Thematic review on neoplastic hematology and medical oncologyNon–Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment
Section snippets
Epidemiology
Lung cancer incidence and mortality rates are highest in the developed countries. In contrast, lung cancer rates in underdeveloped geographic areas, including Central/South America and most of Africa, are estimated to be lower. However, many developing countries lack a centralized reporting system, and it is stipulated that many cases of lung cancer go unreported, obscuring the real incidence of the disease.9 The World Health Organization (WHO) estimates that lung cancer death rates worldwide
Classification
There are 2 main forms of lung cancer: NSCLC (85% of patients) and small cell lung cancer (SCLC) (15%). The WHO has classified NSCLC into 3 main types: adenocarcinoma, squamous cell carcinoma, and large cell.16, 17 There are also several variants and combinations of clinical subtypes.
Adenocarcinoma is the most common type of NSCLC and accounts for approximately 40% of lung cancers.17 Adenocarcinoma arises from alveolar cells located in the smaller airway epithelium and tends to express
Screening
Clinical outcome for NSCLC is directly related to stage at the time of diagnosis, bringing importance to a screening modality that would allow detection. Screening for lung cancer using chest radiographs or sputum cytologic analysis failed to provide a mortality benefit in several clinical trials.19, 20 The National Lung Screening Trial tested computed tomography (CT) vs radiography in 53,454 patients at high risk and found a lung cancer mortality benefit of 20% and a 6.7% decrease in all-cause
Diagnosis
Often, NSCLC is not diagnosed until advanced-stage disease is present.2, 28 Cough, seen in 50% to 75% of patients, is the most common symptom, followed by hemoptysis, chest pain, and dyspnea.28 Other less common symptoms include laboratory abnormalities or paraneoplastic syndromes. Diagnosis requires biopsy for histologic confirmation.
Diagnosis also requires determination of the extent of the tumor to define the TNM stage, which will ultimately guide cancer treatment options. A Danish
Treatment
Treatment of NSCLC is stage specific. Patients with stage I or II should be treated with complete surgical resection when not contraindicated. Nonsurgical patients should be considered for conventional or stereotactic radiotherapy. Percutaneous thermal ablation procedures such as cryoablation, microwave, and radiofrequency ablation have been found to be useful treatment options in the setting of salvage therapy after surgery, radiotherapy, or chemotherapy or for palliation in advanced NSCLC.
Oligometastatic Disease
Oligometastatic NSCLC implies limited metastatic lesions affecting 1 or 2 organ systems that can be treated with local therapy (surgery or radiation) in conjunction with the primary tumor. The treatment options depend on the organ systems affected. Solitary brain metastases are usually treated with surgical resection or stereotactic radiosurgery. In the case of adrenal lesions, these can be resected in patients responding to systemic therapy or receiving local therapy for the primary tumor. In
Chemotherapy for Advanced Disease
Patients who present with metastatic disease require systemic treatment (Table 1). Before the era of immunotherapy, the standard treatment was a platinum doublet with either carboplatin or cisplatin with gemcitabine, vinorelbine, or taxanes (paclitaxel or docetaxel). Several studies have concluded that in patients with NSCLC these doublets have comparable efficacy, with differences in their toxicity profile. Pemetrexed, a multitargeted antifolate, was studied in combination with cisplatin and
Epidermal Growth Factor Receptor Inhibitors
Epidermal growth factor receptor (EGFR) mutations are present in 15% of patients with NSCLC in the United States, with a higher frequency in Asian patients.52, 53 These occur more frequently in women and nonsmokers. There are 2 main approaches to targeting EGFR: tyrosine kinase inhibitors (TKIs) and monoclonal antibodies.
The EGFR TKIs are composed of first-generation erlotinib and gefitinib, second-generation afatinib and dacomitinib, and third-generation osimertinib (Table 2).54, 55, 56, 57, 58
Immunotherapy
Immunotherapy has dramatically changed the landscape of treatment of NSCLC. Because of the rapidly changing landscape, this review is directed to the practicing oncologist, and it focuses on recent clinical developments that have led to the approval of immune checkpoint inhibitors (ICIs) for the treatment of NSCLC. As a premise, an essential role of the immune system is to recognize and destroy neoplastic cells before they become clinically meaningful.96 To limit damage to healthy cells, this
Immunotherapy Monotherapy
A phase 3 clinical study, KEYNOTE-024, randomized 305 patients with NSCLC who had PD-L1 expression of more than 50% of cells (30% of screened samples) to receive the investigator's choice of chemotherapy or pembrolizumab.101 Treatment with pembrolizumab increased the RR (45% vs 28%), PFS (10.3 vs 6 months; HR, 0.50; 95% CI, 0.37-0.68; P<.001), and OS (30 vs 14.2 months), establishing pembrolizumab as the standard of care for this subset of patients.101 In contrast, nivolumab was studied in a
Survivorship
The risk of developing secondary lung cancers is high (approximately 2%-3% annually) for patients with resected stage I and II NSCLC. Vitamin A and selenium have been found to be ineffective as chemoprevention therapy and deleterious in current smokers.139, 140, 141 The National Comprehensive Cancer Network guidelines help physicians determine the appropriate surveillance plans based on lung cancer stage. Smoking, radiation therapy, and systemic cytotoxic therapy are known risk factors for
Conclusion
The use of targeted therapy and ICI has dramatically changed the treatment of patients with NSCLC. In the case of immunotherapy, it has become the standard first-line treatment as monotherapy or combined with chemotherapy. Many questions remain regarding the sequence and combination of these new agents but, thankfully the field is moving at a very aggressive pace as the results of clinical trials and other investigations percolate at a rate not seen previously in NSCLC.
References (141)
- et al.
European cancer mortality predictions for the year 2012
Ann Oncol
(2012) - et al.
The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer
J Thorac Oncol
(2016) - et al.
Epidemiology of lung cancer
Chest
(2003) - et al.
Lung cancer after treatment for Hodgkin's lymphoma: a systematic review
Lancet Oncol
(2005) - et al.
Radiation therapy for invasive breast cancer increases the risk of second primary lung cancer: a nationwide population-based cohort analysis
J Thorac Oncol
(2017) - et al.
Lung cancer: epidemiology, etiology, and prevention
Clin Chest Med
(2011) - et al.
The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification
J Thorac Oncol
(2015) - et al.
Introduction to the 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart
J Thorac Oncol
(2015) - et al.
Design of the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial
Contemporary Clin Trials
(2000) - et al.
Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial
Lancet Oncol
(2016)
New subsolid pulmonary nodules in lung cancer screening: a brief report of the NELSON trial
J Thorac Oncol
Longitudinal analysis of 2293 NSCLC patients: a comprehensive study from the TYROL registry
Lung Cancer
Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial
J Thorac Oncol
Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift
J Thorac Oncol
Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer
Ann Thorac Surg
Survival after sublobar resection versus lobectomy for clinical stage IA lung cancer: an analysis from the National Cancer Data Base
J Thorac Oncol
Oncologic outcomes of segmentectomy versus lobectomy for clinical T1a N0 M0 non-small cell lung cancer
Ann Thorac Surg
Intentional limited resection for selected patients with T1 N0 M0 non-small-cell lung cancer: a single-institution study
J Thorac Cardiovasc Surg
Early results of a prospective study of limited resection for bronchioloalveolar adenocarcinoma of the lung
Ann Thorac Surg
Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review
Lancet
Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases
Lung Cancer
Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study
Lancet Oncol
Local consolidative therapy (LCT) improves overall survival (OS) compared to maintenance therapy/observation in oligometastatic non-small cell lung cancer (NSCLC): final results of a multicenter, randomized, controlled phase 2 trial
Int J Radiat Oncol Biol Phys
A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non–small-cell lung cancer of adenocarcinoma histology (PIONEER)
J Thorac Oncol
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study
Lancet Oncol
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Lancet Oncol
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Lancet Oncol
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
Lancet Oncol
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
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial
Lancet
Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial
Lancet Oncol
First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study
Lancet
Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial
Lancet
Dramatic response to lorlatinib in a heavily pretreated lung adenocarcinoma patient harboring G1202R mutation and a synchronous novel R1192P ALK point mutation
J Thorac Oncol
Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study
Lancet Oncol
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial
Lancet
Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations
Ann Oncol
Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
Lancet Oncol
Genomic landscape of non-small cell lung cancer in smokers and never-smokers
Cell
Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study
Lancet Oncol
Study design and rationale for a randomized, placebo-controlled, double-blind study to assess the efficacy and safety of selumetinib in combination with docetaxel as second-line treatment in patients with KRAS-mutant advanced non-small cell lung cancer (SELECT-1)
Clin Lung Cancer
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial
Lancet
Cancer statistics, 2018
CA Cancer J Clin
Lung cancer and cryptogenic fibrosing alveolitis: a population-based cohort study
Am J Respir Crit Care Med
HIV infection is associated with an increased risk for lung cancer, independent of smoking
Clin Infect Dis
How much incident lung cancer was missed globally in 2012? an ecological country-level study
Geospat Health
Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system
J Natl Cancer Inst
Cancer statistics, 2010
CA Cancer J Clin
Lung cancer epidemiology
Lung cancer incidence in never-smokers
J Clin Oncol
Cited by (0)
Potential Competing Interests: Dr Santana-Davila has received grant support from Abbvie, Merck, Pfizer, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Stemcentrx, Inc., BeyondSpring Pharmaceuticals, Dynavax Technologies, ALX Oncology, AstraZeneca, and ISA Pharmaceuticals, and honoraria from Pharmamar. Bayer, Bristol-Myers Squibb, Lilly, and Genentech.
The Thematic Review Series on Neoplastic Hematology and Medical Oncology will continue in an upcoming issue.