Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :377
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (607 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 »  Materials and Me...
 »  Epidemiology and...
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed449    
    Printed2    
    Emailed0    
    PDF Downloaded60    
    Comments [Add]    

Recommend this journal

 

  Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 59  |  Issue : 5  |  Page : 90-105
 

Evolving trends in lung cancer: Epidemiology, diagnosis, and management


1 Consultant Surgical Oncologist, Asian Institute of Oncology, Mumbai, Maharashtra, India
2 Consultant Radiation Oncologist, Jupiter Hospital, Thane, Maharashtra, India
3 Consultant Medical Oncologist, Manipal Hospital, Bengaluru, Karnataka, India, Indiaz

Date of Submission12-Jan-2021
Date of Decision17-Jan-2021
Date of Acceptance17-Apr-2021
Date of Web Publication24-Mar-2022

Correspondence Address:
Amit Rauthan
Consultant Medical Oncologist, Manipal Hospital, Bengaluru, Karnataka
Indiaz
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_52_21

Rights and Permissions

 » Abstract 


Lung cancer is one of the deadliest cancers globally and accounts for most of the cancer-related deaths in India. Comprehensive data on lung cancer in India are lacking. This review aimed to discuss the epidemiological trends of lung cancers and driver mutations as well as the recent advancements in molecular diagnostics and therapeutic options primarily in non–small cell lung cancer (NSCLC) in India. Electronic databases, such as PubMed and Google Scholar, were searched to retrieve the relevant literature published in the past 5 years. As per the GLOBOCAN 2018 report, lung cancer was ranked the fourth leading cause of cancer (5.9% cases) in India, in all ages and sexes. Furthermore, 63,475 of all cancer-related deaths (8.1%) were attributed to lung cancer (cumulative risk 0.60), making it the third leading cause of cancer-related mortality. The common targets for treatment in lung cancer patients mainly include EGFR mutation, ALK and ROS1 rearrangements and PDL1 expression. In India, EGFR and ALK re-arrangement are commonly reported, but there is limited data of PD-L1 expression. Molecular testing has gained importance as several biomarkers are being targeted to treat lung cancer patients. Surgery, radiotherapy, systemic chemotherapy, and personalized molecular-targeted therapy prolong the overall survival (OS) in patients with NSCLC. Although chemotherapy and molecular-targeted therapies have greatly improved the clinical outcomes, prolonged disease control could not be attained in most NSCLC patients. In this situation, immunotherapy seems to be potentially beneficial to obtain long-lasting disease control with minimal adverse events.


Keywords: Liquid biopsy, lung cancer, non–small cell lung cancer, stereotactic body radiotherapy, targeted therapy
Key MessageThis review discussed the epidemiological trends of lung cancer in India, the driver mutations, and recent advancements in molecular diagnostics and therapeutic options in non–small cell lung cancer in India. Immunotherapy appears to be the potential beneficial therapy with favorable outcomes and minimal adverse effects.


How to cite this article:
Deshpand R, Chandra M, Rauthan A. Evolving trends in lung cancer: Epidemiology, diagnosis, and management. Indian J Cancer 2022;59, Suppl S1:90-105

How to cite this URL:
Deshpand R, Chandra M, Rauthan A. Evolving trends in lung cancer: Epidemiology, diagnosis, and management. Indian J Cancer [serial online] 2022 [cited 2022 May 16];59, Suppl S1:90-105. Available from: https://www.indianjcancer.com/text.asp?2022/59/5/90/340528



 » Introduction Top


Lung cancer is one of the leading causes of cancer-related death globally. Among all the cancers, the number of patients afflicted with lung cancer is the highest, and the number is constantly rising.[1] This international trend of lung cancer is paralleled in India.[2] Lung cancers represent a group of heterogeneous entities both in terms of histology and molecular profile.[3] Histologically, they are categorized into two types: non–small cell lung carcinoma (NSCLC, 85% of all lung cancers) and small cell lung carcinoma (SCLC, 15% of all lung cancers).[3] NSCLCs are typically subdivided into adenocarcinoma, squamous cell carcinoma (SqCC), and large-cell carcinoma.[3] Both NSCLC and SCLC have very low survival rates.[1] Despite recent technological advances in the diagnosis, medical, and surgical treatments, the outcomes remain poor.[4]

The newer molecular diagnostic modalities have made it easier to detect cancer-related driver alterations, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK).[5],[6] Furthermore, accurate staging of cancer is important to plan the treatment for the patients. Recently, an individualized treatment approach, including targeted therapies for driver mutations and immunotherapies, is being used for the patients.[6] However, a comprehensive data on lung cancer in India are lacking.[4]

This review aims to discuss the epidemiological trends of lung cancers and driver mutations in the Indian population. Furthermore, it focuses on the recent advancements in molecular diagnostics and therapeutic options primarily for NSCLC.


 » Materials and Methods Top


The databases such as PubMed and Google Scholar were searched to retrieve the relevant literature. The search terms used were “Lung Cancer,” “NSCLC,” “Epidemiology,” “India,” “Liquid biopsy,” “Diagnosis,” “Surgery,” “Radiotherapy,” “Immunotherapy,” “Targeted Therapy,” “Driver Mutations,” and “Mutations.” The search terms were combined using Boolean operators “AND/OR” and was limited to the past 5 years. Cross-references in the retrieved papers were also referred if found relevant.


 » Epidemiology and Changing Trends in Lung Cancers Top


As per the GLOBOCAN 2018 report, 18.1 million new cancer cases were estimated to occur globally.[1],[7] Of these, 2,093,876 new cases (11.6%) in all ages and sexes were attributed to lung cancers (cumulative risk 2.75), making it the most frequently occurring cancer followed by the breast, prostate, and colorectal cancers.[1],[8] Lung cancer accounted for 18.4% (n = 1,761,007) of all cancer-related mortality (cumulative risk 2.22),[8] making it the most common cause of cancer-related mortality globally, followed by colorectal, stomach, and liver cancers.[1],[8]

According to the GLOBOCAN 2018 report, lung cancer was the fourth leading cause of cancer (5.9%; cases: 67,795; cumulative risk: 0.65) in India, in all ages and sexes, after breast, lip, oral cavity, and cervix or uterine cancers.[9] Furthermore, 63,475 of all cancer-related deaths (8.1%) were attributed to lung cancer (cumulative risk 0.60), making it the third leading cause of cancer-related mortality after breast, lip, and oral cavity cancers.[9] Both the incidence and mortality trends for lung cancer have shown a minor decrease from that estimated by the GLOBCAN report in 2012 (6.9% and 9.3%, respectively).[10]

The India State-Level Disease Burden Initiative collaborators have reported a significant heterogeneity in the trends of age-standardized incidence of top 10 cancers, including lung cancers from the year 1990 to 2016 in different states of India.[11] The heterogeneity varied from 3.3 times to 11.6 times for the four most common cancers, namely, lip and oral, breast, lung, and stomach cancers.[11] In men, the crude lung cancer incidence rate was the highest in Kerala and Mizoram (19.5 [17.5–21.3] and 18.9 [17.2–20.5], respectively), whereas in women, it was the highest in Mizoram and Manipur (18.9 [10.7–20.8] and 8.3 [6.5–9.2], respectively).[11] In 2016, the crude deaths and disability-adjusted life-years (DALY) rate for lung cancer was the highest in Mizoram (502·8) followed by Kerala (276·1), Manipur (274·1), and Jammu and Kashmir (269·0).[11] As per the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) for lung cancer in India, 43.2% of the lung cancer DALYs were attributed to tobacco consumption and 43% to air pollution in 2016[11] and are considered to be the leading risk factors for lung cancers.[11] The most common histology for nonsmokers is adenocarcinoma and SqCC for moderate to heavy smokers.[12]

Adenocarcinoma is the most common variant of lung cancer followed by SqCC in the Western countries and many of the Asian countries[4]; however, in a retrospective analysis of 1,301 lung cancer patients (2011–2015) in North India, adenocarcinoma and SqCC were found to be equally prevalent (36.4% each).[13] On the other hand, NSCLC not otherwise specified (NSCLC-NOS) significantly decreased in prevalence (10.9% in 2012 to 5.1% in 2017; P < 0.001).[13] Majority of all newly diagnosed lung cancer patients (83.4%) had advanced disease (Stages IIIB and IV) and were current/ex-smokers (76.9%).[13] A retrospective study (2018) from Kerala (South India) reported the prevalence of SqCC (29%) to be higher than adenocarcinoma (26%).[14] Although SqCC is considered to be the most common histological type of lung cancer in India, recent studies show an increased prevalence of adenocarcinoma over the SqCC.[15],[16],[17],[18] A retrospective study of prospectively collected data on lung cancer from a tertiary care center in Chennai (South India), during a 5-year period, showed the most common histology to be adenocarcinoma (42.6%), followed by SqCC (15.6%).[16] Another cross-sectional study in Madurai (South India) from 2018 to 2019 detected 50% adenocarcinoma and 36% SqCC in suspected lung cancer patients.[17] In a study by Murali et al. (2017)[18] in Chennai (South India) adenocarcinoma was found in 51% lung cancer patients who underwent treatment.

The highest age-adjusted incidence rates (45 per 100,000 population) and the lowest age-adjusted incidence rates (2 per 100,000 population) of lung cancer have been reported in northeastern India and western India, respectively.[15] Likewise, there are considerable variations in the demographic profile, including age, gender, stage, histology, and driver mutations (prevalence of EGFR mutations and ALK rearrangements) in different regions of India.[15]

The prognosis of lung cancers is poor. The overall 3-year survival of the NSCLC patients after treatment was found to be 31% (95% confidence interval [CI]: 27–36). In patients where the symptom to treatment delay was less than 3 months, the 3-year survival was 11% and in patients with a delay of more than 6 months, the survival was 35%.[19] Murali et al. (2017)[18] reported the median progression-free survival (PFS) and overall survival (OS) for patients with NSCLC to be 6.9 months and 7.6 months, respectively, whereas PFS and OS for SCLC patients was found to be 6 months and 7.2 months, respectively. A study by Malik et al. (2013)[20] reported the median OS of patients with NSCLC and SCLC to be 12.8 months (95% CI: 11.0 –14.7) and 9.1 months (95% CI: 6.8–11.4) and the median PFS to be 7.8 months (95% CI: 6.1–8.8) and 6.8 months (95% CI: 53–8.3), respectively. Lung cancer patients without brain metastases were found to have higher OS 20.6 months (95% CI: 18.3–22.8 months) compared with those patients with brain metastases 15 months (95% CI: 11.7–18.4 months).[21] Shimali et al. (2018)[22] reported a median PFS of 11 months (95% CI: 8.80–1.20) and OS of 20 months (95% CI: 17.54–22.26) in locally advanced NSCLC patients.

Driver mutations in Indian population

Currently, the role of several molecular aberrations in lung cancer development has been widely investigated.[23] Researchers examined the association between some mutations and lung cancer progression, especially in NSCLC. The common mutations that has been detected and targeted for treatment in lung cancer patients include EGFR, ALK and ROS1.[23] The incidence/prevalence of EGFR mutations in India range from 33% to 48% among studies with varied methodology and population demographics.[24],[25],[26] EGFR mutations are more commonly reported in women, non smokers and adenocarcinoma histology.[25],[26],[27]

ALK rearrangement rates of 7% to 22% have also been reported in different Indian studies.[28],[29],[30] Furthermore, in a study by Doval et al.,[26] the incidence of echinoderm microtubule-associated protein such as 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene in EGFR mutation negative cases was reported to be 4.5% and overall incidence of EML4-ALK fusion gene was found to be 3%. Like EGFR mutations, ALK mutations are predominantly seen in nonsmokers (81%).[31]

Additionally, increased expression programmed death ligand–1 (PD-L1) has been detected in lung cancer recently and is considered a promising targeted molecule for immunotherapy; especially in those without driver mutations.[32] The Indian data regarding PD-L1 expression is relatively scarce. PD-L1 positivity rate of 27% was observed in adenocarcinoma patients in one study, and in another study PD-L1 positivity rate in lung cancer patients was found to be 47.7% in SqCC and 50.5% in NSCLC patients.[32],[33] [Table 1] summarizes the literature reports on incidence/prevalence of targeted alterations in NSCLC.[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112]
Table 1: Summary of literature studies on incidence/prevalence of targeted mutations in NSCLC

Click here to view


Screening of Lung cancer

Screening tools for NSCLC consist of some recent clinically available tests and also those studied in clinical trials.[36] Various organizations issued guidelines on lung cancer screening. However, there are no current guidelines recommending mass screening for early detection of lung cancer.[37] The U.S. Preventive Services Task Force reported that the existing indication was insufficient to either recommend or warn against the use of tools to detect lung cancer in asymptomatic patients.[38] Additionally, the American Cancer Society does not advocate screening for at-risk individuals.[39]

Scenario of lung cancer screening in India

Screening of lung cancer in India is associated with several challenges, such as (1) overall expenses and poor infrastructure limiting the availability of diagnostic modalities in remote areas, (2) difficulty in developing an effective lung cancer screening program, and (3) smoking cessation education and individualized screening in high-risk cases to reduce mortality. Hence, before the actual implementation of a screening protocol in practice, a pilot project is recommended in the Indian scenario. Moreover, an affordable strategy should be vital to attain the goal.[40]

Diagnosis

Importance of molecular diagnosis on lung cancer management

Molecular testing has gained importance as several biomarkers are being targeted to provide more individualized treatment to lung cancer patients.[23] Diagnosis of lung cancer has shown a paradigm shift from traditional morphology-based diagnosis to molecular diagnosis. The important molecular subtypes are EGFR, ALK, ROS1, B-RAF, MET, Her2/neu, and RET mutations.[23]

Around half a decade back, tissue biopsy was a gold standard for molecular profiling of tumor. It played a vital role in decision making with regard to treating patients with advanced NSCLC.[41] However, a major challenge with tissue biopsy was the nonavailability or insufficiency of tumor tissue for further detection of gene variations.[25],[26] In addition, rebiopsy in patients resistant to targeted therapy is more challenging, primarily because of clinically suboptimal condition of the patient.[5],[41],[42] A recently introduced noninvasive liquid biopsy technique could be utilized in such cases. It has several advantages over tissue biopsy, including easy accessibility and good repeatability[5],[43] and is increasingly used nowadays for molecular profiling of tumor and monitoring drug resistance.[5]

The U.S. Food and Drug Administration (USFDA) and the European Medical Association (EMA) have approved the use of liquid biopsy.[44] They have also published guidelines and recommendations for use of these modalities in detection of different driver mutations in lung cancers such as EGFR, to aid in adequate monitoring and appropriate use of targeted/immune therapies for NSCLC patients with driver mutations.[44] Many renowned Indian oncologists have also published consensus recommendations for using liquid biopsies in Indian scenario.[43]

Liquid biopsy is beneficial in the management of molecule targeted therapy[5] EGFR and ALK molecules are the major and frequent targets for precise targeted therapy in NSCLC patients, and thus liquid biopsies involve these two molecules.[5] Several specimens, including plasma, serum, urine, sputum, and cerebrospinal fluid (CSF), have been used in liquid biopsy under different clinical scenarios.[5],[45],[46],[47] Among all specimens, plasma is the most commonly used to detect tumor-associated biomarkers.[5] These specimens contain several biomarkers released by the tumor cells such as cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTC), exosomes, platelets, and microRNAs and help assess the tumor-related changes[48],[49] and also monitor changes associated with drug resistance occurring during the treatment. The cfDNA is released passively from the dying cells or from CSF, urine, sputum, saliva, pleural effusion, stool, and seminal fluid.[45],[50] Although about 24-fold higher cfDNA has been reported in serum compared with plasma due to hemolysis during clotting or from leukocyte contamination,[51] increased cfDNA in serum is known to be associated with a higher false-positive rate, making plasma the preferred specimen for evaluation of cfDNA.[51]

The ctDNA, a subset of total cfDNA, occurs in blood ranging from 0.01% to 90%.[52] Its occurrence depends on tumor stage, vascularization, burden, and biological features such as apoptotic rate, metastatic potential of tumor cells, and the factors affecting patients' blood volume.[52] It may be directly secreted by the tumor cells or released due to the lysis of apoptotic and necrotic tumor cells.[52] Its half-life in the bloodstream ranges between 16 minutes and 2.5 hours and is considered as a real-time biomarker that can reflect the tumor burden.[52]

CTCs are tumor cells that are disseminated into blood circulation after their detachment from the solid tumor mass.[52] ctDNA and CTCs are the most commonly used biomarkers in liquid biopsies.[52] ctDNA generally increases with tumor burden. In the early-stage disease, it elevates to 1% of total cfDNA, whereas in late-stage disease, it rises to 40%.[45] Thus, it allows early detection of disease relapse or treatment response monitoring, and its analysis affects therapeutic decision.[45]

Tumor heterogeneity should be considered during NSCLC management[5],[45] since a single type of specimen may not cover all the relevant alterations/mutations.[5] Overall, liquid samples are easy to be examined; therefore, it allows quick diagnosis and monitoring of lung cancers. Ma et al. (2016)[53] assessed the feasibility of ctDNA on testing EGFR mutation using sensitive amplification refractory mutation system (ARMS) in Stages III–IV NSCLC patients and reported 82% concordance rate between the matched plasma and tissue samples.[53] The sensitivity and the specificity of the EGFR mutation test in the plasma compared with tumor tissue was 60% and 97%, respectively.[53]

Douillard et al. (2014)[54] used ARMS to quantify ctDNA in advanced NSCLC patients and revealed that plasma could be a suitable sample for detecting EGFR mutation with a high concordance (94.3%) between plasma and tissue samples, 65.7% sensitivity, and 99.8% specificity.[54] A Phase 2 trial, BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial), reported that EGFR mutation detection in ctDNA is effective for identification of patients who might be benefitted from first-line gefitinib treatment.[55] The trial yielded a 79% concordance.[55]

ALK rearrangements from plasma are also analyzed in liquid biopsy with 79.2% sensitivity and 100% specificity.[56] Apart from EGFR and ALK, other driver mutations in NSCLC include ROS1 and BRAF and can be detected in peripheral blood/plasma samples, but literature pertaining to their detection is relatively scarce.[5]

Numerous advanced methods are available for assessing liquid biopsy samples such as PCR (polymerase chain reaction) and NGS (next-generation sequencing), and their variations such as magnetics (BEAMing) and droplet digital PCR (ddPCR), which increase the reliability and accuracy of detecting mutations in these samples.[57] It also allows for detection of multiple genes parallelly, thus expanding the therapeutic focus.[58] Recently, Gale et al. (2018),[59] developed InVision™ liquid biopsy platform, which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based NGS method for the identification of clinically relevant somatic alterations at low frequency in cfDNA across a panel of 35 cancer-related genes. Using this NGS panel of 35 cancer-related genes, an overall 94% sensitivity of alterations in plasma cfDNA can be achieved.[59]

Liquid biopsy potentially improves the detection of targetable mutations in NSCLC patients. A real-world study, including 323 patients with metastatic NSCLC undergoing plasma NGS with 73-gene commercial platform (Guardant360, Guardant Health) or tissue biopsy, demonstrated that targetable mutations were detected in one third of patients who underwent liquid biopsy only.[60],[61] Additional targetable mutations (including EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF) were detected via liquid biopsy in 35.8% patients.[60],[61] Thus, liquid biopsy, a noninvasive technique, is an effective alternative to analyze tumor-associated genetic aberrations in lung cancer. It also complements the results from tissue biopsy and allows to deliver an appropriate and precise management for better outcomes.[45]

Management of lung cancer

Surgical management

Worldwide, surgeons investigated numerous techniques to make surgical resection least invasive. Sublobar resection and single-port video-assisted thoracoscopic surgery (VATS) have emerged as the most reasonable approach, mainly for pulmonary segmentectomy with satisfactory postoperative outcomes in the early stages of lung cancer.[62]

In a multi-institutional retrospective analysis, single-port VATS segmentectomies and lobectomies were found to be safe and feasible.[63] The study identified that patient age (≥60 years) and tumor size (>3 cm) are the predictors of unfavorable preoperative outcomes.[63] In another study, no significant difference in 10-year survival was observed in the Stage I NSCLC patients treated with sublobar resection or lobectomy.[64] Furthermore, 5-year survival rate was reported to rise by 4% in patients with Stage IB, II, or III NSCLC receiving chemotherapy after surgery with or without radiotherapy than ones having surgery without chemotherapy with or without radiotherapy (hazard ratio [HR]: 0.86, 95% CI: 0.810.92; P < 0.0001].[65]

Radiation therapy

Radiation therapy for lung cancer has two major components: “intent” and “technique.” Surgery was the preferred treatment in patients with lung cancer since 1861. Pean successfully excised a lung tumor by suturing pleura to the lung, then removing it with galvanic current cautery and dressing with carbolic acid.[66] However, radiotherapy forms the principal treatment in patients not suitable for surgery or unwilling to undergo surgery.[67] The intent of treatment is either attempt to cure (Stage I, II, and III) or relieve symptoms (Stage IV). Stage I patients are subjected to highly conformal treatment with respiratory gating under image guidance to deliver a very high dose in small fractionation. For Stages II and III, the intent is to cure with a median OS of 22 to 26 months. These patients are treated with conformal treatment with image guidance and respiratory gating. Stage IV patients are treated generally with palliative intent.

Radiotherapy technique has evolved greatly in the past two decades. There is a shift from two-dimensional approaches to three-dimensional conformal radiation therapy (3DCRT).[68] Newer techniques are capable of delivering radiations specifically to tumors, thus limiting the exposure of normal healthy tissues to radiations. The new radiotherapy being investigated includes stereotactic body radiotherapy (SBRT), intensity-modulated radiation therapy (IMRT), and image-guided radiotherapy (IGRT) with improved treatment outcomes.[69] Among all, SBRT has become a treatment of choice in patients where surgery could not be performed especially in early-stage node-negative NSCLC.[67] SBRT uses ablative doses of radiation, delivered in few fractions and recognized by a biological equivalent dose (BED) > 100 Gy.[70] SBRT has displayed excellent local and regional control with toxicity rates equivalent to surgery.[71] Decrease in fractionation schedules is reported to be both safe and effective. However, distant failure is common with SBRT.[71] Chemotherapy, therefore, may be considered for selected patients.[71]

Wegner et al. (2018)[72] compared the outcomes in patients who underwent lung SBRT either for presumed (n = 100) or proven NSCLC (n = 96) over a 10-year period. There was no difference in OS, local control, regional control, or distant control between the groups.[72] The local control and OS at 3 years were 94% and 58%, respectively.[72] Thus, SBRT is a safe and effective treatment for medically inoperable NSCLC patients.[72] Similarly, Lin et al. (2019)[73] compared the outcomes of lobectomy and SBRT in Stage I NSCLC patients. Both the groups had a comparable 3-year local recurrence-free survival (LRFS; 97% vs. 91.7%; P = 0.768) and recurrence-free survival (RFS; 85.4 vs. 69.5%; P = 0.014).[73] Three-year OS was also similar (88.2 vs. 79.7%; P = 0.027).[73] Overall, SBRT is well tolerated with low toxicity profile and is a promising treatment alternative for NSCLC patients.[73]

IMRT, an advanced technique, can improve therapeutic dose ratio[74] and can be a good alternative treatment of inoperable NSCLC.[74] A retrospective review of 55 patients with Stage I–IIIB inoperable NSCLC treated with IMRT revealed promising outcomes.[74] The 2-year local control for Stage I–II patients of 50% and OS of 55% and for the Stage III patients, 2-year local control of 58% and OS of 58% was reported.[74] Median survival time was 25 months. Acute pulmonary toxicity (Grade 3) occurred in only 11% patients with no acute treatment-related deaths.[74] Recently, Chun et al. (2017)[75] supported the routine use of IMRT for locally advanced NSCLC in their Phase III NRG Oncology clinical trial RTOG (Radiation Therapy Oncology Group) 0617 on Stage IIIB patients and reported that IMRT was associated with minimal rates of severe pneumonitis (7.9% with IMRT vs. 3.5% with 3DCRT; P = 039) and cardiovascular toxicity (P < 0.05).[75] Shimali et al. (2018)[22] published data on Indian patients indicating that IMRT is feasible and well tolerated in NSCLC patients.

Furthermore, the introduction of IGRT has tremendously raised the accuracy of tumor irradiation.[76] The functional imaging in IGRT based on advanced image guidance technology allows differentiation of tumor tissue from surrounding normal tissue,[76] thus reducing irradiation dose delivered to normal surrounding tissues.[76] This technique reduces radiation-associated complications and improves patients' posttreatment quality of life (QoL).[76]

Chemotherapy

Majority of patients newly diagnosed with lung cancer are Stage IV patients,[77] and their treatment aims to improve the survival and QoL.[78] The first-line therapy for Stage IV NSCLC is cytotoxic combination chemotherapy,[78] usually influenced by histology of tumor, age, comorbidities, and the performance status (PS).[78] Platinum-based regimens, including cisplatin or carboplatin along with paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed, are preferred.[78]

A meta-analysis evaluating the effect of cytotoxic chemotherapy on survival favored the current regimens containing cisplatin.[79] Furthermore, chemotherapy when administered with surgery accounted for 13% reduction in the risk of death.[79] Moreover, radical therapy and supportive care therapy along with chemotherapy led to the improvement in survival rate.[79] Randomized trials also demonstrated that chemotherapy is effective for Stage IV NSCLC, especially in elderly patients with comorbid conditions.[80] Overall, systemic chemotherapy contributes to improved survival and QoL in patients with advanced-stage NSCLC.[81]

Targeted therapy

Targeted therapy in NSCLC patients could be personalized by targeting the appropriate molecular targets in tumors and improves the survival rate.[82] Targeted agents in the form of oral tyrosine kinase inhibitors (TKIs) have demonstrated success against various alterations, such as EGFR, ALK, ROS1, B-RAF, MET, RET, Her2neu and NTRK.[82],[83],[84],[85],[86] [Table 2] summarizes the different TKIs used in targeted therapy of NSCLC.
Table 2: Summary of Targeted Therapy in Treatment of NSCLC

Click here to view


Immunotherapy

The chemotherapy and molecularly targeted therapies for lung cancer have greatly improved the clinical outcomes. Despite these therapies, prolonged disease control could not be attained in most NSCLC patients, and 5-year survival rate also remains low.[6] It is mainly attributed to the evasion of immunosurveillance that occurs by the phenomenon of immunosuppressive chemokines, loss of major histocompatibility complex (MHC) antigen expression, and increased T-regulatory cells in the tumor microenvironment.[6] This creates a need for innovative therapies to obtain long-lasting disease control with minimal adverse events.

Immunotherapy in such patients seems to be potentially beneficial. CTLA-4 and PD-1 are the inhibitory receptors that regulate T cells [Figure 1]a and [Figure 1]b[6] and are upregulated in numerous tumors, including NSCLC. Inhibition of the CTLA-4 and PD-1 pathways results in better intratumoral immune responses.[6] Immune checkpoint inhibitors, namely, CTLA-4 inhibitors and PD-1/PD-L1 inhibitors are also currently under the spotlight of Indian oncology.[6] The efficacy and toxicity of the immune checkpoint inhibitors in the Indian patients were similar to that of the international cohorts.[34] Gupta et al. (2019)[34] revealed a median PFS of 3 months and OS of 8 months at a median follow-up of 10 months with immunotherapies in Indian patients with cancer, including NSCLC. [Table 3] summarizes the outcomes of these studies.
Figure 1: (a) CTLA-4 Pathway. (b) PD-1 Pathway

Click here to view
Table 3: Summary of CTLA-4 Inhibitors PD-1/PD-L1 Inhibitors in Treatment of NSCLC

Click here to view



 » Conclusion Top


Worldwide, lung cancer is ranked the topmost among all the cancers, both in terms of incidence and mortality. The survival rates of lung cancer, both NSCLC and SCLC, are very low. Conventional management of NSCLC involves surgery, chemotherapy, and radiotherapy. Radiotherapy is the principal form of treatment in patients not suitable for surgery. The first line of treatment for advanced NSCLC patients is cytotoxic combination chemotherapy. Recently developed molecularly targeted therapy has shown improved clinical outcome for NSCLC patients who has a driver mutation. Despite numerous technological advancements pertaining to diagnosis and therapeutic approaches to improve the survival in patients with advanced-stage lung cancer, the outcomes remain poor. Currently, immunotherapy, a novel approach with minimal adverse events or safety concerns has been proved to be beneficial for the treatment of NSCLC patients who do not have any driver mutations. The efficacy of the immune checkpoint inhibitors in the Indian patients has also been demonstrated in different studies.

Acknowledgments

The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Turacoz Healthcare Solutions in accordance with the GPP3 guidelines (http://www.ismpp.org/gpp3).

Financial support and sponsorship

AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
    
2.
Gardasil Prescribing Information. Available from: https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm111263.pdf. Last updated: April 2015. [Last accessed on 2018 Dec 04].  Back to cited text no. 2
    
3.
Inamura K. Lung Cancer: Understanding its molecular pathology and the 2015 WHO classification. Front Oncol 2017;7:193.  Back to cited text no. 3
    
4.
Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer 2016;5:95-103.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Wu Z, Yang Z, Dai Y, Zhu Q, Chen LA. Update on liquid biopsy in clinical management of non-small cell lung cancer. Onco Targets Ther 2019;12:5097-109.  Back to cited text no. 5
    
6.
Anagnostou VK, Brahmer JR. Cancer immunotherapy: A future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res 2015;21:976-84.  Back to cited text no. 6
    
7.
World Health Organisation. Breast cancer-Early diagnosis and screening. 2018. Available from: http://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/. Updated in 2018. [Last accessed on 2018 Nov 19].  Back to cited text no. 7
    
8.
The Global Cancer Observatory. Globocan 2018 report. Available from: https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. [Last accessed on 2019 Sep 18].  Back to cited text no. 8
    
9.
The Global Cancer Observatory. Globocan 2018 report, India. Available from: https://gco.iarc.fr/today/data/factsheets/populations/356-india-fact-sheets.pdf. [Last accessed on 2019 Sep 18].  Back to cited text no. 9
    
10.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.  Back to cited text no. 10
    
11.
Dhillon PK, Mathur P, Nandakumar A, Fitzmaurice C, Kumar GA, Mehrotra R, et al. The burden of cancers and their variations across the states of India: The global burden of disease study 1990–2016. Lancet Oncol 2018;19:1289-306.  Back to cited text no. 11
    
12.
Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Quantified smoking status and non-small cell lung cancer stage at presentation: Analysis of a North Indian cohort and a systematic review of literature. J Thorac Dis 2012;4:474-84.  Back to cited text no. 12
    
13.
Kaur H, Sehgal IS, Bal A, Gupta N, Behera D, Das 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. Indian J Cancer 2017;54:285-90.  Back to cited text no. 13
[PUBMED]  [Full text]  
14.
Thomas VD, Jose B, Rennis DK. Prevalence of type and etiology of lung cancer among the patients presented to a tertiary care hospital at central Kerala: A descriptive study. Int J Res Med Sci 2018;6:834.  Back to cited text no. 14
    
15.
Behera D. SC17.03 Lung cancer in India: Challenges and perspectives. J Thorac Oncol 2017;12:S114-5.  Back to cited text no. 15
    
16.
Krishnamurthy A, Vijayalakshmi R, Gadigi V, Ranganathan R, Sagar T. The relevance of 'nonsmoking-associated lung cancer' in India: A single-centre exprience. Indian J Cancer 2012;49:82-8.  Back to cited text no. 16
[PUBMED]  [Full text]  
17.
Premananth P, Gnanasekaran R, Nagarjan N, Deiveegan. Lung cancer profile at tertiay care hospital, South Tamilnadu. IP Indian J Immunol Respir Med 2019;4:245-51.  Back to cited text no. 17
    
18.
Murali AN, Radhakrishnan V, Ganesan TS, Rajendranath R, Ganesan P, Selvaluxmy G, et al. Outcomes in lung cancer: 9-year experience from a tertiary cancer center in India. J Glob Oncol 2017;3:459-68.  Back to cited text no. 18
    
19.
Myrdal G, Lambe M, Hillerdal G, Lamberg K, Agustsson T, Stahle E. Effect of delays on prognosis in patients with non-small cell lung cancer. Thorax 2004;59:45-9.  Back to cited text no. 19
    
20.
Malik PS, Sharma MC, Mohanti BK, Shukla NK, Mohan A, Kumar G, et al. Clinico-pathological profile of lung cancer at AIIMS: A changing paradigm in India. Asian Pacific J Cancer Prev 2013;14:489-94.  Back to cited text no. 20
    
21.
Bhatt VR, D'Souza SP, Cushman AM, Noronha V, Verma V, Joshi A, et al. Epidermal growth factor receptor mutational status an brain metastases in non-small cell lung cancer. J Glob Oncol 2017;3:208-17.  Back to cited text no. 21
    
22.
Shimali RK, Nallathambi C, Saha A, Das A, Prasatha S, Mahata A, et al. Radical radiotherapy or chemoradiotherapy for inoperable, locally advanced, non-small cell lung cancer: Analysis of patient profile, treatment approaches, and outcomes for 213 patients at a tertiary cancer center. Indian J Cancer 2018;55:125-33.  Back to cited text no. 22
    
23.
Popovska SL, Dineva TB, Damyanova PD. Molecular diagnosis of lung cancer. J Biomed Clin Res 2017;10:98-103.  Back to cited text no. 23
    
24.
Khullar P. PUB034 profile of lung cancer in developing country: Single centre experience? Changing paradigm. J Thorac Oncol 2017;12:S1467.  Back to cited text no. 24
    
25.
Darling H, Viswanath S, Singh R, Ranjan S, Pathi N, Rathore A, et al. A clinico-epidemiological, pathological, and molecular study of lung cancer in Northwestern India. J Can Res Ther 2020;16:771-9.  Back to cited text no. 25
[PUBMED]  [Full text]  
26.
Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al. Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther 2015;8:117-23.  Back to cited text no. 26
    
27.
Kasana BA, Dar WR, Aziz SA, Lone AR, Sofi NU, Dar IA, et al. Epidermal growth factor receptor mutation in adenocarcinoma lung in a North Indian population: Prevalence and relation with different clinical variables. Indian J Med Paediatr Oncol 2016;37:189-95.  Back to cited text no. 27
[PUBMED]  [Full text]  
28.
Rana V, Ranjan P, Jagani R, Rathi KR, Kumar D, Khera A. A study of therapy targeted EGFR/ALK mutations in Indian patients with lung adenocarcinoma: A clinical and epidemiological study. Med J Armed Forces India 2018;74:148-53.  Back to cited text no. 28
    
29.
Gupta P, Gowrishankar S, Swain M. Epidermal growth factor receptor and anaplastic lymphoma kinase mutation in adenocarcinoma lung: Their incidence and correlation with histologic patterns. Indian J Pathol Microbiol 2019;62:24-30.  Back to cited text no. 29
[PUBMED]  [Full text]  
30.
Bal A, Singh N, Agarwal P, Das A, Behera D. ALK gene rearranged lung adenocarcinomas: Molecular genetics and morphology in cohort of patients from North India. APMIS 2016;124:832-8.  Back to cited text no. 30
    
31.
Bamania A, Sahni D, Mohan A, Malik P, Madan K, Hadda V, et al. Comparison of clinical profile of patients with ALK-positive and EGFR-positive non-small cell lung adenocarcinoma in an indian population. Chest2017;151:A126-A127.  Back to cited text no. 31
    
32.
Vallonthaiel AG, Malik PS, Singh V, Kumar V, Kumar S, Sharma MC, et al. Clinicopathologic correlation of programmed death ligand-1 expression in non-small cell lung carcinomas: A report from India. Ann Diagn Pathol 2017;31:56-61.  Back to cited text no. 32
    
33.
Domadia K, Batra U, Jain P, Sharma M, Gupta S, Bothra S, et al. Retrospective evaluation of PD-L1 expression in tumor tissue of patients with lung carcinoma and correlation with clinical and demographical data from a tertiary care institute of northern India. Ann Oncol 2018;29. doi: 10.1093/annonc/mdy425.009.  Back to cited text no. 33
    
34.
Ashton RW, Jett JR. Screening for non-small cell lung cancer. Semin Oncol 2005;32:253-8.  Back to cited text no. 34
    
35.
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94.  Back to cited text no. 35
    
36.
Force USPST. Lung cancer screening: Recommendation statement. Ann Intern Med 2004;140:738-9.  Back to cited text no. 36
    
37.
Smith RA, von Eschenbach AC, Wender R, Levin B, Byers T, Rothenberger D, et al. American Cancer Society guidelines for the early detection of cancer: Update of early detection guidelines for prostate, colorectal, and endometrial cancers: Also: Update 2001—testing for early lung cancer detection. CA Cancer J Clin 2001;51:38-75.  Back to cited text no. 37
    
38.
Kashyap S, Solanki A. Lung cancer screening in India: Along way to go. Indian J Chest Dis Allied Sci 2014;56:145-6.  Back to cited text no. 38
    
39.
Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, et al. Non-small cell lung cancer, Version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017;15:504-35.  Back to cited text no. 39
    
40.
Chouaid C, Dujon C, Do P, Monnet I, Madroszyk A, Le Caer H, et al. Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: A prospective multicenter study in a real-world setting (GFPC study 12-01). Lung Cancer 2014;86:170-3.  Back to cited text no. 40
    
41.
Doval DC, Deshpande R, Dhabhar B, Babu KG, Prabhash K, Chopra R, et al. Liquid biopsy: A potential and promising diagnostic tool for advanced stage non-small cell lung cancer patients. Indian J Cancer 2017;54(Suppl):S25-30.  Back to cited text no. 41
    
42.
Pennell NA, Arcila ME, Gandara DR, West H. Biomarker testing for patients with advanced non–small cell lung cancer: Real-world issues and tough choices. J Am Soc Clin Oncol Educ Book 2019;39:531-42.  Back to cited text no. 42
    
43.
Neumann MH, Bender S, Krahn T, Schlange T. ctDNA and CTCs in liquid biopsy-Current status and where we need to progress. Comput Struct Biotechnol J 2018;16:190-5.  Back to cited text no. 43
    
44.
Li YS, Jiang BY, Yang JJ, Zhang XC, Zhang Z, Ye JY, et al. Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: A new medium of liquid biopsy. Ann Oncol 2018;29:945-52.  Back to cited text no. 44
    
45.
Carter J, Miller JA, Feller-Kopman D, Ettinger D, Sidransky D, Maleki Z. Molecular profiling of malignant pleural effusion in metastatic non-small-cell lung carcinoma. The effect of preanalytical factors. Ann Am Thorac Soc 2017;14:1169-76.  Back to cited text no. 45
    
46.
Thompson JC, Yee SS, Troxel AB, Savitch SL, Fan R, Balli D, et al. Detection of therapeutically targetable driver and resistance mutations in lung cancer patients by next-generation sequencing of cell-free circulating tumor DNA. Clin Cancer Res 2016;22:5772-82.  Back to cited text no. 46
    
47.
Diaz LA Jr, Bardelli A. Liquid biopsies: Genotyping circulating tumor DNA. J Clin Oncol 2014;32:579-86.  Back to cited text no. 47
    
48.
Ponti G, Manfredini M, Tomasi A. Non-blood sources of cell-free DNA for cancer molecular profiling in clinical pathology and oncology. Crit Rev Oncol Hematol 2019;141:36-42.  Back to cited text no. 48
    
49.
Lee TH, Montalvo L, Chrebtow V, Busch MP. Quantitation of genomic DNA in plasma and serum samples: Higher concentrations of genomic DNA found in serum than in plasma. J Transfusion 2001;41:276-82.  Back to cited text no. 49
    
50.
Saarenheimo J, Eigeliene N, Andersen H, Tiirola M, Jekunen A. The value of liquid biopsies for guiding therapy decisions in non-small cell lung cancer. Front Oncol 2019;9:129.  Back to cited text no. 50
    
51.
Ma M, Shi C, Qian J, Teng J, Zhong H, Han B. Comparison of plasma and tissue samples in epidermal growth factor receptor mutation by ARMS in advanced non-small cell lung cancer. Gene 2016;591:58-64.  Back to cited text no. 51
    
52.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, Cole R, McWalter G, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: Circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 2014;9:1345-53.  Back to cited text no. 52
    
53.
Wang Z, Cheng Y, An T, Gao H, Wang K, Zhou Q, et al. Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): A phase 2, single-arm, multicentre clinical trial. Lancet Respir Med 2018;6:681-90.  Back to cited text no. 53
    
54.
Wang Y, Tian PW, Wang WY, Wang K, Zhang Z, Chen BJ, et al. Noninvasive genotyping and monitoring of anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer by capture-based next-generation sequencing. Oncotarget 2016;7:65208-17.  Back to cited text no. 54
    
55.
Velcheti V, Kim ES, Mekhail T, Dakhil C, Stella PJ, Shen X, et al. Prospective clinical evaluation of blood-based tumor mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC): Interim B-F1RST results. J Clin Oncol 2018;36:12001.  Back to cited text no. 55
    
56.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med 2015;372:2018-28.  Back to cited text no. 56
    
57.
Gale D, Lawson ARJ, Howarth K, Madi M, Durham B, Smalley S, et al. Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA. PLoS One 2018;13:e0194630.  Back to cited text no. 57
    
58.
Aggarwal C, Thompson JC, Black TA, Katz SI, Fan R, Yee SS, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non–small cell lung cancer. J JAMA Oncol 2019;5:173-80.  Back to cited text no. 58
    
59.
Gyawali B, West H. Plasma vs tissue next-generation sequencing in non–small cell lung cancer—either, both, or neither? JAMA Oncol 2019;5:148-9.  Back to cited text no. 59
    
60.
Han KN, Kim HK, Lee HJ, Choi YH. Single-port video-assisted thoracoscopic pulmonary segmentectomy: A report on 30 cases. Eur J Cardio-Thorac Surg 2015;49(Suppl 1):i42-7.  Back to cited text no. 60
    
61.
Hsu PK, Lin WC, Chang YC, Chan ML, Wang BY, Liu CY, et al. Multiinstitutional analysis of single-port video-assisted thoracoscopic anatomical resection for primary lung cancer. Ann Thorac Surg 2015;99:1739-44.  Back to cited text no. 61
    
62.
Altorki NK, Yip R, Hanaoka T, Bauer T, Aye R, Kohman L, et al. Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules. J Thorac Cardiovasc Surg 2014;147:754-62; Discussion 62-4.  Back to cited text no. 62
    
63.
Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux C, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015:CD011430. doi: 10.1002/14651858.CD011430.  Back to cited text no. 63
    
64.
Chang J, Meyers N, Angerpointner T. In: Myers N, editor. Historical Aspects, Pediatric Thoracic Surgery. New York: Springer-Verlag Berlin Heidelberg; 1991. 25-9 p.  Back to cited text no. 64
    
65.
Shojaee S, Nana-Sinkam P. Recent advances in the management of non-small cell lung cancer. F1000Res 2017;6:2110.  Back to cited text no. 65
    
66.
Diwanji TP, Mohindra P, Vyfhuis M, Snider JW 3rd, Kalavagunta C, Mossahebi S, et al. Advances in radiotherapy techniques and delivery for non-small cell lung cancer: Benefits of intensity-modulated radiation therapy, proton therapy, and stereotactic body radiation therapy. Transl Lung Cancer Res 2017;6:131-47.  Back to cited text no. 66
    
67.
Parashar B, Arora S, Wernicke AG. Radiation therapy for early stage lung cancer. Semin Intervent Radiol 2013;30:185-90.  Back to cited text no. 67
    
68.
Abreu CE, Ferreira PP, de Moraes FY, Neves WF Jr, Gadia R, Carvalho Hde A. Stereotactic body radiotherapy in lung cancer: An update. J Bras Pneumol 2015;41:376-87.  Back to cited text no. 68
    
69.
Prezzano KM, Ma SJ, Hermann GM, Rivers CI, Gomez-Suescun JA, Singh AK. Stereotactic body radiation therapy for non-small cell lung cancer: A review. World J Clin Oncol 2019;10:14-27.  Back to cited text no. 69
    
70.
Wegner RE, Ahmed N, Hasan S, Schumacher LY, Van Deusen M, Colonias A. SBRT for early stage lung cancer: Outcomes from biopsy-proven and empirically treated lesions. Lung Cancer Manag 2018;7:LMT01.  Back to cited text no. 70
    
71.
Lin Q, Sun X, Zhou N, Wang Z, Xu Y, Wang Y. Outcomes of stereotactic body radiotherapy versus lobectomy for stage I non-small cell lung cancer: A propensity score matching analysis. J BMC Pulm Med 2019;19:98.  Back to cited text no. 71
    
72.
Sura S, Gupta V, Yorke E, Jackson A, Amols H, Rosenzweig KE. Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: The Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol 2008;87:17-23.  Back to cited text no. 72
    
73.
Chun SG, Hu C, Choy H, Komaki RU, Timmerman RD, Schild SE, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non–small-cell lung cancer: A secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial. J Clin Oncol 2017;35:56-62.  Back to cited text no. 73
    
74.
Ren X-C, Liu Y-E, Li J, Lin Q. Progress in image-guided radiotherapy for the treatment of non-small cell lung cancer. World J Radiol 2019;11:46-54.  Back to cited text no. 74
    
75.
Walters S, Maringe C, Coleman MP, Peake MD, Butler J, Young N, et al. Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: A population-based study, 2004–2007. Thorax 2013;68:551-64.  Back to cited text no. 75
    
76.
Zappa C, Mousa SA. Non-small cell lung cancer: Current treatment and future advances. Transl Lung Cancer Res 2016;5:288-300.  Back to cited text no. 76
    
77.
Non-small Cell Lung Cancer Collaborative G. Chemotherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2000:CD002139. doi: 10.1002/14651858.CD002139.  Back to cited text no. 77
    
78.
Earle CC, Tsai JS, Gelber RD, Weinstein MC, Neumann PJ, Weeks JC. Effectiveness of chemotherapy for advanced lung cancer in the elderly: Instrumental variable and propensity analysis. J Clin Oncol 2001;19:1064-70.  Back to cited text no. 78
    
79.
Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: Recent advances and future directions. Oncologist 2008;13(Suppl 1):5-13.  Back to cited text no. 79
    
80.
Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016;17:577-89.  Back to cited text no. 80
    
81.
Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. New Eng J Med 2018;378:113-25.  Back to cited text no. 81
    
82.
Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. New Eng J Med 2014;371:2167-77.  Back to cited text no. 82
    
83.
Subbiah V, Gervais R, Riely GJ, Hollebecque A, Blay J-Y, Felip E, et al. Efficacy of vemurafenib in patients (pts) with non-small cell lung cancer (NSCLC) with BRAF V600 mutation. J Clin Oncol 2017;35:9074.  Back to cited text no. 83
    
84.
Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: An international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 2017;18:1590-9.  Back to cited text no. 84
    
85.
Gupta VG, Rangaraju RR, Abbas W, Bajpai P, Khetrapal R. Immune checkpoint inhibitors: Real-world experience from India in advanced solid cancers that have progressed on chemotherapy. South Asian J Cancer 2019;8:65-8.  Back to cited text no. 85
[PUBMED]  [Full text]  
86.
Batra U, Sharma M, Jain P, Bothra S, Pasricha S. EGFR & PD L1: An (im) perfect union. Annals Oncol 2019;30(Suppl 2). doi: 10.1093/annonc/mdz063.  Back to cited text no. 86
    
87.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature 2018;553:446-54.  Back to cited text no. 87
    
88.
Zhang Y-L, Yuan J-Q, Wang K-F, Fu X-H, Han X-R, Threapleton D, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: A systematic review and meta-analysis. Oncotarget 2016;7:78985-93.  Back to cited text no. 88
    
89.
Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:1454-66.  Back to cited text no. 89
    
90.
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829-38.  Back to cited text no. 90
    
91.
Faehling M, Schwenk B, Kramberg S, Eckert R, Volckmar AL, Stenzinger A, et al. Oncogenic driver mutations, treatment, and EGFR-TKI resistance in a Caucasian population with non-small cell lung cancer: Survival in clinical practice. Oncotarget 2017;8:77897-914.  Back to cited text no. 91
    
92.
Planchard D, Mazieres J, Riely GJ, Rudin CM, Barlesi F, Quoix EA, et al. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. J Clin Oncol 2013;31:8009.  Back to cited text no. 92
    
93.
Planchard D, Smit E, Groen H, Mazieres J, Besse B, Helland Å, et al. Phase 2 trial (BRF113928) of dabrafenib (D) plus trametinib (T) in patients (pts) with previously untreated BRAF V600E–mutant metastatic non-small cell lung cancer (NSCLC). Ann Oncol 2017;28(Suppl 5):v605-49.  Back to cited text no. 93
    
94.
Naidoo J, Drilon A. KRAS-mutant lung cancers in the era of targeted therapy. Adv Exp Med Biol 2016;893:155-78.  Back to cited text no. 94
    
95.
Dizon DS, Krilov L, Cohen E, Gangadhar T, Ganz PA, Hensing TA, et al. Clinical cancer advances 2016: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 2016;34:987-1011.  Back to cited text no. 95
    
96.
Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: Results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 2012;30:2046-54.  Back to cited text no. 96
    
97.
Govindan R, Szczesna A, Ahn M-J, Schneider C-P, Gonzalez Mella PF, Barlesi F, et al. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 2017;35:3449-57.  Back to cited text no. 97
    
98.
Ribas A, Hanson DC, Noe DA, Millham R, Guyot DJ, Bernstein SH, et al. Tremelimumab (CP-675,206), a cytotoxic T lymphocyte–associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist 2007;12:873-83.  Back to cited text no. 98
    
99.
AstraZeneca presents Imfinzi (durvalumab) plus tremelimumab combination data at AACR Annual Meeting. Available from: https://www.astrazeneca.com. [Last accessed on 2019 Sep 16].  Back to cited text no. 99
    
100.
Zatloukal P, Heo DS, Park K, Kang J, Butts C, Bradford D, et al. Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2009;27 (15 Suppl):8071.  Back to cited text no. 100
    
101.
Chaft J, Cho BC, Ahn M-J, Le Moulec S, Cho EK, Papadimitrakopoulou V, et al. Abstract CT113: Safety and activity of second-line durvalumab+tremelimumab in non-squamous advanced NSCLC. AACR Annual Meeting, Chicago, IL, April 14-18, 2018.  Back to cited text no. 101
    
102.
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078-92.  Back to cited text no. 102
    
103.
Rizvi NA, Chul Cho B, Reinmuth N, Lee KH, Ahn MJ, Luft A, et al. Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. Ann Oncol 2018;29(Suppl 10). doi: 10.1093/annonc/mdy511.  Back to cited text no. 103
    
104.
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-75.  Back to cited text no. 104
    
105.
Brahmer JR, Horn L, Antonia S, Spigel DR, Gandhi L, Sequist LV, et al. Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC). J Clin Oncol 2012;30(15 Suppl):7509.  Back to cited text no. 105
    
106.
Brahmer JR, Horn L, Antonia SJ, Spigel DR, Gandhi L, Sequist LV, et al. Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2013;31:8030.  Back to cited text no. 106
    
107.
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med 2017;376:2415-26.  Back to cited text no. 107
    
108.
Gadgeel SM, Stevenson JP, Langer CJ, Gandhi L, Borghaei H, Patnaik A, et al. Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study. Lung Cancer 2018;125:273-81.  Back to cited text no. 108
    
109.
Weinberg F, Gadgeel S. Combination pembrolizumab plus chemotherapy: A new standard of care for patients with advanced non-small-cell lung cancer. Lung Cancer 2019;10:47-56.  Back to cited text no. 109
    
110.
Fehrenbacher L, von Pawel J, Park K, Rittmeyer A, Gandara DR, Aix SP, et al. Updated efficacy analysis including secondary population results for OAK: A randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non–small cell lung cancer. J Thorac Oncol 2018;13:1156-70.  Back to cited text no. 110
    
111.
Kim ES, Velcheti V, Mekhail T, Leal TA, Dowell JE, Tsai ML, et al., editors. Primary Efficacy Results from B-F1RST, A Prospective Phase II Trial Evaluating Blood-Based Tumour Mutational Burden (bTMB) as a Predictive Biomarker for Atezolizumab (atezo) in 1L Non-Small Cell Lung Cancer (NSCLC) 2018: OXFORD UNIV PRESS GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND.  Back to cited text no. 111
    
112.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 2017;377:1919-29.  Back to cited text no. 112
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer | Privacy Notice
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow