Lung cancer is a major public health problem. In the United States approximately one third of male cancer deaths and one quarter of female cancer deaths are secondary to lung cancer. Efforts at early detection and treatment have been frustrating to date and hence the overall prognosis remains poor. Just over 1 in 8 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-related products. Unfortunately, data on worldwide tobacco consumption suggest that lung cancer will remain an epidemic for years to come. Advances in understanding the pathogenesis, early detection, and therapy of lung cancer are in progress.

In 2004, there will be approximately 173,770 new cases of lung cancer diagnosed in the United States. Lung cancer is the second most frequently diagnosed cancer in both men and women (prostate and breast are the most frequent in men and women, respectively (Figure 1). The incidence of lung cancer peaked in men in 1984 (86.5 per 100,000 men) and has subsequently been declining (69.1 per 100,000 in 1997). In women, the incidence increased during the 1990s, with a leveling off toward the end of the decade (43.1 per 100,000 women). These trends parallel the smoking patterns of these 2 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, while a slow increase occurred in women. These rates again parallel the smoking patterns of these two groups (Figures 2 and 3). There will be an estimated 160,440 deaths in 2004 in the United States secondary to lung cancer. This means that lung cancer will account for approximately 28% 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 the group 60 and older.¹

Risk Factors
Eighty-five percent to 90% of individuals 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 (see below) 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 sidestream smoke, or passive smoking, may lead to an increased risk of lung cancer. The risk may vary with the level and duration of exposure. It is generally a much lower risk than is active smoking. Some suggest the risk may be negligible.³

Many other risk factors have been identified (Table 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. 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, and/or an effect of hormone differences, are thought to account for the increased susceptibility.⁴ 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 may lead to a higher risk. Supplementation with vitamins A, E, and/or beta-carotene has not positively influenced risk.⁵ The presence of chronic obstructive pulmonary disease is an independent risk factor. This risk increases as the forced expiratory volume in 1 second (FEV₁) decreases.⁶

Classification
Pathologic features, visible on light microscopy, are used to categorize lung cancers. Lung cancers are divided into two major groups, small cell and non-small cell. These groups guide current evaluation and therapeutic decisions. The non-small cell cancer category consists of adenocarcinoma (including bronchoalveolar cell carcinoma), squamous cell carcinoma, large cell carcinoma, and variants (Figure 4).

Over the past 2 decades, the proportions of lung cancers that are adenocarcinoma 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 thought to account for this change.

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.

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 (Table 2).

Local growth in a central location can cause cough, hemoptysis, or features of large-airway obstruction. Peripheral growth may also cause cough and dyspnea. If the pleura or chest wall becomes involved, pain may occur. Regional growth may 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 may lead to Pancoast's syndrome, with shoulder pain radiating in an ulnar distribution. The superior vena cava can become obstructed and involvement of the heart and pericardium can occur. Lymphatic obstruction and spread can lead to dyspnea, hypoxia, and pleural effusions.

Distant metastatic disease can affect most organs. Neurologic symptoms may suggest brain metastases or spinal cord compression, and pain could indicate bone metastases. Laboratory abnormalities may point to bone marrow or liver involvement. Imaging may detect adrenal involvement.

Paraneoplastic syndromes may occur before the primary tumor appears, and thus 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, as 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 presents with ataxia, nystagmus, dysarthria, and diplopia; and paraneoplastic opsoclonus-myoclonus features involuntary eye movements, myoclonus, truncal ataxia, dysarthria, and encephalopathy. Each of these is more common with small cell carcinoma, may occur in the presence of anti-Hu antibodies, and may occur as part of a more diffuse "anti-Hu syndrome" (the encephalomyelitis/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, present in 3% of small cell carcinomas. Proximal muscle weakness (which may improve with exercise), most prominent in the lower extremities, and autonomic features predominate. Autoantibodies directed against P/Q type voltage-gated calcium channels are thought to be responsible.

Other paraneoplastic syndromes include skeletal/connective tissue syndromes (clubbing, hypertrophic pulmonary osteoarthropathy); coagulation/hematologic disorders; cutaneous and renal manifestations; and systemic symptoms (anorexia, cachexia, and weight loss).⁷

From 85% to 95% of patients with lung cancer will be symptomatic at presentation. In the remainder, lung cancer is detected by radiographic evaluation initiated for an unrelated problem. This proportion may change in the future if currently investigative screening techniques prove beneficial. Most patients have a chest radiograph and computed tomography (CT) of the chest performed in their initial evaluation. Clinical and radiographic features of the presentation dictate further evaluation.

Clinical features suggestive of malignancy on initial evaluation include older age, current or history of tobacco abuse, the presence of hemoptysis, and a history of a previous malignancy. Radiographic features suggestive of 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 (greater than 3 cm = 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) utilizing [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.⁸ Single-photon emission computed tomography and lung nodule enhancement with contrast-enhanced CT are less well established.

Ultimately, tissue needs to be obtained to confirm the diagnosis of lung cancer. Flexible bronchoscopy (FB) and transthoracic needle biopsy (TNB) are the invasive, nonsurgical approaches used to obtain tissue. If they fail or are deemed unnecessary, a surgical approach is used.

FB 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 FB for peripheral lesions include the size of the lesion, its location, and the presence of a "bronchus sign" on CT. Smaller, more-peripheral lesions, without a visible bronchus within or leading directly to them, are unlikely to be diagnosed by FB.

TNB, 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 TNB; thus, FB is often attempted first.⁹

Staging
Accurately characterizing the anatomic extent of disease in a patient with lung cancer guides treatment and prognosis. Non-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 metastases). The most recent revision¹⁰ to this staging system occurred in 1997 (Table 3; Figure 5). For patients with small cell lung cancer, the TNM staging system is less useful. Instead, small cell lung cancer is staged as limited or extensive disease. Limited-stage disease is indicated 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 indicated 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 proper utilization of testing to stage a patient with lung cancer is addressed in a recent set of guidelines.¹¹ The history and physical examination are important in guiding testing. The extent of locoregional 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) has not proven to be more accurate except in the setting of a Pancoast tumor. The sensitivity and specificity of CT for the evaluation of regional lymph-node involvement is modest, commonly noted to be as low as 60% and rarely above 75%. PET seems to have better test characteristics for staging mediastinal nodes, with sensitivities and specificities above 90%.¹² Integrated PET-CT scanning appears to have better test characteristics than PET and CT used alone or in conjunction.¹³ As non-invasive tests have false-positive results, tissue confirmation is necessary. Bronchoscopy with transbronchial needle aspiration is useful to stage the mediastinum. If 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 the above-listed testing, including mediastinoscopy) is not infrequently 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 extended through the adrenals, since metastatic disease to these organs is usually asymptomatic and frequently no alterations are seen in routine laboratory tests. A contrast-enhanced CT, ultrasound, or MRI of the liver should be performed if the chest CT, laboratory results, or clinical evaluation suggests metastatic disease to this organ. A head CT should be performed if symptoms or signs of metastatic disease are present or when evaluating what appears to be stage IIIA or B disease. Head CTs are frequently performed despite a lack of symptoms, in deference to the published guidelines. This is probably justifiable in small cell carcinoma, but is debatable in others. Many choose to use MRI scanning of the brain as it has greater sensitivity to detect metastatic disease. This is not currently recommended in the published guidelines. Bone scanning should be performed if symptoms or signs suggest bone involvement, if the patient has an elevated calcium or alkaline phosphatase level, or in stage IIIA/B disease. PET has been used to stage all but brain metastases. The rate of detection of distant metastases using PET appears to be higher than that using the above-described standard approach.¹⁴

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 an individual will tolerate lung resectional surgery, reports of activity tolerance and pulmonary function testing are used. Although no one pulmonary function study or absolute cutoff has proven ideal, the FEV₁ and diffusing capacity for carbon monoxide (DLCO) are the most frequently used measures. Traditional pre-operative 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 above 40%, then the patient should be able to tolerate surgery. Thus, as would be expected, a pneumonectomy requires better pre-operative lung function than does a lobectomy. When doubt remains, or when measured values and predictions seem discordant with an individual's reported activity tolerance, a cardiopulmonary exercise study should be performed. If the maximum 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.

Screening for Lung Cancer
Given the poor prognosis for advanced-stage lung cancer and the high proportion of patients who present in an advanced stage, there has been great interest in screening for lung cancer. The earliest efforts at radiographic screening were from the analysis of mass chest x-ray (CXR) screenings from the population of an individual city. This was followed by large efforts in the 1970's to use CXR, sputum, or a combination of the two, as screening tools. Despite considerable ongoing debate about the design and analysis of these randomized studies, they have been interpreted as not showing that screening with plain CXR and/or sputum examination has a beneficial effect on mortality from lung cancer.

Given the somewhat disappointing overall results from CXR as a screening technique, more recent efforts have centered on the use of low-dose CT imaging as a screening tool. In a cross-sectional (eg, prevalence) screen of 1000 high-risk individuals, non-calcified nodules were detected 3 times more often than on CXR, malignant tumors 4 times more often, and stage 1 cancer 6 times more often. Twenty-three percent of screened individuals had non-calcified nodules and 2.7% had lung cancer (11.6% of those with a non-calcified nodule). Most of these were stage I.¹⁵ In a follow-up to this report, repeat screening has been performed. Based on 1184 repeat CT screens, 30 new nodules were detected (2.5%). On follow-up CT scanning of these 30 new nodules, 8 (26.7%) demonstrated growth and hence underwent biopsy. Seven of these (87.5%) were malignant, 5 stage IA, 1 stage IIIA, and 1 limited stage small cell. Two individuals developed symptoms and were diagnosed with lung cancer between screening studies (1-year interval). The conclusion was that false positives are uncommon and are usually managed without biopsy, that CT screening permits diagnosis at earlier stages, and that the 1-year interval is appropriate.¹⁶

Other sites have reported results from similar screening programs. A Japanese report of an employee screening program with 7,956 individuals (smokers, former smokers and never smokers) undergoing prevalence screening and 5,568 who were rescreened detected 2,865 nodules at baseline, 37 of which were cancerous (0.44%). Incidence screening detected an additional 4 cancers (0.07%). 35/41 of these tumors were stage I.¹⁷ A report from the Mayo Clinic on prevalence and incidence scans of 1,520 individuals (>age 50, 20+ pack-years of smoking) described nodules in 66% of the participants after the incidence screen. Twenty-two cancers were detected with the prevalence screen (1.4%) and 3 at the incidence screen. 12/21 non-small cell cancers were stage IA.¹⁸ A report out of Italy described 1,035 individuals (>age 50, 20+ pack-years of smoking) who underwent prevalence and incidence screens with an algorithm employing PET scanning to assist with the assessment of detected nodules. Twenty-nine percent of their population had nodules detected. Twenty-two cancers were found (11 prevalence and 11 incidence), 17 of which were stage I. PET had a sensitivity of 90% and specificity of 82% (6 false positives). Nodules < 5mm were safely followed at 1 year intervals.¹⁹

Issues highlighted in these studies include the high number of benign nodules detected and the intense follow-up protocols required to ensure that resection was performed when the risk warranted it, while the resection of benign nodules was minimized. Yet to be proven is whether overall and disease-specific mortality will be reduced using this tool. A cost-effectiveness analysis has suggested CT screening is unlikely to be highly cost-effective.²⁰

As it is still to be proven whether CT screening will reduce overall and disease-specific mortality, currrent guidelines do not recommend lung cancer screening for asymptomatic individuals at risk for lung cancer. Individual patients at risk for lung cancer are being advised of their risk and educated about the current state of early detection. If testing is to occur, it should be in a trial setting in which multidisciplinary specialty groups exist.^21,22

Non-Small Cell Lung Cancer (Tables 4, and 5)
Surgical resection offers the best chance of cure for early-stage non-small cell lung cancer (stages I and II). Survival after resection in pathologic stage IA approaches 70% at 5 years, and in pathologic stage IB it is closer to 55%. Vascular invasion and tumor differentiation may be prognostic factors. There does not seem to be a difference in survival between patients who have adenocarcinoma or squamous cell carcinoma. Recurrence usually involves distant metastases. Limited resections in individuals unable to tolerate lobectomy produce slightly lower survival with higher rates of local recurrence. Survival after resection in pathologic stage IIA is 50% to 55% at 5 years, and that in pathologic stage IIB is around 40%. Patients with adenocarcinoma may have poorer survival than those with squamous cell carcinoma. Again, most recurrences involve distant metastases.

Radiotherapy has been used with curative intent in early-stage non-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. Adjuvant therapy has been attempted in early-stage non-small cell lung cancer patients who have undergone surgical resection. Adjuvant radiotherapy may improve local control but it does not improve survival (with the possible exception of those who have undergone incomplete resection). Adjuvant chemotherapy has recently shown benefit in selected individuals with completely resected stage I-IIIA lung cancers, so should be strongly considered.²³

Locally advanced tumors (T3) can frequently be completely resected, although central T3 tumors are somewhat less resectable than those involving the chest wall. The survival in T3 patients with chest-wall involvement and negative nodes approximates that 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. T3 involvement of the mediastinum or mainstem bronchus portends a poorer prognosis, with 5-year survival rates below 30%.

When a Pancoast tumor is present, chemoradiotherapy followed by surgical resection (lobectomy and chest-wall resection) is 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 incompletely resected cases 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 becoming the standard of care for 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 may 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 an individual with a reasonable performance status. Survival is in the 5% to 13% range at 5 years. There is a suggestion that newer agents may be as effective with less toxicity.²⁴ Further study is ongoing.

In stage IV lung cancer, platinum-based chemotherapy regimens have been shown to improve survival and enhance quality of life, and are also cost-effective. This treatment is most appropriate for individuals with a good performance status. Studies of novel agents and non-platinum-based regimens are ongoing. Resection of an isolated brain metastasis in patients with a good performance status can improve survival.

Small Cell Lung Cancer (Table 4)
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, but trials with newer agents are ongoing. Prophylactic cranial radiation is generally recommended for patients who have a complete response to chemoradiotherapy. Surgery is limited to cases in which the diagnosis is in doubt or in cases that have not responded to chemoradiotherapy but remain resectable. In patients with extensive-stage disease, combination chemotherapy improves the quality of life and median survival. Etoposide and a platinum agent are standard although we are awaiting trials of newer agents. 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.²⁵

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 (laser ablation, electrocautery, stent placement, and so forth) may palliate patients with airway obstruction.

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