|Year : 2014 | Volume
| Issue : 7 | Page : 155-159
Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation
Xiao Zhao1, Guangqin Zhu2, Huoming Chen3, Ping Yang4, Fang Li5, Nan Du1
1 Department of Medical Oncology, Affiliated Hospital of PLA General Hospital, Beijing, China
2 Department of Medical Oncology, General Hospital of the Air Force of People's Liberation Army, Beijing, China
3 Department of Medical Oncology, Second Artillery General Hospital of People's Liberation Army, Beijing, China
4 Department of Medical Oncology, Navy General Hospital of People's Liberation Army, Beijing, China
5 Department of Medical Oncology, General Hospital of People's Liberation Army, Beijing, China
|Date of Web Publication||29-Nov-2014|
Cancer Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing-100853
Department of Medical Oncology, Affiliated Hospital of PLA General Hospital, No. 51 Fucheng Road, Beijing 100 048
Source of Support: None, Conflict of Interest: None
Objective: This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma.
Patients and Methods: This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance were determined using the log-rank test.
Results: The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups.
Conclusion: Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR-sensitive mutation.
Keywords: Brain metastasis, epidermal growth factor receptor mutation, icotinib, lung adenocarcinoma
|How to cite this article:|
Zhao X, Zhu G, Chen H, Yang P, Li F, Du N. Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation. J Can Res Ther 2014;10, Suppl S3:155-9
|How to cite this URL:|
Zhao X, Zhu G, Chen H, Yang P, Li F, Du N. Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation. J Can Res Ther [serial online] 2014 [cited 2019 Oct 17];10:155-9. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/155/145851
Fang Li and Nan Du contribute equally to this work
| > Introduction|| |
Lung cancer is the most commonly diagnosed cancer worldwide, representing the most common cause of cancer-related death. ,, Approximately, 85% of all cases are of nonsmall cell lung cancer (NSCLC), with lung adenocarcinoma being the most common pathological subtype. Adenocarcinoma accounts for approximately 40% of all lung cancer cases and its diagnosis has been increasing recently.  The disease subtype presents a particularly high incidence of local recurrence and distant metastasis, most commonly to the brain. , Brain metastasis from lung adenocarcinoma is a significant cause of death due to the disease. Although multi-modality treatment including chemotherapy, surgery, and radiotherapy has been reported to reduce the incidence of extra-cranial distant recurrence, its efficacy against brain metastasis is dismal. Therefore, 40-50% of lung adenocarcinoma patients die of brain metastasis within 3 years after treatment.  Previous studies have suggested that chemotherapeutic agents, despite their systemic effectiveness, could not decrease the risk of brain metastasis from lung adenocarcinoma, possibly due to their inability to efficiently cross the blood-brain barrier. These results demonstrate the limited effects of traditional therapy in preventing and treating brain metastasis, prompting us to urgently explore new treatment options to improve the quality of life and prolong the survival of lung cancer patients.
In recent years, with the advancement of research on cancer-related cell receptors, as well as gene and molecular-regulated mechanisms, development of targeted drugs directed at signal transduction has met with some degree of progress and these agents have gradually gained clinical attention. The epidermal growth factor receptor (EGFR), with its tyrosine kinase activity and abundant expression on lung adenocarcinoma cells, is a member of the type I growth factor family (also known as the ERBB family with other members being the human EGF receptor (HER-2, HER-3, and HER-4). EGFR can regulate the transcription of various genes through different signaling pathways to control tumor cell proliferation, differentiation, and apoptosis. It is also involved in tumor metastasis. The introduction of tyrosine kinase inhibitors (TKIs) targeting EGFR brought a new hope for advanced NSCLC patients. Previous studies have shown that EGFR-TKI drugs such as gefitinib and erlotinib offered favorable efficacy in NSCLC patients, especially those with EGFR-sensitive mutation. ,, More recently, gefitinib and erlotinib have been suggested to not only exert effects on brain metastasis in NSCLC patients with EGFR-sensitive mutation, but also reduce the risk of brain metastasis in patients with advanced disease.  Icotinib is a new type of oral EGFR-TKI. It has demonstrated similar efficacy, but less adverse effects compared to gefitinib in a phase III clinical trial (ICOGEN).  However, no study on the relationship between icotinib treatment and brain metastasis has been reported. Therefore, we performed a retrospective nonrandomized controlled study to investigate the role of icotinib as first-line therapy on preventing brain metastasis in advanced lung adenocarcinoma patients with EGFR-sensitive mutation.
| > Patients and methods|| |
0 Clinical data
We retrospectively reviewed the clinical data of patients with advanced (stage IIIB or IV) lung adenocarcinoma with EGFR-sensitive mutation who received icotinib or traditional chemotherapy as first-line treatment between March 2009 and March 2012.  Treatments were conducted in subordinate units of Chinese Army Lung Cancer Group Patients were excluded if they showed brain metastasis or had severe heart, liver, kidney, and hematologic system diseases. Clinical data, including sex, onset age, smoking history, Eastern Cooperative Oncology Group performance status score, tumor grade, treatment history, EGFR mutation status of the tumor, and complete laboratory and imaging examination results were collected. EGFR gene mutation status was tested using the amplification-refractory mutation system (ARMS). Tumors were graded according to the International Association for the Study of Lung Cancer version 7 NSCLC tumor-node-metastasis (TNM) clinical staging standard. The histology of the tumor was classified according to the 2004 World Health Organization criteria. A total of 396 patients were included and divided into the icotinib group and the chemotherapy group according to their first-line therapy regimen, which lasted for at least a month. There were 131 patients in the icotinib group and 265 patients in the chemotherapy group. All enrolled patients provided written informed consent.
Epidermal growth factor receptor gene mutation test
Chinese Army Lung Cancer Group conventionally adopted the Scorpions' ARMS to evaluate EGFR mutation status in all tumor samples.  All procedures were performed strictly following the Scorpions' ARMS kit manual from the manufacturing company (QIAGEN, Valencia, CA, USA). In this study, the following EGFR mutations were considered sensitive mutations: deletion, repetition, or insertion of exon 19, L858R and L861Q point mutations, and G719 missense mutation.
Patients in the icotinib group received 125 mg icotinib orally, 3 times a day for more than 30 days. Those in the chemotherapy group received standard first-line platinum-based chemotherapy regimens: 94 received a pemetrexed plus platinum combination, 79 received a docetaxel plus platinum combination, 47 received a gemcitabine plus platinum combination, 28 received an etoposide plus platinum combination, and 17 received a navelbine plus platinum combination.
Evaluation of efficacy and toxicity
Baseline assessment of all patients was completed within 1 week before systemic chemotherapy. The assessment included clinical evaluation, chest computed tomography (CT), enhanced magnetic resonance imaging (MRI) of the skull, and examination of critical organs such as the liver and bone. Efficacy was evaluated 3 weeks after systemic therapy in both groups. Patients with the response or stable disease (SD) underwent a comprehensive evaluation every 8 weeks. Efficacy was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (StataCorp, College Station, TX, USA), as complete response (CR), partial response (PR), SD, or progressive disease (PD). The response rate (RR) included CR and PR. The disease-control rate (DCR) included CR, PR, and SD. Drug-related toxicity was graded according to the National Cancer Institute toxicity classification standard version 3.0. 
Follow-up and survival analysis
The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Brain metastasis was assessed according to clinical signs and symptoms, and was confirmed by CT, MRI, or pathology. The time from diagnosis of lung adenocarcinoma to brain metastasis (here after referred to as the time to brain metastasis occurrence) was measured in months, from the day when lung adenocarcinoma was accurately diagnosed to the day when brain metastasis was diagnosed, with 30 days being considered as 1 month. OS was calculated as the time from the 1 st day of treatment until death or the last outpatient follow-up visit. Follow-up was conducted from the day of treatment and was continued despite PD-related therapy termination. OS of patients who neither progressed nor died by the last day of follow-upon (May 1, 2013) was assessed as per the last tumor evaluation.
All data were analyzed using Stata12.0 software (StataCorp, College Station, TX, USA). Baseline characteristics between groups were compared using the Chi-square test or Fisher's exact test. The Kaplan-Meier method and log-rank test were used for survival analysis. The cumulative risk of brain metastasis was estimated using the cumulative incidence curve. Death without brain metastasis was used as a competitive risk for calculating the cumulative risk of brain metastasis. P < 0.05 was considered as statistically significant.
| > Results|| |
0 Patient characteristics
Baseline characteristics of all patients are shown in [Table 1]. Onset age, sex, and TNM stage were distributed equally in the two groups. However, the proportion of smokers and performance status score before treatment in the icotinib group was significantly higher than that in the chemotherapy group (P < 0.01).
All 131 patients in the icotinib group could be evaluated for curative efficacy. The clinical efficacy of icotinib on advanced lung adenocarcinoma was as follows: No cases of CR (0%), 75 cases of PR (57.3%), 40 cases of SD (30.5%), and 16 cases of PD (12.2%). The objective RR (ORR) was 57.3%, and the DCR was 87.8%.
The median follow-up time was 25.2 months. As of the last day of follow-up (May 1, 2013), brain metastasis occurred in 14 (10.7%) of 131 patients in the icotinib group and in 85 (32.1%) of 265 patients in the chemotherapy group. The cumulative risk of brain metastasis in the icotinib group at 6, 12, and 24 months was 2.1%, 3.9%, and 10.2%, respectively. The corresponding values were 5.6%, 11.4%, and 30.1% respectively in the chemotherapy group. As shown in [Figure 1], there was a significant difference in the cumulative risk of brain metastasis between the two groups (P < 0.001, hazard ratio [HR]: 3.32, 95% CI: 1.89-5.82). Our results suggest that the risk of brain metastasis in the chemotherapy group was significantly higher than that in the icotinib group.
|Figure 1: Cumulative incidence of brain metastasis in all eligible patients|
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As of the follow-up deadline, 38 patients (29.0%) remained alive in the icotinib group, whereas only 41 patients (15.5%) were alive in the chemotherapy group. The median OS was 22.5 months for the icotinib group and 21.2 months for the chemotherapy group. Although the cumulative risk of brain metastasis was significantly lower in the icotinib group, no significant difference in OS was observed between the two groups [P = 0.132, [Figure 2].
The most common toxicities observed in the icotinib group were rash (33 patients, 25.2%) and diarrhea (30 patients, 22.9%). In addition, 7 cases (5.3%) of asthenia, 5 cases (3.8%) of transaminase abnormalities, and 1 case (0.7%) of paronychia were observed. Except for two cases of grade III rash and diarrhea, all events were of grades I-II. They were also transient and relieved with symptomatic therapy without the need for chemotherapy dose reduction or withdrawal. No grade IV toxicity was observed. No interstitial pneumonia and drug-related death occurred during treatment. Dose reduction and therapy withdrawal were not required in any patient [Table 2].
|Table 2: Toxicity observed in advanced lung adenocarcinoma patients receiving icotinib treatment |
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| > Discussion|| |
Worldwide, the morbidity and mortality of lung cancer is the highest among all malignant tumors. In addition, brain metastasis often predicts poor prognosis. The current conventional treatments including whole brain radiotherapy, stereotactic radiotherapy, surgery, and chemotherapy are not effective for the treatment of brain metastasis.  Furthermore, therapy-associated adverse effects often restrict the application of these modalities in advanced patients. With the improvement of lung adenocarcinoma treatment, the search for a high efficiency and low toxicity option to control the occurrence of brain metastasis becomes the key issue to improve patients' survival and quality of life. Multiple clinical trials such as the IPASS, OPTIMAL, and ICOGEN studies have drawn much clinical attention to EGFR-TKI drugs as they have been reported to significantly improve the survival and quality of life in patients with advanced lung adenocarcinoma.  They, therefore, have become the treatment of choice in patients with EGFR-sensitive mutations. Icotinib, approved for marketing in China in 2011, is a new type of EGFR-TKI and is mainly used as second-line therapy for advanced NSCLC. , It has been reported to offer efficacy similar to that of gefitinib in a phase III clinical trial. Moreover, icotinib have shown a higher liposolubility and can pass through the blood-brain barrier easier compared to gefitinib.  However, questions remained on the efficacy of icotinib in lung adenocarcinoma patients with EGFR-sensitive mutations. In addition, whether icotinib could reduce the incidence of brain metastasis in these patients was also unclear. Owing to the lack of such data, we conducted a retrospective nonrandomized controlled study to investigate the issue.
First, we assessed the safety and efficacy of icotinib as the first-line treatment in advanced lung adenocarcinoma patients with EFGR-sensitive mutations. Our data revealed an ORR of 57.3% and a DCR of 87.8%. The ORR of icotinib was consistent with that of gefitinib and erlotinib in previous reports (the ORR was 83% in the OPTIMAL study, 71% in the EURTAC and the IPASS studies, 62% in the WJTOG3405 study, and 74% in the NEJ002 study). The higher efficacy observed in our study may be because all enrolled patients were pathologically diagnosed with lung adenocarcinoma, and icotinib was administrated as first-line therapy. All patients experienced good tolerance, with related adverse events mainly involving rash (25.2%) and diarrhea (22.9%). None of the patients required therapy withdrawal due to adverse effects. Our findings were similar to data reported by the ICOGEN study, with the incidence of icotinibhydrloride-related rashes being 39.5% and that of diarrhea being 18.5%. Therefore, icotinib has demonstrated a good efficacy and safety profile in advanced lung adenocarcinoma patients, with mild adverse effects, suggesting its potential as a favorable therapeutic choice.
In addition, we investigated the relationship between icotinib therapy and the incidence of brain metastasis. Brain metastasis from lung adenocarcinoma is common, accounting for approximately 43-62% of all cases of brain metastasis. These patients often experience a decreased quality of life, accompanied by a poor prognosis with a median survival time of only 1 to 2 months. The morbidity of lung cancer has been increasing in the recent years, accompanied by the increased reports of brain metastasis, which has been reported to occur in up to 30-50% of all lung cancer patients.  Brain metastasis from lung cancer is a complex multi-stage and multi-step pathological process, with significantly different pathological and clinical prognosis from other metastases. It is one of the most challenging problems in clinical treatment of tumors. Medical treatment for brain metastasis from lung cancer is generally limited mostly due to the natural blockade by the blood-brain barrier. Theoretically, the blood-brain barrier is partially compromised upon brain metastasis from lung cancer, which promotes the permeation of drugs. However, in clinical practice, the curative efficacy is not ideal even when the extra-cranial lesions are sensitive to the therapy or when the therapeutic agent can partly cross the blood-brain barrier. As a mechanism of brain metastasis is still under investigation, the hope to improve patient prognosis via inhibition of tumor metastasis to the brain remains. Targeted EGFR-TKIs such as gefitinib and erlotinib, with their small molecular weight and ability to effectively permeate the blood-brain barrier, have been shown to provide promising curative effect and relatively less adverse reactions compared with traditional chemotherapy. Although their efficacy against primary lung cancer has been demonstrated, whether TKIs can offer a new opportunity for the treatment of brain metastasis from lung cancer is unclear. Preliminary study results have indicated that gefitinib and erlotinib exerted certain effects on the prevention and treatment of brain metastasis from NSCLC, with the status of EGFR mutation playing crucial roles.  Compared with traditional chemotherapy, gefitinib and erlotinib when used as first-line treatment reduced the risk of brain metastasis in advanced NSCLC patients with EGFR mutations. The RR of intracranial lesions to gefitinib and erlotinib used as first-line treatment could be up to 70-80% in NSCLC patients with EGFR mutation who had brain metastasis. These data indicated that brain metastases in NSCLC patients with EGFR mutations were sensitive to gefitinib and erlotinib, which was not the case with traditional chemotherapy drugs. However, the use of EGFR-TKI for the prevention and treatment of brain metastasis in NSCLC patients with EGFR-TKI remains controversial. Icotinib is a new type of targeted anti-tumor drug, which suppresses tumor growth by blocking the downstream signal transduction and cell proliferation via inhibition of EGFR phosphorylation. Previous studies have confirmed that the mutation status of EGFR strongly predicted the efficacy of EGFR-TKI in NSCLC. Our study specifically selected patients with EGFR-sensitive mutation. We then compared the ability of icotinib versus traditional chemotherapy when administered as first-line treatment to reduce the incidence of brain metastasis from lung adenocarcinoma. Data from 396 lung adenocarcinoma patients who received initial treatment were retrospectively analyzed. Our results indicated that the cumulative risk of brain metastasis in patients receiving icotinib was significantly lower than that in those receiving traditional chemotherapy. The cumulative risks of central nervous system progression in the icotinib group at 6, 12, and 24 months were 2.1%, 3.9% and 10.2% respectively, whereas the rates were 5.6%, 11.4%, and 30.1% respectively in the chemotherapy group. The HR of chemotherapy versus icotinib was 3.32 (95% CI: 1.89-5.82). As the risk of brain metastasis in the chemotherapy group was 3.3 times higher than that in the icotinib group, icotinib seems to prevent the occurrence of brain metastasis in advanced lung adenocarcinoma patients with EGFR-sensitive mutation. However, despite a significantly reduced risk of brain metastasis, the OS of patients receiving icotinib was not statistically different from that of patients receiving traditional chemotherapy (P = 0.132; 22.5 months vs. 21.2 months). This result may be due to the subsequent choice of therapy.
| > Conclusion|| |
Our results suggest that the icotinib, when administered as first-line treatment for advanced lung adenocarcinoma with EGFR-sensitive mutation, can effectively reduce the risk of brain metastasis. To the best of our knowledge, the present report is the first retrospective study comparing the effectiveness of icotinib and traditional chemotherapy on reducing the risk of brain metastasis in patients with confirmed EGFR gene mutation status. Our findings offer an alternative option for the treatment of advanced lung adenocarcinoma patients. However, as this study was a retrospective analysis, it has many confounding factors. For example, it is very common for patients to crosswise select EGFR-TKI or chemotherapy as second-line therapy after first-line treatment. Patients with brain metastases are often administered regimens preferably targeting the brain lesions in addition to systemic, comprehensive treatment. Therefore, OS needs to be confirmed by further prospective studies with large sample sizes.
| > References|| |
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.
Chen WQ, Zheng RS, Zhang SW, Zou XN, Zhao P, He J. Lung cancer incidence and mortality in China, 2009. Thorac Cancer 2013;4:102-8.
Zeng HM, Zheng RS, Zhang SW, He J, Chen WQ. Lung cancer incidence and mortality in China, 2008. Thorac Cancer 2013;4:53-8.
Travis WD. Pathology of lung cancer. Clin Chest Med 2011;32:669-92.
Nathoo N, Chahlavi A, Barnett GH, Toms SA. Pathobiology of brain metastases. J Clin Pathol 2005;58:237-42.
Kim J, Lee SM, Yim JJ, Yoo CG, Kim YW, Han SK, et al.
Prognosis for non-small cell lung cancer patients with brain metastases. Thorac Cancer 2013;4:167-73.
Mamon HJ, Yeap BY, Jänne PA, Reblando J, Shrager S, Jaklitsch MT, et al.
High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation. J Clin Oncol 2005;23:1530-7.
Schaake EE, Kappers I, Codrington HE, Valdés Olmos RA, Teertstra HJ, van Pel R, et al.
Tumor response and toxicity of neoadjuvant erlotinib in patients with early-stage non-small-cell lung cancer. J Clin Oncol 2012;30:2731-8.
Rizvi NA, Rusch V, Pao W, Chaft JE, Ladanyi M, Miller VA, et al.
Molecular characteristics predict clinical outcomes: Prospective trial correlating response to the EGFR tyrosine kinase inhibitor gefitinib with the presence of sensitizing mutations in the tyrosine binding domain of the EGFR gene. Clin Cancer Res 2011;17:3500-6.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al.
Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.
Heon S, Yeap BY, Lindeman NI, Joshi VA, Butaney M, Britt GJ, et al.
The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res 2012;18:4406-14.
Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, et al.
Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): A randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 2013;14:953-61.
Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol 2005;40:90-7.
Jänne PA, Borras AM, Kuang Y, Rogers AM, Joshi VA, Liyanage H, et al.
A rapid and sensitive enzymatic method for epidermal growth factor receptor mutation screening. Clin Cancer Res 2006;12:751-8.
Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al.
CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81.
Preusser M, Capper D, Ilhan-Mutlu A, Berghoff AS, Birner P, Bartsch R, et al.
Brain metastases: Pathobiology and emerging targeted therapies. Acta Neuropathol 2012;123:205-22.
Lee YJ, Park IK, Park MS, Choi HJ, Cho BC, Chung KY, et al.
Activating mutations within the EGFR kinase domain: A molecular predictor of disease-free survival in resected pulmonary adenocarcinoma. J Cancer Res Clin Oncol 2009;135:1647-54.
Lv C, Ma Y, Feng Q, Fang F, Bai H, Zhao B, et al.
A pilot study: Sequential gemcitabine/cisplatin and icotinib as induction therapy for stage IIB to IIIA non-small-cell lung adenocarcinoma. World J Surg Oncol 2013;11:96.
Camidge DR. Icotinib: Kick-starting the Chinese anticancer drug industry. Lancet Oncol 2013;14:913-4.
Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, et al.
Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res 2010;16:5873-82.
Porta R, Sánchez-Torres JM, Paz-Ares L, Massutí B, Reguart N, Mayo C, et al.
Brain metastases from lung cancer responding to erlotinib: The importance of EGFR mutation. Eur Respir J 2011;37:624-31.
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[Table 1], [Table 2]