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 Table of Contents  
Year : 2021  |  Volume : 5  |  Issue : 3  |  Page : 104-110

Epidemiological, clinical profile, and treatment outcome of stage iv nonsquamous nonsmall cell lung cancer patients presenting to tertiary care hospital in North India

1 Department of Medical Oncology, Assam Cancer Care Foundation, Tezpur, Assam, India
2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India
3 Department of Pathology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India

Date of Submission24-Aug-2021
Date of Decision07-Nov-2021
Date of Acceptance27-Nov-2021
Date of Web Publication14-Dec-2021

Correspondence Address:
Venkata Pradeep Babu Koyyala
Department of Medical Oncology, Assam Cancer Care Foundation, Tezpur - 784 153, Assam
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/oji.oji_34_21

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Background: Better planning of limited resources in oncology is possible with more real-world data of lung cancer, one of the most common causes of cancer related mortality in India and Globe. Aim: This study aimed to evaluate the clinical profile and treatment outcomes in patients with Stage IV adenocarcinoma of lung at our center. Materials and Methods: One hundred and eighty-two patients with Stage IV adenocarcinoma of lung were prospectively screened and analyzed, of which 107 patients who met the inclusion criteria were included in the final analysis. Patients with epidermal growth factor receptor (EGFR) and echinodermal microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) genomic alterations were treated with tyrosine kinase inhibitors and others were treated as per standard chemotherapy regimens. Response rates (RRs), progression-free survival (PFS), and overall survival (OS) were measured. Results: Median age of patients was 55.6 years (range, 26–82) with a male-to-female ratio of 1.23:1. Analyses for EGFR and EML4-ALK alterations were possible for 104 (96.3%) patients and were detected in 31.7% and 8.7% patients, respectively. The overall RR for the entire cohort was 51.4%, while median PFS and median OS were 6.9 and 13.7 months, respectively. Median PFS for the EGFR-mutated and ALK-rearranged group was 9.6 and 10.2 months, respectively, which was higher than non-EGFR non-ALK patients. Median OS for the whole cohort was 13.7 months, while median OS was not reached for EGFR and ALK altered groups. Conclusions: As patients with driver mutations like EGFR and ALK have better prognosis than those who do not, every patient diagnosed with advanced nonsmall cell lung cancer should be offered mutational analysis.

Keywords: Advanced lung cancer, anaplastic lymphoma kinase rearrangement, epidermal growth factor receptor mutation, survival

How to cite this article:
Koyyala VP, Sharma M, Goyal P, Goel V, Bommera S, Agrawal M, Domadia K, Choudhary K, Bothra S, Jajodia A, Amrith B P, Joga S, Pasricha S, Batra U. Epidemiological, clinical profile, and treatment outcome of stage iv nonsquamous nonsmall cell lung cancer patients presenting to tertiary care hospital in North India. Oncol J India 2021;5:104-10

How to cite this URL:
Koyyala VP, Sharma M, Goyal P, Goel V, Bommera S, Agrawal M, Domadia K, Choudhary K, Bothra S, Jajodia A, Amrith B P, Joga S, Pasricha S, Batra U. Epidemiological, clinical profile, and treatment outcome of stage iv nonsquamous nonsmall cell lung cancer patients presenting to tertiary care hospital in North India. Oncol J India [serial online] 2021 [cited 2022 Jan 21];5:104-10. Available from: https://www.ojionline.org/text.asp?2021/5/3/104/332509

  Introduction Top

Lung cancer is still the leading cause of cancer-related mortality in India and across the globe, as per the latest Globocan data. Although lung cancer is the most commonly diagnosed cancer in men across the world, in India, its incidence ranks after lip and oral cavity cancers, ranking fourth in the overall population. Lung cancer accounted for 5.5% of all new cancer cases in India, and 8% among new cases in males, according to Globacon 2020.[1] Among all histologies of lung cancer, adenocarcinoma is the most common subtype, in both nonsmokers and smokers. Most of the lung cancers (more than 70%) are diagnosed in advanced stage (Stage IIIb and IV) at diagnosis, leading to incurability with poor prognosis.[2]

The discovery that several subsets of adenocarcinoma lung are driven by oncogenic addiction made targeted therapies as the treatment of choice and made the concept of personalized medicine drive into reality. 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, ROS 1, BRAF mutation, NTRK1/2/3 fusions, and RET rearrangement testing in specific groups of patients with newly diagnosed nonsmall cell lung cancer (NSCLC) along with several other newer targets and targeted therapies in pipeline. EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) and ALK, and ROS 1 inhibitor (crizotinib, ceritinib, alectinib, brigatinib and lorlatinib) have been approved by the FDA (The Food and Drug Administration, USA) for first-line treatment of patients with these molecular aberrations detected in their tumors. However, these molecular tests show positivity in less than half of all advanced lung cancers diagnosed, which indicates the need for palliative chemotherapy in those patients. Chemotherapy is also needed in those who progress after all the available TKIs usage.[3] The incidence of EGFR mutations in the Indian population ranges from 25% to 51% and ALK rearrangement from 4% to 8%.[4],[5],[6] Various studies from India have reported the demographic and molecular profiles of patients with NSCLC, but very few have reported on the outcomes of these patients on EGFR-TKIs or ALK inhibitors. Moreover, there is a paucity of data on response rates (RRs) and survivals with palliative chemotherapy in Stage IV patients with adenocarcinoma.[7],[8],[9],[10] Here, we present the demographic and 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 Top

Patients with Stage IV adenocarcinoma of lung diagnosed at our institute between April 2016 and March 2017 were included in the study. The Institutional Ethics Committee approved the study (letter number: RGCIRC/IRB/57/2016).

Inclusion criteria

  1. All cases of diagnosed Stage IV nonsmall cell lung cancer patients of adenocarcinoma histology
  2. Treated at our institute either with chemotherapy or molecular-directed targeted therapy.

Exclusion criteria

  1. Stage IV lung cancer patients with inadequate sample for molecular testing
  2. Patients diagnosed with dual malignancy.

Based on previous studies, the prevalence of Stage IV lung cancers among all diagnosed lung cancers was 75%.[11] Taking this value as reference, the minimum required sample size with 10% margin of error and 5% level of significance is 72 patients. Hence, to reduce margin of error, the total sample size taken is 100. Demographic parameters analyzed were age, sex, and smoking history. The diagnosis was confirmed by biopsy in most of the cases or fine-needle aspiration cytology with cell block and reported as per the International Association for the Study of Lung Cancer classification. Immunohistochemistry with appropriate antibody was done whenever required for confirmation of histology. Stage IV was established by 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 performed whenever clinically indicated. For EGFR mutation analysis, real-time amplification refractory mutation system-polymerase chain reaction method was used for the detection of mutations in exons 18–21 and EML4-ALK translocation was done on Ventana platform using paraffin-embedded tissue.

Informed consent was obtained from all patients before starting treatment. Patients were treated with various chemotherapy regimens as per the standard dose schedule such as cisplatin or carboplatin and pemetrexed, carboplatin and paclitaxel or gemcitabine, and cisplatin and etoposide every 3 weeks as per standard doses. Pemetrexed is administered at 500 mg/m2 on day 1, carboplatin at AUC5 on day 1, cisplatin at 75 mg/m2 on day 1, paclitaxel 175 mg/m2 day 1, gemcitabine at 1000 mg/m2 on day 1, and etoposide 100 mg/m2 on day 1 to day 3 basis for the above combinations. EGFR- and EML4-ALK-negative patients who achieved complete response, partial response (PR), or stable disease (SD) at the end of 4–6 cycles of chemotherapy were offered maintenance pemetrexed chemotherapy at a dose of 500 mg/m2 at 3-weekly intervals. EGFR-mutated patients received the EGFR-TKIs such as erlotinib, gefitinib, or afatinib either upfront or after 2–4 cycles of chemotherapy as per pending mutation results. EML4-ALK-rearranged patients received crizotinib either upfront or after 2–4 cycles of chemotherapy. Depending on the clinical condition, patients also received locoregional treatment such as pleurocentesis and pleurodesis, palliative radiotherapy to skeletal metastasis, brain metastasis, and superior vena cava syndrome, either before start of treatment or during treatment as required. Response assessment using RECIST 1.1 criteria was done after 2–3 cycles of chemotherapy treatment, at the end of first-line treatment and then every 2–3 months for patients on maintenance treatment (chemotherapy or TKI) and for patients on follow-up.

Statistical methods

The data analysis was done using Statistical Package for Social Sciences (SPSS Inc., Chicago, III, USA) version 21.0. Significance P value was set at <0.05 and Kaplan–Meier curves were plotted for PFS and OS. Log-rank test was used to compare PFS and OS between different groups.

  Results Top

Patients were enrolled from April 2016 to March 2017 at our institution, a tertiary care cancer in New Delhi.

There were 182 histologically proven patients of Stage IV adenocarcinoma of lung enrolled as the study population. Twelve patients were kept on best supportive care after histological diagnosis because of poor performance status and were excluded. Among the remaining 170 patients, 15 patients were not willing to give consent and 48 patients were treated elsewhere after diagnosis at our center. The remaining 107 patients who were diagnosed and treated at our institute and met the inclusion criteria were included as study sample for the analysis. Molecular analysis for EGFR mutations and ALK rearrangements was done in all available patients. Three patients were unable to undergo molecular analysis due to logistic issues. Patients who were tested negative for these molecular alterations were offered chemotherapy. Patients who were symptomatic and those who wished to have therapy before molecular lab results were also offered chemotherapy. Those who tested positive for either EGFR or ALK were shifted to TKIs immediately after test results or after the completion of 4 cycles as per the patients' wish. All the patients were available to follow-up till the end of study or till death of the patient.

Hence, 107 patients as a study sample were analyzed in the study. The median age of the patients was 55.6 years (range: 26–82) with a male-to-female ratio of 1.23:1. Both EGFR and EML4-ALK mutation analyses were possible for 104 (97.2%) patients. EGFR mutation and EML4-ALK translocation were detected in 33 (31.7%) and 9 (8.7%) patients, respectively. The demographic and molecular characteristics are presented in [Table 1]. Among EGFR-positive patients, male-to-female ratio is 0.8:1, one patient was a smoker among males, and there were no smokers in female patients. The mean age of EGFR-positive population is 54.5 years.
Table 1: Demographic characteristics of whole cohort

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EGFR-mutated patients have a female (1.2:1) and nonsmoker (32:1) preponderance than nonmutated patients. Similarly, for EML4-ALK rearrangement, there was female preponderance (2:1) and all the patients were nonsmokers.

EGFR mutations detected were deletions in exon 19 in 23 patients (69.7%), exon 21 in 7 patients (21.3%), exon 18 in 1 patient (3%), exon 20 in 1 patient (3%), and a combined deletion 19 and exon 21 mutation in one patient (3%).

For EML4-ALK gene rearrangements positive (n = 9), patients younger than 50 years constituted 55.6% and females constituted 66.7% among patients tested positive for ALK mutation. None of the patients among ALK positivity were smokers.

Among EGFR-mutated patients, 54.5% of patients received gefitinib, 39.3% of patients received erlotinib, and 6% patients received afatinib. About 27% of patients received EGFR-TKI after some chemotherapy which was started pending mutation testing. The median number of chemotherapy cycles received by patients before start of TKI was 4. All patients positive for EML4-ALK rearrangement received crizotinib, among which one patient has received chemotherapy before crizotinib. In non-EGFR non-ALK (without driver mutation) group, the most common chemotherapy regimen used was pemetrexed/platinum in 62 (95.3%) patients, followed by paclitaxel/platinum in 2 (3.08%) and etoposide/platinum in 1 patient (1.54%).

Treatment results

Response assessment, median PFS, median OS, and 1-year OS for whole cohort, non-EGFR non-ALK-mutated, EGFR- mutated, and ALK-rearranged patients are depicted in [Table 2] and [Figure 1], [Figure 2], [Figure 3]. Objective RR (CR + PR) for whole cohort, non-EGFR non-ALK, EGFR, and ALK cohorts were 48.6%, 46.1%, 48.5%, and 66.7%, respectively. SD rates for entire cohort, non-EGFR non-ALK, EGFR, and ALK cohorts were 26.2%, 24.6%, 27.3%, and 33.3%, respectively. Progressive disease rates for entire cohort, non-EGFR non-ALK, EGFR, and ALK cohorts were 25.2%, 29.3%, 24.2%, and 0%, respectively [Table 2].
Table 2: Treatment outcome of study cohort, nonepidermal growth factor receptor nonanaplastic lymphoma kinase-mutated, epidermal growth factor receptor-mutated, and anaplastic lymphoma kinase-rearranged patients

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Figure 1: Progression-free survival of epidermal growth factor receptor-mutant, anaplastic lymphoma kinase-positive, and nonepidermal growth factor receptor nonanaplastic lymphoma kinase (chemotherapy) patient groups

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Figure 2: Kaplan–Meier distribution of progression-free survival of the entire cohort

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Figure 3: Kaplan–Meier distribution of overall survival of the entire cohort

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In non-EGFR non-ALK (without driver mutation) group, most common chemotherapy regimen used was pemetrexed/platinum in 62 (95.3%) patients, followed by paclitaxel/platinum in 2 (3.08%) and etoposide/platinum in 1 patient (1.54%).

Response assessment for non-EGFR non-ALK group patients (n = 65) who received different chemotherapy regimens is depicted in [Table 3]. Of the 62 patients who received pemetrexed/platinum regimen, 39 patients (62.9%) progressed on first-line therapy and the remaining 26 patients went on to receive maintenance pemetrexed. PFS of patients who received maintenance pemetrexed was 6.4 months compared to 5.2 months in patients who have not received maintenance pemetrexed, and the difference was statistically not significant (P = 0.198) [Table 4]. OS of patients who did not receive maintenance was 8.2 months, while median OS was not reached for patients who have received maintenance.
Table 3: Response rates in nonepidermal growth factor receptor nonanaplastic lymphoma kinase group patients who received chemotherapy

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Table 4: Univariate Cox proportional hazard for progression-free survival on chemotherapy

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Among patients who were positive for EGFR mutation, 22 patients have received upfront EGFR TKI, whereas 11 patients have received chemotherapy before receiving TKI. The median number of chemotherapy cycles administered before TKI was 4. None of the patients progressed on chemotherapy before receiving TKI.

The median follow-up period for the study was 16 months. Median PFS for whole cohort, non-EGFR non-ALK, EGFR, and ALK cohorts was 6.9 months, 5.9 months, 9.6 months, and 10.2 months, respectively [Table 2]. Median OS for whole cohort and non-EGFR non-ALK patients was 13.7 months and 13.6 months, respectively. Median OS has not reached for EGFR and ALK cohorts [Table 2] and [Figure 1], [Figure 2], [Figure 3]. One year OS rate for whole cohort, non-EGFR non-ALK, EGFR-mutant, and ALK-positive cohorts was 63.28%, 54.43%, 72.05%, and 100%, respectively [Table 2] and [Figure 1].

Univariate Cox proportional hazard regression was used to find out the significant factors [Table 4], [Table 5], [Table 6]. Male had significantly lower OS as compared to female (P = 0.028; hazard ratio of 2.4). Smoking significantly reduces the OS (P = 0.004; hazard ratio of 3.681. Mutation had significantly higher OS than nonmutated patients (P = 0.003; hazard ratio of 0.203). After adjusting for the confounding factors, none of the factors independently affect OS.
Table 5: Univariate Cox proportional hazard regression for progression-free survival on tyrosine kinase inhibitors

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Table 6: Univariate Cox proportional hazard regression for overall survival

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  Discussion Top

There has been a paucity of data on epidemiological and molecular profile in the Asian continent, particularly in India where there is a wide gap in health-care availability and accessibility within various regions of the country. Revolutionary developments in the treatment approaches of lung cancer became possible with better understanding of molecular underpinnings. The understanding about the oncogenic addicted pathways lead to formulation of several targeted therapies. The present prospective analysis describes epidemiological profile, the pattern of driver mutations, treatment, and outcome among patients with Stage IV adenocarcinoma of lung in an Indian setting.

Smokers constituted 35.5% and nonsmokers were 64.5%. The proportion of smokers in this patient population was the same as the results in a study by Doval et al.,[7] which was 32.8%. But compared to 32.6% of female population in Doval et al. study, the percentage of female population is higher in our study which was 44.9%. A study from eastern India by Mandal et al.[11] reported a higher incidence of female population (57.1%) compared to males and higher incidence of smoking rates (56.4%) which may be due to cultural differences between geographical areas with different smoking habits in people. A study by Noronha V et al.[9] from western India revealed 23.8% of smokers in the study population with 77.7% male and 33.3% female patients with a male-to-female ratio of 3.5:1. Another study from Northern India by Malik et al.,[12] with 434 patients of lung cancer in their study and adenocarcinoma as commonest histology, smokers constituted 68% and male-to-female ratio was 4.6:1. The wide variations in smoking patterns reveal the differences in cultural aspects of various regions in India as well as adaptation toward westernization with more trends of increasing smoking trends in female population in those particular regions.

The median age of patients in the present study was 55.6 years and most of the patients (57.94%) were between 41 and 60 years. Similar to our observations, an Indian study by Noronha et al.[9] reported the median age of 55 years. However, another Indian study by Mandal et al.[11] reported elderly patients >60 years constituted 67.8% of their study population whereas only 29.3% patients in 40–60 years age group.

The frequency of EGFR mutations varies widely based on region and ethnicity. The incidence rates reported in India vary from 25.9% to 51.8% in various series, and this rate is different in each region of the country.[7],[8],[9],[13],[14] The reported incidence rates from north and south Indian regions were 33% and 65%, respectively.[15] The wide variation in these reports may be due to differences in patient selection for mutational analysis, smoking patterns in populations, and the type of institute in which the study was carried out.

In the present study which predominantly included North Indian patients, the observed incidence of EGFR mutation rate is 31.7%. This rate is in concordance with most of the studies from other countries in Asia but is lesser than the reported rate in the South Indian population.[15] In this study, female patients (54.5%) account for the predominant proportion of EGFR mutation positive compared to male patients (45.5%). Predominance of female sex in EGFR-mutated population was seen in several reports from India. Doval et al. reported 41.7% of female patients with EGFR mutated, whereas only 28.5% of male patients with EGFR mutated.[7] In our study, only 3% of EGFR-mutated patients were smokers and the rest 97% were nonsmokers. This higher incidence of mutations in nonsmokers was reported from other studies in India, Asia as well as Europe.[3],[7],[16],[17],[18]

The most commonly reported type among EGFR mutation was exon 19 deletion in several studies from Asia.[3],[16],[17] In our study, the detected percentage of exon 19 deletion among all EGFR mutations was 69.7%. We found exon 21 mutations as the second most common EGFR mutation and were seen in 21.2% of patients. Several studies also reported exon 21 mutation as the second common EGFR mutation.[3],[16],[17] One patient had double mutation involving both exon 19 deletion and exon 21. Exon 18 and exon 20 mutations were found in one patient each.

Majority of studies reported the incidence rates of ALK mutation around 3% such as Shinmura et al.[19] (2.6%), Inamura et al.[20] (3.4%), Koivunen et al.[21] (3%), and an Indian study by Desai et al.[22] (2.7%). The ALK positivity detection rate in the present study was 8.7%, which is higher than most reported series. In support of our data, few studies also reported a higher incidence rate of ALK mutation such as Soda et al.[23] (6.7%) and Shaw et al.[24] (13%). In most of the reported series on ALK-positive lung cancers, patients were younger than 50 years and with female preponderance.[4],[22] In our study, females accounted for 66.6% and among 9 patients positive for ALK, none were smokers, which is like the above-quoted series.

Several studies on advanced NSCLC patients reported an overall RR (ORR) of 21% to 46%, median survival of 8.2–11.3 months, and 1-year OS of 25% to 40% with the use of various platinum-based doublets.[25],[26],[27],[28] Rajappa et al. reported RRs of 35.4%, median survival of 6 months and 1-year OS of 29.8% in advanced NSCLC patients who received chemotherapy.[29] Compared to all these studies, 1-year OS rate (63.3%), RR (48.6%), and median survival (13.7 months) were higher in our study, probably because of more use of targeted therapies in EGFR- and ALK-mutant patients which has higher RRs and PFS rates compared to chemotherapy.

In our study, 72% of patients received at least one cycle of chemotherapy, which included 33.3% of EGFR-mutant patients who received chemotherapy before starting on EGFR TKI. This was possible as a result of evolution of better techniques in obtaining tissue for molecular analysis as well a decrease in turnover time for results of molecular diagnostic tests.

Efficacy of pemetrexed–platinum combination over gemcitabine–platinum combination among NSCLC patients of adenocarcinoma histology has been shown in a Phase III study.[30] The most commonly used chemotherapy regimen in the present study was pemetrexed–platinum combination which accounted for 95.4% of total chemotherapy given. Other regimens used were paclitaxel–platinum and etoposide–platinum combinations in 3.1% and 1.5%, respectively.

In our study, clinical benefit rate (CR + PR + SD) was 71% with pemetrexed plus platinum chemotherapy regimen. Similar RRs were reported in PARAMOUNT trial (75%),[31] study by Paliwal et al.,[10] and the study by Bhatt et al.[8] Paliwal et al. reported a clinical benefit rate of 69.7% among patients with non-EGFR and non-ALK-mutated Stage IV adenocarcinoma of lungs who received pemetrexed plus platinum regimen.[10] Moreover, several trials reported improved outcomes with pemetrexed maintenance therapy.[31] Only 41.9% of patients had received maintenance in the present study who received pemetrexed-based chemotherapy initially. Reasons for not receiving maintenance were disease progression, patient's preference, and logistical and financial constraints.

Among 33 patients who tested positive for EGFR mutation, 22 patients received EGFR TKI upfront, whereas 11 patients received TKI after chemotherapy. The reason for administering chemotherapy before TKI was the turnover time required for the arrival of results of molecular diagnostic tests, symptomatic patients, and patient's preference after counseling about the possible treatment options. The median number of chemotherapy cycles administered before TKI was 4 (range 1–6). The median PFS for EGFR cohort in this study was 9.6 months which is similar to outcomes in several other national and international studies where TKI was started upfront like in IPASS study[32] (9.5 months), EURTAC[33] (9.7 months), and Noronha V et al.(10 months).[9]

In our study, the median PFS of ALK-positive patients was 10.2 months and the median OS has not reached by 1 year. Comparison of crizotinib upfront with pemetrexed platinum combination was done in a study by Solomon et al.[34] in ALK-positive NSCLC, and reported ORR was 74% and 45%, median PFS was 10.9 months versus 7 months in TKI and chemotherapy arms, respectively. Although a smaller number of patients with ALK positivity were included in our study, the outcomes were similar to larger study by Solomon et al.[34]

  Conclusions Top

As patients with driver mutations like EGFR and ALK have better prognosis than those who do not, every patient diagnosed with advanced nonsmall cell lung cancer should be offered mutational analysis.

Larger studies with representative population from all areas of particular region help in getting a clear picture of demographic profile and help in planning resource allocation by government, planning medical facilities, and preventive and educational measures.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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