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Year : 2016  |  Volume : 12  |  Issue : 5  |  Page : 126-129

Prolonged overall survival of patients with leptomeningeal carcinomatosis from nonsmall cell lung cancer

Department of Oncology, Chinese PLA General Hospital, Beijing, China

Date of Web Publication7-Oct-2016

Correspondence Address:
Shunchang Jiao
Department of Oncology, Chinese PLA General Hospital, Beijing 100853
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.191638

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 > Abstract 

Leptomeningeal metastasis (LM) carries a devastating prognosis. Treatment selection is limited for patients with LM. We introduced to use nimotuzumab (also known as h-R3) for treating LM of nonsmall cell lung cancer. Here, we report two patients in our treatment who had prolonged overall survival over 1 year each. The pressure of cerebrospinal fluid of the patients decreased remarkably after intrathecal therapy. Symptoms of the patients had been improved quickly after one or two times of intrathecal therapy. Nimotuzumab was well tolerated used in intrathecal therapy.

Keywords: Intrathecal therapy, leptomeningeal metastasis, nimotuzumab, nonsmall cell lung cancer

How to cite this article:
Ju Y, Sun S, Wang J, Jiao S. Prolonged overall survival of patients with leptomeningeal carcinomatosis from nonsmall cell lung cancer. J Can Res Ther 2016;12, Suppl S1:126-9

How to cite this URL:
Ju Y, Sun S, Wang J, Jiao S. Prolonged overall survival of patients with leptomeningeal carcinomatosis from nonsmall cell lung cancer. J Can Res Ther [serial online] 2016 [cited 2022 Aug 17];12, Suppl S1:126-9. Available from: https://www.cancerjournal.net/text.asp?2016/12/5/126/191638

 > Introduction Top

Leptomeningeal carcinomatosis (LMC), also termed leptomeningeal metastasis (LM), neoplastic meningitis, is the result of seeding of the leptomeninges and cerebrospinal fluid (CSF) by malignant cells. The brain or the leptomeninges is a common site for metastasis of nonsmall cell lung cancer (NSCLC). Patients with central nervous system metastasis in general suffer from deterioration of performance status and therefore do not have a long survival time.

Intrathecal chemotherapy combined with radiotherapy is a major treatment of choice for LMC in clinic. Methotrexate (MTX) is the most frequently used drug for intrathecal administration although it has limited curative success and serious toxicities.[1] Although there were so many efforts that have been made to improve the response rate and survival by combining MTX with other agents, such as Ara-C and thiotepa, the efficacy of intrathecal chemotherapy with MTX for LM of NSCLC is still unsatisfactory.[2]

Several reports have described the use of these drugs in sequence or in concurrence with MTX and most of the reports failed to find any superiority of combination therapy versus single MTX therapy.[3],[4],[5],[6] To treat LMC more efficiency, we introduced a new strategy which involved monoclonal antibody (mAb) in our treatment. We used nimotuzumab (also known as h-R3) combined with MTX for treating LMC from NSCLC. Here, we report two patients in our treatment who had prolonged overall survival (OS) over 1 year each, with minimal adverse effects.

 > Case Reports Top

Case 1

A 45-year-old female presented a headache which became more severe gradually in September 2006. In January 2007, the patient was diagnosed with NSCLC (adenocarcinoma) with brain and bone metastasis in our hospital. The patient showed frequent and severe headache, and even the omens of cerebral hernia raised. The CSF pressure reached 400 mmH2O. The level of tumor marker (carcinoembryonic antigen [CEA]) in CSF was abnormal with positive CSF cytology. We treated the patient with gefitinib (250 mg/day) therapy, but the symptom of headache did not improve. Two days later, the patient received intrathecal therapy (h-R3, 25 mg). After one intrathecal therapy, the clinical symptoms improved obviously. The frequency of the paroxysmal headaches was decreased from every 2 h to every 4 h after the treatment. Hence, continued intrathecal therapy (h-R3, 25 mg) was given at the 3rd day. One week later, the patient had slight headache occasionally. Then, the patient received intrathecal therapy (h-R3 50 mg) weekly. Two weeks later, the CSF pressure dropped to 120 mmH2O [Figure 1]. Then, the patient received the whole-brain radiotherapy. As showed by the result of brain magnetic resonance imaging [Figure 2], the LMC was improved after 1 month treatment. Then, the patient received intrathecal therapy (h-R3, 50 mg) combined with MTX weekly for three times. Three months later, the patient received intrathecal therapy for two times. The patient lived for 35 months after diagnosis with LMC and never had a headache during the lifetime after the intrathecal therapy.
Figure 1: The changes of cerebrospinal fluid pressure: After three times of intrathecal therapy, the patient's cerebrospinal fluid pressure decreased from 400 to 120 mmH2O (Case 1)

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Figure 2: The changes of meninges: the meninges metastasis had been improved after 1 month treatment (Case 1). (a) Pretreatment. (b) Posttreatment

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Case 2

The patient was a 45-year-old female. In January 2007, the patient was diagnosed with NSCLC (adenocarcinoma) with bone metastasis and received one cycle chemotherapy based on cisplatin. In February 2007, the patient was diagnosed with NSCLC with brain metastasis. Then, she received gefitinib and whole-brain radiotherapy. The lesion in the lung of the patient shrinked obviously according to the result of lung computed tomography a month later. However, the patient still suffered from weakness of both lower extremities after 8 months treatment. Then, she was diagnosed with LMC after 9 months treatment. The patient had positive CSF cytology, but the CSF pressure reaches 220 mmH2O, and the level of tumor marker (CEA) in CSF was 2340 µg/L. The patient received intrathecal therapy (h-R3 50 mg) weekly. After intrathecal therapy, the symptom of weakness of both lower extremities disappeared. The level of tumor marker (CEA) in CSF decreased to 1039 µg/L after three times intrathecal therapy [Figure 3], and the CSF pressure decreased to 140 mmH2O. Then, the patient received h-R3 and MTX intrathecal therapy alternately. The level of tumor marker (CEA) in CSF decreased continuously [Figure 4]. Three months later, CSF cytology was negative. The patient lived for 12.5 months after diagnosis with LMC.
Figure 3: The level of CEA in cerebrospinal fluid: The level of tumor marker (carcinoembryonic antigen) in cerebrospinal fluid decreased from 2340 to 1039 μg/L after three times intrathecal therapy (Case 2)

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Figure 4: The level of CEA in cerebrospinal fluid: The level of carcinoembryonic antigen in cerebrospinal fluid decreased continuously after intrathecal therapy (Case 2)

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 > Discussion Top

LMC is a clinically important neurological complication of systemic cancer,[2] the presence of which usually indicates a prognosis of 4–6-month median survival.

For intrathecal chemotherapy, the common drug in use is MTX. Cytarabine and thiotepa are also used. An earlier study by Hitchins et al. of 44 patients with LM from solid tumors showed a significant median OS for MTX alone (12 weeks) compared with the combination of MTX and cytarabine (7 weeks).[4] However, another study by Kim et al. of 55 patients with LMC from solid tumors showed that the combination of intrathecal MTX and cytarabine had a superior median survival (18.6 weeks) compared with MTX alone (10.4 weeks).[7]

Hence, there are no definitive guidelines for the management of LMC. To improve the response rate, studies tried other agents for intrathecal such as topotecan, etoposide, and mafosfamide.[8],[9],[10],[11],[12]

We tried a new agent for intrathecal therapy to treat LMC from NSCLC. We used mAb (nimotuzumab, also known as h-R3) to manage LMC from NSCLC.

Nimotuzumab is a humanized IgG1 isotype mAb. The antibody blocks epidermal growth factor (EGF) binding to the receptor and inhibits its intrinsic tyrosine kinase activity. In a preclinical study, nimotuzumab showed remarkable antiproliferative, proapoptotic, and antiangiogenic effects in tumors that overexpress EGF receptor (EGFR).[13] Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation.[14] Nimotuzumab could also be cytolytic on target tumors by its capacity to cause antibody-dependent, cell-mediated cytotoxicity and complement-dependent cytotoxicity.[15]

Nimotuzumab has demonstrated a unique clinical profile, where antitumor activity was observed in the absence of severe skin, renal, gastrointestinal mucosa toxicities commonly associated with EGFR-targeting antibodies (e.g., cetuximab).

EGFRs are present on epithelial cells which give rise to the majority of cancers, overexpressed in many cancers, and mutated in a subset of NSCLC with adenocarcinoma or adenocarcinoma with bronchoalveolar cancer histologies. Responses in patients treated with mAbs to EGFR (e.g., cetuximab) demonstrate that interruption of growth factor signaling can be a useful strategy for cancer therapy.[16] Inhibitors of the EGFR pathway now have an established role in the treatment of head and neck, colon, and lung cancer.

We used nimotuzumab in an intrathecal injection at a dose of 50 mg/week. Two patients received intrathecal chemotherapy. The presence of LMC from NSCLC usually indicates a prognosis of 3-month median survival. However, after our treatment, patients had prolonged OS. The OS of one patient was 12.5 months. Another patient lived over 3 years.

This therapy improved not only survival but also clinical symptoms dramatically (e.g., Case 1). For the patient, after one time of intrathecal therapy, the number of headache reduced. After three times of intrathecal therapy, the patient's CSF pressure decreased from 400 to 120 mmH2O [Figure 1]. Moreover, it can decrease the level of tumor marker (CEA) in the CSF rapidly (e.g., Case 2). The two patients had clinical symptoms before intrathecal treatment, such as headache, vomiting, vision disorder, neck stiffness, weakness of both lower extremities, and so on. After intrathecal treatment for one or two times, symptoms of the patients had been improved, especially the headache. The quality of life had also been improved. After the treatment, LMC had been improved [Figure 2]. Maybe intrathecal therapy benefited the control of tumor cells in CSF. In the past studies, people usually used chemotherapy for LMC from NSCLC and rarely used mAb in intrathecal therapy. In our experience, we found that nimotuzumab can be used in intrathecal therapy safely and have good tolerance and results. Intrathecal therapy using targeted agent may be a reasoned selection for LMC from NSCLC.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Bleyer WA, Drake JC, Chabner BA. Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia. N Engl J Med 1973;289:770-3.  Back to cited text no. 1
Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: Experience with 90 patients. Cancer 1982;49:759-72.  Back to cited text no. 2
Giannone L, Greco FA, Hainsworth JD. Combination intraventricular chemotherapy for meningeal neoplasia. J Clin Oncol 1986;4:68-73.  Back to cited text no. 3
Hitchins RN, Bell DR, Woods RL, Levi JA. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 1987;5:1655-62.  Back to cited text no. 4
Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999;25:103-19.  Back to cited text no. 5
Sullivan MP, Moon TE, Trueworthy R, Vietti TJ, Humphrey GB, Komp D. Combination intrathecal therapy for meningeal leukemia: Two versus three drugs. Blood 1977;50:471-9.  Back to cited text no. 6
Kim DY, Lee KW, Yun T, Park SR, Jung JY, Kim DW, et al. Comparison of intrathecal chemotherapy for leptomeningeal carcinomatosis of a solid tumor: Methotrexate alone versus methotrexate in combination with cytosine arabinoside and hydrocortisone. Jpn J Clin Oncol 2003;33:608-12.  Back to cited text no. 7
Groves MD, Glantz MJ, Chamberlain MC, Baumgartner KE, Conrad CA, Hsu S, et al. A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol 2008;10:208-15.  Back to cited text no. 8
Gammon DC, Bhatt MS, Tran L, Van Horn A, Benvenuti M, Glantz MJ. Intrathecal topotecan in adult patients with neoplastic meningitis. Am J Health Syst Pharm 2006;63:2083-6.  Back to cited text no. 9
Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer 2006;106:2021-7.  Back to cited text no. 10
Blaney SM, Balis FM, Berg S, Arndt CA, Heideman R, Geyer JR, et al. Intrathecal mafosfamide: A preclinical pharmacology and phase I trial. J Clin Oncol 2005;23:1555-63.  Back to cited text no. 11
Blaney SM, Heideman R, Berg S, Adamson P, Gillespie A, Geyer JR, et al. Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 2003;21:143-7.  Back to cited text no. 12
Crombet-Ramos T, Rak J, Pérez R, Viloria-Petit A. Antiproliferative, antiangiogenic and proapoptotic activity of h-R3: A humanized anti-EGFR antibody. Int J Cancer 2002;101:567-75.  Back to cited text no. 13
Akashi Y, Okamoto I, Iwasa T, Yoshida T, Suzuki M, Hatashita E, et al. Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 2008;98:749-55.  Back to cited text no. 14
Diaz Miqueli A, Blanco R, Garcia B, Badia T, Batista AE, Alonso R, et al. Biological activity in vitro of anti-epidermal growth factor receptor monoclonal antibodies with different affinities. Hybridoma (Larchmt) 2007;26:423-31.  Back to cited text no. 15
O'Mahony D, Bishop MR. Monoclonal antibody therapy. Front Biosci 2006;11:1620-35.  Back to cited text no. 16


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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