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Lung Cancer in India

      Introduction

      India is a land of diversity with a motley of cultures, religions, languages, festivals, and ethnic groups. The country’s population as of 2020 is more than 1.38 billion, which accounts for 17.7% of the total world population with a population density of 464 per km
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      . The average age of Indians is 28.4 years, with more than half of the population below 25 years. Table 1 describes the demographics and key statistics of India. India is the fifth largest economy in the world with nominal gross domestic product (GDP) but ranks third in terms of purchasing power parity.
      Table 1Demographics and Key Statistics of India
      Demographic VariableNumerical Value
      Total population1.38 billion
      Accessed from https://www.worldometers.info/demographics/india.
      Urban population34.5%
      Accessed from https://www.worldometers.info/demographics/india.
      Life expectancy70.42 y
      Accessed from https://www.worldometers.info/demographics/india.
      Languages216
      Sex ratio924 females per 1000 males
      Accessed from http://statisticstimes.com/demographics/country/india-sex-ratio.
      Nominal GDP$3.202 trillion
      "World Economic Outlook Database, October 2019" International Monetary Fund.
      PPP$11.33 trillion
      "World Economic Outlook Database, October 2019" International Monetary Fund.
      Total health care expenditure3.6% of GDP
      Public health expenditure1.29% of GDP
      Health insurance coverage20% of women and 23% of men
      India Fact Sheet. National Family Health Survey (NFHS)-4, Ministry of Health and Family Welfare Government of India. 2015–2016.
      Doctor-population ratio1:1456 (WHO recommendation 1:1000)
      Noncommunicable diseases60% of all deaths
      Tobacco use28.6% of adults
      GLOBOCAN India statistics 2018S1
       Number of new cancer cases1.16 million
       Cancer deaths784,821
       Number of prevalent cancer cases (5-y)2.26 million
       Lung cancer5.9% of all cancer cases (fourth most common)
       Lung cancer incidence67,795
       Lung cancer mortality63,475 (8.1% of all cancer deaths)
      Projected incidence, 2020S2
       All sites1,392,179
      Males679,421
      Females712,758
       Lung cancer98,278
      Males71,788
      Females26,490
      Note: Due to the reference restrictions in this journal, please find a separate reference list of the tables as supplementary materials at https://doi.org/10.1016/j.jtho.2021.02.004.
      GDP, gross domestic product; PPP, purchasing power parity.
      c "World Economic Outlook Database, October 2019" International Monetary Fund.
      d India Fact Sheet. National Family Health Survey (NFHS)-4, Ministry of Health and Family Welfare Government of India. 2015–2016.
      The health care system in India coexists in public and private sectors. The public health system provides free or subsidized medical care to low-income people. However, India’s total expenditure on health care (out-of-pocket and public) as a percentage of GDP is low (3.6% of GDP) as compared with the average of Organization for Economic Co-operation and Development countries (8.8% of GDP in 2018). Furthermore, health insurance coverage is poor. According to the National Family Health Survey 2015 to 2016 (National Family Health Survey-4; http://rchiips.org/nfhs/index.shtml), only 28.7% households have any usual member covered by any health insurance scheme (28.2% in urban area and 28.9% in rural area). Recently, a large government initiative called the Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (https://pmjay.gov.in) aims to provide free access to health care to 500 million beneficiaries and offers an insurance cover of 5 lakh rupees per family per year for secondary and tertiary health care.
      India is the second largest consumer and third largest producer of tobacco in the world. Approximately 28.6% of the Indian population uses tobacco products (42.4% men and 14.2% women), accounting for an estimated 267 million tobacco users in the country (Global Adult Tobacco Survey-2 [GATS]-2 2016–2017: India fact sheet; http://gatsatlas.org). The impact of tobacco consumption on health and in particular for cancer in India is enormous. As per the National Cancer Registry Programme, tobacco-related cancers constitute 27% of all cancers for both sexes combined (https://www.ncdirindia.org/All_Reports/Report_2020/default.aspx), but this ranges widely in different parts of the country (30%–70% for male individuals and 12%–46% for female individuals). The prevalence of tobacco use has reduced considerably in GATS-2 (2016–2017) compared with that in GATS-1 (2009–2010). The National Tobacco Control Program (http://ntcp.nhp.gov.in) was launched by the Government of India in 2007 to 2008 with the aim to raise awareness on the deleterious effects of tobacco, regulate tobacco production and consumption, enact and enforce Cigarette and other Tobacco Product Act, strengthen and support tobacco cessation services, and promote effective implementation of the strategies by the WHO Framework Convention on Tobacco Control. Currently, this program is being implemented in 612 districts across the country.
      Lung cancer is the most often diagnosed cancer and leading cause of cancer-related deaths worldwide. In India, lung cancer accounts for 5.9% of all cancers and 8.1% of all cancer-related deaths.
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      The prevalence of smoking in patients with lung cancer is nearly 80%.
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      Age-standardized incidence and mortality rates of lung cancer in India as compared with neighboring countries are depicted in Figure 1. The National Cancer Registry Programme initiated by the Indian Council of Medical Research (ICMR) initiated in 1982 at select hospitals in the country has expanded over the decades to its current network of 36 population-based cancer registries (PBCRs) and 236 hospital-based cancer registries, which is coordinated and steered by the ICMR’s National Center for Disease Informatics and Research, Bengaluru (Fig. 2). Lung cancer is the leading site of cancer for male individuals at several of the PBCRs (Fig. 3). Furthermore, there has been an increase in the age-adjusted incidence rates over the past 5-year time period (2012–2016) assessment at most of the PBCRs for both sexes (Fig. 4).
      Figure thumbnail gr1
      Figure 1Age-standardized incidence and mortality rates of lung cancer in India as compared with neighboring countries. Data Source: GLOBOCAN 2020 (https://gco.iarc.fr/today/fact-sheets-populations). Map source: https://upload.wikimedia.org/wikipedia/commons/8/8d/India_and_Neighbouring_Countries_Map_%28official_borders%29.png. I, age-standardized incidence per 100,000 population; M, age-standardized mortality per 100,000 population.
      Figure thumbnail gr2
      Figure 2Network of (A) PBCR and (B) HBCR of the NCRP coordinated and steered by the ICMR-NCDIR. Source: https://www.ncdirindia.org/All_Reports/Report_2020/default.aspx & Mathur et al. Reproduced with permission. HBCR, hospital-based cancer registry; ICMR-NCDIR, Indian Council for Medical Research-National Centre for Disease Informatics and Research; NCRP, National Cancer Registry Programme; PBCR, population-based cancer registry.
      Figure thumbnail gr3
      Figure 3Lung cancer is the leading site of cancer for male individuals at several of the population-based cancer registries of the NCRP coordinated and steered by the ICMR-NCDIR. Source: https://www.ncdirindia.org/All_Reports/Report_2020/default.aspx & Mathur et al. Reproduced with permission. ICMR-NCDIR, Indian Council for Medical Research-National Centre for Disease Informatics and Research; NCRP, National Cancer Registry Programme.
      Figure thumbnail gr4
      Figure 4APC in age-AARs of lung cancer over the time period (2012–2016) at the population-based cancer registries of the NCRP coordinated and steered by the ICMR-NCDIR. Source: https://www.ncdirindia.org/All_Reports/Report_2020/default.aspx & Mathur et al. Reproduced with permission. AAR, age-adjusted incidence rate; APC, Annual percent change; ICMR-NCDIR, Indian Council for Medical Research-National Centre for Disease Informatics and Research; NCRP, National Cancer Registry Programme.

      Epidemiology

      Lung cancer epidemiology in India has evolved from being dominated by histologic types strongly associated with tobacco smoking (squamous and small cell) to an era wherein adenocarcinoma became equiprevalent and now ultimately to where it has become the dominant histologic type.
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      • Singh N.
      • Aggarwal A.N.
      • Gupta D.
      • Behera D.
      • Jindal S.K.
      Unchanging clinico-epidemiological profile of lung cancer in North India over three decades.
      • Singh N.
      • Aggarwal A.N.
      • Gupta D.
      • Behera D.
      • Jindal S.K.
      Quantified smoking status and non-small cell lung cancer stage at presentation: analysis of a North Indian cohort and a systematic review of literature.
      This transition in histologic profile has occurred largely in the past decade and in this aspect lagged behind the transition witnessed in the developed countries. Postulated reasons behind this “time lag” have been linked to the fact that in India, “bidi” (handmade tobacco smoking product; primarily, cottage industry based) has been and continues to be the dominant type of smoking product unlike the more regulated and mechanistic cigarette manufacturing, with little change in the manufacturing process of the former with time (unlike the latter wherein low nicotine content and filtered cigarettes have been marketed for a substantial time period).
      • Singh N.
      • Aggarwal A.N.
      • Gupta D.
      • Behera D.
      • Jindal S.K.
      Unchanging clinico-epidemiological profile of lung cancer in North India over three decades.
      Second, improvements in histologic typing by reporting pathologists related to higher utilization of immunochemistry (IHC) have led to reduction in the reported prevalence of NSCLC-not otherwise specified (undifferentiated NSCLC) subtype, with most cases getting classified into the nonsquamous NSCLC adenocarcinoma.
      • Kaur H.
      • Sehgal I.S.
      • Bal A.
      • et al.
      Evolving epidemiology of lung cancer in India: reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key.
      Table 2 summarizes the important epidemiologic studies on lung cancer in India in the past three decades.
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      Most patients with lung cancer in India present with locally advanced and metastatic disease.
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      ,
      • Singh N.
      • Aggarwal A.N.
      • Gupta D.
      • Behera D.
      • Jindal S.K.
      Quantified smoking status and non-small cell lung cancer stage at presentation: analysis of a North Indian cohort and a systematic review of literature.
      ,
      • Kaur H.
      • Sehgal I.S.
      • Bal A.
      • et al.
      Evolving epidemiology of lung cancer in India: reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key.
      Table 2Lung Cancer Demographics Reported From Various Parts of India Between 1990 and 2020
      Author/ReferencePlace/YearPatient NumberMale:FemaleMean Age (y)Smokers (%)SqCC (%)ADC (%)SqCC:ADCSCLC (%)
      Jindal and BeheraS3Chandigarh, 199010094.5:15163.034.325.91.325.9
      Gupta et al.S4Rajasthan, 19982796.1:15781.642.020.02.114.0
      Prasad et al.S5Lucknow, 20044004.3:15771.046.518.52.518.2
      Khan et al.S6Kashmir, 200632111.3:188.477.35.314.617.1
      Prasad et al.S7Lucknow, 20097994.8:180.447.318.22.613.7
      Rawat et al.S8Uttarakhand, 20092038.2:156.481.844.819.42.316.8
      Sheikh et al.S9Kashmir, 20107837.0:157.868.171.32.627.420.8
      Singh et al.
      • Singh N.
      • Aggarwal A.N.
      • Gupta D.
      • Behera D.
      • Jindal S.K.
      Quantified smoking status and non-small cell lung cancer stage at presentation: analysis of a North Indian cohort and a systematic review of literature.
      Chandigarh, 20126545.0:158.276.938.127.51.420.5
      Dey et al.S10Kolkata, 20126074.1:157.967.235.130.81.116.5
      Noronha et al.S11Mumbai, 20124893.5:15652.026.243.80.68.0
      Krishnamurthy et al.S12Tamil Nadu, 20122583.5:15660.515.842.60.413.2
      Sharma et al.S13Himachal Pradesh, 201210510.6:162.789.537.136.21.0
      Malik et al.S14New Delhi, 20134344.6:15567.932.137.10.914.7
      Mandal et al.S15Manipur, 20134661.1:158.573.049.130.81.614.8
      Baburao et al.S16Bangalore, 2015963.0:169.747.928.11.7
      Mohan et al.S17New Delhi, 20163977.4:157.879.025.124.11.014.6
      Murali et al.18Chennai, 20176783.2:153.416.151.20.39.0
      Kaur et al.
      • Kaur H.
      • Sehgal I.S.
      • Bal A.
      • et al.
      Evolving epidemiology of lung cancer in India: reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key.
      Chandigarh, 201713014.6:158.676.936.436.41.019.2
      Mohan et al.
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      Delhi, 202018624.9:15876.228.634.00.816.1
      Note: Table 2 is adapted and modified from reference number 
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      . Due to the reference restrictions in this journal, please find a separate reference list of the tables as supplementary materials at https://doi.org/10.1016/j.jtho.2021.02.004.
      ADC, adenocarcinoma; SqCC, squamous cell carcinoma.

      Molecular Epidemiology and Molecular Testing

      In the current era of precision oncology, in addition to conventional demographic data, molecular epidemiology is becoming increasingly important. The number of targetable oncogenic drivers in NSCLC has expanded substantially in the past decade and includes at least four mutations (EGFR, BRAF, MET, ERBB2 [HER2]) and four fusions or rearrangements (ALK, ROS1, RET, NTRK). Although data on the newer targets are still sparse, recent pooled multi-institutional data analysis indicates that the prevalence of EGFR mutations and ALK rearrangements in India is 30% and 10%, respectively.
      • Singh N.
      Lung cancer in India: the rewards of REWERDS (REal World Evidence from Retrospective Data analysiS).
      ,
      • Nakra T.
      • Mehta A.
      • Bal A.
      • et al.
      Epidermal growth factor receptor mutation status in pulmonary adenocarcinoma: multi-institutional data discussion at national conference of “Lung Cancer Management in Indian context”.
      This is largely based on testing by real-time polymerase chain reaction and D5F3 IHC, respectively (Table 3). Use of broad next-generation sequencing (NGS) panel testing is increasing but limited by both cost and availability.
      • Nakra T.
      • Mehta A.
      • Bal A.
      • et al.
      Epidermal growth factor receptor mutation status in pulmonary adenocarcinoma: multi-institutional data discussion at national conference of “Lung Cancer Management in Indian context”.
      Table 3EGFR Mutation and ALK Rearrangement Status in the Context of Key Baseline Characteristics and Testing Methods
      VariableEGFR-m NegativeEGFR-m Positive
      Distribution of EGFR mutations was as follows: exon 19 deletions (64.8%), exon 21 L858R (23.2%), exon 20 insertions (5.4%), exon 20 T790M mutations (4.4%), exon 21 L861Q (3.0%), exon 20 S768I (1.7%), exon 18 G719X (1.0%), and exon 21 A971G (0.3%). Dual mutations were detected in 3.4%.
      ,
      No patient of squamous cell histology tested positive for either EGFR-m or ALK-r.
      ,
      Mean age was 58.9 (SD = 11.6) years for patients with EGFR-m patients and 52.4 (SD 12.2) years for patients with ALK-r.
      p ValueALK-r NegativeALK-r Positive
      No patient of squamous cell histology tested positive for either EGFR-m or ALK-r.
      ,
      Mean age was 58.9 (SD = 11.6) years for patients with EGFR-m patients and 52.4 (SD 12.2) years for patients with ALK-r.
      p Value
      Sex<0.001<0.001
       Males625 (80.6)150 (19.4)582 (93.1)43 (6.9)
       Females240 (61.9)148 (38.1)
      Female-to-male ratio among patients with EGFR-m was 1.0 (1.1 for exon 19 deletions and 1.2 for exon 21 L858R).
      258 (85.1)45 (14.9)
      Smoking status<0.001<0.001
       Nonsmoker302 (62.5)181 (37.5)335 (84.4)62 (15.6)
       Current/ex-smoker447 (82.9%)92 (17.1)425 (95.5)20 (4.5)
      Testing method<0.001<0.001
      Sanger sequencing: 159 (82.8)Sanger sequencing: 33 (17.2)FISH: 42 (95.5)FISH: 2 (4.5)
      RT-PCR: 702 (73.2)RT-PCR: 257 (26.8)IHC: 798 (90.3)IHC: 86 (9.7)
      NGS: 4 (36.4)NGS: 7 (63.6)
      Seventh TNM stage<0.0010.033
       <IV (M0)232 (84.4)43 (15.6)
      p value for comparison of M0 versus M1.
      <0.001
      227 (94.2)14 (5.8)
      p value for comparison of M0 versus M1.
      0.022
       IV (M1a)237 (67.7)113 (32.3)236 (87.4)34 (12.6)
       IV (M1b)281 (71.9)110 (28.1)293 (90.4)31 (9.6)
      Note: Single-center data from authors’ (NS, DK, KTP) institute over a 10-year period (2011–2019). Numbers depicted and analysis limited to patients with interpretable results. Overall, frequency of noninterpretable testing results was 5.7% for EGFR-m and 4.6% for ALK-r. Noninterpretable results for EGFR-m were significantly lower with real-time PCR (RT-PCR; 2.5%) versus Sanger sequencing (17.9%). For ALK-r testing, noninterpretable results were significantly lower with IHC (3.8%) versus FISH (17.0%). Values are given in number (%).
      ALK-r, ALK rearrangement; EGFR-m, EGFR mutation; FISH, fluorescent in-situ hybridization; IHC, immunohistochemistry; NGS, next-generation sequencing; RT-PCR, real-time polymerase chain reaction.
      a Distribution of EGFR mutations was as follows: exon 19 deletions (64.8%), exon 21 L858R (23.2%), exon 20 insertions (5.4%), exon 20 T790M mutations (4.4%), exon 21 L861Q (3.0%), exon 20 S768I (1.7%), exon 18 G719X (1.0%), and exon 21 A971G (0.3%). Dual mutations were detected in 3.4%.
      b No patient of squamous cell histology tested positive for either EGFR-m or ALK-r.
      c Mean age was 58.9 (SD = 11.6) years for patients with EGFR-m patients and 52.4 (SD 12.2) years for patients with ALK-r.
      d Female-to-male ratio among patients with EGFR-m was 1.0 (1.1 for exon 19 deletions and 1.2 for exon 21 L858R).
      e p value for comparison of M0 versus M1.
      Molecular diagnostic testing facilities are mostly restricted to referral tertiary care hospitals or academic centers or large private laboratories in India. At some of these, routine testing may be limited to the two most common oncogenic alterations (EGFR mutations by real-time polymerase chain reaction and ALK rearrangements by IHC). Accredited facilities and laboratories that offer locally developed and validated broad NGS panel testing have increased in number in the past few years, and given that there is a substantial cost difference compared with the global testing platforms offered by Foundation Medicine and Guardant Health, most NGS testing is being done locally within the country.
      Given the substantial impact of biomarker testing in lung cancer, in particular, the relatively high prevalence of EGFR mutations and ALK rearrangements in India and availability of generic versions of some of the EGFR and ALK tyrosine kinase inhibitors (TKIs) at considerably lower costs, the need to ensure that all eligible patients undergo biomarker testing cannot be overemphasized. This mandates ramping up molecular testing facilities such that these are easily accessible and affordable at all geographic locations in the country. More recently, the Department of Health Research and ICMR have launched a nationwide DHR-ICMR Advanced Molecular Oncology Diagnostic Services project to provide biomarker testing for lung cancer free of cost throughout the country.

      Screening and Early Detection

      Low-dose computed tomography (LDCT) of the chest is an established strategy for the screening of lung cancer. However, despite having a considerable burden of lung cancer, India does not have a formal screening program for lung cancer. Issues such as cost, logistic constraints, and concerns regarding high false-positive rates owing to the high prevalence of tuberculosis have prevented large-scale implementation of LDCT screening.
      • Shankar A.
      • Saini D.
      • Dubey A.
      • et al.
      Feasibility of lung cancer screening in developing countries: challenges, opportunities and way forward.
      In an ongoing study (NCT03909620) evaluating the role of LDCT for lung cancer screening at a tertiary care center in India (n = 221), 33.5% of the subjects had a positive result after the first round of screening and 1.8% were diagnosed as having lung cancer (unpublished data), which is comparable with data from other countries in the region.
      • Triphuridet N.
      • Henschke C.
      Landscape on CT screening for lung cancer in Asia.
      Encouragingly, the presence of radiological sequelae of tuberculosis was not associated with a positive LDCT scan in this study.
      Positron emission tomography (PET)–computed tomography (CT) is often used to characterize lung nodules found during LDCT screening. However, PET-CT may have a high false-positive rate in developing countries such as India owing to infectious conditions limiting its use. In a study evaluating 144 lung solitary pulmonary nodules, nearly one-fourth of the solitary pulmonary nodules were of benign nature most commonly from tuberculosis and nonspecific inflammatory conditions.
      • Purandare N.C.
      • Pramesh C.S.
      • Agarwal J.P.
      • et al.
      Solitary pulmonary nodule evaluation in regions endemic for infectious diseases: do regional variations impact the effectiveness of fluorodeoxyglucose positron emission tomography/computed tomography.
      The maximum standardized uptake value cutoff of 2.5 typically used to distinguish benign and malignant lesions also has a limited utility in India because of its inability to distinguish granulomatous conditions such as tuberculosis and sarcoidosis from malignancy.
      • Purandare N.C.
      • Pramesh C.S.
      • Agarwal J.P.
      • et al.
      Solitary pulmonary nodule evaluation in regions endemic for infectious diseases: do regional variations impact the effectiveness of fluorodeoxyglucose positron emission tomography/computed tomography.
      ,
      • Kumar A.
      • Dutta R.
      • Kannan U.
      • Kumar R.
      • Khilnani G.C.
      • Gupta S.D.
      Evaluation of mediastinal lymph nodes using F-FDG PET-CT scan and its histopathologic correlation.

      Diagnosis and Staging

      Flexible bronchoscopy and transthoracic sampling are the most often used techniques for the diagnosis of lung cancer. In general, lesions in the central one-third of the thorax are accessed bronchoscopically, whereas lesions in the peripheral one-third are accessed transthoracically. Bronchoscopy services have witnessed tremendous growth in India over the past decade, although there seems to be a concentration of services in major metropolitan cities.
      • Madan K.
      • Mohan A.
      • Agarwal R.
      • Hadda V.
      • Khilnani G.C.
      • Guleria R.
      A survey of flexible bronchoscopy practices in India: the Indian bronchoscopy survey (2017).
      Advanced bronchoscopic techniques such as endobronchial ultrasound (EBUS) are offered by several pulmonologists. Transthoracic sampling is generally performed under image guidance (ultrasonogram or CT) by interventional radiologists. However, at present, less than 1% of hospitals in India have a dedicated setup for interventional radiology.
      • Madhusudhan K.S.
      • Srivastava D.N.
      • Sharma S.
      • Sharma S.
      Interventional radiology in India.
      Lesions in the middle one-third of the chest can be accessed by either of the modalities depending on patient-specific factors and the expertise available. Bronchoscopic techniques for the sampling of peripheral lesions include radial EBUS, virtual bronchoscopic navigation, electromagnetic navigation bronchoscopy, and ultrathin bronchoscopy. However, these bronchoscopic techniques are not widely available. More recently, PET-guided biopsy has emerged as a promising technique for transthoracic sampling.
      • Radhakrishnan R.K.
      • Mittal B.R.
      • Gorla A.K.R.
      • et al.
      Real-time intraprocedural 18F-FDG PET/CT-guided biopsy using automated robopsy arm (ARA) in the diagnostic evaluation of thoracic lesions with prior inconclusive biopsy results: initial experience from a tertiary health care centre.
      Of note, the metabolic characterization provided by the PET-CT may allow targeting of viable tissue during sampling, thereby improving the diagnostic yield. Preliminary results revealed that for thoracic lesions having inconclusive results with previous invasive sampling, a diagnosis could be established in all the patients after PET-CT–guided biopsy.
      • Radhakrishnan R.K.
      • Mittal B.R.
      • Gorla A.K.R.
      • et al.
      Real-time intraprocedural 18F-FDG PET/CT-guided biopsy using automated robopsy arm (ARA) in the diagnostic evaluation of thoracic lesions with prior inconclusive biopsy results: initial experience from a tertiary health care centre.
      Ensuring adequate samples for histologic and molecular characterization is of paramount importance in advanced-stage disease but remains a challenge particularly at smaller centers because of lack of expertise. Liquid biopsy for the detection of driver mutations may be helpful in such situations where adequate tissue is unavailable for further analyses.
      Patients with lung cancer generally undergo noninvasive staging by imaging to assess the local and distant extent of disease. Noninvasive staging is especially important in patients with resectable disease. Whole-body PET-CT scan is the most accurate method for the noninvasive staging of lung cancer. However, in centers where PET-CT is not readily available, a radionuclide bone scan is combined with a contrast-enhanced CT scan of the chest and upper abdomen (including liver and adrenals) for staging.
      • Apurva A.
      • Tandon S.P.
      • Shetmahajan M.
      • Jiwnani S.S.
      • Karimundackal G.
      • Pramesh C.S.
      Surgery for lung cancer—the Indian scenario.
      Because PET-CT is not adequately sensitive for brain metastasis, magnetic resonance imaging of the brain is generally included in the staging evaluation. In patients who are not surgical candidates, most centers in India restrict the staging assessment to a contrast-enhanced CT scan of the chest and upper abdomen and do not routinely perform PET-CT or magnetic resonance imaging brain if the clinical evaluation does not suggest metastatic disease.
      Most patients with resectable disease typically undergo invasive mediastinal staging. Notably, any evidence of nodal involvement on imaging is generally confirmed by invasive mediastinal staging owing to the possibility of false-positive results. Establishing histopathological evidence of nodal involvement is especially relevant in countries such as India where granulomatous diseases, for example, tuberculosis, are endemic. Invasive mediastinal staging is generally not needed in a small proportion of patients with peripheral stage IA disease without evidence of hilar or mediastinal involvement on PET-CT. The practice in India is variable. Some centers prefer to perform invasive mediastinal staging in all patients with resectable disease despite a negative PET-CT because the negative predictive value of a PET-CT is not 100%. Nonetheless, some centers prefer to follow a strategy that advocates liberal neoadjuvant chemotherapy (NACT) in subjects with any N2 disease on PET-CT, thereby restricting the use of invasive mediastinal staging to only those patients in whom PET-CT reveals suspicion of N3 disease.
      • Apurva A.
      • Tandon S.P.
      • Shetmahajan M.
      • Jiwnani S.S.
      • Karimundackal G.
      • Pramesh C.S.
      Surgery for lung cancer—the Indian scenario.
      Endosonographic procedures (EBUS with or without endoscopic ultrasound) and mediastinoscopy are the techniques available for invasive mediastinal staging. Mediastinoscopy is generally considered as the accepted standard for invasive mediastinal staging. Mediastinoscopy offers an opportunity for complete lymphadenectomy (especially when video assisted) and provides a larger amount of tissue for further analyses (compared with endosonographic techniques). However, it is limited by the availability of trained thoracic surgeons and the potential for greater morbidity in comparison with the endosonographic procedures. Albeit, at experienced centers, the morbidity and mortality associated with mediastinoscopy are generally negligible. Evidence indicates that endoscopic procedures have a similar yield and a lower complication rate than mediastinoscopy.
      • Sehgal I.S.
      • Dhooria S.
      • Aggarwal A.N.
      • Behera D.
      • Agarwal R.
      Endosonography versus mediastinoscopy in mediastinal staging of lung cancer: systematic review and meta-analysis.
      ,
      • Muthu V.
      • Sehgal I.S.
      • Dhooria S.
      • Aggarwal A.N.
      • Agarwal R.
      Efficacy of endosonographic procedures in mediastinal restaging of lung cancer after neoadjuvant therapy: a systematic review and diagnostic accuracy meta-analysis.
      However, because concerns regarding the higher false-negative rate of endosonographic procedures compared with mediastinoscopy remain, some centers follow a negative endoscopic mediastinal staging with mediastinoscopy.
      • Apurva A.
      • Tandon S.P.
      • Shetmahajan M.
      • Jiwnani S.S.
      • Karimundackal G.
      • Pramesh C.S.
      Surgery for lung cancer—the Indian scenario.
      Other centers prefer to proceed to surgery directly after a negative endoscopic mediastinal staging.

      Surgery

      Though surgery remains the principal treatment for early-stage lung cancer, the number of patients who are eligible for surgery or undergo surgery varies between 1.5% and 5.3%.
      • Mohan A.
      • Garg A.
      • Gupta A.
      • et al.
      Clinical profile of lung cancer in North India: a 10-year analysis of 1862 patients from a tertiary care center.
      ,
      • Kaur H.
      • Sehgal I.S.
      • Bal A.
      • et al.
      Evolving epidemiology of lung cancer in India: reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key.
      ,
      • Murali A.N.
      • Radhakrishnan V.
      • Ganesan T.S.
      • et al.
      Outcomes in lung cancer: 9-year experience from a tertiary cancer center in India.
      Surgical oncologists and thoracic surgeons in comprehensive cancer care and tertiary centers are responsible for the surgical management, with most centers having dedicated tumor boards. Owing to the overlap between the symptomatology and radiology with tuberculosis and lack of awareness, there is a considerable delay of more than 3 months from onset of symptoms to a definite diagnostic procedure and achieving a diagnosis and more than 4 months to treatment initiation.
      • Vashistha V.
      • Choudhari C.
      • Garg A.
      • et al.
      The time required to diagnose and treat lung cancer in Delhi, India: an updated experience of a public referral center.
      Even in tertiary care centers, the curative treatment option is underutilized with only 31.7% of the patients with stages I to IIIA (33 of 104) receiving treatment with curative intent.
      • Malik P.S.
      • Malik A.
      • Deo S.V.
      • Mohan A.
      • Mohanti B.K.
      • Raina V.
      Underutilization of curative treatment among patients with non small cell lung cancer: experience from a tertiary care centre in India.
      The major reasons for this low volume of curative treatment included progression of disease or loss to follow-up after chemotherapy and inappropriate use of TKI or palliative radiotherapy or both in patients with stages I to IIIB disease.
      Many tests are available to evaluate adequacy of pulmonary reserve before lung surgery. In India, 53% of the surgeons evaluate pulmonary fitness with pulmonary function test alone, whereas 47% use diffusing capacity for carbon monoxide routinely with forced expiratory volume in 1 second. Perfusion scans are performed by 90% of surgeons if results of the pulmonary function test and diffusing capacity for carbon monoxide are borderline.
      • Apurva A.
      • Tandon S.P.
      • Shetmahajan M.
      • Jiwnani S.S.
      • Karimundackal G.
      • Pramesh C.S.
      Surgery for lung cancer—the Indian scenario.
      Preoperative pulmonary rehabilitation and smoking cessation are important for reducing postoperative complications and are widely practiced.
      In NSCLC, lobectomy with mediastinal lymph node dissection for stage I or II and for stage IIIA NACT followed by reassessment for surgery is the standard of care across many centers. Depending on the extent of disease and pulmonary reserve, lobectomy or pneumonectomy is the choice. Limited resection (segmentectomy preferred over wedge resection) is considered if pulmonary reserve is inadequate for lobectomy and for pure ground-glass opacity less than 2 cm in size. Parenchyma-preserving lung resection (vascular and bronchial sleeve) is now being preferred over pneumonectomy if negative margins can be achieved and anatomically appropriate. However, in a select group of patients with centrally located tumors, pneumonectomy may be the only chance of cure, and experienced team of surgeons have reported morbidity with pneumonectomy to be similar to that with lobectomy. Surgery is also being increasingly considered in fit patients with extension to other organs (such as chest wall, superior vena cava, brachiocephalic vein, and vertebra) and oligometastatic disease. Systematic mediastinal lymph node dissection is done by most high-volume centers.
      In a survey conducted among thoracic surgeons, management of N2 disease was different among different surgeons, in which 36% of the respondents preferred to give NACT followed by surgery for all N2 disease and 42% offered NACT only if there was multistation N2 disease.
      • Apurva A.
      • Tandon S.P.
      • Shetmahajan M.
      • Jiwnani S.S.
      • Karimundackal G.
      • Pramesh C.S.
      Surgery for lung cancer—the Indian scenario.
      Furthermore, 21% of the surgeons indicated that they do not offer surgery for multistation N2 disease. Survival outcomes after NACT and surgery have been reported, and the 3-year disease-free survival and overall survival rates were 49.3% and 60.2%, respectively.
      • Kumar S.
      • Saikia J.
      • Kumar Jr., V.
      • et al.
      Neoadjuvant chemotherapy followed by surgery in lung cancer: Indian scenario.
      The most often used surgical approach has traditionally been the open thoracotomy approach, with a general hesitancy to adopt video-assisted thoracoscopic surgery anticipating dense pleural adhesions and inflammatory nodes owing to higher prevalence of tuberculosis. However, the number of thoracoscopic and robotic lung resections is increasing. A single high-volume center reported the safety of video-assisted thoracoscopic surgery with a conversion rate to open thoracotomy of 8.82% and no postoperative complications in 80.4% of patients revealing the feasibility of the technique in our setting.
      • Kumar A.
      • Asaf B.B.
      • Puri H.V.
      • Sharma M.K.
      • Lingaraju V.C.
      • Rajput V.S.
      Video-assisted thoracoscopic surgery lobectomy: the first Indian report.
      The most often used perioperative analgesia is epidural analgesia (84%) followed by paravertebral block (40%), and intercostal block in addition to epidural may not offer any additional benefit.
      • Apurva A.
      • Tandon S.P.
      • Shetmahajan M.
      • Jiwnani S.S.
      • Karimundackal G.
      • Pramesh C.S.
      Surgery for lung cancer—the Indian scenario.
      ,
      • Ranganathan P.
      • Tadvi A.
      • Jiwnani S.
      • Karimundackal G.
      • Pramesh C.S.
      A randomised evaluation of intercostal block as an adjunct to epidural analgesia for post-thoracotomy pain.
      The median hospital stay among patients undergoing surgery for lung cancer is 5 to 6 days.
      • Apurva A.
      • Tandon S.P.
      • Shetmahajan M.
      • Jiwnani S.S.
      • Karimundackal G.
      • Pramesh C.S.
      Surgery for lung cancer—the Indian scenario.
      There are no data on the number of specialized thoracic surgeons in the country. However, it is accepted that there is a lack of surgeons trained in thoracic techniques and paucity of centers performing thoracic surgeries. Until very recently, there was no dedicated thoracic training program in India; however, this is changing. Minimally invasive techniques not only offer the opportunity to allay the fear of major and painful surgery in the minds of the general patient population and referring clinicians but also hold the promise of attracting the next generation of surgeons to train in this highly specialized field without compromising on oncological efficiency.

      Radiation Therapy

      Radiation therapy forms an integral component in the management of lung cancer. It has some role in almost all the stages of lung cancer. According to latest data available with Atomic Energy Regulatory Board, there are 514 radiotherapy facilities throughout India (707 teletherapy machines including 193 telecobalt units and 514 linear accelerators, seven gamma knife, 21 tomotherapy, 7 cyberknife, 321 high dose rate brachytherapy units, and one intraoperative radiotherapy machine). There is huge disparity between rural and urban sectors in terms of accessibility to radiotherapy facilities and cost of treatment. The waiting period in private hospitals is shorter (usually less than a wk) as compared with the public sector (typically ranges from 1 wk to 2 mo). The cost of treatment in private sector is unaffordable to low- and middle-income patients. As per WHO recommendations for a developing country, the requirement of radiotherapy equipment corresponds to 1380 as compared with available 686, the number which is sufficient only to cater roughly half the population of India. This implies the unmet need of further expansion in this area.
      Patients with bulky disease (posing a higher risk of radiation-induced pneumonitis), poor performance status, major comorbidities, and significant weight loss, and older patients are treated with sequential chemoradiation. Conventional fractionation radiotherapy is practiced at most of the radiotherapy centers. There is a dearth of studies on chemoradiation (sequential, concurrent, or altered fractionation) in lung cancer from India. Table 4 summarizes the retrospective and prospective series on chemoradiation in locally advanced NSCLC from India. Studies by Shrimali et al.
      • Shrimali R.K.
      • Chakraborty S.
      • Prasath S.
      • Arun B.
      • Chatterjee S.
      Impact of modern radiotherapy techniques on survival outcomes for unselected patients with large volume non-small cell lung cancer.
      and Kapoor et al.
      • Kapoor R.
      • Das N.
      • Miriyala R.
      • Sood A.
      • Oinam A.
      • Singh N.
      Challenges of radical chemoradiation planning in stage III non-small-cell lung cancer: can volumetric modulated arc radiotherapy overcome an unfavourable location?.
      addressed the challenges of delivery of radical chemoradiation in stage III NSCLC with respect to spatial location of tumor and burden of disease. Volumetric-modulated arc therapy is preferred over three-dimensional conformal radiotherapy in patients with bulky central disease so that dose to target volume is not compromised and organs at risk constraints are met.
      Table 4Review of Retrospective and Prospective Studies on Chemoradiation in Lung Cancer From India
      AuthorStudyStudy PeriodnTreatmentRadiotherapy DoseChemotherapy RegimenOutcome
      Sharma et al.S18Prospective1992–1996506SCRT (3 cycles CCT followed by RT) vs. RT60 Gy/30 fractionsCisplatin (50 mg/m2), ifosfamide (2 g/m2), mitomycin C (6 mg/m2) q3 weekly2-y survival —20% in SCRT arm and 7.4% in the RT arm
      Dasgupta et al.S19ProspectiveNA103RT vs. SCRT vs. CCRTRT arm—65 Gy/30 fractions SCRT—60 Gy/30 fractions CCRT—50 Gy/25 fractionsSCRT arm—3 cycles of cisplatin (80 mg/m2 D1) and etoposide (120 mg/m2 D1–3) q3 weekly before and after RT CCRT arm—cisplatin (20 mg/m2 D1–5, D22–26) and etoposide (50 mg/m2 D1–5, D22–26) concurrently with RT followed by two more cycles of same regimenStatistically significant advantage in terms of OS in SCRT and CCRT arms compared with RT arm
      AgrawalS20Retrospective2007–201155CCRT vs. SCRT45–66 GyCCRT—cisplatin (50 mg/m2 on first and eighth d) and etoposide (50 mg/m2 on d 1–5) of the first and last wk of radiation therapy SCRT—cisplatin (75 mg/m2 on d 1) and etoposide (100 mg/m2 on d 1–3) q3 weekly for four cycles followed by radical radiotherapyMedian survival—12 mo in both SCRT and CCRT
      Agarwal et al.S21Retrospective2008–2012171NACT + CTRT—14.1% CTRT—56.7% CTRT + adjuvant—5.3% NACT/adjuvant—9.9% No chemotherapy—13.5%Median RT dose—60 Gy/30 fractionsPlatinum-based doublets2-y DFS and OS for CTRT group was 18.8% and 61.5% vs. 29.8% and 68.8% for SCRT group (p = 0.089), respectively RT alone—2-y DFS and OS of 6.5% and 34.0%, respectively
      Murali et al.
      • Murali A.N.
      • Radhakrishnan V.
      • Ganesan T.S.
      • et al.
      Outcomes in lung cancer: 9-year experience from a tertiary cancer center in India.
      Retrospective2006–2015Stage III—169 patients CCRT—36 SCRT—39CCRT vs. SCRT as subgroup analysisDetails NADetails NABetter PFS (31% vs. 8%; p = 0.29) and OS (30% vs. 0%; p = 0.51) in CCRT as compared with SCRT
      Shrimali et al.S22Retrospective2011–2016213CCRT/SCRT/RTCCRT—60 Gy/30 fractions SCRT/RT—55 Gy/20 fractions; 60 Gy/30 fractions; altered fractionationCisplatin (50 mg/m2 on d 1, 8, 29, and 36) and etoposide (50 mg/m2 on d 1–5 and 29–33)Median survival—28 mo in CCRT and 13 mo in SCRT and RT (p < 0.001)
      Srivastava et al.S23Retrospective2007–2015114CCRT vs. SCRTDetails NADetails NAMedian survival—15 mo in CCRT and 16 mo in SCRT. The 1-, 3-, and 5-y OS were 56.2%, 20.6%, and 14.7%, in CCRT arm vs. 57.0%, 26.9%, and 21.2%, in SCRT arm, respectively
      Kumar et al.S24Prospective2013–201460NACT followed by CHARTWEL vs. NACT followed by CCRTCHARTWEL—58.5 Gy/39 fractions (1.5 Gy for each fraction) in 17 d, three fractions a d (6 h apart) CCRT—66 Gy/33 fractionsNACT with inj. cisplatin 75 mg/m2 divided into d 1 and d 2 and inj. paclitaxel 175 mg/m2 intravenous on d 1 q3 weekly × 4 cycles in both armsNo statistical difference in grades of toxicities or OS/DFS between two arms
      Sardar et al.S25Prospective2016–201744CCRT vs. SCRT66 Gy/33 fractions in both armsCCRT—paclitaxel (50 mg/m2), carboplatin (AUC-2) SCRT—2 cycles of paclitaxel (175 mg/m2), carboplatin (AUC 5) followed by RTDFS and PFS in the SCRT were numerically superior to CCRT but statistically not significant
      Srinivasa et al.S26Prospective2013–201436CTRT using paclitaxel and carboplatin (study arm) vs. CTRT using cisplatin and etoposide (control arm)60 Gy/30 fractionsControl arm—cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d i.v. on d 1–5 and d 29–33 concurrently with RT Study arm—paclitaxel—50 mg/m2, AUC 2 weekly concurrently with RTNo statistical significant difference in the study or control arm
      Note: Due to the reference restrictions in this journal, please find a separate reference list of the tables as supplementary materials at https://doi.org/10.1016/j.jtho.2021.02.004.
      AUC, area under curve; CCRT, concurrent chemoradiation; CHARTWEL, continuous hyperfractionated accelerated radiotherapy week end-less; DFS, disease-free survival; i.v., intravenous; NA, not available; NACT, neoadjuvant chemotherapy; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; SCRT, sequential chemoradiation.
      The data on practice of stereotactic body radiotherapy (SBRT) in lung cancer from India are sparse. This is due to the presentation of the disease in advanced stage in most parts of the country and lack of infrastructure. Corporate and very limited academic government hospitals have these facilities. There is a huge difference in the treatment cost of SBRT at private (U.S. $700–5000) and government (U.S. $10–200) hospitals in India, but it is considerably less than that in the western countries. The techniques range from free breathing without motion guidance to real-time tumor tracking, gating, and breath control. Surface-guided radiation therapy using sophisticated stereovision technology to track and monitor patient’s external motion before and throughout treatment is available at approximately 10 centers in India. Table 5 summarizes the published studies on SBRT in lung cancer from India.
      Table 5Published Studies on SBRT in Lung Cancer From India
      AuthorStudyStudy PeriodnDoseOutcome
      Kundu et al.S27Retrospective2007–2010848 Gy in six fractions for peripherally located and 48 Gy in eight fractions for centrally located tumorsOS at 1.5 y was 87.5%.
      Pathak et al.S28Retrospective2010–20142248–60 Gy in 4 to 10 fractionsOS, LRFS, and DMFS rates at 12 and 18 mo were 86.4%, 88.2%, and 62% and 64.8%, 75.6%, and 37.2%, respectively.

      Tumors that regressed in volume by >17.9% had significantly worse OS and LRFS compared with those that regressed by <17.9%.
      Madhavan et al.S29Retrospective2014–2016954 Gy in three fractions

      48 Gy in four fractions
      Median time of LR

      postradiation—8 mo

      Median OS—28 mo

      Median DFS—27 mo
      Talapatra et al.S30Retrospective2012–20161860 Gy/5 fractions for peripheral tumors and 48 Gy/6 fractions for central tumors1-y LC—87.5%
      Agarwal et al.S31Retrospective2007–201540Median BED—77 Gy10 from 2007 to 2012

      Median BED—105 Gy10 from 2013 to 2015
      2-y LC, OS, and CSS rates were 94%, 41%, and 62%, respectively
      Shrimali et al.S32Retrospective2014–201815 (included both primary and metastatic)40 to 60 Gy in 5–8 fractionsLocoregional control rate—93.3%
      Note: Due to the reference restrictions in this journal, please find a separate reference list of the tables as supplementary materials at https://doi.org/10.1016/j.jtho.2021.02.004.
      BED, biologically effective dose; CSS, cancer-specific survival; DMFS, distant metastasis-free survival; LC, local control; LR, local recurrence; LRFS, locoregional recurrence-free survival; OS, overall survival.
      Palliative thoracic radiotherapy with 20 Gy in five fractions or 17 Gy in two fractions has been used for effective palliation of symptoms and puts less economic burden on the patient and health care system.
      • Hotwani C.
      • Agarwal J.P.
      • Prabhash K.
      • et al.
      Palliative thoracic radiotherapy in advanced lung cancer: a single institution experience.
      Whole-brain radiotherapy still remains the standard of care in patients with multiple brain metastases. Most centers still use whole brain radiotherapy (WBRT) over stereotactic radiosurgery (SRS) or SBRT for brain oligometastases owing to logistics and lack of facilities for SRS or SBRT. The fractionation schemes used are 30 Gy in 10 fractions, 20 Gy in five fractions, or 6 to 8 Gy in single fraction depending on the performance status and age of the patient and the associated prognosis. Singh et al.
      • Singh S.
      • Sarin A.
      • Semwal M.
      • Bhatnagar S.
      • Gill M.
      • Sharma S.
      Gamma knife-based stereotactic radiosurgery boost after whole-brain radiotherapy in patients with up to three brain metastases: effects on survival, functional independence, and neurocognitive function.
      compared WBRT with WBRT followed by SRS boost in patients with up to three brain metastases. In this prospective comparative study, 58% of the patients had the lung as the primary malignancy. The combination of WBRT and SRS revealed a trend toward improved survival and local control.
      The advancements in technology and treatment techniques of radiotherapy available in India are at par with those in the western countries, but the major challenges are the advanced stage at presentation (leading to weight loss and poor performance status), large population burden and skewed distribution of radiotherapy facilities in urban regions, and high out-of-pocket costs for treatment in private sector.

      Systemic Therapy

      Systemic Therapy in NSCLC

      Systemic therapy in advanced NSCLC is largely biomarker driven. Targeted therapy remains the preferred treatment approach for patients with advanced or metastatic NSCLC with EGFR mutations and ALK rearrangements, respectively.

      EGFR TKIs

      Currently, erlotinib and gefitinib (first generation), afatinib and dacomatinib (second generation), and osimertinib (third generation) are approved and available in India for the treatment of EGFR-mutated advanced or metastatic NSCLC. Erlotinib and gefitinib are the most often used TKIs because generic versions are available (Table 6). A generic version of afatinib has become available within this year. First-line use of osimertinib is restricted to patients who can afford and those with substantial reimbursement or insurance. Combination of gefitinib with pemetrexed-carboplatin chemotherapy is a valid treatment strategy now, particularly for young and fit patients after the recent randomized phase 3 trial conducted at a large referral oncology center in India.
      • Noronha V.
      • Patil V.M.
      • Joshi A.
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      However, patient willingness (for chemotherapy) and the added toxicity with this strategy remain very important considerations and perhaps barriers to widespread implementation of the same. This is an alternative “best treatment first” strategy (in lieu of upfront osimertinib) while being considerably cheaper. However, most patients end up with the “sequencing of EGFR TKIs” approach in which osimertinib is offered after progression on first- or second-generation TKIs and with exon 20 T790M mutation demonstrable either in liquid or repeat tissue biopsy. Because affordability for osimertinib remains limited, most patients after progression on first-line TKI treatment are offered platinum-based chemotherapy if they are not candidates for or do not have access to osimertinib. The other mechanisms for EGFR TKI resistance are seldom evaluated in resource-constrained settings.
      Table 6Estimated Treatment Costs in India for Typically Indicated Targeted and Immunotherapy Drugs Related to Management of Lung Cancer
      DrugCost
      On the basis of MRP.
      of Innovator Brand
      Cost
      On the basis of MRP.
      of Generic Brand
      IndicationDoseDrug Type
      Targeted therapy
      EGFR TKIMonthly cost, US$Monthly costEGFR-mutant advanced/metastatic NSCLC
      Gefitinib17540–150250 mg odfirst-generation EGFR TKI
      Erlotinib165050–400150 mg odfirst-generation EGFR TKI
      Afatinib790

      760
      80

      60
      40 mg od

      30 mg od
      second-generation EGFR TKI
      Dacomitinib870

      820
      N/A45 mg od

      30 mg od
      second-generation EGFR TKI
      Osimertinib8200N/A80 mg odthird-generation EGFR TKI
      ALK TKIMonthly costMonthly costALK-rearranged advanced/metastatic NSCLC
      Crizotinib1420N/A250 mg bidfirst-generation ALK TKI
      Ceritinib1050640450 mg od (with low fat meal)second-generation ALK TKI
      Alectinib6720N/A600 mg bidsecond-generation ALK TKI
      BrigatinibN/A
      Only under compassionate access.
      N/A90 mg odsecond-generation ALK TKI
      Lorlatinib4160N/A100 mg odthird-generation ALK TKI
      ImmunotherapyCost per vialCost per vial
      Nivolumab1325

      530
      N/ARelapsed advanced/metastatic NSCLC100 mg

      40 mg
      PD-1 ICI
      Pembrolizumab2800N/ATreatment-naive and relapsed advanced/metastatic NSCLC100 mgPD-1 ICI
      Atezolizumab5300N/ATreatment-naive and relapsed advanced/metastatic NSCLC Treatment-naive ES-SCLC1200 mgPD-L1 ICI
      Durvalumab2530

      600
      N/AStage III NSCLC postchemoradiation and treatment-naive ES-SCLC500 mg

      120 mg
      PD-L1 ICI
      ES-SCLC, extensive-stage SCLC; ICI, immune checkpoint inhibitor; MRP, maximum retail price; N/A, not available; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1; TKI, tyrosine kinase inhibitor.
      a On the basis of MRP.
      b Only under compassionate access.

      ALK TKI

      Crizotinib (first generation), alectinib and ceritinib (second generation), and lorlatinib (third generation) are now available in India. With substantial difference in cost, availability of a generic version of ceritinib, and use of 450 mg (with low-fat meal) (Table 6), crizotinib and ceritinib are the two most often used first-line ALK TKIs. However, nonaffordability still remains a major issue and not all patients with ALK-rearranged NSCLC actually receive an ALK TKI either in the treatment-naive or pretreated setting. Furthermore, the proportion of patients with ALK-rearranged NSCLC who receive a second ALK TKI after progression on first-line ALK TKI is even smaller. A real-world experience of ALK TKIs from five major cancer centers in India was recently reported (Table 7) and reveals almost comparable outcomes and toxicity profiles.
      Table 7Summary of Recently Published Pooled Data Analysis From Large-Volume Referral Centers for Lung Cancer in India [Reproduced With Permission From Singh
      • Singh N.
      Lung cancer in India: the rewards of REWERDS (REal World Evidence from Retrospective Data analysiS).
      ]
      Pooled analysis from large-volume referral centers for lung cancer in India:
      • 1.
        Prevalence of EGFR analysis in the Indian population is approximately 30%.
      • 2.
        Real-time PCR and immunochemistry are the most often used methods currently in India for EGFR mutation and ALK rearrangement testing, respectively.
      • 3.
        Clinical benefit with use of EGFR TKIs for EGFR-mutated metastatic NSCLC and with use of ALK TKIs in ALK-rearranged metastatic NSCLC have both been of a similar magnitude as that observed in randomized clinical trials despite inclusion of patients with suboptimal performance status and brain metastases (typically excluded from randomized trails).
      • 4.
        Patients with EGFR mutations or ALK rearrangements (and possibly other oncogenic drivers) should be offered the appropriate targeted therapies even in the presence of suboptimal performance status or presence of brain metastases or both.
      • 5.
        Newer-generation EGFR and ALK inhibitors are used only in a small percentage of patients and this is distinctly different from high-income countries and developed nations primarily owing to cost of therapy. Consequently, isolated CNS progression remains an important site for therapeutic failure as the 1st-generation EGFR and ALK inhibitors have limited CNS efficacy.
      • 6.
        Maintenance chemotherapy with pemetrexed is associated with clinical benefit of similar magnitude as the registration trials. However, renal toxicity is a major concern during maintenance treatment.
      • 7.
        Preliminary experience from use of PD-1 and PD-L1 ICIs which was primarily in the relapsed/refractory setting indicates that the magnitude of survival benefit (both PFS and OS) closely approximates that of the registration trials. Good ECOG PS (and not high PD-L1 levels) predicted OS and PFS of pretreated patients subjected to ICI therapy.
      CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; ICI, immune checkpoint inhibitor; OS, overall survival; PCR, polymerase chain reaction; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

      Other Targeted Therapies

      Given the relatively low frequency of occurrence of oncogenic drivers as compared with EGFR mutations and ALK rearrangements and the fact that testing for these is largely sequential (after negative reports of EGFR and ALK are received), data related to treatment with targeted therapies for this heterogeneous non-EGFR, non-ALK cohort of oncogenic drivers remain sparse. Crizotinib and ceritinib are both available for the treatment of ROS1-rearranged NSCLC, whereas dabrafenib-trametinib combination has become recently available for BRAF-mutated NSCLC.

      Immunotherapy

      Two programmed cell death protein-1 (PD-1) immune checkpoint inhibitors (ICIs), nivolumab and pembrolizumab, and two programmed death-ligand 1 (PD-L1) ICIs, atezolizumab, and durvalumab, have received regulatory approval and are available for the treatment of advanced or metastatic NSCLC. Because Indian patients were not part of most of the registration trials for these PD-1 and PD-L1 ICIs, the Central Drugs Standard Control Organisation has granted conditional approval to these agents while mandating safety data in Indian population through phase 4 clinical trials, several of whom are currently ongoing. For nivolumab, the earliest ICI to have received regulatory approval in India for NSCLC, no new safety signals were observed in the postregulatory approval (phase 4) study. Published literature on use of ICI from India is greatest in the pretreated (relapsed) setting (Table 7). Owing to high cost, use of immunotherapy (Table 6) as first-line treatment either alone or in combination with chemotherapy is limited to the patients who can afford this per se or with substantial reimbursement or insurance cover, and most eligible patients actually end up receiving platinum-based doublet chemotherapy instead. Another important thing (in addition to cost of treatment) and more relevant for patients with nonsquamous NSCLC is that clinicians do not initiate ICI treatment (even if PD-L1 testing results are available) until the results of common targetable genetic alterations such as EGFR mutation and ALK gene rearrangement testing are available and are negative.
      • Saxena P.
      • Singh P.K.
      • Malik P.S.
      • Singh N.
      Immunotherapy alone or in combination with chemotherapy as first-line treatment of non-small cell lung cancer.
      Some oncologists here even advocate that all potentially targetable oncogenic drivers are tested on an NGS platform and are known to be negative before initiating ICI treatment. There are three main reasons: (1) targeted therapies are the preferred treatment for patients with oncogenic drivers, (2) patients with EGFR-mutated or ALK-rearranged NSCLC have innate resistance to immune checkpoint blockade and exhibit very low response rates to ICI treatment, and (3) administration of ICI before initiation of TKIs is associated with unacceptable incidence of toxicities (especially hepatotoxicity) that may occasionally be fatal. Overall, for a low- to middle-income country such as India, it is important that treating oncologists discuss efficacy, toxicity, and treatment-related costs with each and every eligible patient to help them decide if they are willing to go ahead with PD-1 or PD-L1 ICI treatment. This holds true whether the setting is for monotherapy (treatment naive with high PD-L1 expression or relapsed disease) or for combination with chemotherapy (treatment naive with no or low PD-L1 expression).

      Chemotherapy

      Platinum-based doublet is the mainstay of treatment for most patients in the absence of oncogenic drivers (mutations and rearrangements). Pemetrexed-platinum is the preferred regimen for nonsquamous NSCLC followed by maintenance pemetrexed in eligible patients.
      • Singh N.
      • Aggarwal A.N.
      • Kaur J.
      • Behera D.
      Association of graded folic acid supplementation and total plasma homocysteine levels with hematological toxicity during first-line treatment of nonsquamous NSCLC patients with pemetrexed-based chemotherapy.
      ,
      • Prasad K.T.
      • Muthu V.
      • Biswas B.
      • et al.
      Utility and safety of maintenance chemotherapy in advanced non–small cell lung cancer across various performance status categories: real-world experience.
      For squamous NSCLC, paclitaxel-carboplatin or gemcitabine-platinum combinations are preferred. Generic version of pemetrexed, gemcitabine, and taxanes (including nab-paclitaxel) are available and affordable for vast most patients. A recently randomized trial revealed that same-day initiation of vitamin B12 and folate administration along with pemetrexed-based chemotherapy was safe and associated with similar hematological toxicity profile as the conventional approach of giving vitamin supplementation for 5 to 7 days before chemotherapy.
      • Singh N.
      • Baldi M.
      • Kaur J.
      • et al.
      Timing of folic acid/vitamin B12 supplementation and hematologic toxicity during first-line treatment of patients with nonsquamous non-small cell lung cancer using pemetrexed-based chemotherapy: the PEMVITASTART randomized trial.
      Moreover, this approach has led to avoidance of an extra visit solely for purpose of vitamin supplementation.

      Systemic Therapy in SCLC

      The mainstay of systemic treatment in SCLC remains combination of platinum-etoposide both in limited-stage and extensive-stage (ES) diseases. Although cisplatin is preferred for younger fit patients, carboplatin is frequently used instead for older patients or those with comorbidities in whom potential toxicity from cisplatin use is a major concern. An acceptable alternative to etoposide-platinum is irinotecan-platinum, especially in ES-SCLC wherein concurrent chemoradiation is not done.
      • Singh N.
      • Aggarwal A.N.
      • Behera D.
      Management of advanced lung cancer in resource-constrained settings: a perspective from India.
      More recently, the PD-L1 ICIs atezolizumab and durvalumab both have become available for use in ES-SCLC in combination with platinum-etoposide chemotherapy. However, their actual use remains limited owing to cost constraints.

      Specific Issues, Challenges, and Summary

      Prospective studies have revealed that assessment of respiratory symptoms and total symptom burden at diagnosis by means of simple questionnaires is feasible and should be incorporated into routine clinical practice as symptom scores are prognostic (correlate with overall survival).
      • Singh P.S.
      • Aggarwal A.N.
      • Behera D.
      • Kapoor R.
      • Singh N.
      Simplified graded baseline symptom assessment in patients with lung cancer undergoing first-line chemotherapy: correlations and prognostic role in a resource-constrained setting.
      ,
      • Yogananda M.N.
      • Muthu V.
      • Prasad K.T.
      • Kohli A.
      • Behera D.
      • Singh N.
      Utility of the revised Edmonton symptom assessment system (ESAS-r) and the patient-reported functional status (PRFS) in lung cancer patients.
      In addition to symptoms, patients should also undergo evaluation for comorbid illnesses as these offer an opportunity for appropriate palliative interventions and specific treatment directed at both of these.
      • Singh N.
      • Aggarwal A.N.
      • Behera D.
      Management of advanced lung cancer in resource-constrained settings: a perspective from India.
      ,
      • Singh N.
      • Singh P.S.
      • Aggarwal A.N.
      • Behera D.
      Comorbidity assessment using Charlson comorbidity index and simplified comorbidity score and its association with clinical outcomes during first-line chemotherapy for lung cancer.
      Despite being one-fifth of global population, representation of India in global clinical trials is only 1.5%. Recently, regulatory rules and administrative processes for pharmaceutical clinical trials have been smoothened, which would encourage the major pharmaceutical companies to bring new drug trials to India.
      Overall cancer care infrastructure in India remains suboptimal to the population and burden of patients with cancer. Failure to address these deficiencies may result in higher mortality rates and lower survival of Indian patients with cancer as compared with developed countries. Seeking treatment in the private health sector is associated with substantially higher treatment costs and treatment-related financial burden. Furthermore, most patients who cannot afford private health care facilities generally seek treatment at government-funded health care facilities. However, availability of expertise and facilities for cancer treatment remains generally limited to large hospitals and big academic centers. Figure 5 depicts the typical flow of evaluation and management of a patient with lung cancer in India at such referral centers. The second version of the countrywide health insurance scheme sponsored by the Government of India (Ayushman Bharat Pradhan Mantri Jan Arogya Yojana; https://pmjay.gov.in) scheduled to be launched this year would increase the scope of essential anticancer drugs (including targeted therapies) covered by this scheme. Almost 100 million families from poor socioeconomic strata are expected to benefit from this new scheme.
      Figure thumbnail gr5
      Figure 5Typical flow of evaluation and management of a patient with lung cancer in India. Reproduced with permission from Singh.
      • Singh N.
      Lung cancer in India: the rewards of REWERDS (REal World Evidence from Retrospective Data analysiS).
      In summary, lung cancer is an important cause of morbidity and mortality in India, especially for male individuals, with the burden from this disease expected to rise further in the future. The spectrum of disease has evolved over the decades from being one predominantly affecting elderly tobacco smoking men (with squamous or small cell carcinoma) to one wherein an increasing number of younger age group individuals, light or nonsmokers, and female individuals are being affected (with predominance of adenocarcinoma). Tuberculosis remains an important confounder for diagnostic workup and staging and an important barrier cum deterrent for widespread implementation of LDCT screening. Most patients present with advanced/metastatic disease and are treated by nonsurgical modalities. Advances in molecular testing andradiation delivery techniques and availability of generic drugs targeting common oncogenic drivers have made treatment more effective and better tolerated while being affordable to select subgroups of patients with lung cancer. Only a fraction of eligible patients get treated with PD-1 or PD-L1 ICIs (in combination with or in lieu of chemotherapy) owing to the exorbitant cost of these immunotherapy drugs and nonavailability of any generics or biosimilars. Most of these patients with nononcogene-addicted NSCLC and SCLC instead receive standard platinum doublet chemotherapy with generic drugs.

      Supplementary Data

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