Carcinoma of the lung is responsible for roughly 160,000 deaths each year in the United States. This represents one-fourth of all deaths due to cancer and more than the number of deaths due to breast, colon, and prostate cancers combined.¹ Because early-stage lung tumors are often asymptomatic and, until recently, there has been no proven approach to radiographic screening, most patients are diagnosed with advanced-stage disease. Approximately 85% of cases are histologically classified as non-small-cell lung cancer (NSCLC), of which adenocarcinoma, squamous cell carcinoma, and large cell carcinoma are the primary subtypes. Small-cell lung cancer (SCLC) accounts for the remaining 15% of cases. The biology, staging, and treatment of SCLC differ substantially from NSCLC. Thus, these two groups are addressed in two separate sections.

Lung cancer is predominantly a disease of smokers, although some studies suggest the rate of NSCLC is increasing in never smokers.² Eighty-five percent of lung cancer occurs in active or former smokers, and an additional 5% of cases are estimated to occur as a consequence of passive exposure to tobacco smoke. Tobacco smoke causes an increased incidence of all four histologic types of lung cancer, although adenocarcinoma (particularly the adenocarcinoma in situ (AIS) variant) is also found in nonsmokers. Other risk factors for lung cancer include exposure to asbestos or radon. Familial factors such as polymorphisms in carcinogen-metabolizing hepatic enzyme systems may also play a role in determining an individual’s propensity to develop lung cancer.³

Numerous genetic changes have been associated with lung tumors. Most common among these include activation or overexpression of the myc family of oncogenes in SCLC and NSCLC and of the KRAS oncogene in NSCLC, particularly adenocarcinoma. Inactivation or deletion of the p53 and retinoblastoma tumor suppressor genes and a tumor suppressor gene on chromosome 3p (the FHIT gene) have been found in 50% to 90% of patients with SCLC. Abnormalities of p53 and 3p have been associated with 50% to 70% of cases of NSCLC. The KRAS mutation is more frequently found in smokers, those with
adenocarcinoma, and those with poorly differentiated tumors. It is also associated with poor prognosis.⁴,⁵,⁶

Epidermal growth factor receptor (EGFR) is expressed or overexpressed in the majority of NSCLC tumors. Binding of ligand to the extracellular domain of EGFR causes receptor dimerization, which in turn activates an intracellular tyrosine kinase domain.⁷ Autophosphorylation of the receptor induces a cascade of signal transduction events leading to cell proliferation, inhibition of apoptosis, angiogenesis, and invasion, all resulting in tumor growth and spread. Tumors harboring activating EGFR gene mutations render the cancer highly dependent on EGFR for proliferation and survival. The most common activating mutations are found in exons 19 and 21, which result in in-frame deletions of amino acids 747 to 750 and L858R substitutions, respectively. Agents targeting mutated EGFR include tyrosine kinase inhibitors (TKIs), such as gefitinib,⁸ erlotinib,⁹ and afatinib.¹⁰ In NSCLC harboring EGFR gene mutation, these treatments often result in dramatic and sustained responses, with response rates exceeding 60% and median survival exceeding 2 years for stage IV cases. However, most patients often progress in about 9 months, and studies have shown that in about 50% of cases, this is due to a secondary mutation in exon 20, the T790M mutation.¹¹ Drugs that target this mutation are currently being developed and one has recently gained FDA approval.¹² KRAS and EGFR mutations are rarely found in the same tumor.¹³

Abnormalities in the anaplastic lymphoma kinase (ALK) gene have been identified in a subset of lung cancers. These gene rearrangements, which appear mutually exclusive with both EGFR and KRAS gene mutations, render cancers highly responsive to ALK inhibitors including crizotinib¹⁴ and ceritinib.¹⁵

Additional mutations found in smaller subsets (<2% to 3%) of NSCLC patients predict for variable sensitivity to targeted agents including BRAF V600E mutations (vemurafenib), MET amplification (crizotinib), ROS1 rearrangements (crizotinib), RET rearrangements (cabozantinib), and HER2 mutations (trastuzumab and afatinib).¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹

Three US randomized screening studies in the 1980s failed to detect an impact on mortality of screening high-risk patients with chest radiography or sputum cytology, although earlier-stage cancers were detected in the screened groups. Since then, however, low-dose spiral computed tomography (CT) has emerged as a new tool for lung cancer screening. Spiral CT is CT imaging in which only the pulmonary parenchyma is scanned, thus negating the use of intravenous contrast medium and the necessity of a physician having to be present. This type of scan can usually be done quickly (within one breath) and involves low doses of radiation. A large randomized controlled trial conducted by the National Cancer Institute (the National Lung Screening Trial [NLST]) involving over 50,000 participants demonstrated a 20%
reduction in lung cancer mortality with screening by low-dose CT compared to chest radiograph in high-risk individuals. The high-risk population that benefitted has been defined as being 55 to 74 years old, current or former smoker (if quit less than 15 years prior) with 30 or more pack-year smoking history.²² Disadvantages of screening, which need to be discussed with the patient, include the very high rate of false-positive scans (24%), with the need for frequent follow-up scans and/or invasive procedures. Other factors to be discussed include costs, risks of radiation exposure, impact on smoking cessation efforts, and the psychosocial ramifications of identifying radiographic abnormalities.

Until recently, the histologic subtype of NSCLC, while thought to influence the presentation and natural history of disease, did not affect patient management. Due to differences in both efficacy and safety, histologic designation now represents a primary consideration in treatment selection. For instance, some adenocarcinoma variants, such as AIS, which was formerly classified as bronchioloalveolar carcinoma,²³ have a predilection for younger, never-smoking women, and are frequently associated with EGFR gene mutations and a high likelihood of response to EGFR inhibitors. Pemetrexed, a multitargeted antifolate, has greater efficacy for the treatment of nonsquamous tumors, presumably due to higher thymidylate synthase levels in squamous cell cancers. Bevacizumab, a monoclonal antibody (MoAb) directed against vascular endothelial growth factor (VEGF), is contraindicated in patients with squamous cell tumors due to unacceptably high rates of life-threatening hemoptysis in early-phase clinical trials. (However, the anti-VEGF receptor MoAb ramucirumab is indicated for all NSCLC subtypes.) These histology-dependent safety and efficacy distinctions have highlighted the importance of accurate pathologic classification.

The prognosis and treatment of NSCLCs are dependent primarily on stage of disease at the time of diagnosis. Major changes in the staging of lung cancer were adopted in 2009. These changes are based on an analysis of 68,463 patients with NSCLC worldwide; by contrast, the previous (1997 and 2002) editions of the TNM classification of lung cancer were based on data from 5,319 patients in North America. The 2010 TNM staging classification is outlined in the AJCC Cancer Staging Manual, 7th edition.²⁴ Major changes include subclassification of T1 and T2 by tumor size, reclassification of additional nodule(s) in the same lobe or another ipsilateral lobe, and reclassification of malignant effusions as M1a. This reflects the similar prognosis and treatment (typically chemotherapy alone) of patients with malignant effusions and patients with distant
disease. As before, a pleural or pericardial effusion is generally considered malignant if it has any of the following characteristics: positive cytology, exudative, or hemorrhagic. Survival based on the 2010 staging classification ranges from 47% to 50% for stage I patients, 26% to 36% for stage II patients, 19% for stage IIIA patients, 7% for stage IIIB patients to 2% for stage IV patients.²⁵

The diagnosis of lung cancer is usually made by bronchial biopsy or percutaneous needle biopsy. A CT scan of the chest is necessary to evaluate the extent of the primary disease, mediastinal extension or lymphadenopathy, and the presence or absence of other parenchymal nodules in patients in whom surgical resection is a consideration. The upper abdomen is included to evaluate for hepatic or adrenal metastases. Nuclear bone scans should be obtained for the patient with bone pain or an elevated calcium or alkaline phosphatase level. Because the presence of mediastinal nodal metastases is a key factor in determining tumor resectability, lymph node sampling by mediastinoscopy, Chamberlain procedure (anterior mediastinotomy, which samples station 5 and 6 nodes not accessible by mediastinoscopy), and/or endobronchial ultrasound is recommended in most instances when there is not clear evidence of distant disease.

Positron emission tomography (PET), a metabolic imaging scan using fluorodeoxyglucose (FDG), is a useful staging modality. PET scans are more sensitive and specific than CT scans and could thus potentially save patients with advanced disease, either within or outside of the chest, from unnecessary invasive procedures. However, it is generally recommended that PET-positive mediastinal findings be confirmed pathologically since the scan can be falsely positive in inflammatory processes and falsely negative in lung tumors with low metabolic activity such as bronchioloalveolar carcinoma or carcinoid tumors. Furthermore, due to high background FDG uptake in the brain, PET-CT scans are generally not sufficient to evaluate for brain metastases, and a head magnetic resonance imaging (MRI) should be performed. PET scans are frequently performed in conjunction with CT imaging (PET-CT scans) to assess for metastatic disease, or guide the surgeon toward particular lymph nodes during mediastinoscopy. Randomized clinical trials have demonstrated that use of PET-CT scans decreases the total number of thoracotomies and number of futile thoracotomies performed. Population-based studies suggest that increasing use of PET-CT scans may have resulted in stage shifting.²⁶,²⁷

Pulmonary function testing is generally recommended before surgery and, if severe pulmonary disease is clinically apparent, before radiation therapy. Increased postoperative morbidity is associated with a predicted postoperative 1-second forced expiratory volume (FEV1) of less than 800 to 1,000 mL, a preoperative maximum voluntary ventilation less than 35% of predicted, a carbon
monoxide diffusing capacity (Dlco) less than 60% of predicted, and an arterial oxygen pressure of less than 60 mm Hg or a carbon dioxide pressure of more than 45 mm Hg.

Surgical resection is the mainstay of treatment for stage I NS-CLC, with cure rates of 60% to 80%. Anatomic resection such as lobectomy is considered superior to smaller procedures such as wedge resection. Exceptions may include smaller peripheral AIS nodules that spread by lepidic (airway) growth rather than hematogenous or lymphatic spread and may be adequately treated with more focal excision.²⁸ If not performed preoperatively, it is recommended that mediastinal lymph nodes be sampled at the time of resection to complete staging.

In patients with medical contraindications to surgery but with adequate pulmonary function, conventional fractionated radiotherapy (e.g., 6,000 cGy in 30 fractions of 200 cGy each) results in cure in about 20% of patients. Advances in imaging and radiation delivery have led to the use of stereotactic body radiation therapy (SBRT) for lung tumors. With this technology, radiation delivery to surrounding normal lung parenchyma is substantially less than that occurring with conventional radiation. Thus, it is possible to give much higher, “ablative” radiation doses over a small number of fractions (e.g., 20 Gy per fraction for three fractions). To date, SBRT in early-stage NSCLC can achieve 5-year local control rates of 85% to 90%.²⁹,³⁰,³¹,³²,³³ Clinical trials of stereotactic radiation for early-stage lung cancer in both medically operable and inoperable patients are ongoing.

The rationale for adjuvant chemotherapy in patients with early-stage lung cancer is based on the observation that distant metastases are the most common site of failure following potentially curative surgery. Interest in this treatment strategy grew after a 1995 meta-analysis of over 4,300 patients, in which those who received cisplatin-based regimens had a survival benefit nearing statistical significance (p = 0.07).³⁴ Since then, a number of randomized clinical trials have evaluated the role of adjuvant chemotherapy following resection of early-stage NSCLC (see Table 7.1). In a pooled analysis of five of these trials, the hazard ratio (HR) for death was 0.89 (95% confidence interval [CI], 0.82 to 0.96; p = 0.005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. Importantly, the benefit of chemotherapy varied considerably by stage. For stage IA NSCLC, adjuvant chemotherapy resulted in a trend toward worse survival (HR for death 1.40; 95% CI, 0.95 to 2.06). For stage IB disease, the HR was 0.93 (95% CI, 0.78 to 1.10), whereas the HR rate was 0.83 (95% CI, 0.73 to 0.95) for stage II disease.³⁵ Similarly, in the CALGB 9633 trial of patients with stage IB disease randomized

to surgery alone or surgery followed by carboplatin-paclitaxel, only those patients with tumors of more than or equal to 4 cm demonstrated a significant survival difference in favor of adjuvant chemotherapy (HR, 0.69; 95% CI, 0.48 to 0.99; p = 0.04).³⁶ Given these data, it seems reasonable to discuss the option of adjuvant platinum-based doublet chemotherapy with good performance status (PS) patients with completely resected stage IB disease, particularly those with tumors of more than or equal to 4 cm. Additional studies are needed for stage IA disease before adjuvant therapy can be routinely recommended for this group of patients. Recently, a meta-analysis of individual patient data for more than 11,000 patients across 47 different trials found a survival benefit (approximately 4% at 5 years) for adjuvant chemotherapy regardless of whether this was in the context of radiation or not.³⁷

Patients with resected stage I NSCLC are also at high risk for the development of second lung cancers (about 2% to 3% per year). To date, however, secondary prevention efforts have proven unsuccessful. Neither vitamin A nor its derivatives, β-carotene or cis-retinoic acid, have been found to have any benefit in chemoprevention, and contrary to predictions, they may even be deleterious.³⁸ A recent phase III trial of selenium for secondary prevention was closed early when an interim analysis showed no benefit.³⁹

Surgical resection is a standard component of the treatment of stage II NSCLC. Patients with peripheral chest wall invasion (T3N0) should undergo resection of the involved ribs and underlying lung. Chest wall defects are then repaired with chest wall musculature or surgical mesh and methylmethacrylate. Postoperative radiotherapy is often given. Five-year survival rates as high as 50% have been reported.

The role of adjuvant chemotherapy for resected stage II NS-CLC is clearer than for stage I disease. In the Adjuvant Navelbine International Trialist Association (ANITA) trial,⁴⁰ patients with stages IB to IIIA NSCLC were randomized to surgery alone versus surgery followed by four cycles of cisplatin plus vinorelbine. Overall survival (OS) was significantly improved at 5 years (51% vs. 43%), although the survival benefit was restricted to patients with stages II and IIIA disease. In the pooled analysis of cisplatin-based adjuvant chemotherapy trials, patients with stage II NSCLC had a significant survival benefit (HR 0.83; 95% CI, 0.73 to 0.95). Accordingly, adjuvant chemotherapy is generally recommended following complete resection of stage II NSCLC.

Issues in the use of adjuvant therapy have also included identification of the most appropriate drugs. Given the toxicity and tolerability of cisplatin, there was an interest in substituting carboplatin for adjuvant treatment of NSCLC. On the basis
of available data, it is generally accepted that carboplatin should not routinely be used in lieu of cisplatin, but can be considered in patients who would be considered high risk for cisplatin-associated toxicities.

The International Adjuvant Lung Cancer, BR10, and ANITA trials all used vinca alkaloids in combination with cisplatin.⁴⁰,⁴¹,⁴² Given that there is no major difference in chemotherapy doublets in advanced disease, many clinicians have extrapolated that data in advanced disease to earlier-stage disease and are using other “third-generation” drugs in combination with cisplatin (such as pemetrexed, docetaxel, and gemcitabine), albeit without level I data.

Neoadjuvant (preoperative) chemotherapy has also been studied for resectable NSCLC. Compared to adjuvant chemotherapy, it offers the potential advantages of reducing tumor volume before surgery (which might simplify resection), demonstrating in vivo chemosensitivity, addressing micrometastatic disease earlier, and possibly being better tolerated. Although phase III trials comparing neoadjuvant platinum-based regimens with surgery alone have demonstrated the feasibility of this approach, there is no level I data showing a benefit for neoadjuvant compared to adjuvant therapy. In addition, patients who undergo a pneumonectomy following induction chemoradiation have a higher incidence of treatment-related deaths.⁴³

Pancoast tumors are upper lobe tumors that adjoin the brachial plexus and are frequently associated with Horner syndrome or shoulder and arm pain; the latter is due to rib destruction, involvement of the C8 or T1 nerve roots, or both. These tumors are often treated with preoperative chemoradiation, surgery, and then additional postoperative chemotherapy. With this approach, the preoperative chemoradiation facilitates resection in an area where neural structures might otherwise limit surgical options. Five-year survival rates range from 25% to 50%.⁴⁴

Treatment of locally advanced NSCLC is one of the most controversial issues in the management of lung cancer. Interpretation of the results of clinical trials involving patients with locally advanced disease has been clouded by a number of issues including changing diagnostic techniques, different staging systems, and heterogeneous patient populations that may have disease that ranges from “nonbulky” stage IIIA (clinical N1 nodes, with microscopic N2 nodes discovered only at the time of surgery or mediastinoscopy) to “bulky” N2 nodes (enlarged adenopathy clearly visible on chest radiographs or multiple nodal level involvement) to clearly inoperable stage IIIB disease.

The optimal treatment for nonbulky stage IIIA generally consists of a local approach (surgery or radiation therapy) plus a systemic treatment (chemotherapy). Current investigational efforts are directed at identifying the optimal combined-modality approach. Possibilities include surgery followed by adjuvant chemotherapy, preoperative (neoadjuvant) chemotherapy followed by surgery, chemotherapy plus radiation therapy (either concurrent or sequential), or a trimodality approach.

The potential benefit of adding surgery to combined chemoradiation for stage IIIA NSCLC has been evaluated in a 2009 randomized phase III intergroup trial.⁴³ In this study, 396 patients with stage T1-3N2M0 NSCLC were randomized to concurrent chemoradiation (45 Gy) with cisplatin-etoposide followed by either surgical resection or continuation of radiation therapy to 61 Gy total, followed by additional cycles of chemotherapy. Although progression-free survival (PFS) was significantly longer in the surgery arm (12.8 vs. 10.5 months; p = 0.02), there was no significant difference in OS (23.6 vs. 22.2 months; p = 0.24). There were greater treatment-related mortalities in the surgery arm as compared to the chemoradiation alone arm (8% vs. 2%), particularly for patients undergoing a pneumonectomy.

Several studies have shown, in subset analyses, that those patients receiving neoadjuvant therapy who subsequently have their N2 nodes “cleared” with preoperative therapy do better than those who do not. As of this writing, there is no level I evidence to recommend neoadjuvant chemotherapy over adjuvant chemotherapy, although several theoretical reasons for doing so include the fact that patients are more likely to tolerate preoperative chemotherapy over postoperative chemotherapy.

Occasionally, despite preoperative staging, patients thought to have stage I or II disease are found to have N2 nodal involvement at the time of surgery. For these stage III patients, postoperative radiation therapy (PORT; 50 to 54 Gy) may be considered for fit patients, preferably after completion of adjuvant chemotherapy, based on retrospective and nonrandomized studies demonstrating benefit. Currently, PORT is not recommended for patients with less than N2 nodal involvement.⁴⁵

Bulky stages IIIA and IIIB tumors are generally considered unresectable, with treatment consisting of combined chemoradiation in medically fit patients.

1) Chemotherapy plus radiation therapy. Chemotherapy plus radiotherapy is the treatment of choice for patients with
bulky or inoperable stage IIIA or IIIB disease. Numerous randomized studies have demonstrated an improvement in median and long-term survival with chemotherapy plus radiation therapy versus radiation therapy alone. Active areas of investigation include choice of chemotherapy, fractionation, and treatment fields.

A phase III Japanese trial reported a 3-month survival advantage with concurrent chemoradiation over a sequential approach.⁴⁶ A randomized Radiation Therapy Oncology Group trial demonstrated an OS benefit for concurrent cisplatin and vinblastine with daily radiation over sequential chemoradiation, albeit with more acute toxicities, making concurrent chemoradiation therapy the treatment of choice for good PS patients.⁴⁷ Chemotherapy can be given in full “systemic” doses with radiotherapy, in weekly “radiosensitizing” doses, or a combination of both. One of the most commonly used chemotherapy regimens for stage III NSCLC is carboplatin in combination with paclitaxel (Table 7.2). Although single-agent weekly carboplatin alone has not resulted in a survival benefit when given with radiotherapy, weekly doses of paclitaxel at 50 mg/m² and carboplatin area under the curve (AUC) 2 with concurrent radiation confer a similar benefit to concurrent radiation with cisplatin and vinblastine in randomized phase
II studies.⁴⁸,⁴⁹ Generally, concurrent therapy is followed by two cycles of full-dose carboplatin AUC 6 plus paclitaxel at 200 mg/m² every 21 days to treat micrometastatic disease. By contrast, with concurrent radiation therapy and commonly used cisplatin-etoposide chemotherapy regimens, drug doses during radiation therapy are considered “systemic” and may not require additional chemotherapy after radiation therapy is completed. No survival benefit has been shown for “consolidation” therapy, maintenance therapy with EGFR inhibitors, or radiotherapy doses higher than 6,000 cGy.⁵⁰,⁵¹,⁵²

Chemotherapy improves survival in patients with metastatic NS-CLC (about 10% 1-year survival rate in untreated patients vs. 30% to 35% 1-year survival rate with treatment). The principal factors predicting response to chemotherapy and survival are PS and extent of disease. Patients with a poor PS (Eastern Cooperative Oncology Group [ECOG] PS of 2 to 4) are less likely to respond to treatment and will tolerate the therapy poorly, although recent retrospective subset analysis has suggested that PS2 patients may also enjoy a modest benefit in survival with treatment. Favorable prognostic factors include female sex, absence of bone or liver metastases, and absence of weight loss.⁵³ Total radiographic burden of disease has also been associated with survival.⁵⁴

Systemic treatment for patients with metastatic NSCLC and adequate PS (ECOG, 0 to 1) generally includes platinum-based doublet chemotherapy. A meta-analysis of large randomized trials indicated that there is a small but significant survival advantage with platinum-based therapy compared with best supportive care.³⁴ Whereas best supportive care resulted in median survival rates of 4 to 5 months and 1-year survival rates of 5% to 10%, current third-generation regimens of platinums combined with paclitaxel (and albumin-bound paclitaxel) and docetaxel, gemcitabine, vinorelbine, and pemetrexed have yielded median survivals of 8 to 9 months and 1-year survivals of 35% to 40%. In addition, randomized studies have shown an improvement in symptoms and quality of life compared with patients treated with best supportive care.⁵⁵,⁵⁶,⁵⁷,⁵⁸

The common chemotherapy regimens for advanced NSCLC are shown in Table 7.3. Historically, randomized studies have failed to show a major advantage of one new doublet regimen over another.⁵⁵,⁵⁷,⁵⁹ More recently, however, certain agents have been restricted to specific histologies. For instance, pemetrexed, a multitargeted antifolate, has greater efficacy for the

treatment of nonsquamous tumors,⁵⁶ presumably due to higher thymidylate synthase levels in squamous cell cancers; pemetrexed is approved only for nonsquamous NSCLC in all settings (first-line, maintenance, and second-line). Bevacizumab, a MoAb directed against VEGF, is contraindicated in patients with squamous cell tumors due to unacceptably high rates of life-threatening hemoptysis in early-phase clinical trials.⁶⁰