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Last updated: 10/31/2023
Years published: 2019, 2023
NORD gratefully acknowledges Angel Qin, MD, Medical Oncology and Internal Medicine, Michigan Medicine, University of Michigan, for assistance in the preparation of this report.
Summary
Small cell lung cancer (SCLC) is an aggressive form of lung cancer. It is characterized by rapid, uncontrolled growth of certain cells in the lungs. Eventually, a tumor forms and the cancer can spread (metastasize) to other areas of the body. The primary risk factor is tobacco use; almost all affected individuals smoke or have a history of smoking. Symptoms can vary from one person to another, and there are rarely any symptoms early in the course of the disease. Generally, SCLC is broken down into two main stages: limited stage disease, which is potentially curable in about 20%-25% of people, and extensive stage disease, which is more difficult to treat. Affected individuals are treated with chemotherapy and often radiation therapy. In a small group of people with very early-stage cancer, surgery may be recommended. Although there has been only slight progress in treatment over the last couple of decades, there has been a renewed interest in SCLC over the past several years and multiple clinical trials are underway for newer, targeted therapies to treat the disorder.
Introduction
Small cell lung cancer is characterized as a neuroendocrine carcinoma because the cancer cells have features of nerve cells and endocrine (hormone-secreting) cells. Endocrine tissue is specialized tissue that contains hormone-secreting cells. These hormones have a variety of functions within the body.
The signs and symptoms of small cell lung cancer can vary from one person to another. Specific findings depend on numerous factors including the exact location and size of the tumor, the extent of invasion of the tumor into nearby tissue or organs and whether the disease has remained localized or spread to other areas of the body (metastasized). Early in the course of the disease, there may be no symptoms (asymptomatic) or only a few, mild symptoms. As the tumor grows, more signs and symptoms develop.
Common symptoms include a cough that doesnโt get better, chest pain that is worse when coughing, laughing or taking a deep breath, shortness of breath, coughing up of blood (hemoptysis) and hoarseness or wheezing. Some affected individuals can develop loss of appetite, unintended weight loss, fatigue and recurrent episodes of lung infections such as pneumonia or bronchitis.
When SCLC spreads (metastasizes) the most commonly affected areas are the lymph nodes, brain, liver, adrenal glands, bone and bone marrow. The symptoms that develop will vary depending upon the specific area(s) affected and the extent of the disease. Symptoms can include bone pain from spread to bones; yellowing of the eyes, skin and mucous membranes (jaundice) from cancer spreading to the liver; headaches, dizziness, double vision, seizures or a sensation of numbness or tingling in the hands and arms and feet and legs when cancer spreads to the brain; or small lumps or growths on the skin when cancer has spread to the skin or lymph nodes.
Individuals with SCLC can also develop paraneoplastic syndromes. These syndromes are rare disorders that are caused by either abnormal production of hormones or an abnormal response of the immune system to the cancer. It is believed that white blood cells, which normally help to protect the body from bacteria, viruses and other foreign invaders, can mistakenly attack healthy tissue causing a variety of neurologic problems, such as weakness, loss of sensation, imbalance or confusion. A common paraneoplastic syndrome in SCLC is called the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This syndrome is characterized by excessive production of antidiuretic hormone, which causes people to retain water and lowers salt (sodium) levels in the body which can cause fatigue, lethargy and confusion.
SCLC is primarily caused by cancer causing chemicals (carcinogens) that are found in tobacco smoke. These carcinogens cause damage to the DNA (deoxyribonucleic acid; genes) in cells which leads to cancer formation. However, the exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the development of SCLC in certain people. Current research suggests that abnormalities of DNA, which is the carrier of the bodyโs genetic code, are the underlying basis of normal cells transforming into cancer cells.
In SCLC, genetic changes can affect oncogenes (genes that promote cancer growth) or tumor suppressor genes (genes that stop cancer growth). These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are altered (mutated), cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing.
There are many different oncogenes or tumor suppressor genes that have been linked to SCLC. Two tumor suppressor genes that have been linked to many people with SCLC are the TP53 gene, which has been associated with many cancers, and the RB1 gene, which is associated with retinoblastoma and other cancers. The TP53 gene is altered in 75% of SCLCs and the RB1 gene is altered in 90% of SCLCs.
There are several risk factors associated with SCLC. A risk factor is anything that increases a personโs risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition. The main risk factor for SCLC is smoking with over 95% of affected individuals being current or former smokers. Heavy smokers are particularly at risk for SCLC. Chronic exposure to secondhand smoke also increases the risk of lung cancer. Other environmental risk factors are less common, but include exposure to chloromethyl esters, which are used in chemical manufacturing, asbestos, or radon. Radon is a colorless, odorless, radioactive gas. It occurs naturally in the environment when uranium breaks down in the soil or rock. Radon exposure in concentrated amounts, which can sometimes occur inside a home, usually in a basement, can increase the risk of lung cancer.
The incidence of small cell lung cancer in the United States has been declining over the last two decades, which most researchers attribute to the decline in smoking in the country. Lung cancer, as a group, is the second most common form of cancer in the United States. SCLC accounts for about 10%-15% of people who have lung cancer. There are about 30,000 to 35,000 new patients diagnosed with SCLC each year in the United States. Almost everyone who develops SCLC has a history of smoking. It is extremely rare in individuals who have never smoked.
A diagnosis of small cell lung cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. SCLC is an aggressive cancer and in many affected individuals the cancer has already spread when the diagnosis is made.
Clinical Testing and Workup
A plain x-ray (radiography) of the chest can show a tumor or mass in the lungs. If a mass is found, more specialized imaging techniques can be used to determine whether cancer is present, the extent of the disease and whether the cancer has spread to other areas. Such imaging techniques may include computerized tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create cross-sectional images of the inside of the body. A CT scan of the chest can show smaller tumors that do not show up on conventional x-rays and can also show whether cancer has spread to nearby lymph nodes. A CT scan of other areas of the body can show whether cancer has spread (metastasized) to specific areas.
Another advanced imaging technique known as positron emission tomography (PET scan) may also be used. During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading and will soak up the radioactive sugar. When the scan is taken, areas that take up the radioactive sugar, including SCLC, may show up as bright spots on the film. A PET scan is often used to help show whether SCLC has spread to other parts of the body. For example, a PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary. Nowadays, PET scans are almost always done in conjunction with a CT scan (PET/CT). The PET/CT gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has while also mapping the adjacent body structures (CT).
During a bone scan, a relatively harmless radioactive dye is injected into the blood and is taken up by abnormal areas of bone. A special camera that can detect the dye in the bones is used to create a picture of the skeleton to determine whether SCLC has spread to other areas of the body.
An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An MRI of the brain may be ordered to determine whether cancer has spread to the brain.
Obtaining a piece of the tumor (biopsy) from the lungs or another site of the body needs to be performed to determine the specific type of cancer. To obtain a tumor sample, physicians usually recommend a bronchoscopy or a needle biopsy. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down into the affected individualโs lungs to obtain a sample of tissue to be analyzed (biopsy). Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor.
During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room or similar setting and may require a general anesthetic with a temporary breathing tube.
Sometimes, doctors may order a mediastinoscopy to evaluate whether the cancer has spread to the lymph nodes in the middle of the chest. This involves making a small cut near the top of the breastbone, which is the thin bone that runs down the center of the chest. A small thin tube called a mediastinoscope is passed behind the breastbone along the windpipe to allow doctors to view and take tissue samples from the mediastinum, which is the area between the lungs in the central region of the chest.
Staging
The most commonly used staging system for SCLC is the Veterans Administration Lung Study Group (VALG) staging system. This system basically breaks the disorder into two categories โ limited stage SCLC and extensive stage SCLC. Limited stage refers to when the cancer is confined to one side of the chest and can be treated within one radiation field or port. A radiation field or port is the area of the body where radiation (high beams of energy) is directed to kill cancer cells. If the cancer is contained in a small area, it can be treated within one radiation field or port.
Extensive stage refers to when the cancer has spread beyond just one side of the chest. The primary goal of staging in SCLC is to determine whether the cancer has spread.
The International Association of the Study of Lung Cancer has proposed that physicians should adopt a different staging system called the Tumor Node Metastasis (TNM) Staging System, which is a common staging system for cancer developed by the American Joint Committee on Cancer. This system is based on the extent of the tumor (T), whether and to what extent cancer has spread to the lymph nodes (N), and whether cancer has spread (metastasized) to other areas of the body (M). It is a more complex staging system. For more information on this staging system for SCLC, visit: https://emedicine.medscape.com/article/2006716-overview.
Treatment
The therapeutic management of individuals with small cell lung cancer may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and drug treatment of cancer (medical oncologists), physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), physicians who specialize in interpreting x-rays and advanced imaging scans (radiologists), surgeons who specialize in removing cancer by surgery (surgical oncologists), physicians who specialize in the diagnosis and treatment of lung disease (pulmonologists); nurses who specialize in the care and treatment of cancer (oncology nurses), psychiatrists, nutritionists and other healthcare specialists.
Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on lung cancer or lung disease. Individuals who have SCLC and who still smoke are strongly encouraged to quit smoking. The importance of quitting smoking cannot be overemphasized.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; whether the cancer has spread (metastasized) and to which organs it has spread; the presence or absence of certain symptoms; an individualโs age and general health; and/or other factors. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her situation; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.
Limited Stage Disease
In rare instances, individuals with limited stage SCLC who have a small tumor that has not spread to nearby lymph nodes (early stage or stage 1 SCLC) can sometimes be treated with surgical removal of the tumor. However, in most people, the tumor is not localized and because it is usually a fast-growing cancer, often has spread at least to nearby lymph nodes or other areas of the chest.
Most affected individuals with limited stage SCLC are treated with a combination of chemotherapy and radiation therapy given at the same time. Chemotherapy is the use of certain medications to kill or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. The most common chemotherapeutic regimen used for SCLC is etoposide combined with cisplatin or carboplatin. This may be referred to as platinum-based chemotherapy because carboplatin and cisplatin are platinum-containing compounds. Carboplatin is generally associated with fewer and less severe side effects than cisplatin. SCLC is highly responsive to chemotherapy and sometimes improvement can be rapid and dramatic. However, cancer often returns and may become resistant to the chemotherapy regimen that was successful in the past.
Radiation therapy is usually used in combination with chemotherapy (chemoradiotherapy) to treat individuals with limited stage SCLC. Radiation therapy uses high-powered x-rays to directly destroy cancer cells. Radiation therapy is directed at the chest (thoracic radiotherapy) to the main lung tumor and the lymph nodes to which the cancer has spread.
Individuals who are successfully treated with chemotherapy and radiation therapy to the chest may also receive preventive radiation therapy to the brain called prophylactic cranial irradiation (PCI). Because SCLC is an aggressive cancer and can spread to the brain, PCI is used to destroy any microscopic cancer cells that may have reached the brain. PCI is generally given to individuals who have a good response to initial therapy and are healthy enough to undergo the treatment.
About 25% of individuals with limited stage SCLC can be cured with prompt treatment with chemotherapy and radiation therapy.
Extensive Stage Disease
The treatment for extensive stage SCLC is primarily platinum-based chemotherapy, similar to that which is used in limited stage disease. Sometimes, instead of using etoposide along with cisplatin or carboplatin, doctors may use a drug called irinotecan. The combination of irinotecan plus a platinum-drug appears to be more effective in Japanese people; in Caucasians, etoposide appears to be equally effective and is associated with less severe side effects. The addition of immunotherapy drugs (atezolizumab or durvalumab), which boost the bodyโs immune system to fight the cancer, to the standard regimen of carboplatin plus etoposide has been shown to improve the outcome of some patients with extensive stage SCLC. This is now considered the standard of care for patients who can safely receive immunotherapy. Although extensive stage disease is not curable, most patients will have shrinkage of their cancer, improvement in symptoms and prolongation of life with chemotherapy with or without immunotherapy. The goals of treatment are to improve symptoms, maintain quality of life and prolong life. In some situations, thoracic radiation will be recommended after chemotherapy in people with extensive stage SCLC. Because of the high risk of spread of SCLC to the brain, frequent MRI scans of the brain are usually recommended.
Recurrence
Although SCLC is highly responsive to initial chemotherapy, the cancer often comes back (recurs). When the cancer returns, it is usually more resistant to the previously effective chemotherapy regimens. Different chemotherapy regimens can be tried but are usually not as effective. When the cancer comes back, it can be extremely aggressive. There are two second-line therapy approved for SCLC in the U.S. โ topotecan and lurbinectedin โ and they are both chemotherapy drugs. There are other chemotherapy drugs that can also be used as they have been shown in smaller clinical trials to have some benefit. Newer drugs are being studied in clinical trials for second-line therapy for individuals with SCLC.
Supportive Therapy
Affected individuals may require supportive therapies. Many individuals with SCLC have a significant decrease in lung function and may need therapies to assist with breathing. This can include drugs called bronchodilators, which widen the airways of the lungs, or supplemental oxygen therapy.
Affected individuals are encouraged to explore participating in clinical trials. Participating in a clinical trial can give an affected individual access to new therapies. This decision should be made after close consultation with an individualโs oncologist and entire medical team.
Targeted therapies are being explored as potential treatments for individuals with small cell lung cancer. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the development of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. Several research studies are ongoing to test various targeted therapies for SCLC. More research is necessary to determine what genetic factors (e.g., altered genes) play a role in the development SCLC and what types of targeted therapies may be possible to treat these tumors.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial [published correction appears in Lancet Oncol. 2020 Dec;21(12):e553]. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220-2229. https://www.ncbi.nlm.nih.gov/pubmed/30280641
Tsoukalas N, Aravantinou-Fatorou E, Baxevanos P, et al. Advanced small cell lung cancer (SCLC): new challenges and new expectations. Ann Transl Med. 2018;6:145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952028/
Gadgeel SM. Targeted therapy and immune therapy for small cell lung cancer. Curr Treat Options Oncol. 2018;19:53. https://www.ncbi.nlm.nih.gov/pubmed/30203184
Oronsky B, Reid TR, Oronsky A, Carter CA. Whatโs new in SCLC? A review. Neoplasia. 2017;19:842-847. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596356/
Kalemkerian GP, Schneider BP. Advances in small cell lung cancer. Hematol Oncol Clin North Am. 2017;31:143-156. https://www.ncbi.nlm.nih.gov/pubmed/27912830
Santarpia M, Daffina MG, Karachaliou N, et al. Targeted drugs in small-cell lung cancer. Transl Lung Cancer Res. 2016;5:51-70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758978/
Koinis F, Kotsakis A, Georgolias V. Small cell lung cancer (SCLC): no treatment advances in recent years. Transl Lung Cancer Res. 2016;5:39-50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758968/
Kalemkerian GP. Small cell lung cancer. Semin Respir Crit Care Med. 2016;37:783-796. https://www.ncbi.nlm.nih.gov/pubmed/27732999
Qin A, Kalemkerian GP. Cisplatin, etoposide, and irinotecan for relapsed small-cell lung cancer. Transl Cancer Res. 2016;5:S1142-S1144. https://www.ncbi.nlm.nih.gov/pubmed/28523239
Semenova EA, Nagel R, Berns A. Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes Dev. 2015;29:1447-1462. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526731/
Malik SM, Korn E, Thomas A. Small lung cell cancer: why has it become an orphan disease? J Clin Oncol. 2015;33: 7578-7578. https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.7578
Kanaji N, Watanabe N, Kita N, et al. Paraneoplastic syndromes associated with lung cancer. World J Clin Oncol. 2014;5:197-223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127595/
Morabito A, Carillio G, Daniele G, et al. Treatment of small cell lung cancer. Crit Rev Oncol Hematol. 2014;91:257-270. https://www.ncbi.nlm.nih.gov/pubmed/24767978
Van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011;378:1741-1755. https://www.ncbi.nlm.nih.gov/pubmed/21565397
INTERNET
Baldini EH, Kalemkerian GP. Limited-stage small cell lung cancer: initial management. UpToDate, Inc. Sep 29, 2021. Available at: https://www.uptodate.com/contents/limited-stage-small-cell-lung-cancer-initial-management Accessed Oct 31, 2023.
Kalemkerian GP. Patient education: small cell lung cancer (Beyond the Basics). UpToDate, Inc. Jun 22, 2022. Available at: https://www.uptodate.com/contents/small-cell-lung-cancer-treatment-beyond-the-basics Accessed Oct 31, 2023.
Kelly K. Extensive-stage small cell lung cancer: initial management. UpToDate, Inc. Dec 05, 2022.Available at: https://www.uptodate.com/contents/extensive-stage-small-cell-lung-cancer-initial-management Accessed Oct 31, 2023.
Genetic and Rare Diseases Information Center. Syndrome of Inappropriate antidiuretic hormone. July 5, 2014. Available at: https://rarediseases.info.nih.gov/diseases/10306/syndrome-of-inappropriate-antidiuretic-hormone Accessed Oct 31, 2023.
National Cancer Institute. Small Cell Lung Cancer Treatment (PDQยฎ)โPatient Version. May 17, 2023. Available at: https://www.cancer.gov/types/lung/patient/small-cell-lung-treatment-pdq Accessed Oct 31, 2023.
Vachani C, Simone II CB. OncoLink. All About Small Cell Lung Cancer. May 9, 2023. Available at: https://www.oncolink.org/cancers/lung/small-cell-lung-cancer/all-about-small-cell-lung-cancer Accessed Oct 31, 2023.
Tan WW. Small Cell Lung Cancer.Medscape. June 19, 2023. Available at: https://emedicine.medscape.com/article/280104-overview Accessed Oct 31, 2023.
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