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Table of Contents
LETTER TO EDITOR
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 619-621

Leptomeningeal metastasis in lung cancer: Not always a gloomy picture


Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India

Date of Submission11-Apr-2020
Date of Decision01-May-2020
Date of Acceptance02-May-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Joydeep Ghosh
Department of Medical Oncology, Tata Medical Centre, 14, Major Arterial Road (East.West), Action Area 1, DD Block (Newtown), Kolkata - 700 156, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_151_20

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How to cite this article:
Basu A, Chatterjee M, Ghosh J, Ganguly S, Biswas B, Dabkara D. Leptomeningeal metastasis in lung cancer: Not always a gloomy picture. Cancer Res Stat Treat 2020;3:619-21

How to cite this URL:
Basu A, Chatterjee M, Ghosh J, Ganguly S, Biswas B, Dabkara D. Leptomeningeal metastasis in lung cancer: Not always a gloomy picture. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 25];3:619-21. Available from: https://www.crstonline.com/text.asp?2020/3/3/619/295532



We wish to report three cases of epidermal growth factor receptor (EGFR)-positive lung cancer with leptomeningeal metastasis (LM) that presented at our hospital. The patients had long-term survival following the diagnosis of central nervous system (CNS) involvement, which is contrary to the historically reported poor outcomes of such patients. LM has an overall incidence of 5%,[1] with lung cancer contributing to 10%–26% of the cases.[2] After the diagnosis is made, an average survival of 1–2 months is commonly observed.[3] Among patients with non-small cell lung carcinoma (NSCLC) harboring EGFR mutations, LM is seen in almost 9% of the cases, with 3 months being the average survival.[4],[5],[6],[7],[8]


  Case 1 Top


A 57-year-old male, diabetic, smoker, with performance status (PS) of 1 presented with cough and dyspnea. The chest X-ray was suggestive of a lung mass. A contrast-enhanced computed tomography scan of the thorax and whole abdomen (CECT T/A) confirmed a lung mass with bulky ipsilateral hilar lymph nodes. The biopsy was suggestive of adenocarcinoma. The baseline magnetic resonance imaging (MRI) of the brain was normal. Deemed bulky disease, he was given four cycles of neoadjuvant chemotherapy with gemcitabine + carboplatin; the last dose was administered in June 2008. He tolerated the chemotherapy well. Response evaluation with CECT T/A revealed partial response. His tumor became resectable, and thus, right pneumonectomy was performed in September 2008. Post operative histopathological examination revealed a residual tumor of 3.5cm size, all margins free, ypT2N0. He was put on observation. After a disease-free interval of 4 years, in March 2013, he presented with headache and vomiting. At presentation, his PS was 3, and he had no definite neurologic deficit clinically, with the exception of mild neck rigidity. MRI of the brain showed leptomeningeal enhancement, with multiple nodules in both the lungs and right-sided pleural effusion. A repeat biopsy from the lung nodules confirmed adenocarcinoma, which was positive for EGFR mutation (exon 19 deletion). Cerebrospinal fluid (CSF) analysis confirmed the presence of malignant cells. He was started on intrathecal administration of methotrexate 12 mg twice a week, along with oral erlotinib 150 mg once daily. After 4 weeks of therapy, his CSF cytology became negative for malignant cells, so the frequency of intrathecal methotrexate was reduced to once every 15 days. His last follow-up was in November 2013. CSF studies did not show any malignant cells, MRI of the brain was normal, and CECT T/A showed partial response. He was tolerating erlotinib well and was planned for the continuation of intrathecal therapy every 15 days. After his last OPD visit, he was lost to follow-up. Thus, the patient's disease was under control for at least 8 months.


  Case 2 Top


A 51-year-old female, nonsmoker, with no comorbidities, was diagnosed with carcinoma lung in September 2010. She initially presented with a 3-month history of cough with occasional, minimal hemoptysis; her PS was 1. A positron emission tomography (PET)-CT scan revealed a mass lesion in the left upper lobe with N2 lymph nodes. The biopsy revealed adenocarcinoma. She received three cycles of neoadjuvant chemotherapy with pemetrexed and cisplatin because of the bulky nodal disease. Restaging with a PET-CT scan done after three cycles of chemotherapy showed nearly complete morphologic and metabolic response to chemotherapy. She underwent left upper lobectomy in December 2010. Histopathology revealed residual foci of adenocarcinoma, 0.1 cm in size (ypT1N0M0). She was on regular follow-up since then. She presented with headache and occasional vomiting (PS 2) in August 2012, approximately 20 months after surgery. Clinical examination, including neurological examination, was normal. MRI of the brain revealed extensive leptomeningeal enhancement in the right parietal and occipital lobes, without any parenchymal disease. CECT T/A did not show any visceral metastasis. The CSF cytology was positive for metastatic carcinoma. Her tumor sample was found to harbor an exon 19 deletion. An Ommaya reservoir was placed followed by weekly intrathecal methotrexate injections. She was also started on oral gefitinib 250 mg once daily. After 3 months of weekly intrathecal methotrexate administration, her symptoms improved remarkably and the repeat MRI showed early features of leukoencephalopathy, with clearance of CSF. Hence, further doses of intrathecal methotrexate were withheld, and she was continued on gefitinib alone. She was asymptomatic for 6 months after relapse. There was subsequent disease progression thereafter, and she died in March 2013, 7 months after the diagnosis of LM.


  Case 3 Top


A 63-year-old male with PS 1 presented in September 2010 with shortness of breath along with episodic headache, dizziness, and a few seizure episodes. Evaluation with CECT T/A revealed a left lower lobe mass along with other similar small, rounded densities in the posterior basal segment of the left lower lobe, inferior to the larger lesion. MRI of the brain done at baseline revealed multiple parenchymal metastases along with adjacent meningeal enhancement. A transbronchial biopsy from the lung mass was suggestive of a bronchoalveolar carcinoma. The tumor cells expressed the thyroid transcription factor-1. His tumor was also tested for the presence of EGFR mutations and was found to be positive for exon 19 deletion. There was deterioration of his ECOG PS to 3 during the time he was being evaluated. He was started on erlotinib 150 mg once daily in July 2011, along with intrathecal therapy (methotrexate 12 mg and hydrocortisone 25 mg) twice a week for 4 weeks and then once a week for another 4 weeks. He had significant improvement in his symptoms, especially the seizures and headache, with normalization of CSF cytology by 4 weeks. A CT scan done 2 months after starting erlotinib showed partial response in the lung mass and nodes. His disease remained controlled on erlotinib for 18 months. Subsequently, his disease progressed, and he was not suitable for any further therapy. He died 2 months later.

As per our departmental policy, none of the patients received oral leucovorin along with intrathecal methotrexate. None of the patients developed myelosuppression or renal toxicity from intrathecal methotrexate. There were no treatment gaps between the intrathecal doses for the management of toxicity.


  Discussion Top


The outcome of patients with LM has historically been poor with standard intrathecal chemotherapy. Craniospinal irradiation is poorly tolerated because of the increased toxicities.[9],[10] Intrathecal therapy is considered most suitable for the management of LM in adults. The drugs used are methotrexate, depot cytarabine, and thiotepa (less common). Various new agents have been tried, such as mafosfamide, nimustine, dacarbazine, and gemcitabine, but none have improved the overall survival (OS) significantly.

Recently, some promising results have been obtained with the use of oral tyrosine kinase inhibitors in the setting of lung cancer, which have shown survival up to 19 months in a Korean series.[11],[12] Kuiper et al. reported excelled survival of more than 6 months in mutation-positive patients with NSCLC.[13] Another report evaluated patients being treated with afatinib, which showed an impressive 60% CNS control rate.[14] In another Phase 1 study of osimertinib in LM NSCLC, the median OS was 11 months.[15] Even for patients with a T790M mutation, the median OS was reported to be 18.8 months with osimertinib.[16]

Our cases have shown similar long-term disease control in EGFR-positive tumors with LM. The three cases in our study had a mean progression-free survival of 13 months and an OS of 14 months, which is consistent with published data from the Western world on the survival of such patients.


  Conclusion Top


Just like visceral disease, the outcome of LM in EGFR-positive metastatic NSCLC has significantly improved over time. Gone are the days when the median survival was 4–6 months. With effective therapies leading to penetration of the blood–brain barrier and effective systemic control, more patients are having durable and deeper leptomeningeal response. Our case series depicts the same in the Indian scenario.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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2.
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Bokstein F, Lossos A, Siegal T. Leptomeningeal metastases from solid tumors: Acomparison of two prospective series treated with and without intra-cerebrospinalfluid chemotherapy. Cancer 1998;82:1756-63.  Back to cited text no. 3
    
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Chooback N, Lefresne S, Lau SC, Ho C. CNS metastases in epidermal growth factor receptor mutation–positive non–small-cell lung cancer: Impact on health resource utilization. J Oncol Practice 2018;14:e612-20.  Back to cited text no. 5
    
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Chamberlain MC. Leptomeningeal metastases: A review of evaluation and treatment. J Neurooncol 1998;37:271-84.  Back to cited text no. 9
    
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Chamberlain MC, Kormanik P. Carcinomatous meningitis secondary to non-small cell lung cancer: Combined modality therapy. Arch Neurol 1998;55:506-12.  Back to cited text no. 10
    
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Hata A, Kaji R, Fujita S, Katakami N. High-dose erlotinib for refractory brain metastases in a patient with relapsed non-small cell lung cancer. J Thorac Oncol 2011;6:653-4.  Back to cited text no. 11
    
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Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53.  Back to cited text no. 12
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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. 13
    
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Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schütz M, 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;10:156-63.  Back to cited text no. 14
    
15.
Yang JC, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, et al. Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: The BLOOM study. J Clin Oncol 2020;38:538-47.  Back to cited text no. 15
    
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Ahn MJ, Chiu CH, Cheng Y, Han JY, Goldberg SB, Greystoke A, et al. Osimertinib for patients with leptomeningeal metastases associated with EGFR T790M-positive advanced NSCLC: The AURA leptomeningeal metastases analysis. J Thorac Oncol 2020;15:637-48  Back to cited text no. 16
    




 

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