VOLUME

27

NUMBER

22

AUGUST

2009

JOURNAL OF CLINICAL ONCOLOGY

D I A G N O S I S

I N

O N C O L O G Y

Carcinomatous Meningitis in NonSmall-Cell Lung Cancer: Response to High-Dose Erlotinib

A 56-year-old woman who never smoked presented with cough and progressive dyspnea. Chest x-ray and computed tomography (CT) scan revealed right pleural effusion and innumerable small pulmonary nodules (Fig 1A). CT scan of the abdomen, bone scan, and magnetic resonance imaging (MRI) of the brain were negative for distant disease. Poorly differentiated adenocarcinoma was established by transbronchial biopsy. Given her never smoker status and stage IV disease, she entered into a clinical trial and received erlotinib (150 mg daily) alone. She had a dramatic response of her pulmonary disease (Fig 1B) with complete resolution of her cough and dyspnea. She remained on erlotinib for 7 months, at which point her cough returned, and her chest CT scan revealed an increase in the size and number of pulmonary nodules. Erlotinib was discontinued, and she received treatment with carboplatin, paclitaxel, and bevacizumab for six cycles followed by an additional two cycles of bevacizumab alone with minimal response radiographically, but her cough resolved. The patient then developed diplopia, and left cranial nerve IV palsy was demonstrated. Subsequent brain MRI revealed diffuse leptomeningeal disease most prominent near the cerebellum. She received a course of whole-brain radiotherapy to a dose of 30 Gy. As her systemic disease was still in a minor response without evidence of disease progression, bevacizumab was continued every 3 weeks. Four months later, her chest CT and brain MRI (Fig 2A) were stable; however, her diplopia worsened, and she developed mild ataxia. A lumbar puncture (LP) was performed revealing ndings consistent with carcinomatous meningitis (Table 1, LP 1). Given the stability of her systemic disease, bevacizumab was continued. Erlotinib was added at a dose of 600 mg orally every 4 days based on an ongoing phase I trial at the Lineberger Comprehensive Cancer Center (Chapel Hill, NC).1 Her CNS symptoms improved along with her performance status. Subsequent LPs done 3 and 6 months later revealed improvements in her biochemical parameters as well as clearing of her malignant cells (Table 1; LP 2, 3). A repeat brain MRI at 6 months after erlotinib initiation displayed resolution of the leptomeningeal ndings, which were most notable

Table 1. Summary of Cerebrospinal Fluid Findings Lumbar Puncture 1 2 3 TNC 9 3 1 Protein (mg/dL) 127 75 67 Glucose (mg/dL) 20 69 61 Cytology Positive Negative Negative CSF Lactate 8.3 ND 2.1

Abbreviations: TNC, total nucleated cells; ND, not detected.

Fig 1.
Journal of Clinical Oncology, Vol 27, No 22 (August 1), 2009: pp e31-e32

on the coronal T1weighted images (Fig 2B). The patient remained on erlotinib at 600 mg orally every 4 days for a total duration of 10 months with minimal skin and gastrointestinal toxicity. She continued to have minimal diplopia and ataxia with relatively good performance status. During this time, her cough worsened coincident with disease progression on her chest CT despite changes in treatment with addition of pemetrexed and then gemcitabine. She was placed on hospice and passed away shortly thereafter, 28 months from initial diagnosis of stage IV disease. The treatment of carcinomatous meningitis in advanced non small-cell lung cancer (NSCLC) is less than satisfying; without treatment, median survival ranges from 4 to 6 weeks.2 Palliation of symptoms represents an important but challenging treatment goal in this condition.3 Recent reports describe responses in selected patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).4-8 This case exemplies the unique biology of advanced NSCLC in selected patients. Scant data exists on the pharmacokinetics of EGFR TKIs with regard to penetration into the CSF; however, this patient clinically responded to pulse dose erlotinib. She was not known to have an EGFR mutation, but her baseline demographic (nonsmoking female with adenocarcinoma) and clinical course suggest that the presence of a mutation was likely. Previously reported in the literature is a case in which the presence of an EGFR sensitivity mutation (exon 19) persisted in the disease which relapsed in the CNS, while the systemic disease was characterized by a resistance mutation (T790M).5 Increasing the dose of orally administered getinib increased the CSF concentration,5 which was the rationale for the strategy employed in our patient. The difference between the existing reports in the literature and this case is that our patient had a prior exposure to erlotinib and exhibited progression of systemic disease while on rst-line erlotinib. She then received bevacizumabbased therapy and progressed within the meninges while her systemic disease was stable. The notable features are the clinical improvement as well as improvement in CSF parameters as a result of high intermittent doses of erlotinib, along with a radiographic response. This response suggests that the CSF disease remained sensitive to erlotinib, and the higher doses led to higher CSF penetration. Although this remains speculative as we did not measure levels of erlotinib in the CSF, preliminary data from the ongoing phase I trial at our institution has shown this to be true,1 which mirrors the experience of others with getinib.5 The most compelling facet of this case is the prospect that
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Dhruva and Socinski

Fig 2.

higher doses of EGFR TKIs such as erlotinib might offer prolonged survival and palliation in a notably dismal condition desperate for improved therapy.

REFERENCES
1. Buie LW, Lindley C, Shih T, et al: Plasma pharmacokinetics and cerebrospinal uid concentrations of erlotinib in high-grade gliomas: A novel, phase I, dose escalation study. J Clin Oncol 25:88s, 2007 (suppl; abstr 2054) 2. Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis. Cancer Treat Rev 25:103-119, 1999 3. Pentheroudakis G, Pavlidis N: Management of leptomeningeal malignancy. Expert Opin Pharmacother 6:1115-1125, 2005 4. Sakai M, Ishikawa S, Ito H, et al: Carcinomatous meningitis from nonsmallcell lung cancer responding to getinib. Int J Clin Oncol 11:243-245, 2006 5. Jackman DM, Holmes AJ, Lindeman N, et al: Response and resistance in a nonsmall-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose getinib. J Clin Oncol 24:4517-4520, 2006 6. Choong NW, Dietrich S, Seiwert TY, et al: Getinib response of erlotinibrefractory lung cancer involving meninges: Role of EGFR mutation. Nat Clin Pract Oncol 3:50-57, 2006 7. Fukuhara T, Saijo Y, Sakakibara T, et al: Successful treatment of carcinomatous meningitis with getinib in a patient with lung adenocarcinoma harboring a mutated EGF receptor gene. Tohoku J Exp Med 214:359-363, 2008 8. Wagner M, Besse B, Balleyguier C, et al: Leptomeningeal and medullary response to second-line erlotinib in lung adenocarcinoma. J Thorac Oncol 3:677-679, 2008

Nirav Dhruva and Mark A. Socinski

Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Mark A. Socinski, Eli Lilly, Genentech Research Funding: Mark A. Socinski, Eli Lilly, Genentech, Pzer, Abraxis, Celgene Expert Testimony: None Other Remuneration: None

DOI: 10.1200/JCO.2008.21.0963; published online ahead of print at www.jco.org on June 1, 2009

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