Context: Oral tyrosine kinase inhibitors (TKIs) have been proven to improve response rates (RRs) and progression-free survival in a chemo-naïve setting in the epidermal growth factor receptor (EGFR)-mutant advanced lung adenocarcinoma patients in studies conducted in Western countries. Similar data from India are currently sparse. Aims: The aim is to study the epidemiological, clinical, and radiological profile of advanced-stage of lung adenocarcinoma patients harboring an EGFR mutation and to assess the response of TKIs in these patients. Settings and Design: This was a prospective observational study performed at a tertiary care hospital. Materials and Methods: A total of 40 advanced-stage lung adenocarcinoma patients who harbored an EGFR mutation and received an oral TKI (gefitinib) were included in the study and response was evaluated using the Response Evaluation Criteria for Solid Tumors. Statistical Analysis Used: Qualitative variables were compared using the Chi-square test/Fisher's exact test as appropriate. Results: A total of 30 (75%) patients had an exon 19 mutation and 3 (7.5%) patients had an exon 21 mutation. The overall RR to gefitinib was 57.5%. Eleven (27.5%) patients had partial response, 12 (30%) patients had stable disease (SD), and 6 (15%) patients had progressive disease. The RR was more favorable among females, rural residents, nonsmokers, patients having good performance score, and stage III disease. Conclusions: The overall RR to gefitinib was comparable to those reported in western studies but lower than those reported in Asian studies at our center.

Introduction

Lung cancer is the most common cancer affecting humanity, and is the leading cause of cancer-related deaths. While worldwide lung cancer accounts for 13% of all new cancer cases, it constitutes 6.9% of all cases in India.[1] According to the GLOBOCAN 2012, it is the fourth most common cancer in India and it holding the second position among males and the sixth position among females.[2] Lung cancer is responsible for around 10% of all deaths due to cancer in India.[1]

Among the histological variants of lung cancer, nonsmall cell lung cancer (NSCLC) constitutes around 85%, whereas SCLC constitutes 15% of all cases. Squamous and adenocarcinoma are the two most prevalent cell types of NSCLC. While adenocarcinoma is more common worldwide, in India, there appears to be a conflict with different centers providing different data in the absence of a countrywide registry.

Till 2004, the treatment of all types of advanced NSCLC was similar, irrespective of histology. In 2004, there was a historic breakthrough when activating the epidermal growth factor receptor (EGFR) mutations were discovered in lung cancer.[3] EGFR is transmembrane receptors responsible for cellular functioning. On ligand binding, there is phosphorylation of receptor, which causes downstream signaling through tyrosine kinases, leading to cell maturation and differentiation. Lynch et al. reported that certain lung cancers have activating EGFR mutations (across exon 19–21). These mutant receptors do not require ligand binding for activation and thus cause unregulated cellular proliferation and growth. These activating mutations are commonly found in adenocarcinoma, female patients, never smokers, and patients of East Asian origin.[4]

The discovery of EGFR mutations led to renewed interest in targeted therapy for lung cancer. Tyrosine-kinase inhibitors (TKIs) such as gefitinib and erlotinib are small-molecule inhibitors which bind to intracellular domain of EGFR, preventing autophosphorylation and downstream signaling. In comparison to conventional chemotherapy, EGFR-TKIs provide longer progression-free survival (PFS), a better quality of life and are better tolerated in EGFR-mutant lung cancer. TKIs are approved as both first and second line therapy as well as maintenance therapy in patients with advanced lung adenocarcinoma.

Although lung cancer has been extensively researched elsewhere in the world, research in India is still in its nascent stage. Limited data are available regarding incidence, histological and stage-wise distribution, chemotherapy response, mortality, and survival for lung cancer in general and adenocarcinoma in particular.

We conducted a prospective observational study at our tertiary care center to evaluate the clinico-epidemiological profile of advanced lung adenocarcinoma patients and response to gefitinib with the following aims and objectives:

To study the epidemiological, clinical, and radiological profile of advanced lung adenocarcinoma patients harboring an EGFR mutationTo study the response of gefitinib in these patients at 6 and 12 months and to assess the correlation of response rates (RR) to clinical parameters.

Materials and Methods

This was a prospective observational study carried out at the respiratory medicine department of a tertiary care center in North India. On the basis of a questionnaire, the basic demographic, clinical, radiological, and histological features of each patient were recorded. The diagnosis of lung adenocarcinoma was established by cytology or histopathology of samples obtained by computed tomography (CT)-guided transthoracic fine-needle aspiration (FNA) and/or biopsy, endobronchial biopsy or pleural biopsy (thoracoscopic and/or closed). The staging of disease was done using contrast-enhanced computed tomography (CECT) thorax with abdomen or ultrasonography of the abdomen and CT head whenever relevant according to the tumor, node, metastasis (TNM) eight staging. Patients having advanced disease (stage III and IV; according to the TNM eight staging) were included in the study.[5] The functional status of the patients was measured using the Eastern Cooperative Oncology Group (ECOG).[6]

Inclusion criteria

Newly diagnosed (chemo-naïve) advanced-stage (III and IV) lung adenocarcinoma patients harboring EGFR mutations who are receiving 250 mg oral gefitinib once daily were included.

Exclusion criteria

Lung adenocarcinoma with unknown EGFR statusLung adenocarcinoma patients who have previously received or those who were receiving conventional chemotherapy were excluded.

The samples which were positive for adenocarcinoma were subjected to EGFR mutation analysis. Immune-histochemistry on the tissue sample was performed using cell signaling technology. The EGFR mutations in exon 19 were detected through E746-A750 deletion specific monoclonal antibodies while the EGFR mutation in exon 21 was detected through L858R mutant-specific monoclonal antibodies. This method for immune-staining for EGFR mutation-specific antibody has a sensitivity of 81.4% and a specificity of 97.5%.[7]

A total of 81 advanced-stage lung adenocarcinoma patients were diagnosed at our center over a period of 1 year. Of these, 40 patients who harbored EGFR mutation and were receiving gefitinib were included in the study.

After the initiation of gefitinib, the patients were followed up monthly by chest radiographs and clinical status. A CECT thorax was performed at 4, 6, and 12 months, and other relevant investigations were done whenever required. Based on CT, response was evaluated using Response Evaluation Criteria for Solid Tumors (version 1.1, 2009).[8]

Study protocol

Of 40 patients receiving gefitinib, 6 patients expired and 5 patients were lost to follow-up. Hence, the assessment was made for 29 patients at 6 months. Subsequently, out of these, 6 patients have completed 12 months of treatment and 2 patients have completed 18 months of treatment at the time of data compilation [Figure 1].{Figure 1}

Statistical tools employed

The data were entered into MS Excel spreadsheet and analysis was performed using Statistical Package for Social Sciences software version 21.0, manufactured by IBM, USA. Categorical variables were presented in number and percentage (%), and continuous variables were presented as mean and standard deviation. Qualitative variables were compared using the Chi-square test/Fisher's exact test as appropriate. A value of P < 0.05 was considered statistically significant.

Results

The age of patients varied from 34 to 78 years, with a mean age of 55.95 years. The male-to-female ratio was 1.2:1 [Table 1]. Around two-thirds of patients (60%) were from a rural background, with the majority of males being farmers (42.5%) and all the females being homemakers. Nearly 57.5% of patients were nonsmokers, whereas 42.5% were smokers.{Table 1}

The common symptoms reported by the patients were cough (70%), dyspnea (70%), and chest pain (67.5%). A few patients reported hemoptysis (12.5%) and hoarseness of voice (15%). Fever was a chief complaint in 32.5% of patients. As far as performance status is concerned, maximum number of patients were in the ECOG functional grade 2 (50%) at the time of diagnosis, followed by grade 3 (37.5%) and grade 4 (12.5%).

Regarding radiological features, all the tumors were unilateral, with more preponderance to the left side (57.5%) [Table 2]; three-fourths of the tumors (75%) were peripheral. Nearly 77.5% of patients had the presence of pleural effusion and 25% of patients had evidence of distant metastasis at the time of diagnosis. Being peripheral, the majority (70%) of patients were diagnosed through transthoracic FNA and biopsy, 20% were diagnosed through closed pleural biopsy and 5% each through thoracoscopic pleural biopsy and endobronchial biopsy. Majority (87.5%) of patients were diagnosed in stage IV, 10% in stage IIIB, and 2.5% in stage IIIA.{Table 2}

On mutation analysis, 30 (75%) patients had an exon 19 mutation and 3 (7.5%) patients had an exon 21 mutation. In 7 (17.5%) patients, the exon analysis could not be performed due to the small sample size and the EGFR mutation was only quantitative.

On response evaluation at 6 months, the overall RR was 57.5%. Eleven patients either expired or were lost to follow-up. The remaining 29 patients were assessed. 11 (27.5%) patients had partial response (PR), 12 (30%) patients had stable disease (SD), and 6 (15%) patients had progressive disease (PD). The patients having progressive disease were switched over to conventional chemotherapy depending on the performance statusOn evaluation at 12 months, out of six patients, 3 patients had SD, 2 patients had PR, and one patient had PDAt 18 months, one patient had SD and one had PR.

The RR was more favorable among females, rural residents, nonsmokers, patients having good performance score and stage III disease; while it was poorer among patients having pleural effusion, distant metastasis and stage IV disease; although, these figures were no statistically significant [Figure 2] and [Table 3].{Figure 2}{Table 3}

Discussion

In this study, the age of patients varied from 34 to 78 years, with a mean age of 55.95 years. This result is similar to national figures according to the GLOBOCAN 2008 which reported the mean age at diagnosis among patients with lung cancer in India to be 54.6 years during the period of 1985–2001.[9]

The gender-wise distribution among the patients in our study was almost equal (male: female = 1.2:1). Noronha et al. analyzed the demographic data collected from 489 Indian lung cancer patients. They reported a male-to-female ratio of 3.5:1.[10] Over the last three decades, adenocarcinoma has remained the predominant tumor type among females; explaining the preponderance of females in our study.[11]

In this study, 57.5% of the patients were nonsmokers (which include those who have never smoked and those who have smoked <100 cigarettes/bidis in their lifetime). This is in accordance with other studies which state that lung adenocarcinoma is more common in nonsmokers.[12] Noronha et al. reported that 52% of lung cancer patients were nonsmokers.[10] Worldwide, among nonsmokers; lung cancer is the 7th leading cause of cancer mortality.[13]

Another common risk factor for lung cancer among Indian patients, especially those from a rural background is biomass fuel exposure. Biomass fuel includes wood, coal, dung cakes, etc. These constitute a cooking means in around 60% of Indian homes and most of this is done on an open fire.[14] About 40% patients in the study had this exposure. Only those patients were included who had direct exposure to smoke, i.e., women who cook on chulhas and men who are exposed to burning fuel because of the kitchen being inside the house. Emissions from house-hold coal combustion are labeled as Group 1 and biomass combustion as Group 2A carcinogen, according to the International Agency for Research on Cancer (IARC 2006).[15]

Surprisingly, 35% of patients in the study had a history of anti-tuberculosis treatment (ATT) intake, either in the past 1 year or were taking ATT at the time of diagnosis of lung cancer. Out of this, only two patients had any evidence of pulmonary or pleural tuberculosis (TB). This implies that around 1/3rd patients were incorrectly diagnosed with TB and were prescribed ATT, leading to a substantial delay in diagnosis. Agarwal et al. similarly reported that out of 195 cases of lung cancer, 40% of patients had taken ATT; although, only 5% of patients had co-existent TB and cancer.[16] They also stated that the mean delay in diagnosis of lung cancer in such patients was 3.2 months.

Over a period of 1 year, a total of 81 advanced lung adenocarcinoma patients were diagnosed at our center. Of these, 40 (49.38%) were found to have EGFR mutation and were included in the study. Doval et al. enrolled 500 lung adenocarcinoma patients from six centers across India.[17] They found that 32.8% of patients were positive for EGFR mutation. Various Indian studies have reported the prevalence of EGFR mutation in lung cancer between 25% and 50%.[18],[19],[20],[21]

In this study, 75% of patients had an exon 19 mutation and 7.5% of patients had an exon 21 mutation. In 17.5% of patients, the exon analysis could not be performed due to small sample size and the EGFR mutation was only qualitative. None of the patients had a co-existence of both exon 19 and 21 mutations. In the data collected from 907 Indian lung adenocarcinoma patients, Chougule et al. reported 50% of patients having exon 19 mutation, 42% having exon 21 mutation, and 3% having exon 20 mutation.[20] In another study conducted by Bhatt et al. among 104 histologically confirmed NSCLC, 80% of patients had exon 19 mutation.[22] In this study, we found no association between exon, age, and gender. Similarly, Bhatt et al. found no significant association between exon, histology, age, and gender.[22]

On response evaluation of gefitinib at 6 months, the majority (57.5%) of patients had a favorable response (either SD or PR, 15% had PD, and 27.5% of patients either expired or were lost to follow-up, thus the overall RR was 57.5%. Various studies have been conducted globally using EGFR TKIs as first-line treatment for EGFR-mutant patients. Among these, the RRs from Japanese and Chinese studies have been encouraging, with RR of 73.7% and 83% reported by Maemondo et al. and Zhou et al., respectively.[23],[24] On the other hand, European studies such as EURTAC (Rosell et al., 2011)[25] and American studies (Sequist et al., 2008)[26] have reported comparatively lower RR of 58% and 55%, respectively. Going by this trend, our study compares with European and North American statistics rather than Asian data as was previously thought.

No significant association was found between gender and response to Gefitinib therapy in our study. A similar study conducted in China (n = 33) also found no association between female gender and response to TKIs.[27] Previous studies have found female gender to be a positive predictor for response to TKIs in lung adenocarcinomas.[28],[29]

As compared to smokers (10%–20%), nonsmokers have 40%–60% incidence of harboring EGFR mutation.[30],[31] TKIs have been consistently shown to have favorable response in nonsmokers.[32] in our study also, RR was more favorable in nonsmokers; although, the data were not statistically significant.

Choi et al. conducted a retrospective study among 130 patients of stage IV adenocarcinoma harboring EGFR mutations.[33] They evaluated the CT features in these patients which favor a positive response to TKIs. They found that patients with pleural effusion, pleural metastasis or both tend to have shorter -PFS. Our findings resonate with this study as we found a poorer response in patients with pleural effusion or distant metastases.

Choi et al. also reported that the patients having exon 19 deletion are more sensitive to TKI therapy.[34] Kosaka et al. also reported that although the RR of each mutation group was different (93% for exon 19 and 75% for exon 21), there was no difference in overall survival between these two groups of patients.[34] We also did not find any statistically significant difference in RR according to exon.

In the present study, the RR was more favorable among females, rural residents, nonsmokers, patients having good performance score, and stage III disease; while it was poorer among patients having pleural effusion, distant metastasis, and stage IV disease; although, these figures were not statistically significant.

This study had certain shortcomings. The number of patients was small to generalize the results to the whole population. Since the patients were enrolled at different points of time, at the time of compilation of data, only few patients had completed 12 and 18 months of treatment. Furthermore, survival data (PFS and OS) could not be evaluated because the duration of the study was small.

Conclusions

We found an overall RR of 57.5% to Gefitinib, lesser than figures reported by Asian studies and comparable to European and American studies. We also noted that the RR was more favorable among females, rural residents, nonsmokers, patients having good performance score, and stage III disease; while it was poorer among patients having pleural effusion, distant metastasis and stage IV disease. Further studies enrolling a larger number of patients are mandated to consolidate or refute these findings. A nation-wise registry for advanced lung adenocarcinoma would be insightful for a broader perspective regarding lung cancer patients in India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.