Small Cell Lung Cancer (SCLC) 

Updated: Jun 19, 2020
Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD 

Overview

Practice Essentials

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. See the image below.

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.

SCLC 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, including hypercalcemia, Eaton-lambert syndrome, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and many others. (See Pathophysiology, Etiology, and Presentation.)[1, 2, 3]

In patients who present with SCLC, it is important to determine whether the cancer is limited or at an extensive stage. Limited-stage cancer, which is potentially curable, is treated with chemotherapy and radiation, with surgical resection reserved for selected patients with stage I disease. Extensive-stage cancer is incurable; systemic chemotherapy is used to improve quality of life and prolong survival.[4]

See Small Cell Lung Cancer: Beating the Spread, a Critical Images slideshow, to help identify the key clinical and biologic characteristics of small cell lung cancer, the staging criteria, and the common sites of spread.

Also see the Clinical Presentations of Lung Cancer: Slideshow and Lung Cancer Staging -- Radiologic Options slideshows for additional information on SCLC staging and treatment.

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.

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. In addition, 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.[5, 6] 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.[7]

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 overall 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.[8, 9, 10]  In both sexes, lung cancer is the most common cause of cancer death. Although less than half as many new cases of lung cancer than breast cancer are diagnosed in US women each year, 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, as smoking rates have fallen.[10] SCLC once accounted for 20-25% of all newly diagnosed lung cancers; it now comprises only about 13% of all lung cancers.[11]

For 2020, the estimates for lung cancer overall in the United States are 228,820 new cases and 135,720 deaths.[10]

International occurrence

Globally, lung cancer is the most frequent malignancy in men (in Europe, lung cancer is second only to prostate cancer[12] ) 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 2.09 million new cases of lung cancer and 1.76 million deaths from lung cancer occur annually throughout the world.[13]

Separate worldwide data for SCLC are not available. The incidence of lung cancer started to decline among men 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 did not begin to decline until the mid-2000s.[8, 10]

Age- and sex-related demographics

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

Over the past two decades, the incidence of lung cancer has generally decreased in both men and women 30 to 54 years of age in all races and ethnic groups. However, the incidence has declined more steeply in men. As a result, lung cancer rates in younger women have become higher than those in younger men. In non-Hispanic whites and Hispanics ages 44 to 49 years, for example, the female-to-male rate ratio for lung cancer incidence rose from 0.88 during 1995-1999 to 1.17 during 2010-2014.[14]

This reversal can be explained in part by increased rates of cigarette smoking in women born since 1965. However, while the difference in smoking rates in that age group has narrowed, rates in women have generally not exceeded the rates in men, so other factors may be playing a role. For example, women may be more susceptible to the oncogenic effects of smoking.[14]

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.[15] 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.[16]

Genome-wide association studies have identified single-nucleotide polymorphisms (eg, within the promoter region of YAP1 on chromosome 11q22) that may affect survival in patients with SCLC.[17, 18]  

Indicators of poor prognosis include the following:

  • Relapsed disease
  • Weight loss of greater than 10% of baseline body weight
  • Poor performance status
  • Hyponatremia [19]

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. For patient education information, see the Lung Cancer Health Center and the Smoking Cessation Health Center.

 

Presentation

History

Fewer than 5% of patients with small cell lung cancer (SCLC) are asymptomatic at presentation. Common presenting signs and symptoms of the disease, which very often occur in advanced-stage disease, include the following:

  • Shortness of breath
  • Cough
  • Bone pain
  • Weight loss
  • Fatigue
  • Neurologic dysfunction

Most patients with this disease present with a short duration of symptoms, usually only 8-12 weeks before presentation. The clinical manifestations of SCLC can result from local tumor growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes.

Local tumor growth

SCLCs 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 SCLC, 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

SCLCs 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. The symptoms depend upon the site of spread.

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:

  • Headache - Usually worse in the morning
  • Blurred vision
  • Photophobia
  • Nausea
  • Vomiting
  • Slurred speech
  • Confusion
  • Localizing symptoms - Such as extremity weakness

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  Paraneoplastic Diseases for more information.

Table 1. Paraneoplastic Syndromes Affecting Endocrine and Neurologic Function in SCLC (Open Table in a new window)

Organ System

Syndrome

Mechanism

Frequency

Endocrine

SIADH

Antidiuretic hormone

15%[20]

Ectopic secretion of ACTH

ACTH

2-5%[21]

 

 

 

Neurologic

Eaton-Lambert reverse myasthenic syndrome

 

3%[22]

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[20] ; (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[21] ; (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.[22]

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. Very often patients are asymptomatic but may have mild elevation of liver enzyme levels.

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.

Complications

Multiple complications may be noted, depending on the site of metastasis or the metabolic factor that the tumor affects. Hypercalcemia could initially be asymptomatic but in late stages could lead to weakness, fatigue, and sleepiness, and in extreme cases to severe constipation and lethargy.

Brain metastasis is often asymptomatic but could manifest as a unilateral eye abnormality, focal neurologic deficit, or at times with a new-onset headache that wakes the patient up. Seizures are a possible manifestation.

 

DDx

Differential Diagnoses

 

Workup

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.[23, 24]  The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (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.[24]

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.[23]

A study by researchers from the National Cancer Institute (NCI) and the American Cancer Society that reviewed nine risk prediction models determined that the following four models were more accurate than the others for predicting lung cancer risk and for selecting patients who had ever-smoked for lung cancer screening:

  • Bach model
  • Ovarian Cancer Screening Trial Model 2012 (PLCO-M2012)
  • Lung Cancer Risk Assessment Tool (LCRAT)
  • Lung Cancer Death Risk Assessment Tool (LCDRAT)

Although the researchers concluded that that any of those models could be used to select US smokers who are at the greatest risk for lung cancer incidence or death, all the models have limitations. The Bach model does not account for race/ethnicity, family history of lung cancer, or presence of chronic obstructive pulmonary disease; the PLCO-M2012 model underestimated lung cancer risk in people of Hispanic descent by a factor of 2 to 3, and the LCRAT and LCDRAT models both underestimated risk in the "Asian/other" subgroup.[25, 26]

Initial workup

A thorough history and physical examination usually provides 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[27, 28, 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.

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 potential for 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.

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.

Computed tomography

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.[27] In the United States, CT scans of the chest and upper abdomen to include the liver and adrenal glands are standard.

Brain and Spinal Cord Imaging Studies

Brain metastasis may be present in as many as 10-15% of patients at diagnosis[27] and may be occult in 5% of patients. Consequently, magnetic resonance imaging (MRI) of the brain should be ordered in asymptomatic patients as well as in those with neurologic symptoms.[27] 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.

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-related symptoms develop or if the serum calcium or alkaline phosphatase level is elevated.

PET Scanning

Positron emission tomography (PET) scanning (see the image below) remains under evaluation for the staging of small cell lung cancer (SCLC).[29, 30] 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.[27] 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.[29] 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.[31] The full role of PET imaging in this setting remains to be determined.[29, 30]

Bronchoscopy and Fine Needle Aspiration

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) 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.[32] 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.)[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.[27]

Staging Overview

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.[34] 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.[35]

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.[27] 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.[27]

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.[27]

The American Joint Committee on Cancer (AJCC) adopted the new TNM system in 2010.[31] 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 current NCCN guidelines.[27]

For more details, see VALSG and TNM Staging, below.

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).[27, 34]

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.[27, 34]

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.[31]

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).[31, 34] Approximately two thirds of patients with SCLC present with extensive-stage disease at diagnosis.[34] 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.[31]

Table 2, below, summarizes the AJCC lung cancer TNM staging system categories, and Table 3, below, summarizes the lung cancer stage groupings.[31] The TNM assignments define the cancer growth and disease extent, and the stage groupings combine cancers with a similar prognosis.[27] Generally, lower stage numbers result in a better prognosis.[27]

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 greatest dimension

Surrounded by lung or visceral pleura; no invasion more proximal than lobar bronchus

 

T1a

≤1 cm in greatest dimension

 
 

T1b

 >1 cm but ≤2 cm in greatest dimension

 
 

T1c

>2 cm but ≤3 cm in greatest dimension

 

T2

  • >3 cm but ≤5 cm in greatest  dimension, 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 ≤4 cm in greatest  dimension

 
 

T2b

>5 cm but ≤7 cm in greatest  dimension

 

T3

  • >5 cm but ≤7 cm in greatest  dimension, 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

  • >7 cm or

  • (see right column)

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 cannot 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

  • Tumor with pleural nodules or malignant pleural or pericardial effusion

 

M1b

Single extrathoracic metastasis in a single organ and involvement of a single distant (nonregional) node

 

M1c

Multiple extrathoracic metastases in one or more organs

AJCC = American Joint Committee on Cancer.

Adapted from: (1) Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2010:299-330[31] ; (2) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Small Cell Lung Cancer [serial online]. 2018;v.2. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.[31]

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 IA

IA1

T1a

N0

M0

IA2

T1b

N0

M0

IA3

T1c

N0

M0

Stage IIA

T2b

N0

M0

Stage IIB

T1a,b,c

N1

M0

T2a,b

N1

M0

T3

N0

M0

Stage IIIA

T1a,b,c

N2

M0

T2a,b

N2

M0

T3

N1-2

M0

T4

N0-1

M0

Stage IIIB

T1a,b,c

N3

M0

T2a,b

N3

M0

T3

N2

M0

T4

N2

M0

Stage IIIC

T3-4

N3

M0

Stage IVA

Any T

Any N

M1a,b

Stage IVB

Any T

Any N

M1c

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; 2016[36] ; (2) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Small Cell Lung Cancer [serial online]. 2018;v.2. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.[31]

 

Treatment

Approach Considerations

Small cell lung cancer (SCLC) is characterized by rapid growth and early dissemination. Prompt initiation of treatment is important.

Patients with clinical stage Ia (T1N0) after standard staging evaluation may be considered for surgical resection, but combined treatment with chemotherapy and radiation therapy is the standard of care. Radiation therapy is often added at the second cycle of chemotherapy.

For patients with a good performance status and nonbulky disease, intensive radiation therapy early in the course of treatment is indicated. However, radiation therapy can often be delayed for patients with either a poor performance status or very bulky disease. Delaying the initiation of radiation therapy until the third cycle of chemotherapy does have the advantage of avoiding the significant myelosuppression seen with full-dose chemotherapy and large-volume radiation therapy .

For the approximately 30% of patients with SCLC who have limited-stage disease at the time of diagnosis (ie, tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes), management 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).[11, 15]

Although many patients with limited-stage SCLC have comorbidity, a Norwegian study found that patients with comorbidity complete and tolerate chemo-radiotherapy as well as other patients. No significant differences in response rates, progression-free survival, or overall survival were identified.[37]

Extensive-stage SCLC (ie, SCLC that has spread beyond the supraclavicular areas, or with distant metastases) 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.

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.[27, 28]

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.[28]

In contrast with non-SCLC, for which identification of molecular targets and targeted therapies has proceeded at a brisk pace, SCLC has not been shown to respond well to most targeted therapies.[28] Studies of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors have yielded disappointing results: bevacizumab,[38] aflibercept, and vandetanib have failed to demonstrate significant improvements in survival.[39]

Consequently, there has been little change in survival over the past 2 decades for limited- or extensive-stage SCLC.[40, 39] In 2018, however, the IMpower133 study may have inaugurated a new standard of care for first-line treatment of extensive-stage SCLC, by demonstrating a significant improvement in survival with the addition of atezolizumab—a humanized monoclonal anti–programmed death ligand 1 (PD-L1) antibody—to chemotherapy with carboplatin and etoposide.[41, 42]  In March 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult patients with extensive-stage SCLC.

See Small Cell Lung Cancer Treatment Protocols for summarized information.

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 systematic review that compared the effectiveness of these regimens, Amarasena et al 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 result in higher 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.[43]

Cisplatin plus etoposide or irinotecan

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 has shown 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).[43]

The PE combination has also been compared with other platinum-based regimens (eg, cisplatin and irinotecan [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).[44]

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.[45] In addition, the overall response rate between PE and IP treatment groups did not differ.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.[46] Therefore, the PE combination remains the first-line combination chemotherapy choice for most physicians.

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 systematic review that compared the effectiveness of these regimens, Amarasena et al 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 result in higher 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.[47]

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).[43]

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).[44]

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.[45] In addition, the overall response rate between PE and IP treatment groups did not differ.[45] 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.[46] Therefore, the PE combination remains the first-line combination chemotherapy choice for most physicians.

Cisplatin-based versus carboplatin-based chemotherapy

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.[48]

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. This meta-analysis included 4 trials with a total of 663 patients (328 treated with cisplatin; 335 treated with carboplatin).[49]

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. However, hematologic toxicity was higher with carboplatin, whereas nonhematologic toxicity was higher with cisplatin.[49]

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).[27, 28, 12] 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 demonstrate improved survival.[50]

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.[51] 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 and concurrent thoracic radiotherapy. Therefore, it is necessary to refer patients to a radiation oncologist, as well as a medical oncologist. For combination chemotherapy, the American College of Chest Physicians (ACCP) recommends four cycles of a platinum agent and etoposide.[28]

For patients receiving chemotherapy and radiotherapy, National Comprehensive Cancer Network guidelines recommend a maximum of four to six cycles of cisplatin and etoposide.[27] Continuing chemotherapy beyond four to six cycles has not been shown to significantly improve overall survival in most randomized controlled trials, and has been associated with considerable risk of increased toxicity; indeed, many oncologists now stop after four cycles of therapy.[27, 28, 12]

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, preferably within 30 days of the start of chemotherapy.[28, 12] For patients who are eligible for early concurrent chemoradiotherapy, the American College of Chest Physicians (ACCP) recommends concurrent accelerated hyperfractionated radiotherapy (twice-daily treatment) with platinum-based chemotherapy.[28]

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.[52] 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.[53] 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. However, a major flaw in this trial was that the biologic equivalent dose of radiotherapy was not equivalent between the 2 treatment arms.

The European Society for Medical Oncology (ESMO) notes that twice-daily radiotherapy is inconvenient and is associated with a significantly elevated rate of transient grade 3 esophagitis.Nevertheless, ESMO guidelines recommend considering twice-daily 1.5 Gy in a 30-fraction regimen in clinical practice, for fit patients who are willing to accept temporarily increased toxicity.[12]

Prophylactic cranial irradiation

The ACCP and the 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.[27, 28]

The use of PCI was initially considered controversial.[54] 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.[54]

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.[51] 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. Dose fractionation appeared to be important, and PCI was associated with an increase in specific and overall grade 3+ adverse events.[55]

Extensive-Stage SCLC - Standard Management

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

However, the combination of chemotherapy with atezolizumab—a humanized monoclonal anti–programmed death ligand 1 (PD-L1) antibody—may represent a new standard of care. The IMpower133 demonstrated a significant improvement in survival with the addition of atezolizumab to carboplatin and etoposide.[41, 42]  In March 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult patients with ES-SCLC.

In IMpower133, at a median follow-up of 13.9 months, the median overall survival in patients who received atezolizumab plus chemotherapy (n=201) was 12.3 months compared with 10.3 months in patients who received chemotherapy only (n=202; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). Median progression-free survival was 5.2 months for the atezolizumab group compared with 4.3 months for the placebo group (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The 1-year overall survival rate was 51.7% in the atezolizumab group and 38.2% in the placebo group.[41]

In March 2020, the FDA approved another PD-L1 inhibitor, durvalumab, in combination with etoposide and either carboplatin or cisplatin as first-line treatment for ES-SCLC. Approval was based from the CASPIAN trial, a randomized, multicenter, open-label phase II study (n=268), in which durvalumab in combination with platinum, etoposide, and/or tremelimumab was associated with a significant improvement in overall survival, with a hazard ratio of 0.73; median overall survival was 13 months in the durvalumab plus platinum-etoposide group compared with 10.3 months in the platinum-etoposide group, with 34% versus 25% of patients alive at 18 months.[56]

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).[27, 28, 12]

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.[44]

However, a confirmatory study in the United States failed to show the superiority of either regimen.[57]

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.[57]

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.[58]

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.[28]

In a phase III randomized controlled trial, Slotman et al showed that patients with extensive-stage SCLC who had responded to chemotherapy may benefit from thoracic radiotherapy (30 Gy in 10 fractions). Although overall survival at 1 year was not significantly different in the patients who received thoracic radiotherapy, 2-year overall survival was 13% with radiotherapy versus 3% without (P=0.004). At 6 months, progression-free survival was 24% with radiotherapy versus 7% without (P=0.001). No severe toxic effects from radiotherapy were noted.[59]

Prophylactic cranial irradiation

As with limited-stage disease, offer prophylactic cranial irradiation (PCI) to all responding patients with extensive stage SCLC[27, 28, 12] ; 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.[54] 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.[12]

In a phase III Japanese trial conducted in patients with extensive stage SCLC, PCI did not result in longer overall survival compared with observation; on final analysis, median overall survival was 11.6 months in the PCI group (n=113) and 13.7 months in the observation group (n=111). These authors concluded that PCI is not essential for patients with extensive-stage SCLC who have had  any response to initial chemotherapy and in whom periodic follow-up MRI scans confirm the absence of brain metastases.[60]

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.[61]

 

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.[62] 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.[63]

The American College of Chest Physicians (ACCP) recommends offering second-line, single-agent chemotherapy to patients with relapsed or refractory SLCL. Single agents with demonstrated activity in second-line SCLC therapy include topotecan, irinotecan, paclitaxel, docetaxel, vinorelbine, oral etoposide, and gemcitabine. The ACCP notes that "although response rates are generally higher with combination therapy, overall survival does not appear to be improved and the toxicity of combination regimens is frequently problematic." For patients who relapse more than 6 months after completion of initial chemotherapy, the ACCP recommends reusing the previously administered first-line chemotherapy regimen. Enrollment in a clinical trial is encouraged.[28]

In contrast, on the basis of a phase III trial in 180 patients, Goto et al concluded that combination chemotherapy with cisplatin, etoposide, and irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed SLCL. In their study, overall survival with combination chemotherapy was 18.2 months (95% confidence index [CI] 15.7-20.6), versus 12.5 months (95% CI, 10.8-14.9) in patients with topotecan monotherapy (hazard ratio 0.67, 90% CI 0.51-0.88; P=0.0079). Patients in the combination chemotherapy arm did experience higher rates of toxicity, however.[64]

In June 2020, the FDA granted accelerated approval to the alkylating drug lurbinectedin (Zepzelca) for adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. Approval was based on the results from the PM1183-B-005-14 trial, a multicenter open-label, multi-cohort study in 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The overall response rate (ORR) was 35% (95% CI: 26%, 45%), with a median response duration of 5.3 months (95% CI: 4.1, 6.4). The ORR as per independent review committee was 30% (95% CI: 22%, 40%) with a median response duration of 5.1 months (95% CI: 4.9, 6.4).[65]

Immune checkpoint modulation

In August 2018, the FDA granted accelerated approval of nivolumab for metastatic SCLC in patients with progression after platinum-based chemotherapy and at least 1 other line of therapy. Nivolumab is a monoclonal antibody to programmed cell death–1 protein (PD-1). Approval was based on evidence from the CheckMate-032 trial, in which 13 of 109 patients (12%) responded (95% confidence interval [CI], 6.5 - 19.5). Twelve patients (11%) had a partial response and one (0.9%) had a complete response. The median duration of response was 17.9 months (95% CI, 7.9 - 42.1; range, 3.0 - 42.1 months).[66]

The FDA granted accelerated approval for pembrolizumab in patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. Approval was based on results from the phase 1b KEYNOTE-028 trial and the phase 2 KEYNOTE-158 trial.[67, 68]

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.[28]

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.[69, 12] 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.[28]

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.[19]

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.[12]

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.[7]

 

Guidelines

Guidelines Summary

Guidelines on lung cancer screening have been issued by the following organizations:

  • American Cancer Society (ACS)
  • American College of Chest Physicians (ACCP)
  • American Association for Thoracic Surgery (AATS)
  • National Comprehensive Cancer Network (NCCN)
  • U.S. Preventive Services Task Force (USPSTF)

The guidelines are in agreement that annual screening with low-dose, computed tomography (LDCT) scanning should be offered to patients aged 55 to 74 years and who have at least a 30 pack-year smoking history and either continue to smoke or have quit within the past 15 years.[23, 28, 27, 71, 24]

ACCP Diagnosis and Management Guidelines

The American College of Chest Physicians (ACCP) updated its comprehensive set of lung cancer guidelines in 2013. The guideline set of more than 275 recommendations includes an executive summary of current recommendations for diagnosis and treatment, along with additional recommendations for screening, chemoprevention, and treatment of tobacco use in patients with lung cancer.[28]

In 2015, the American Society of Clinical Oncology (ASCO) endorsed the ACCP guidelines, with the addition of minor qualifying statements.

Diagnosis of Pleural Abnormalities

The ACCP recommendations for diagnosis of pleural abnormalities include the following[28, 72] :

  • In patients suspected of having SCLC based on the radiographic and clinical findings, the diagnosis should be confirmed by the least invasive method (eg, sputum cytology, thoracentesis, fine needle aspiration (FNA), bronchoscopy including transbronchial needle aspiration), as dictated by the patient's presentation

  • For individuals who have a solitary extrathoracic site suspicious of a metastasis, tissue confirmation of the metastatic site should be obtained if FNA or biopsy of the site is feasible

  • In individuals in whom biopsy of a metastatic site would be technically difficult, diagnosis of the primary lung lesion should be obtained by the least invasive method

  • In patients suspected of having lung cancer who have an accessible pleural effusion, thoracentesis is recommended to identify the cause of the pleural effusion; ultrasound-guided thoracentesis is recommended for performing diagnostic thoracentesis

  • In patients suspected of having lung cancer who have an accessible pleural effusion, if pleural fluid cytology is negative, pleural biopsy (via image-guided pleural biopsy, medical or surgical thoracoscopy) is recommended as the next step

Diagnosis of Primary Tumor

The ACCP recommendations for diagnosis of primary tumor include the following[28, 72] :

  • If lung cancer is suspected and sputum cytology is negative for carcinoma, further testing should be performed

  • In patients who have a central lesion, bronchoscopy should be used to confirm the diagnosis; however, further testing should be performed if bronchoscopy results are non-diagnostic and suspicion of lung cancer remains

  • As an adjunct imaging modality when a tissue sample is required due to diagnostic uncertainty or poor surgical candidacy, radial endobronchial ultrasound can confirm in real time the ideal location of bronchoscopic sampling and increase the diagnostic yield over conventional bronchoscopy for peripheral nodules.

  • With peripheral lung lesions difficult to reach with conventional bronchoscopy, electromagnetic navigation guidance can be used if the equipment and the expertise are available; otherwise, transthoracic needle aspiration (TTNA) is recommended

  • In patients who have a peripheral lesion and who require tissue diagnosis before further management can be planned, TTNA is diagnostic option; however, further testing should be performed if TTNA results are nondiagnostic and suspicion of lung cancer remains

  • The possibility of an erroneous diagnosis of SCLC on a cytology specimen must be kept in mind if the clinical presentation or clinical course is not consistent with that of SCLC; in such a case, further testing should be performed to establish a definitive cell type

Staging

The American Joint Commission for Cancer (AJCC) adopted the new tumor, node, metastasis (TNM) system in 2010.[31] 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 current NCCN and European Society for Medical Oncology (ESMO) practice guidelines.[27, 12] However, the American College of Chest Physicians (ACCP) guidelines recommend use of both the TNM system and the Veterans Administration Lung Study Group (VALSG) system (limited-stage vs extensive-stage) to classify the tumor stage.[28]

SCLC consists of two stages: limited-stage and extensive-stage. Under the AJCC TNM staging system, 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.[31]

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). The AJCC TNM staging system classifies extensive-stage disease as any T, any N, M1a/b, and T3-4, due to involvement of multiple nodules.[31]

The ACCP does not recommend positron emission tomography (PET) scanning in the routine staging of SCLC.[28] However, in a qualifying statement, the American Society of Clinical Oncology (ASCO) recognizes that PET scanning is a widely used initial staging tool in patients with lung cancer, and recommends that when a PET scan is obtained for patients with either limited-stage or extensive-stage disease, a bone scan may be omitted.[73] The NCCN guidelines recommend combined PET–computed tomography scanning if limited-stage disease or metastasis is suspected.[27]

Treatment for Limited-Stage SCLC

The American College of Chest Physician (ACCP) guidelines recommend that limited-stage small cell lung cancer (LS-SCLC) be treated with curative intent, based on an expected 20% to 25% 5-year survival.[28] The ACCP recommendations for treatment of LS-SCLC also include the following: 

  • Surgical resection is indicated for carefully selected stage I SCLC after a thorough evaluation of distant and invasive mediastinal stage

  • Patients who have undergone surgical resection should be treated with platinum-based adjuvant chemotherapy

  • Accelerated hyper-fractionated radiation therapy (twice-daily treatment) should be administered early in the course of treatment, concurrently with chemotherapy consisting of four cycles of a platinum agent and etoposide

The ACCP and the National Comprehensive Cancer Network (NCCN) guidelines recommend prophylactic cranial irradiation in patients with limited-stage disease who have achieved a complete remission or in those with stage I disease who have undergone a complete resection, although the NCCN advises against its use in patients with poor performance status or impaired neurocognitive function.[27, 28] The 2013 European Society for Medical Oncology (ESMO) practice guidelines recommends patients with T1, 2 N0, 1 M0 should be considered for prophylactic cranial irradiation (PCI) if they have responded to initial treatment using the same dose and fractionation as for patients with stage III SCLC.[12]

In addition, the NCCN clinical practice guidelines recommend sequential therapy for patients unable to tolerate concurrent chemoradiation. Chemotherapy is given first, followed by radiation therapy, because of the high rate of responsiveness to chemotherapy for SCLC.[27] .

Treatment for Extensive-Stage SCLC

Guidelines from the American College of Chest Physicians (ACCP), the National Comprehensive Cancer Network (NCCN), and the European Society for Medical Oncology (ESMO) recommend that patients with extensive-stage disease be treated with combination chemotherapy alone.[12, 27, 28]

The ACCP recommends combining palliative care with standard oncology care early in the treatment course. Conversations about the goals of care and end-of-life options should be initiated with all patients with extensive-stage SCLC.[28]

In patients who have mixed histologic features of SCLC and non-SCLC, the ACCP and NCCN guidelines recommend following treatment recommendations for SCLC.[27, 28]

According to the NCCN guidelines, dose-dense or dose-escalation chemotherapy regimens are not recommended outside of a randomized clinical trial.[27]

The ACCP recommends offering further chemotherapy to patients with relapsed or refractory SLCL.[28] However, except in the setting of a clinical trial, the ACCP does not recommend either of the following:

  • Maintenance treatment for patients with limited- or extensive-stage disease that is in partial (PR) or complete remission (CR)

  • Dose-dense/intense initial/induction or maintenance treatment for limited- or extensive-stage disease

Treatment of SCLC in the Elderly

The American College of Chest Physicians (ACCP) recommends that elderly patients with small-cell lung cancer (SCLC) who have a good performance status (PS) (ie, Eastern Cooperative Oncology Group [ECOG] PS 0 or 1) and intact organ function receive standard carboplatin-based chemotherapy. However, even patients 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.[28]

Long-Term Monitoring

The National Comprehensive Cancer Network recommends that after recovery from primary therapy, patients should receive oncology follow-up visits on the following schedule[27] :

  • Years 1-2: Every 3–4 mo
  • Years 3-5: Every 6 mo
  • Subsequent years: Annuallly

At every visit, the patient should receive the following:

  • History and physical examination
  • Chest imaging (with workup for potential new primary if a new pulmonary nodule is detected)
  • Blood work as clinically indicated
  • Smoking cessation intervention, if necessary

Positron emission tomography/computed tomography (PET/CT) is not recommended for routine follow-up.

 

Medication

Medication Summary

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Antineoplastics, Alkylating

Cyclophosphamide (Cytoxan, Neosar)

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)

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

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)

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.

Lurbinectedin (Zepzelca)

Lurbinectedin is an alkylating drug. It binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. The adduct formation triggers a cascade of events that can affect the subsequent activity of DNA-binding proteins, including some transcription factors, and DNA repair pathways. FDA granted accelerated approval for adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. 

Topoisomerase Inhibitors

Irinotecan (Camptosar)

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)

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).

Antineoplastics, Anthracycline

Doxorubicin (Adriamycin, Caelyx, Rubex)

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.

Antineoplastics, Vinca Alkaloid

Vincristine (Oncovin)

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)

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

Antineoplastics, Antimicrotubular

Paclitaxel (Taxol, Abraxane)

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)

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.

Antineoplastics, Antimetabolite

Gemcitabine (Gemzar)

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.

Antineoplastics, Podophyllotoxin Derivatives

Etoposide (Toposar, VePesid)

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)

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.

PD-1/PD-L1 Inhibitors

Class Summary

Immunotherapy consisting of monoclonal antibodies that target programmed cell death-1 protein (PD-1) by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2. These ligands are expressed on the surface of activated T cells.

Atezolizumab (Tecentriq)

Indicated in combination with carboplatin and etoposide as first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Nivolumab (Opdivo)

Indicated for patients with metastatic SCLC who have progressed after platinum-based chemotherapy and at least 1 other line of therapy. Provides an option for patients who have progressed after platinum-based chemotherapy as first-line treatment, and for those with progression after second-line chemotherapy (eg, topotecan).

Pembrolizumab (Keytruda)

Pembrolizumab is indicated for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy.

Durvalumab (Imfinzi)

Indicated, in combination with etoposide and carboplatin or cisplatin, for first-line treatment for adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Corticosteroids

Dexamethasone (Decadron, Dexamethasone Intensol, Dexasone)

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).

Antiemetic Agents

Metoclopramide (Metozolv ODT, Reglan)

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)

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

Granisetron (Kytril, Granisol, Sancuso)

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

Dolasetron (Anzemet)

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)

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.

 

Questions & Answers

Overview

What are the practice essentials of small cell lung cancer (SCLC)?

What is the pathophysiology of small cell lung cancer (SCLC)?

What causes small cell lung cancer (SCLC)?

What is the epidemiology of small cell lung cancer (SCLC) in the US?

What is the global incidence of small cell lung cancer (SCLC)?

What are the age- and sex-related demographics of small cell lung cancer (SCLC)?

What is the prognosis of small cell lung cancer (SCLC)?

What patient education is indicated in small cell lung cancer (SCLC)?

Presentation

What are the symptoms of small cell lung cancer (SCLC)?

What is the typical presentation of metastatic small cell lung cancer (SCLC)?

What are the symptoms of metastatic small cell lung cancer (SCLC)?

Which paraneoplastic syndromes are associated with small cell lung cancer (SCLC)?

What physical findings are associated with small cell lung cancer (SCLC)?

Which cardiovascular findings are associated with small cell lung cancer (SCLC)?

What is the role of funduscopy in the physical exam for small cell lung cancer (SCLC)?

Which GI findings are associated with small cell lung cancer (SCLC)?

What lymphatic system findings are associated with small cell lung cancer (SCLC)?

What complications are associated with small cell lung cancer (SCLC)?

DDX

What are the differential diagnoses for Small Cell Lung Cancer (SCLC)?

Workup

What are the screening guidelines on small cell lung cancer (SCLC)?

What is the initial workup of small cell lung cancer (SCLC)?

How is small cell lung cancer (SCLC) staged?

Which lab studies are indicated in the workup of small cell lung cancer (SCLC)?

Which CBC findings are associated with small cell lung cancer (SCLC)?

What is the role of serum chemistries in the workup of small cell lung cancer (SCLC)?

Which plain radiography studies are indicated in small cell lung cancer (SCLC)?

How is CT scanning used in the workup of small cell lung cancer (SCLC)?

Which brain and spinal cord imaging studies are indicated in small cell lung cancer (SCLC)?

What is the role of radionuclide imaging in the workup of small cell lung cancer (SCLC)?

How is PET scanning used in the workup of small cell lung cancer (SCLC)?

How is biopsy performed in the workup of small cell lung cancer (SCLC)?

What is the role of sputum cytology in the workup of small cell lung cancer (SCLC)?

What is the role of thoracentesis in the workup of small cell lung cancer (SCLC)?

What are the histologic findings of small cell lung cancer (SCLC)?

How is small cell lung cancer (SCLC) staged?

What is the American Cancer Society approach to staging small cell lung cancer (SCLC)?

How does the Veterans Administration Lung Group (VALSG) stage small cell lung cancer (SCLC)?

What is the role of the TNM staging system in small cell lung cancer (SCLC)?

How is the IASLC TNM system used in the staging of small cell lung cancer (SCLC)?

How is the VALSG staging system used in the workup of small cell lung cancer (SCLC)?

What is the AJCC staging system for small cell lung cancer (SCLC)?

Treatment

What are the approach considerations in the treatment of limited-stage small cell lung cancer (SCLC)?

What are the approach considerations in the treatment of extensive-stage small cell lung cancer (SCLC)?

How is combination chemotherapy used in the treatment of small cell lung cancer (SCLC)?

How is cisplatin plus etoposide or irinotecan used in the treatment of small cell lung cancer (SCLC)?

What is the most common combination chemotherapy choice for the treatment of small cell lung cancer (SCLC)?

How is combination cisplatin and etoposide used in the treatment of small cell lung cancer (SCLC)?

How is combination cisplatin and irinotecan used in the treatment of small cell lung cancer (SCLC)?

Is cisplatin-based or carboplatin-based chemotherapy more effective in the treatment of small cell lung cancer (SCLC)?

What is the chemotherapy protocol for the treatment of small cell lung cancer (SCLC)?

Is bone marrow or stem cell transplantation indicated in the treatment of small cell lung cancer (SCLC)?

What is the standard treatment for limited-stage small cell lung cancer (SCLC)?

How is radiotherapy used in the treatment of limited-stage small cell lung cancer (SCLC)?

How is prophylactic cranial irradiation used in the treatment of limited-stage small cell lung cancer (SCLC)?

What is the standard treatment for extensive-stage small cell lung cancer (SCLC)?

What is the role of radiotherapy in the treatment of extensive-stage small cell lung cancer (SCLC)?

What is the role of prophylactic cranial irradiation in the treatment of extensive-stage small cell lung cancer (SCLC)?

What is the role of gamma knife stereotactic radiosurgery in the treatment of limited-stage small cell lung cancer (SCLC)?

How is a relapse of small cell lung cancer (SCLC) managed?

How are symptoms of brain metastases managed in the treatment of small cell lung cancer (SCLC)?

How is spinal cord compression managed in the treatment of small cell lung cancer (SCLC)?

What is the role of surgical resection in the treatment of small cell lung cancer (SCLC)?

How are the potential complications of small cell lung cancer (SCLC) managed?

How is tumor lysis syndrome managed in the treatment of small cell lung cancer (SCLC)?

How are electrolyte abnormalities managed in the treatment of small cell lung cancer (SCLC)?

Which specialist consultations are indicated in the treatment of small cell lung cancer (SCLC)?

What long-term monitoring is indicated in the treatment of small cell lung cancer (SCLC)?

Guidelines

What are the consensus guidelines on screening for small cell lung cancer (SCLC)?

What are the ACCP diagnosis and management guidelines on small cell lung cancer (SCLC)?

What are the ACCP recommendations on the diagnosis of pleural abnormalities in the workup of small cell lung cancer (SCLC)?

What are the ACCP recommendations on the diagnosis of primary tumors in the workup of small cell lung cancer (SCLC)?

What are the staging guidelines on small cell lung cancer (SCLC)?

What are the treatment guidelines on limited-stage small cell lung cancer (SCLC)?

What are the treatment guidelines on extensive-stage small cell lung cancer (SCLC)?

What are the recommendations on chemotherapy for relapsed or refractory extensive-stage small cell lung cancer (SCLC)?

What are the treatment guidelines for small cell lung cancer (SCLC) in the elderly?

What are the recommendations for long-term monitoring in the treatment of small cell lung cancer (SCLC)?

How are long-term monitoring visits conducted in the treatment of small cell lung cancer (SCLC)?

Medications

Which medications in the drug class Corticosteroids are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Antineoplastics, Podophyllotoxin Derivatives are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Antineoplastics, Antimetabolite are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Antineoplastics, Antimicrotubular are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Antineoplastics, Vinca Alkaloid are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Antineoplastics, Anthracycline are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Topoisomerase Inhibitors are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Antineoplastics, Alkylating are used in the treatment of Small Cell Lung Cancer (SCLC)?

Which medications in the drug class Antiemetic Agents are used in the treatment of Small Cell Lung Cancer (SCLC)?