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Non-Small-Cell Lung Cancer

Non-Small-Cell Lung Cancer


Lung cancer has been the leading cause of cancer death among men in the United States for years, and since 1988, it has become the number-one cause of cancer death among women. An estimated 224,210 new cases of lung cancer are expected in 2014, and 159,260 deaths due to this disease are expected to occur, roughly 27% of all cancer deaths. This exceeds the combined number of deaths from cancer of the next leading sites (breast, prostate, and colon). Lung cancer accounts for 6% of all deaths in the United States.

Lung cancer develops from pulmonary parenchymal or bronchial supportive tissues. Although multiple cell types are often found within a single lung tumor, one type usually predominates. Based on the therapeutic approach, there are two major subdivisions of lung cancer: small-cell lung cancer (SCLC) and non–small-cell lung cancer (NSCLC). Non–small-cell tumors account for approximately 85% of all lung cancers. The three major tumor types included under this category are adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.

This chapter provides basic information on the epidemiology, etiology, screening, prevention, and signs and symptoms of lung cancer in general and then focuses specifically on the diagnosis, staging, pathology, and treatment of NSCLC, as well as on the pulmonary evaluation of lung cancer patients and follow-up of long-term survivors.

A separate chapter provides information on the staging, pathology and pathophysiology, and treatment of the far less common SCLC and concludes with brief discussions of mesothelioma and thymoma.

FDA Approvals

In May 2013, the US Food and Drug Administration (FDA) approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) gene exon 19 deletions or exon 21 (L858R) substitution mutations. The approval was based on the results of a randomized, multicenter, open-label trial comparing erlotinib (n = 86) to platinum-based doublet chemotherapy (n = 88) in patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations determined by a clinical trial assay. The trial’s primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival and objective response rate. The median progression-free survival was 10.4 months in the erlotinib arm and 5.2 months in the platinum-based chemotherapy arm (hazard ratio [HR] = 0.34; 95% confidence interval [CI], 0.23–0.49; P < .001). The median overall survival was 22.9 months in the erlotinib arm and 19.5 months in the platinum-based chemotherapy arm (HR = 0.93; 95% CI, 0.64–1.35; P = .6482). The overall response rate was 65% for patients in the erlotinib arm and 16% in the platinum-based chemotherapy arm. The majority of the patients in the platinum-based chemotherapy arm (82%) subsequently received an EGFR tyrosine kinase inhibitor following investigator-determined disease progression.

In July 2013, the FDA approved afatinib (Gilotrif) tablets for the first-line treatment of patients with NSCLC whose tumors have EGFR gene exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. The safety and efficacy of afatinib have not been established in patients whose tumors have other EGFR mutations. Concurrent with this action, FDA approved the therascreen EGFR RGQ PCR Kit (QIAGEN) for detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. The approval of afatinib was based on the demonstration of improved progression-free survival in a multicenter, international, open-label, randomized (2:1) trial. This trial enrolled 345 patients with metastatic NSCLC whose tumors tested positive for EGFR mutations. Patients were randomized to receive afatinib at 40 mg orally once daily (n = 230) or pemetrexed/cisplatin, (n = 115, with pemetrexed given at 500 mg/m2 and cisplatin at 75 mg/m2 intravenously once every 21 days, up to six cycles. A statistically significant prolongation of progression-free survival determined by the independent review committee was demonstrated for patients assigned to the afatinib treatment arm (HR = 0.58; 95% CI, 0.43–0.78; P < .001, stratified log-rank test). The median progression-free survival was 11.1 months in the afatinib arm and 6.9 months in the chemotherapy arm. Objective response rates were 50.4% and 19.1% in the afatinib and chemotherapy arms, respectively. No statistically significant difference in overall survival between the two arms was demonstrated. In patients whose tumors have exon 19 deletions or exon 21 (L858R) substitution mutations, the median progression-free survival was 13.6 months in the afatinib arm and 6.9 months in the chemotherapy arm.

In November 2013, the FDA approved crizotinib (Xalkori) capsules for the treatment of patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This approval was based on demonstration of superior progression-free survival and overall response rate for crizotinib-treated patients compared with chemotherapy in patients with ALK-positive NSCLC with disease progression after platinum-based doublet chemotherapy. An open-label, active-controlled, multinational, randomized trial enrolled 347 patients with ALK-positive, metastatic NSCLC. Patients were required to have progressed following platinum-based chemotherapy and to have ALK expression in tumor specimens detected by fluorescence in situ hybridization on central laboratory testing. Patients were randomized to receive either crizotinib at 250 mg orally twice daily (n = 173) or chemotherapy (n = 174). Approximately 64% of patients on the chemotherapy arm subsequently received crizotinib. The trial demonstrated significantly prolonged progression-free survival for patients treated with crizotinib compared with chemotherapy (HR = 0.49; 95% CI, 0.37–0.64; P < .0001). Median progression-free survival was 7.7 months and 3 months on the crizotinib and chemotherapy arms, respectively. The overall response rate was significantly higher for patients on the crizotinib arm (65% vs 20%), with median response durations of 7.4 months and 5.6 months in the crizotinib and chemotherapy arms, respectively. No difference in overall survival was noted between the two arms (HR = 1.02; 95% CI, 0.68–1.54) in a planned interim analysis, however 64% of patients on the chemotherapy arm subsequently received crizotinib, thus potentially confounding the overall survival measure.

Meeting and Study Highlights

Kratz et al found that, in stage I NSCLC, a quantitative polymerase chain reaction 14-gene expression assay on formalin-fixed paraffin-embedded tissues was found capable of identifying low-, intermediate-, and high-risk patients for recurrence (P = .0003).

Long-term lung cancer survivors who engaged in regular physical activity for 30 minutes or more 5 days per week had higher QOL scores and better symptom control than their less active counterparts (Solberg et al: Lung Cancer 2012).

RTOG 0617 was a randomized phase III comparison of standard dose (60 Gy) vs high dose (74 Gy) conformal radiotherapy (RT) with concurrent and consolidation carboplatin/paclitaxel with or without cetuximab in patients with stage III non-small lung cancer (NSCLC). The results showed a significantly lower survival on the high vs. standard dose RT arm (20 months vs 29 months median survival, P = .0007). While there was a higher rate of grade 3+ esophagitis on the high dose vs standard dose RT arm (21% vs 7%), there was no clear reason for the poorer survival on the high dose (RT) arm. Possible explanations include unreported toxicities, increased heart dose, increased local failure, or possibly a combination of these factors. RTOG is exploring new strategies (involving functional imaging) to more effectively escalate the radiation dose in this setting. Results recently presented at IASLC showed that there was no survival difference based upon the use of cetuximab.

Movsas et al presented the quality of life (QOL) analysis of the RTOG 0617 study at the plenary session at ASTRO 2013. QOL was collected prospectively by a validated lung cancer instrument: Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI), which includes the Physical Well-Being (PWB), Functional Well-Being (FWB) and the Lung Cancer Subscale (LCS). The primary QOL hypothesis predicted for a clinically meaningful decline (CMD) in the lung cancer subscale (LCS) on the high-dose RT arm at 3 months. Indeed, the CMD in LCS for the 74 Gy arm was significantly higher at 3 months than for the 60 Gy arm (P = .024), confirming the primary QOL hypothesis. This difference in QOL decline between arms resolved by 12 months. The baseline QOL significantly predicted for survival on multivariate analysis. While this study was not randomized by technology, intensity modulated RT (IMRT) was used to treat patients with higher stages and larger volumes. Nevertheless, significantly fewer patients who received IMRT (vs 3D conformal RT) had a clinically meaningful decline in the lung cancer subscale (LCS) at 12 months (P = .005), suggesting that improved RT treatment techniques may help enhance the therapeutic window of patients with lung cancer.

At ASCO 2013, Sorensen et al presented the results of a prospective randomized phase III trial by the Nordic Thoracic Oncology Group studying the role of surgery for pathologically verified N2 NSCLC. The chemotherapy involved paclitaxel and carboplatin. Of note, the study was stratified by histology. Overall, the trial showed no improvement in survival with the addition of surgery to chemotherapy and radiation alone. However, there was a significant benefit in survival in the surgical arm for patients with adenocarcinoma (as well with T1N2 stage). Of note, the chemotherapy and radiation in this trial were administered sequentially, not concurrently. While N2 status was confirmed preoperatively, the N2 nodal localizations and numbers were not recorded.

At ASCO 2013, Butts et al presented the results of a phase III randomized study of L-BLP25 (tecemotide) antigen–specific cancer immunotherapy for unresectable stage III NSCLC. MUC1 is a mucinous glycoprotein which is overexpressed in many human malignancies. L-BLP25 is a peptide vaccine strategy that targets the exposed core of MUC1 tumor associated antigen. Overall, this strategy did not meet the primary endpoint of significantly improving overall survival. However, in a prespecified group treated with initial concurrent chemoradiation (N = 806), a 10-month difference in median overall survival favored the patients who received L-BLP25. Overall, the treatment was well tolerated. Further studies are required to confirm these observations.

The American College of Radiology (ACR) has published appropriateness criteria (AC) to guide the use of postoperative adjuvant therapy in NSCLC (Decker et al: Am J Clin Oncol 2011). The ACR appropriateness criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development includes an extensive analysis of current medical literature and the application of a consensus methodology (modified Delphi) to rate the appropriateness of treatment recommendations by the panel. The ACR appropriateness criteria also include other topics related to lung cancer and other disease sites.

Findings with programmed death-1 (PD1) and programmed death-ligand 1 (PD-L1) immune checkpoint blockade have shown promise in advanced NSCLC. At ASCO 2013, Brahmer et al reported a 17.2% overall response rate with the anti-PD1 antibody, nivolumab, in heavily pretreated advanced NSCLC; the median duration of response was 18.5 months, much longer than expected with non immune-based therapy. The anti-PD-L1 antibody, MPDL3280a, has also led to prolonged responses in advanced NSCLC, with an overall response rate of 21% and 24-week progression-free survival of 45% reported at ASCO 2013.

Also at ASCO 2013, the addition of ganetespib, an inhibitor of heat shock protein 90 (HSP-90), to second-line docetaxel chemotherapy significantly improved progression-free and overall survival compared with docetaxel alone in a phase II trial of patients with advanced NSCLC. The effect on progression-free and overall survival appeared to be amplified in patients with a diagnosis of advanced disease for > 6 months, and a phase III study is under way in this group.



In the United States, the estimated number of new lung cancer cases for 2014 is 116,000 for men and 108,210 for women. Although the incidence of lung cancer had been rising in women, the figures have stabilized and begun to decline recently. The incidence is decreasing in men.


The age of patients at which lung cancer is diagnosed varies widely, but the median age at diagnosis is approximately 70 years.


In the United States, the highest incidence of lung cancer in men and women is found in African Americans (94.7/100,000 for men and 50.4/100,000 for women), followed by Caucasians (82.9/100,000 for men and 59.9/100,000 for women).


There are geographic variations in the incidence of lung cancer, with the highest rates worldwide observed in North America and Eastern Europe; in the United States, the highest rates are found in northern urban areas and along the southern coast from Texas to Florida. The state with the highest incidence of lung cancer is Kentucky, with an incidence of 125.9/100,000 in men and 80.3/100,000 in women.


The overall 5-year survival rate for lung cancer is 18%; this has improved from a rate of approximately 12% in the 1970s.

Etiology and Risk Factors

Cigarette Smoking

Approximately 87% of all cases of lung cancer in the United States are related to cigarette smoking. There is a relatively strong dose-response relationship between cigarette smoking and the development of this cancer. The greater the number of cigarettes smoked on a daily basis and the greater the number of years of smoking, the greater is the risk of lung cancer. An individual who smokes one pack of cigarettes daily has a 20-fold increased risk of lung cancer compared with a nonsmoker.

The overall incidence of cigarette smoking decreased from 1974 through 1992. Smoking cessation decreases the risk of lung cancer, but a significant decrease in risk does not occur until approximately 5 years after discontinuation, and the risk remains higher in former smokers than in nonsmokers for at least 25 years. The benefit of smoking cessation is greater if it occurs at a younger age.

Smoking cessation is difficult. Recent data have suggested that a variety of hereditary factors increase the risk of addiction to nicotine among some individuals. Nevertheless, millions of former smokers have quit successfully. Smoking cessation programs that address both physical withdrawal from nicotine and psychological dependence appear to be more effective than either of these approaches alone. In addition, continued efforts are needed to prevent adolescents and preadolescents from beginning to smoke and to encourage them to quit after a brief period of experimentation.

Several cancer centers have recently reported that more than half of their patients with newly diagnosed lung cancer are former smokers, having quit more than 1 year before diagnosis. Healthy ex-smokers represent a large group of individuals who may benefit from effective tools for early detection and/or chemoprevention of lung cancer.

Secondhand Smoke

Not only is smoking risky for those who smoke, but it also poses a hazard to nonsmokers who either live or work with smokers. It is estimated that approximately 3,000 lung cancer deaths per year in the United States are due to secondhand smoke. Individuals who live in a household with a smoker have a 30% increase in the incidence of lung cancer compared with nonsmokers who do not live in such an environment.

Asbestos Exposure

Exposure to asbestos is another risk factor for lung cancer. Cigarette smokers who are exposed to asbestos develop lung cancer at an extremely high rate. There is a 90-fold increase compared with unexposed individuals. Exposure to asbestos is also a major risk factor for the development of mesothelioma (see discussion of this cancer in the chapter on small cell lung cancer).

Radioactive Dust and Radon Exposure

Uranium miners who have been exposed to radioactive dust and radon gas also have an increased incidence of lung cancer. Although there has been some controversy about the risk posed by exposure to residential radon gas, a study conducted in Sweden showed an increased incidence of lung cancer in individuals who were exposed to a high level of radon in their homes.


Human papilloma virus (HPV) has been implicated as a cause of NSCLC; nearly 25% of cases in non-smokers may be associated with the virus. Recurrent respiratory papillomatosis (RRP) is a disease typically found in young patients with laryngo-tracheobronchial HPV polyps. RRP may cause cough and obstruction, and may eventually degenerate into malignancy. HPV 16/18 infection is associated with the p53 mutation.


Family history has been considered a risk factor, and often a smoking-related history is uncovered. More recently, inheritable mutations have been discovered. One in particular is T790M, a germline mutation of EGFR gene, and is associated with adenocarcinoma.

Air Pollution

Particulate matter in air pollution has been shown to increase the risk of lung cancer, especially adenocarcinoma. The risk is associated with the size and volume of the particulate matter.


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