Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 12  |  Issue : 7  |  Page : 181--185

Nimotuzumab treatment and outcome analysis in patients with leptomeningeal metastasis from nonsmall cell lung cancer


Yanfang Ju, Jinliang Wang, Shengjie Sun, Shunchang Jiao 
 Department of Oncology, Chinese PLA General Hospital, Beijing, China

Correspondence Address:
Shunchang Jiao
Department of Oncology, Chinese PLA General Hospital, Beijing 100853
China

Abstract

Objective: Leptomeningeal metastasis (LM) leades a devastating consequence in patients with nonsmall cell lung cancer(NSCLC). Treatment is very limited for patients with LM. We introduced to use nimotuzumab (also known as h-R3) combined with methotrexate for treating LM in NSCLC patients. Patients and Methods: In the present report, twenty patients with LM of NSCLC were included, and the clinicopathology information and outcomes after treatment were analyzed. Results: All the twenty patients with LM were lung adenocarcinoma. Thirteen patients had poor Eastern Cooperative Oncology Group performance status (≥ 3) before treatment, fifteen patients received combined administration of h-R3 and methotrexate, and another five patients received h-R3 treatment alone. The median survival time after the diagnosis of LM was 5 months (range, 2.4–7.6 months) for these twenty patients. The mean cerebrospinal fluid opening pressure was 270mmH2O before treatment and decreased significantly after treatment (140 mmH2O) (P < 0.001). Associated symptoms were relieved quickly after one or two cycles of intrathecal therapy. Conclusion: These findings indicated that nimotuzumab might be a potential drug for treatment of LM in NSCLC patients.



How to cite this article:
Ju Y, Wang J, Sun S, Jiao S. Nimotuzumab treatment and outcome analysis in patients with leptomeningeal metastasis from nonsmall cell lung cancer.J Can Res Ther 2016;12:181-185


How to cite this URL:
Ju Y, Wang J, Sun S, Jiao S. Nimotuzumab treatment and outcome analysis in patients with leptomeningeal metastasis from nonsmall cell lung cancer. J Can Res Ther [serial online] 2016 [cited 2022 May 18 ];12:181-185
Available from: https://www.cancerjournal.net/text.asp?2016/12/7/181/200596


Full Text

 Introduction



The brain or the leptomeninges is a common site for metastasis of nonsmall cell lung cancer (NSCLC). Patients of NSCLC with central nervous system metastasis in general suffer from deterioration of performance status (PS) and often have poor overall survival (OS). The recent advancement of radiation and surgery treatment improves local control of brain metastases from lung cancer; however, there is currently no efficient treatment for leptomeningeal metastases of lung cancer. Leptomeningeal metastasis (LM), also termed neoplastic meningitis, is caused by cancer cells implanting in leptomeninges and cerebrospinal fluid (CSF) and results in poor overall survival despite appropriate therapy.

LM is diagnosed by finding cancer cells in CSF and intrathecal (IT) chemotherapy and/or radiotherapy is the major treatment pattern for LM.[1] Although with various toxicities, methotrexate (MTX) is the most commonly used drug for IT administration currently.[2] Because of the limited treatment effect of MTX in IT chemotherapy,[3] the combination therapy by taking MTX with other agents, such as Ara-C and thiotepa, have been developed with attempt to improve the response rate and OS in patients of NSCLC with LM. However, no significant improved curative effects of combination therapy compared to MTX single drug treatment was observed, whether sequential administration or coadministration in combination therapy.[1],[4],[5],[6] In the present study, the combination of nimotuzumab (also known as h-R3) and MTX was used for treatment of LM from NSCLC. Nimotuzumab might be a potential drug for treatment of LM in NSCLC patients.

 Patients and Methods



Patients

A total of twenty patients with LM from NSCLC received therapy in Chinese PLA General Hospital between February 2007 and September 2014 were enrolled in the present study. The inclusion criteria were as follows (1) identifying cancer cells in CSF or (2) showing multifocal enhancing subarachnoid nodules in image of magnetic resonance scan. The clinicopathology information of these twenty patients was reviewed, and treatment pattern and clinical outcomes were analyzed.

Treatment

These twenty patients were treated with weekly IT therapy. Fifteen of them received combination of h-R3 (50 mg/week) and MTX (5–10 mg/week) IT therapy and the other five patients received h-R3 (50 mg/week) IT therapy alone.

Statistical analysis

Statistical analysis was performed using SPSS 17.0 (Chicago, IL, USA). OS and median survival time were calculated using the Kaplan–Meier method. The difference between before and after treatment was analyzed using t-test.

 Results



Patient characteristics

The clinicopathological characteristics of these twenty patients are listed in [Table 1]. There were 9 males and 11 females. The median age at the time of diagnosis of LM was 49 years (range, 40–68 years). The median time from diagnosis of NSCLC to LM was 12 months (range, 0–112 months). Among these 20 patients, 13 patients had poor Eastern Cooperative Oncology Group (ECOG) PS (≥ 3). All the patients were lung adenocarcinoma. Eleven patients (55%) received more than two lines of chemotherapy before the diagnosis of LM. All the patients showed clinical symptoms associated with LM, and 12 had coexisting brain metastasis.{Table 1}

Cerebrospinal fluid examination

The CSF analysis result of these 20 patients was available, and 12 (60%) patients were positive for CSF cytology. The mean CSF opening pressure was 270 mmH2O (range, 202–338 mmH2O). The mean CSF cancer cell number was 44.8/mm 3 (range, 0–140/mm 3). The mean CSF protein level was 105.6 mg/dL (range, 23.6–400.4 mg/dL). The mean CSF glucose level was 40.8 mg/dL (range, 7.4–90 mg/dL).

Treatment regime

MTX and h-R3 were used in IT chemotherapy. Fifteen patients received combined administration of h-R3 and MTX, five patients received h-R3 treatment alone. IT chemotherapy was well tolerated in all patients, and one patient received 35 cycles treatment. Among the 20 patients, 14 received epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment, 12 received radiotherapy, 13 received systemic chemotherapy. The detailed information was shown in [Table 2].{Table 2}

Clinical outcomes

The median OS time after the diagnosis of LM of these twenty patients was 5 months (95% confidence interval, 2.4–7.6 months) [Figure 1]. The average number of IT therapy was 8.9 (range, 1–35). The mean CSF opening pressure was 270 mmH2O (range, 202–338 mmH2O) before treatment and decreased significantly after treatment (140 mmH2O, range, 127–153 mmH2O) (P < 0.001). All the twenty patients had symptoms associated with LM before treatment, including headache, nausea, vomiting, double vision, neck stiffness, vision disorder, hearing losing, confusion, and weakness of both lower extremities. We found that these symptoms, especially the headache, were relieved after IT chemotherapy.{Figure 1}

 Discussion



LM occurs in only about 5% of patients with solid tumors;[7] however, it led to the devastating consequence. It was reported that the OS time of NSCLC patients with LM was no more than 3 months. Currently, treatment for LM includes IT chemotherapy, whole-brain radiation therapy, and systemic chemotherapy.[3],[8],[9]

MTX is the most commonly used drug in IT chemotherapy for LM, and cytarabine and thiotepa are also agents now used in clinic. Hitchins et al. reported that treatment with MTX alone showed better prognosis (median OS, 12 weeks) than combination of MTX and cytarabine (7 weeks) in a cohort of 44 patients with LM from solid tumors.[4] However, Kim et al. found the combination of MTX and cytarabine IT therapy had superior median OS (18.6 weeks) compared with MTX alone (10.4 weeks) in another cohort of 55 patients with LM from solid tumors.[10] To improve the response rate, other agents such as topotecan, etoposide, and mafosfamide were used in IT therapy for LM patients.[11],[12],[13],[14],[15]

Anti-EGFR mAbs and inhibitors have been demonstrated to be a useful strategy for treatment of head and neck cancer, colon and lung cancer by interrupting epidermal growth factor signaling pathway.[16] In the present study, nimotuzumab, a monoclonal antibody drug, was used in IT therapy for patients with LM from NSCLC. Nimotuzumab is a humanized IgG1 isotype monoclonal antibody, which was obtained by transplanting the complementarity determining regions of the murine IgG2a ior egf/r3 to a human framework, assisted by computer modeling.[17] The parental murine monoclonal ior egf/r3 was generated by fusing the murine myeloma cells SP2/Ag14 with splenocytes from Balb/c mice immunized with a purified human placenta fraction enriched in EGFR and not with EGFR purified from cultured cells.[18] Nimotuzumab recognizes an epitope located in the extracellular domain of human EGFR and blocks the EGF binding site, by which the intrinsic tyrosine kinase activity of EGFR was inhibited.

In preclinical study, nimotuzumab showed remarkable antiproliferative, proapoptotic, and antiangiogenic effects in cancers with EGFR overexpression.[19] It was reported that nimotuzumab enhanced the antitumor efficacy of radiation in some human NSCLC cell lines in vitro and in vivo, which might be related to the EGFR level on the cell surface rather than to EGFR mutation.[20] Nimotuzumab could also play cytolytic active by causing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).[21] It was shown that nimotuzumab was well tolerated and promoted the efficacy of radiation in patients with advanced head and neck cancer in a Phase I/II trial.[22] There were no remarkable adverse event and side effect, such as severe skin, renal, and gastrointestinal mucosa toxicities in nimotuzumab treatment while its clinical benefit was equivalent or superior to other anti-EGFR monoclonal antibody drugs.[23]

In the present study, nimotuzumab was used in IT injection at a dose of 50 mg/week for treatment of LM of NSCLC patients.

The occurrence of LM from NSCLC usually indicates poor prognosis with median OS of no more than 3 months. In the present study, IT chemotherapy improved the survival of patients with LM from NSCLC, the median OS was 5 months for these twenty patients, and ten of them lived longer than 6 months. The less number of IT chemotherapy was one of reasons for poor survival of patients with LM from NSCLC. The OS was <3 months in eight patients who received <4 cycles of IT chemotherapy. However, the OS was >10 months in six patients who received >8 cycles of IT chemotherapy, one of whom even lived longer than 3 years. In addition, the effect of IT nimotuzumab therapy might be related to ADCC induced by nimotuzumab, and the effects of ADCC often be observed 1–3 months after treatment. Therefore, the number of intrathecal therapy should be enough during the treatment.

IT nimotuzumab therapy also markedly improved symptoms associated with LM. All the twenty patients had clinical symptoms before IT treatment, such as headache, vomiting, vision disorder, neck stiffness, and so on. After one or two times of IT nimotuzumab treatment, the symptoms were relieved and the living quality was improved in most of patients. After three times of IT therapy, the CSF pressure decreased from 400 to 120 mmH2O in one patient. In addition, CEA level in CSF was decreased markedly, and the size of leptomeningeal carcinomatosis was reduced in magnetic resonance imaging after treatment.

Chemotherapy was often used in IT therapy for patients with LM from NSCLC. In the present report, the results indicated that nimotuzumab could be a safety treatment for LM patients of NSCLC, with good tolerance and outcome.

In this report, most patients received combined therapy of EGFR-TKI and systemic chemotherapy. Currently, EGFR-TKIs are the common treatment for NSCLC patients with sensitive EGFR mutations. However, the role of EGFR-TKIs in LM patients of NSCLC with EGFR mutation is not clear yet as well as the impacts of systemic chemotherapy. It was reported that NSCLC patients with LM benefited from systemic chemotherapy; however, we did not found significant longer OS in patients received systemic chemotherapy, which might due to the small number of cases in our study.

Aggressive treatment was recommended to patients with good ECOG PS,[24] who have better immunomicroenvironment. h-R3 should be used in patients with good ECOG PS as the ADCC and CDC effect induced by it. More cases should be included in the future study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Giannone L, Greco FA, Hainsworth JD. Combination intraventricular chemotherapy for meningeal neoplasia. J Clin Oncol 1986;4:68-73.
2Bleyer WA, Drake JC, Chabner BA. Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia. N Engl J Med 1973;289:770-3.
3Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: Experience with 90 patients. Cancer 1982;49:759-72.
4Hitchins 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.
5Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999;25:103-19.
6Sullivan 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.
7Gerrard GE, Franks KN. Overview of the diagnosis and management of brain, spine, and meningeal metastases. J Neurol Neurosurg Psychiatry 2004;75 Suppl 2:ii37-42.
8Chowdhary S, Chamberlain M. Leptomeningeal metastases: Current concepts and management guidelines. J Natl Compr Canc Netw 2005;3:693-703.
9Balm M, Hammack J. Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol 1996;53:626-32.
10Kim 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.
11Groves 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.
12Gammon 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.
13Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer 2006;106:2021-7.
14Blaney 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.
15Blaney 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.
16O'Mahony D, Bishop MR. Monoclonal antibody therapy. Front Biosci 2006;11:1620-35.
17Mateo C, Moreno E, Amour K, Lombardero J, Harris W, Pérez R. Humanization of a mouse monoclonal antibody that blocks the epidermal growth factor receptor: Recovery of antagonistic activity. Immunotechnology 1997;3:71-81.
18Fernandez A, Spitzer E, Perez R, Boehmer FD, Eckert K, Zschiesche W, et al. A new monoclonal antibody for detection of EGF-receptors in western blots and paraffin-embedded tissue sections. J Cell Biochem 1992;49:157-65.
19Crombet-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.
20Akashi 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.
21Diaz 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.
22Crombet T, Osorio M, Cruz T, Roca C, del Castillo R, Mon R, et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 2004;22:1646-54.
23Allan DG. Nimotuzumab: Evidence of clinical benefit without rash. Oncologist 2005;10:760-1.
24Park JH, Kim YJ, Lee JO, Lee KW, Kim JH, Bang SM, et al. Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era. Lung Cancer 2012;76:387-92.