Overview of Small Cell Lung Cancer
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 3/2020
Small cell lung cancers (SCLC) account for roughly 13% of all lung cancers and are primarily diagnosed in smokers or former smokers. They differ from other types of lung cancer in that they spread very quickly throughout the body via the blood and lymphatic system.
Accurate staging of small cell lung cancer is essential before definitive therapy can begin. For many years, a simple staging system has been used to separate small cell lung cancer into two stages: limited and extensive. More recently, the International Association for the Study of Lung Cancer (IASLC) developed a new TNM (tumor, node, metastasis) system of staging that classifies small cell lung cancer into several categories ranging from Stage 0 to Stage IV. Because the two-stage system continues to guide treatment decisions, that is the system that is used on this website.
Limited and extensive small cell lung cancer are treated differently; therefore, your primary cancer doctor will perform a variety of tests to determine the stage of the disease and thus, the optimal treatment strategy. If these staging tests suggest that your cancer is confined to one side of your chest, then you will be diagnosed with limited stage small cell lung cancer. Otherwise, you will be diagnosed with extensive disease.
- Limited Small Cell Lung Cancer
- Extensive Small Cell Lung Cancer
- Recurrent Small Cell Lung Cancer
- Strategies to Improve Treatment of Small Cell Lung Cancer
Staging of Small Cell Lung Cancer
Determining the stage or extent of spread of the cancer is essential in order to understand treatment options or interpret published cancer treatment information. Determining the stage of lung cancer may require many tests, which often include the following:
- Mediastinoscopy: A mediastinoscopy is a procedure that can indicate whether the cancer has spread to the lymph nodes in the chest. During a mediastinoscopy, a surgeon inserts a mediastinoscope (lighted tube) through a small incision in the neck while a patient is under general anesthesia. This mediastinoscope allows the surgeon to examine the center of the chest (mediastinum) and nearby lymph nodes, as well as remove a tissue sample.
- Computed Topography or CT Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body. This method is more sensitive and precise than the chest x-ray.
- Magnetic Resonance Imagery or MRI: During MRI, a powerful magnet linked to a computer makes detailed pictures of areas inside the body.
- Positron emission tomography (PET): Positron emission tomography (PET) scanning has been used to improve the detection of cancer in lymph nodes. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that spontaneously emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons). The positrons react with electrons in the cancer cells, which creates the production of gamma rays. The gamma rays are then detected by the PET machine, which transforms the information into a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.
- Bone Scan: A bone scan is used to determine whether cancer has spread to the bones. Prior to a bone scan, a surgeon injects a small amount of radioactive substance into a vein. This substance travels through the bloodstream and collects in areas of abnormal bone growth. An instrument called a scanner measures the radioactivity levels in these areas and records them on x-ray film.
Treatment of Limited Small Cell Lung Cancer
Patients with limited disease small cell lung cancer have cancer that is confined to a single location in the chest that is not detectable outside the lung. Patients with this type of cancer are potentially curable, although many patients have undetectable areas of cancer outside of the chest at the time of diagnosis. The median overall survival with limited SCLC has historically been about 20 months.1,2,3
Systemic therapy is any treatment directed at destroying cancer cells throughout the body, and may include chemotherapy or newer precision cancer medicines or immunotherapy. Systemic treatment of patients with limited disease SCLC is the standard because many cancer cells will have spread away from the lungs and these cannot be eradicated with local treatments like surgery or radiation.
Chemotherapy —Chemotherapy uses drugs to kill cancer cells. A single drug or a combination of drugs may be used. Chemotherapy drugs may be given intravenously (through a vein that carries the drugs throughout the body) or in the form of a pill. Chemotherapy drugs are usually given in cycles so that a recovery period follows every treatment period.
Chemotherapy delivered in combination with radiation therapy—is the mainstay of treatment for limited SCLC. Although the cancer often eventually returns, many SCLC’s have a good initial response to treatment with combination chemotherapy. Chemotherapy is a systemic (whole-body) treatment.
Precision Cancer Medicine The purpose of precision cancer medicine is to define the specific genomic alterations in the lung cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the lung cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision cancer medicines are increasingly being used for the treatment of SCLC alone or in combination with chemotherapy.
Radiation therapy is a local treatment that treats cancer in the chest. It is often delivered at the same time as chemotherapy (concurrent treatment). In other cases, it may be given after completion of chemotherapy (sequential treatment).
Because SCLC tends to spread quickly, most people with this type of cancer are not candidates for surgery. In a small number of cases, however, the cancer may involve only a single, small area of the lung. In these cases, surgery may be able to remove the cancer. After surgery, patients often receive additional treatment with chemotherapy (or chemotherapy plus radiation therapy) in order to treat undetectable areas of cancer that may remain in the body.
Prophylactic Cranial Irradiation
Small cell lung cancer commonly spreads to the brain. For people without detectable brain metastases at the time of diagnosis, preventive treatment of the brain with radiation therapy can reduce the likelihood of brain metastases and prolong survival. This treatment is called prophylactic cranial irradiation. Prophylactic cranial irradiation is typically reserved for patients who have had a good response to their initial treatment with chemotherapy and radiation therapy.
Treatment of Extensive Small Cell Lung Cancer
When small cell lung cancer has spread to both lungs or is detectable beyond the lungs, it is referred to as extensive.
Patients with extensive disease SCLC are rarely curable with currently available standard treatment strategies although many patients experience a response to treatment. Because the cancer has spread outside the chest, it cannot be eliminated with radiation or removed surgically.
Currently the standard treatment for extensive SCLC is chemotherapy using a combination of chemotherapy drugs, typically cisplatin or carboplatin combined with etoposide or irinotecan. Approximately 60%-80% of patients will experience a response to this chemotherapy and 15% to 20% of individuals respond completely. Before chemotherapy was used, patients on average only survived approximately 1.5 months. Single-agent chemotherapy improved the average survival to four months and the development of combination chemotherapy regimens has further increased the average survival to approximately nine months with some patients surviving two years or longer.
Some patients with extensive SCLC also receive radiation therapy. Radiation therapy can reduce symptoms from cancer that has spread outside of the lungs, and also helps to manage cancer that has spread to the brain (brain metastases). Radiation therapy to the head may also be used to reduce the likelihood of brain metastases. This preventive treatment—called prophylactic cranial irradiation—is usually reserved for patients who have had a good response to chemotherapy.(1,2,3)
Recurrent Small Cell Lung Cancer
When lung cancer has been detected or has returned following an initial treatment with surgery, radiation and/or chemotherapy, it is referred to as recurrent or relapsed. Recurrent SCLC is treated with chemotherapy, radiation, or precision cancer medicines to control the spread of the cancer and reduce symptoms. Because none of these therapies are curative patients with recurrent SCLC should consider participation in a clinical trial evaluating newer treatment strategies.
Strategies to Improve Treatment
The progress that has been made in the treatment of SCLC has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving treatment.
Precision Cancer Medicine: A targeted or precision therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Precision cancer medicines that “target” cancer cells offer the advantage of reduced treatment-related side effects and improved outcomes.
- Keytruda confers clinical benefit after previous treatments for small cell lung cancer. Therapies directed at PD-1 and PD-L1 have already improved the treatment of NSCLC and appear promising in the treatment of SCLC as well. ALL SCLC patients should undergo genomic testing in order to benefit from this area of active research.(4) According to a pooled analysis from the KEYNOTE-028 and KEYNOTE-158 clinical trials published in Journal of Thoracic Oncology Keytruda (pembrolizumab) has significant anticancer activity in patients with recurrent or metastatic small cell lung cancer.
A total of 83 patients who had received two or more lines of previous therapy for small cell lung cancer were treated with Keytruda on the trials. Sixty-four percent of patients had two prior lines of therapy, 57% had PD-L1-positive tumors and 80% had previously undergone radiation therapy.
With a median follow-up of 7.7 months 19% of patients were observed to respond to treatment with 61% of responses lasting at least 18 months. The average duration of response has not been reached and responses are ongoing between 4 and 36 months. Two patients, one of whom had a PD-L1-positive tumor, achieved complete response, and 14 patients, including 13 with PD-L1-positive tumors, achieved partial response. Average overall survival is 7.7 months and 21% survive 2 years from initiation of Keytruda therapy.
The results for the global, randomized phase 3 study of chemotherapy with or without pembrolizumab in the first-line setting among patients with extensive-stage small-cell lung cancer (KEYNOTE-604) were recently disclosed and will be presented at an upcoming meeting.
- The poly ADP-ribose polymerase (PARP) enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.(5)
Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate that targets a protein associated with the small cell lung cancer cells and is the first biomarker-directed treatment being developed in SCLC. In SCLC, a proportion of the malignant cells display Delta-like protein 3 (DLL3) which is not seen on the surface of normal cells. Rova-T is a combination of an antibody that binds to DLL3 that delivers a toxic substance called tesirine directly to the cancer cells. Overall 18% of refractory patients had a confirmed response regardless of the level of DLL3 expression, and the rate among those who were DLL3-high was 39%. A confirmed clinical benefit rate defined as stable disease or better was achieved in 89% of patients who were DLL3-high expressers.(6)
New Combination Chemotherapy Regimens: Clinical trials continue to evaluate new drugs and new combinations of drugs in an effort to improve upon the treatment results achieved with standard chemotherapy regimens.
High-Dose Chemotherapy: High-doses of chemotherapy are more effective at killing cancer cells than lower doses. However, high-dose chemotherapy (HDC) destroys many other cells in the body, including stem cells. Stem cells are immature blood cells produced in the bone marrow which mature into either red blood cells, which carry oxygen to tissues; white blood cells, which fight infection; and platelets, which aid the blood in clotting. A stem cell transplant (SCT) is a procedure that replaces the stem cells that are destroyed by high-dose chemotherapy and/or radiation therapy with healthy stem cells. There are two main types of stem cell transplants. Autologous stem cell transplants use a patient’s own stem cells, which are collected prior to the high-dose treatment and then re-infused after the treatment. Allogeneic stem cell transplants use stem cells collected from the blood or bone marrow of a related or unrelated donor.
Early attempts at using very high doses of chemotherapy and bone marrow transplant produced very high cancer response rates, but the treatment was associated with significant side effects. In the 1990s, several technologic advances have made high-dose chemotherapy safer and easier to deliver. This treatment approach continues to be evaluated at some cancer centers.
- Govindan R, Page N, Morgensztern D et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiologic, and End Results database. Journal of Clinical Oncology. 2006; 24:4539-44.
- Shepherd FA, Crowley J, Van Houtte P, et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol. 2007;2:1067-1077
- Neal JW, Gubens MA, Wakelee HA. Current management of small cell lung cancer. Clin Chest Med. 2011;32:853-863
- Ott P, Felip E, Hiret S, et al. Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer: Updated Survival Results from KEYNOTE-028. Presented at the 17th World Conference on Lung Cancer. December 4-7, 2016. Vienna, Austria. Abstract #OA05.01.
- PARP inhibitor improves overall response rates in small cell lung cancer patients
- Rudin CM, Pietanza M, Bauer T, et al. Safety and efﬁcacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). J Clin Oncol 34, 2016 (suppl; abstr LBA8505). Can be accessed at: abstracts.asco.org/176/AbstView_176_162941.html
- [Chung HC, et al. J Thorac Oncol. 2019;doi:10.1016/j.jtho.2019.12.109.](https://www.jto.org/article/S1556-0864(19%2933850-X/fulltext)