Small Cell Lung Cancer Workup

  • Author: Winston W Tan, MD, FACP; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
 
Updated: Aug 26, 2016
 

Approach Considerations

Lung cancer screening

The U.S. Preventive Services Task Force (USPSTF) and the American Cancer Society (ACS) have issued similar guidelines on lung cancer screening.[27, 28]  The USPSTF recommends annual screening for lung cancer with low-dose CT (LDCT) in adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. The USPSTF recommends that screening be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.[28]

The ACS recommends LDCT screening in apparently healthy patients 55-74 years of age who have at least a 30 pack-year smoking history and who currently smoke or have quit within the past 15 years. The ACS stresses that the decision to initiate lung cancer screening should be shared between the clinician and patient and should involve discussion of the potential benefits, limitations, and harms associated with such screening.[27]

Initial workup

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 the primary tumor should be obtained using bronchoscopy or any of the following techniques[12] :

  • Mediastinoscopy
  • Endobronchial ultrasound (EBUS)
  • Endoscopic ultrasound
  • Transthoracic needle aspiration
  • Thoracoscopy (if necessary)

A metastatic lesion, if easily and safely accessible, may be the preferred option for a biopsy specimen; this will also provide pathological staging.[12]

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[24, 29, 12] :

  • Complete history and physical examination (see Presentation)
  • Complete blood count (CBC) with differential
  • Serum electrolytes levels, including calcium
  • Liver function tests (LFTs)
  • Renal function tests (RFTs)
  • Serum lactate dehydrogenase (LDH) level
  • Serum alkaline phosphatase (ALP) level
  • Chest radiography
  • CT scanning of the chest and abdomen with intravenous contrast (including liver and adrenal glands)
  • CT scanning/magnetic resonance imaging (MRI) of the brain with IV contrast
  • Bone scanning
  • Bone marrow aspiration and biopsy if abnormalities are present in the CBC or peripheral smear

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.

See Small Cell Lung Cancer Staging for summary tables.

See Lung Cancer Staging -- Radiologic Options, a Critical Images slideshow, to help identify stages of the disease process.

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Routine Laboratory Studies

A complete blood cell count (CBC) 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.

Complete blood cell count

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:

  • Absolute neutrophil count (ANC) - Should be greater than 1000 x 10 3/µL
  • Hemoglobin level - Should be above 10 g/dL
  • Platelet count - Should be more than 100 x 10 3/µL

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.

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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.

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 contrast agents should be used whenever possible.[24] In the United States, CT scans of the chest and upper abdomen to include the liver and adrenal glands are standard.

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Brain and Spinal Cord Imaging Studies

Brain metastasis may be present in as many as 10-15% of patients at diagnosis[24] and may be occult in 5% of patients. Consequently, magnetic resonance imaging (MRI) of the brain should be ordered in asymptomatic patients and in those with neurologic symptoms.[24] 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.

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.

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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.

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.

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PET Scanning

Positron emission tomography (PET) scanning (see the image below) remains under evaluation for the staging of small cell lung cancer (SCLC).[30, 31] 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.[24] PET-CT imaging is superior to PET scanning alone. (PET scanning is inferior to MRI or CT scanning for the detection of brain metastases.)

This coronal positron emission tomogram shows a la 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.

In small, uncontrolled studies, PET scanning has shown good accuracy (83-99%) in staging extensive- versus limited-stage SCLC.[30] 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.[24] The full role of PET imaging in this setting remains to be determined.[30, 31]

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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.

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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.

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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.[32] The currently preferred agent for pleurodesis is sterilized talc, which can be instilled either as a slurry or as a powder during pleuroscopy.

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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.)[33]

High-power photomicrograph of small cell carcinoma 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.

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.[24]

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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).[24, 22]

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.[24, 22]

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.[24]

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).[24, 22] Approximately two thirds of patients with SCLC present with extensive-stage disease at diagnosis.[22] 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.[24]

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.[25] The TNM assignments define the cancer growth and disease extent, and the stage groupings combine cancers with a similar prognosis.[24] Generally, lower stage numbers result in a better prognosis.[24]

Table 2. AJCC TNM Categories for Lung Cancer (Open Table in a new window)

Primary Tumor (T) Tumor Size Location of Involvement
TX Primary tumor can’t be assessed, or sputum cytology reveals tumor cells but the tumor is not seen on radiologic or bronchoscopic evaluation
T0 No evidence of a primary tumor
Tis Carcinoma in situ
T1 ≤3 cm in diameter Surrounded 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)
T4 Any size Invasion 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
NX Regional lymph nodes can’t be assessed
N0 No regional lymph node metastasis
N1
  • Ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and
  • Intrapulmonary nodes, including direct extension
N2 Ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Contralateral mediastinal, contralateral hilar, ipsilateral/contralateral scalene, or supraclavicular lymph node(s)
Metastasis (M) Location of Distant Metastatic Involvement
M0 No distant metastasis
M1 Distant metastasis
  M1a
  • Contralateral lobe tumor with separate tumor nodule(s), or
  • Malignant pleural effusion, or
  • Malignant pericardial effusion
  M1b Distant 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[25] ; (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.[24]



Table 3. AJCC Stage Groupings for Lung Cancer (Open Table in a new window)

  Primary Tumor (T) Regional Node (N) Metastasis (M)
Occult Cancer TX N0 M0
Stage 0 Tis N0 M0
Stage I A T1 N0 M0
B T2a N0 M0
Stage IIA T2b N0 M0
T1 N1 M0
T2a N1 M0
Stage IIB T2b N1 M0
T3 N0 M0
Stage IIIA T1-2 N2 M0
T3 N1-2 M0
T4 N0-1 M0
Stage IIIB T1-2 N3 M0
T3 N3 M0
T4 N2-3 M0
Stage IV Any T Any N M1a
Any T Any N M1b
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[25] ; (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.[24]



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Contributor Information and Disclosures
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; Vice Chairman of Education, Division of Hematology/Oncology, Mayo Clinic Florida

Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, Texas Medical Association, American Society of Clinical Oncology, Philippine Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

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

Irfan Maghfoor, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

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

Jules E Harris, MD, FACP, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, Central Society for Clinical and Translational Research, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Acknowledgements

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.
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.
Table 1. Paraneoplastic Syndromes Affecting Endocrine and Neurologic Function in SCLC
Organ System Syndrome Mechanism Frequency
Endocrine SIADH Antidiuretic hormone 15%[19]
Ectopic secretion of ACTH ACTH 2-5%[20]
     
Neurologic Eaton-Lambert reverse myasthenic syndrome   3%[21]
Subacute cerebellar degeneration    
Subacute sensory neuropathy    
Limbic encephalopathy Anti-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[19] ; (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[20] ; (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.[21]



Table 2. AJCC TNM Categories for Lung Cancer
Primary Tumor (T) Tumor Size Location of Involvement
TX Primary tumor can’t be assessed, or sputum cytology reveals tumor cells but the tumor is not seen on radiologic or bronchoscopic evaluation
T0 No evidence of a primary tumor
Tis Carcinoma in situ
T1 ≤3 cm in diameter Surrounded 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)
T4 Any size Invasion 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
NX Regional lymph nodes can’t be assessed
N0 No regional lymph node metastasis
N1
  • Ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and
  • Intrapulmonary nodes, including direct extension
N2 Ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Contralateral mediastinal, contralateral hilar, ipsilateral/contralateral scalene, or supraclavicular lymph node(s)
Metastasis (M) Location of Distant Metastatic Involvement
M0 No distant metastasis
M1 Distant metastasis
  M1a
  • Contralateral lobe tumor with separate tumor nodule(s), or
  • Malignant pleural effusion, or
  • Malignant pericardial effusion
  M1b Distant 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[25] ; (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.[24]



Table 3. AJCC Stage Groupings for Lung Cancer
  Primary Tumor (T) Regional Node (N) Metastasis (M)
Occult Cancer TX N0 M0
Stage 0 Tis N0 M0
Stage I A T1 N0 M0
B T2a N0 M0
Stage IIA T2b N0 M0
T1 N1 M0
T2a N1 M0
Stage IIB T2b N1 M0
T3 N0 M0
Stage IIIA T1-2 N2 M0
T3 N1-2 M0
T4 N0-1 M0
Stage IIIB T1-2 N3 M0
T3 N3 M0
T4 N2-3 M0
Stage IV Any T Any N M1a
Any T Any N M1b
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[25] ; (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.[24]



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