WHO defines lung cancer as tumors arising from the respiratory epithelium and divides them into four major cell types—SCLC, adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.¹ Historically, the major pathological distinction was simply between SCLC and the others which were grouped and referred to as NSCLC. SCLC tumors grow faster, spread earlier and are more sensitive to cytotoxic chemotherapeutic agents.² All histologic types of lung cancer can be found in current and former smokers although squamous and small-cell carcinomas are most commonly associated with heavy tobacco use. Squamous carcinoma was the most commonly diagnosed subtype of NSCLC through the first half of the 20th century. However, the decline in cigarette consumption and changes in their composition made adenocarcinoma the most frequent histologic subtype of lung cancer.^3,4 In lifetime never-smokers, women, and younger adults (< 60 years), adenocarcinoma tends to be the dominant histology.

Until recently, there was no need to distinguish among the various subtypes of NSCLC as there were no clear differences in therapeutic outcome based on histology alone.² This perspective radically changed in 2004 with the discovery of the epidermal growth factor receptor (EGFR) mutation is present in lung adenocarcinoma and is related to a favorable response to EGFR tyrosine kinase inhibitors (TKI).^5,6 Anaplastic lymphoma kinase (ALK) fusions were later found to also be limited to adenocarcinoma⁷ and current guidelines recommend initial EGFR and ALK testing in patients with adenocarcinoma or mixed tumors with adenocarcinoma components.⁸ The subsequent recognition that pemetrexed was active only in nonsquamous NSCLC, but not squamous cell or SCLC, emphasized the need for specific histologic diagnosis for therapy selection.^9,10 Further, the recognition that bevacizumab had excess toxicities in squamous carcinoma emphasized the need for specific histologic diagnosis.¹¹ These findings established the need for modifications in the existing WHO lung cancer classification system.¹² The revised classification system, developed jointly in 2011 by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society,¹³ recognizes that most lung cancers are diagnosed on small biopsies or cytological specimens rendering clear histologic distinctions difficult. Previously, tumors failing to show definite glandular or squamous morphology in a small biopsy or cytologic specimen were simply classified as “non–small-cell carcinoma, not otherwise specified.” However, as the distinction between adenocarcinoma and squamous carcinoma is critical to optimal therapeutic decision making, the modified approach recommends these lesions be further characterized using a limited special stain work-up. This distinction can be achieved using a single marker for adenocarcinoma (thyroid transcription factor-1 or napsin-A) plus a squamous marker (p40 or p63) and/or mucin stains.¹² The modified classification system also recommends preservation of sufficient specimen material for appropriate molecular testing (eg, EGFR or ALK) necessary to help guide therapeutic decision making.^8,12

Another significant modification to the WHO classification system is the discontinuation of the term “bronchioloalveolar carcinoma.”¹² The term was dropped due to its inconsistent use and because it caused confusion in routine clinical care and research. As formerly used, the term encompassed at least five different entities with diverse clinical and molecular properties. The terms “adenocarcinoma in situ” and “minimally invasive adenocarcinoma” are now recommended for small solitary adenocarcinomas (≤ 3 cm) with either pure lepidic growth or predominant lepidic growth with ≤ 5 mm invasion.^12,13 Individuals with these entities experience 100% or near 100% 5-year disease-free survival with complete tumor resection. Invasive adenocarcinomas, representing more than 70% to 90% of surgically resected lung adenocarcinomas, are classified by their predominant pattern—lepidic, acinar, papillary, and solid patterns. Prognostically speaking, lepidic-predominant subtype has a favorable outlook, acinar and papillary have an intermediate prognosis, and solid-predominant has a poor prognosis.¹⁴ The terms signet ring and clear-cell adenocarcinoma have been eliminated from the variants of invasive lung adenocarcinoma whereas the term “micropapillary,” a subtype with a particularly poor prognosis, has been added.¹³

Current diagnostic biopsies are limited in size and amount of DNA that can be extracted. Individual tests, especially immunohistochemistry and fluorescent in situ hybridization, consume large amount of tissue. Thus, there may be insufficient material for testing all genetic abnormalities. Individual and sequential testing will also cost more and take more time than panel testing. Next Generation sequencing can solve these problems but is quite difficult to establish. It is likely that panel testing will become widely used in the future, especially as drugs are also developed for the drivers in squamous and small-cell cancer as well as adenocarcinomas.^21–23

Randomized controlled trials conducted in the 1960s to 1980s failed to show an impact on lung cancer-specific mortality in high-risk patients using chest radiographs (CXR; ± sputum cytology).²⁴ Accordingly, screening for lung cancer was not encouraged. In response to criticisms of early studies, the National Cancer Institute (NCI) initiated the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) that differed from the previous screening trials in that women and never-smokers were eligible plus the study was adequately powered to detect a 10% reduction in lung cancer mortality in the screened population.^25,26 The interventional group received annual CXR screening for 4 years while the others received only their usual medical care. Through 13 years of follow-up, cumulative lung cancer incidence rates (20.1 per v 19.2 per 10,000 person-years; rate ratio [RR], 1.05) and lung cancer mortality were identical between the two groups (1,213 v 1,230).²⁶ The stage and histology of detected cancers in the two groups also were similar. These data corroborated previous recommendations against CXR screening for lung cancer.

In nonrandomized studies conducted in the latter part of the 20th century, low-dose, spiral chest computed tomography (LDCT) appeared to be a potentially more effective screening tool for lung cancer and detected more lung nodules as compared with standard CXR.^27,28 Moreover, up to 85% of the lung cancers were stage I and therefore amenable to curative surgical resection.²⁹ These data spurred the NCI to initiate the National Lung Screening Trial (NLST), a randomized study designed to determine if LDCT screening could reduce lung cancer mortality in high-risk populations as compared with standard CXR.²⁷ High risk was defined as individuals between 55 and 74 years of age with a ≥ 30 pack-years history of cigarette smoking; former smokers must have quit within the previous 15 years. Any noncalcified nodule measuring ≥ 4 mm in any diameter found on LDCT and CXR images with any noncalcified nodule or mass were classified as positive. A total of 53,454 persons were enrolled. Overall, 39.1% of participants in the LDCT group had at least one positive screening result as compared with 16% in the CXR group. Of those who screened positive, the false-positive rate was 96.4% in the LDCT group and 94.5% in the CXR group. In the LDCT group 1,060 cancers were identified compared with 941 cancers in the CXR group (645 per v 572 per 100,000 person-years; RR, 1.13). The overall rates of lung cancer death were 247 and 309 deaths per 100,000 participants, respectively, representing a 20% reduction in lung cancer mortality in the LDCT screened population (P = .004).²⁷ The number needed to screen to prevent one lung cancer death was calculated to be 320. As compared with the CXR group, the rate of death in the LDCT group from any cause was reduced by 6.7% (P = .02).

The risks associated with LDCT screening include a high rate of false-positive results, false-negative results, the potential for unnecessary follow-up testing, radiation exposure, overdiagnosis, anxiety, depression, and changes in quality of life, as well as substantial financial costs.^30,31 At $300 per scan (NCI-estimated cost); the outlay for initial LDCT alone could run into the billions of dollars annually, an expense that only further escalates when factoring in various downstream expenditures an individual might incur in the assessment of positive findings. A formal cost-effectiveness analysis of the NLST is expected soon.

Despite the aforementioned caveats, screening of individuals who meet the NLST criteria for lung cancer risk or, in some cases, modified versions of these criteria seems warranted,³⁴ provided comprehensive multidisciplinary coordinated care and follow-up similar to those provided to NLST participants are available.³⁵ Algorithms to improve candidate selection are under development.³⁶ When discussing the option of LDCT screening, use of absolute risks rather than relative risks is helpful as studies indicate the public can process absolute terminology more effectively than relative risk projections. A useful guide has been developed to help patients and physicians assess the benefits and harms of LDCT screening for lung cancer.³⁷ Finally, even a small negative effect of screening on smoking behavior (either lower quit rates or higher recidivism) could easily offset the potential gains in a population. To date no such impact has been reported.³⁸ Nonetheless, smoking cessation must be included as an indispensable component of any screening program.

The majority (approximately 90%) of patients with SCLC present with disease spread to at least regional lymph nodes and/or distant metastatic sites. However, a small number of patients present with small tumors that have no lymph node or other metastases and a few present with only ipsilateral pulmonary lymph node involvement (N1). The International Association for the Study of Lung Cancer staging committee collected a large number of resected cases to inform the seventh edition of the TNM Staging Classification of the International Union Against Cancer/American Joint Committee on Cancer.³⁹ The data showed that 5-year survival for patients with Stage 1A (T1N0M0), stage IB (T2, N0M0) and stage IIA (T1N1M0) exceeded 50% whereas survival of resected patients with stage IIB and III was not superior to the survival of patients with limited stage SCLC treated with concurrent chemoradiotherapy. Therefore, the group recommended routine use of the TNM classification for all patients with newly diagnosed SCLC with surgery followed by adjuvant chemotherapy for those with stage IA, IB and IIA.

Studies conducted in the late 1970s and 1980s suggested that the combined use of both chemotherapy and chest radiotherapy (chemoRT) would provide superior outcomes compared with the use of either modality alone (Table 1).⁴⁰ Subsequent meta-analyses of all randomized trials conclusively demonstrated the benefit.⁴¹ At that point, the remaining questions were the optimal dose and schedule of chest radiotherapy, the optimal timing of the chest radiotherapy, and the optimal chemotherapy regimen. Based on preclinical repopulation studies, the Eastern Cooperative Oncology Group (ECOG) conducted a phase III randomized trial in which all patients received etoposide/cisplatin (EP) chemoRT. The RT was delivered twice daily in 1.5 Gy fractions to a total dose of 45 Gy or the same daily and total doses delivered once daily.⁴² Patients randomly assigned to twice per day radiation had a superior outcome with respect to local recurrence and overall survival (OS). The majority of studies reported that early institution of chest radiation is superior to late institution,⁴³ and most guidelines indicate that radiation may start at the outset or after two cycles of chemotherapy. For large tumors, a delay in the start of radiation until after two cycles of chemotherapy may reduce the volume of chest irradiation.

Table 1. Summary of Therapeutic Advances in Lung Cancer

The EP combination was used in the majority of randomized trials although the dose and schedule of the two drugs differed in the ECOG⁴² and Southwest Oncology Group (SWOG)⁴⁴ combinations. This two-drug combination produced more acceptable toxicity compared with CAV (cyclophosphamide, adriamycin, vincristine) –based combinations and no combination to date has been shown to be superior to EP which is recommended in all guidelines.^45,46

Randomized trials showed that prophylactic cranial irradiation reduced subsequent brain relapse frequency and improved overall survival in patients with limited and extensive stage SCLC patients who had responded to chemoradiotherapy.^47,48 Recent studies have noted decreased late cognitive improvement with doses of 25 Gy in 10 fractions with equal survival and brain relapse rates compared with higher doses.⁴⁹ Thus, this dose has been adopted as a standard of care in both limited and extensive stages in patients with good responses to their initial therapy.

Studies during the 1970s demonstrated that many chemotherapeutic agents produced high response rates in SCLC patients and that two- or three-drug combinations produced superior outcomes compared with single agents. Toward the end of the 1970s, studies had demonstrated high response rates for both etoposide and cisplatin and this EP combination was shown to produce equivalent efficacy with less frequent grade 3 and 4 toxicities, especially myelosuppression and cardiac toxicities compared with CAV and similar combinations.^50,51 Therefore, the EP combination was adopted as standard in extensive as well as limited stage (Table 1).^45,46

Subsequent studies attempted to increase dose intensity of the chemotherapy by increasing frequency of administration, increasing the dose with or without granulocyte colony-stimulating factor support, and by adding additional drugs. In some studies the dose intensity was increased to the point that autologous bone marrow support was required. No randomized trial showed advantage to these approaches and they were largely abandoned.

Topoisomerase-1 inhibitors, topotecan and irinotecan, were shown to have considerable activity in both first-line and second-line settings. Topotecan is approved in second line.^52–54 Taxanes and vinorelbine have some activity and are sometimes used in second or third line. Patients who respond initially to EP and relapse more than 10 weeks later should be re-treated with EP because response rates are superior to second-line therapy with other agents.⁵⁶ Pemetrexed/cisplatin was shown to be inferior to EP in a large randomized first-line trial and should not be used in this setting.¹⁰

The optimal radiation dose and schedule need to be defined for limited stage. The fact that the biologic effect of the twice daily RT is greater than once daily raises the question of whether twice daily radiation to a total of 45 Gy is superior to once daily to a higher total dose such as 60 Gy. Recent studies have added targeted therapies such as angiogenesis inhibitors, EGFR inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, Bcl2 inhibitors, histone deacetylase inhibitors, proteosome inhibitors, and other novel drug classes to EP or as second-line therapy. To date, none of these have shown sufficient benefit to warrant phase III study. Ongoing studies are evaluating fibroblast growth factor receptor (FGFR) inhibitors and PARP inhibitors. The DNA repair or other mechanisms that produce rapid and near universal chemoresistance after initial chemotherapy need to be identified and overcome.

Immunotherapeutic approaches have so far failed to improve outcomes in SCLC. The anti–cytotoxic T cell antigen (CTLA) antibody, ipilimumab in combination with paclitaxel and carboplatin appeared to produce a small benefit which has led to an ongoing phase III trial comparing EP chemotherapy with the same chemotherapy plus ipilimumab.⁵⁸ The anti–programmed death 1 (PD1) and anti–programmed death receptor ligand 1 antibodies are being studied in SCLC, but no results are available to date.

p53 is inactivated in nearly 100% of SCLC tumors. However, there are no effective p53 therapies at present. Rb is also in more than 50% of SCLC tumors, but once again, there are no effective strategies to restore Rb function at present. The FGFR gene is amplified in 5% to 10% of SCLC's and FGFR inhibitors will be studied in these tumors. SOX2 is mutated in a small fraction of SCLC tumors and SOX2 inhibitors will be tested. The myc family of oncogenes is frequently amplified in SCLC tumors and there is some evidence that aurora kinase A and B inhibitors have increased activity in myc amplified tumors. Additional studies are planned. Other common genetic abnormalities and signal pathology abnormalities are described in the results of large studies conducted by the Cancer Genome Atlas and by Genentech.^21–23

The two major approaches to angiogenesis pathway inhibition have been monoclonal antibodies, aimed at either the ligand or the receptor, or small-molecule vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs). A randomized phase II study showed superior survival of NSCLC patients treated with bevacizumab plus paclitaxel/carboplatin compared with paclitaxel/carboplatin alone.¹¹ However, excess bleeding was noted in patients with squamous cancers precluding further study of bevacizumab in this subtype. This phase II study prompted initiation of Eastern Cooperative Oncology Group (ECOG; E4599), a phase III trial which randomly assigned 878 patients to chemotherapy (paclitaxel and carboplatin) or to the same chemotherapy plus 15 mg/kg of bevacizumab every 3 weeks.⁹⁹ Median survival for patients who received chemotherapy plus bevacizumab was 12.3 months compared with 10.3 months for patients given chemotherapy alone (HR = 0.79, P = .003). It should be noted, however, that a second randomized study of bevacizumab (the Avastin in Lung [AVAiL] trial) while showing a prolonged PFS, was negative for survival.¹⁰⁰ Unlike the ECOG study, AVAiL randomly assigned patients to gemcitabine and cisplatin plus either placebo; 7.5 mg/kg of bevacizumab every 3 weeks; or 15 mg/kg of bevacizumab every 3 weeks. It is unclear whether the lack of survival benefit is a result of the differences in chemotherapy doublets between the ECOG and AVAiL trials, differences in bevacizumab dose, or other differences in study design.

A number of small-molecule vascular endothelial growth factor TKIs have been developed, including sorafenib, sunitinib, vandetanib and other none of which has shown improvement in survival. It is not known if the reason for the negative results is due to lack of inhibition of the target. Unfortunately, no good biomarkers for angiogenesis inhibition have been identified.¹⁰¹

Arguably, the most important clinically relevant advances have been discovery of driver oncogenes that are constitutively activated by mutation, translocation or fusion and the discovery that oral small-molecule TKIs of these oncogenes produce high response rates and relatively long duration of these responses. In 2004, three separate investigative teams demonstrated an association between the presence of EGFR mutations (deletions in exon 19 or point mutations in exon 21) that activate the EGFR by altering the ATP binding site and response to gefitinib.^5,6 These mutations were found to be more common in females, in light or never smokers in patients of Asian ethnicity and were nearly always in adenocarcinoma histology. Subsequently, randomized trials demonstrated that EGFR TKIs produced higher response rates, less toxicity, and improved PFS rates compared with platinum-based doublets for chemotherapy-naive patients with advanced lung cancer having these mutations.^102–107 Based on these findings, current guidelines suggest all patients with stage IV NSCLC with any adenocarcinoma component to their tumor should undergo molecular testing for EGFR mutations before instituting first-line therapy.⁸ Those with activating mutations should receive an EGFR TKI due to superior PFS whereas chemotherapy is superior if no mutation is present.^102,108

Unfortunately, TKI-treated patients with EGFR mutations are not cured by the EGFR TKI therapy, and progress after a median of 9 to 10 months. The mechanisms of resistance reported to date include secondary gatekeeper mutations in the EGFR gene at T790M,¹⁰⁹ the outgrowth of small-cell lung cancer cells, and activation of other pathways such as MET, FGFR and AXL, HER2 amplification and epithelial to mesenchymal transition.¹⁰⁹ New TKIs that bind to T790M and activating EGFR mutations but not to wild-type EGFR receptors have been developed and hold promise for improved results.¹¹⁰

In 2007, Soda et al⁷ reported that the ALK oncogene is activated in lung cancer by fusion with a gene partner caused by a chromosomal break and rearrangement between ALK and the EML4 gene on the same chromosome 2 (a gene fusion). A break-apart fluorescent in situ hybridization probe test was used to verify the presence of the fusion.¹¹¹ An expanded phase I trial of crizotinib (a TKI that also inhibits MET and ROS) showed an objective response rate of approximately 60% with a median PFS of about 10 months in patients with a EML4/ALK fusion.¹¹² These results were confirmed in a phase II study¹¹³ that led to accelerated US Food and Drug Administration approval and to a subsequent randomized second-line study versus pemetrexed or docetaxel showing response and PFS superiority for crizotinib compared with chemotherapy.¹¹⁴ Clinical features associated with ALK fusions include adenocarcinoma histology, younger age, never smoking status, and female sex.¹¹⁵ The frequency of ALK fusions did not vary by ethnicity (ie, similar frequency in Asians and Europeans). ALK testing before institution of first-line therapy is now recommended in most guidelines, irrespective of clinical features for those with any adenocarcinoma component in their tumor.⁸

Additional potential drivers in patients with lung cancer have been found in adenocarcinomas including mutations in KRAS, BRAF, HER2, AKT1 and fusions involving the RET, ROS, and NTRAK oncogenes.^15–20 These observations have led to clinical trials using specific TKIs. Data on preliminary results for crizotinib for patients with ROS fusions have been reported. The US Lung Cancer Mutation consortium (LCMC) assessed 1,000 advanced lung adenocarcinomas for 12 potential molecular drivers. Nearly two thirds of these patients had a molecular driver abnormality; however, the presence of two simultaneous mutations was rare.¹⁵ Patients with a molecular driver that received an appropriate molecularly targeted therapy had the best survival. These studies suggest that multiple oncogene abnormalities will need testing before institution of therapy in the future.

Until recently the history of vaccine therapy for lung cancers has been dismal. In 2013, encouraging phase II data were reported with a vaccine targeting the MAGE antigen.¹¹⁶ A gene signature was found to associate with a better outcome.¹¹⁷ A phase III trial (MAGRIT [MAGE A3 as Adjuvant Non–Small-Cell Lung Cancer Immunotherapy]) has completed accrual; results are pending. The vaccine BLP25 was reported to improve outcomes after chemoRT in patients with stage IIIB NSCLC but did not approve outcomes after chemotherapy in stage IV.¹¹⁸ A follow-up randomized phase III study showed a trend toward improved survival that failed to reach statistical significance. A subset analysis demonstrated that survival was significantly improved in patients who received concurrent chemoRT. A follow-up phase III trial in this subset is planned.

More recent studies have indicated that monoclonal antibodies to antigens involved in immune regulatory checkpoints may be useful for lung cancer as well as other cancers.¹¹⁹ The anti CTLA-4 antibody, ipilumumab was studied in combination with paclitaxel plus carboplatin in patients with both SCLC and NSCLC.^58,120 There appeared to be a small, but not statistically significant, advantage to the combination when the ipilumumab was instituted after several cycles of chemotherapy. A randomized phase III trial in SCLC is ongoing.

Antibodies to the programmed cell death receptor 1 called nivolumab and lambrolizumab have been shown to produce responses in lung cancer and melanoma.^122,123 Many of these responses have had long duration (eg, > 1 year). Monoclonal antibodies to the PD1 ligand (anti-PDL1) have also been shown to produce responses in patients with melanoma and lung cancer.¹²⁴ Preliminary studies in melanoma suggest that the combination of ipilimumab and nivolumab could produce higher response rates compared with either alone.¹²⁵