Lung Cancer

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. Efforts at early detection and treatment have been frustrating, and hence 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. Advances in understanding the pathogenesis, early detection, and therapy of lung cancer are in progress.

Prevalence
In 2007, approximately 213,380 new cases of lung cancer were diagnosed in the United States. 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 (Fig. 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 (Figs. 2and 3). There were an estimated 160,390 deaths in 2007 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.

Risk factors
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.
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Exposure to sidestream 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. Some suggest the risk is negligible.
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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. 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.
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Box 1: Lung Cancer Risk Factors Tobacco Smoke Exposure

Active (mainstream) Cigarette Cigar Passive (sidestream)

Occupational and Environmental Exposures

Arsenic Asbestos Beryllium Bis(chloromethyl)ether Cadmium Chromium Nickel Polycyclic aromatic hydrocarbons Radon Vinyl chloride

Other Factors

Chronic obstructive pulmonary disease Dietary factors Gender

Genetic predisposition

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.
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Chronic obstructive pulmonary disease is an independent risk factor. This risk increases as the forced expiratory volume in 1 second (FEV1) decreases.

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

Figure 4: Click to Enlarge 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.

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Pathophysiology
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.

igns 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

Neoplastic Local Growth

Cough Dyspnea Hemoptysis Pain

Regional Growth

Dysphagia Dyspnea Hoarseness Horner's syndrome Hypoxia Pancoast's syndrome Pericardial or pleural effusions Superior vena cava syndrome

Metastatic Disease

Headache Hepatomegaly

Mental status change Pain Papilledema Seizures Skin or soft tissue mass Syncope Weakness

Paraneoplastic Cutaneous, Skeletal

Acanthosis nigricans Clubbing Dermatomyositis Hypertrophic osteoarthropathy

Endocrine

Cushing's syndrome Humoral hypercalcemia SIADH Tumor necrosis factor (cachexia)

Hematologic

Anemia Polycythemia DIC Eosinophilia Granulocytosis Thrombophlebitis

Neurologic

Cancer-associated retinopathy Encephalomyelitis Lambert-Eaton syndrome

Neuropathies Cerebellar degeneration

Renal

Glomerulonephritis Nephrotic syndrome

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 opsoclonusmyoclonus 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).

Diagnosis
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 if currently investigated screening techniques prove beneficial. 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
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fluorodeoxyglucose is the most-studied ancillary imaging technique. It has a sensitivity of 97% and a specificity of 78% as used in clinical practice. CT are less well established.
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Single-photon emission CT and lung nodule enhancement with contrast-enhanced

Ultimately, tissue needs to be obtained to confirm the diagnosis of lung 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. Smaller, more peripheral lesions, without a visible bronchus within or leading directly to them, are unlikely to be diagnosed by flexible bronchoscopy.

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.

Staging
Accurately characterizing the anatomic extent of disease in a patient with lung cancer guides the treatment and prognosis. Nonsmall 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). The most recent revision
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to this staging system occurred in 2009

(Tables 1 and 2). 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 history and physical examination are important in guiding testing.
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The proper use of testing to stage a patient with lung cancer is addressed in a set of guidelines. Table 1: TNM Descriptors Descriptor Description Criteria

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

Metastases (M)

M0

Local or regional disease

No distant metastases

M1

Disseminated disease

m1a Presence of satellite tumor nodule(s) in contralateral lung malignant pleural or paranodal effusion

m1b Distant metastases present

Table 2: NonSmall Cell Lung Cancer Staging Stage Description

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 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) 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 seems to have better test characteristics for staging mediastinal nodes, with sensitivities and specificities greater than 90%.
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Integrated PET-CT scanning appears to have better test characteristics than PET and CT used alone or in
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conjunction.

Because noninvasive tests have false-positive results, tissue confirmation is necessary. Bronchoscopy with transbronchial needle aspiration is useful to stage the mediastinum. Endobronchial and endoscopic ultrasoundguided needle sampling of the mediastinum has been reported to accurately stage the mediastinum.
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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).

Metastasis
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.

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 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.

PET is used to stage all but brain metastases. The rate of detection of distant metastases using PET is higher than previously used approaches.
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Performance Status
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 resectional surgery, reports of activity tolerance and pulmonary function testing are used. Although no one pulmonary function study or absolute cutoff has proved ideal, the FEV 1 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 FEV 1 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 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. Patients with marginal lung function might tolerate resection if a lesser resection is possible (wedge resection or segmentectomy) or if resection can be combined with a lung volume reduction procedure.

Screening for lung cancer

Given the 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 screening for lung cancer. The earliest efforts at radiographic screening were from the analysis of mass chest x-ray screenings from the population of one city. This was followed by large efforts in the 1970s to use chest x-ray or 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 chest x-ray or sputum examination (or both) has a beneficial effect on mortality from lung cancer.

Given the somewhat disappointing overall results from chest x-ray as a screening technique, more recent efforts have centered on the use of low-dose CT scanning as a screening tool. Important highlights of several available CT studies include the ability to find many early-stage lung cancers and the long survival times of patients with lung cancer diagnosed at an early stage. Difficulties with CT as a screening test and limitations of the trial designs that have been identified in these studies include an inability to comment on mortality specific to lung cancer, a large number of benign nodules being identified (5%-50% of participants on the initial scan), intense testing protocols required to follow the identified nodules to ensure they are not cancerous, invasive procedures performed on some benign nodules, and questionable cost effectiveness. Recent major publications highlight the contentious nature of this topic. One report suggests a survival of 80% for all patients with screen-detected lung cancers, and the other suggests that lung cancer is found and treated in more persons who are screened, but the mortality rate from lung cancer is not lower.
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Because it is still to be proved whether CT screening will reduce overall and disease-specific mortality rates, current guidelines do not recommend lung cancer screening for asymptomatic persons 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 involving multidisciplinary specialty groups.

Treatments and outcomes

Treatments and outcomes for lung cancer are shown in Box 3 and Tables 2 and 3.

Box 3: Options for Treating Lung Cancer

NonSmall 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 Limited 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 Consider adjuvant chemotherapy

Stage IIIA

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

Stage IIIB

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

Stage IV

Platinum-based chemotherapy regimen in patients with adequate performance status

Small Cell Lung Cancer Limited-Stage

Combination chemotherapy with concurrent hyperfractionated radiotherapy if performance status is adequate Prophylactic cranial radiation for those with a complete response to chemoradiotherapy

Extensive-Stage

Combination chemotherapy if performance status is adequate

2002 The Cleveland Clinic Foundation.

Table 3: NonSmall Cell Lung Cancer Five-Year Survival (%)

Stage

Clinical

Pathologic

IA

50

73

IB

43

58

IIA

36

46

IIB

25

36

IIIA

19

24

IIIB

IV

Data from Goldstraw P. J Thorac Oncol 2007;2:706-714.

NonSmall Cell Lung Cancer

Surgical resection offers the best chance of cure for early-stage nonsmall cell lung cancer (stages I and II). Survival after resection in pathologic stage IA approaches 73% at 5 years, and in pathologic stage IB it is closer to 50%. Vascular invasion and tumor differentiation may be 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. Limited resections in persons unable to tolerate lobectomy produce slightly lower survival rates, with higher rates of local recurrence when broadly applied. may perform as well as traditional anatomic resection.
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In an elderly population, limited resection

Survival after resection in pathologic stage IIA is 46% at 5 years, and that in pathologic stage IIB is around 37%. Patients with adenocarcinoma may have poorer survival rates than those with squamous cell carcinoma. Again, most recurrences involve distant metastases.

Traditional radiotherapy has been used with curative intent in early-stage nonsmall 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.
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Adjuvant therapy has been attempted in early-stage nonsmall 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 shown benefit in select patients with completely resected stages IB to IIIA lung cancers, and so it should be strongly considered.
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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. T3 involvement of the mediastinum or mainstem bronchus portends a poorer prognosis, with 5-year survival rates of less than 30%.

When a Pancoast tumor is present, chemoradiotherapy followed by surgical resection (lobectomy and chest-wall 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. Unselect 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.
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Further studies are ongoing.

In stage IV lung cancer, platinum-based chemotherapy regimens have been shown to improve survival and enhance quality of life, and they are also cost effective. This treatment is most appropriate for patients with a good performance status. The addition of a VEGF inhibitor to treatment in those without squamous cell carcinoma, hemoptysis, or brain metastases, has led to improved outcomes. EGFR inhibitors are used as second or third line therapy. They are most effective for women, those who have never smoked, or those with adenocarcinoma. Studies of other novel agents and nonplatinum-based regimens are ongoing. Resection of an isolated brain metastasis in patients with a good performance status can improve survival. Molecular markers may guide the choice of therapies in the near future.

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, 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.
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Palliation
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.

Reference: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/pulmonary/lungcancer/ http://www.scribd.com/doc/11823788/Lung-Cancer