Lung cancer is a major public health problem. In the United States, 31% of cancer deaths in men and 26% of cancer deaths in women are secondary to lung cancer. The overall prognosis remains poor. Just over one in eight lung cancer patients will be living 5 years after their diagnosis. Most cases of lung cancer would be prevented if people did not smoke tobacco products. Unfortunately, data on worldwide tobacco consumption suggest that lung cancer will remain an epidemic for years to come. Recent advances in early detection and targeted therapies have changed evaluation and treatment paradigms, leading to a meaningful impact on patient outcomes.
In 2012, it is estimated that 226,160 people in the United States will be diagnosed with lung cancer, including 116,470 men and 109,690 women. Lung cancer is the second most frequently diagnosed cancer in both men and women; prostate and breast cancers are the most frequent in men and women, respectively (Figure 1). The incidence of lung cancer peaked in men in 1984 (86.5/100,000 men) and has subsequently been declining (69.1/100,000 men in 1997). In women, the incidence increased during the 1990s, with a leveling off toward the end of the decade (43.1/100,000 women). These trends parallel the smoking patterns of these two groups.
Lung cancer is the leading cause of cancer-related mortality in both men and women. It surpassed colon cancer in the early 1950s in men and breast cancer in the late 1980s in women. Mortality rates in men declined significantly in the 1990s, whereas a slow increase occurred in women. These rates again parallel the smoking patterns of these two groups (Figures 2 and 3). There were an estimated 158,590 deaths in 2008 in the United States secondary to lung cancer. This means that lung cancer accounts for approximately 29% of all cancer deaths. In men, lung cancer becomes the leading cause of cancer-related mortality from age 40 onward. In women, lung cancer surpasses breast cancer in those 60 years and older.1
About 85% to 90% of patients with lung cancer have had direct exposure to tobacco. Many tobacco-related carcinogens have been identified; the two major classes are the N-nitrosamines and polycyclic aromatic hydrocarbons. A dose-response relation exists between the degree of exposure to cigarette smoke and the development of lung cancer. The age at which smoking began, the number of cigarettes smoked per day, and the duration of smoking all influence the likelihood of developing lung cancer. Also, the intensity of smoking, the depth of inhalation, and the composition of the cigarette influence the risk.
All cell types of lung cancer are associated with smoking. The strongest associations are with small cell and squamous cell carcinomas. The risk of developing lung cancer decreases over time after smoking cessation, although it never reaches that of a lifelong nonsmoker. Cigar smoking is also an independent risk factor for developing lung cancer.2
Exposure to side stream smoke, or passive smoking, might lead to an increased risk of lung cancer. The risk varies with the level and duration of exposure. It is generally a much lower risk than is active smoking.3 Some suggest the risk is negligible.4
Many other risk factors have been identified (Box 1). Occupational agents are known to act as lung cancer carcinogens. Arsenic, asbestos, and chromium have the highest risk. An estimated 2% to 9% of lung cancers are related to occupational exposures. An inherited genetic predisposition has epidemiologic support as a risk factor, but the mechanisms are theoretical at this time.5 Women appear to have a higher baseline risk of developing lung cancer as well as a greater susceptibility to the effects of smoking. Differences in the metabolism of tobacco-related carcinogens and their metabolites or an effect of hormone differences are believed to account for the increased susceptibility.6
|Box 1: Lung Cancer Risk Factors|
|Tobacco Smoke Exposure|
|Occupational and Environmental Exposures|
|Polycyclic aromatic hydrocarbons|
|Chronic obstructive pulmonary disease|
Dietary factors can modify risks. Higher consumption of fruits and vegetables is associated with a reduced lung cancer risk, and an increased dietary fat intake might lead to a higher risk. Supplementation with vitamins A and E, and beta carotene has not positively influenced risk.7
Chronic obstructive pulmonary disease is an independent risk factor. This risk increases as the forced expiratory volume in 1 second (FEV1) decreases.8,9
An accurate prediction may help motivate smoking cessation, tailor early detection strategies, and identify patients to enroll in chemoprevention trials. There are many lung cancer risk prediction models proposed. The most recent, from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, has been shown to discriminate between high and low-risk patients with reasonable accuracy.10 Risk prediction models including biomarkers and genetic polymorphisms are being studied.11
Pathologic features, visible on light microscopy, are used to categorize lung cancers. Lung cancers are divided into two major groups, small cell and nonâ€“small cell. The nonâ€“small cell cancer category consists of adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and variants (Figure 4). Since the 1980s, the proportions of lung cancers that are adenocarcinomas and squamous cell carcinomas have changed. In North America, approximately 40% of all lung cancers are adenocarcinomas, and 20% to 25% are squamous cell. These figures were reversed in the past. The increased incidence of lung cancer in women (who are more likely to have adenocarcinomas) and changes in smoking habits are believed to account for this change.
Dividing lung cancer into small and non-small cell groups is no longer sufficient for clinical purposes. The current standard of care for advanced nonâ€“small cell lung carcinoma is to determine the chemotherapies to use on the basis of precise histologic subtype. In advanced, non-squamous cell carcinoma, molecular characterization for epidermal growth factor receptor (EGFR) mutations and/or anaplastic lymphoma kinase (ALK) alterations also helps to guide treatment decisions.
The pathophysiology of lung cancer development is complex and incompletely understood. The genes influenced in the pathogenesis of lung cancer produce proteins involved in cell growth and differentiation, cell cycle processes, apoptosis, angiogenesis, tumor progression, and immune regulation. Unveiling these mechanisms should translate into novel means of risk stratification, prevention, early detection, and therapy.
Signs and Symptoms
The clinical manifestations of lung cancer result from the effects of local growth of the tumor, regional growth or spread through the lymphatic system, hematogenous distant metastatic spread, and remote paraneoplastic effects from tumor products or immune cross-reaction with tumor antigens (Box 2).
Box 2: Lung Cancer Manifestations
|Pericardial or pleural effusions|
|Superior vena cava syndrome|
|Mental status change|
|Skin or soft tissue mass|
|Tumor necrosis factor (cachexia)|
|Cerebellar degeneration; DIC, disseminated intravascular coagulation; SIADH, secretion of inappropriate diuretic hormone.|
Local growth in a central location can cause cough, hemoptysis, or features of large-airway obstruction. Peripheral growth can also cause cough and dyspnea. If the pleura or chest wall becomes involved, pain can occur. Regional growth can lead to esophageal compression (dysphagia), recurrent laryngeal nerve paralysis (hoarseness), phrenic nerve paralysis with an elevated hemidiaphragm (dyspnea), and sympathetic nerve paralysis leading to Horner's syndrome (ptosis, miosis, anhidrosis, and enophthalmos). Apical growth can lead to Pancoast's syndrome, with shoulder pain radiating in an ulnar distribution. The superior vena cava can become obstructed and the heart and pericardium can become involved. Lymphatic obstruction and spread can lead to dyspnea, hypoxia, and pleural effusions.
Distant metastatic disease can affect most organs. Neurologic symptoms can suggest brain metastases or spinal cord compression, and pain could indicate bone metastases. Laboratory abnormalities can point to bone marrow or liver involvement. Imaging might detect adrenal involvement.
Paraneoplastic syndromes can occur before the primary tumor appears and thus can be the first sign of disease or an indication of tumor recurrence. Paraneoplastic endocrine syndromes occur when the tumor produces hormones. The three most common are ectopic Cushing's syndrome, the syndrome of inappropriate antidiuretic hormone (SIADH), and humoral hypercalcemia of malignancy. Ectopic Cushing's syndrome occurs in 2% to 10% of patients with small cell carcinoma. The clinical manifestations are less prominent than in Cushing's disease; biochemical abnormalities predominate, whereas the physical changes are less prominent. The SIADH is also more common in small cell carcinoma, occurring in 7% to 11% of patients. The manifestations of hyponatremia (mental status changes, lethargy, or seizures) are often absent despite very low sodium levels, because the rate of decline is typically prolonged. Humoral hypercalcemia of malignancy, resulting from the production of parathyroid hormone-related protein by the tumor, is most commonly associated with squamous cell carcinoma. Fatigue, mental status changes, weakness, gastrointestinal symptoms, polyuria, and electrocardiogram changes may occur.
Paraneoplastic neurologic syndromes affect all parts of the nervous system. An immune response to tumor antigens that cross-react with common antigens expressed in the nervous system seems to take place. This leads to manifestations that vary depending on where in the nervous system these antigens are expressed. Paraneoplastic limbic encephalitis is characterized by mood and behavior changes, memory problems, and seizures; paraneoplastic cerebellar degeneration manifests with ataxia, nystagmus, dysarthria, and diplopia; and paraneoplastic opsoclonus-myoclonus manifests with involuntary eye movements, myoclonus, truncal ataxia, dysarthria, and encephalopathy. Each of these is more common with small cell carcinoma, can occur in the presence of anti-Hu antibodies, and can occur as part of a more diffuse anti-Hu syndrome (the encephalomyelitis and subacute sensory neuropathy syndrome).
Other paraneoplastic neurologic syndromes include cancer-associated retinopathy and the Lambert-Eaton myasthenic syndrome. In cancer-associated retinopathy (most common with small cell carcinoma), rapid vision loss, ring scotomata, photosensitivity, night blindness, and color vision loss can occur in association with autoantibodies directed against retinal proteins. Lambert-Eaton myasthenic syndrome is the most common of the neurologic paraneoplastic syndromes and is present in 3% of small cell carcinomas. Proximal muscle weakness (which might improve with exercise) is most prominent in the lower extremities, and autonomic features predominate. Autoantibodies directed against P/Q type voltage-gated calcium channels are believed to be responsible.
Other paraneoplastic syndromes include skeletal and connective tissue syndromes (clubbing, hypertrophic pulmonary osteoarthropathy), coagulation and hematologic disorders, cutaneous and renal manifestations, and systemic symptoms (anorexia, cachexia, and weight loss).12
Approximately 85% of patients with lung cancer are symptomatic at presentation. In the remainder, lung cancer is detected by radiographic evaluation initiated for an unrelated problem. This proportion might change in the future with the development of lung cancer screening programs. Chest radiography and computed tomography (CT) are performed at most patients' initial evaluation. Clinical and radiographic features of the presentation dictate further evaluation.
Clinical features that suggest malignancy on initial evaluation include older age, current or past history of tobacco abuse, hemoptysis, and the presence of a previous malignancy. Radiographic features suggesting malignancy include the absence of a benign pattern of calcification in the detected lesion, a nodule or mass that is growing, a nodule with a spiculated or lobulated border, a larger lesion (>3 cm is considered malignant unless proven otherwise), and a cavitary lesion that is thick walled. Modern imaging techniques are used to alter the clinical probability of malignancy and hence influence biopsy decisions. Positron emission tomography (PET) using 18F fluorodeoxyglucose is the most-studied ancillary imaging technique. It has a sensitivity of 97% and a specificity of 78% as used in clinical practice.13 Single-photon emission CT and lung nodule enhancement with contrast-enhanced CT are less well established.
The detection of lung nodules (<3cm) is likely to increase with CT based screening for lung cancer. The probability of malignancy in a solid lung nodule is related to patient age, risk factors and radiographic features (size, border, calcification, density, growth and ground glass appearance).14,15 Solid nodules that have low probability for malignancy will generally be followed with serial imaging. Indeterminate nodules need a decision between observation, further characterization, biopsy or resection. Serial imaging is usually appropriate for a solid nodule smaller than 1 cm given the low probability for malignancy and absence of accurate adjuvant testing. A solid nodule with an intermediate probability for malignancy that is 1 cm or larger may benefit from further characterization with PET imaging. Solid nodules that show clear evidence of malignant growth, strong PET avidity, or have an otherwise very high probability of malignancy, should be resected in those well enough to tolerate surgery.16â€“18 Recommendations on how to proceed once a lung nodule is detected are available and will be further discussed elsewhere.19 Patients are also increasingly being detected with ground glass nodules (GGN). These are defined as a focal, hazy lung opacity on CT, that have preserved bronchial and vascular markings. A GGN may be seen in different contexts such as pneumonia and interstitial lung disease. However, a persistent GGN may represent a slow growing malignancy, specifically an adenocarcinoma. A pure GGN ≤10mm in diameter has a 25% chance of being an adenocarcinoma in situ (AIS) and less than 5% chance of being an invasive adenocarcinoma. A semisolid GGN (part ground glass and part solid) has approximately a 50% chance of being AIS and 25% chance of being adenocarcinoma if ≤10 mm. The risk of being and adenocarcinoma increases to 50% if >10 mm.20â€“22 A PET scan is usually not helpful to evaluate GGNs as the nodule often has low metabolic activity and thus may not be PET avid.23,24 Even a GGN that has been stable for over 2 years needs to be followed with imaging, or may need additional work-up if the lesion is highly suspicious for malignancy. Growth of the GGN, the development of a solid component, or growth of an existing solid component are all highly related to the presence of malignancy.
Ultimately, tissue needs to be obtained to confirm the diagnosis of lung cancer. Due to advances in the treatment of non-small cell cancer, appropriate and sufficient tumor specimens are required to allow accurate histologic subtyping and molecular characterization of the cancer. Flexible bronchoscopy and transthoracic needle biopsy are the invasive, nonsurgical approaches used to obtain tissue. If they fail or are deemed unnecessary, a surgical approach is used.
Flexible bronchoscopy has a high diagnostic yield for endoscopically visible lesions. The addition of endobronchial needle aspiration to conventional sampling techniques (washing, brushing, and endobronchial biopsy) improves this yield. The diagnostic yield from peripheral lesions is lower. Conventional sampling techniques and peripheral transbronchial needle aspiration complement each other. Factors that influence the diagnostic yield of flexible bronchoscopy for peripheral lesions include the size of the lesion, its location, and a bronchus sign on CT. Several new bronchoscopic technologies have improved the yield of biopsies for the diagnosis of peripheral nodules and have become the standard of care in large centers. They include electromagnetic navigation, virtual bronchoscopy, radial and convex endobronchial ultrasound, the use of an ultrathin bronchoscope, and guide sheath. These guided bronchoscopic techniques have a higher yield than traditional transbronchial biopsies, approaching that of transthoracic needle aspiration.25 The small samples obtained by bronchoscopic techniques appear to be adequate for histologic and molecular characterization of the tumor. Recommendations on how to handle and process the specimens are available.26,27
Transthoracic needle biopsy, using fluoroscopic or CT guidance, can be used to obtain tissue. The positive predictive value of this procedure is high, the negative predictive value is modest, and the rate of establishing a specific benign diagnosis is low. Smaller nodules in central locations have lower diagnostic rates. A higher rate of pneumothorax occurs with transthoracic needle biopsy; thus, flexible bronchoscopy is often attempted first.28
Accurately characterizing the anatomic extent of disease in a patient with lung cancer guides the treatment and prognosis. Nonâ€“small cell lung cancer is staged using the TNM system (T for extent of primary tumor, N for regional lymph node involvement, and M for metastasis) (Figure 5). The most recent revision to this staging system occurred in 2009 (Tables 1 and 2).29 Small cell lung cancer can also be staged with the TNM system. Traditionally, small cell carcinoma of the lung has been staged instead as limited or extensive disease. Limited-stage disease is present when the tumor is confined to a hemithorax (including ipsilateral mediastinal and supraclavicular lymph nodes), and thus can be encompassed in a radiotherapy port. Extensive-stage disease is present when the tumor extends beyond these boundaries. The overall condition of the patient should be considered as well as the anatomic extent of the tumor. The history and physical examination are important in guiding testing. The proper use of testing to stage a patient with lung cancer is addressed in a set of guidelines.30
Table 1: TNM Descriptors
|Primary Tumor (T)|
|T1||A small tumor that is not locally advanced or invasive||<3 cm in diameter; T1a ≤2 cm; T1b >2 cm ≤3 cm
Surrounded by lung or visceral pleura
Does not extend into the main bronchus
|T2||A larger tumor that is minimally advanced or invasive||>3 cm in diameter, ≤7 cm; T2a >3 cm ≤5 cm; T2b >5 cm ≤7 cm
Might invade the visceral pleura
Might extend into the main bronchus but remains >2 cm from the main carina
Might cause segmental or lobar atelectasis
|T3||Any size tumor that is locally advanced or invasive up to but not including the major intrathoracic structures||>7 cm or
Might involve the chest wall, diaphragm, mediastinal pleura, parietal pericardium, main bronchus within 2 cm of the main carina (not involving the main carina)
Might cause atelectasis of the entire lung
Presence of satellite tumor nodule(s) within the primary tumor lobe
|T4||Any size tumor that is advanced or invasive into the major intrathoracic structures||Any size
Invades the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, main carina
Presence of satellite tumor nodule(s) in a different ipsilateral tumor lobe
|Regional Lymph Node Involvement (N)|
|N1||Metastatic disease to nodes within the ipsilateral lung||Direct extension to intrapulmonary nodes
Metastasis to ipsilateral peribronchial and/or hilar nodes (nodal stations 10 through 14)
|N2||Metastatic disease to nodes beyond the ipsilateral lung but not contralateral to the primary tumor||Metastasis to the ipsilateral mediastinal and/or subcarinal nodes (nodal stations 1 through 9)|
|N3||Metastatic disease to nodes distant to those included in N2||Metastasis to contralateral mediastinal and/or hilar nodes ipsilateral or contralateral scalene and/or supraclavicular nodes|
|M0||Local or regional disease||No distant metastases|
|M1||Disseminated disease||m1a â€“ Presence of satellite tumor nodule(s) in contralateral lung malignant pleural or paranodal effusion
m1b â€“ Distant metastases present
Table 2: Nonâ€“Small Cell Lung Cancer Staging
|IA||T1a, b N0 M0|
|IB||T2a N0 M0|
|IIA||T1a, b N1 M0; T2a N1 M0; T2b N0 M0|
|IIB||T2b N1 M0, T3 N0 M0|
|IIIA||T3 N1 M0, T(1-3) N2 M0, T4N(0-1) M0|
|IIIB||T4 N(2-3) M0, T(1-4) N3 M0|
|IV||T(any) N(any) M1a, b|
Local and Regional Disease
The extent of local regional spread is best evaluated using CT of the chest extending to the upper abdomen to include the liver and adrenals. This should be ordered in all patients. The detection of parietal pleural, chest wall, and mediastinal invasion by the primary tumor is limited with CT. Magnetic resonance imaging (MRI) is not more accurate except in the setting of a Pancoast tumor. The sensitivity and specificity of CT for evaluating regional lymph node involvement are modest, commonly noted to be as low as 60% and rarely greater than 75%. PET has better test characteristics for staging mediastinal nodes, with sensitivities and specificities greater than 90% and 70% respectively.31 Integrated PET-CT scanning has better test characteristics than PET and CT used alone or in conjunction.32
Because imaging tests have false-positive and negative results, tissue confirmation of imaging findings is necessary. Bronchoscopy with transbronchial needle aspiration is useful to stage the mediastinum. Endobronchial and endoscopic ultrasound-guided needle sampling of the mediastinum has been reported to accurately stage the mediastinum.33 In large centers endosonographic guided sampling of the mediastinum has become the first step in staging the mediastinum.34 If sampling is negative, then mediastinoscopy, mediastinotomy, or thoracoscopy will confirm the nodal status. Debate exists about mediastinal sampling in the face of negative imaging. Despite the advances in imaging technology and sampling techniques, definitive surgical resection and mediastinal dissection remains the gold standard. The assigned clinical stage (determined by testing, including mediastinoscopy) is often lower than the pathologic staging (assigned after surgery).
The evaluation of metastatic disease also takes into consideration the history, physical examination, laboratory results (electrolytes, calcium, alkaline phosphatase, liver profile, and creatinine), and pathology results. All patients should have their chest CT scanning extended through the adrenals, because metastatic disease to these glands is usually asymptomatic, and often no alterations are seen in routine laboratory tests. A contrast-enhanced CT scan, ultrasound, or MRI of the liver should be performed if the chest CT, laboratory results, or clinical evaluation suggests metastatic disease to this organ.
Brain imaging should be performed if symptoms or signs of metastatic disease are present or when evaluating what appears to be stage IIIA or B disease. Brain imaging is often performed despite a lack of symptoms, in deference to the published guidelines. This is probably justifiable in small cell carcinoma, but it is debatable in other lung cancers. Many choose to use MR imaging of the brain because it has greater sensitivity to detect metastatic disease.
FDG-PET imaging is used to stage all but brain metastases. The rate of detection of distant metastases using PET is higher than previously used approaches.35,36
Coincident with the evaluation of the anatomic stage of disease should be an evaluation of the patient's performance status. This is important in determining an individual patient's ability to tolerate any proposed treatment. Like anatomic staging, performance status is a predictor of outcome. The two most commonly employed scales of performance status are the Zubrod scale and the Karnofsky scale. Although their definitions differ, their general principles are the same, with ratings based on activity level, independence in daily activities, and severity of symptoms.
Further evaluation of performance status may be necessary in those for whom surgical resection is indicated. To determine if a patient will tolerate lung resection surgery, reports of activity tolerance and pulmonary function testing are used. Although no one pulmonary function study or absolute cutoff has proved ideal, the FEV1 and diffusing capacity for carbon monoxide (DLCO) are the most commonly used measures.
Traditional preoperative cutoff values are being replaced by percent predicted postoperative values. Percent predicted postoperative values of FEV1 and DLCO can be calculated by multiplying the percent predicted preoperative value by the fraction of the total number of lung segments that will remain postoperatively. Alternatively, quantitative perfusion imaging can be used to guide the calculation. If the percent predicted postoperative FEV1 and DLCO are greater than 40%, then the patient should be able to tolerate surgery. Thus, as would be expected, a pneumonectomy requires better preoperative lung function than does a lobectomy.
When doubt remains, or when measured values and predictions seem discordant with a patient's reported activity tolerance, a cardiopulmonary exercise study should be performed. If the peak oxygen consumption is greater than 15 mL/kg/min, a lobectomy should be reasonably well tolerated. If it is less than 10 mL/kg/min, conventional surgery should not be performed. Values between these two should be considered on a case-by-case basis. Patients with marginal lung function might tolerate resection if a sublobar resection is possible (wedge resection or segmentectomy) or if resection can be combined with a lung volume reduction procedure.37,38
Screening for Lung Cancer
Given the high incidence of lung cancer, poor prognosis for advanced-stage lung cancer, and the high percentage of patients who present in an advanced stage, there has been great interest in early detection of lung cancer. In the 1970s and 1980s, chest x-ray with or without sputum cytology have been studied as screening tools. Despite considerable debate about the design and analysis of these randomized studies, they have been interpreted to show that screening chest x-ray, sputum examination, or both, did not have a beneficial effect on mortality from lung cancer. This was confirmed recently in a large multi-center randomized trial (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial).39 Thus standard chest radiography should not be used for lung cancer screening.
Recent efforts have centered on the use of low-dose CT scanning as a screening tool. The National Lung Screening Study is the first lung cancer screening study to show that screening for lung cancer with low-dose CT in a well-define high risk cohort, leads to a reduction in lung cancer mortality.40 This large trial of very high risk subjects compared annual low-dose chest CT to chest x-ray screening over 2 years. After 6 to 7 years of follow-up, lung cancer-associated mortality was found to be 20% lower in the CT screened group. The number needed to screen to prevent one death from lung cancer was approximately 320. The American College of Chest Physicians/American Society of Clinical Oncology now recommends annual low-dose CT scan screening for high-risk individuals (age 55 to 74 years with 30 pack-year history of smoking and current smoker or quit within past 15 years). However, debate over the cost-effectiveness of low-dose CT screening programs and the potential harms of screening are ongoing.
Treatments and Outcomes
|Box 3: Options for Treating Lung Cancer|
|Non–Small Cell Lung Cancer|
|Stages IA, IB, IIA, and IIB|
|Surgical resection is the standard of care if the patient is deemed able to tolerate it|
|Sublobar resection is used if the patient is unable to tolerate larger resection|
|Radiotherapy is used if the patient is unable to tolerate resection or chooses not to undergo resection|
|Adjuvant radiotherapy is possibly of use if incomplete resection was performed|
|Adjuvant platinum based chemotherapy for stage IIA, IIB and good performance status|
|Consider adjuvant chemotherapy in large stage IB (>4 cm) and good performance status|
|Concurrent chemoradiotherapy using a platinum-based regimen if performance status is reasonable|
|Induction chemoradiotherapy followed by resection in select patients, ideally as part of a study protocol|
|Concurrent chemoradiotherapy using a platinum-based regimen if performance status is reasonable|
|Induction chemoradiotherapy followed by resection in highly select patients, only as part of a study protocol|
|Platinum-based doublet chemotherapy regimen in patients with adequate performance status; Consider pemetrexted and bevacizumab in addition to platinum in non-squamous cell carcinoma|
|Targeted therapies in patients with positive molecular markers (EGFR activating mutation, EML4-ALK translocation)|
|Consider maintenance therapy in those who have a good response to 4 cycles of platinum-based doublet chemotherapy|
|Small Cell Lung Cancer|
|Combination chemotherapy with concurrent hyperfractionated radiotherapy if performance status is adequate|
|Prophylactic cranial radiation for those with a complete response to chemoradiotherapy|
|Combination chemotherapy if performance status is adequate|
|Prophylactic cranial radiation|
Table 3:Nonâ€“Small Cell Lung Cancer29
|Five-Year Survival (%)
Nonâ€“Small Cell Lung Cancer
Treatment of patients with lung cancer depends on the histology, tumor stage, and performance status. With the more recent personalized approach, specific histologic subtyping and molecular characterization also determine the choice of treatment. Surgical resection offers the best chance of cure for early-stage nonâ€“small cell lung cancer (stages I and II). Survival after resection in pathologic stage IA is 73% at 5 years, and in pathologic stage IB is 58%. Vascular invasion and tumor differentiation are other reported prognostic factors. There does not seem to be a difference in survival in patients who have adenocarcinoma and those who have squamous cell carcinoma. Recurrence usually involves distant metastases. Survival after resection in pathologic stage IIA is 46% at 5 years, and that in pathologic stage IIB is 36%. Patients with adenocarcinoma may have poorer survival rates than those with squamous cell carcinoma. Again, most recurrences involve distant metastases. Lobectomy and/or pneumonectomy are considered the standard approach. Sublobar resections in persons unable to tolerate lobectomy produce slightly lower survival rates, with higher rates of local recurrence when broadly applied.41 In an elderly population with small tumors (<2 cm), sublobar resection may perform as well as traditional anatomic resection. The benefits in this group includes the preservation of lung function and lower perioperative morbidity.42 However, lobectomy is still considered a superior method. The surgical approach may be open thoracotomy or video-assisted thoracoscopy (VATS). The latter is a minimally invasive procedure associated with lower morbidity. It is more likely to be performed in large, high volume academic centers.43,44 Robotic lung resection seems to have comparable results to VATS. It may be available in selected centers but it needs to be studied further.45
Traditional radiotherapy has been used with curative intent in early-stage nonâ€“small cell lung cancer, either in patients who cannot tolerate surgery or in those who elect not to undergo surgery. A 5-year survival rate in combined stages I and II disease approaches 15% with radiotherapy alone. There is a high rate of local recurrence, and most deaths are due to lung cancer. Advances in stereotactic body radiotherapy have provided an additional tool for treating this group. This tool gives us the ability to target the tumor with minimal effect on surrounding normal lung tissue. Impressive response rates are being reported.46,47
Adjuvant therapy has been attempted in early-stage nonâ€“ small cell lung cancer patients who have undergone surgical resection. Adjuvant radiotherapy might improve local control but it does not improve survival (with the possible exception of those who have undergone incomplete resection). Adjuvant chemotherapy has improved survival in select patients with completely resected stages IIA to IIIA lung cancers (and possibly large stage IB). It should be considered standard of care for this group in those well enough to tolerate it.48,49
Locally advanced tumors (T3) can often be completely resected, although central T3 tumors are somewhat less resectable than those involving the chest wall. The survival rates in T3 patients with chest-wall involvement and negative nodes approximates those of other stage IIB patients. The best results occur when complete resection is possible. With nodal involvement at any level, survival falls dramatically and thus is classified in a higher stage.50
When a Pancoast tumor is present, chemoradiotherapy followed by surgical resection are performed if possible. The invasion of local structures (rib, vertebral body, subclavian artery, or sympathetic chain) is a poor prognostic sign. Two thirds of patients have a recurrence, and two thirds of these are local.
The approach to N2 (stage IIIA) disease varies somewhat from place to place. Unselected patients have a low rate of complete resection with primary surgery, and patients with incompletely resected lesions do poorly. Patients without radiographic evidence of N2 disease but who are found at surgery to have N2 disease do better than those with preoperative evidence of N2 disease. The more advanced the node involvement (number, extension, or location), the poorer the prognosis. Given this, protocols using multimodal therapy are being investigated. Induction with chemotherapy with or without radiotherapy leads to objective responses in most patients, many of whom are downstaged. Downstaging predicts survival. A greater percentage of patients treated with induction therapy are able to undergo complete resection. Although multimodality therapy is often offered to those who can tolerate it, the selection of patients and therapy is best served in the setting of a study. Advances in each of the modes of therapy will lead to evolution of treatment over time.
T4 disease without advanced nodal status (stage IIIB) may be considered surgical in a few settings. T4 disease involving the main carina may be considered for resection at centers with expertise. The role of induction therapy in this setting is yet to be defined. Disease at the N3 level (stage IIIB) is generally considered nonsurgical. Advances in induction therapy might alter this notion in time, and trials of multimodality therapy are ongoing. When surgery is not considered in stage IIIA or IIIB disease, concurrent chemoradiotherapy, using a platinum-based regimen, is the standard of care in a patient with a reasonable performance status. Survival is in the 9% to 24% range at 5 years. There is a suggestion that newer agents may be as effective with less toxicity.51 Further studies are ongoing.
In stage IV lung cancer, platinum-based doublet chemotherapy regimens have been shown to improve survival, enhance quality of life, and be cost effective. The decision to treat with chemotherapy and the agents selected must consider each patient's comorbidites and overall performance status. In addition, it has been recognized that chemotherapy choices should be based on the specific histologic subtype. For example, pemetrexed combined with a platinum agent has been shown to be more effective and less toxic than traditional agents combined with a platinum in the treatment of advanced nonsquamous cell carcinomas. In patients who do not progress during the traditional 4 cycles of platinum based doublet chemotherapy, maintenance therapy with a single low toxicity agent has the potential to prolong survival.52
Therapies targeting the consequences of alterations in normal physiology or driver oncogenes have been developed. The addition of a VEGF inhibitor to treatment in those without squamous cell carcinoma, hemoptysis, or brain metastases, has led to improved outcomes. The presence of activating mutations in the epidemeral growth factor receptor is a marker of improved response to EGFR inhibitors as upfront therapy. EGFR mutations are most commonly found in women, those who have never smoked, and those with adenocarcinoma. Similarly, the presence of an EML4-ALK translocation, identified by FISH testing, is a marker of improved response to an ALK inhibitor. Other novel agents targeting alterations in the pathobiology of the cancer cell are being developed.
Small Cell Lung Cancer
Treatment of small cell lung cancer is based on its staging (limited versus extensive). In limited-stage disease, combination chemotherapy with concurrent hyperfractionated radiotherapy is recommended. Etoposide and a platinum agent are standard. Prophylactic cranial radiation (PCI) is recommended for patients who have a complete response to chemoradiotherapy. Surgery is limited to cases in which the diagnosis is in doubt, there is a solitary lung nodule focus, or in cases that have not responded to chemoradiotherapy but remain resectable. This should be combined with neoadjuvant or adjuvant chemotherapy. In patients with extensive-stage disease, combination chemotherapy improves the quality of life and median survival. Etoposide and a platinum agent are standard. A poor performance status and an elevated lactate dehydrogenase level portend a poor prognosis. Radiotherapy to the chest may be used in patients who have a complete response to chemotherapy in disease residing outside the chest.53 PCI has been shown to reduced the rate of brain metastasis and prolong survival.54
Palliation of symptoms related to lung cancer is an important aspect of the overall management. The judicious use of analgesic agents for pain, antiemetics for nausea, and antidepressants can improve quality of life. Radiotherapy can be used to palliate bone pain related to metastatic disease, hemoptysis, or symptoms of airway obstruction. Invasive bronchoscopic procedures (e.g., laser ablation, electrocautery, stent placement) can palliate patients with airway obstruction.
- Lung cancer causes more cancer-related deaths in the United States than the next four causes of cancer-related mortality combined.
- The most important and easily modifiable risk factor for lung cancer is cigarette smoking.
- Symptoms are often absent until lung cancer has advanced; thus, only 15% of lung cancer patients live for 5 years after their diagnosis.
- The histologic subtype, molecular markers, stage of lung cancer and the patient's performance status guide treatment decisions and influence the prognosis.
- Surgery is the treatment of choice for early stage nonâ€“small cell lung cancer. Chemotherapy is the modality of choice for advanced nonâ€“small cell lung cancer. Chemotherapy with or without radiation therapy is used to treat small cell lung cancer.
- Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012 [published online ahead of print January 4, 2012]. CA Cancer J Clin 2012; 62:10â€“29. doi:10.3322/caac.20138.
- Iribarren C, Tekawa IS, Sidney S, Friedman GD. Effect of cigar smoking on the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer in men. N Engl J Med 1999; 340:1773â€“1780.
- Vineis P, Airoldi L, Veglia F, et al. Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study [published online ahead of print January 28, 2005]. BMJ 2005; 330:277. doi:http://dx.doi.org/10.1136/bmj.38327.648472.82.
- Enstrom JE, Kabat GC. Environmental tobacco smoke and tobacco related mortality in a prospective study of Californians, 1960-98. BMJ 2003; 326:1057.
- Nitadori J, Inoue M, Iwasaki M, et al. Association between lung cancer incidence and family history of lung cancer: data from a large-scale population-based cohort study, the JPHC study. Chest 2006; 130:968â€“975.
- Dresler CM, Fratelli C, Babb J, Everley L, Evans AA, Clapper ML. Gender differences in genetic susceptibility for lung cancer. Lung Cancer 2000; 30:153â€“160.
- Virtamo J, Pietinen P, Huttunen JK, et al; ATBC Study Group. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 2003; 290:476â€“485.
- Mannino DM, Aguayo SM, Petty TL, Redd SC. Low lung function and incident lung cancer in the United States: data from the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med 2003; 163:1475â€“1480.
- Wasswa-Kintu S, Gan WQ, Man SF, Pare PD, Sin DD. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax 2005; 60:570â€“575.
- Tammemagi CM, Pinsky PF, Caporaso NE, et al. Lung cancer risk prediction: Prostate, Lung, Colorectal And Ovarian Cancer Screening Trial models and validation [published online ahead of print May 23, 2011]. J Natl Cancer Inst 2011; 103:1058â€“1068. doi:10.1093/jnci/djr173.
- Field JK, Youngson JH. The Liverpool Lung Project: a molecular epidemiological study of early lung cancer detection. Eur Respir J 2002; 20:464â€“479.
- Gerber RB, Mazzone P, Arroliga AC. Paraneoplastic syndromes associated with bronchogenic carcinoma. Clin Chest Med 2002; 23:257â€“264.
- Gould MK, Maclean CC, Kuschner WG, Rydzak CE, Owens DK. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 2001; 285:914â€“924.
- Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules: application to small radiologically indeterminate nodules. Arch Intern Med 1997; 157:849â€“855.
- Gurney JW, Lyddon DM, McKay JA. Determining the likelihood of malignancy in solitary pulmonary nodules with Bayesian analysis. Part II. Application. Radiology 1993; 186:415â€“422.
- Libby DM, Smith JP, Altorki NK, Pasmantier MW, Yankelevitz D, Henschke CI. Managing the small pulmonary nodule discovered by CT. Chest 2004; 125:1522â€“1529.
- Wahidi MM, Govert JA, Goudar RK, Gould MK, McCrory DC; American College of Chest Physicians. Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132(suppl 3):94Sâ€“107S.
- Nair A, Baldwin DR, Field JK, Hansell DM, Devaraj A. Measurement methods and algorithms for the management of solid nodules. J Thorac Imaging 2012; 27:230â€“239.
- MacMahon H, Austin JH, Gamsu G, et al; Fleischner Society. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 2005; 237:395â€“400.
- Kodama K, Higashiyama M, Yokouchi H, et al. Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years. Ann Thorac Surg 2002; 73:386â€“393.
- Kim TJ, Goo JM, Lee KW, Park CM, Lee HJ. Clinical, pathological and thin-section CT features of persistent multiple ground-glass opacity nodules: comparison with solitary ground-glass opacity nodule [published online ahead of print September 16, 2008]. Lung Cancer 2009; 64:171â€“178. doi:10.1016/j.lungcan.2008.08.002.
- Nakata M, Saeki H, Takata I, et al. Focal ground-glass opacity detected by low-dose helical CT. Chest 2002; 121:1464â€“1467.
- Nomori H, Watanabe K, Ohtsuka T, Naruke T, Suemasu K, Uno K. Evaluation of F-18 fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules less than 3 cm in diameter, with special reference to the CT images. Lung Cancer 2004; 45:19â€“27.
- Detterbeck FC, Falen S, Rivera MP, Halle JS, Socinski MA. Seeking a home for a PET, part 1: defining the appropriate place for positron emission tomography imaging in the diagnosis of pulmonary nodules or masses. Chest 2004; 125:2294â€“2299.
- Wang Memoli JS, Nietert PJ, Silvestri GA. Meta-analysis of guided bronchoscopy for the evaluation of the pulmonary nodule. Chest 2012; 142:385â€“393.
- Bulman W, Saqi A, Powell CA. Acquisition and processing of endobronchial ultrasound-guided transbronchial needle aspiration specimens in the era of targeted lung cancer chemotherapy [published online ahead of print October 27, 2011]. Am J Respir Crit Care Med 2012; 185:606â€“611. doi:10.1164/rccm.201107-1199CI.
- Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6:244â€“285.
- Mazzone P, Jain P, Arroliga AC, Matthay RA. Bronchoscopy and needle biopsy techniques for diagnosis and staging of lung cancer. Clin Chest Med 2002; 23:137â€“158, ix.
- Goldstraw P, Crowley J, Chansky K, et al; on behalf of the International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007; 2:706â€“714.
- Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007; 132(suppl 3):178Sâ€“201S.
- Vansteenkiste JF, Stroobants SG, De Leyn PR, et al; Leuven Lung Cancer Group. Mediastinal lymph node staging with FDG-PET scan in patients with potentially operable non-small cell lung cancer: a prospective analysis of 50 cases. Chest 1997; 112:1480â€“1486.
- Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 2003; 348:2500â€“2507.
- Herth FJ, Eberhardt R, Vilmann P, Krasnik M, Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes [published online ahead of print May 31, 2006]. Thorax 2006; 61:795â€“798. doi:10.1136/thx.2005.047829.
- Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010; 304:2245â€“2252.
- Pieterman RM, van Putten JW, Meuzelaar JJ, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 2000; 343:254â€“261.
- Ung YC, Maziak DE, Vanderveen JA, et al; Lung Cancer Disease Site Group of Cancer Care Ontarioâ€™s Program in Evidence-Based Care. 18Fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a systematic review [published online ahead of print November 27, 2007]. J Natl Cancer Inst 2007; 99:1753â€“1767. doi:10.1093/jnci/djm232.
- Mazzone PJ, Arroliga AC. Lung cancer: preoperative pulmonary evaluation of the lung resection candidate. Am J Med 2005; 118:578â€“583.
- von Groote-Bidlingmaier F, Koegelenberg CF, Bolliger CT. Functional evaluation before lung resection. Clin Chest Med 2011; 32:773â€“782.
- Oken MM, Hocking WG, Kvale PA, et al; for the PLCO Project Team. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial [published online ahead of print October 26, 2011]. JAMA 2011; 306:1865â€“1873. doi:10.1001/jama.2011.1591.
- National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening [published online ahead of print June 29, 2011]. N Engl J Med 2011; 365:395â€“409. doi:10.1056/NEJMoa1102873.
- Lung Cancer Study Group. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Ann Thorac Surg 1995; 60:615â€“623.
- Narsule CK, Ebright MI, Fernando HC. Sublobar versus lobar resection: current status. Cancer J 2011; 17:23â€“27.
- Mentzer SJ, DeCamp MM, Harpole DH Jr, Sugarbaker DJ. Thoracoscopy and video-assisted thoracic surgery in the treatment of lung cancer. Chest 1995; 107(suppl 6):298Sâ€“301S.
- Farjah F, Wood DE, Mulligan MS, et al. Safety and efficacy of video-assisted versus conventional lung resection for lung cancer [published online ahead of print May 9, 2009]. J Thorac Cardiovasc Surg 2009; 137:1415â€“1421. doi:10.1016/j.jtcvs.2008.11.035.
- Louie BE, Farivar AS, Aye RW, ValliÃ¨res E. Early experience with robotic lung resection results in similar operative outcomes and morbidity when compared with matched video-assisted thoracoscopic surgery cases [published online ahead of print March 20, 2012]. Ann Thorac Surg 2012; 93:1598â€“1605. doi:10.1016/j.athoracsur.2012.01.067.
- Song DY, Kavanagh BD, Benedict SH, Schefter T. Stereotactic body radiation therapy: rationale, techniques, applications, and optimization. Oncology (Williston Park) 2004; 18:1419â€“1430; 1432, 1435â€“1436.
- Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010; 303:1070â€“1076.
- The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonâ€“small-cell lung cancer. N Engl J Med 2004; 350:351â€“360.
- Pignon J-P, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group [published online ahead of print May 27, 2008]. J Clin Oncol 2008; 26:3552â€“3559. doi:10.1200/JCO.2007.13.9030.
- Rami-Porta R, Ball D, Crowley J, et al; on behalf of the International Staging Committee, Cancer Research and Biostatistics, Observers to the Committee, and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2007; 2:593â€“602.
- Georgoulias V, Papadakis E, Alexopoulos A, et al; for the Greek Oncology Cooperative Group (GOCG) for Lung Cancer. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001; 357:1478â€“1484.
- Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study [published online ahead of print September 18, 2009]. Lancet 2009; 374:1432â€“1440. doi:10.1016/S0140-6736(09)61497-5.
- Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004; 350:379â€“392.
- Aupérin A, Arriagada R, Pignon JP, et al; for the Prophylactic Cranial Irradiation Overview Collaborative Group. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 1999; 341:476â€“484.