Lung Cancer
Non–Small Cell Lung Cancer
DEFINITION
Lung cancer is the development of cancer in any area of the lungs or bronchus, generally in the bronchial endothelium. Lung cancer is generally divided into two major types: small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC).
INCIDENCE
Lung cancer will be the second most commonly diagnosed cancer in men and women in 2007. According to the American Cancer Society, estimated new cases for 2007 are almost 213,380 with 160,390 expected deaths from the disease. Incidence is finally declining significantly in men, and since 1998, after a long period of increases, the rate has been stable in women. It is the leading cause of cancer-related deaths in the United States and worldwide. NSCLC is the most common lung cancer type, representing about 87% of lung cancer diagnoses.
ETIOLOGY AND RISK FACTORS
• Tobacco is the primary risk factor. Long-term exposure to cigarette or cigar smoking is the major risk factor in development of lung cancer. Risk increases with number of years of smoking, number of cigarettes smoked, young age when smoking started, increased degree of inhalation, high tar and nicotine content, and use of unfiltered cigarettes. Risk does decrease after cessation. Second-hand smoke exposure contributes to a lesser extent.
• Environmental and occupational exposures to arsenic, benzene, radon, asbestos (especially in smokers), copper, silica, lead, diesel exhaust, chromium, and air pollution
• Radiation exposure from occupational, medical, and environmental sources
• Current and former smokers who take pharmacological doses of beta-carotene
• Scars from tuberculosis or inflammatory processes
• Although evidence is increasing that genetic factors can contribute to risk, no genetic abnormality has been found that causes lung cancer.
SIGNS AND SYMPTOMS
Unfortunately there are few to no symptoms of early stage lung cancer. Symptoms that occur as the cancer progresses include the following:
Later-stage symptoms include pain from bone metastasis, fatigue, anorexia, central nervous system changes from brain metastasis, and weight loss. Paraneoplastic syndromes, which are more common in lung cancer than in any other kind of cancer, may cause humoral hypercalcemia of malignancy (especially in squamous cell), hypercoagulable states, and skin conditions such as acanthosis nigricans (in adenocarcinoma).
DIAGNOSTIC WORKUP
The purpose of the diagnostic workup is to determine where the primary cancer is, where a biopsy can be done, and whether there are sites of metastatic disease.
• History and physical examination to determine signs and symptoms of lung cancer and metastatic disease. Smoking and carcinogenic exposure history is important.
• Chest x-ray is probably the most helpful initial examination, but peripheral nodules must be 1 cm or larger to be visualized on radiographs. Other changes include lymphadenopathy, atelectasis, and pleural effusions.
• Computed tomographic (CT) scan of chest, abdomen, and pelvis to identify location of primary tumor and sites of metastatic disease (lymph nodes, liver, adrenal glands, bones)
• Biopsy under CT scan guidance, or bronchoscopy
• Mediastinoscopy to determine whether tumor has spread to mediastinal nodes if surgical resection is to be considered.
• Brain magnetic resonance imaging and bone scan looking for metastatic disease.
• Positron emission tomographic scans have become increasingly popular to find metastatic disease.
• Laboratory testing: alkaline phosphatase (bone/liver disease), calcium (hypercalcemia), complete blood cell count, kidney function, and liver function tests
• Pulmonary function tests to determine whether patient can tolerate removal of part of the lung
HISTOLOGY
There are three common histologies:
• Adenocarcinoma is the most common type (about 40%), and the incidence is increasing. Adenocarcinoma is associated with irritation and scarred areas. About one half of cases are not resectable at diagnosis. Includes subtypes of acinar, papillary, and bronchoalveolar
• Squamous carcinoma compromise about 30% of all lung cancers and are generally associated with smoking. These tend to be slow growing and therefore stay localized for a longer period. It usually presents as masses in large bronchi with local extension that may result in atelectasis and pneumonitis. When detected early, squamous carcinoma may be resectable and can be associated with longer survival.
• Large cell carcinoma represents about 10% to 15% of lung cancers. It is more undifferentiated and difficult to treat. It usually arises as peripheral nodules and metastasizes early, often to the gastrointestinal tract. It can be further classified into clear cell and giant cell, but they are treated the same.
CLINICAL STAGING
Lung cancers have predictable patterns of growth, and can spread locally, by lymphatic invasion, and through the bloodstream. NSCLC spreads locally initially and can occlude the bronchial lumens; grow into the pleura and chest wall; spread to hilar, mediastinal, and supraclavicular lymph nodes; and finally to bone, liver, adrenal glands, and the brain.
The purpose of staging is to determine how far the cancer has spread, so that appropriate treatment can be offered and a prognosis can be estimated. Patients can be divided into cases that are resectable and those that are not because only in the early stages can surgery be considered. NSCLC uses the TNM (tumor size, lymph nodes, and metastasis) system adopted by the American Joint Commission on Cancer. Histology or type of cancer is not a factor in staging. The stage of cancer determines the most appropriate treatment. See the table on page 118 for staging of lung cancer.
TREATMENT
When the cancer is localized and small (stages I, II, and some IIIA), surgery is usually the treatment of choice if the patient is a good surgical risk and can have a good quality of life after removal of that part of the lung (adequate pulmonary function tests). Surgical procedures include a wedge resection that removes small peripheral nodules (most conservative), segmentectomy that removes part of a lobe of the lung, lobectomy that removes a lobe of the lung (most common), or pneumonectomy that removes either the right or left lung. Only about 25% of patients with NSCLC are operable at diagnosis. Recent studies have shown that adjuvant chemotherapy after surgery in localized NSCLC can improve survival.
Unfortunately, some patients who are surgical candidates are found during surgery to have tumors that cannot be totally removed. These patients will require further treatment with radiation or chemotherapy. Patients who are not surgical candidates or who refuse surgery can receive radiation therapy, which can be curative in some patients with stage I or II disease. Adjuvant radiation therapy may be used after surgery for stage IIIA disease and as primary therapy for unresectable stage IIIA disease. Patients with stage IIIB disease generally receive a combination of chemotherapy and radiation therapy.
Neoadjuvant therapy (chemotherapy with or without radiation before surgery) has been an area of intense study in recent years as a way of treating undetectable metastatic disease and shrinking the tumor to improve successful resection and improve survival. Although survival rates have improved in stages IB through IIIA with neoadjuvant therapy, it does carry a greater risk of complications.
Stage IIIB and IV NSLC is considered to be inoperable. At times, solitary metastatic lesions in the lung and brain can be resected.
Most patients with NSLC will receive chemotherapy because many are initially seen with unresectable disease and 80% of those with resectable disease will have relapses. Treatment with chemotherapy alone for metastatic disease produces only moderate response rates (up to 30% with the newer drugs) and a median survival time of 25 to 30 weeks.
First-line regimens of choice are usually combination therapies including carboplatin/paclitaxel, paclitaxel/cisplatin, vinorelbine/cisplatin, docetaxel/cisplatin, docetaxel/carboplatin, docetaxel/gemcitabine, gemcitabine/cisplatin, or gemcitabine/vinorelbine. Bevacizumab recently received Food and Drug Administration approval for use in non–squamous cell non–small cell cancers with carboplatin and paclitaxel as first-line treatment. Contraindications are brain metastasis or hemoptysis. Patients with poor performance status are generally treated with either single agents or with supportive care.
Once the disease progresses, single agents such as docetaxel, gemcitabine, topotecan, vinorelbine, and pemetrexed are used, depending on which drugs have already been given. Targeted therapies, those that target specific aspects of tumor development at the molecular level, are the latest group of drugs to become available. Because they target specifically the tumor, it is hoped these will be more effective and less toxic to the rest of the body. These include the epidermal growth factor receptors that are expressed in the majority of NSCLC tumors, of which gefitinib (Iressa) and erlotinib (Tarceva) are examples. Finally, participation in a clinical trial should be considered.
Palliative radiation is done for symptomatic treatment of bone pain, spinal cord compression, brain metastasis, and postobstructive pneumonia.
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