Small Cell Lung Cancer

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Background

Small cell lung cancer (SCLC), previously known as oat cell carcinoma, is considered distinct from other lung cancers, which are called non–small cell lung cancers (NSCLCs) because of their clinical and biologic characteristics. Small cell lung cancer is a neuroendocrine carcinoma that exhibits aggressive behavior, rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes (see the image below). (See Pathophysiology, Etiology, and Presentation.)[1, 2, 3]


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High-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the ....

Pathophysiology

Small cell lung carcinoma (SCLC) arises in peribronchial locations and infiltrates the bronchial submucosa. Widespread metastases occur early in the course of the disease, with common spread to the mediastinal lymph nodes, liver, bones, adrenal glands, and brain. (See the images below.)


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The adrenal glands are a common site for metastatic small cell lung cancer. This nonenhanced computed tomography scan of the abdomen at the level of t....


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The brain is one of the predominant sites for small cell lung cancer (SCLC) metastasis. This is a contrast-enhanced magnetic resonance imaging (MRI) s....

In addition, production of various peptide hormones leads to a wide range of paraneoplastic syndromes; the most common of these are the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. Moreover, autoimmune phenomena may lead to various neurologic syndromes, such as Lambert-Eaton syndrome.

Etiology

The predominant cause of small cell lung cancer (SCLC) (and non-SCLC) is tobacco smoking. Of all histologic types of lung cancer, SCLC and squamous cell carcinoma have the strongest correlation to tobacco.[12, 52] Approximately 98% of patients with SCLC have a smoking history. Patients with SCLC should be encouraged to stop smoking, as smoking cessation is associated with improved survival.[13]

All types of lung cancer occur with increased frequency in uranium miners, but SCLC is the most common. The incidence of lung cancer is increased further in these individuals if they also smoke tobacco.

Exposure to radon, an inert gas that is a product of uranium decay, has also been reported to cause SCLC.

Epidemiology

Occurrence in the United States

Lung cancer is the second most common malignancy in both sexes in the United States, exceeded in frequency only by prostate cancer in men and breast cancer in women.[14, 15, 16, 17, 18, 19, 20] Almost twice as many US women die of lung cancer each year than from breast cancer.

The incidence of small cell lung cancer (SCLC) has declined over the last few years.[15, 19, 20] SCLC once accounted for 20-25% of all newly diagnosed lung cancers; it now comprises only about 15% of all lung cancers.

International occurrence

Globally, lung cancer is the most frequent malignancy in men (in Europe, lung cancer is second only to prostate cancer[57] ) and the fifth most common cancer in women. Although the incidence of lung cancer has been falling in the US, it is increasing at a staggering pace in developing countries due to the rising prevalence of tobacco use. According to World Health Organization (WHO) statistics, about 1.4 million deaths from lung cancer occur annually throughout the world.[67]

Separate worldwide data for small cell carcinoma are not available. The incidence of lung cancer started to decline among males in the early 1980s and has continued to do so over the past 20 years. In contrast, the incidence in women started to increase in the late 1970s and has only recently reached a plateau.[14, 18, 19, 20, 60]

Age-related demographics

As with other histopathologic cases of lung cancer, most cases of SCLC occur in individuals aged 60-80 years.

Prognosis

Approximately 60-70% of patients with small cell lung cancer (SCLC) have clinically disseminated or extensive disease at presentation. Extensive-stage SCLC is incurable. When given combination chemotherapy, patients with extensive-stage disease have a complete response rate of more than 20% and a median survival longer than 7 months; however, only 2% are alive at 5 years.[62] For individuals with limited-stage disease that is treated with combination chemotherapy plus chest radiation, a complete response rate of 80% and survival of 17 months have been reported; 12-15% of patients are alive at 5 years.[63]

Indicators of poor prognosis include relapsed disease, weight loss of greater than 10% of baseline body weight, and poor performance status. For all patients with SCLC, activity should be encouraged and a dietary consultation should be obtained.

Patient Education

Because tobacco smoking is the predominant cause of lung cancer, the only means of decreasing the incidence of this disease overall, as well as that of small cell lung cancer (SCLC) specifically, is to decrease the prevalence of smoking. The evidence is clear that the declining incidence of lung cancer in men in the United States has coincided with a decrease in smoking among males.

Concerted efforts are required from government, public health agencies, and healthcare providers to increase public awareness of the hazards of smoking, devise tougher laws to restrict teen smoking, and restrict smoking in public places.

For patient education information, see the Cancer Center, as well as Lung Cancer and Bronchoscopy.

History

Less than 5% of patients with small cell lung cancer (SCLC) are asymptomatic at presentation. Common presenting symptoms of the disease include the following:

This disease typically presents with a short duration of symptoms, usually lasting for only 8-12 weeks before presentation. The symptoms of SCLC can result from local tumor growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes.

Local tumor growth

Small cell carcinomas are usually centrally located and may cause irritation and/or obstruction of the major airways. Common symptoms resulting from local tumor growth include cough, dyspnea, and hemoptysis. Squamous cell cancer also presents as a central lesion, but unlike small cell carcinoma, it frequently exhibits central cavitation.

Rapid tumor growth may lead to obstruction of major airways, with distal collapse leading to postobstructive pneumonitis, infection, and fever.

Intrathoracic spread

Small cell carcinomas usually grow rapidly and metastasize to mediastinal lymph nodes relatively early in the course of the disease. At presentation, patients may have very large intrathoracic tumors, and distinguishing the primary tumor from lymph node metastases may be impossible.

Pressure on mediastinal structures can cause various symptoms, including the following:

SCLC causes SVC obstruction more often than non-SCLC (NSCLC). Patients present with swelling of the face and upper extremities, and can develop stridor due to laryngeal edema or headache, dizziness, and other neurologic symptoms due to cerebral edema. Hoarseness of recent onset can be caused by compression of the left recurrent laryngeal nerve by a mediastinal mass involving the aortopulmonary window (ie, primary tumor or lymph node metastasis).

Compression of the phrenic nerve causes paralysis of the ipsilateral hemidiaphragm, contributing to shortness of breath. In addition, esophageal compression can lead to dysphagia and odynophagia, and compression of the mainstem bronchi and trachea can cause severe shortness of breath and stridor or wheezing.

Symptoms from distant spread

Common sites of hematogenous metastases include the brain, bones, liver, adrenal glands, and bone marrow (see the image below). The symptoms depend upon the site of spread.


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This coronal positron emission tomogram shows abnormal areas of increased metabolic activity in the left hilar and left adrenal regions that are consi....

Neurologic dysfunction can occur due to brain metastases or spinal cord compression. Patients with symptomatic brain metastases may have raised intracranial pressure secondary to mass lesions and vasogenic edema. Common symptoms include the following:

Suspected spinal cord compression is an oncologic emergency. Early recognition of vertebral and paraspinal metastases is important, because a delay in diagnosis and treatment frequently results in permanent loss of neurologic function. The initial symptom is usually back pain, with or without neurologic dysfunction. Once present, neurologic dysfunction can progress very rapidly (ie, within hours) to cause quadriplegia or paraplegia, depending upon the location of the lesion.

Other symptoms from distant metastasis may include pain from bone metastasis, as well as jaundice or abdominal/right upper quadrant pain due to liver metastasis.

Paraneoplastic syndromes

Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm or ectopic production of a hormone or cytokine. Table 1, below, shows some examples of the paraneoplastic syndromes affecting the endocrine and neurologic systems in patients with SCLC.

See the Medscape Reference topic Paraneoplastic Diseases for more information.

Table 1. Paraneoplastic Syndromes Affecting Endocrine and Neurologic Function in SCLC


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Physical Examination

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 experience shortness of breath; physical examination may reveal use of the accessory muscles of respiration (scalene muscles, intercostal muscles) and flaring of the nasal alae. In addition, by virtue of a central tumor location, patients may develop distal atelectasis and postobstructive pneumonia. With pleural effusion, the examination reveals dullness to percussion and decreased or absent breath sounds on the side of the effusion.

Cardiovascular system

Pericardial effusions may be asymptomatic when small, or they may result in tamponade if they are large or accumulate over a short period. Patients are usually short of breath and their heart sounds may be distant on auscultation. Jugular venous pulsation is elevated, and, paradoxically, it rises with inspiration.

Tamponade is an emergency and requires immediate decompression of the pericardium. Pulsus paradoxus is a classic sign of pericardial tamponade. If tamponade is suspected, an echocardiogram should be performed. The definitive diagnosis is established with cardiac catheterization, which reveals equalization of pressures in cardiac chambers. Definitive management may include chemotherapy and/or surgical creation of a pleuropericardial window.

Examination of the extremities may reveal clubbing, cyanosis, or edema. In the presence of superior vena cava (SVC) obstruction, the right upper extremity is usually edematous.

Central nervous system

Asymptomatic brain metastases occur in 5-10% of patients with SCLC (see Workup). Patients with symptomatic brain metastases may have raised intracranial pressure secondary to mass lesions and surrounding brain edema. The physical findings depend on the site of the brain lesions.

Perform funduscopy to look for signs of raised intracranial pressure, as well as a thorough neurologic examination and an evaluation of cerebellar function, coordination, and gait.

Gastrointestinal system

The liver is a common site of metastatic spread. Physical examination may reveal icterus (secondary to widespread liver metastasis or obstruction of biliary outflow) and/or hepatomegaly. However, most patients do not have any specific finding related to the gastrointestinal (GI) tract on examination.

Lymphatic system

Carefully perform a lymph node examination. Currently, enlarged ipsilateral supraclavicular lymph nodes are included in limited-stage disease, but enlarged axillary lymph nodes upstage the diagnosis to extensive-stage disease.

Staging Overview

Small cell lung cancer (SCLC) is staged by stage type and staging system.

Types of staging

The American Cancer Society (ACS) uses 2 types of staging—clinical and pathologic—for SCLC.[31] Clinical staging involves physical examination, biopsy examinations, and imaging scans; the majority of patients are staged with clinical staging, and this type of staging is usually used to describe SCLC tumor extent.

Pathologic staging is generally more accurate, as it includes clinical staging and adds postsurgical findings. Occasionally, findings between the 2 stages may be different, such as during procedures in which cancer is in an area that is not seen on radiologic studies. The surgical findings may give the cancer a more advanced pathologic stage.[31]

Staging systems

VALSG 2-stage system

The staging system most commonly used for SCLC is the Veterans Administration Lung Group (VALSG) 2-stage system, which defines limited-stage and extensive-stage disease.[68] Patients with disease confined to one hemithorax, with or without involvement of the mediastinal, contralateral hilar or ipsilateral supraclavicular, or scalene lymph nodes are considered to have limited-stage disease, whereas those with disease involvement at any other location are considered to have extensive-stage disease.[68]

The key factor in defining limited-stage disease is the ability to encompass all of the disease within 1 tolerably safe radiation therapy port.

TNM system

Almost all solid tumors, including lung carcinomas, are staged using the tumor, node, metastasis (TNM) system, because it provides important prognostic information and is used to design management plans. However, older literature has stated that the TNM system fails to provide important prognostic information in patients with SCLC and is useful only for the few patients (< 5%) who might be eligible for surgical resection.

IASLC TNM system

The International Association of the Study of Lung Cancer (IASLC) developed a new TNM staging system for lung cancer in 2007; this staging system included non-SCLC (NSCLC) and SCLC.[22]

The American Joint Commission for Cancer (AJCC) adopted the new TNM system in 2010.[47] In addition, the 2011 National Comprehensive Cancer Network (NCCN) clinical practice guideline for SCLC incorporated TNM staging into its diagnostic and therapeutic algorithms; the NCCN suggested that researchers begin to use the TNM staging system in an effort to more accurately assess prognoses and to more specifically personalize therapeutic options. This recommendation is also reflected in the 2013 NCCN guidelines.[22]

For more details, see VALSG and TNM Staging under Workup.

Approach Considerations

A thorough history and physical examination usually provide clues to the organ systems involved in small cell lung cancer (SCLC), and these are used to guide further workup (see Presentation). Investigations are performed to delineate the extent of disease and to assess organ function before therapy begins. In general, depending on tumor localization, biopsies from either the primary tumor or a metastatic lesion should be obtained using any of the following techniques[57] :

Staging workup

The purpose of a staging workup for small cell lung cancer (SCLC) is to determine the prognosis and management of this disease. Patients with limited-stage disease are usually treated with combined chemoradiotherapy, whereas those with extensive-stage disease are usually treated with chemotherapy alone. Staging workup of SCLC is as follows[22, 23, 57] :

Staging should be adequate before making the diagnosis of limited-stage SCLC. Any pleural effusion should be tested cytologically for malignant cells, and isolated liver or adrenal lesions should be sampled by fine-needle aspiration (FNA) before a diagnosis of limited-stage disease is made. Some authorities suggest a bone marrow examination in the absence of any other evidence of spread.

Routine Laboratory Studies

A complete blood cell (CBC) count with differential, serum electrolyte levels, renal function studies, and liver function tests (LFTs) are all part of the routine staging workup, and in some cases, these studies may reveal the sites of metastasis (eg, elevated serum calcium and/or alkaline phosphatase [ALP] levels with bone metastasis). These tests are also important to assess organ function before starting therapy.

Serum lactate dehydrogenase (LDH) and sodium levels also provide prognostic information. Increased uric acid levels and impaired renal function may indicate the possibility of rapid tumor lysis syndrome with therapy.

CBC

In 5-10% of patients, small cell lung cancer (SCLC) may have spread to bone marrow at presentation. Bone marrow examination is not routinely performed in SCLC unless abnormalities are identified in the CBC or peripheral smear examination, raising the possibility of bone marrow spread. These abnormalities may include cytopenia or the presence of immature white and red blood cells (a leukoerythroblastic blood picture), which raises the possibility of myelophthisic anemia.

Additionally, before instituting initial full-dose combination chemotherapy, the CBC should demonstrate the following:

Serum chemistries

The presence of elevated serum calcium and ALP levels raises the suspicion of bone metastasis, and in such cases a bone scan should be ordered even in the absence of symptoms. Serum electrolytes should be obtained to look for paraneoplastic syndromes, such as syndrome of inappropriate antidiuretic hormone (SIADH) secretion. The presence of hyponatremia is considered an adverse prognostic indicator.

Elevated serum LDH indicates an increased tumor mass and high cell turnover; this finding is also an adverse prognostic indicator. Abnormal liver function findings raise the possibility of hepatic metastasis and may require adjustments to planned therapy.

Thoracic Imaging Studies

Radiography

Good posteroanterior and lateral radiographs are useful in identifying the primary tumor, as well as concurrent parenchymal abnormalities. Mediastinal widening may indicate mediastinal lymph node involvement. (See the radiographs below.)


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This frontal chest radiograph shows extensive disease in a patient with small cell lung cancer. A large mass is noted in the left mid lung, with an op....


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Small cell lung cancer frequently appears as a hilar or mediastinal mass. In this frontal chest radiograph, there is increased opacity in the right hi....


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This frontal chest radiograph shows obstructive pneumonitis with atelectasis of the right upper lobe in a patient with small cell lung cancer. The inc....

CT scanning

Computed tomography (CT) scanning of all common sites of metastasis should be performed to stage the disease adequately. Evaluation via CT scanning of the thorax (lungs and mediastinum) and commonly involved abdominal viscera (ie, liver, adrenals) is the minimum requirement in standard staging workup of SCLC. Intravenous and oral contrast agents should be administered whenever possible.[22] In the United States, CT scans of the chest and upper abdomen to include the liver and adrenal glands are standard. (See the images below.)


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This contrast-enhanced computed tomography scan of the chest from a patient with small cell lung cancer shows a large left lung and a hilar mass, with....


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This image is a contrast-enhanced computed tomography scan of the abdomen from a patient with small cell lung cancer. The axial section through the li....


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The adrenal glands are a common site for metastatic small cell lung cancer. This nonenhanced computed tomography scan of the abdomen at the level of t....


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This computed tomography scan of the chest at the level of the hila from a patient with small cell lung cancer shows a large hilar tumor on the right ....


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Small cell lung cancer occasionally appears as a peripheral lung nodule. This axial computed tomography scan through the lungs shows a solitary pulmon....

Brain and Spinal Cord Imaging Studies

Brain metastasis may be present in as many as 10-15% of patients at diagnosis[22] and may be occult in 5% of patients (see the image below). Consequently, magnetic resonance imaging (MRI) of the brain should be ordered in asymptomatic patients and in those with neurologic symptoms.[22] Because MRI is more sensitive than computed tomography (CT) scanning with contrast for detection of brain metastasis, MRI is used as the first-line imaging study in many institutions.


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The brain is one of the predominant sites for small cell lung cancer (SCLC) metastasis. This is a contrast-enhanced magnetic resonance imaging (MRI) s....

MRI has an increased ability to detect disease in proximity to neurovascular structures and is also considered standard in the workup of patients in whom spinal cord compression is suspected. Although a CT myelogram can establish the diagnosis of vertebral and paraspinal metastases, it is currently rarely used. MRI is noninvasive and very sensitive in establishing the diagnosis in almost all cases.

Skeletal Radionuclide Imaging

Bone is a common site of metastasis for small cell lung cancer (SCLC). A radionuclide bone scan should therefore be obtained to identify bone metastases.

Bone metastases from SCLC usually contain both osteolytic and osteoblastic components, and a bone scan is superior to plain radiographs in detecting osteoblastic lesions. However, because some benign lesions can also cause abnormalities on bone scans, obtaining plain radiographs of abnormal areas for radiographic correlation is important, particularly in weight-bearing bones at risk for fracture. (See the image below.)


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The bones are commonly affected in patients with small cell lung cancer. These whole-body bone scans with anterior and posterior images reveal multipl....

Bone scans should be obtained in all patients with SCLC at diagnosis or during follow-up if new bone symptoms develop or if the serum calcium or alkaline phosphatase level is elevated.

PET Scanning

Positron emission tomography (PET) scanning remains under evaluation for the staging of small cell lung cancer (SCLC).[54, 59] The American College of Chest Physicians (ACCP) does not recommend PET scanning in the routine staging of SCLC, although the National Comprehensive Cancer Network (NCCN) guidelines recommend combined PET-CT (computed tomography) scanning if limited-stage disease or metastasis is suspected.[22] PET-CT imaging is superior to PET scanning alone. (PET scanning is inferior to MRI or CT scanning for the detection of brain metastases.)

In small, uncontrolled studies, PET scanning has shown good accuracy (83-99%) in staging extensive- versus limited-stage SCLC.[54] Although PET scanning may improve the accuracy of staging, however, any lesion identified using this modality that would alter staging requires pathologic confirmation due to the possibility of a false-positive finding.[22] The full role of PET imaging in this setting remains to be determined.[54, 59]

Bronchoscopy and FNA

Small cell lung cancer (SCLC) is usually centrally located and can be approached easily with a bronchoscope. The advantage of endoscopy is direct visualization of the tumor, allowing for direct biopsy as well as cytologic examination of bronchial washings.

For tumors that cannot be diagnosed with transbronchial biopsy, transthoracic percutaneous fine-needle aspiration (FNA) carried out under computed tomography (CT) ̶ scan guidance is a reasonable alternative.

Sputum Cytology

Sputum cytology is a noninvasive test and, if positive, can provide an accurate diagnosis of central lung cancers. Although small cell lung cancer (SCLC) usually presents as a large, central tumor, tumor cells frequently involve the submucosal layer of the bronchus with little or no exophytic endobronchial extension. Therefore, sputum cytology is not as useful for diagnosing SCLC as it is for the diagnosis of squamous cell carcinoma.

Thoracentesis

In small cell lung cancer (SCLC), the presence of malignant pleural effusion upstages the disease to extensive-stage SCLC. 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 of symptomatic effusions. The Cancer and Leukemia Group B (CALGB) reported similar outcomes in patients undergoing pleurodesis via use of talc slurry or poudrage.[69] The currently preferred agent for pleurodesis is sterilized talc, which can be instilled either as a slurry or as a powder during pleuroscopy.

Histologic Findings

Small cell lung cancer (SCLC) is typically centrally located, arising in peribronchial locations. These tumors are thought to develop from neuroendocrine Kulchitsky cells and are composed of sheets of small, round to spindled cells with dark nuclei, scant cytoplasm, and fine, granular (“salt and pepper”) nuclear chromatin with indistinct nucleoli. (See the image below.)[25]


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High-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the ....

Very high rates of cell division are observed, and necrosis, sometimes extensive, may be seen. Because of the central location, the tumor cells may exfoliate into sputum and bronchial washings. Crush artifact of the relatively fragile tumor cells is a common finding in small biopsies, but this feature is not considered diagnostic in and of itself.

Neurosecretory granules can be identified with the aid of electron microscopy. The neuroendocrine nature of the neoplasm is suggested by its frequent association with neurologic and endocrine paraneoplastic syndromes.

Immunohistochemical stains for chromogranin, neuron-specific enolase, CD56, and synaptophysin are usually positive, but these are not an absolute requirement for the diagnosis.

Approximately 5% of SCLCs exhibit features of mixed small cell and non-small cell components, suggesting phenotypic plasticity and lending support to the cancer stem cell hypothesis. Patients with mixed SCLC/NSCLC histology are managed according to the same guidelines as those for patients with SCLC.[22]

VALSG and TNM Staging

VALSG staging system

The Veterans Administration Lung Group (VALSG) staged small cell lung cancer (SCLC) into limited- and extensive-stage disease to distinguish between patients who may benefit from more aggressive, potentially curative treatments, such as chemotherapy combined with radiation therapy (limited-stage SCLC), and those individuals whose cancer is not likely to be cured with such therapy (extensive-stage SCLC).[22, 31]

Limited-stage disease is confined not only to the ipsilateral hemithorax but also to an area that is small enough to be treated with radiation therapy in 1 tolerably safe radiation treatment port.[22, 31]

AJCC staging system

Under the new tumor, node, metastasis (TNM) staging system, from the American Joint Committee on Cancer (AJCC) (see tables 2 and 3, below), limited-stage SCLC is defined as any T, any N, M0; the exception is T3-4, owing to multiple lung nodules that extend beyond a single radiation field.[22]

Extensive-stage disease describes tumors that extend beyond the ipsilateral hemithorax, such as those that reach the contralateral lung and/or contralateral lymph nodes or that find their way to distant organs (eg, bone marrow).[22, 31] Approximately two thirds of patients with SCLC present with extensive-stage disease at diagnosis.[31] The new TNM staging system classifies extensive-stage disease as any T, any N, M1a/b, and T3-4, due to involvement of multiple lung nodules.[22]

Table 2, below, summarizes the American Joint Committee on Cancer (AJCC) lung cancer TNM staging system categories, and Table 3, below, summarizes the lung cancer stage groupings.[47] The TNM assignments define the cancer growth and disease extent, and the stage groupings combine cancers with a similar prognosis.[22] Generally, lower stage numbers result in a better prognosis.[22]

Table 2. AJCC TNM Categories for Lung Cancer


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Table 3. AJCC Stage Groupings for Lung Cancer


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Approach Considerations

Small cell lung cancer (SCLC) is characterized by rapid growth and early dissemination. Management of limited-stage SCLC typically involves combination platinum-based chemotherapy and thoracic radiation therapy given with curative intent. Patients who achieve a complete or partial response should be offered prophylactic cranial irradiation (PCI).

Extensive-stage SCLC remains incurable with current management options, and patients are treated with combination chemotherapy. Several chemotherapy combinations are active in SCLC, but usually a platinum-containing regimen is chosen. However, despite strides in the management of SCLC, there has been little change in survival over the past 2 decades for limited- and extensive-stage disease.[28, 29] Indeed, very few new agents with activity in SCLC have been identified, even as identification of molecular targets and targeted therapies has proceeded at a brisk pace in non-SCLC.

The American College of Chest Physicians (ACCP) and the National Comprehensive Cancer Network (NCCN) guidelines recommend following treatment recommendations for SCLC in patients who have mixed histologic features of SCLC and non–SCLC.[22, 23]

Elderly patients with SCLC who have a good performance status (PS) (ie, Eastern Cooperative Oncology Group [ECOG] PS 0 or 1) and intact organ function should receive standard carboplatin-based chemotherapy. However, even those who have poor prognostic factors (eg, poor PS, medically significant concomitant conditions) may still be considered for chemotherapy if appropriate precautions are taken to avoid excessive toxicity and further decline in PS.[23]

Combination Chemotherapy

A number of randomized trials have tried to answer questions concerning the superiority of combination over single-agent chemotherapy, the number of drugs to be used in combination, and dose intensity. Nonrandomized trials of combination chemotherapy have shown superior response rates and survival compared with single-agent chemotherapy. Common combinations include cisplatin/etoposide (PE), cisplatin/irinotecan (IP), carboplatin/etoposide, and carboplatin/irinotecan.

Several platinum-based and non–platinum-based chemotherapy regimens have been used in the treatment of small cell lung cancer (SCLC) with varying results.

In a review by Amarasena et al that analyzed the data from trials to compare the effectiveness of these regimens, the investigators concluded that platinum-based chemotherapy regimens did not provide a statistically significant benefit over non–platinum-based agents in survival or overall tumor response. However, platinum-based agents did increase complete response rates, albeit with an associated higher incidence of nausea, vomiting, anemia, and thrombocytopenia. The investigators suggested that non–platinum-based chemotherapy regimens may have a better risk-benefit profile.[27]

Cisplatin and etoposide

PE is currently the most widely used regimen in both limited- and extensive-stage SCLC. The combination of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) has been compared with PE in at least 2 randomized trials of previously untreated extensive-stage SCLC and showed similar survival outcomes. The PE combination is associated with less myelosuppression, whereas CAV has the convenience of administration in a single day (PE requires a 3-day program).[32]

Cisplatin and irinotecan

The PE combination has also been compared with other platinum-based regimens (eg, IP) and has been found to be effective for metastatic SCLC. A large Japanese study that compared PE with IP in patients with extensive-stage disease showed a 3-month-longer survival period with the IP combination (12.8 mo) relative to the PE combination (9.4 mo).[37]

Nonetheless, a more recent meta-analysis of 12 randomized, controlled trials found that, although the IP regimen significantly reduced mortality risk compared with the PE regimen, it also produced more hematologic toxicities in patients with extensive-stage SCLC.[56] In addition, the overall response rate between PE and IP treatment groups did not differ.[56] One of the trials in this meta-analysis suggested overall survival may be prolonged with a PCDE (etoposide, cisplatin, epirubicin, cyclophosphamide) regimen.

Several subsequent trials comparing the same combinations did not show a survival advantage with the IP combination, including a US trial that demonstrated an overall median survival time of 9.3 months for those in the IP group versus 10.2 months for those in the PE group.[38] Therefore, the PE combination remains the first-line combination chemotherapy choice for most physicians.

Carboplatin and etoposide versus carboplatin and irinotecan

The combination of carboplatin and etoposide has been used in patients with compromised renal function. A study by Schmittel et al found that the combination of carboplatin/irinotecan was not superior to that of carboplatin/etoposide.[30]

Cisplatin- versus carboplatin-based chemotherapy

A systematic review of randomized trials comparing cisplatin- to carboplatin-based chemotherapy as the first-line treatment for SCLC found no significant difference in efficacy between the 2 treatments.[55] This meta-analysis included 4 trials with a total of 663 patients (328 treated with cisplatin; 335 treated with carboplatin).

In the study, median overall survival was 9.6 months among cisplatin-treated patients and 9.4 months among carboplatin-treated patients. Median progression-free survival was 5.5 months among cisplatin-treated patients and 5.3 months among carboplatin-treated patients. The objective response rate was 67.1% and 66.0%, respectively.[55] However, hematologic toxicity was higher with carboplatin, whereas nonhematologic toxicity was higher with cisplatin.[55]

Chemotherapy Dose Intensity and Density

Patients with extensive-stage small cell lung cancer (SCLC) should receive 4-6 cycles (but not >6 cycles) of cisplatin- or carboplatin-based combination chemotherapy (eg, cisplatin plus etoposide or irinotecan).[22, 23, 57] Several trials have tested the use of higher doses of standard chemotherapeutic regimens in previously untreated SCLC. Despite early enthusiasm brought on by higher initial response rates, most of these trials have failed to improve survival.[33]

A trial by Arriagada et al comparing standard and higher doses of cyclophosphamide and cisplatin in the first cycle of chemotherapy yielded a superior survival rate only in patients receiving higher-dose chemotherapy.[21] Higher-dose regimens, however, may cause life-threatening myelosuppression and, in the absence of survival advantage, should not be used outside of a clinical trial.

Another approach to increase the intensity of chemotherapy is to shorten the interval between cycles (increased dose density). Again, although phase II trials suggested the superiority of such an approach, randomized trials failed to show an advantage to the use 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 to show 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 high-dose chemotherapy with bone marrow or stem cell transplantation, because no randomized trials have evaluated this approach to assess whether it will produce better survival rates than standard management and whether it is associated with greater immediate and delayed toxicity.

Limited-Stage SCLC - Standard Management

Standard management of patients with limited stage small cell lung cancer (SCLC) involves combination chemotherapy with a cisplatin-containing regimen and concurrent thoracic radiotherapy.[23] Therefore, it is necessary to refer patients to a radiation oncologist, as well as a medical oncologist.[23]

Chemotherapy cycles are repeated every 4 weeks during radiotherapy; currently, no data support continuation of chemotherapy beyond 6 cycles, and many oncologists now stop after 4 cycles of therapy.[22, 23, 57]

Patients who experience a complete or partial response to initial therapy and those who have undergone resection followed by adjuvant chemotherapy should be offered prophylactic cranial irradiation (PCI).

Radiotherapy

Patients with limited stage SCLC typically receive concurrent chemotherapy and thoracic radiotherapy, which should begin as early as possible.[23, 57] For patients who are eligible for early concurrent chemoradiotherapy, the American College of Chest Physicians (ACCP) recommends concurrent accelerated hyperfractionated radiotherapy with platinum-based chemotherapy.[23]

In a randomized trial by Takada and colleagues in which treatment using cisplatin plus etoposide (PE) with concurrent thoracic radiotherapy was compared with treatment using PE with sequential thoracic radiotherapy, the investigators reported superior 2- and 5-year survival rates (2-y survival, 35.1% vs 54.4%, respectively; 5-y survival, 18.3% vs 23.7%, respectively) with the concurrent approach.[34] However, hematologic toxicity was greater in the concurrent arm.

In another randomized trial, Turrisi and colleagues demonstrated superiority of concurrent hyperfractionated radiotherapy administered with 4 cycles of PE in limited-stage SCLC relative to once-daily radiotherapy and concurrent PE.[35] The 10% survival improvement reported in this trial is the largest survival improvement ever noted in SCLC. In addition, 5-year survival rates were 26% versus 16%, respectively, in favor of hyperfractionated radiotherapy.[35] However, a major flaw in this trial was that the biologic equivalent dose of radiotherapy was not equivalent between the 2 treatment arms.

At present, the optimal fractionation (ie, total radiation dose spread out over time), dose, and overall duration of radiotherapy remain undetermined in patients with limited-stage disease (eg, twice-daily fractionation vs once-daily fractionation, with biologically equivalent doses). In addition, it is unclear what the optimal target volume should be in these patients.[57]

Prophylactic cranial irradiation

The ACCP and the 2013 National Comprehensive Cancer Network (NCCN) guidelines recommend PCI in patients with limited-stage disease who have achieved a complete remission or in those with stage I disease who have undergone resection.[22]

The use of PCI was initially considered controversial.[36] Several randomized trials showed a decrease in central nervous system (CNS) relapse rate with PCI but no survival advantage. Additionally, patients receiving PCI had a higher incidence of neuropsychiatric dysfunction than did those who did not receive PCI.[36]

Arriagada et al performed a meta-analysis of randomized trials of PCI in limited-stage SCLC and showed a 5% overall survival advantage in patients who received PCI.[21] Although such an analysis has inherent limitations, PCI is currently offered to patients with limited-stage SCLC who have achieved a complete or partial response after having completed initial chemoradiotherapy.

In a pooled analysis that evaluated outcomes of PCI in 739 SCLC patients with stable disease or better after treatment with chemotherapy with or without thoracic radiation therapy, Schild et al found that PCI resulted in a significant survival benefit in patients with either limited or extensive SCLC.[62] Dose fractionation appeared to be important, and PCI was associated with an increase in specific and overall grade 3+ adverse events.[61]

Extensive-Stage SCLC - Standard Management

Patients with extensive-stage small cell lung cancer (SCLC) are treated with combination chemotherapy alone. The administration of carboplatin or cisplatin plus etoposide remains the standard of care in North America for extensive SCLC.

The American College of Chest Physicians (ACCP), the National Comprehensive Cancer Network (NCCN), and the European Society for Medical Oncology (ESMO) guidelines recommend that patients with extensive-stage disease receive 4-6 cycles (but not >6 cycles) of cisplatin- or carboplatin-based combination chemotherapy (eg, cisplatin plus etoposide or irinotecan).[22, 23, 57]

Although cisplatin/etoposide (PE) remains the most widely used combination, a randomized trial that compared the combination of cisplatin with either etoposide or irinotecan in extensive-stage disease demonstrated that the combination of cisplatin and irinotecan (IP) was superior to that of PE. The median survival was 12.8 months with IP, versus 9.4 months with the PE combination. The 2-year survival rate was also superior at 19.5% for IP, versus 5.2% for PE.[37]

However, a confirmatory study in the United States failed to show the superiority of either regimen.[38]

Possible reasons for these contrasting results may have to do with differences in doses and schedules of the chemotherapeutic agents, as well as with genetic changes within different study populations. Although PE and IP had comparable overall response rates and survival outcomes, the IP combination had more gastrointestinal (GI) toxicity.[39]

A German clinical trial reported that topotecan/cisplatin had a similar overall response rate to PE in extensive SCLC but a better time to progression and objective response rate than did PE.[40]

Radiotherapy

In general, radiotherapy is used only to palliate symptoms, if required (eg, for painful bone metastases) in extensive-stage SCLC. Response rates are excellent, but patients invariably relapse. The ACCP indicates that consolidative thoracic radiotherapy to the chest is a treatment option for patients who achieve a complete response (CR) outside the chest and complete or partial (PR) response in the chest.[23]

Prophylactic cranial irradiation

As with limited-stage disease, offer prophylactic cranial irradiation (PCI) to all responding patients with extensive stage SCLC[22, 23, 57] ; this treatment should be considered standard therapy for this stage of the disease in these patients. Brain metastases at the time of initial diagnosis in extensive SCLC are present in about 18% of patients and increase to about 80% at 2 years.

A study by the European Organization for Research and Treatment of Cancer (EORTC) that randomized patients responding to systemic chemotherapy into 2 groups, those who received PCI and those who did not, found that the 1-year survival rate for the PCI-treated group was 27.1%, compared with 13.3% for patients who did not receive PCI.[36]

In the study, PCI not only reduced the incidence of brain metastases but also improved disease-free and overall survival rates.

However, the 2010 European Society for Medical Oncology (ESMO) practice guidelines noted that safety data on PCI administered concurrently with chemotherapy are lacking; therefore, this combination is not recommended outside of a clinical trial.[57]

Gamma knife stereotactic radiosurgery

Gamma knife stereotactic radiosurgery is a salvage option for patients with brain metastases for whom previous whole-brain irradiation has failed.[41]

Management of Relapsed SCLC

Patients with relapsed small cell lung cancer (SCLC) have an extremely poor prognosis. Individuals whose disease does not respond to or that progresses on initial treatment (ie, patients with refractory disease) or those whose SCLC relapses within 6 months of completion of therapy have little chance of responding to additional chemotherapy.

In general, the administration of cisplatin and etoposide (PE) after vincristine (CAV) failure produces better response rates than does CAV given after PE.

Topotecan received US Food and Drug Administration (FDA) approval in 2007 for use in chemotherapy-sensitive disease after failure of front-line chemotherapy.[71] Because of the lack of long-term benefit of this therapy, however, patients with relapsed or refractory SCLC should be encouraged to enroll in clinical trials, if their condition permits.[42]

The American College of Chest Physicians (ACCP) recommends offering further chemotherapy to patients with relapsed or refractory SLCL.[23] However, except in the setting of a clinical trial, the ACCP does not recommend either (1) maintenance treatment for patients with limited- or extensive-stage disease that has achieved a partial (PR) or complete remission (CR) or (2) dose dense/intense initial/induction or maintenance treatment for limited- or extensive-stage disease.

Management of Brain Metastases and Spinal Cord Compression

Brain metastases

Management of symptomatic brain metastases includes high-dose corticosteroids (eg, intravenous [IV] dexamethasone 10 mg initially, followed by an IV or oral [PO] dose of 4-6 mg q6h) and immediate whole brain radiation therapy.

For patients with asymptomatic brain metastases, systemic chemotherapy may be initiated, with plans for close surveillance of the central nervous system (CNS) metastases and initiation of brain radiation after completion of systemic treatment.

In patients with small cell lung cancer (SCLC), brain metastases usually respond to systemic chemotherapy, but radiation can be sandwiched between cycles of chemotherapy if there is any clinical or radiographic evidence of progression of CNS disease.

Spinal cord compression

Spinal cord compression is an oncologic emergency, because patients rarely regain neurologic function once it has been lost. 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 are indicated with any suspicion of spinal cord compression. The goal is to prevent the development of neurologic deficit, since such a deficit, once present, can progress within hours to cause complete paraplegia. Any delay in instituting appropriate therapy may result in permanent neurologic deficit.

Patients in whom spinal cord compression is suspected should receive IV corticosteroids even before being sent for magnetic resonance imaging (MRI). The typical dose is 10 mg of dexamethasone IV, followed by 4-6 mg IV/PO every 6 hours.

If spinal cord compression occurs in a patient with known SCLC, definitive management consists of radiation therapy and/or neurosurgical decompression, which should be undertaken without delay.

Surgical Resection

Historically, patients undergoing surgery for small cell lung cancer (SCLC) had a dismal prognosis. However, more recent data suggest that patients with true stage I SCLC may benefit from surgical resection. The American College of Chest physicians (ACCP) recommends that patients being considered for resection undergo invasive mediastinal staging and extrathoracic imaging, such as cranial computed tomography (CT) scanning or magnetic resonance imaging (MRI), abdominal CT scanning, and bone scanning.[23]

Fewer than 5% of patients with SCLC present with such early stage disease, but those who are found to have clinical stage T1/T2 N0 disease after initial staging work-up should undergo invasive mediastinal lymph node evaluation via mediastinoscopy, mediastinotomy, or endobronchial ultrasound-guided biopsy.[4, 57] If there is no evidence of mediastinal lymph node involvement, then surgical exploration with resection of the primary tumor and mediastinal lymph node sampling is a reasonable treatment option.

Due to the systemic nature of SCLC, all patients should receive adjuvant platinum-based chemotherapy and prophylactic cranial irradiation (PCI) after successful resection.[23]

In a review by Anraku and Waddel, the investigators indicated that surgical resection combined with chemotherapy for T1-2, N0, M0 SCLC may offer better local control of the disease than does chemotherapy alone.[70] In addition, curative resection following induction chemoradiotherapy has shown a control of local relapse in almost 100% of patients. Likewise, 5- and 10-year survival rates were 39% and 35%, respectively, for all included patients, resected or not, and they were 44% and 41%, respectively, for patients with stage IIB to IIIA disease treated with a trimodality approach that included adjuvant surgery.[70]

Management of Complications

Physicians should be aware of potential complications in patients with small cell lung cancer (SCLC), including tumor lysis syndrome and electrolyte abnormalities.

Tumor lysis syndrome

Tumor lysis can occur rapidly in patients with SCLC on institution of chemotherapy, especially in cases of extensive-stage disease. The laboratory features of tumor lysis syndrome 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.

Electrolyte abnormalities

SCLC is associated with a number of electrolyte abnormalities because of frequent production of peptide hormones. The most common abnormality is hyponatremia, which, if severe, may cause neurologic symptoms and signs, including seizures, coma, and death. Prompt recognition of hyponatremia and its severity is important.

Evidence that supports the prognostic value of this abnormality was shown in a retrospective study of 395 SCLC patients with limited and extensive disease in which patients with hyponatremia had a significantly shorter median survival time than did patients without hyponatremia.[58]

Hyponatremia results from inappropriate secretion of antidiuretic hormone (ADH), which results in the inability of the kidneys to excrete free water. Syndrome of inappropriate ADH (SIADH) is reported in 5-10% of patients with SCLC. The serum sodium level 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 the usual forms of management.

Consultations

Patients in whom lung cancer is suspected may require consultation with a pulmonologist to establish a diagnosis. Once a diagnosis has been made, medical and radiation oncologists should be consulted to complete the staging workup and devise a management plan. In addition, owing to the importance of weight loss as an indicator of poor prognosis in persons with small cell lung cancer (SCLC), obtain a dietary consultation for patients with persistent weight loss.

Long-Term Monitoring

Patients with small cell lung cancer (SCLC) require close monitoring for adverse effects and response to therapy. Blood work, including a complete blood count (CBC) with differential, is needed before 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.

Serum lactate dehydrogenase (LDH), if elevated before the start of therapy, is a good marker for response and should be monitored. In addition, computed tomography (CT) scans should be obtained after 2 cycles of therapy to assess response before chemotherapy is continued. In general, patients who are asymptomatic require follow-up only as clinically needed.[57]

Patients who smoke cigarettes should be encouraged to quit. A meta-analysis by Parsons et al suggested that smoking cessation after diagnosis of early stage lung cancer may improve prognosis, probably by reducing cancer progression. Evaluation of data from 9 studies showed that the estimated 5-year survival rate in limited-stage SCLC was 63% in patients who quit smoking, versus 29% in those who continued to smoke.[13]

Medication Summary

Combination platinum-based chemotherapy, as well as thoracic radiation therapy, is typically administered in the treatment of limited-stage small cell lung cancer (SCLC).

Combination chemotherapy is also administered to patients with extensive-stage SCLC, although this form of the disease remains incurable with current management options.

Despite strides in the management of SCLC, there has been little change in survival over the past 2 decades for either the limited- or extensive-stage forms of the disease, and very few new agents with activity in SCLC have been identified.[28, 29]

Dexamethasone (Decadron, Dexamethasone Intensol, Dexasone)

Clinical Context:  Dexamethasone is a synthetic adrenocortical steroid with multiple indications. This agent is widely used in combination with serotonin (5-HT) receptor antagonists to prevent nausea and vomiting caused by highly emetogenic agents (eg, cisplatin).

Class Summary

Corticosteroids reduce inflammation by decreasing the production of inflammatory mediators, suppressing neutrophil migration, and reversing increased capillary permeability. Dexamethasone also has antiemetic activity, but its mechanism of action is unknown.

Metoclopramide (Metozolv ODT, Reglan)

Clinical Context:  Metoclopramide is a dopamine antagonist that enhances the response to acetylcholine of tissue in the upper GI tract, causing antiemetic activity. At higher doses, metoclopramide blocks serotonin receptors in the chemoreceptor trigger zone of the central nervous system (CNS).

Ondansetron (Zofran, Zofran ODT, Zuplenz)

Clinical Context:  Ondansetron is a selective serotonin (5-HT3)-receptor antagonist that is used to prevent chemotherapy-induced nausea and vomiting.

Granisetron (Kytril, Granisol, Sancuso)

Clinical Context:  Granisetron is a selective 5-HT3-receptor antagonist that is used to prevent chemotherapy-induced nausea and vomiting.

Dolasetron (Anzemet)

Clinical Context:  Dolasetron binds to 5-HT3 receptors located on vagal neurons in the GI tract, blocking signals to the vomiting center, thus preventing nausea and vomiting.

Palonosetron (Aloxi)

Clinical Context:  Palonosetron is a selective 5-HT3 receptor antagonist with long half-life (40 h) that blocks 5-HT3 receptors peripherally and centrally in the chemoreceptor trigger zone. This agent is indicated for the prevention of chemotherapy-induced nausea and vomiting.

Class Summary

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 the CTZ or acetylcholine in the 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 gastrointestinal (GI) tract. With 5-HT 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 that are so intolerable that a patient may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and following cancer treatment is often essential to ensure the administration of the entire chemotherapy regimen.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:  Cyclophosphamide is chemically related to the nitrogen mustards. As an alkylating agent, the mechanism of action of its active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells. Fatal cardiotoxicity has been reported with coadministration of pentostatin.

Carboplatin (Paraplatin)

Clinical Context:  Carboplatin is a platinum alkylating agent that interferes with the function of DNA by producing interstrand DNA cross-links. It can be used for the treatment of small cell lung cancer (SCLC), which is an off-label indication. Carboplatin has black box warnings, including bone marrow suppression, anaphylactic reactions, and vomiting.

Cisplatin

Clinical Context:  Cisplatin is a platinum-containing compound that exerts an antineoplastic effect by covalently binding to DNA, with preferential binding to the N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. The platinum complex can also bind to nuclear and cytoplasmic protein. Cisplatin has black box warnings, including anaphylacticlike reactions, ototoxicity, and renal toxicity.

Ifosfamide (Ifex)

Clinical Context:  Ifosfamide is a nitrogen mustard alkylating agent that inhibits DNA and protein synthesis. Although not FDA approved, ifosfamide is often used as a treatment for relapsed SCLC.

Class Summary

Alkylating antineoplastic agents inhibit cell growth and proliferation. They inhibit DNA synthesis by the formation of DNA cross-links. Alkylating agents can have serious adverse effects, such as bone marrow suppression, anaphylactic-like reactions, ototoxicity, renal toxicity, and vomiting.

Irinotecan (Camptosar)

Clinical Context:  Irinotecan binds reversibly to the topoisomerase I-DNA complex and prevents the ligation of the cleaved DNA strand. It has been used off label for the treatment of extensive-stage small cell lung cancer. Black box warnings for irinotecan include bone marrow suppression and diarrhea.

Topotecan (Hycamtin)

Clinical Context:  Topotecan inhibits topoisomerase I and thereby inhibits DNA replication. This agent may interact with other antineoplastic drugs to cause prolonged neutropenia and thrombocytopenia in addition to increasing morbidity/mortality. Topotecan is indicated for the treatment of relapsed or refractory small cell lung cancer (SCLC).

Class Summary

Topoisomerase-inhibiting agents prevent cell growth and proliferation. They work by binding to topoisomerase and causing single-strand DNA breaks.

Doxorubicin (Adriamycin, Caelyx, Rubex)

Clinical Context:  Doxorubicin is an anthracycline antineoplastic that causes DNA strand breakage through its effects on topoisomerase II and through direct intercalation into DNA, which causes DNA polymerase inhibition. It has a labeled indication for the treatment of small cell lung cancer (SCLC). Doxorubicin has several black box warnings, including bone marrow suppression, myocardial toxicity, and secondary malignancy.

Class Summary

Anthracycline antineoplastic agents inhibit DNA and RNA synthesis by steric obstruction. They intercalate between DNA base pairs and trigger DNA cleavage by topoisomerase II.

Vincristine (Oncovin)

Clinical Context:  Vincristine inhibits tubulin polymerization during mitosis. This agent is G2-phase specific. Vincristine may interact with mitomycin-C and cause an acute pulmonary reaction.

Vinorelbine (Navelbine)

Clinical Context:  Vinorelbine is a vinca alkaloid that inhibits tubulin polymerization during G2 phase of cell division, thereby inhibiting mitosis.

Class Summary

Vinca alkaloid antineoplastic agents bind to tubulin and inhibit microtubule formation. These drugs arrest the cell at metaphase; they are specific to M and S phases.

Paclitaxel (Taxol, Abraxane)

Clinical Context:  Paclitaxel promotes microtubule assembly, interferes with the G2 mitotic phase, and inhibits cell replication. It has an off-label indication for the treatment of small cell lung cancer (SCLC). Black box warnings for paclitaxel include bone marrow suppression and hypersensitivity reactions.

Docetaxel (Taxotere, Docefrez)

Clinical Context:  Docetaxel inhibits the depolymerization of tubulin, which inhibits DNA, RNA, and protein synthesis. It can be used for the treatment of relapsed SCLC, which is an off-label indication. Docetaxel has several black box warnings, such as bone marrow suppression, fluid retention, and hypersensitivity reactions. This drug is not recommended for use in certain patients with hepatic impairment. Patients undergoing docetaxel treatment should be premedicated with corticosteroids the day before administration, to help reduce fluid retention and hypersensitivity reactions.

Class Summary

Antimicrotubular antineoplastic agents prevent cell growth and proliferation. They work by enhancing tubulin dimers, stabilizing existing microtubules, and inhibiting their disassembly.

Gemcitabine (Gemzar)

Clinical Context:  Gemcitabine is a pyrimidine analog. After intracellular metabolism to its active nucleotide, it inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Although use of this drug as a treatment for refractory or relapsed small cell lung cancer (SCLC) has not been approved by the US Food and Drug Administration (FDA), gemcitabine is often used for this purpose.

Class Summary

Antimetabolite antineoplastic agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.

Etoposide (Toposar, VePesid)

Clinical Context:  Etoposide inhibits topoisomerase II and appears to cause DNA strand breakage. It has been shown to delay transit of cells through the S phase and arrest cells in the late S or early G2 portion of the cell cycle. Etoposide is used in combination chemotherapy for the treatment of small cell lung cancer (SCLC).

Teniposide (vm 26, Vumon)

Clinical Context:  Teniposide inhibits topoisomerase II and appears to cause DNA strand breakage, preventing mitosis. This agent is used in combination chemotherapy for the treatment of SCLC. Black box warnings for teniposide include myelosuppression and hypersensitivity reactions.

Class Summary

Podophyllotoxin is a nonalkaloid toxin lignan from which etoposide and teniposide derive. These derivative agents have been shown to delay transit through the S phase and arrest cells in late S or early G2 phase. They appear to be topoisomerase II inhibitors and cause DNA strand breaks.

Author

Winston W Tan, MD, FACP, Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville

Disclosure: Nothing to disclose.

Coauthor(s)

Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Disclosure: Nothing to disclose.

Additional Contributors

Michael Perry, MD, MS, MACP† Former Nellie B Smith Chair of Oncology Emeritus, Former Director, Division of Hematology and Medical Oncology, Former Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

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High-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the image.

The adrenal glands are a common site for metastatic small cell lung cancer. This nonenhanced computed tomography scan of the abdomen at the level of the adrenal gland shows a large adrenal mass on the left side. The high attenuation values on this image and the large size of the adrenal mass suggest a malignant lesion.

The brain is one of the predominant sites for small cell lung cancer (SCLC) metastasis. This is a contrast-enhanced magnetic resonance imaging (MRI) scan of the brain in a patient with known SCLC. The axial section at the level of lateral ventricles shows at least 2 ring-enhancing metastatic lesions in the periventricular region.

This coronal positron emission tomogram shows abnormal areas of increased metabolic activity in the left hilar and left adrenal regions that are consistent with a hilar tumor with left adrenal metastasis.

This frontal chest radiograph shows extensive disease in a patient with small cell lung cancer. A large mass is noted in the left mid lung, with an opacity extending to the upper lung. Also present is a right lower lung nodule that suggests a metastatic deposit. The increased right paratracheal opacity indicates lymphadenopathy. A small left pleural effusion is present, with blunting of the costophrenic recess.

Small cell lung cancer frequently appears as a hilar or mediastinal mass. In this frontal chest radiograph, there is increased opacity in the right hilar and paratracheal region, with thickening of the right paratracheal stripe. Some volume loss can also be seen in the right lower pulmonary lobe.

This frontal chest radiograph shows obstructive pneumonitis with atelectasis of the right upper lobe in a patient with small cell lung cancer. The increased opacity in the right tracheobronchial and paratracheal region suggests a mass or lymphadenopathy in that region.

This contrast-enhanced computed tomography scan of the chest from a patient with small cell lung cancer shows a large left lung and a hilar mass, with invasion of the left pulmonary artery.

This image is a contrast-enhanced computed tomography scan of the abdomen from a patient with small cell lung cancer. The axial section through the liver shows multiple hypoattenuating areas in the liver. Poorly defined margins, attenuation greater than that of water, and scattered distribution in a patient with known lung cancer is most consistent with metastatic disease.

The adrenal glands are a common site for metastatic small cell lung cancer. This nonenhanced computed tomography scan of the abdomen at the level of the adrenal gland shows a large adrenal mass on the left side. The high attenuation values on this image and the large size of the adrenal mass suggest a malignant lesion.

This computed tomography scan of the chest at the level of the hila from a patient with small cell lung cancer shows a large hilar tumor on the right side, with loculated pleural effusion. Nodular thickening of the pleura suggests pleural metastasis. The tumor mass is difficult to differentiate from the adjacent atelectatic lung.

Small cell lung cancer occasionally appears as a peripheral lung nodule. This axial computed tomography scan through the lungs shows a solitary pulmonary nodule in the peripheral part of the right lung.

The brain is one of the predominant sites for small cell lung cancer (SCLC) metastasis. This is a contrast-enhanced magnetic resonance imaging (MRI) scan of the brain in a patient with known SCLC. The axial section at the level of lateral ventricles shows at least 2 ring-enhancing metastatic lesions in the periventricular region.

The bones are commonly affected in patients with small cell lung cancer. These whole-body bone scans with anterior and posterior images reveal multiple abnormal areas of increased radiotracer activity in the pelvis, spine, ribs, and left scapula. Such findings are consistent with bony metastatic disease.

High-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the image.

High-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the image.

This frontal chest radiograph shows extensive disease in a patient with small cell lung cancer. A large mass is noted in the left mid lung, with an opacity extending to the upper lung. Also present is a right lower lung nodule that suggests a metastatic deposit. The increased right paratracheal opacity indicates lymphadenopathy. A small left pleural effusion is present, with blunting of the costophrenic recess.

Small cell lung cancer frequently appears as a hilar or mediastinal mass. In this frontal chest radiograph, there is increased opacity in the right hilar and paratracheal region, with thickening of the right paratracheal stripe. Some volume loss can also be seen in the right lower pulmonary lobe.

This frontal chest radiograph shows obstructive pneumonitis with atelectasis of the right upper lobe in a patient with small cell lung cancer. The increased opacity in the right tracheobronchial and paratracheal region suggests a mass or lymphadenopathy in that region.

This contrast-enhanced computed tomography scan of the chest from a patient with small cell lung cancer shows a large left lung and a hilar mass, with invasion of the left pulmonary artery.

This image is a contrast-enhanced computed tomography scan of the abdomen from a patient with small cell lung cancer. The axial section through the liver shows multiple hypoattenuating areas in the liver. Poorly defined margins, attenuation greater than that of water, and scattered distribution in a patient with known lung cancer is most consistent with metastatic disease.

The adrenal glands are a common site for metastatic small cell lung cancer. This nonenhanced computed tomography scan of the abdomen at the level of the adrenal gland shows a large adrenal mass on the left side. The high attenuation values on this image and the large size of the adrenal mass suggest a malignant lesion.

This computed tomography scan of the chest at the level of the hila from a patient with small cell lung cancer shows a large hilar tumor on the right side, with loculated pleural effusion. Nodular thickening of the pleura suggests pleural metastasis. The tumor mass is difficult to differentiate from the adjacent atelectatic lung.

Small cell lung cancer occasionally appears as a peripheral lung nodule. This axial computed tomography scan through the lungs shows a solitary pulmonary nodule in the peripheral part of the right lung.

The brain is one of the predominant sites for small cell lung cancer (SCLC) metastasis. This is a contrast-enhanced magnetic resonance imaging (MRI) scan of the brain in a patient with known SCLC. The axial section at the level of lateral ventricles shows at least 2 ring-enhancing metastatic lesions in the periventricular region.

This coronal positron emission tomogram shows abnormal areas of increased metabolic activity in the left hilar and left adrenal regions that are consistent with a hilar tumor with left adrenal metastasis.

The bones are commonly affected in patients with small cell lung cancer. These whole-body bone scans with anterior and posterior images reveal multiple abnormal areas of increased radiotracer activity in the pelvis, spine, ribs, and left scapula. Such findings are consistent with bony metastatic disease.

This coronal positron emission tomogram shows a large, focal, hypermetabolic area on the right that is consistent with a large mass in the central portion of the right upper pulmonary lobe. Multiple other smaller hypermetabolic areas suggest lymph-node metastatic disease in the chest, abdomen, and right supraclavicular region.

Organ System Syndrome Mechanism Frequency
EndocrineSIADHAntidiuretic hormone15%[64]
Ectopic secretion of ACTHACTH2-5%[65]
NeurologicEaton-Lambert reverse myasthenic syndrome3%[66]
Subacute cerebellar degeneration
Subacute sensory neuropathy
Limbic encephalopathyAnti-Hu, anti-Yo antibodies
ACTH = adrenocorticotropic hormone; SCLC = small cell lung cancer; SIADH = syndrome of inappropriate antidiuretic hormone.

Sources: (1) Campling BG, Sarda IR, Baer KA, et al. Secretion of atrial natriuretic peptide and vasopressin by small cell lung cancer. Cancer. May 15, 1995;75(10):2442-51[64] ; (2) Shepherd FA, Laskey J, Evans WK, et al. Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol. Jan 1992;10(1):21-7[65] ; (3) Sher E, Gotti C, Canal N, et al. Specificity of calcium channel autoantibodies in Lambert-Eaton myasthenic syndrome. Lancet. Sep 16, 1989;2(8664):640-3.[66]

Primary Tumor (T) Tumor Size Location of Involvement
TXPrimary tumor can’t be assessed, or sputum cytology reveals tumor cells but the tumor is not seen on radiologic or bronchoscopic evaluation
T0No evidence of a primary tumor
TisCarcinoma in situ
T1≤3 cm in diameterSurrounded by lung or visceral pleura; no invasion more proximal than lobar bronchus
T2
  • >3 cm but ≤7 cm diameter, or
  • (see right column)
  • Main bronchus, ≥2 cm distal to carina, or
  • Visceral pleura, or
  • Hilar region, but not entire lung, associated with atelectasis/obstructive pneumonitis
T2a>3 cm but ≤5 cm diameter
T2b>5 cm but ≤7 cm diameter
T3
  • >7 cm diameter, or
  • (see right column)
Direct invasion of:
  • Parietal pleural chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or
  • Main bronchus < 2 cm distal to carina (but not carina itself), or
  • Entire lung with associated atelectasis/obstructive pneumonitis, or
  • Same lobe, separate tumor nodule(s)
T4Any sizeInvasion of:
  • Mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina
  • Different ipsilateral lobe, separate tumor nodule(s)
Node (N)Location of Regional Metastatic Involvement
NXRegional lymph nodes can’t be assessed
N0No regional lymph node metastasis
N1
  • Ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and
  • Intrapulmonary nodes, including direct extension
N2Ipsilateral mediastinal and/or subcarinal lymph node(s)
N3Contralateral mediastinal, contralateral hilar, ipsilateral/contralateral scalene, or supraclavicular lymph node(s)
Metastasis (M)Location of Distant Metastatic Involvement
M0No distant metastasis
M1Distant metastasis
M1a
  • Contralateral lobe tumor with separate tumor nodule(s), or
  • Malignant pleural effusion, or
  • Malignant pericardial effusion
M1bDistant metastasis
AJCC = American Joint Committee on Cancer.

Adapted from: (1) Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:299-330[47] ; (2) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Small Cell Lung Cancer [serial online]. 2013;v.2. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed December 5, 2011.[22]

Primary Tumor (T) Regional Node (N) Metastasis (M)
Occult CancerTXN0M0
Stage 0TisN0M0
Stage IAT1N0M0
BT2aN0M0
Stage IIAT2bN0M0
T1N1M0
T2aN1M0
Stage IIBT2bN1M0
T3N0M0
Stage IIIAT1-2N2M0
T3N1-2M0
T4N0-1M0
Stage IIIBT1-2N3M0
T3N3M0
T4N2-3M0
Stage IVAny TAny NM1a
Any TAny NM1b
AJCC = American Joint Committee on Cancer.

Adapted from: (1) Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:299-330[47] ; (2) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Small Cell Lung Cancer [serial online]. 2013;v.2. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed December 5, 2011.[22]