|MINI SYMPOSIUM: LUNG
|Year : 2012 | Volume
| Issue : 1 | Page : 74-81
Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience
V Noronha1, R Dikshit2, N Raut3, A Joshi1, CS Pramesh4, K George4, JP Agarwal5, A Munshi5, K Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, India
2 Department of Epidemiology, Tata Memorial Hospital, Parel, Mumbai, India
3 Department of Medical Oncology, Seven Hills Hospital, Andheri (East), Mumbai, India
4 Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, India
5 Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai, India
|Date of Web Publication||25-Jul-2012|
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai
Source of Support: None, Conflict of Interest: None
Context: Lung cancer has varied epidemiology depending on the geographic region. Globally, there have been important changes in incidence trends amongst men and women, histology, and incidence in non-smokers. Indian epidemiological data on lung cancer is scarce. Aims: We set out to study the epidemiological patterns and clinical profile of lung cancer in India. Materials and Methods: We interviewed patients discussed in the thoracic oncology multidisciplinary meetings between 2008 and 2009. Demographic data, smoking history, place of residence, histology, stage at presentation, and treatment details were collected. Data was entered and analyzed in SPSS. Results: There were 489 patients, with a median age of 56 years, of which 255 (52%) were non-smokers and 234 (48%) were smokers. One hundred and thirty-three patients had consumed smokeless tobacco. The male-to-female ratio was 3.5:1. Sixty-nine patients (14.1%) were incorrectly diagnosed and treated with anti-tuberculosis treatment, which delayed the diagnosis of lung cancer by four months. Eight percent of patients had small-cell carcinoma; of the 92% patients with non-small-cell carcinoma (NSCLC), the most common histology was adenocarcinoma (43.8%), followed by squamous cell (26.2%), large cell (2.1%) and other (8.3%). Eighteen percent of patients were diagnosed by cytology, therefore were diagnosed as NSCLC, without further histologic subtyping. Most patients (43%) were in Stage III at presentation. Lung followed by bone were the common sites of metastases. The majority of the patients (49%) received palliative chemotherapy. Among definitive therapy, concurrent chemo-radiation (13%) was offered more frequently than surgery (6%). Conclusion: Considerably higher numbers of Indian patients with lung cancer are non-smokers, compared to the West. The global trend of rise in adenocarcinoma is paralleled in India. Non-tobacco-related risk factors need further investigation.
Keywords: Epidemiology, India, lung carcinoma, non-smoker
|How to cite this article:|
Noronha V, Dikshit R, Raut N, Joshi A, Pramesh C S, George K, Agarwal J P, Munshi A, Prabhash K. 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
|How to cite this URL:|
Noronha V, Dikshit R, Raut N, Joshi A, Pramesh C S, George K, Agarwal J P, Munshi A, Prabhash K. Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience. Indian J Cancer [serial online] 2012 [cited 2017 Mar 25];49:74-81. Available from: http://www.indianjcancer.com/text.asp?2012/49/1/74/98925
| » Introduction|| |
Lung cancer is the most commonly diagnosed cancer annually since 1985. Worldwide, there are 1.61 million new cases of lung cancer per year, with 1.38 million deaths, making lung cancer the leading cause of cancer-related mortality.  In India, approximately 63,000 new lung cancer cases are reported each year.  The major risk factor for developing lung cancer is tobacco use and this disease is often viewed solely as a smoker's disease. However, a significant number of patients with lung cancer have no history of smoking. In a study of 975 patients with non-small-cell lung cancer (NSCLC) from Singapore, 31.5% of males and 68.5% of female patients were never-smokers, overall accounting for 32.4% of lung cancer patients.  The proportion of lung cancer in never-smokers is expected to increase as successful smoking prevention and cessation programmes are implemented.
Globally, lung cancer in never-smokers demonstrates a marked gender bias, occurring more frequently among women. In particular, a high proportion of Asian women diagnosed with lung cancer are never-smokers. Although smoking-related carcinogens act on both proximal and distal airways inducing all the major forms of lung cancer, cancers arising in never-smokers target the distal airways and favour adenocarcinoma histology.  Smokeless tobacco is a relatively weak carcinogen and there is little evidence to support a role in causing lung cancer in never-smokers.  Although multiple risk factors, including environmental, hormonal, genetic and viral have been implicated in the pathogenesis of lung cancer in never-smokers, no distinct etiologic factor has emerged that can explain the relatively high incidence of lung cancer in never-smokers and the marked geographic differences in gender proportions. Molecular studies, in particular of the TP53, KRAS and epidermal growth factor receptor (EGFR) genes, demonstrate strikingly different mutation patterns and frequencies between lung cancers in never-smokers and smokers. , Major gender, clinico-pathological, and molecular differences in lung cancers arising in never-smokers strongly suggest a disease distinct from the more common tobacco-associated forms of lung cancer. Non-smoking status is the strongest clinical predictor of benefit from the EGFR tyrosine kinase inhibitors.  Never-smokers with lung cancer present with more advanced disease, usually at an earlier age, again suggesting a biologically different disease from tobacco-related lung cancer. 
In our study, we set to find out clinically meaningful differences between never-smokers and smokers with NSCLC in terms of patient-related, disease-related and treatment-related characteristics. We hope that the results of our study will increase the understanding of this distinct clinical entity and guide further efforts to identify the major causes of lung cancers arising in never-smokers and subsequently, help develop successful strategies for prevention, early diagnosis and novel therapies.
| » Materials and Methods|| |
This is a retrospective analysis of prospectively collected data of patients with a diagnosis of lung cancer, discussed in the thoracic oncology multidisciplinary meeting at a tertiary care oncology hospital in Mumbai, India, during a one year period. The survey was conducted by trained clinical research coordinators under the supervision of physicians using a detailed questionnaire. Patients were interviewed regarding their history of smoking (current and former), smoking pattern and use of smokeless tobacco. A particular note was made of a past history of tuberculosis and whether the patient was ever treated for tuberculosis. We attempted to find out if there was a delay in the diagnosis of lung cancer due to an incorrect initial diagnosis of tuberculosis. Following the interview, all patients underwent the routine workup for lung cancer, including imaging (computed tomography (CT) scan of the thorax and upper abdomen) and pathologic confirmation of the diagnosis. The final therapy plan was noted. Data was entered and analyzed using SPSS software (SPSS for Windows, Version 18).
| » Results|| |
We see approximately 1300 lung cancer patients in a year at Tata Memorial Hospital. We present the data of 489 patients who were discussed in the multidisciplinary thoracic oncology meeting between November 2008 and November 2009. A summary of the patient data is provided in [Table 1].
The median age of the patients in our study was 56 years (S.D =11.87) with a range from 30-80 years. The median age of non-smokers was significantly lower than that of smokers (53 versus 59 years, P< 0.05). Eleven percent of patients were in the 0-40 age group, 57% in the 40-60 age group, and 32% patients were above 60 years of age. A larger proportion of non-smokers with lung cancer were noted in the younger age range. Seventy-five percent of lung cancer patients below the age of 40 years were non-smokers as opposed to only 40% of patients over 60 years of age [Table 2].
Of the 489 patients, 255 patients (52.1%) had no history of smoking at any time in their life as compared to 234 patients (47.9%) who had smoked at some point. Amongst the smokers, beedi smoking was more common (25.4%) than cigarette smoking (19.4%) in both the sexes; 3.1% of patients had smoked both cigarettes and beedis.
A total of 133 patients also consumed smokeless tobacco in some form .These were predominantly non-smokers (32.5%) as compared to smokers (21.4%).
Out of 489 patients, there were 380 (77.7%) males and 109 (23.3%) females i.e. a male: female ratio of approximately 3.5:1. A larger proportion of females (88.1%) were non-smokers as compared to only 41.8% of males who were non-smokers.
A total of 54 patients (11%) had suffered from tuberculosis in the past and were successfully treated. As compared to non-smokers (9.4%), the smokers were more in number; however, this was not statistically significant (P= 0.249, 2-sided Chi square test). Sixty-nine of the 489 (14.1%) patients while undergoing diagnostic workup for the present symptoms were given anti-tuberculosis treatment, delaying the diagnosis and initiation of anticancer treatment.
Small-cell carcinoma was diagnosed in 8% of patients, while 92% of the patients had NSCLC. Within NSCLC, the most common histology was adenocarcinoma (43.8%) followed by squamous-cell carcinoma (26.2%), large-cell carcinoma (2.1%) and other (8.3%). In many cases, only cytology was performed, hence in 19.6% of patients, only NSCLC was reported, no further sub-classification was possible. There was a statistically higher occurrence of adenocarcinoma in the non-smokers (P= 0.001 by Chi square test). Small-cell and squamous histology were more commonly found among the smokers than non-smokers.
Irrespective of the smoking status, the majority of the patients (almost half) received chemotherapy with palliative intent. For patients offered definitive therapy, concurrent chemoradiation (13%) was offered more often than surgery (6%). A significant number of patients (11.2%) received neoadjuvant chemotherapy, followed by either surgery, chemoradiation or radiation alone. Forty-nine percnt of patients were offered palliative chemotherapy and 2.5% patients were offered best supportive care. Non-smoking status influenced our decision to use tyrosine kinase inhibitors, however, this was this was prior to routine EGFR mutation testing, and the number of patients was small.
| » Discussion|| |
Fifty-two percent of the patients with lung cancer in our study were non-smokers. This is the highest proportion reported so far. In a study by Toh et al., from Singapore, 32.5% of lung cancer patients were never-smokers,  while in the United States, approximately 10% of lung cancer cases occur in non-smokers  [Table 3]. The large proportion of non-smokers in our study allowed us to better detect any significant differences from patients with a history of smoking.
We found statistically significant differences between the non-smoker group and the smokers with regard to gender, age at presentation, use of smokeless tobacco and histopathology. The non-smokers were more likely to be female, present at a younger age (median age 53 years), have a history of use of smokeless tobacco and pathologically, to be diagnosed with adenocarcinoma. Non-smokers appeared to present at a more advanced stage, however this was not statistically significant as compared to the smokers. There was no difference regarding the patient's place of residence, co-morbidities, underlying lung disease, past history of tuberculosis, site of metastases or the type of treatment received. Our study was consistent with prior studies where lung cancer in never-smokers was associated with female gender, ,,, lower median age at diagnosis, adenocarcinoma subtype, , and a more advanced stage at presentation. 
We noted a significantly higher proportion of females among lung cancer patients who are non-smokers. This was consistent with findings noted in prior studies from Asia including China,  Japan,  and Northern India  where 65%, 70% and 94% of the lung cancer patients who were non-smokers were female. In the United States, however, only 9-13% of female lung cancer patients are never-smokers. ,,,, [Table 3]. This geographic variation is probably due to ethnic and cultural differences. This is something to consider when evaluating the higher proportion of EGFR mutation in the Asian population. 
The median age of non-smokers was significantly lower as compared to smokers, similar to that seen in studies from other Asian countries, including Singapore,  Japan  and Hong Kong.  This is in contrast to studies from the United States and Europe.  There are three possible explanations for this differing pattern between Western and other countries.  First, the contribution of risk factors unrelated to smoking may be greater in Asian countries.  Second, because ever-smokers initiate smoking at a later age in Asian countries, compared with the United States and Europe, the age at cancer diagnosis for Asian smokers may be higher even with induction periods similar to Western countries. And third, varying degrees of detection bias may account for part of the differences between countries.
Our hypothesis that the temperature variations across various latitudes in the country could correlate with the smoking patterns in these patients and cause varying occurrence of lung cancer was not correct. There was no predilection for non-smoking lung cancer in any particular region of the country. No study in the Indian subcontinent has studied this pattern till date.
We hypothesized that smokers would have a higher occurrence of co-morbidities including coronary artery disease, cerebrovascular disease and chronic obstructive pulmonary disease, limiting their ability to receive optimal management of lung cancer. Surprisingly, we found a similar occurrence of co-morbidities between the smokers and non-smokers and this was supported by the finding that the treatment offered to the two groups was the same. This could be due to the limitations of the interview process, the lack of knowledge of the patients regarding their exact prior diagnoses and our inability to grade the severity of the co-morbidities in our study. It may also reflect the general limitations of our diagnostic testing.
We found a higher use of smokeless tobacco in the non-smokers. Whether smokeless tobacco has a causal relationship can only be answered by a case-control study. If a causal association is found, this could explain the increased risk of lung cancer in non-smokers. Thus far, there is no strong evidence of correlation between smokeless tobacco and lung cancer in the Western literature  or in other Indian studies. 
Over the past four decades, there has been a shift in the pathologic distribution of NSCLC. Prior to the 1970s, squamous-cell carcinoma was the most common histological type of NSCLC, however, since about 1975, there has been a dramatic increase in the incidence of adenocarcinoma, making it the predominant histological subtype of NSCLC  [Table 4]. Thus far, not much information was available as to the distribution of the histological subtypes in India. A review article from 2004 stated that squamous-cell carcinoma was still the predominant histological subtype of NSCLC in India.  We found that adenocarcinoma accounts for 44% of NSCLC, while only 26% are squamous-cell carcinoma. Results from our study suggest that a pathologic shift may have occurred in India as well.
|Table 4: Distribution of pathological subtypes of lung cancer in non-smokers|
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Traditionally, squamous-cell carcinoma of the lung was thought to be smoking-related, rather than adenocarcinoma. The increase in the incidence of adenocarcinoma was thought to be mainly attributable to a change in smoking pattern and an increased preference for filter cigarettes that have low tar, but high nitrate content.  Earlier studies reported that the increased incidence of adenocarcinoma was confined to smokers. , In contrast, we found a statistically higher occurrence of adenocarcinoma in non-smokers as compared to smokers. This is supported by other studies in the literature. ,,,,,,,,,,,, Thus, our study and other recent studies suggest that the increase in adenocarcinoma is not solely due to a change in pattern of cigarette smoking, but must be due to non-smoking-related factors, since the increase is demonstrated in non-smokers as well.
Beedis are more carcinogenic than cigarettes,  however, it is not known if beedi-smoking preferentially causes a particular cancer subtype or if there are any clinical or pathologic features that are different in a lung cancer caused by beedi-smoking as compared to that caused by regular cigarette-smoking. Among our patients with a history of smoking, the proportion of beedi smokers (25.4%) was higher than the so-called "safe" cigarettes (19.4%). Given the wide prevalence of beedi-smoking in our country, this may be an important factor to consider while evaluating the Indian epidemiologic profile. Whether there were any significant differences between cancers in beedi smokers compared to that in cigarette smokers is beyond the scope of this study.
The observation that lung cancer in non-smokers is diagnosed at a more advanced stage is probably because of the fact that when a non-smoker presents with a lung mass, cancer is not at the top of the list of differential diagnoses. Chandra and colleagues found that the median symptom to diagnosis delay was 143 days in all patients with lung cancer. Another confounding factor is the high prevalence of tuberculosis in India. A study by Singh et al., found that 14 of 70 (20%) patients of lung cancer wrongly received anti-tuberculosis treatment for a median duration of 4.46+/-3.15 months.  Wang et al., observed that the diagnosis of lung cancer in 47 patients (70% of all patients below 40 years) was delayed, with an erroneous diagnosis of tuberculosis in 55% of patients.  In our study as well, anti-tuberculosis therapy was empirically started in 14% of the patients. A paradigm shift is needed in the thinking of clinicians that lung cancer is not purely a smoking-related disease, nor should every chest shadow raise a suspicion of only tuberculosis.
Irrespective of the performance status and co-morbidities, there were an equal number of smokers and non-smokers who were offered a particular treatment option. This is a reflection of the reality that NSCLC is still considered a single disease entity being treated the same even though the oral tyrosine kinase inhibitors have stood the test of trials. ,
A strength of our study is that all patients were interviewed in person, no data were obtained from the next of kin or other surrogates. Use of closely supervised trained interviewers and standardized questionnaires also serve to increase confidence in the results. However, a major limitation of our study is that it was entirely conducted at a single tertiary care facility, with the inherent referral bias. These results may not be representative of the general population. This is especially true for our hospital, which is one of the apex referral centres, drawing referrals from all over the country. Culturally, Indian women are less likely to travel far to seek therapy at a higher centre. Ideally, this study should be expanded to a multicentre analysis and should include data from the general population and cancer registry data.
In non-smokers, various factors are thought to contribute to the risk of lung cancer, including environmental tobacco smoke (second-hand smoke), , other environmental exposures including asbestos and arsenic, , radon,  viruses like human papilloma virus,  benign lung diseases like idiopathic pulmonary fibrosis,  estrogens  and possibly genetic factors, especially in patients with a family history of early-onset cancer.  In our patients from rural India, there may be an additional contribution from indoor air pollutants, like the fumes from cooking oil and the smoke from a coal stove.  At the molecular level, mutations of EGFR,  HER2,  EML4-ALK  and less frequently KRAS mutations (especially transition mutations)  may play a role. Routine molecular testing is still not the standard of care; hence we do not know the molecular profile of the cancers of the patients in our study.
In conclusion, lung cancer in non-smokers represents a distinct clinical entity with unique epidemiological, clinical and molecular characteristics. A high level of suspicion leading to prompt diagnosis and treatment with targeted agents in suitable cases should be the prime goal for clinicians. Future concerted efforts should focus on conducting studies in this part of the globe to further delineate underlying biologic differences, identify potential non-tobacco-related risk factor(s), molecular differences and further refine treatment strategies for these groups of patients.
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[Table 1], [Table 2], [Table 3], [Table 4]
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| ||Noronha, V. and Prabhash, K. and Thavamani, A. and Chougule, A. and Purandare, N. and Joshi, A. and Sharma, R. and Desai, S. and Jambekar, N. and Dutt, A. and Mulherkar, R. |
| ||PLoS ONE. 2013; 8(4) |
|| result 2 Document Clinico-pathology of lung cancer in a regional cancer center in Northeastern India
| || Mandal, S.K., Singh, T.T., Sharma, T.D., Amrithalingam, V. |
| ||Source of the Document Asian Pacific Journal of Cancer Prevention. 2013; |
|| result 3 Document Frequency of EGFR Mutations in 907 Lung Adenocarcioma Patients of Indian Ethnicity
| || Authors of Document Chougule, A., Prabhash, K., Noronha, V., (...), Jambhekar, N., Dutt, A. |
| ||Source of the Document PLoS ONE. 2013; |
|| result 4 Document Lung cancer epidemiology and clinical profile in North India: Similarities and differences with other geographical regions of India
| || Singh, N., Behera, D. |
| ||Source of the Document Indian Journal of Cancer. 2013; |
|| result 9 Document Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients
| || Choughule, A., Noronha, V., Joshi, A., (...), Prabhash, K., Dutt, A. |
| ||Source of the Document Indian Journal of Cancer. 2013; |
||Personalized medicine: Lung Cancer leads the way
| || Authors of Document Parikh, P., Puri, T. |
| ||Source of the Document Indian Journal of Cancer. 2013; |
||Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status
| || Authors of Document Bhatt, A.D., Pai, R., Rebekah, G., (...), Korula, A., Chacko, R.T. |
| ||Source of the Document Indian Journal of Cancer. 2013; |
||Smoking Cessation Intervention in Rural Kerala, India: Findings of a Randomised Controlled Trial
| ||Radhakrishnan Jayakrishnan,Antti Uutela,Aleyamma Mathew,Anssi Auvinen,Preethi Sara Mathew,Paul Sebastian |
| ||Asian Pacific Journal of Cancer Prevention. 2013; 14(11): 6797 |
|[Pubmed] | [DOI]|