Chapter 18: Non–Small Cell Lung Cancer

Lung cancer is the third most commonly diagnosed cancer, after breast and prostate cancers, but it is the most common cause of cancer-related death (¹). Every year, 1.5 million patients die of lung cancer worldwide (¹). About 70% of patients will be diagnosed with advanced stages that are not amenable to curative therapies. Only 15% of all patients diagnosed with lung cancer are alive 5 years after diagnosis.

Lung cancer is broadly divided into small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). Approximately 85% of lung cancer is NSCLC. This chapter briefly describes the epidemiology, etiology, histology, prevention, and molecular biology of NSCLC. The major focus will be clinical presentation, diagnosis, staging, and treatment based on current clinical knowledge, with an emphasis on our approach at the University of Texas MD Anderson Cancer Center (MDACC).

Lung cancer is rarely diagnosed in people younger than 35 years old. Incidence and death rates rise exponentially until age 75, when a plateau is reached. Non–small cell lung cancer accounts for the greatest number of deaths from cancer in both men and women over age 60.

The geographic, social, and temporal trends of the incidence of NSCLC are closely related to tobacco consumption. In developed Western countries, the incidence of NSCLC has been declining; however, it has been increasing in Asia, Eastern Europe, and developing countries (¹).

Worldwide, NSCLC is more common in men, and this difference has been attributed to higher tobacco consumption. In some regions, like Eastern Europe and South America, there was an uptake of smoking by women in the 1980s, and these areas are currently experiencing a rise in NSCLC cases in women. In the United States, the incidence has been declining for both men and women as tobacco use declines; the male-to-female ratio from 2007 to 2011 was 1.4:1 (²).

There is some evidence that African Americans might be more susceptible to the carcinogenic effects of tobacco smoke (³); however, smoking behaviors might also account for socioeconomic and racial differences in lung cancer incidence.

Smoking

The causal relationship between tobacco smoke and lung cancer was established in the 1950s in case-control and cohort studies. This led to the 1964 report of the US Surgeon General, concluding that smoking can cause lung cancer. Currently, it is estimated that 85% to 90% of lung cancers are due to smoking. Nonsmokers who are exposed to secondhand smoke are also at an increased risk. There is a dose-response relationship between smoking and lung cancer risk, and smoking cessation leads to a significant risk reduction (Table 18-1) (⁴).

Tobacco smoke is a complex mixture of chemicals that includes multiple carcinogens, most importantly the N-nitrosamines (nicotine-derived nitrosamino ketone [NNK] and N’-nitrosonornicotine [NNN]) and polycyclic aromatic hydrocarbons [benzo(a)pyrene and dimethylbenz(a)anthracene]. They are activated through hydroxylation by the P450 enzyme system and exert their action through the formation of DNA adducts.

Smokeless tobacco is frequently advocated as a safer alternative. There has not been a clear association between smokeless tobacco and lung cancer; however, it increases the risk of head and neck, pancreatic, and gastric cancer. E-cigarettes deliver water vapor with scents and different amounts of nicotine containing lower amounts of nitrosamines. However, they still contain high levels of propylene glycol and glycerin, and their long-term effects on health are unknown. Their use should not be recommended to nonsmokers, and use as part of a smoking cessation approach needs further study.

Approximately 10% to 15% of cases of NSCLC occur in never smokers, corresponding to approximately 20,000 deaths annually. In addition to secondhand smoke exposure, several other agents have also been linked to the development of lung cancer (Table 18-2).

Asbestos

Asbestos exists in many natural forms. The silicate fiber has been implicated in carcinogenesis, is chemically inert, and can remain in a person’s lungs for a lifetime. Epidemiologic studies have confirmed the association between asbestos exposure and certain lung diseases, such as pulmonary fibrosis, mesothelioma, and lung cancer (⁵). Most exposure occurs in the workplace. When smoking is combined with asbestos exposure, the relative risk of lung cancer is strikingly increased (⁵).

Radon

Radon is a naturally occurring decay product of uranium. It is a colorless, odorless, chemically inert gas that can penetrate the earth’s crust and accumulates in buildings. It emits heavy ionizing alpha particles, which may damage DNA. It was shown that many households in Europe, Canada, and the United States have some degree of radon radiation that may increase NSCLC risk among smokers and nonsmokers (⁶).

Diet

The majority of studies that have examined vegetable consumption in relation to lung cancer have shown a protective effect (reviewed in Alberg and Samet [⁷]), but there are inherent biases in these population studies. There is also epidemiologic evidence that dietary intake of certain vitamins decreases lung cancer risk; however, trials of vitamin supplementation for cancer prevention have ultimately been unsuccessful (see later “Chemoprevention” section).

Other Factors

Environmental or industrial exposure to arsenic, chromium, chloromethyl ether, vinyl chloride, and polycyclic aromatic hydrocarbons increases lung cancer risk (reviewed by Field and Withers [⁸]). Preexisting lung disease such as tuberculosis, silicosis, pulmonary fibrosis, and chronic obstructive pulmonary disease are also associated with an increased lung cancer incidence even when correcting for the degree of cigarette consumption. This suggests that common pathways to these conditions, such as chronic inflammation, may drive the tumorigenic process.

Genetic Predisposition

Family history of lung cancer is associated with a two- to three-fold increase in lung cancer risk, even after correction for smoking, and this risk seems to be inherited in a Mendelian co-dominant fashion (⁹).

Many studies describe weak but consistent associations between some polymorphisms and lung cancer risk. The cytochrome P450 (CYP) family is responsible for the metabolism of tobacco smoke, and the polymorphism CYP1A1 Ile⁴⁶²Val is associated with a higher risk in Asians (odds ratio [OR], 1.61) (¹⁰). The glutathione S-transferase (GST) enzyme prevents oxidative damage, and the polymorphism GSTM1 increases risk in Asians (OR, 1.17) (¹¹). Finally, individuals with impaired DNA repair capacity are at higher risk for developing lung cancer, even if they are nonsmokers, and the polymorphism Lys⁷⁵¹Gln in the DNA-repairing enzyme ERCC2 was associated with lung cancer (OR, 1.15) (¹²).

Large genome-wide association studies (GWAS) (¹³) have identified three loci strongly associated with lung cancer risk in different populations: 15q25, 5p15, and 6p21. The 15q25 susceptibility region encodes three cholinergic nicotine receptor genes (CHRNA3, CHRNA5, CHRNB4), and alterations in those regions have been associated with a higher risk for nicotine dependence and higher smoking burden. In nonsmokers, they have also been associated with impaired healing of the respiratory mucosa, suggesting a higher sensitivity to toxin-induced airway damage. The 5p15 region encodes the TERT gene, responsible for telomerase function, which is frequently altered in many cancers.

Smoking Cessation and Prevention

The most effective method of preventing lung cancer is reducing tobacco exposure, either through encouraging smoking cessation or preventing young people from starting to smoke. In the United States, campaigns to reduce smoking rates have been successful. The estimated percentage of Americans who actively smoke decreased from 42.4% in 1965 to 25% in 1990 and to 18.1% in 2012. However, former smokers retain an increased risk of lung cancer, and there are still a considerable number of smokers, highlighting the need for better education and prevention strategies, especially those targeted to youths.

Early Detection and Screening

Previous studies examined the role of chest x-ray, with or without cytologic analysis of sputum, to screen for lung cancer, and none showed a clear benefit. Most of them were confounded by lead time, length time, and overdiagnosis biases.

Spiral computed tomography (CT)—also called helical CT or low-dose CT—is much more sensitive to detect early NSCLC than chest x-ray. In 2011, the results of the National Lung Screening Trial (NLST) were published (¹⁴). In this trial, 53,454 current or former smokers age 55 to 74 years old with at least a 30-pack-year smoking history and no symptoms that could be related to lung cancer were randomized to undergo yearly chest x-rays or low-dose CT for 3 years. After a median follow-up of 6.5 years, the low-dose CT group had a 20% reduction in the rate of lung cancer–specific mortality, from 309 to 247 per 100,000 person-years, as well as a 6.7% reduction in overall mortality. In the CT group, 39% of patients had suspicious lung nodules (vs 16% in the control arm), and the majority of these (96%) were considered false-positive results. Sensitivity and specificity of low-dose CT were 93.8% and 73.4%, respectively, compared to 73.5% and 91.3% for chest radiography. Cost-effectiveness analysis showed a median cost of $43,000 per quality-adjusted life-year gained for current smokers assigned to the low-dose CT group. Based on these results, the US Preventive Services Task Force currently recommends lung cancer screening with yearly low-dose CT for current or past smokers, age 55 to 80, with a smoking history of at least 30 pack-years. Screening should be discontinued once a person has not smoked for 15 years. Another trial is currently being conducted in Belgium and the Netherlands (the NELSON study) looking at the 10-year impact of lung cancer screening using low-dose CT scan.

Despite recent developments, low-dose CT screening still has significant limitations, including high false-positive ratios and the development of interval lung cancers, which can be aggressive. Positron emission tomography (PET)-CT scan, epigenetic markers, and cell-free tumor DNA are additional approaches under investigation, which are only recommended in the setting of a clinical trial.

Chemoprevention

Cigarette smoking has an effect of field cancerization, with the accumulation of genetic mutations and other premalignant changes throughout the lungs and the aerodigestive tract. Patients treated and cured of early-stage lung cancer have a high risk of developing second primary tumors. Therefore, a series of chemoprevention trials has focused on smokers and survivors of lung and head and neck cancers.

Multiple studies evaluated supplementation with vitamins and oligo-elements, but none showed a benefit to supplementation, and several studies showed risk, with increased lung cancer incidence and mortality (Table 18-3) (^{15,16,17,18,19,20,21}).

Given the potential connection between inflammation and tumorigenesis, phase II studies have used anti-inflammatory agents, such as celecoxib, and prostaglandin analogues, such as iloprost. These agents have been able to reduce proliferation and dysplasia of oral and bronchial epithelium in smokers and former smokers, but their benefit in cancer prevention remains to be proven. There are currently no proven agents for the chemoprevention of lung cancer.

Most lung tumors arise from epithelial cells and are called bronchogenic carcinomas. Neuroendocrine tumors also arise in the lung and can appear as SCLC, carcinoids, or large cell neuroendocrine carcinomas. Bronchogenic carcinomas include NSCLCs, a category comprising three major types: adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma.

The most current histologic classification of NSCLC was proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011 (²²) and uses immunohistochemistry to identify subgroups with different molecular profiles and clinical behaviors (Tables 18-4 and 18-5). Adenocarcinomas usually stain positive for cytokeratin 7, thyroid transcription factor 1 (TTF-1), and surfactant apoprotein A and are negative for cytokeratin 20. Metastatic adenocarcinomas from other sites except the thyroid stain negative for TTF-1. All carcinoids and most SCLCs stain positive for chromogranin and synaptophysin, whereas NSCLC is usually negative for these two markers. Mesothelioma is distinguished from adenocarcinoma by the presence of calretinin and cytokeratin 5/6 and the absence of carcinoembryonic antigen (CEA), B72.3, Ber-EP4, and MOC-31.

Adenocarcinoma

Adenocarcinoma is the most common subtype of NSCLC in the United States, representing 40% of cases in men and 50% in women. It is predominant in nonsmokers, and its incidence has been rising. These tumors are classically peripheral and, on histologic examination, demonstrate gland formation, papillary structures, or mucin production (Fig. 18-1).

Non–small cell lung cancer is one of the cancer types with the highest mutation burden, with an average of 360 exonic mutations per sample (²³). However, the patterns of mutations are different for adenocarcinomas and SCCs.

About 75% of lung adenocarcinomas have alterations in driver genes that activate intracellular pathways leading to proliferation, cell survival, and oxidative stress response (²⁴) (Fig. 18-2). Up to 79% of those alterations are in the RTK/RAS/RAF pathway, including mutations in the ErbB family member EGFR (ErbB1).

The prevalence of EGFR mutations ranges from 5% to 10% in smokers to 40% to 50% in nonsmokers in the Western population (²⁵). The alterations are usually in the tyrosine kinase domain of the gene within exons 18 to 24, most specifically in the intracellular adenosine triphosphate (ATP)-binding domain (Table 18-6) (^25,26,27).

Frequencies of EGFR, KRAS, ALK, ROS1, and other driver genetic alterations commonly found in lung adenocarcinoma samples are listed in Table 18-7 (^{24,25,28,29,30,31,31,32}). This is a rapidly changing landscape that is defining the many molecular subsets of this heterogeneous disease.

Squamous Cell Carcinoma

Squamous cell carcinoma is now the second most frequent histology, accounting for 30% of NSCLC in men and 20% in women. This tumor arises most frequently in the proximal bronchi and has the strongest association with smoking. Pathologically, it is characterized by visible keratinization, with prominent desmosomes and intercellular bridges (Fig. 18-3).

Squamous cell carcinomas frequently have amplifications in chromosome 3q, which contains genes involved in squamous differentiation (SOX2 and TP53) and cell proliferation (PI3K). About 81% to 90% of patients with SCCs have TP53 mutations, and 47% have alterations in the PI3K/AKT/mTOR pathway, whereas only 26% of SCCs have activations of the RTK/RAS/RAF pathway (²³). The prevalence of EGFR mutations is 1% to 3%, 6% of patients have EGFR amplifications, and 1% to 6% have KRAS mutations (²³) (Fig. 18-4).

Large Cell Carcinoma

The least common subtype of NSCLC, large cell carcinoma, accounts for approximately 8% of all NSCLCs (Fig. 18-5). Refinements in histopathologic techniques have led to the diagnosis of adenocarcinoma or SCC in cases previously diagnosed as undifferentiated large cell carcinoma.

Non–small cell lung cancer is often asymptomatic at diagnosis and may be found incidentally on imaging performed for other reasons. If symptoms are present, they are often related to the specific locations of tumor masses and the occurrence of paraneoplastic syndromes. The symptoms of centrally located lesions include cough, hemoptysis, wheezing, stridor, dyspnea, and postobstructive pneumonia. Peripheral lesions can cause pain due to pleural or chest wall invasion, cough, or restrictive dyspnea.

The involvement of thoracic and cervical structures can also lead to classical clinical presentations:

• Pancoast syndrome: Shoulder pain radiating to the arm in an ulnar distribution caused by invasion of the eighth cervical and first thoracic nerves in the superior sulcus.

• Horner syndrome: Enophthalmos, ptosis, miosis, and ipsilateral dyshidrosis caused by involvement of the paravertebral sympathetic nerves.

• Hoarseness: Involvement of the left recurrent laryngeal nerve as it passes through the aortopulmonary window.

• Elevation of the hemidiaphragm: Involvement of phrenic nerve at the mediastinum.

• Superior vena cava syndrome: Swelling of the face and arm and superficial venous engorgement caused by compression of the superior vena cava.

The production of hormones or hormone-like substances can lead to paraneoplastic syndromes:

• Cancer cachexia: The most common paraneoplastic syndrome, characterized by weight loss, impaired immune function, and weakness that are not completely explained by poor oral intake. The exact mechanism for development of cachexia is unknown, but tumor-elaborated cytokines have been implicated.

• Hypercalcemia: The second most common paraneoplastic syndrome in NSCLC, hypercalcemia is caused by ectopic production of a parathyroid hormone-related protein (PTHrP) or bone metastases. It is more common in the squamous cell subtype.

• Hypertrophic pulmonary osteoarthropathy: Arthropathy and clubbing of the fingers and toes with evidence of periostitis of the long bones (Fig. 18-6). Its etiology is unknown, and it is more common in adenocarcinomas and large cell carcinoma.

Non–small cell lung cancer is frequently metastatic, and symptoms secondary to metastases are common. The most common sites for metastases are intrathoracic nodes, pleura, contralateral lung, liver, adrenal glands, bone, and brain.

Solitary Pulmonary Nodule

A solitary pulmonary nodule is a single asymptomatic mass that is surrounded by lung tissue, is well circumscribed, measures less than 3 cm, and does not show evidence of mediastinal or hilar adenopathy. The differential diagnosis includes primary cancer, metastatic cancer, infection, benign tumors (eg, hamartomas), vascular abnormalities, and inflammation (eg, granulomatous disease). The American College of Chest Physicians has issued guidelines on the evaluation of solitary lung nodules, based on their size (≤ or >8 mm), the clinical probability of malignancy, and the patient’s surgical risk (³³) (Table 18-8 and Fig. 18-7).

The management of small nodules (<8 mm) is less clear. Lesions that are too small to be biopsied (<5 mm) should be followed with CT scans in 6 months (any risk factors for lung cancer) or 12 months (no risk factors for lung cancer). For lesions 5 to 8 mm, some recommend close follow-up with CT scans in 3, 6, and 12 months, and others recommend nonsurgical biopsies (³³).

Pulmonary Mass

Lesions that are large (>3 cm), multiple, or with enlarged hilar, mediastinal, and/or supraclavicular lymph nodes should undergo complete lung cancer staging and a nonsurgical biopsy. Fiberoptic bronchoscopy is appropriate for central lesions and is able to establish the diagnosis in 97% of cases. For peripheral lesions, the diagnostic yield of bronchoscopy is only 55%, and percutaneous transthoracic biopsies can be considered. Because of the tissue requirements for immunohistochemistry and molecular marker testing of lung cancers, at MDACC, we usually perform an image-guided core-needle biopsy. Mediastinoscopy or endobronchial ultrasound (EBUS) can be used to obtain biopsy samples from mediastinal nodes.

Staging

Once the histologic diagnosis of NSCLC has been established, the extent of disease must be determined (Fig. 18-8).

The stage of disease will dictate therapy. All patients must undergo a complete history and physical examination, chest x-ray, CT scan of the chest and upper abdomen (to include the adrenal glands), a complete blood count, and blood chemistry tests that include electrolyte and liver enzyme studies. All patients with stage II to IV disease should have evaluation of the brain, with magnetic resonance imaging (MRI) if possible. Central nervous system (CNS) imaging may be considered for patients with stage I disease. For stage I to III NSCLC, ¹⁸F-fluorodeoxyglucose (FDG)-PET should be performed to evaluate mediastinal nodes and for distant metastases. Because the involvement of mediastinal lymph nodes will influence surgical decisions (see section “Treatment”), the presence of FDG-avid mediastinal lymph nodes in a PET-CT scan should be confirmed with either mediastinoscopy or EBUS (see “Commentary”). Routine use of mediastinoscopy or EBUS in patients with a normal-appearing mediastinum on PET-CT scans is controversial.

After the completion of staging evaluation, the disease is assigned a TNM stage (Figs. 18-9,18-10,18-11,18-12,18-13,18-14,18-15,18-16,18-17; Tables 18-10 and 18-11). The TNM staging for NSCLC was revised and updated in 2009 in the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer staging system (³⁴).

Clinical staging has inherent inaccuracies and therefore typically underestimates the true extent of disease. In patients who undergo surgical tumor resection, surgical/pathologic staging should be done to predict recurrence and to evaluate the need for adjuvant therapy. Patients’ 5-year survival rates by tumor stage are shown in Table 18-11.

Stages I and II Disease

Surgery

Surgery is standard treatment for stages I and II NSCLC (Figs. 18-18 and 18-19).

The extent of lung resection will be dictated by the size and location of the tumor. The entire tumor must be removed, with margins negative for cancer. Wedge resection and segmentectomy are associated with higher rates of local recurrence than lobectomy and pneumonectomy and are not considered standard of care, although they may be an option for patients who cannot tolerate a larger surgery due to poor pulmonary function (³⁵). All patients should also undergo complete ipsilateral mediastinal lymph node dissection or systematic mediastinal sampling for accurate staging (³⁶).

Any patient who is being considered for surgery must undergo pulmonary function tests to assess the ability to withstand pulmonary resection. Split-lung function studies can further help to predict lung function after the planned resection. There is no single accepted value, criterion, or cutoff for pulmonary resection. Published criteria that have been shown to predict high risk for lung resection include estimated posttreatment forced vital capacity <2 L, forced expiratory volume in 1 second <1 L, and diffusing capacity of the lungs for carbon dioxide <40% to 60% (³⁷).

Radiation Therapy

For patients with early-stage lung cancer who cannot undergo surgery because of poor pulmonary reserve or medical comorbidities, stereotactic radiosurgery is a feasible option with local control rates of 90% and cancer-specific survival of 88% at 3 years (³⁸).

There is controversy regarding whether stereotactic radiosurgery should be considered in patients who are candidates for surgery and who have small primary tumors and no lymph node involvement. Retrospective series suggest that outcomes with radiation may be similar to those of surgery (³⁸). Surgery, however, remains the standard of care for patients who can tolerate it.

Adjuvant Chemotherapy

Even after complete resection, rates of recurrence of NSCLC are high, prompting the study of adjuvant chemotherapy in this disease. The potential benefit of adjuvant chemotherapy is the eradication of micrometastatic disease before it becomes clinically evident, thus potentially increasing cure rates. For patients with completely resected stage II or III NSCLC, multiple meta-analyses demonstrate that adjuvant platinum-based chemotherapy is associated with an absolute benefit in 5-year survival of about 5% (³⁹) and should be offered to all patients with good performance status (Table 18-12) (^{40,41,42,43,44}). For patients with no lymph node involvement and a primary tumor smaller than 4 cm, adjuvant chemotherapy is not recommended. For node-negative tumors larger than 4 cm, the Cancer and Leukemia Group B 9633 trial suggested a benefit of adjuvant platinum-based chemotherapy, and it should be considered (⁴⁰) (see Table 18-12).

Cisplatin-vinorelbine is the most studied regimen for adjuvant chemotherapy; in practice, other cisplatin-based doublets are frequently used. Acceptable second agents include pemetrexed (for nonsquamous NSCLC), docetaxel, etoposide, and gemcitabine. Cisplatin is preferred over carboplatin, but if cisplatin is not feasible, carboplatin/paclitaxel is an appropriate alternative (⁴⁰). There is no evidence that targeted agents such as bevacizumab, erlotinib, and crizotinib are effective in the adjuvant setting, although the National Cancer Institute ALCHEMIST trial will assess the benefit for specific molecular subsets of patients.

Neoadjuvant chemotherapy offers several real and theoretical advantages over postoperative therapy: better patient compliance, improved tumor resectability, earlier treatment of micrometastatic disease, and earlier assessment of clinical and pathologic response. There has been one randomized trial and one meta-analysis (⁴⁵) that suggest the equivalence of the neoadjuvant and adjuvant approaches. Adjuvant treatment is the standard of care, but neoadjuvant chemotherapy could be considered in special situations, such as for stage III disease when response to chemotherapy may help to determine whether a patient should undergo surgery or chemoradiation.

Adjuvant radiation or chemoradiation for resected stage I and II NSCLC has been shown to be detrimental and should not be recommended (⁴⁶).

Stage III Disease

Patients with stage III disease have better outcomes with multimodality rather than single-modality therapy, and their care should be managed by a multidisciplinary team. For patients with stage IIIB disease, chemoradiation represents the standard of care. Chemoradiation is often used for patients with stage IIIA disease as well, but surgery with adjuvant treatment can be considered for carefully selected patients.

In a randomized trial of chemoradiation alone versus chemoradiation followed by resection, the patients who benefited from the surgical approach were those with stage IIIA disease who had limited involvement of mediastinal lymph nodes and who underwent lobectomy (as opposed to pneumectomy) (⁴⁷). Neoadjuvant chemoradiation followed by surgery has been compared to neoadjuvant chemotherapy followed by surgery and adjuvant radiation (⁴⁸) and was associated with more toxicity with no survival benefit. At MDACC, we consider surgical treatment in patients with stage IIIA disease with good performance status and without multistation mediastinal adenopathy. These patients are typically treated with neoadjuvant chemotherapy followed by consideration of surgery. Adjuvant radiation therapy is typically given if there is evidence of mediastinal node involvement based on assessment of surgical pathology (Fig. 18-20).

Patients with stage IIIA disease and extensive mediastinal involvement or IIIB disease should be treated with concurrent chemoradiation. When compared with sequential radiotherapy and chemotherapy, this approach is associated with higher survival rates (23.8% vs 18.1% at 3 years; hazard ratio [HR], 0.84; P = .004) but increased toxicity (acute esophageal toxicity, 18% vs 4%; relative risk [RR], 4.9; P = .001) (⁴⁹).

Standard radiotherapy for stage III NSCLC consists of radiation given once daily for 6 weeks (30 fractions) to a total dose of 60 Gy. All attempts to increase efficacy through hyperfractionation, acceleration, or increased radiation dose have failed (⁵⁰). In the recent Radiation Therapy Oncology Group 0617 trial, patients receiving high-dose radiation (74 Gy) had higher rates of locoregional failure (44% vs 35.3%; P = .04) and worse median survival (19.5 vs 28.7 months; P = .0007) than those receiving standard-dose radiation (60 Gy) (⁵¹). Proton therapy is a newer technique that is able to deliver a higher dose to the tumor while delivering lower doses to normal surrounding tissue; it is currently being compared to standard radiation in a randomized phase III trial (NCT00915005).

Multiple concurrent chemotherapy regimens have been tested against radiation alone with proven benefit (⁵²); however, these regimens have not been directly compared to each other, and multiple regimens are considered acceptable (Table 18-13). At MDACC, many physicians favor carboplatin and paclitaxel because retrospective data suggest that this regimen is less toxic than cisplatin and etoposide (⁵³).

The use of consolidation docetaxel after concurrent chemoradiation with cisplatin and etoposide was detrimental in the phase III Hoosier Oncology Group LUN 01-24 trial (⁵⁴). However, most studies with carboplatin/cisplatin and pemetrexed or carboplatin and paclitaxel included consolidation chemotherapy after radiation. It is reasonable to consider consolidation chemotherapy for patients who received those regimens and have a good performance status at the end of concurrent therapy.

There are no definitive data on adjuvant anti-EGFR tyrosine kinase inhibitors (TKIs) in stage III NSCLC patients with activating EGFR mutations. In a population not selected for EGFR mutations, adjuvant gefitinib was detrimental (⁵⁵). There is no proven benefit for any targeted therapies in combination with chemoradiation for locally advanced lung cancer, although this is an active area of investigation.

Tumors in the lung apex invading apical structures, termed Pancoast tumors (Fig. 18-21), are challenging. Tumors that are N0 to N1 should undergo preoperative concurrent chemoradiation followed by resection. For these patients, 5-year disease-free survival rates are 40% to 50% (⁵⁶). Patients with N2 to N3 disease should be treated with concurrent chemoradiation alone.

Stage IV Disease

Stage IV NSCLC remains an incurable disease, and management should include adequate palliation of symptoms. Patients with symptomatic brain or spinal cord metastases, hemoptysis, postobstructive pneumonia, or painful bone metastases should receive radiotherapy before any consideration for systemic therapy. Early referral to specialized palliative care services has also been shown to improve overall survival (⁵⁷).

Decisions about systemic therapy demand the classification into SCC versus nonsquamous carcinoma and the testing of adenocarcinoma cases for actionable alterations (eg, EGFR mutations, ALK and ROS1 rearrangements). The most recent guidelines (⁵⁸) recommend that all adenocarcinomas, mixed adenosquamous carcinomas, and NSCLCs not otherwise specified should undergo evaluation for EGFR mutations using polymerase chain reaction–based tests and testing for ALK and ROS1 translocations using fluorescent in situ hybridization. Often, in practice, more complete molecular profiling is being performed, which also includes testing for less common alterations such as BRAF and HER2 mutations and RET fusions. Pure SCC with no immunohistochemistry markers of adenocarcinoma should not undergo molecular testing. Because of the importance of molecular testing, attempts should be made to obtain core biopsies rather than fine-needle aspirations to ensure sufficient tissue for profiling.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for EGFR Mutant Lung Adenocarcinoma

Epidermal growth factor receptor (EGFR) TKIs should be considered first-line therapy in patients with metastatic lung adenocarcinoma with EGFR exon 19 deletion or L858R mutation. Exon 20 mutations (including T790M), which are found in 5% of cases at diagnosis, have an intrinsic resistance to EGFR-TKIs (²⁷) and should be treated with standard chemotherapy.

The EGFR-TKIs erlotinib, afatinib, and gefitinib have been tested against standard chemotherapy as first-line agents in patients with NSCLC with EGFR-activating mutations and showed improvement in response rates (70% vs 33%, P < .001), progression-free survival (PFS) (9.5 to 13.1 months vs 4.1 to 6.3 months, P < .0001), and quality of life (^59,60,61). No benefit in overall survival (OS) has been detected because most trials allowed for cross-over after progression (Table 18-14) (^{59,60,61,62,63,64,65}). Gefitinib is not available in the United States, so either erlotinib or afatinib can be used in the frontline setting. There are no head-to-head data comparing erlotinib to afatinib, and afatinib has higher reported rates of toxicity. There is some evidence that combining EGFR-TKIs with the anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab improves response rates and PFS (⁶⁶), but benefits in OS have not been confirmed.

Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Patients with activating EGFR mutations who progress on EGFR-TKIs and those with unknown mutation status who have a prolonged response to EGFR TKIs (>6 months) and then progress are classified as having acquired resistance to EGFR-TKIs. For these patients, a postprogression biopsy is recommended to identify the mechanisms of resistance (^67,68) (Fig. 18-22).

In about half of cases, the mechanism of resistance is the development of an acquired exon 20 T790M mutation, which occurs at the binding site of the TKI to EGFR, displacing the TKI. The growth of those tumors still shows EGFR dependence, and multiple trials are currently evaluating the effects of third-generation TKIs (eg, AZD9291 and CO-1686) with specific affinity for EGFR with T790M mutation. Early data look promising, and these agents may receive regulatory approval in the near future. There are also phase I/II data on using the combination of afatinib with the anti-EGFR monoclonal antibody cetuximab in patients with acquired EGFR resistance (response rate, 29%; PFS, 4.7 months) (⁶⁹). Interestingly, efficacy was similar in patients with and without T790M mutations. Currently, however, there are no approved targeted agents for patients with resistance to first-line TKIs.

About 5% of patients experience small cell transformation. These patients should be treated similarly to de novo SCLC with combination chemotherapy such as platinum-etoposide (see Chapter 17 on SCLC for further details on SCLC chemotherapy regimens) (⁶⁷).

Because erlotinib has poor penetration through the blood-brain barrier, patients with controlled extracranial disease who are progressing in the CNS may benefit from pulsatile high-dose erlotinib (1,500 mg once a week), with response rates in the CNS of 67% and median time to CNS progression of 2.7 months (⁷⁰). This approach is also being further studied in clinical trials. Another option is treating the brain metastases with radiation and continuing with erlotinib (⁷¹).

Outside of clinical trials, patients with resistance to frontline TKIs should receive standard chemotherapy (see below). Postprogression continuation of EGFR-TKIs in combination with chemotherapy has recently been addressed with two clinical trials. The data demonstrate that despite increases in response rates compared to chemotherapy alone, PFS and OS are not improved (⁷²).

ALK Inhibitors for Patients With Adenocarcinomas With ALK Translocations or ROS1 Fusions

Approximately 5% of patients with adenocarcinoma have tumors harboring an ALK fusion, and another 1% to 2% of patients have a ROS1 fusion. For patients with an ALK translocation, treatment with crizotinib is associated with response rates greater than 60% and median PFS around 8 months (⁶²). Crizotinib is similarly effective in patients with ROS1 translocations, with response rates over 70% and median PFS over 19 months (⁶⁵). Crizotinib is the standard first-line therapy in patients with advanced lung adenocarcinoma with EML4-ALK translocations or ROS1 fusions (see Table 18-14).

The mechanisms of resistance to crizotinib therapy have been studied. About 46% of patients develop further alterations in the ALK gene (28% secondary ALK mutations, 18% ALK copy number gains), 8% develop EGFR mutations, and 18% develop KRAS mutations (⁷³). The most common resistance mutations are L1196M and G1269A, which occur at the crizotinib binding site. Another proposed mechanism of resistance is the overexpression of insulin-like growth factor receptor 1 (IGF-1), which activates the same downstream pathways as ALK.

Regardless of the mechanism of resistance, patients with acquired resistance to crizotinib should receive second-line treatment with one of the second-generation ALK inhibitors. Ceritinib has shown promising results in a large phase I trial and is US Food and Drug Administration (FDA) approved for ALK-positive patients following progression on crizotinib (⁶³). Other second-generation ALK inhibitors, including alectinib, AP26113, and X-396, are currently in clinical development (see Table 18-14).

Frontline Chemotherapy for Advanced Non–Small Cell Lung Cancer

Most patients with lung cancer do not have a tumor that is targetable with an approved therapy. For these patients, as well as for patients with EGFR mutation or ALK or ROS1 fusions progressing on targeted therapies, cytotoxic chemotherapy represents the standard of care.

When compared to best supportive care, chemotherapy is associated with a modest improvement in median OS (1.5 months) and significant gains in symptom control (⁷⁴). Multiple platinum-based doublets are equally effective with response rates around 18% to 35%, PFS of 3 to 6 months, and OS of 8 to 12 months (^75,77,78,79) (Table 18-15). Acceptable agents to combine with platinum include paclitaxel (⁷⁵), docetaxel (⁷⁵), pemetrexed (^76,77) (nonsquamous only), gemcitabine (⁷⁵), and nab-paclitaxel (⁷⁸). One trial showed that cisplatin-pemetrexed is superior to cisplatin-gemcitabine in patients with adenocarcinoma but inferior in patients with SCC (^76,77). Because this combination is relatively well tolerated and has a convenient once every 3 weeks dosing schedule, it is often used as first-line therapy in patients with adenocarcinoma.

In the past, trials suggested that cisplatin was associated with better response rates and PFS than carboplatin, but a meta-analysis focusing only on modern regimens (docetaxel, paclitaxel, vinorelbine, or gemcitabine combined with platinum) (⁸⁰) showed that carboplatin and cisplatin lead to similar outcomes. The toxicity profile is different, and cisplatin has a higher risk for nausea, whereas carboplatin has higher rates of myelosuppression.

The addition of the VEGF monoclonal antibody bevacizumab to carboplatin/paclitaxel can be considered in patients with adenocarcinomas. The phase III Eastern Cooperative Oncology Group (ECOG) 4599 trial (⁷⁹) randomized patients with nonsquamous NSCLC to carboplatin and paclitaxel with or without bevacizumab. The bevacizumab-containing arm had better response rates (35% vs 15%, P < .001), PFS (6.2 vs 4.5 months, P < .001), and OS (12.3 vs 10.3 months, P = .003), although there were higher rates of adverse events, including a higher risk of severe bleeding (4.4% vs 0.7%, P < .001). Patients with squamous histology, hemoptysis, or uncontrolled hypertension and those older than 70 are at higher risk for bleeding with bevacizumab and are not candidates for this therapy.

Maintenance Chemotherapy

For patients who do not progress after four to six cycles of therapy with a platinum doublet, multiple trials have studied maintenance therapy—either continuation maintenance (continuing the same nonplatinum drug) or switch maintenance (initiating a non-cross-resistant nonplatinum drug) (Table 18-16) (^{81,82,83,84,85,86,87}).

Patients receiving either pemetrexed or bevacizumab as part of their initial therapy should continue these drugs as long as tolerated or until progression (^79,85,86). For patients who are treated with other frontline regimens, maintenance therapy is more controversial. Switch maintenance to either pemetrexed (for nonsquamous NSCLC) (⁸²) or docetaxel (⁸¹) is associated with benefits in PFS, although effects on OS are unclear, particularly for patients who go on to receive second-line therapy. Maintenance pemetrexed in patients with SCC has been shown to be associated with shorter PFS (⁸²) than observation alone; based on these data and the other data described earlier, pemetrexed should not be used for patients with NSCLC with predominantly squamous histology.

Chemotherapy for Patients With Platinum-Refractory Disease

Patients with disease progression after platinum-based therapy who maintain good performance status are candidates for second-line therapy. The agents with proven efficacy in this setting are single-agent docetaxel, pemetrexed (in nonsquamous NSCLC only), and ramucirumab in combination with docetaxel (Table 18-17) (^{77,88,89,90,91,92,93,94,95}). Second-line pemetrexed is equivalent to docetaxel in nonsquamous histologies (response rate, 12.8% vs 9.9%; OS, 9 vs 9.2 months) but inferior in squamous NSCLC (response rate, 2.8% vs 8.1%; OS, 6.2 vs 7.4 months; P = .018).

Reexposure to platinum in second-line therapy increases response rates, but not PFS or OS, even in patients with long (>6 months) platinum-free intervals (⁹¹) and is not frequently used. The only combination therapy approved in the second-line setting is docetaxel with the anti-VEGF receptor 2 (anti-VEGFR2) monoclonal antibody ramucirumab (⁹²). In the pivotal REVEL trial comparing docetaxel alone to docetaxel plus ramucirumab in patients with NSCLC of any histology, the combination arm had better PFS (4.5 vs 3 months, P < .0001) and OS (10.5 vs 9.1 months, P = .023) with no increased risk of severe bleeding. It is important to highlight that only 14% of patients enrolled in REVEL had received prior bevacizumab, making it difficult to draw conclusions about this group. Also, unlike the phase III bevacizumab trials that excluded patients with SCC, 25% of patients on this trial had squamous histology, and there was no increased risk of bleeding seen in this group.

For patients with wild-type EGFR, docetaxel and pemetrexed appear to be better second-line options than erlotinib (^93,95), although erlotinib remains an FDA-approved option for third-line therapy (⁹⁴).

Treatment of Stage IV Non–Small Cell Lung Cancer in the Elderly

Treatment of advanced NSCLC in the elderly has been addressed in several prospective studies and retrospective analyses, and the International Society of Geriatric Oncology (SIOG) has issued clear guidelines (⁹⁶). Basically, patients older than age 70 years should undergo functional evaluation, and those with good functionality should receive standard therapy.

For lung adenocarcinomas with actionable mutations, TKIs should be recommended. For patients without actionable mutations, platinum-based doublets should be offered. In the IFCT-0501 trial (⁹⁷), patients older than age 70 were randomized to carboplatin-paclitaxel or single-agent therapy with vinorelbine or gemcitabine. The combination arm had a significant improvement in OS (10.3 vs 6.2 months, P < .0001) and better pain control rates with a small increase in the rates of toxic death (4.4% vs 1.3%). Based on the subgroup analysis from ECOG 4599 (⁹⁸) and on other trials, bevacizumab should not be added to chemotherapy in elderly patients because of lack of benefit and increased risk of severe side effects.

Immunotherapy in Advanced Non–Small Cell Lung Cancer

Immunotherapy has recently achieved significant outcomes in the treatment of metastatic melanoma, leading to the approval of immune checkpoint inhibitors such as anti-PD-1/PD-L1 and anti-CTLA4 antibodies (see chapter on cancer immunotherapy). Lung cancers are among the malignancies with the highest mutation burden, averaging 360 exonic mutations per sample (²³). Many of those mutations generate neoantigens potentially able to stimulate effector CD8⁺ T cells. It has also been shown that NSCLC with high tumor-infiltrating lymphocytes have better outcomes after resection and in the metastatic setting (⁹⁹), suggesting lung cancers as good candidates for the investigational use of immunotherapies.

Previous trials focused on cancer vaccines in NSCLC, which were shown to induce tumor-specific immune responses but failed to improve survival (¹⁰⁰). The development of immune checkpoint inhibitors has renewed the interest in immunotherapy approaches for NSCLC (Table 18-18) (^{101,102,103,104,105,106}).

The CTLA4 receptor on T cells interacts with the B7-1 and B7-2 proteins on antigen-presenting cells and downregulates the T-cell response to tumor-related antigens. There are two anti-CTLA4 antibodies currently approved for the treatment of melanoma: ipilimumab and tremelimumab. In a randomized phase II trial for NSCLC patients (¹⁰¹), the addition of ipilimumab during cycles 3 to 6 of first-line chemotherapy with carboplatin and paclitaxel was associated with better response rates and a nonsignificant increase in OS. There are multiple trials under way to investigate how best to use these agents in patients with metastatic disease (eg, alone or in combination, timing in combinations, incorporation of molecular markers for selection), such as the randomized trial with carboplatin/paclitaxel with or without ipilimumab for patients with squamous histology (NCT01285609).

PD-1 is another receptor expressed on T cells that, upon interaction with its ligand, PD-L1, suppresses immune cell activation. Expression of PD-L1 on antigen-presenting cells and on tumor cells is believed to be a key player in local tumor microenvironment-mediated immunosuppression. Approximately 35% to 50% of stage IV NSCLC patients have moderate to high staining of PD-1 or PD-L1 depending on the methodology for staining and scoring.

Two anti-PD-1 antibodies have been studied in phase I and II trials of NSCLC: nivolumab and pembrolizumab (see Table 18-18). In general, the response rates have been 15% to 25% both in the first- and second-line settings, and the OS has been around 8 to 10 months, with no difference between adenocarcinoma and SCC. However, some responders have prolonged disease control, sometimes for more than 12 months. No predictor of response has been validated yet, but it appears that tumors with higher expression of PD-L1 (¹⁰⁵) and those with PD-L1–positive tumor-infiltrating lymphocytes (¹⁰⁶) have better outcomes when treated with anti-PD-1/PD-L1 agents. There are also data emerging from several groups on regulation of the dynamic PD-L1 expression of tumor cells, including the effect of epithelial-to-mesenchymal transition to drive CD8⁺ T-cell suppression through PD-L1 activation (¹⁰⁷).

The use of anti-PD-1/anti-PD-L1 therapy currently remains investigational, but the pending results of phase II and III trials of pembrolizumab and nivolumab in metastatic NSCLC could substantially change the landscape of treatments options in the near future.

Other Therapies for Advanced Disease and Management of Oligometastatic Disease

Radiotherapy and surgery may be helpful in managing selected patients with stage IV NSCLC. Radiotherapy can be used to palliate pain or to manage hemoptysis and obstructive symptoms in large primary tumors.

In patients with solitary brain metastasis as their only site of metastatic disease, resection or stereotactic radiation of the brain lesion followed by definitive therapy to the primary tumor (resection or radiation) is associated with significant improvement in median OS (26 months vs 13 months in patients who do not undergo therapy to the primary tumor), and 5-year survival rates are 34% versus 0% (¹⁰⁸).

In patients with solitary adrenal metastasis, adrenalectomy associated with definitive therapy to the primary tumor also has good outcomes, with a median OS of 26 months and 5-year survival rates of 30%, which has been consistent in multiple studies (¹⁰⁹). Patients who develop isolated adrenal metastasis more than 6 months after the resection of the primary tumor are the ones with the most benefit.

Patients with oligometastatic disease (one to five lesions) should undergo extensive workup including PET-CT scan and brain MRI. They can then be classified into three subgroups (¹¹⁰):

• Low risk: Development of oligometastatic disease more than 2 months after resection of the primary tumor (5-year OS, 47.8%).

• Intermediate risk: Synchronous metastases (at presentation or within 2 months of the resection of the primary) and no lymph node involvement (N0) disease (5-year OS, 36.2%).

• High risk: Synchronous metastases and N1/N2 disease (5-year OS, 13.8%).

There is currently one randomized trial ongoing evaluating the effect of definitive treatment (surgery or radiation) for oligometastatic disease (NCT01725165). However, observational studies have shown that, in patients who received two cycles of systemic therapy and did not have progression, definitive therapy to oligometastasis was associated with improvements in OS (27 vs 13 months; HR, 0.37; 95% confidence interval [CI], 0.2-0.7; P < .01) (¹¹¹). There are also data suggesting that, for patients with oligometastatic disease receiving chemotherapy, radiation therapy to the primary tumor is associated with improved OS (HR, 0.65; 95% CI, 0.43-0.93; P = .019) (¹¹²).

The treatment for NSCLC, especially in the metastatic setting, has witnessed remarkably rapid change over the last 10 years. This change has been driven primarily by the recognition of the significant molecular heterogeneity of the disease and identification of targetable genetic changes defining the many subgroups. We expect that this trend will continue to facilitate the successful application of targeted agents, especially for the squamous cell histology where there are still no approved targeted agents. Examples of molecular alterations under investigation are BRAF, MEK, MET, mTOR, and HER2, as well as new approaches to target KRAS mutant disease. There is also continued research on new-generation TKIs able to overcome acquired resistance to erlotinib and crizotinib. Because the molecular profile of tumors is dynamic, with variability at each tumor site and varying over time at any one site, the need for repeat biopsies has become increasingly accepted and therapeutic options are more frequently based on the changing genetics of an individual patient’s tumor. In the future, this personalized evaluation of mutations in circulating tumor cells or circulating cell-free tumor DNA might be an important tool in the process.

For patients with early-stage disease, large centralized trials like ALCHEMIST have been developed to evaluate molecular testing and the application of targeted agents in the adjuvant setting. The hope is to achieve more cures and/or produce longer periods of disease-free recurrence in this group of patients who have undergone curative-intent therapy.

Certainly the future of oncology and lung cancer, in particular, will be substantially impacted by the incorporation of immunotherapies. However, it is difficult to predict how this landscape might emerge as the currently available agents and new agents are developed. The investigation of single-agent immune checkpoint molecule (PD-1 and CTLA4) inhibitors in the refractory metastatic setting is moving very rapidly, with the expectation that one or more of the PD-1/PD-L1 axis inhibitors will be approved soon. Research is also focusing on evaluating combination strategies and on moving their use to the frontline and adjuvant settings. As with all other therapies, one particularly challenging aspect of applying immunotherapies to the clinic is the determination of which biomarkers are useful to select patients more or less likely to respond and to monitor response. However, given the complexity of the immune system and our limited experience in developing drugs of this type, the technical and conceptual challenges of marker development may lag behind the efficacy trials. It is hard to understate the current excitement around the immunotherapy agents, and it will be intriguing to see how they finally find their proper role in the treatment of patients with NSCLC.

Non–small cell lung cancer remains one of the most devastating illnesses in the United States and worldwide in terms of incidence and overall mortality rates. Primary prevention by smoking cessation and secondary prevention with screening have managed to reduce the incidence of NSCLC and NSCLC-related deaths in some areas of the world, but the incidence of lung cancers not related to smoking is still rising. Surgery and chemoradiation offer a potential for long-term survival in patients with localized disease, but metastatic disease remains lethal. In recent years, the evolving understanding of the molecular pathology of NSCLC has produced effective targeted agents, with high response rates and low toxicity, but resistance is still an issue. The development of new targeted agents able to overcome resistance and the effective implementation of cancer immunotherapy have the potential to further improve outcomes for patients with NSCLC.