Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis

doi:10.1016/j.lungcan.2015.05.023

Lung Cancer

Volume 89, Issue 3, September 2015, Pages 255-261

https://doi.org/10.1016/j.lungcan.2015.05.023 Get rights and content

Highlights

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This is the largest study reporting on leptomeningeal metastasis (LM) in EGFR-mutated NSCLC-patients.
•
Median survival of EGFR-mutated NSCLC-patients with LM was 3.1 months.
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Survival after LM-diagnosis in EGFR-mutated NSCLC-patients with LM may not be superior compared to existing data on that in EGFR-wild type NSCLC patients.
•
Six- and 12-month survival rates were 43.8% and 18.8%, respectively.

Abstract

Objectives

Development of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC)-patients is associated with a poor prognosis. It has been suggested that LM-patients with epidermal growth factor receptor mutated (EGFR+) NSCLC have a superior prognosis compared to EGFR-wild type NSCLC. Studies in EGFR+ NSCLC-patients with LM are scarce. We retrospectively evaluated a multi-institutional cohort of EGFR+ NSCLC-patients for LM to assess clinical outcome in relation to patient characteristics and treatment modalities.

Material and methods

Medical records of advanced-stage EGFR+ NSCLC-patients (diagnosed between August 2000 and June 2014) from 11 Dutch hospitals were evaluated for LM as diagnosed by MRI and/or cytopathological liquor analysis. Data on patient characteristics, treatment and outcome were collected.

Results

Thirty-two of 356 (9.0%) advanced-stage EGFR+ NSCLC-patients (median follow-up 21.0 months), were diagnosed with LM between 2006 and 2014. LM was diagnosed by MRI (59.4%), liquor analysis (9.4%) or by both MRI and liquor analysis (31.3%). Median survival after LM-diagnosis was 3.1 months (95% CI: 0.0–7.3). Six- and 12-month survival rates were 43.8% and 18.8%, respectively. Patients with performance status (PS) 0–1 at time of diagnosis of LM had a significantly higher chance to be alive after 6 months and had a significantly longer survival after diagnosis of LM compared to patients with PS ≥ 2. Age, treatment with high-dose EGFR-TKI, radiotherapy and whether LM was the only site of progressive disease did not influence survival after LM-diagnosis.

Conclusion

Although median survival after LM-diagnosis in EGFR-mutated NSCLC-patients was poor, a substantial part of the patients had a prolonged survival of more than 6 months. PS of 0–1 at time of diagnosis of LM was associated with prolonged survival. No other patient- or treatment-related characteristics were identified. Further research is warranted to identify treatment strategies that improve survival in EGFR+ NSCLC-patients with LM.

Introduction

Neoplastic meningitis, or leptomeningeal metastasis (LM), is the result of spread of malignant cells to the subarachnoid space within the compartment of the cerebrospinal fluid (CSF) [1]. It occurs in many types of cancer, including non-small cell lung cancer (NSCLC). LM is associated with poor prognosis and rapid deterioration of performance status [1]. Radiotherapy, surgery and intrathecal chemotherapy all have been described as treatment options for NSCLC-patients with LM. However, the efficacy of these treatments for LM-patients is unclear and there is no consensus which (combination) provides the optimal therapeutic strategy [2], [3]. Treatment should be discussed in a multidisciplinary team involved in the treatment of this complication of cancer.

It has been reported that central nervous system (CNS) metastases (including LM) are more often diagnosed in epidermal growth factor receptor (EGFR)-mutated (EGFR+) NSCLC-patients [4]. This may be due to the prolonged survival of EGFR+ NSCLC-patients and/or the poor penetration of first generation tyrosine kinase inhibitors (TKIs) across the blood–brain barrier (BBB) into the CSF [5]. Several studies have reported on LM in NSCLC-patients. However, in most studies, EGFR-mutation status was not provided or only in a small subset (N = 6–23) of patients [2], [3], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15].

Small series suggest that EGFR-TKI naïve EGFR+ patients who received EGFR-TKI treatment after diagnosis of LM may experience a better survival than patients who do not receive EGFR-TKI treatment after diagnosis of LM [3], [6], [15]. However, since LM is usually a late event, most EGFR+ NSCLC-patients have already been treated with EGFR-TKIs prior to diagnosis of LM. In addition to the previous mentioned treatment modalities for LM, high-dose EGFR-TKIs and switch of EGFR-TKI-treatment have been described as treatment option for EGFR+ NSCLC-patients with LM [7], [14], [16], [17].

Altogether, data on LM in EGFR+ NSCLC are scarce. We therefore retrospectively evaluated a multi-institutional cohort of EGFR+ NSCLC-patients for diagnosis of LM. The purpose of this study was to describe diagnosis of LM and treatment modalities and survival after diagnosis of LM, in EGFR+ NSCLC-patients.

Section snippets

Materials and methods

Medical records of EGFR+ NSCLC-patients from 11 Dutch hospitals (4 academic and 7 non-academic) who were diagnosed with advanced-stage (stage IIIB or IV) NSCLC between August 2000 and June 2014 were retrospectively reviewed for diagnosis of LM. A diagnosis of LM was defined as focal or diffuse enhancement of leptomeninges, nerve roots or ependymal surface diagnosed by magnetic resonance imaging (MRI) and/or a cytopathological diagnosis of malignant cells in the CSF. Detection of atypical and/or

Leptomeningeal metastases in EGFR+ NSCLC-patients

Medical records of 356 advanced-stage NSCLC-patients with an EGFR-mutation were screened for diagnosis of LM. Median follow-up of these patients was 21.0 months (range 0.2–144.9). Two patients were lost to follow-up after 24.5 and 44.5 months. LM was diagnosed in 9.0% of the patients (32 patients). Patient and tumour characteristics are provided in Table 1.

In 19 patients (59.4%) LM was diagnosed by MRI, in three patients (9.4%) by CSF cytology and in 10 patients (31.3%) by both MRI and CSF

Discussion

In this cohort of EGFR+ NSCLC-patients LM was detected in 9.0%, comparable to the previously reported rate of LM in EGFR-wild type NSCLC-patients [19]. To the best of our knowledge, this report describes the largest group of EGFR+ NSCLC-patients with LM. The median survival after diagnosis of LM was a disappointing 3.1 months, which is similar to unselected NSCLC-patients with LM [2], [3]. Interestingly, a considerable part of the patients had a longer than expected survival with 43.8% and

Conflicts of interest

A.M.C. Dingemans received consultancy fees from Roche, Eli Lilly, Boehringer Ingelheim, Novartis and Pfizer. H.J.M. Groen received fees for participation in review activities from Roche and consultancy fees from Roche, MSD, GSK, Eli Lilly and Pfizer. F.H. Krouwels received consultancy fees from Boehringer and payment for lectures from GSK, Boehringer and Novartis. A.J. van der Wekken received money through his institution for board membership from Pfizer, Boehringer Ingelheim and Eli Lilly and

Acknowledgements

The authors would like to thank Lian Roebers (Rijnstate hospital) for her assistance in data collection.

There was no funding source and no writing assistance.

References (37)

B. Gleissner et al.
Neoplastic meningitis
Lancet Neurol
(2006)
H.S. Gwak et al.
Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer
J Thorac Oncol
(2013)
P.G. Morris et al.
Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy
J Thorac Oncol
(2012)
E. Lee et al.
Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer
J Thorac Oncol
(2013)
S.J. Lee et al.
Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors
J Thorac Oncol
(2013)
J.H. Park et al.
Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era
Lung Cancer
(2012)
J.W. Riess et al.
Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era
Clin Lung Cancer
(2014)
M. Shingyoji et al.
Detection of epithelial growth factor receptor mutations in cerebrospinal fluid from patients with lung adenocarcinoma suspected of neoplastic meningitis
J Thorac Oncol
(2011)
H.G. Yi et al.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI
Lung Cancer
(2009)
S. Umemura et al.
Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group
Lung Cancer
(2012)

T. Katayama et al.

Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib

J Thorac Oncol

(2009)

E.A. Eisenhauer et al.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)

Eur J Cancer

(2009)

J.L. Kuiper et al.

High-dose, weekly erlotinib is not an effective treatment in EGFR-mutated non-small cell lung cancer-patients with acquired extracranial progressive disease on standard dose erlotinib

Eur J Cancer

(2014)

J.L. Kuiper et al.

High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases-One with a remarkable thoracic response as well

Lung Cancer

(2013)

P. Hoffknecht et al.

Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small cell lung cancer patients with brain metastases or leptomeningeal disease

J Thorac Oncol

(2015)

L. Gaspar et al.

Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials

Int J Radiat Oncol Biol Phys

(1997)

A.M. Omuro et al.

High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib

Cancer

(2005)

Y. Togashi et al.

Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer

Cancer Chemother Pharmacol

(2012)

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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.
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Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis

Highlights

Abstract

Objectives

Material and methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Leptomeningeal metastases in EGFR+ NSCLC-patients

Discussion

Conflicts of interest

Acknowledgements

Lancet Neurol

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

Lung Cancer

Clin Lung Cancer

J Thorac Oncol

Lung Cancer

Lung Cancer

J Thorac Oncol

Eur J Cancer

Eur J Cancer

Lung Cancer

J Thorac Oncol

Int J Radiat Oncol Biol Phys

High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib

Cancer

Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer

Cancer Chemother Pharmacol