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CASE REPORT
Year : 2020  |  Volume : 16  |  Issue : 4  |  Page : 930-932

Successful treatment of nonsmall cell lung cancer patients with leptomeningeal metastases using whole brain radiotherapy and tyrosine kinase inhibitors


Department of Radiology, Nihon University School of Medicine, Tokyo, Japan

Date of Submission29-Nov-2016
Date of Decision01-Jul-2017
Date of Acceptance25-Feb-2018
Date of Web Publication27-Apr-2018

Correspondence Address:
Masakuni Sakaguchi
Department of Radiology, Nihon University School of Medicine, Tokyo
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1343_16

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 > Abstract 


The efficacy of treatments in patients with nonsmall cell lung cancer (NSCLC) with leptomeningeal metastases (LMs) remains unclear. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) play an important role in the treatment of patients with NSCLC. However, few studies have investigated the efficacy of combination therapy with TKIs and whole brain radiotherapy (WBRT) in patients with NSCLC/LM. We report here the case of a male patient in his 60s with adenocarcinoma who underwent lobectomy of the right upper lobe. The cancer was classified as pT1bN1M0 Stage IIA, and a mutational analysis revealed the presence of an EGFR mutation. However, 6 months after standard chemotherapy, LM had developed and WBRT was administered. Gefitinib (250 mg/day) was administered after WBRT. The patient remained free of significant recurrent disease for 57 months after WBRT was administered. Combination therapy with TKIs and WBRT is associated with relatively long survival times in patients with LM.

Keywords: Epidermal growth factor receptor, leptomeningeal metastases, nonsmall cell lung cancer, tyrosine kinase inhibitors, whole brain radiotherapy


How to cite this article:
Sakaguchi M, Maebayashi T, Aizawa T, Ishibashi N, Saito T. Successful treatment of nonsmall cell lung cancer patients with leptomeningeal metastases using whole brain radiotherapy and tyrosine kinase inhibitors. J Can Res Ther 2020;16:930-2

How to cite this URL:
Sakaguchi M, Maebayashi T, Aizawa T, Ishibashi N, Saito T. Successful treatment of nonsmall cell lung cancer patients with leptomeningeal metastases using whole brain radiotherapy and tyrosine kinase inhibitors. J Can Res Ther [serial online] 2020 [cited 2020 Sep 30];16:930-2. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/930/231448




 > Introduction Top


The efficacy of treatments such as whole brain radiotherapy (WBRT) and tyrosine kinase inhibitors (TKIs) and the differential effects of distinct therapeutic combinations in patients with nonsmall cell lung cancer (NSCLC) and leptomeningeal metastases (LMs) remain unclear.[1] Epidermal growth factor receptor TKIs (EGFR-TKIs) play an important role in the treatment of patients with NSCLC. Combination therapy with EGFR-TKIs and WBRT might improve long-term survival rates in patients with intracranial metastases. However, few studies have evaluated the efficacy of these treatments in patients with LM. Here, we provide case reports of patients with NSCLC treated with combination therapy with TKIs and WBRT who experienced relatively long overall survival times. In addition, we discuss the role of WBRT in patients with LM.


 > Case Report Top


A male patient in his 60s with adenocarcinoma underwent lobectomy of the right upper lobe. After the surgery, the cancer was classified as pT1bN1M0 Stage IIA, and a mutational analysis revealed the presence of an EGFR mutation in exon 19. The patient was treated with four cycles of a standard dose of carboplatin and paclitaxel as prescribed for cases of complete resection for lung cancer with lymph node metastasis. We did not use EGFR-TKIs with the consideration that resistance might occur and decided to hold it back for use in case of recurrence. However, 6 months later, magnetic resonance imaging (MRI) revealed small enhanced nodules on the brain surface without parenchymal edema, indicating that LM had developed [Figure 1]. A decision was made to treat the patient with WBRT using 10 MV photons with opposing four-port (field in field) irradiation delivered intermittently at 2.5 Gy doses until a total dose of 37.5 Gy had been administered. Gefitinib (250 mg/day) was administered after WBRT, and a subsequent MRI revealed that LM had disappeared.
Figure 1: Leptomeningeal metastases in lung cancer. T1-weighted images in axial planes revealed the presence of multiple nodular enhancements along the cerebral and cerebellar sulci without parenchymal edema. Therefore, all the multiple enhanced nodules observed were diagnosed as leptomeningeal metastases

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However, approximately 43 months after WBRT, carcinoembryonic antigen (CEA) levels increased. It appeared that the patient had acquired resistance to gefitinib, and the higher CEA levels were not accompanied by systemic disease progression. Based on these observations, the patient was treated with standard daily doses of erlotinib (150 mg/day). Although CEA levels remained high, the patient was still free of significant recurrent disease 57 months after WBRT was administered.


 > Discussion Top


LMs result from the dissemination of malignant cells to the subarachnoid space within the cerebrospinal fluid (CSF) compartment. CSF analysis and enhanced MRI are standard procedures for diagnosing LM. Straathof et al. concluded that the sensitivity of enhanced MRI was equivalent to that of CSF analysis and that the specificity of CSF examination was higher than that of enhanced MRI (100% and 77%, respectively).[2] In the present study, patients were diagnosed using MRI only, and standard clinical practices at other institutions might differ. A differential diagnosis of parenchymal metastases is more difficult to determine when leptomeningeal nodules are located along the deep sulci or Virchow–Robin spaces.[3] Because of the increased permeability of tumor vessels, perifocal vasogenic edema is typically more widespread compared with the size of the metastatic lesion. As nodule/s were present on the brain surface with widespread parenchymal edema, parenchymal metastases were considered.

WBRT is commonly administered to patients with LM; however, efficacy data associated with WBRT in patients with NSCLC/LM are limited.[1] Patients with a good performance score might be better candidates for aggressive treatments, such as high-dose EGFR-TKI, whereas clinicians are more likely to administer radiotherapy to patients in poor physical health. The median survival time of patients with cancer and LM ranges from 1.8 to 5.8 months.[4],[5] In contrast with the results of previous studies, the survival time of patients with LM described in this report was very long (57 months), and no disease recurrence was detected.

The efficacy of anticancer agents for intracranial metastases depends on their ability to penetrate the blood–brain barrier (BBB). Previous studies demonstrated that the small-molecule drug gefitinib (446.9 daltons) might be capable of penetrating BBB to a greater extent than other anticancer drugs, and it has been shown to be effective in the treatment of intracranial metastases.[6] Anticancer drugs can be effectively delivered to LM when the function of BBB is impaired. Subarachnoidal LM might compromise BBB and facilitate drug delivery to CSF.[7]

Previous studies have reported that brain radiation therapy can enhance the delivery of various anticancer drugs, including irinotecan and cisplatin, to CSF.[8] WBRT can disrupt BBB. Consistent with this observation, d'Avella et al.[8] reported that WBRT (40 Gy/20 f) disrupted BBB and significantly enhanced the transport of 14C-alpha-aminoisobutyric acid across BBB into the cerebral cortex 15 days after WBRT. Radiotherapy increases the permeability of BBB and enhances the ability of TKIs to penetrate the brain.[9]

In diseases of the neuraxis, such as LM, CSF dynamically circulates through the intracranial and intraspinal compartments. Therefore, it is reasonable to assume that administering WBRT to a single CSF compartment (e.g., the intracranial compartment) might not impact patient survival. However, metastases within the brain parenchyma can destroy brain structures or induce edema in the vicinity of the metastatic lesion. Compared with these patients, prognosis of patients with LM limited to the brain surface might be more favorable if the lesion size can be reduced using WBRT. Because of the constant circulation of CSF, administering WBRT to only one segment cannot effectively eliminate metastases in CSF. However, LMs are assumed to be associated with solid tumors by their adherence to the brain and spinal cord surface; therefore, it is reasonable to assume that administering WBRT only to intracranial lesions is significantly more effective in this context.

Thus, it is important to make a differential diagnosis of asymptomatic LM when small enhanced nodules on the brain surface are observed similar to that observed in our case. We predict that a low number of lesions adhering to the brain surface and the absence of disease circulating in CSF are indicators of a favorable prognosis. Combination therapy with TKIs and WBRT is associated with relatively long survival times in patients with asymptomatic LM.

Consent for publication

Written informed consent for the publication of this case report as well as any accompanying images was obtained from the patients.

Declaration of patient consent

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

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, et al. Leptomeningeal metastasis from non-small cell lung cancer: Survival and the impact of whole brain radiotherapy. J Thorac Oncol 2012;7:382-5.  Back to cited text no. 1
    
2.
Straathof CS, de Bruin HG, Dippel DW, Vecht CJ. The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 1999;246:810-4.  Back to cited text no. 2
    
3.
Maroldi R, Ambrosi C, Farina D. Metastatic disease of the brain: Extra-axial metastases (skull, dura, leptomeningeal) and tumour spread. Eur Radiol 2005;15:617-26.  Back to cited text no. 3
    
4.
Lee EK, Lee EJ, Kim MS, Park HJ, Park NH, Park S 2nd, et al. Intracranial metastases: Spectrum of MR imaging findings. Acta Radiol 2012;53:1173-85.  Back to cited text no. 4
    
5.
Herrlinger U, Förschler H, Küker W, Meyermann R, Bamberg M, Dichgans J, et al. Leptomeningeal metastasis: Survival and prognostic factors in 155 patients. J Neurol Sci 2004;223:167-78.  Back to cited text no. 5
    
6.
Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: Vascularisation and brain metastases. Lancet Oncol 2002;3:53-7.  Back to cited text no. 6
    
7.
Oechsle K, Lange-Brock V, Kruell A, Bokemeyer C, de Wit M. Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: A retrospective analysis. J Cancer Res Clin Oncol 2010;136:1729-35.  Back to cited text no. 7
    
8.
d'Avella D, Cicciarello R, Albiero F, Mesiti M, Gagliardi ME, Russi E, et al. Quantitative study of blood-brain barrier permeability changes after experimental whole-brain radiation. Neurosurgery 1992;30:30-4.  Back to cited text no. 8
    
9.
Zeng YD, Liao H, Qin T, Zhang L, Wei WD, Liang JZ, et al. Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. Oncotarget 2015;6:8366-76.  Back to cited text no. 9
    


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