osimertinib, Dabrafenib, and Trametinib: A Case Report
2023, JTO Clinical and Research Reports
Oncogene-addicted NSCLC inevitably becomes resistant to targeted therapy by developing acquired resistance through on- or off-target mechanisms, potentially detectable by liquid biopsy. We present the first reported case of a patient with pretreated EGFR^del19/BRAF^V600E lung adenocarcinoma and symptomatic leptomeningeal metastasis obtaining durable clinical benefit on osimertinib, dabrafenib, and trametinib treatment.
Imaging of brain metastasis in non-small-cell lung cancer: indications, protocols, diagnosis, post-therapy imaging, and implications regarding management
2023, Clinical Radiology
Increased survival (due to the use of targeted therapies based on genomic profiling) has resulted in the increased incidence of brain metastasis during the course of disease, and thus, made it essential to have proper imaging guidelines in place for brain metastasis from non-small-cell lung cancer (NSCLC). Brain parenchymal metastases can have varied imaging appearances, and it is pertinent to be aware of the various molecular risk factors for brain metastasis from NSCLC along with their suggestive imaging appearances, so as to identify them early. Leptomeningeal metastasis requires additional imaging of the spine and an early cerebrospinal fluid (CSF) analysis. Differentiation of post-therapy change from recurrence on imaging has a bearing on the management, hence the need for its awareness. This article will provide in-depth literature review of the epidemiology, aetiopathogenesis, screening, detection, diagnosis, post-therapy imaging, and implications regarding the management of brain metastasis from NSCLC. In addition, we will also briefly highlight the role of artificial intelligence (AI) in brain metastasis screening.
Treatment pattern and outcomes of leptomeningeal carcinomatosis in India – a retrospective study
2023, The Lancet Regional Health - Southeast Asia
Leptomeningeal carcinomatosis (LMC), the metastatic spread of cancer to the leptomeninges, is a rare complication and has a dismal prognosis. Due to limited data available on LMC from India, we conducted a country-wise audit of LMC across 15 centres in India.
The current study conducted in 2020, was a retrospective, multicentric audit of adult patients (aged ≥18 years) with diagnosis of LMC and who received treatment during 2010–2020. Baseline characteristics, details related to previous treatments, cancer sites, LMC diagnosis, treatment pattern and overall survival (OS) were collected. Descriptive statistics were performed, and Kaplan Meier analysis was performed for the estimation of OS.
Among the patients diagnosed with LMC (n = 84), diagnosis was confirmed in 52 patients (61.9%) and ‘probable’ in 32 (38.1%) patients. The three most common cause of malignancy were non-small cell lung cancer (NSCLC), breast cancer and gastrointestinal cancer with 45 (53.6%), 22 (26.1%) and 9 (10.7%) patients respectively. Intrathecal therapy was offered in 33 patients (39.3%). The most common intrathecal agent was methotrexate in 23 patients (27.4%). The median OS was 90 days (95% CI 48–128). Among tested variables, intrathecal therapy administration (hazard ratio [HR] = 0.36, 95% CI 0.19–0.68) and primary in lung (HR = 0.43, 95% CI 0.23–0.83) had a favourable impact on OS.
Prognosis with leptomeningeal carcinomatosis is poor with a significant burden of morbidity and mortality in India. This data aims to highlight the current outcomes and facilitate further research on LMC.
None.

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¹: Gustave Roussy Cancer Campus, 114 Rue Edouard Vaillant, 94805 Villejuif, France. Fax: +33 (0)1 42 11 52 19.

²: Neuro-oncology, Neurosurgery Department, Salengro Hospital, Rue Emile Laine, 59037 Lille cedex, France. Fax: +33 (0)3 20 44 68 08.

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Anti-Tumour TreatmentLeptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era

Highlights

Abstract

Introduction

Section snippets

Diagnostic

Treatment

Molecularly-selected lung cancer patients

Immunotherapy

Conclusions

Conflicts of interests

Ann Oncol

Lancet Oncol

Eur J Cancer

J Thorac Oncol

Lung Cancer

Clin Lung Cancer

Cancer Treat Rev

J Thorac Oncol

Respir Investig

Eur J Cancer

J Thorac Oncol

Lung Cancer

Ann Oncol

Lancet

J Thorac Oncol

Lung Cancer

Clin Lung Cancer

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

Lancet Oncol

J Thorac Oncol

J Thorac Oncol

Lung Cancer

Lancet Oncol

Lancet Oncol

J Thorac Oncol

Cancer Cell

Ann Oncol

Leptomeningeal metastases in the MRI era

Neurology

Carcinomatous meningitis: Leptomeningeal metastases in solid tumors

Surg Neurol Int

Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials

Neuro-Oncology

Leptomeningeal metastasis

Curr Opin Oncol

Intracranial leptomeningeal metastases: comparison of depiction at FLAIR and contrast-enhanced MR imaging

Radiology

Novel method for the detection and quantification of malignant cells in the CSF of patients with leptomeningeal metastasis of lung cancer

Oncol Lett

Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors

Neurology

A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis

J Clin Oncol

Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group

J Clin Oncol

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis

J Clin Oncol

A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors

Clin Cancer Res

Route of intracerebrospinal fluid chemotherapy administration and efficacy of therapy in neoplastic meningitis

Cancer

Intrathecal chemotherapy as a treatment for leptomeningeal metastasis of non-small cell lung cancer: a pooled analysis

Oncol Lett

Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials

PLoS ONE

Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates

Cancer Chemother Pharmacol

Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value

Br J Cancer

Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma

J Neurooncol

Bevacizumab prevents brain metastases formation in lung adenocarcinoma

Mol Cancer Ther

A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients with leptomeningeal carcinomatosis

BMC Cancer

Anti-Tumour Treatment
Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era