"Lung Cancer Non Small Cell"
MINISTRY OF PUBLIC HEALTH OF UKRAINE KHARKOV NATINAL MEDICAL UNIVERSITY МИНИСТЕРСТВО ЗДРАВООХРАНЕНИЯ УКРАИНЫ ХАРЬКОВСКИЙ НАЦИОНАЛЬНЫЙ МЕДИЦИНСКИЙ УНИВЕРСИТЕТ Lung Cancer Рак легкого Утверждено ученым советом ХНМУ Протокол № 6 от 12.04.2005 г. Kharov KNMU- 2005 Харьков ХНМУ – 2005 Рак легкого: Метод. указ. к практ. занятиям для студентов V-VI курсов медицинских вузов, обучающихся на английском языке / Сост. В.И. Стариков, А.Н. Белый.– Харьков: ХНМУ, 2005.– 24 с. Lung cancer is approved by the Scientific Committee of the Kharkov state medical university and is recommended for V-th, VI-th year students of medical faculty / Authors: V.I. Starikov, A.N. Bely.– Kharkov: KNMU.2005. – 24 p. Authors: Starikov V.I. Bely A.N. 2 Introduction Lung cancer is the leading cause of cancer-related mortality in both men and women throughout the world. The prevalence of lung cancer is second only to that of prostate cancer in men and breast cancer in women. Lung cancer recently surpassed heart disease as the leading cause of smoking-related mortality. Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. The need to diagnose lung cancer at an early and potentially curable stage is obvious. In addition, most patients who develop lung cancer have been smokers and have smoking-related damage to the heart and lungs, making aggressive surgical or multimodality therapies less viable options. Lung cancers are generally divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Non–small cell lung cancer accounts for approximately 85% of all lung cancers. Non-small cell lung cancer is divided further into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma histologies. All share similar treatment approaches and prognoses but have distinct histologic and clinical characteristics. Recently, advanced molecular techniques have identified amplification of oncogenes and inactivation of tumor suppressor genes in non-small cell lung cancer. The most important abnormalities detected are mutations involving the ras family of oncogenes. The ras oncogene family has 3 members: H-ras, K-ras, and N-ras. These genes encode a protein on the inner surface of the cell membrane with GTPase activity and may be involved in signal transduction. Studies performed on mice suggest the involvement of ras mutations in the molecular pathogenesis of non-small cell lung cancer. Studies in humans suggest that ras activation contributes to tumor progression in persons with lung cancer. The ras gene mutations occur almost exclusively in adenocarcinoma and are found in 30% of such cases. These mutations were not identified in adenocarcinomas that developed in persons who do not smoke. The K-ras mutation appears to be an independent prognostic factor. Studies are ongoing to develop management plans according to the presence or absence of ras gene mutations. Other molecular abnormalities found in non-small cell lung cancer include mutations in c- myc and c-raf among oncogenes and retinoblastoma (Rb) and p53 among tumor suppressor genes. Although tobacco smoking is the major cause of lung cancer, it now believed that there may be differences in susceptibility to carcinogenic effects of tobacco smoke among males and females. This may be due to differences in DNA repair mechanisms. Although still considered controversial, it is well known that women are more likely to develop adenocarcinomas, and stage for stage women live longer than men. In addition, differences in response to certain biologic therapies (ie, epidermal growth factor inhibitors) and anti-angiogenic agents have been observed between sexes. A minority of lung cancers develop in those who have never smoked. These lung cancers are genetically distinct from smoking-related non-small cell lung cancer and may have therapeutic implications. The observed genetic differences include a lower frequency of K-ras and a higher frequency of mutations in epidermal growth factor receptor and likely are responsible for the higher efficacy of epidermal growth factor receptor inhibitors in this patient population. Lung cancer remains the most common malignancy in the world. In 2007, an estimated 1.5 million new cases of lung cancer were diagnosed globally, accounting for approximately 12% of the global cancer burden. An estimated 1.35 million lung cancer deaths occurred in 2007. Several differences exist in lung cancer incidence according to geographic area. Among males, the highest incidence of lung cancer occurs in Eastern Europe, North America, and Russia, while incidence is lowest in Africa and South Asia. Despite a very low rate of smoking, Chinese females have a higher incidence of lung cancer than European females. 3 Global lung cancer trends have followed the trends in smoking with a lag time of several decades. Lung cancer incidence has been declining in several countries, including the United States, Canada, the United Kingdom, and Australia, following the decreasing rate of smoking. Lung cancer incidence among women, however, continues to increase in several parts of the globe, although it has begun to plateau in the United States. Mortality/Morbidity Worldwide, an estimated 1,351,000 deaths due to lung cancer occurred in 2007 (975,000 in men and 376,000 in females). Lung cancer is highly lethal, with the highest recorded 5-year patient survival rates (15%) observed in the United States. In Europe, the 5-year overall survival rate is 8%, similar to that of the developing world. The American Cancer Society projected that deaths related to lung cancer would total 159,390 (88,900 in males and 70,490 in females) in the United States in 2009, accounting for 28% of all cancer-related deaths. Women diagnosed with non-small cell lung cancer (NSCLC) who take estrogen-progestin were found to have an increased mortality compared with women who have NSCLC and do not take hormone therapy. Secondary analyses of the Women’s Health Initiative (WHI) randomized, placebo- controlled trial were performed on those taking daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg). The analyses included 16,608 multiethnic postmenopausal women aged 50-79 years and assessed the association of hormone therapy on lung cancer incidence and mortality. Confirmation of lung cancers was completed by medical record review. Results showed that the use of CEE plus MPA for more than 5 years increased a woman's risk for non-small cell lung cancer mortality, the leading cause of cancer death in women. This area deserves more attention and study to determine the risks and benefits of hormone therapy for postmenopausal women who smoke. Race Trends in 5-year survival rates in lung cancer from 1975-2003 revealed that while modest gains occurred in 5-year survival rates among whites, survival rates remained unchanged in the African American population. Current 5-years survival rates are estimated to be 16% among whites and 13% among non-whites. Sex Lung cancer is more common in men than in women. In the United States, Northern Europe, and Western Europe, the prevalence of lung cancer has been decreasing in men. In Eastern and Southern European countries, the incidence of lung cancer has been rapidly increasing. Most Western countries have encountered a disturbing trend of increasing prevalence in women and younger patients. In the United States, the probability of developing lung cancer remains equal in both sexes until age 39 years (0.03% or approximately 1 in 3,000). It then starts to increase among men compared with women, reaching a maximum in those older than 70 years (6.74% vs 4.61% or 1 in 15 vs 1 in 22, among men and women respectively). Age The probability of developing lung cancer remains very low until age 39 years in both sexes. It then slowly starts to rise and peaks among those older than 70 years. The risk of developing lung cancer remains higher among men in all age groups after age 40 years. 4 Clinical History Lung cancers manifest with symptoms produced by the primary tumor, locoregional spread, metastatic disease, or ectopic hormone production. See the image below for a summary of all signs and symptoms. Approximately 7-10% of patients with lung cancer are asymptomatic and their cancers are diagnosed incidentally after a chest radiograph (CXR) performed for other reasons. The symptoms produced by the primary tumor depend on its location (ie, central, peripheral). Symptoms due to primary tumor o Central tumors are generally squamous cell carcinomas and produce symptoms of cough, dyspnea, atelectasis, postobstructive pneumonia, wheezing, and hemoptysis. o Most peripheral tumors are adenocarcinomas or large cell carcinomas and, in addition to causing cough and dyspnea, can cause symptoms due to pleural effusion and severe pain as a result of infiltration of parietal pleura and the chest wall. Because of their peripheral location, adenocarcinomas may not call attention to themselves until they have developed extrathoracic metastases. For example, patients may present with clinical signs of bone spread or intracranial metastatic disease. Symptoms due to locoregional spread o These symptoms can include superior vena cava obstruction, paralysis of the recurrent laryngeal nerve, and phrenic nerve palsy, causing hoarseness and paralysis of the diaphragm; pressure on the sympathetic plexus, causing Horner syndrome; dysphagia resulting from esophageal compression; and pericardial effusion. o Superior sulcus tumors (Pancoast tumors) can cause compression of the brachial plexus roots as they exit the neural foramina, resulting in intense, radiating neuropathic pain in the ipsilateral upper extremity. Paraneoplastic syndromes: Most paraneoplastic syndromes are caused by small cell lung cancer. However many paraneoplastic syndromes also occur in non-small cell lung cancer patients. Some examples include: o Squamous cell carcinomas are more likely to be associated with hypercalcemia due to parathyroid like hormone production. o Clubbing and hypertrophic pulmonary osteoarthropathy and Trousseau syndrome of hypercoagulability are caused more frequently by adenocarcinomas. o The syndrome of inappropriate antidiuretic hormone production (SIADH) is more common in small cell lung cancer but can also occur in non-small cell lung cancer. o Ectopic ACTH production can result in Cushing syndrome. Summary of clinical characteristics by histologic subtype o Adenocarcinoma, arising from the bronchial mucosal glands, is the most frequent non- small cell lung cancer in the United States, representing 35-40% of all lung cancers. It usually occurs in a peripheral location within the lung. Adenocarcinoma is the most common histologic subtype, and may manifest as a "scar carcinoma." This is the subtype observed most commonly in persons who do not smoke. This type may manifest as multifocal tumors in a bronchoalveolar form. o Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with a classic manifestation as an interstitial lung disease on chest radiograph. Bronchoalveolar carcinoma arises from type II pneumocytes and grows along alveolar septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease, or a rapidly progressing pneumonic form. A characteristic finding in persons with advanced disease is voluminous watery sputum. o Squamous cell carcinoma accounts for 25-30% of all lung cancers. The classic manifestation is a cavitary lesion in a proximal bronchus. This type is characterized histologically by 5 the presence of keratin pearls and can be detected with cytologic studies because it has a tendency to exfoliate. It is the type most often associated with hypercalcemia. o Large cell carcinoma accounts for 10-15% of lung cancers, typically manifesting as a large peripheral mass on chest radiograph. Histologically, this type has sheets of highly atypical cells with focal necrosis, with no evidence of keratinization (typical of squamous cell carcinoma) or gland formation (typical of adenocarcinomas). o Improved histopathologic procedures and the use of electron microscopy allow for most large cell tumors to be identified as undifferentiated adenocarcinomas and less frequently as squamous cell cancers. Large cell undifferentiated cancers have the same prognosis as do adenocarcinomas and are combined with them in clinical trials. Physical 6 In approximately two thirds to three fourths of patients, the cancer is diagnosed at an advanced stage; patients may have lost weight and may have obvious respiratory distress. Head and neck o Commonly, no signs are found upon examination of the head and neck regions, but when the cancer has spread to the supraclavicular lymph nodes, careful examination may reveal enlargement of involved nodes, which helps in the clinical staging process. o Superior sulcus tumors, because of their presence at the apex of the lung, can compress the cervical sympathetic plexus, causing classic Horner syndrome. Findings involve ipsilateral ptosis, miosis, enophthalmos, and anhidrosis (ie, lack of sweating). o The superior vena cava syndrome is commonly caused by small cell carcinomas, but any centrally located tumor or mediastinal spread can give rise to the superior vena cava syndrome. This results from obstruction of blood flow to the heart from the head and neck regions and upper extremities due to tumor compression of the superior vena cava. Patients have facial edema, dusky skin coloration, and, possibly, conjunctival edema. Edema of the upper extremities and prominent veins on the upper thoracic wall with retrograde flow may be present. Respiratory system o Findings are variable and depend on location and spread. o Centrally located obstructing tumors can cause collapse of the entire lung with an absence of breath sounds on the side of the lesion. o Peripheral lesions can cause individual segments or lobes to collapse, leading to findings of dullness to percussion and/or decreased breath sounds. o Pleural effusions give rise to characteristic findings of dullness and decreased breath sounds, depending on the size. Cardiovascular system: Cardiac findings are usually noted when the tumor causes an effusion. Findings can range from simple effusion to tamponade. Direct cardiac involvement may also occur. Gastrointestinal system: The most common site of metastatic spread is the liver, which may manifest as tender hepatomegaly. Musculoskeletal system o Bone is another common site of spread for lung carcinomas. o Patients may report bone pain, and tender spots may be found during examination. o The examination should include fist percussion of the spine to look for tender spots, which may suggest vertebral column metastases. Central nervous system: A neurologic examination should be performed to look for focal neurological deficits caused by brain metastases and/or signs of spinal cord compression. Causes Smoking o Unlike many other malignancies, whose causes are largely unknown, the cause of lung cancer is tobacco smoking in as many as 90% of patients (78% in men, 90% in women). o Tobacco smoke contains more than 300 harmful substances with at least 40 known potent carcinogens. Poly-aromatic hydrocarbons and the nitrosamine-NNK are known to cause DNA damage by forming DNA adducts in animal models. Benzo-A-pyrine also appears to induce molecular signaling such as AKT as well as inducing mutations in p53 and other tumor suppressor genes. o The development of lung cancer is directly related to number of cigarettes smoked, length of smoking history, and the tar and nicotine content of the cigarettes. Risk is highest among current 7 smokers and lowest among nonsmokers. A large trial showed that persistent smokers had a 16-fold elevated lung cancer risk, which was further doubled in those who started smoking when younger than 16 years.3 The age-adjusted incidence rates range from 4.8-20.8 per 100,000 among nonsmokers to 140-362 among active smokers. o The risk of lung cancer declines slowly after smoking cessation. Long-term follow-up studies show that the relative risk remains high in the first 10 years after cessation and gradually declines to 2-fold approximately 30 years after cessation. This long-term risk explains the development of almost 50% of United States lung cancer cases in past smokers. o Smoking prevalence in the United States has gradually declined over last 4 decades. In 2008, there were an estimated 46 million active smokers in the United States, with highest prevalence among Native Americans and lowest prevalence among Hispanic and Asian Americans. Overall, the prevalence was highest in adults aged 25 years or older with low educational attainment.4 Worldwide, the incidence of smoking in developing countries is on the rise, with almost 320 million smokers in China alone. o Because not all persons who smoke develop lung cancer and because not all patients with lung cancer have a history of smoking, other factors, including genetic susceptibility, also play a causative role. Passive smoking o As many as 25% of the lung cancers in persons who do not smoke are believed to be caused by secondhand smoke.5 The US Environmental Protection Agency has recognized passive smoking as a potential carcinogen. About 3000 cases of lung cancer appear to be related to passive exposure. This awareness has led to local ordinances restricting smoking in enclosed public places, including restaurants and government buildings. o Cigarette smoke containing the carcinogenic N -nitrosamines and aromatic polycyclic hydrocarbons can be inhaled passively by nonsmokers. Urinary levels of these carcinogens are 1-5% of those found in active smokers. Asbestos o Asbestos exposure has been shown to be strongly associated with the causation of lung cancer, malignant pleural mesothelioma, and pulmonary fibrosis. o The silicate type of asbestos fiber is an important carcinogen. o Asbestos exposure increases the risk of developing lung cancer by as much as 5 times. o Tobacco smoke and asbestos exposure act synergistically, and the risk of developing lung cancer for persons who currently smoke tobacco and have a history of asbestos exposure approaches 80-90 times that of control populations. Radon o Radon is an inert gas produced as a result of uranium decay. Radon exposure is a well- established risk factor for lung cancer in uranium miners. Approximately 2-3% of lung cancers annually are estimated to be caused by radon exposure. o The US National Research Council's report of the Sixth Committee on Biological Effects of Ionizing Radiation has estimated that radon exposure causes 2100 new lung cancers each year, while it contributes to lung cancer causation in approximately 9100 persons who smoke. o Household exposure to radon has never been clearly shown to cause lung cancer. HIV infection: A recent report from the State of Texas Health Department suggested a 6.5- fold increase in lung cancer in patients infected with HIV. 6 Other large series do not support an increased prevalence of lung cancers in subjects with HIV infection. 7 Other environmental agents 8 o Beryllium, nickel, copper, chromium, and cadmium have all been implicated in causing lung cancer. o Dietary fiber and vegetables have been suggested as protective from lung cancer. o Although diets rich in fruits and vegetables appear to be associated with lower rates of lung cancer, trials of supplemental beta-carotene, alone or in combination with vitamin E or retinyl palmitate, in persons at high risk for lung cancer found that this supplementation increased the incidence of lung cancers. Laboratory Studies Apart from a handful of asymptomatic patients in whom lung cancer is diagnosed incidentally, virtually all patients with lung cancer are symptomatic at presentation. In a patient with a long history of smoking or other risk factors for lung cancer, the presence of persistent respiratory symptoms should prompt a chest radiograph. Because benign conditions and metastatic malignancies can mimic lung cancer on radiographs, histologic confirmation is necessary. This can be achieved by sputum cytologic studies, bronchoscopy, or CT-guided transthoracic needle biopsy of the mass, depending on the location of the tumor. The authors' approach to diagnosing lung cancer is illustrated in the image below. Sputum cytologic studies o Centrally located endobronchial tumors may exfoliate malignant cells into sputum. (This location and tendency to exfoliate are most common in squamous cell carcinomas.) Therefore, sputum cytology can be a quick and inexpensive diagnostic test if results are positive. 9 o The false-positive rate for sputum cytology is 1%, but the false-negative rate is as high as 40%. o A positive finding for malignancy from a cytologic specimen is accurate in as many as 90% of cases, but any distinction between different histologic subtypes is not accurate. Discordant results are often observed between cytologic and histologic findings of specimens obtained from bronchoscopy or transthoracic biopsy. o With the development of advanced x-ray imaging techniques and biopsy procedures, sputum cytology is not commonly employed in the diagnosis of non-small cell lung cancer. Complete blood cell count: This should be obtained in every patient, especially before instituting chemotherapy. Electrolytes and renal function studies: Because of the propensity of lung cancers to cause paraneoplastic syndromes, serum electrolyte levels should be evaluated. For a complete listing of common paraneoplastic syndromes associated with lung cancer, consult the table below. Staging workup for non-small cell lung cancer o Because of the importance of stage on the therapeutic decision-making process, all patients with non-small cell lung cancer must be staged adequately. o In the United States, the standard staging workup for NSCLC includes at least the following: Staging workup for non–small cell lung cancer. Complete history and physical examination CT scan of the chest and upper abdomen (including liver and adrenals) Complete blood cell counts Liver and kidney function tests Serum electrolytes o Information obtained from these tests can then be used to guide further testing (eg, imaging studies). o Invasive staging procedures such as mediastinoscopy and mediastinotomy may be required to assess mediastinal lymph nodes in patients who are candidates for potentially curative surgical resection. PET scans may be useful in the detection of involved nodes, the presence of which may influence decisions about operability. 10 Imaging Studies A complete staging workup for non-small cell lung cancer should be used to evaluate the extent of disease. A chest radiograph is usually the first test ordered in patients in whom a lung malignancy is suggested. o If the tumor is clearly visible and measurable, chest radiography can sometimes be used to monitor response to therapy. o Popcorn calcification is usually a radiologic characteristic of benign lesions. CT scan o Common sites of spread of a non-small cell lung cancer include the liver and adrenals; hence, a CT scan of the chest and upper abdomen, to include the liver and adrenals, is the minimum standard for a staging workup for a person newly diagnosed with non-small cell lung cancer. o A CT scan or MRI of the brain may be required if neurological symptoms or signs are present. Most thoracic surgeons perform imaging of the brain before attempting definitive resection of a lung malignancy. Bone scintigraphy: The skeletal system is another common site of metastases for lung cancers. If patients report bone pain or if their serum calcium and/or alkaline phosphatase levels are elevated, a bone scan should be obtained to search for bone metastases. Positron emission tomography o Positron emission tomography (PET) scanning is approved by the US Food and Drug Administration (FDA) for the workup of solitary lung nodules. o Recent studies suggest that PET scanning is useful for searching for systemic spread if other diagnostic modalities cannot clarify an abnormality that may change the treatment of the patient's condition. However, false-positive and false-negative results occur. o Recently, additional data have emerged that underscore the importance of PET scanning in patients with non-small cell lung cancer. PET scans appear to be more sensitive, specific, and accurate than CT scans for staging mediastinal disease. While radiographs and CT scans show images of structures, PET scans reveal the nature of the area under study. PET scans often detect abnormalities not demonstrated on CT scans. o Published reports suggest that staging of non-small cell lung cancer may be influenced by PET scan results in up to 60% of the cases and as many as 25% may be up-staged after PET scanning. o Caution is required when interpreting the results of PET scans in patients who may be denied potentially curative surgical resection based on PET results. MRI: MRI is most useful when evaluating a patient in whom spinal cord compression is suggested. In addition, brain MRI has a greater sensitivity than CT scan for detection of central nervous system metastasis. Procedures Bronchoscopy o When a lung cancer is suggested, especially if centrally located, bronchoscopy provides a means for direct visualization of the tumor, allows determination of the extent of airway obstruction, and allows collection of pathologic material under direct visualization. o Fiberoptic bronchoscopy has the advantage of providing direct visualization of the bronchial tree. Diagnostic material can be obtained with direct biopsy of the visualized tumor, bronchial brushings and washing, and transbronchial biopsies. 11 Mediastinoscopy: This is usually performed to evaluate the status of enlarged mediastinal lymph nodes (seen on CT scan) before attempting definitive surgical resection of lung cancer. Thoracoscopy: This is usually reserved for tumors that remain undiagnosed after bronchoscopy or CT-guided biopsy. Thoracoscopy is also an important tool in the management of malignant pleural effusions. CT-guided biopsy: This procedure is preferred for tumors located in the periphery of the lungs because peripheral tumors may not be accessible through a bronchoscope. Biopsy of other sites: Diagnostic material can also be obtained from other abnormal sites (eg, enlarged palpable lymph nodes, liver, pleural, or pericardial effusions). Histologic Findings The updated World Health Organization classification of lung cancer is widely used. Non- small cell lung cancer includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Sometimes, lung cancers can exhibit 2 or more histologic patterns. Adenocarcinoma appears to be increasing in incidence, especially in women, compared with squamous cell carcinoma, which was previously the most common type of non-small cell lung cancer. Histologically, adenocarcinomas form glands and produce mucin. Mucin production can be identified with mucicarmine or periodic acid-Schiff staining. The World Health Organization classification of lung cancer divides adenocarcinomas into (1) acinar, (2) papillary, (3) bronchoalveolar, and (4) mucus-secreting. Bronchoalveolar carcinoma is a distinct clinicopathologic entity that appears to arise from type II pneumocytes and may manifest as a solitary peripheral nodule, multifocal disease, or a pneumonic form, which can spread rapidly from one lobe to another. Stages for stage adenocarcinomas are associated with worse prognoses than squamous cell carcinomas, with the exception of T1 N0 M0 tumors. Squamous cell carcinoma has a distinct dose-response relationship to tobacco smoking and usually develops in proximal airways, progressing through stages of squamous metaplasia to carcinoma in situ. Well-differentiated squamous cell carcinomas contain keratin pearls, while poorly differentiated squamous cell carcinomas may stain positive for keratin. Microscopic examination reveals cells with large, irregular nuclei and coarse nuclear chromatin with large nucleoli. Cells are arranged in sheets, and the presence of intercellular bridging is diagnostic. Large cell carcinoma is the least common of all non-small cell lung cancers. It is composed of large cells with prominent nucleoli, and no mucin production or intercellular bridging is identified. Many tumors previously diagnosed as large cell carcinomas are identified as poorly differentiated adenocarcinomas or squamous cell carcinomas after advanced immunohistochemical staining, electron microscopy, and monoclonal antibody studies. A variant of large cell carcinoma has been identified; it contains neuroendocrine features and is called large cell neuroendocrine carcinoma. Large cell neuroendocrine carcinomas are associated with a worse prognosis than large cell carcinomas. Staging The staging of all non-small cell lung cancers follows the TNM (Tumor, Node, Metastasis) system. The current 6th edition of the TNM staging system came into effect in 1997 after revisions for stage groupings for stages I, II, and III. The following images also list stages and stage groupings. Stage grouping for TNM system of non–small cell lung cancer. The most important prognostic indicator in lung cancer is the extent of disease and lymph node involvement. The American Joint Committee for Cancer Staging and End Results Reporting has developed the TNM staging system, which takes into account the degree of spread of primary 12 tumor, the extent of regional lymph node involvement, and the presence or absence of distant metastases. The TNM system is used for all lung carcinomas except small cell lung carcinomas. For TNM staging, non-small cell lung cancer is divided into 4 stages, with further subdivision of stages I-III into A and B subtypes. These stages have important therapeutic and prognostic implications, which are discussed later. Tumor (T) o TX - Positive malignant cytology results, no lesion seen o T1 - Diameter 3 cm or smaller o T2 - Diameter larger than 3 cm o T3 - Extension to pleura, chest wall, diaphragm, pericardium, within 2 cm of carina, or total atelectasis o T4 - Invasion of mediastinal organs (eg, esophagus, trachea, great vessels, heart), malignant pleural effusion, or satellite nodules within the primary lobe Regional lymph node involvement (N) o N0 - No lymph nodes involved o N1 - Ipsilateral bronchopulmonary or hilar nodes involved o N2 - Ipsilateral mediastinal or subcarinal nodes o N3 - Contralateral mediastinal, hilar, any supraclavicular nodes involved Metastatic involvement (M) o M0 - No metastases o M1 - Metastases present Stage groupings o IA - T1 N0 M0 o IB - T2 N0 M0 o IIA - T1 N1 M0 o IIB - T2 N1 M0 or T3 N0 M0 o IIIA - T1-3 N2 M0 or T3 N1 M0 o IIIB - Any T4 or any N3 M0 o IV - Any M1 This staging system is scheduled to be modified in late 2009, drawing upon the results of a large International Association for the Study of Lung Cancer (IASLC) analysis of 100,879 patients drawn from 19 countries. Prominent anticipated changes include the following: Change in primary tumor size cut offs of 2, 3, 5, and 7 cm Further subdivision of T1 and T2 disease into a and b, based on size Satellite nodules in same lobe to be considered as T3 instead of T4 Satellite nodules in different lobes of the same lung will be classified as T4 instead of M1 lesions Malignant pleural effusions, nodules or pericardial effusions to be considered M1 disease instead of T4 M1 disease further classified into M1a – implying local metastases to pleura, pericardium or opposite lung or M1b – for distant metastases This will impact the staging of lung cancer, and is believed to better correlate with lung cancer survival, as well as more consonant with management paradigms. It is expected that the American Joint Committee on Cancer (AJCC) and its international counterpart, the International Union against Cancer (UICC) will accept these proposed changes. 13 Medical Care The roles of surgery, chemotherapy, and radiation therapy for non-small cell lung cancer are discussed in this section. For an overview, see the image below. Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment of patients with non-small cell lung cancer. Surgery o Surgical resection remains the mainstay of treatment for all patients with stage I and II non-small cell lung cancer—that is, those patients with no evidence of mediastinal disease or invasion of local organs. The role of surgery for stage III disease is controversial (see discussion below). Patients with completely resectable primary tumors (ie, T4 N0) have a much better prognosis than those with spread to ipsilateral mediastinal or subcarinal lymph nodes (ie, N2), signifying that spread beyond the primary tumor is associated with a poor prognosis. Patients with stage IIIB or IV tumors are almost never surgical candidates. o Lobectomy: The standard surgical approach remains a lobectomy, which helps preserve pulmonary function, while allowing a good resection. Hilar and other proximal tumors may require more extensive surgery, including a pneumonectomy, which carries significant operative mortality and long-term morbidity. In such patients, alternative approaches such as sleeve resection may be of value. 14 o Wedge resection/segmentectomy: Sublobar resections are used for patients with poor pulmonary reserve and are increasingly being used in conjunction with video-assisted thoracoscopic surgery (VATS). An older Lung Cancer Study Group trial, of stage IA cancers randomized to standard lobectomy versus sublobar resections, suggested a much higher local recurrence rate (75%), with a near-significant trend towards an increased cancer-specific mortality of 50% (P =0.09). A retrospective SEER analysis, however, showed no difference in overall survival in patients older than 74 years. However, smaller single-institution studies show good long-term survival in stage I patients treated with sublobar approaches. A Cancer and Leukemia Group B (CALGB) phase III trial randomizing patients to lobectomy or limited resection for small peripheral IA lesions is ongoing, and should provide more clarity in this area. o Video-assisted thoracoscopic surgery (VATS): This is a minimally invasive surgical modality being used for both diagnostic and therapeutic lung cancer surgery. It offers low perioperative morbidity and mortality as well as decreased pain and hospitalization. Recurrence rates and 5-year and long-term overall survival appear similar to those with traditional open thoracotomies. This approach is also better tolerated in older populations. Finally, patients treated with VATS appear to have fewer delays and dose reductions in adjuvant chemotherapy. Practice guidelines suggest that VATS is feasible as long as adequate resection is possible. o Mediastinal lymphadenectomy: The role of routine mediastinal lymphadenectomy versus lymph node sampling remains controversial. A large randomized trial comparing these modalities for patients with N0 or hilar N1 disease is still in progress. The authors recommend that an adequate mediastinal lymphadenectomy should include exploration and removal of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right-sided cancers and stations 4L, 5, 6, 7, 8, and 9 for left-sided cancers. o Preoperative evaluation: This should include a careful assessment of resectability, cardiopulmonary reserve, and perioperative risk. o Pulmonary function tests: As a general guideline, most patients with a preoperative forced expiratory volume in one second (FEV 1) of greater than 2.5 L are able to tolerate pneumonectomy. With an FEV1 of 1.1-2.4 L, a lobectomy is possible. With an FEV1 of less than 1 L, patients are not considered candidates for surgery. These factors are further modified by the presence of cardiac disease or other comorbid conditions. o Postoperative evaluation: Residual pulmonary function after surgical resection is estimated using pulmonary function tests and radionuclide lung scans. o Complications: The perioperative mortality rate is 6% for pneumonectomy, 3% for lobectomy, and 1% for segmentectomy. These rates reflect improvements in anesthesia and surgical techniques. Radiation therapy o In the treatment of stage I and stage II non-small cell lung cancer, radiation therapy alone is considered only when surgical resection is not possible because of limited pulmonary reserve or the presence of comorbidities. o Radiation therapy alone as local therapy, in patients who are not surgical candidates, has been associated with 5-year cancer specific survival rates of 13-39% in early-stage non-small cell lung cancer (ie, T1 and T2 disease). o This inferior survival reflects the poor functional status of these patients, as well as the likelihood of these patients actually having a higher stage, given the known limitations of clinical staging. Survival appears to be enhanced by the use of hyperfractionation schedules, such as continuous hyperfractionated accelerated radiotherapy (CHART) at 1.5 Gy 3 times a day for 12 days, as opposed to conventional radiation therapy at 60 Gy in 30 daily fractions. Overall survival at 4 years was 18% vs 12%. 15 o Other techniques for nonoperative treatment for early stage lung cancers include stereotactic body radiotherapy (SBRT) that uses precise targeting of high-dose radiation to the tumor, typically in 1-2 fractions, while minimizing toxicity to normal tissues. A large Japanese retrospective analysis showed that patients treated with SBRT at doses higher than 100 Gy had a local recurrence rate of 8.4%, and a 5-year overall survival of 70.8%. This is being studied in a randomized fashion by Radiation Therapy Oncology Group (RTOG). Patients best suited for SBRT include those with a peripheral node-negative tumor that is less than 5 cm, in whom definitive surgery is contraindicated. o A nonrandomized study by Grills et al compared outcomes in patients with stage T1- 2N0M0 non-small cell lung cancer who were ineligible for lobectomy; these patients underwent either wedge resection (n = 69) or, if deemed medically inoperable, SBRT (n = 55). Compared with surgery, SBRT was associated with shorter overall survival but similar recurrence rates and cause- specific mortality. o Radiofrequency ablation (RFA) has also been used for inoperable patients who have peripheral tumors that are less than 3 cm in size, and occasionally in a palliative setting. In a single small nonrandomized prospective study, 2-year overall survival with stage I non-small cell lung cancer was 75% (45-92%). This may be an option for patients in whom both surgery as well as traditional external beam radiation therapy may be contraindicated. o The role of adjuvant radiation therapy after resection of the primary tumor remains controversial. Radiation therapy reduces local failures in completely resected (stages II and IIIA) non-small cell lung cancer but has not been shown to improve overall survival rates. In one study, 5- year overall survival was actually worse (30% vs 53%). A retrospective SEER analysis also showed that survival was lower for this population. A single phase III study using small fractions, with 3D treatment planning, showed a 5-year survival benefit in the radiation treatment arm (67% vs 48%). This finding has not been replicated; hence, at this time, postoperative radiation therapy for stage I and II lung cancer is reserved for positive margins, until further trials are conducted with modern radiation therapy planning and delivery. Combined chemoradiation therapy o The current standard of care in the management of good-risk (ie, Karnofsky performance score of 70-100, minimal weight loss) patients with locally advanced unresectable (stage IIIA) non- small cell lung cancer is combined-modality therapy consisting of platinum-based chemotherapy and radiation. This results in statistically significant improvement in both disease-free and overall survival rates compared with either modality used alone. o Randomized studies show longer survival in patients with unresectable stage III disease when treated with concurrent (rather than sequential) platinum-based chemotherapy and radiation therapy. An RTOG study compared cisplatin/vinblastine either given concurrently with radiation therapy or followed by radiation therapy. The concurrent group showed better median survival as well as overall survival (17 vs 14.6 mo and 21% vs 12%, respectively). o Chemotherapy regimens that have been studied in combination with radiation therapy include cisplatin/vinblastine and cisplatin/etoposide (5-y survival of 15%). In elderly patients or those with comorbidities and contraindications to cisplatin, weekly carboplatin/paclitaxel may be used, based on a phase II study that showed a median survival of 16.7 months. o Consolidation chemotherapy after chemoradiation had initially been shown to be beneficial in phase II studies, with docetaxel after chemoradiation with cisplatin/etoposide showing a median survival of 26 months and a 5-year survival of 29%. This regimen did not show improved survival in a phase III setting, and proved to be more toxic, hence, is no longer recommended outside a clinical trial setting. 16 o Chemoradiation followed by surgical resection has been studied given the high locoregional failure rate with chemoradiation alone. Uncontrolled phase II studies suggested possible survival benefit from this approach, but a phase III study showed only a nonsignificant trend toward better 5-year overall survival (27% vs 20%) despite an improvement in progression-free survival. The postoperative mortality rate was higher in those patients undergoing surgical resection. o A European Organization for Research and Treatment of Cancer (EORTC) study failed to show any benefit of resection over radiation therapy after neoadjuvant chemotherapy in patients with stage IIIA (N2) disease. Systemic therapy: chemotherapy o Only 30-35% of patients with non-small cell lung cancer present with sufficiently localized disease at diagnosis to attempt curative surgical resection (stages IA and IB, IIA and IIB, and IIIA). Approximately 50% of patients who undergo surgical resection experience local or systemic relapse; thus, approximately 80% of all patients with lung cancer are considered for chemotherapy at some point during the course of their illness. o At present, chemotherapy alone has no role in potentially curative therapy for non-small cell lung cancer. Relapse rate after surgical resection of localized non-small cell lung cancer is high. Recent trials have shown a survival benefit with adjuvant chemotherapy (ie, chemotherapy given after surgery) in resected stage IIA, IIB, and IIIA non-small cell lung cancer. o Two small, randomized trials have suggested that neoadjuvant chemotherapy (ie, chemotherapy given prior to surgery) prolongs survival in subjects with stage IIIA disease. Other similarly designed trials fail to confirm this. (See discussion below.) Chemotherapy may be considered as part of multimodality therapy for locally advanced non-small cell lung cancer and is used alone in the palliative treatment of stage IIIB non-small cell lung cancer (owing to malignant pleural effusion) and stage IV non-small cell lung cancer. o In advanced non-small cell lung cancer, patients with good performance status (ie, 0-2 on the Zubrod or Eastern Cooperative Oncology Group scale), greater than 70% on Karnofsky scale (shown below), and less than 10% body weight loss are good candidates for chemotherapy. Large meta-analyses from 16 randomized trials showed a significant survival advantage to patients getting chemotherapy as opposed to best supportive care. One-year survival in the chemotherapy arm was 29% as opposed to 20% in those receiving supportive care alone. This survival benefit was present irrespective of age or histology. There appears to be no detriment in quality of life in the patients treated with chemotherapy; hence, palliative chemotherapy should be offered to all patients who are willing and able to receive chemotherapy. o Non-small cell lung cancer is only moderately sensitive to chemotherapy, with single- agent response rates in the range of 15% or better. Newer agents (eg, gemcitabine, pemetrexed, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates from 20- 25%. Multiple randomized, controlled trials and large meta-analyses all confirm the superiority of combination chemotherapy regimens upfront for advanced non-small cell lung cancer. Two drug combinations showed better response rate (26% vs 13%) as well as improved 1-year survival (35% vs 30%). Addition of a third cytotoxic drug increased toxicity with a modest improvement in response rate, but no survival benefit. (See discussion on biologics below.) Hence, most first-line patients should be offered a chemotherapy doublet. o Cisplatin has been the cornerstone of most combination regimens studied in advanced non- small cell lung cancer. A recent meta-analysis of 16 trials comparing platinum-based regimens to nonplatinum agents, showed a statistically significant improved response rate as well as 1-year survival favoring cisplatin. A beneficial trend was noted with carboplatin-based combinations but this was not significant. Gastrointestinal toxicity was higher with cisplatin. ASCO guidelines 17 recommend that first-line treatment for non-small cell lung cancer should include a platinum combination. In younger patients, with a good performance status or in the adjuvant setting, cisplatin is preferred, but in older patients or those with significant comorbidities, carboplatin may be substituted. Some recent trials have studied nonplatinum combinations such as gemcitabine with a taxane, which have shown noninferiority, and may be an option for selected patients. (Also see newer chemotherapy combinations below.) o Several randomized controlled trials have failed to show a clear superiority of one platinum-containing combination over another. A landmark ECOG trial comparing cisplatin- gemcitabine, cisplatin-paclitaxel, cisplatin-docetaxel, and carboplatin-paclitaxel, suggested similar overall response rates (approximately 19%), and median survival (7.9 mo). One- and 2-year overall survival was also similar at 33% and 11%, respectively. The cisplatin-gemcitabine did appear to have an increased progression free survival, compared to the standard treatment arm of cisplatin-paclitaxel (4.2 mo vs 3.4 mo), with increased renal toxicity. This finding was confirmed by 2 Italian and Japanese studies, which showed similar efficacy of these combinations as measured by response rates or survival. However, a meta-analysis comparing cisplatin-gemcitabine with other platinum-containing regimens suggested an improved median survival (9 vs 8.2 mo), and an absolute improvement in 1- year overall survival of 3.9% as compared to nongemcitabine combinations. This effect was not sustained when compared against other third-generation cisplatin combinations. o For some time, non-small cell lung cancer histology was thought to not impact chemotherapy responsiveness. A phase III trial compared upfront cisplatin-pemetrexed to cisplatin- gemcitabine in stage III and IV non-small cell lung cancer showed similar response rates (30.6% vs 28.2%), median survival (10.3 mo each), and 2-year overall survival (18.9% vs 14%). These were statistically similar. However, in a preplanned subset analysis, patients with nonsquamous histology had a statistically better median survival with the cisplatin-pemetrexed combination: for adenocarcinoma (12.6 vs 10.9 mo) and large cell histology (10.4 vs 6.7 mo). In contrast, the patients with squamous cell histology did better with the cisplatin-gemcitabine combination (10.8 vs 9.4 mo). Cisplatin-pemetrexed is now the preferred combination for adenocarcinoma. o Selected patients with good responses to first-line chemotherapy, good performance status, and a long disease-free period between initial chemotherapy and relapse may be candidates for second-line chemotherapy. Docetaxel (Taxotere) and pemetrexed (Alimta) have been approved by the FDA in this clinical setting, but other drugs (eg, gemcitabine, vinorelbine), if not used in the first-line regimen, may result in similar palliation and clinical benefit. A phase III study published in 2009 compared immediate and delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer and found a statistically significant improvement in progression-free survival when docetaxel was administered immediately after front-line gemcitabine plus carboplatin, without increasing toxicity or decreasing quality of life. The increase in overall survival was not statistically significant. Another phase III trial of pemetrexed versus docetaxel showed similar efficacy for both agents in recurrent non-small cell lung cancer when administered as single-agent chemotherapy in second-line settings. Response rates (9.1% vs 8.8%) and overall survival (8.3 mo vs 7.9 mo) were similar. o Although platinum-based chemotherapy is currently standard of care in non-small cell lung cancer, data suggest that certain individual tumors may have inherent resistance to platinum compounds. Excision Repair Cross-Complementation Group 1 (ERCC1) is one such genetic abnormality and high levels of ERCC1 mRNA in tumor tissue have been associated with resistance to platinum. Holm et al found that, in patients receiving carboplatin and gemcitabine for inoperable 18 non–small cell lung cancer, the expression of ERCC1 had different effects on survival in men and women. In a retrospective study in 163 patients, men whose tumors were ERCC1 negative survived significantly longer than men with ERCC1 -positive tumors (median survival, 11.8 mo vs 7.9 mo; P = .005). Conversely, ERCC1 status had no effect on survival in women. o As with ERCC1, increased expression of Ribonucleotide Reductase subunit 1 (RRM1) has been associated with decreased response to gemcitabine and platinum. o In the future, therapy for non-small cell lung cancer may need to be tailored based on genetic characteristics of individual tumors. Gene expression profiling has been studied for accurate classification of histology of non-small cell lung cancer as well as prognostication, but this remains experimental. o A randomized, controlled, clinical trial found that patients with metastatic non-small cell lung cancer randomized to early palliative care had a better quality of life and, surprisingly, longer median survival than those randomized to standard oncologic care alone. The palliative care group also had less depressive symptoms, and fewer patients in this group received aggressive end-of-life care. Systemic therapy: the biologics o With the increased understanding of molecular abnormalities in lung cancer, recent research efforts have focused heavily on identifying molecular targets and using this knowledge to develop molecular-targeted therapies. o One such abnormality, which is common in non-small cell lung cancer, is overexpression of the epidermal growth factor receptor (EGFR). Stimulation of the EGFR pathway leads to increased autophosphorylation of a tyrosine kinase pathway associated with EGFR. This leads to a series of intracellular events culminating in increased mitotic and growth potential, increased ability to metastasize, and increased angiogenesis (new blood vessel formation) in the cancer cells. Cancers overexpressing EGFR have been shown to have increased resistance to therapy, increased metastatic potential, and poorer prognoses. o Gefitinib (Iressa) represents a class of EGFR tyrosine kinase inhibitors (TKI) that act intracellularly to block activation of EGFR pathway.Two large phase II trials led to the expedited approval of gefitinib in the United States as a third-line therapy. However, the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, a large phase III randomized trial that compared gefitinib with placebo in patients who had progressed following first-line chemotherapy found no significant improvement in median survival (5.6 vs 5.1 mo) overall and also in the adenocarcinoma subset (6.3 vs 5.4 mo). Planned subset analyses in patients who had never been smokers and those of Asian ethnicity showed significantly longer survival (8.9 vs 6.1 mo and 9.5 vs 5.5 mo) as compared to placebo. The INTEREST trial studied gefitinib in comparison to docetaxel in the second-line setting, which showed no significant difference in survival (7.6 vs 8 mo). Based on these data, gefitinib is no longer available in the United States to new patients. Mok et al conducted a large phase III study that compared gefitinib with carboplatin-paclitaxel in the first-line setting in Asian patients who had adenocarcinoma and had never smoked or were former light smokers (none in last 15 years). Patients receiving gefitinib had a higher response rate (43% vs 32%), with similar median survival (18.6 vs 17.3 mo). Patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation (n=261) had significantly longer progression-free survival in the gefitinib group compared with those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% confidence interval [CI], 0.36-0.64; P<0.001). Conversely, patients who were negative for 19 the mutation (n=176) had significantly longer progression-free survival in the carboplatin-paclitaxel group (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05-3.98; P<0.001). o A second EGFR TKI, erlotinib (Tarceva), improved survival rates compared to placebo in the second- and third-line setting. Erlotinib demonstrated improved response rates (8% vs <1%), and overall survival (6.7 vs 4.6 mo). This led to the FDA approval of erlotinib in the second-line setting. Similar to the experience with gefitinib, no benefit was seen when erlotinib was combined with chemotherapy. Earlier studies also showed better response rates and survival with females, Asian persons, nonsmokers, particularly those with adenocarcinoma histology especially bronchioalveolar cancer, as was seen with gefitinib. o Rosell et al evaluated the feasibility of large-scale screening for EGFR mutations in patients with advanced non-small-cell lung cancer. EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were found more frequently in women (69.7%), patients who had never smoked (66.6%), and those with adenocarcinomas (80.9%) (P<0.001 for all comparisons). These researchers concluded that large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment with gefitinib or erlotinib. o Cetuximab, a monoclonal antibody that binds the EGFR receptor is used in colorectal cancer as well as squamous cell cancer of the head and neck. It was studied in the first-line setting, in combination with cisplatin-vinorelbine, compared to cisplatin-vinorelbine alone, in patients with non-small cell lung cancer that expressed EGFR by immuno-histochemistry. The chemotherapy was given in combination with cetuximab for up to 6 cycles, and in responding patients, the cetuximab was continued until progression. Patients receiving cetuximab had an increased response rate (36% vs 29%), and improved median survival (11.3 vs 10.1 mo). Whites appeared to benefit more than Asian persons, who seemed to do worse with this regimen. K -ras mutations have been shown to demonstrate resistance to cetuximab in colon cancer, and this probably holds true for non-small cell lung cancer as well. Further studies on these molecular markers are ongoing, and are awaited to determine optimal strategies for the use of these agents. o An ECOG study has shown that addition of an anti-angiogenesis agent bevacizumab (Avastin) to standard first-line carboplatin-paclitaxel resulted in significant prolongation of survival. Bevacizumab was continued in patients who appeared to respond to 4-6 cycles of chemotherapy. The median overall survival was improved (12.3-10.3 mo), as was the response rate (35% vs 15%) compared to chemotherapy alone. Patients with squamous cell histology, brain metastases, clinically significant hemoptysis and ECOG performance status of greater than 1 were excluded. Despite increased hemorrhagic complications and treatment-related deaths, bevacizumab has now been approved for use in this setting in combination with chemotherapy. Bevacizumab has also been studied in combination with cisplatin-gemcitabine as first-line therapy for nonsquamous non-small cell lung cancer, with improved response rates (20.1% vs 34.1%) with modest improvement in progression-free survival (6.7 vs 6.1 mo).Overall survival was not different. o In a phase II trial, Karp et al studied the effect of combined anti-insulinlike growth factor 1 receptor antibody CP-751,871 (figitumumab) with paclitaxel and carboplatin in advanced treatment- naive non-small-cell lung cancer (NSCLC). Patients were randomized (2:1) to receive paclitaxel 200 mg/m2, carboplatin (area under the concentration-time curve [AUC] of 6), and CP-751,871 10-20 mg/kg (ie, PCI(10), PCI(20)) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to 6 cycles. In this phase II trial, PCI(20)/PC hazard ratio for progression-free survival was 0.8-0.56, 20 concluding PCI(20) to be safe and effective in NSCLC. A randomized, open-label, phase III trial is currently underway. Stage-based management Stage I (T1N0M0 and T2N0M0) o Surgery is the treatment of choice for stage I non-small cell lung cancer. A careful preoperative assessment of residual pulmonary reserve should be carried out prior to surgical planning. Although lobectomy is generally considered to be optimum procedure, those with limited pulmonary reserve may be considered for more limited resection with either a segmental or a wedge resection. The risk of local recurrence is higher with limited resection but no adverse effect on overall survival was reported in a randomized trial by the Lung Cancer Study Group. VATS may be used for surgical resection, given the apparently similar resection capability, and decreased postoperative morbidity. Patients with insufficient pulmonary reserve to undergo a resection may be treated with radiation therapy alone with curative intent. Retrospective data report a 5-year survival ranging from 10-25% with radiation therapy alone in this setting. Selected patients may be candidates for either stereotactic body radio therapy or radio frequency ablation for isolated lesions. o The role of postoperative radiation has been explored and a meta-analysis of 9 randomized trials revealed a reduction in overall survival with postoperative radiation therapy in stage I and II non-small cell lung cancer. However, it remains to be seen that with use of modern radiation techniques with better definition of target volume and cardiac sparing could alter these outcomes. o Adjuvant chemotherapy has been extensively explored in non-small cell lung cancer. A meta-analyses concluded that adjuvant cisplatin-based therapy improved survival in resected stage IB, II, and III non-small cell lung cancer. The absolute benefit in survival at 5 years was 6.9%, but in subset analyses, the benefit in stage IB was not statistically significant. No impact of age, sex, histology, or type of surgery was noted. The CALGB 9633 study randomized resected stage IB patients to 4 cycles of carboplatin-paclitaxel versus observation. This study initially showed improved overall survival at 4 years (71% vs 59%), but a longer term follow-up at 74 months showed no change in overall survival, except in patients with a tumor size greater than 4 cm. This contrasted with the results of a Canadian study that showed significantly improved 5- year survival for stage IB and II patients treated with adjuvant cisplatin-vinorelbine for 4 cycles. Patients with resected stage IB non-small cell lung cancer should, therefore, be counseled about risks and benefits of adjuvant chemotherapy and may be offered either 4 cycles of platinum-based doublet chemotherapy, preferably cisplatin or observation. Stage II (T1N1M0, T2N1M0, T3N0M0) o Surgical resection is the treatment of choice, except for those who are not surgical candidates because of comorbid conditions or poor pulmonary reserve. A long-term survival of 10- 25% has been reported in patients with radiation therapy alone delivered with curative intent. In such cases, however, the dose of radiation therapy should be approximately 60 Gy with careful planning to define tumor volume and avoid critical structures. Frequently a cone-down boost is used to enhance local control. Patient with resected stage II disease are candidates for platinum-based adjuvant chemotherapy (see discussion above) and should be offered 4 cycles of platinum-based adjuvant chemotherapy. Stage IIIA (T1N2M0, T2N2M0, T3N1M0, T3N2M0) o The management of stage IIIA non-small cell lung cancer is quite controversial, and surgical resection, chemotherapy, radiation therapy, or a combination of any of these modalities may be the optimal choice based on the clinical situation. Overall 5-year survival of stage IIIA (N2) 21 ranges from 10-15%. Stage IIIA has been an area of active research due to poor long-term result because of low resectability rates and very few patients (5-10%) who achieve long-term benefit with radiation therapy alone. o Patients who have mediastinal nodes involved with non-small cell lung cancer (N2 or N3 stage) have poor results from surgery, hence should be considered for definitive chemoradiation therapy. (See discussion above.) Cisplatin-based combinations (eg, with etoposide) are preferred, with carboplatin an acceptable alternative in patients with contraindications. Radiation is usually given in daily fractions for a total of 60 Gy. A cone-down boost may be useful. Hyperfractionation schedules appear to be better, but are not widely available. There does not appear to be significant survival benefit for further chemotherapy or surgery in patients treated upfront with chemoradiation. o A large randomized trial conducted by EORTC compared surgery versus radiation therapy following neoadjuvant chemotherapy and found no significant difference between the 2 approaches in stage IIIA N2 disease. Neoadjuvant chemotherapy followed by surgery may, however, be considered for younger patients with good performance status with stage IIIA disease. o Patients with stage III (T3-4, N1) disease of the superior sulcus are usually treated with neoadjuvant chemotherapy followed by surgical resection, since 2-year survival in this group is 50- 70%. o Patient with stage IIIA (T3, N1) disease who are candidates for surgical resection should be offered adjuvant chemotherapy after a definitive surgical resection, based on the results of IALT (International Adjuvant Lung Trial) and meta-analysis of adjuvant chemotherapy trials showing a hazard ratio of 0.87 with adjuvant chemotherapy. These patients should also undergo a mediastinal node dissection. In patients with positive margins, radiation therapy may be considered concurrently with chemotherapy. Several retrospective series have suggested that postoperative radiation therapy may improve local control in those with involved mediastinal nodes. Prospective trials also have revealed similar results and have been conflicting with regard to reduction in local recurrence with postoperative radiation therapy. A meta-analysis of 9 randomized trials of postoperative radiation therapy did not result in survival benefit in the entire group as well as the subgroup with N2 disease. o Neoadjuvant chemotherapy: Two small reports have shown improvement in disease-free and overall survival rates with neoadjuvant cisplatin-based chemotherapy for stage IIIA non-small cell lung cancer; this approach may be considered in patients with good performance status. This approach may also be employed for patients who have tumors that are too large for a radiation port, prior to definitive chemoradiation. Stage IIIB (T4 any N M0 or any TN3M0) o Patients with satellite lesions (T4 N0-1) should undergo a surgical resection if possible, followed by adjuvant chemotherapy. o All other patients with stage IIIB disease are usually not candidates for surgical resection and are best managed with chemotherapy, combination of chemotherapy and radiation therapy, or radiation therapy alone, depending on extent of disease, sites of involvement, and performance status of the patient. Patients who have malignant pleural effusion are not candidates for radiation therapy and are managed as stage IV (see below). o In an open-label, phase III study in chemotherapy-naive patients with stage IIIB NSCLC (n=676), cetuximab combined with first-line taxane/carboplatin chemotherapy did not reach statistical significant improvement for progression-free survival or overall survival; however, significant improvement was shown in overall response rate. o A meta-analysis of 10 randomized trials of combined chemoradiation therapy revealed a 10% reduction in risk of death with combined modality therapy compared with radiation alone. It appears that in appropriate candidates (with good performance status), chemotherapy given 22 concurrently with radiation results in superior survival compared to chemotherapy followed by radiation therapy. Patient with stage IIIB non-small cell lung cancer and poor performance status are not good candidates for chemotherapy or combined modality approach. These patients may benefit from radiation therapy alone to palliate the symptoms of shortness of breath, cough, and hemoptysis. Patients with invasive airway obstruction may be candidates for palliative endobronchial curettage or stenting to relieve obstructive atelectasis and dyspnea. Stage IV (distant metastases) o Patients with advanced non-small cell lung cancer should be evaluated for the presence of distant metastases. Patients with solitary brain lesions may benefit from a surgical resection, or stereotactic radiosurgery, if their primary disease is well controlled. Isolated adrenal masses should be resected, since many adrenal masses are benign and even oligometastatic adrenal disease can occasionally be well controlled. o Patients with isolated synchronous nodules (either in same or opposite lung) should be treated as 2 separate primaries. These patients may need PET scanning to identify occult metastases or serial scans prior to definitive surgical resection that may be counter-productive. o In first-line systemic therapy for stage IV disease, cisplatin-based regimens have provided clear evidence of improved median survival and reductions in risk of death. Patients with good performance status should be offered chemotherapy with a platinum-based combination. Older patients (>70 y) or those with contraindications may be treated with a carboplatin-based regimen, such as carboplatin-paclitaxel. o Younger patients (<70 y) with nonsquamous histology may be candidates for treatment with cisplatin-pemetrexed, which appears to be somewhat better than cisplatin-gemcitabine. Patients with nonsquamous histology, absence of cranial metastases, and no hemoptysis may be candidates for treatment with bevacizumab, which has been studied in combination with carboplatin-paclitaxel and cisplatin-gemcitabine. Antiangiogenic therapy is very expensive and potentially toxic even in carefully selected patients; hence, a detailed discussion with patients about its modest benefits versus the risks and costs is important. o Two-drug combinations have been found to be superior to single-agent treatment, and no therapeutic advantage is obtained with the use of 3 drugs. o Updated guidelines from the American Society of Clinical Oncology recommend stopping first-line cytotoxic chemotherapy at disease progression or after 4 cycles in patients who are not responding to treatment, and stopping 2-drug cytotoxic chemotherapy at 6 cycles, even in patients who are responding to therapy. o No clear survival benefit is observed from maintenance non-cross resistant chemotherapy, though this is being studied with agents such as pemetrexed. For example, Ciuleanu et al conducted a randomized, placebo-controlled, double-blind phase 3 study of maintenance therapy with pemetrexed in 663 patients with stage IIIB or IV disease who had not progressed on 4 cycles of platinum-based chemotherapy. Although pemetrexed was associated with toxic effects, pemetrexed therapy significantly improved progression-free survival (4.3 mo [95% CI, 4.1-4.7] vs 2.6 mo [1.7- 2.8]; hazard ratio [HR], 0.50; 95% CI, 0.42-0.61; p<0.0001) and overall survival (13.4 mo [11.9- 15.9] vs 10.6 mo [8.7-12.0]; HR, 0.79; 0.65-0.95; p=0.012) compared with placebo. o Small-molecule epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors such as gefitinib and erlotinib may benefit nonsmokers with adenocarcinomas, particularly bronchio- alveolar carcinoma, especially those females of Asian origin. In such patients, it may be helpful to evaluate for EGFR mutations and use these agents first line. o Similarly, patients with EGFR expression and absence of K -ras mutations may be considered for the addition of cetuximab to first-line chemotherapy. The combination of anti-VEGF 23 agents such as bevacizumab with anti-EGFR antibodies appears to detrimental in other settings, and its use in non-small cell lung cancer should be avoided. o Patients with progressive disease and good performance status may be candidates for treatment with single agent cytotoxic drugs such as docetaxel, pemetrexed, or gemcitabine, if not exposed to these drugs in the first-line setting. Selected patients can also be treated with erlotinib, though this is typically used in the third-line setting. o Patients with ECOG/Zubrod performance scores greater than 2 should be considered for palliative care, focused on symptom control. These patients should be recommended for enrollment in hospice care programs. Medication Unresectable non-small cell lung cancer is treated with chemotherapy or a combination of chemotherapy and radiation therapy. Aggressive antiemetic support and growth-factor support, when appropriate, are other integral parts of medical treatment of affected patients. Antibiotics are commonly required for treatment of infectious complications but are not discussed in this article. Aggressive antiemetic support to prevent, not treat, nausea and vomiting is essential because of the highly emetogenic potential of chemotherapy drugs and the doses used in the treatment of non-small cell lung cancer. This holds especially true for platinum-based chemotherapeutic regimens. The most common and effective agents are corticosteroids and the serotonin receptor antagonists, which include ondansetron (Zofran), granisetron (Kytril), and dolasetron (Anzemet). Deterrence/Prevention Cigarette smoking is the most common etiologic factor for lung cancer. The primary way to decrease the prevalence of lung cancer is to decrease the prevalence of smoking. Some measures for doing so include the following: Public education about the hazards of smoking More stringent legislation for tobacco control, including the increase of tax levies Banning of tobacco smoking in public areas Offering comprehensive strategies for smoking cessation to smokers, which include behavioral counseling, pharmaceutical aids such as varenicline, bupropion, and nicotine replacement therapy (eg, gum, transdermal patches). Screening No established role exists at this time for screening modalities for non-small cell lung cancer. Prevention is the more effective modality for decreasing the prevalence of non-small cell lung cancer. Current modalities including chest radiograph, chest computed tomography (CT), and sputum cytology has been studied. While both chest radiograph and CT scanning have the potential to pick up early lung cancer, they have not been proven to decrease cancer-specific mortality. The controversial I-ELCAP study was an observational cohort study that showed that lung cancers could be diagnosed at an early stage with protocol-based CT screening, but this study had no control group to determine the mortality benefits of such an approach. The authors’ conflicts of interest have also caused the findings of this study to be questioned. A large National Cancer Institute (NCI)- sponsored national lung cancer screening trial is ongoing to evaluate screening CTs as compared to screening chest radiographs.65 Complications Spinal cord compression o The skeletal system is a common site of spread of lung cancer. When cancer metastasizes to the axial skeleton, it may grow and compress the spinal cord. 24 o Patients usually report back pain and neurological symptoms in the form of decreased sensation in the lower half of the body, decreased strength, loss of bowel control, and loss of bladder control. A careful neurologic examination usually localizes the level of compression. o Suspected spinal cord compression is an emergency. Patients should immediately receive an adequate dose of a corticosteroid (usually intravenous dexamethasone at 10 mg followed by 4 mg q6h) and should undergo an immediate MRI scan of the vertebral column. If documented, spinal cord compression should be treated emergently with radiation therapy, and steroids should be tapered slowly. Metabolic complications o The most common metabolic complication associated with non-small cell lung cancer is hypercalcemia, which is usually associated with squamous cell carcinoma. o Other findings can include hyponatremia, and syndrome of inappropriate secretion of antidiuretic hormone should be considered. Complications of therapy: Chemotherapy can give rise to various adverse effects. o Febrile neutropenia or bleeding may result from bone marrow suppression. o Hyponatremia or hypomagnesemia may result from cisplatin nephrotoxicity. o Renal failure or ototoxicity may result from cisplatin. o Peripheral neuropathy may result from cisplatin, paclitaxel, and vinorelbine. Prognosis Estimated 5-year survival rates are as follows: Stage IA - 75% Stage IB - 55% Stage IIA - 50% Stage IIB - 40% Stage IIIA - 10-35% Stage IIIB - Less than 5% Stage IV - Less than 5% 25 Lung Cancer, Oat Cell (Small Cell) Small cell lung cancer (SCLC) is considered distinct from other lung cancers, which are called non–small cell lung cancers (NSCLCs), because of its clinical and biologic characteristics. Small cell lung cancer exhibits aggressive behavior, with rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes. Surgery usually plays no role in its management, except in rare situations.1 Small cell carcinomas arise in peribronchial locations and infiltrate the bronchial submucosa. Widespread metastases occur early in the course of the disease, with common spread to mediastinal lymph nodes, liver, bones, adrenal glands, and brain. In addition, production of a variety of peptide hormones leads to a wide range of paraneoplastic syndromes. The most common paraneoplastic syndromes are the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. In addition, autoimmune phenomena may lead to various neurological syndromes. Molecular pathogenesis Recent studies have identified both activation of oncogenes and inactivation of tumor suppressor genes in small cell lung cancer. To what extent these changes are causal events in the development of small cell lung cancer is not clearly known and remains an area of active research. Oncogenes Amplification of the myc family of oncogenes is the most common molecular abnormality identified in small cell lung cancer cell lines, xenografts in nude mice, and fresh tumor specimens. This change, however, is not identified in all small cell lung cancer tumors. Therefore, myc expression is unlikely to be an initial event in the pathogenesis of small cell lung cancer. C-myc, a member of the myc family, is found more commonly in relapsed tumors than in untreated tumors, and its expression in small cell lung cancer may carry a worse prognosis. Other members of the myc oncogene family include N-myc and L-myc, which have been found to be amplified in small cell lung cancer. N-myc amplification in small cell lung cancer also has been associated with resistance to therapy and poorer prognosis. Overall, the exact role of amplification of the myc family of oncogenes in the pathogenesis of small cell lung cancer is not clearly understood at present and requires further study. Other oncogenes that have been found to be amplified in small cell lung cancer include c-raf, c-erb -b1, and c-fms, but their association with pathogenesis and prognosis is even less clear. Tumor suppressor genes The retinoblastoma (RB) tumor suppressor gene is on chromosome 13 (13q14), and a high percentage of small cell lung cancers (as many as 60%) do not express RB messenger ribonucleic acid (mRNA). This high frequency of inactivation of a tumor suppressor gene suggests that this may be an important step in the molecular pathogenesis of small cell lung cancer. The most common molecular abnormality, however, is deletion of part of chromosome 3 (3p14). Mutations of the p53 tumor suppressor gene are commonly found in both small cell lung cancer and non-small-cell lung cancer, but their precise role in pathogenesis is not clear. Tobacco smoking and radon exposure are associated with p53 gene mutations. Frequency Globally, lung cancer is the most frequent malignancy in males, while it is the fifth most common cancer in females. According to World Health Organization (WHO) statistics, slightly more than 1 million cases of lung cancer are diagnosed annually around the world. This is less than expected, and the disparity most likely results from lack of diagnosis and/or underreporting in the developing countries. 26 Mortality/Morbidity Approximately 65-70% of patients with small cell lung cancer have disseminated or extensive disease at presentation. Extensive-stage small cell lung cancers are incurable, and patients with extensive disease have a median survival duration of 6 weeks. Patients presenting with localized disease (ie, limited stage) have a median survival duration of about 12 weeks. These survival figures are for untreated patients. The median survival of patients with small cell lung cancer who are treated with multiple agent chemotherapy and multimodality therapy are as follows: For limited disease, 20 months with a 2-year survival rate of 45% and a 5-year survival rate of 20% For extensive disease, 12 months with a 2-year survival rate in 1973 of 1.5% and 2-year survival rate in 2000 of 4.6% Race Separate data for small cell carcinoma are not available. Among men, the age-adjusted incidence of lung cancer (per 100,000) ranges from 14 in Native Americans, 42-53 for Hispanic and Chinese Americans, 71-89 for Vietnamese and whites, to 117 among blacks. Among women, the age-adjusted incidence of lung cancer ranges from 15 among Japanese persons, 16-25 among Hispanic and Chinese persons, 31-44 among Vietnamese, white, and black persons to 51 among Alaskan natives. Among each ethnic group, the incidence is at least twice as high in males as in females. Age-adjusted mortality rates among different ethnic groups follow a similar pattern. Sex The incidence of lung cancer is twice as high in males as in females. See Frequency. The incidence of lung cancer started to decline among males in the early 1980s and has continued to do so over past 20 years. By contrast, the incidence in women started to increase in the late 1970s and only recently reached a plateau. Age According to information from the American Cancer Society, the probabilities of developing lung cancer among males are as follows: from birth to 39 years, 0.04%; 40-59 years, 1.24%; 60-79 years, 6.29%; and from birth to death, 8.09%. Among females, the probabilities are as follows: from birth to 39 years, 0.03%; 40-59 years, 0.92%; 60-79 years, 4.04%; and birth to death, 5.78%. As with other histopathological cases of lung cancer, most cases of small cell lung cancer occur in individuals aged 35-75 years; incidence peaks in persons aged 55-65 years. Clinical History For patients with small cell lung cancer (SCLC) to present without any symptoms is very unusual. Fewer than 5% of patients have a small, asymptomatic primary tumor at presentation. Small cell lung cancer typically presents with a relatively short duration of symptoms. The onset of symptoms is usually within 8-12 weeks prior to presentation. The symptoms can result from local tumor growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes. Symptoms include the following: Constitutional symptoms o Fatigue o Anorexia o Weight loss Symptoms due to primary tumor o Cough o Dyspnea o Hemoptysis 27 Symptoms due to intrathoracic spread o Superior vena cava obstruction o Hoarseness (ie, palsy of the recurrent laryngeal nerve) o Phrenic nerve palsy o Dysphagia (ie, compression of esophagus) o Stridor (ie, compression of the trachea mainstem bronchus) Symptoms due to distant spread o Neurological dysfunction (ie, brain metastasis, spinal cord compression) o Bone pain (bone metastasis) o Abdominal/right upper quadrant pain (ie, liver metastasis) Local tumor growth: Small cell carcinomas usually are centrally located and may cause irritation, obstruction, or both of the major airway. Common symptoms resulting from local tumor growth include cough, dyspnea, and hemoptysis. Patients give a short history of symptoms of recent onset, with rapid worsening. Rapid tumor growth may lead to obstruction of major airways, with distal collapse and consequent postobstructive pneumonitis. Fever may result from infections distal to obstruction or from the tumor itself. Intrathoracic spread: Small cell carcinomas grow in size rapidly and metastasize to the mediastinal lymph nodes relatively early in the course of the disease. At presentation, patients may have a very large intrathoracic tumor, and distinguishing primary tumor from lymph node metastasis may be impossible. Pressure on mediastinal structures can cause a variety of symptoms. o Superior vena cava obstruction: Malignancy is the most common cause of superior vena cava (SVC) obstruction, and lung cancer accounts for the overwhelming majority of cases (60-90%). Small cell lung cancer causes SVC obstruction more often than non-small-cell lung cancer (NSCLC) does. Patients present with swelling of the face and upper extremities. Headache, dizziness, and other neurological symptoms are late occurrences. o Paralysis of the recurrent laryngeal nerve: The recurrent laryngeal nerve may be compressed by a mediastinal mass (ie, primary tumor or lymph node metastasis) as it traverses up on the left to supply the vocal cords. Patients complain of hoarseness of recent onset. o Phrenic nerve palsy: Compression of the phrenic nerve causes paralysis of the ipsilateral hemidiaphragm, contributing to respiratory symptoms. o Esophageal compression: Compression of the esophagus can lead to dysphagia and odynophagia. o Tracheal compression: Compression of the mainstem bronchi and trachea can cause severe shortness of breath and stridor. Symptoms from distant spread: These symptoms depend upon the site of spread. Common sites of spread include brain, bones, liver, adrenals, and bone marrow. Physical Physical findings in small cell lung cancer (SCLC) depend upon the extent of local and distant spread and the organ system involved. Respiratory system: Patients usually complain of shortness of breath, and examination may reveal use of accessory muscles of respiration (scalene muscles, intercostal muscles, flaring of alae of nose). In addition, by virtue of central tumor location, patients may develop distal atelectasis and postobstructive pneumonia. With pleural effusion, examination reveals dullness to percussion and decreased or absent breath sounds on the side of the effusion. Cardiovascular system: Small cell lung cancer may cause pericardial effusion and is the malignancy that most often causes obstruction of the SVC. 28 o Pericardial effusion: Pericardial effusions may be asymptomatic when small or may result in tamponade if they are large or accumulate over a short period. Patients are usually short of breath. Heart sounds may be distant on auscultation. Jugular venous pulsation is elevated; paradoxically, it rises with inspiration. o Pulsus paradoxus is a classic sign of pericardial tamponade. The diagnosis is established with cardiac catheterization, which reveals equalization of pressures in cardiac chambers. Tamponade is an emergency and requires immediate decompression of the pericardium. Definitive management may include chemotherapy and/or surgical creation of a pleuropericardial window. Central nervous system: Patients with small cell lung cancer may have asymptomatic brain metastasis in 5-10% of cases, which may be picked up on staging workup. o Brain metastasis: Patients with symptomatic brain metastases may have raised intracranial pressure secondary to mass lesions, as well as surrounding brain edema, and may complain of headache (usually worse early in the morning), blurring of vision, photophobia, nausea, vomiting, and various localizing symptoms, such as weakness of an extremity. The physical findings again are dependent upon site of the brain lesions. The examination should include funduscopy to look for signs of raised intracranial pressure and a detailed neurologic examination, including evaluation of cerebellar function, coordination, and gait. The diagnosis is established with a CT scan of the brain with contrast (if renal function is adequate). In difficult cases, a magnetic resonance scan of the brain may be appropriate. Since MRI is more sensitive than CT scan with contrast for detection of brain metastasis, it is used as the first- line imaging study in many institutions. Management includes high doses of corticosteroids (eg, dexamethasone 10 mg IV initially, followed by 4-6 mg IV/PO q6h) and immediate radiation therapy. o Vertebral and paraspinal metastases: The importance of early recognition of these metastases is due to their close proximity to the spinal cord, potentially leading to permanent loss of neurological function if diagnosis is delayed. The initial symptom is usually back pain, with or without neurological dysfunction. The main objective is to establish diagnosis early, before neurological dysfunction is established. Once present, neurological dysfunction can progress very rapidly (ie, within hours) to cause quadriplegia or paraplegia, depending upon the location. This condition is an oncologic emergency. Even though a CT myelogram can establish the diagnosis, MRI is noninvasive and very sensitive in establishing the diagnosis. Patients in whom spinal cord compression is suspected should receive a dose of intravenous corticosteroids even before being sent to the MRI suite. The typical dose is 10 mg of dexamethasone IV, followed by 4-6 mg IV/PO every 6 hours. The authors prefer the intravenous route because of the reliability of drug delivery. If the etiological cause is known (ie, a prior histologic diagnosis of SCLC), definitive management is radiation therapy, which should be started without any delay. Otherwise, if the patient presents with spinal cord compression and no prior diagnosis of cancer, surgical resection, if technically feasible, provides both immediate decompression and tissue diagnosis of the cancer. Gastrointestinal system: The liver is the common site of spread, and physical examination may reveal icterus (secondary to widespread liver metastasis or obstruction of biliary outflow) or hepatomegaly. However, most patients do not have any specific finding related to the gastrointestinal tract on examination. 29 Lymphatic system: Lymph node examination should be carried out carefully. Currently, enlarged ipsilateral supraclavicular lymph nodes are included in limited stage, but enlarged axillary lymph nodes upstage the diagnosis to extensive-stage disease. Extremities: Examination of the extremities may reveal clubbing, cyanosis, or edema. In the presence of SVC obstruction, the right upper extremity usually is edematous. Causes The predominant cause of small cell lung cancer, as of non-small-cell lung cancer, is tobacco smoking. Of all histologic types of lung cancer, in fact, small cell lung cancer and squamous cell carcinoma have the strongest correlation to tobacco. Some 98% of patients with small cell lung cancer have a smoking history. Patients with diagnosed small cell lung cancer should be encouraged or required to stop smoking; this may contribute to improved survival. Uranium mining: All types of lung cancers occur with increased frequency in uranium miners, but small cell lung cancer is most common. The incidence is increased further in persons who smoke tobacco. Radon exposure: Exposure to radon, which is an inert gas developing from the decay of uranium, also has been reported to cause small cell lung cancer. Laboratory Studies Investigations are performed to identify limited-stage disease (ie, potentially curable and requiring the addition of radiotherapy to its management), as well as to assess organ function before starting therapy. CBC count: In 5-10% of patients, the disease may have spread to bone marrow at presentation. Bone marrow examination is not routinely performed unless abnormalities are identified in the CBC count or peripheral smear examination, raising the possibility of bone marrow spread. These may include variable degrees of cytopenias; the presence of immature white and red blood cells (a leukoerythroblastic blood picture) raises the possibility of myelophthisic anemia. Additionally, the absolute neutrophil count should be >1000 x 103/µL, hemoglobin >10 g/dL, and platelet count >100 x 103/µL before instituting initial full-dose combination chemotherapy. Serum chemistries: Elevated serum calcium and alkaline phosphatase raise the suspicion of bone metastasis, and bone scan should be ordered even in the absence of symptoms. Serum electrolytes should be obtained to look for paraneoplastic syndromes, as already discussed. The presence of hyponatremia is considered an adverse prognostic indicator. Elevated serum lactate dehydrogenase (LDH) indicates increased tumor mass and cell turnover and is an adverse prognostic indicator. Abnormal liver function findings raise the possibility of hepatic metastasis and may provide a clue to the cause (eg, biliary outflow obstruction versus parenchymal liver metastasis). Imaging Studies CT scans: The patient in whom lung cancer is suspected or diagnosed should undergo imaging of the thorax and all common sites of metastasis to stage the disease adequately. In the United States, CT scans of the chest and upper abdomen to include the liver and adrenal glands are standard. Even though some controversy exists regarding routine pretreatment CT/MRI scanning of the brain in asymptomatic patients, most authors consider it prudent to obtain a baseline scan of the brain in all patients. Magnetic resonance imaging: MRI scans are not part of the routine staging workup of small cell lung cancer, even though they have been shown to detect abnormal bone marrow signal in patients with bone marrow metastasis. MRI scans have an increased ability to detect disease in proximity to neurovascular structures. MRI examination is considered standard in the workup of patients in whom spinal cord compression is suspected. 30 Radionuclide imaging: Bone metastases from small cell lung cancer are predominantly osteoblastic, and a bone scan is superior to plain radiographs in detecting osteoblastic lesions. Bone scans should be obtained in all patients with small cell lung cancer at diagnosis or during follow-up if new bone symptoms develop or if serum calcium or alkaline phosphatase level is elevated. Positron emission tomography: Positron emission tomography (PET) scanning still is under evaluation for lung cancers and, to date, has had its greatest application in non-small-cell lung cancer, in which it is used to more accurately stage patients prior to anticipated surgery. Other Tests Sputum cytology is a noninvasive test, and, if positive, usually allows more invasive diagnostic tests to be averted. The highest yield of this test is with large, central tumors. However, because small cell lung cancer cells involve the submucosal layer of the bronchi with little or no exophytic endobronchial extension sputum cytology may be uncommonly positive. This may be true as well of bronchial washings. Bronchoscopy: Small cell lung cancer is usually centrally located and can be approached easily with a bronchoscope. The advantage of endoscopy is direct visualization of the tumor, allowing direct biopsy as well as cytologic examination of bronchial washings. Transthoracic percutaneous fine-needle aspiration: For accessible tumors, this test is less invasive than bronchoscopy and is carried out under CT scan guidance. Procedures Thoracentesis: The presence of malignant pleural effusion upstages the disease to extensive stage. For adequate staging, pleural effusions should be aspirated and examined for malignant cells if no other sites of distant spread are identified. If a large symptomatic pleural effusion is present, therapeutic thoracentesis provides symptomatic relief. In patients with resistant, relapsed, or nonresponding disease, thoracentesis can be combined with pleurodesis to prevent recurrence. The preferred agent is currently sterilized talc, which can be instilled either as a slurry or as a powder during pleuroscopy. A large randomized study conducted by Cancer and Leukemia Group B will likely answer the question of whether slurry or poudrage is superior. Bone marrow aspiration and biopsy: Bone marrow examination is necessary in patients in whom myelophthisic anemia (leukoerythroblastic peripheral blood) is suspected. Histologic Findings Small cell lung cancer is typically centrally located, arising in peribronchial locations. They are thought to arise from Kulchitsky cells. The tumor is composed of sheets of small, round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. Crush artifact leading to nuclear molding is a common finding, but it is not considered diagnostic. Very high rates of cell division are observed, and necrosis, sometimes extensive, may be seen. Because of the central location, the cells exfoliate in sputum and bronchial washings. Neurosecretory granules can be identified on electron microscopy, and the neuroendocrine nature of the neoplasm is suggested by its frequent association with paraneoplastic syndromes caused by peptide hormones. Immunohistochemical stains for chromogranin, neuron-specific enolase, and synaptophysin are usually positive. Approximately 5% of small cell lung cancers exhibit features of mixed small cell and large cell components and, less frequently, may exhibit mixed small cell and squamous cell components. 31 The World Health Organization (WHO) classified small cell lung cancers into 3 subcategories: oat cell carcinoma, intermediate cell type, and combined oat cell carcinoma. This subclassification has been difficult to reproduce, however, even by expert lung cancer pathologists, and in 1988, the International Association for the Study of Lung Cancer recommended dropping the intermediate cell type from the classification and adding the category of mixed small cell carcinoma and large cell carcinoma. Staging Almost all solid tumors are staged using the tumor, node, metastases (TNM) system because it provides important prognostic information and is used to design management plans. However, the TNM system has failed to provide important prognostic information in patients with small cell lung cancer and is useful only in a few patients (<5%) who may benefit from a very detailed staging according to the TNM system. The 2-stage system used for small cell lung cancer initially was proposed by the Veterans Administration Lung Group. Patients with disease confined to one hemithorax, with or without mediastinal, contralateral hilar, or ipsilateral supraclavicular or scalene lymph nodes are considered to have limited-stage disease, while those with disease involvement at any other location are considered to have extensive-stage disease. (The involvement of supraclavicular nodes and the presence of cytologically positive pleural effusion subsequently have been placed in different stage groupings in slightly revised staging classifications.) The key variable in this purposely vague staging definition is the ability to encompass the entire disease within one radiation therapy port. A slight modification of this system is used currently and is as follows: Limited stage: Disease confined to one hemithorax; includes involvement of mediastinal, contralateral hilar, and/or supraclavicular and scalene lymph nodes. Malignant pleural effusion is excluded. Extensive stage: Disease has spread beyond the definition of limited stage, or malignant pleural effusion is present. The purpose of the staging workup is to determine the prognosis and management of small cell lung cancer. Patients with limited-stage disease are offered combined chemoradiotherapy, while those with extensive-stage disease are usually treated with chemotherapy alone. Staging workup of small cell lung cancer is as follows: o Complete history and physical examination o Chest radiograph o CT scans of chest and abdomen o CT scan/MRI of brain o Bone scan o CBC count with differential o Bone marrow aspiration and biopsy if abnormalities in CBC count or peripheral smear o Serum electrolytes, including calcium o Liver function tests o Renal function tests o Serum LDH o Serum alkaline phosphatase History and physical examination: A thorough history and physical examination usually provide clues to the organ systems involved and are used to guide further workup. Chest roentgenogram: Good posteroanterior and lateral radiographs are useful in identifying the primary tumor as well as concurrent parenchymal abnormalities. Mediastinal widening may be noticed as well. 32 CT scans of chest and abdomen: Evaluation via CT scan of thorax (lungs and mediastinum) and commonly involved abdominal viscera (ie, liver, adrenals) is the minimum requirement in standard staging workup of small cell lung cancer. Bone scan: Bone is a common site of metastasis for small cell lung cancer, and a radionuclide bone scan should be obtained to identify bone metastases. Since some benign etiologies can also cause abnormalities on bone scan, obtaining plain radiographs of abnormal areas for radiographic correlation is important. CT scan/MRI of brain: Brain metastasis may be present in as many as 10% of patients at diagnosis and may be occult in 5% of patients. Even though obtaining imaging scans of brain in all patients at diagnosis is controversial, the policy of most authors is to obtain a scan of the brain at diagnosis for adequate staging. Bone marrow examination: Even though some authorities recommend a bone marrow examination in patients in whom no other site of spread is identified (ie, in cases in which detection of bone marrow involvement would change the staging from limited to extensive disease), the majority of authors recommend bone marrow examination only in patients in whom bone marrow involvement is suspected owing to abnormal findings on CBC count or peripheral smear. Blood workup o CBC count with differential, serum electrolytes, renal function studies, and liver function tests are all are part of the routine staging workup, and in some cases they may identify the site of metastasis, for instance elevated serum calcium level with bone metastasis. These tests are also important to assess organ function prior to starting therapy. o Serum LDH and sodium levels also provide prognostic information. Increased uric acid levels may indicate the possibility of rapid tumor lysis syndrome with therapy. Medical Care Small cell lung cancer (SCLC) differs from other lung cancer types because of its rapid growth and propensity for early dissemination. Surgery plays little, if any, role in the management of small cell lung cancer, except in a small minority of patients who present with very early stage disease confined to lung parenchyma. Patients with limited stage disease with apparent clinical stage T1/T2, N0 should undergo mediastinoscopy. Should the mediastinoscopy prove to be negative, they might have a surgical resection to involve lobectomy, wedge resection, or pneumonectomy together with mediastinal lymph node removal.1 If mediastinal lymph node involvement is not found, then consideration should be given to a 4-6 cycle course of adjuvant chemotherapy with combinations of agents known to be effective in limited or extensive disease, that is etoposide and either cisplatin or carboplatin. This would be a reasonable recommendation despite the relative lack of evidence-based data to support it because of the aggressive nature of small cell lung cancer and its known tendency to metastasize early and often. Management of limited-stage small cell lung cancer involves combination chemotherapy, usually with a platinum-containing regimen, and thoracic radiation therapy. If the patient achieves a complete remission, he or she would be offered prophylactic cranial irradiation. A number of platinum- and nonplatinum-based chemotherapy regimens have been used in the treatment of small cell lung cancer with varying results. A recent review by Amarasena et al analyzed the data from trials to compare effectiveness. They concluded that platinum-based chemotherapy regimens did not provide a statistically significant benefit over nonplatinum-based agents in survival or overall tumor response, but they did increase complete response rates, with an associated higher incidence of nausea, vomiting, anemia, and thrombocytopenia. They suggest the nonplatinum chemotherapy regimens may have a better risk-benefit profile. 33 Extensive-stage small cell lung cancer remains incurable with current management options, and patients are treated with combination chemotherapy. Several chemotherapy combinations are active in small cell lung cancer, but usually a platinum-containing regimen is chosen. It should be noted, however, that despite great enthusiasm of 2 decades ago, little change in survival has been shown for both limited- and extensive-stage small cell lung cancer. Very few new agents with activity in small cell lung cancer have been identified. While identification of molecular targets and targeted therapies has proceeded at a brisk pace in non-small-cell lung cancer, the same has not been true for small cell lung cancer. Treatment strategies involving angiogenesis blocking agents are currently being tested. Treatment recommendations can be summarized as follows: Single-agent chemotherapy: Several chemotherapeutic agents have been identified in the last 3 decades that yield response rates in excess of 30% in previously untreated patients who have small cell lung cancer. Even though cisplatin is currently the most widely used agent in combination chemotherapy programs, response rate data for single-agent cisplatin in previously untreated patients with small cell lung cancer are lacking. In previously treated patients, however, cisplatin has shown a response rate of 17%. o Currently cisplatin, etoposide, vincristine, doxorubicin, and cyclophosphamide are the agents most commonly employed to treat previously untreated patients with small cell lung cancer. Scheduling of etoposide has been demonstrated to be important in achieving a higher response rate, and currently etoposide is given over 3 days. o Protracted oral administration of etoposide has been an acceptable initial therapy in elderly patients with extensive-stage small cell lung cancer, especially in those with poor performance status, but more recent studies suggest combination chemotherapy may be better than single-agent oral etoposide in those with good performance status. o The taxanes and topotecan have emerged as active agents in previously untreated patients with small cell lung cancer. The response rates range from approximately 40% with topotecan to 50% with paclitaxel. Combination chemotherapy: Even though a few studies have suggested that the response rates and survival may be comparable between single-agent etoposide and more standard combination chemotherapy regimens in previously untreated patients with small cell lung cancer, combination chemotherapy is accepted widely as being associated with superior response rates and survival. A number of randomized trials have tried to answer the questions of superiority of combination over single-agent chemotherapy, the number of drugs in combination, and dose intensity, and nonrandomized trials of combination chemotherapy have shown superior response rates and survival compared to single-agent chemotherapy. o The combination of cisplatin and etoposide (PE) is currently the most widely used regimen in both limited- and extensive-stage small cell lung cancer. o The combination of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) has been compared to PE in at least 2 randomized trials of previously untreated extensive-stage small cell lung cancer showing similar survival outcomes. o The combination of cisplatin and etoposide is associated with less myelosuppression, while CAV has the convenience of administration in a single day (PE requires a 3-day program). Dose intensity and density: Several trials have tested the use of higher doses of standard chemotherapeutic regimens in previously untreated small cell lung cancer. Despite early enthusiasm brought on by higher initial response rates, most of these trials have failed to improve survival. o A trial reported by Arriagada et al comparing standard and higher doses of cyclophosphamide and cisplatin in the first cycle of chemotherapy only yielded a superior survival 34 rate in patients receiving higher dose chemotherapy.4 Higher dose regimens, however, may cause life-threatening myelosuppression and, in the absence of survival advantage, should not be used outside a clinical trial. o Another approach to increase the intensity of chemotherapy is to shorten the interval between cycles (increased dose density). Again, even though phase II trials suggested the superiority of such an approach, randomized trials failed to show an advantage of intensive weekly chemotherapy over standard regimens. One of the problems has been myelosuppression with weekly programs such that the planned dose intensity has not been reached. Growth factor support may overcome this, but until randomized trials are reported showing clear superiority of such an approach, it remains investigational. High-dose chemotherapy with bone marrow or stem cell transplantation: The available data do not support the use of such an approach because it has not yielded better survival rates than standard management and is associated with greater immediate and delayed toxicity. Standard management of limited-stage small cell lung cancer: Staging should be adequate. Any pleural effusion should be tested cytologically for malignant cells, and isolated liver or adrenal lesions should be sampled by fine-needle aspiration before a diagnosis of limited stage is made. Some authorities suggest a bone marrow examination in the absence of any other evidence of spread. o Standard management involves combination chemotherapy with a cisplatin-containing regimen and concurrent thoracic radiotherapy. The chemotherapy cycles are repeated every 3 weeks, and currently no data support continuation of chemotherapy beyond 6 cycles. In North America, the chemotherapy regimen used is etoposide and cisplatin. (Should the patient relapse after 6 months of completion of induction therapy, an attempt may be made to repeat the induction regimen. Relapses prior to the 6 month point would require salvage therapy.) Patients are started on thoracic radiotherapy, which should be begun as early as possible according to some authorities. Others advocate giving the radiation therapy concomitantly with the fourth cycle of chemotherapy. A randomized trial reported by Takada and colleagues that compared cisplatin and etoposide with concurrent versus sequential thoracic radiotherapy reported superior 2- and 5-year survival rates (2-y survival 35.1% versus 54.4%, and 5-y survival 18.3% versus 23.7% in favor of concurrent chemotherapy and radiation) with concurrent approach. Hematologic toxicity was greater in concurrent arm.5 Another randomized trial by Turrisi and colleagues demonstrated a slight superiority of concurrent hyperfractionated radiotherapy given with 4 cycles of PE in limited-stage small cell lung cancer. Five-year survival rates in this trial were 26% versus 16% in favor of hyperfractionated radiotherapy.6 o Prophylactic cranial irradiation: The use of prophylactic cranial irradiation (PCI) was initially considered controversial.7 Several randomized trials showed a decrease in CNS relapse rate with PCI but no survival advantage. Additionally, patients receiving PCI had a higher incidence of neuropsychiatric dysfunction than those who did not receive PCI. Arriagada et al reported a meta- analysis of randomized trials of PCI in limited-stage small cell lung cancer and showed a 5% overall survival advantage in those receiving PCI.4 Even though such an analysis has inherent limitations, PCI is currently offered to patients with limited-stage small cell lung cancer who have achieved complete remission after having completed the full chemoradiotherapy regimen. Such therapy decreases the incidence of later intracranial metastases and prolongs survival. It should be regarded as standard therapy. Standard management of extensive-stage small cell lung cancer: Patients with extensive- stage disease are treated with combination chemotherapy alone. Even though a combination of 35 cisplatin and etoposide remains most widely used, a recently reported randomized trial compared the combination of cisplatin with either etoposide or irinotecan in extensive-stage small cell lung cancer. The combination of cisplatin and irinotecan was found superior to that of cisplatin and etoposide, with a median survival of 12.8 months with the cisplatin/irinotecan combination versus 9.4 months with cisplatin and etoposide. The 2-year survival rate was also superior at 19.5% versus 5.2%. However, a confirmatory study in the United States failed to show superiority of either regimen. Possible reasons for these results may be different dose and schedule of chemotherapeutic agents as well as genetic changes within different study populations. Although etoposide/cisplatin and irinotecan/cisplatin had comparable overall response rates and survival outcomes, the combination irinotecan/cisplatin had more gastrointestinal toxicity. Etoposide/cisplatin remains the standard of care in North America for extensive small cell lung cancer. A recent clinical trial in Germany reported that topotecan/cisplatin had a similar overall response rate to etoposide/cisplatin in extensive small cell lung cancer but a better time to progression and objective response rate than did etoposide/cisplatin. 11 A trial comparing the two regimens in North America has not yet been performed. o Radiation therapy is used only to palliate symptoms, if required (eg, for painful bone metastases). Response rates are excellent, but patients invariably relapse. o Brain metastases at the time of initial diagnosis in extensive small cell lung cancer are present in about 18% of patients. This incidence increases to about 80% at 2 years. A recent study by the European Organization for Research and Treatment of Cancer (EORTC) randomized patients responding to systemic chemotherapy between prophylactic cranial radiation (PCI) versus no PCI. One-year survival for PCI group was 27.1% compared to 13.3% for those without PCI. Prophylactic cranial radiation not only reduced the incidence of brain metastases but also improved disease-free and overall survival rates. Thus, PCI should be offered to all responding patients with extensive stage small cell lung cancer and should be considered standard of therapy for this stage of the disease in these patients. o Management of relapse: Patients with relapsed small cell lung cancer have an extremely poor prognosis. Those whose disease does not respond to or progresses on initial treatment (ie, those with refractory disease) or those whose disease relapses within 6 months of completion of therapy have little chance of responding to additional chemotherapy. In general, PE given after CAV failure produces better response rates than CAV given after PE. Topotecan received US Food and Drug Administration (FDA) approval for use in chemotherapy-sensitive disease after failure of front-line chemotherapy. Because of the lack of long-term benefit of this therapy, however, patients with relapsed or refractory small cell lung cancer should be encouraged to enroll in clinical trials, if their condition permits. Consultations Patients in whom lung cancer is suspected may require consultation with a pulmonologist to establish a diagnosis. Once a diagnosis is established, medical and radiation oncologists should be consulted to complete the staging workup and devise a management plan. Diet Weight loss is an important factor indicating poor prognosis in patients with small cell lung cancer. A dietary consultation should be obtained for patients with persistent weight loss. Activity Performance status is another important prognostic factor. Patients who are ambulating less than 50% of waking hours have a worse prognosis. Activity should be encouraged. Medication The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications. 36 Antiemetic agents Vomiting induced by antineoplastic agents is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ or acetylcholine in VC, appears to be a major mediator in inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3 receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting. Antineoplastic agents may cause nausea and vomiting so intolerable that some patients refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents prior to and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen. Further Outpatient Care Patients with small cell lung cancer (SCLC) require close monitoring for adverse effects and response to therapy. Blood work, including CBC with differential, is needed prior to each cycle of chemotherapy to ensure marrow recovery before the next dose of chemotherapy is administered. Renal function should be monitored because of nephrotoxicity from cisplatin. CT scans should be obtained after 2 cycles of therapy to assess response before chemotherapy is continued. Serum LDH, if elevated before start of therapy, is a good marker for response and should be monitored. Patients who smoke cigarettes should be encouraged to quit. A meta-analysis by Parsons et al suggests that smoking cessation after diagnosis of early-stage lung cancer may improve prognosis, probably by reducing cancer progression.12 Evaluation of data from 9 studies showed that estimated 5-year survival in limited-stage small cell lung cancer was 63% in patients who quit smoking versus 29% in those who continued to smoke. Deterrence/Prevention Smoking cessation: Since tobacco smoking is the predominant cause of lung cancer, the only means of decreasing the incidence is decreasing the prevalence of smoking. The evidence is clear that the incidence of lung cancer is decreasing in men in the United States, and this decrease has coincided with a decrease in smoking among males. Concerted efforts are required from government, public health agencies, and health care providers to increase public awareness of the hazards of smoking, devise tougher laws to restrict teen smoking, and restrict smoking in public places. Complications Tumor lysis syndrome: Tumor lysis can occur rapidly in patients with small cell lung cancer on institution of chemotherapy, especially in extensive-stage disease. The laboratory features of tumor lysis syndrome (TLS) are hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Patients should be well hydrated and, preferably, premedicated with allopurinol. The management of established tumor lysis syndrome is urinary alkalinization, correction of electrolyte abnormalities, and dialysis, if necessary. Spinal cord compression: A thorough neurologic examination and radiologic evaluation of the spine is indicated with any suspicion of spinal cord compression. The goal is to prevent development of neurological deficit. Hyponatremia results from inappropriate secretion of ADH, which results in the inability of the kidneys to excrete free water. SIADH is reported in 5-10% of patients with small cell lung 37 cancer. Serum sodium is usually less than 130 mEq/L. Other causes of hyponatremia (ie, volume depletion, abnormal renal function) must be excluded. Fluid restriction and pharmacologic therapy in the form of demeclocycline (a tetracycline antibiotic that decreases the sensitivity of renal tubules to the action of ADH) are usual forms of management. Medicolegal Pitfalls Delay in diagnosis and treatment: Because of rapid tumor growth and early dissemination, any delay in instituting therapy may result in upstaging of the tumor from limited to extensive stage, thus converting a potentially curable illness to incurable disease. Effects of therapy: Small cell lung cancers may respond very quickly to chemotherapy, which carries a risk of rapid tumor lysis, especially in extensive-stage disease, with associated life- threatening electrolyte abnormalities and risk of renal shutdown. Therefore, treating physicians must remember this potential adverse effect, and patients should be hydrated adequately and, preferably, premedicated with allopurinol. Spinal cord compression: New onset of back pain in patients known to have malignant disease should raise the suspicion of cord compression. A thorough neurologic examination and radiologic evaluation of the spine is indicated with any suspicion of spinal cord compression. The goal is to prevent development of neurological deficit. Once present, a neurological deficit can progress within hours to cause complete paraplegia. Any delay in instituting appropriate therapy may result in permanent neurological deficit. Electrolyte abnormalities: Small cell lung cancer is associated with a number of electrolyte abnormalities because of frequent production of peptide hormones. The most common abnormality is hyponatremia, and, if severe, it may cause neurological symptoms and signs, including seizures, coma, and death. Prompt recognition of abnormality and severity is important. Management has been discussed already. 38