Elsevier

Mayo Clinic Proceedings

Volume 94, Issue 8, August 2019, Pages 1623-1640
Mayo Clinic Proceedings

Thematic review on neoplastic hematology and medical oncology
Non–Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment

https://doi.org/10.1016/j.mayocp.2019.01.013Get rights and content

Abstract

Lung cancer remains the leading cause of cancer deaths in the United States. In the past decade, significant advances have been made in the science of non–small cell lung cancer (NSCLC). Screening has been introduced with the goal of early detection. The National Lung Screening Trial found a lung cancer mortality benefit of 20% and a 6.7% decrease in all-cause mortality with the use of low-dose chest computed tomography in high-risk individuals. The treatment of lung cancer has also evolved with the introduction of several lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations. Similarly, immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of NSCLC treatment. Furthermore, the results of new trials continue to help us understand the role of these novel agents and which patients are more likely to benefit; ICIs are now part of the first-line NSCLC treatment armamentarium as monotherapy, combined with chemotherapy, or after definite chemoradiotherapy in patients with stage III unresectable NSCLC. Expression of programmed cell death protein-ligand 1 in malignant cells has been studied as a potential biomarker for response to ICIs. However, important drawbacks exist that limit its discriminatory potential. Identification of accurate predictive biomarkers beyond programmed cell death protein-ligand 1 expression remains essential to select the most appropriate candidates for ICI therapy. Many questions remain unanswered regarding the proper sequence and combinations of these new agents; however, the field is moving rapidly, and the overall direction is optimistic.

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.

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  • 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.

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