|Year : 2017 | Volume
| Issue : 1 | Page : 197-202
Clinical profile and outcomes of patients with Stage IV adenocarcinoma of lung: A tertiary cancer center experience
P Paliwal1, S Rajappa1, A Santa1, MVTK Mohan1, S Murthy2, N Lavanya2
1 Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital, Hyderabad, Telangana, India
2 Department of Pathology, Basavatarakam Indo American Cancer Hospital, Hyderabad, Telangana, India
|Date of Web Publication||1-Dec-2017|
Dr. S Rajappa
Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
BACKGROUND: There is limited Indian data on clinical profile and treatment outcomes for patients with Stage IV adenocarcinoma of lung. AIM: We aimed to prospectively study the clinical profile and treatment outcomes for patients with Stage IV adenocarcinoma of lung at a tertiary cancer center. MATERIALS AND METHODS: One hundred and ninetyfour patients with Stage IV adenocarcinoma of lung were prospectively analyzed for demographic and molecular profile (epidermal growth factor receptor [EGFR] and echinodermal microtubuleassociated proteinlike 4anaplastic lymphoma kinase [EML4ALK] mutations). Patients with EGFR and EML4ALK mutations were treated with tyrosine kinase inhibitors. Patients without these mutations were treated with standard chemotherapy regimens. Maintenance chemotherapy was offered to patients as per standard guidelines. Clinical outcomes measured were response rate (RR), progressionfree survival (PFS), and overall survival (OS). RESULTS: Median age of patients was 56 years (range, 26–82) with a male:female ratio of 2.3:1. EGFR and ALK mutation testing was feasible in 169 (87.1%) and 164 (84.5%), respectively, and detected in 37.9% and 5.5% patients, respectively. Overall RR, PFS and OS of whole cohort were 44.3%, 6.9, and 15.5 months, respectively. PFS and OS of mutated group (EGFR, EML4ALK) were longer than nonmutated group (10.5 vs. 5.4 months, P < 0.0001 and 21.5 vs. 11 months, P = 0.0001, respectively). PFS and OS of patients who received pemetrexed maintenance were longer than those who did not receive maintenance (8.5 vs. 6.5 months, P = 0.1613 and 18.5 vs. 12.5 months, P = 0.0219, respectively). CONCLUSIONS: Mutation testing at diagnosis is feasible in the vast majority of patients with Stage IV adenocarcinoma of the lung. Patients with EGFR or EML4ALK mutation and those who received pemetrexed maintenance had better clinical outcomes.
Keywords: Adenocarcinoma of lung, echinodermal microtubule-associated protein-like 4-anaplastic lymphoma kinase, epidermal growth factor receptor, maintenance chemotherapy
|How to cite this article:|
Paliwal P, Rajappa S, Santa A, Mohan M, Murthy S, Lavanya N. Clinical profile and outcomes of patients with Stage IV adenocarcinoma of lung: A tertiary cancer center experience. Indian J Cancer 2017;54:197-202
|How to cite this URL:|
Paliwal P, Rajappa S, Santa A, Mohan M, Murthy S, Lavanya N. Clinical profile and outcomes of patients with Stage IV adenocarcinoma of lung: A tertiary cancer center experience. Indian J Cancer [serial online] 2017 [cited 2020 Apr 5];54:197-202. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/197/219595
| » Introduction|| |
Lung cancer is the most commonly diagnosed cancer in men and leading cause of death due to cancer worldwide. In India, lung cancer is the most common cancer in men and the fourth most common cancer in the overall population. In both smokers and nonsmokers, adenocarcinoma is the most common histological subtype. Adenocarcinoma accounts for 40% of all types of lung cancer. More than 70% of patients are diagnosed in advanced stage (Stage IIIb and IV) where the disease is incurable and associated with poor outcomes.
Deeper understanding of signaling pathways and discovery of oncogenic driver mutations have resulted in better molecular characterization of adenocarcinoma patients and made targeted or personalized medicine feasible. It is now recommended to test for epidermal growth factor receptor (EGFR) mutation, echinodermal microtubule-associated protein-like 4-anaplastic Lymphoma kinase (EML4-ALK) rearrangement, and ROS 1 rearrangement in specific groups of patients with newly diagnosed nonsmall cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) and ALK and ROS 1 inhibitor (crizotinib) have been approved by the Food and Drug Administration for upfront treatment of patients with these molecular abnormalities. These abnormalities constitute less than half of all patients with lung cancer. Hence, the vast majority of patients will still need palliative chemotherapy upfront or after failure of these TKIs.,
The incidence of EGFR mutations in Indian population ranges from 25% to 51% and ALK rearrangement from 4% to 8%. Previous studies from India have reported the demographic and molecular profiles of patients with NSCLC. Very few have reported on the outcomes of these patients on EGFR-TKIs or ALK inhibitors. There is also paucity of data on response rates (RRs) and survivals with palliative chemotherapy in Stage IV patients with adenocarcinoma.,,
We present demographic profile, molecular profile of patients with Stage IV adenocarcinoma of lung, and their clinical outcome in terms of RR, progression-free survival (PFS), and overall survival (OS).
| » Materials And Methods|| |
Patients with Stage IV adenocarcinoma of lung diagnosed at our institute between March 2013 and October 2014 were included in the study. Demographic parameters analyzed were age, sex, and smoking history. Molecular profile included EGFR mutation and EML4-ALK rearrangement analysis. Diagnosis was confirmed by biopsy (most of cases) or fine-needle aspiration cytology with cell block and reported as per International Association for the Study of Lung Cancer classification. Staging workup included computed tomography (CT) scan of chest and abdomen and bone scan or whole-body positron emission tomography-CT scan wherever possible. Magnetic resonance imaging brain was done whenever clinically indicated. Molecular testing for EGFR mutation and EML4-ALK translocation was done on paraffin-embedded tissue block. Testing was outsourced to different laboratory - MedGenome, Oncoquest, and Tata Memorial Hospital, Mumbai, for molecular testing. An informed consent was taken from all patients before starting treatment and the Institutional Ethics Committee approved the study. Patients were treated with standard doses of various chemotherapy regimen including cisplatin/carboplatin and pemetrexed, carboplatin/paclitaxel, and cisplatin/etoposide. Patients who were EGFR and EML4-ALK negative and achieved complete, partial response (PR), or stable disease (SD) at the end of 4–6 cycles of chemotherapy were offered maintenance chemotherapy with pemetrexed. Patients with EGFR mutation received the EGFR-TKIs-erlotinib, gefitinib, or afatinib either upfront or after 2–4 cycles of chemotherapy pending mutation results. Patients with EML4-ALK mutation received crizotinib either upfront or after 2–4 cycles of chemotherapy. Patients also received locoregional treatment – pleurocentesis and pleurodesis, palliative radiotherapy to skeletal metastasis, brain metastasis, and superior vena cava syndrome, either before start of treatment or during treatment whenever required.
Response criteria used
Initial response evaluation was done after 2–3 cycles of chemotherapy and a second evaluation after 4–6 cycles of chemotherapy and every 3–4 months thereafter during maintenance therapy or follow-up.
Complete response (CR), PR, SD, and progressive disease (PD) were defined as per RECIST1.1 criteria. PFS was defined as the time from start of chemotherapy to the time that PD was documented, death or lost for follow-up. OS was defined as the time from start of chemotherapy to death due to any cause.
Statistical analysis was done using software GraphPad Prism 6 (GraphPad software, California, USA). Significance P value was set at 0.05. Kaplan–Meier curves were plotted for PFS and OS and log-rank test was used to compare PFS and OS between different groups.
| » Results|| |
One hundred and ninety-four patients with Stage IV adenocarcinoma of lung who presented from March 2013 to October 2014 were included in this analysis. Median age of the patients was 56 years (range, 26–82) with a male:female ratio of 2.3:1. EGFR and EML4-ALK mutation analyses were possible for 169 (87.1%) and 164 (84.5%) patients, respectively. EGFR mutation and EML4-ALK translocation were detected in 64 (37.9%) and 9 (5.5%) patients, respectively. Demographic and molecular characteristics are depicted in [Table 1]. There was a female (2:1) and nonsmoker (10:1) preponderance in the EGFR and EML4-ALK-mutated patients. Most common mutation detected in EGFR-mutated patients was in exon 19 (57.8%) followed by in exon 21 (35.9%), exon 18 (4.7%), and exon 21 in one patient.
|Table 1: Demographic characteristics of whole cohort, epidermal growth factor receptor mutated and echinodermal microtubule associated protein-like 4-anaplastic lymphoma kinase translocated patients|
Click here to view
Out of 194 patients, 86 (44.3%) had response (CR and PR) to first-line therapy. At a median follow-up of 16 months, median PFS and OS for whole cohort were 6.9 and 15.5 months, respectively [Figure 1] and [Figure 2]. RR, PFS, and OS for non-EGFR non-ALK-mutated, EGFR-mutated, and EML4-ALK-translocated patients is shown in [Table 2].
|Figure 1: Kaplan–Meier projection for progression-free survival and overall survival: Progression-free survival of whole cohort|
Click here to view
|Figure 2: Kaplan–Meier projection for progression-free survival and overall survival: Overall survival of whole cohort|
Click here to view
|Table 2: Response rate, progression-free survival, and overall survival of whole cohort, nonepidermal growth factor receptor nonanaplastic lymphoma kinase mutated, epidermal growth factor receptor mutated, and echinodermal microtubule-associated protein-like 4-anaplastic lymphoma kinase translocated patients|
Click here to view
In patients without mutation (121 patients), most patients (81.8%) received pemetrexed/platinum followed by paclitaxel/carboplatin and cisplatin/etoposide. RR to various chemotherapy regimen is shown in [Table 3].
|Table 3: Response rate to various chemotherapy regimens in nonepidermal growth factor receptor nonanaplastic lymphoma kinase-mutated patients|
Click here to view
Out of 99 patients treated with pemetrexed/platinum doublet, 30 patients progressed. Of the remaining 69 patients, 36 (52.2%) received maintenance chemotherapy with pemetrexed. Median number of chemotherapy cycles received was 6 (range, 1–25). None who took paclitaxel or etoposide with platinum received maintenance chemotherapy. Patients on maintenance chemotherapy had better OS compared to those who did not receive it - 18.5 months versus 12.5 months (P - 0.0219) [Figure 3].
|Figure 3: Kaplan–Meier projection for progression-free survival and overall survival: Overall survival of pemetrexed maintenance versus no maintenance in of nonepidermal growth factor receptor nonanaplastic lymphoma kinase cohort|
Click here to view
Of the 64 patients who were positive for EGFR mutation, 22 patients received upfront TKI (15 gefitinib and 7 erlotinib) and 38 received EGFR-TKI after some cytotoxic chemotherapy which was started pending mutation results. Median number of chemotherapy cycles given before TKI started was 4. Three patients received upfront afatinib and one patient could not receive any treatment because of poor performance status. [Table 4] shows RR, PFS, and OS of various EGFR mutation subgroups.
|Table 4: Response rate, progression-free survival, and overall survival of various epidermal growth factor receptor mutation subgroups|
Click here to view
| » Discussion|| |
In our study, 194 Stage IV adenocarcinoma of patients were analyzed for demographics, molecular profile, and clinical outcomes (RR, PFS, and OS). Median age of patients (56 years) and male/female incidence were similar to most of the recent studies from India. Significant number of patients with adenocarcinoma of lung patients are nonsmokers. Similar findings were seen in our study [Table 5]. Higher smoking rate and higher proportion of female patients were reported from East India study by Mandal et al. Geographical differences and high smoking rate may be responsible for these differences.
|Table 5: Demographic characteristics of nonsmall cell lung cancer (including adenocarcinoma) in Indian studies|
Click here to view
Molecular testing of tumor samples from patients with advanced NSCLC is now recommended by oncology societies worldwide. A recent global survey reported that 81% advanced NSCLC patients were tested for EGFR mutation. The main reasons for not testing all patients, aside from tumor histology, were insufficient tissue/uncertainty of sufficient tissue, poor patient fitness, and test results taking too long to come back. In recent Indian study, EGFR testing was not possible in 24.5% of nonsquamous NSCLC. Compared to these, in our study, EGFR and EML-ALK mutation testing was possible in 87.1% and 84.5% of patients, respectively.
There is a large variation in the EGFR mutation rate across various ethnicities and geographies. The mutation rate ranges from 10% to 15% in Caucasians and 30% to 51% in Asian population. Studies from India have reported EGFR mutation rate of 25%–51.8%. In our study, incidence of EGFR mutation rate was 37.9%. It was more common in females (62.7%), nonsmoking males (34.5%), and in younger patients (30% in 41–50 years). Deletion 19 was the most common mutation type which is similar to most of the studies from India [Table 6] and Asian countries. The incidence of EGFR mutations in females was much higher than previously reported from India.
|Table 6: Epidermal growth factor receptor mutation, subtypes, and echinodermal microtubule-associated protein-like 4-anaplastic lymphoma kinase frequency in Indian studies|
Click here to view
Incidence of EML4-ALK rearrangement has been estimated from 3% to 8% and up to 12% from Asian population. In our study, EML4-ALK rearrangement was detected in 5.5%, which is similar to other study from India.
In recent years, clinical outcomes have significantly improved for patients with adenocarcinoma of lung. This can be attributed to histology-based chemotherapy, targeted therapy with TKIs based on mutations, and the use of maintenance therapy. One-year OS rate was 56.3% in our study compared to 29% in advanced NSCLC as reported in one meta-analysis in 2008, showing that outcome has improved for these patients. Median OS for all patients was 15.5 months in our study which is higher than that reported by Rajappa et al. for NSCLC (7 months) and in recent study by Noronha et al. (13 months, 96% adenocarcinoma of patients) and Malik et al. (12.8 months, 45% adenocarcinoma of patients)., The improved survival in the more recent reports reflects the better outcomes when treatment is tailored based on histology and mutation status.
Improved outcome of patients with EGFR mutation has been attributed to use of EGFR-TKIs. Outcomes of patients with EGFR mutation in our study were similar to that reported in literature. In our study, the median PFS for this group was 10.5 months. Similar results are reported by Bhatt et al. (11 months), Kota et al. (10 months), and Noronha et al. (10 months) from India,,, and the IPASS study where patients were treated with upfront EGFR-TKIs. In our study, out of 69 patients with EGFR mutation, 22 patients received upfront TKI and 37 received TKIs after a few cycles of cytotoxic chemotherapy. This reflects the delay in getting results of mutation analysis and needs to start chemotherapy for symptomatic patients and also taking into account patients' preference. Best ORR achieved was 73.4% which is similar to IPASS study (72%) and one study from India (73%)., Estimated median OS of these patients is 20.1 months. In some recent studies, it was shown that patients with exon 19 mutation do better than exon 21, especially if treated with upfront afatinib. In our study, RR, PFS, and OS were numerically better in exon 19 mutation compare to exon 21 mutation but not statistically significant.
Median PFS and OS in non-EGFR non-ALK-mutated patients were 6.5 months and 11 months, respectively. Most common chemotherapy regimen used was pemetrexed/platinum in 99 patients (81.8%). Pemetrexed/platinum doublet has shown improved efficacy in patients with adenocarcinoma of the lung. Furthermore, pemetrexed maintenance therapy has shown benefit in improving the outcome of these patients., In our study, almost half (39 of 69) of all patients who did not progress on first-line pemetrexed/platinum doublet went on to receive maintenance therapy with pemetrexed. Median cycles of maintenance chemotherapy were 6 (range, 1–25). OS of patients who received maintenance chemotherapy (18.5 months) were better than those who did not receive maintenance chemotherapy (12.5 months). These findings are comparable to PARAMOUNT trial (OS-16.9 months) and POINTBREAK trial (OS-17.7 months)., Only 33% of non-EGFR, non-EML4-ALK-mutated patients received second-line chemotherapy compared to 60%–65% in other trials. In spite of lower number of patients receiving second-line chemotherapy, our results were numerically better than reported in Western studies. The small numbers in our study may be one of the reasons for this improved outcome.
Most of the improvements seen in outcome of advanced adenocarcinoma of lung patients are due to discovery of subset of patients with oncogenic driver mutation and targeting this mutation with upfront TKIs. Furthermore, it is known that patients with EGFR mutation do better than wild EGFR type even without EGFR-TKIs., Median PFS of patients with targetable mutation and those without these mutations were 10.4 and 5.4 months, respectively (P< 0.0001), and median OS was 21.5 and 11 months, respectively (P< 0.0001) [Figure 4] and [Figure 5], reinforcing the fact that it is imperative to test for targetable mutations in patients with nonsquamous carcinoma and selected patients with squamous carcinoma.
|Figure 4: Kaplan–Meier projection for progression-free survival and overall survival: Comparison of progression-free survival and overall survival between epidermal growth factor receptor, echinodermal microtubule-associated protein-like 4 - anaplastic lymphoma kinase and nonepidermal growth factor receptor|
Click here to view
|Figure 5: Kaplan–Meier projection for progression-free survival and overall survival: Comparison of progression-free survival and overall survival between epidermal growth factor receptor, echinodermal microtubule-associated protein-like 4-anaplastic lymphoma kinase and nonechinodermal microtubule-associated protein-like 4-anaplastic lymphoma kinase|
Click here to view
Although our study was prospective, the pitfalls include small numbers and the lack of data regarding adverse events and quality of life. Quality of life is the most important intent of treatment in patients with advanced lung cancer patients.
| » Conclusions|| |
Demographic and molecular profile of patients with adenocarcinoma of lung is similar to most previously published studies from India and East Asia. Mutation analysis is feasible in the vast majority of patients and should be performed at diagnosis. The improved outcomes in our study compared to those published a few years ago reflect the improved understanding of disease biology and treatment based on histology and molecular analysis. The RR, PFS, and OS of patients who were positive for EGFR and EML4-ALK mutation were better than patients without these mutations. Maintenance chemotherapy resulted in significant improvement in OS.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al.
GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://www.globocan.iarc.fr
. [Last accessed on 2014 Mar 21].
Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, editors. World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. p. 12-5.
Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al.
A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62.
Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, et al.
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14:4275-83.
Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al.
Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther 2015;8:117-23.
Bhatt AD, Pai R, Rebekah G, Nehru GA, Dhananjayan S, Samuel A, et al.
Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status. Indian J Cancer 2013;50:94-101. [Full text]
Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, et al.
EGFR mutations in Indian lung cancer patients: Clinical correlation and outcome to EGFR targeted therapy. PLoS One 2013;8:e61561.
Mandal SK, Singh TT, Sharma TD, Amrithalingam V. Clinico-pathology of lung cancer in a regional cancer center in Northeastern India. Asian Pac J Cancer Prev 2013;14:7277-81.
Noronha V, Dikshit R, Raut N, Joshi A, Pramesh CS, George K, et al.
Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience. Indian J Cancer 2012;49:74-81.
] [Full text]
Malik PS, Sharma MC, Mohanti BK, Shukla NK, Deo S, Mohan A, et al.
Clinico-pathological profile of lung cancer at AIIMS: A changing paradigm in India. Asian Pac J Cancer Prev 2013;14:489-94.
Spicer J, Tischer B, Peters M. EGFR Mutation Testing and Oncologist Treatment Choice in Advanced NSCLC: Global Trends and Differences. Presented at ELCC; 2015. [Abstract Number LBA2_PR].
Kota R, Gundeti S, Gullipalli M, Linga VG, Maddali LS, Digumarti R. Prevalence and outcome of epidermal growth factor receptor mutations in non-squamous non-small cell lung cancer patients. Lung India 2015;32:561-5.
] [Full text]
Veldore VH, Rao RM, Kakara S, Pattanayak S, Tejaswi R, Sahoo R, et al.
Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: A retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India. Indian J Cancer 2013;50:87-93. [Full text]
Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, et al.
Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One 2013;8:e76164.
NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617-25.
Rajappa S, Gundeti S, Talluri MR, Digumarti R. Chemotherapy for advanced lung cancer: A 5-year experience. Indian J Cancer 2008;45:20-6.
] [Full text]
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al.
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N
Engl J Med 2009;361:947-57.
Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al.
Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015;16:141-51.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al.
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543-51.
Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al.
PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31:2895-902.
Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, et al.
PointBreak: A randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31:4349-57.
Mak RH, Doran E, Muzikansky A, Kang J, Neal JW, Baldini EH, et al.
Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC. Oncologist 2011;16:886-95.
Ahn HK, Choi YL, Han JH, Ahn YC, Kim K, Kim J, et al.
Epidermal growth factor receptor mutation and treatment outcome of mediastinoscopic N2 positive non-small cell lung cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery. Lung Cancer 2013;79:300-6.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]