Pulmonary Medicine

Small Cell Lung Cancer

What every physician needs to know:

Small-cell lung cancer (SCLC) accounts for about 15 percent of all lung cancers, or approximately 30,000 cases in the United States each year. SCLC is an aggressive cancer that, in about 10 percent of patients, may present with signs and symptoms related to a paraneoplastic syndrome. It has a rapid doubling time, and the majority of patients present with distant metastatic disease at the time of diagnosis. Despite increased sensitivity to chemotherapy and radiation therapy, most patients relapse after treatment and develop drug resistance, which, along with the lack of effective second-line therapy, makes SCLC a disease with a poor prognosis.

hile the overall incidence of SCLC has decreased, the percentage of those with SCLC who are women has almost doubled from 28 percent in 1973 to 50 percent today. This increase may be due to the increased incidence of smoking among women since the 1960s, which was once less common than it was among men because of social pressures.. 

Classification:

SCLC is divided into limited stage disease (LS) and extensive stage disease (ES). LS-SCLC is disease that is confined to one hemithorax, the mediastinum, and the supraclavicular nodes and can be encompassed in a tolerable radiation port. Various groups also include patients with malignant pleural effusions, contralateral hilar and supraclavicular lymph nodes in the LS-SCLC category. ES is thoracic disease that is too widespread to be included in the LS-SCLC category and patients with distant metastasis (liver, bone, brain, etc.). The International Association of the Study of Lung Cancer (IASLC) conducted an analysis of clinical TNM staging for SCLC using the TNM staging system for lung cancer. The survival of patients with clinical stage I and II SCLC is significantly different than for patients with stage III disease (N2, N3 involvement). Because survival of patients with malignant pleural effusions is intermediate, malignant pleural effusion in SCLC will be classified as ES-SCLC in the revised staging system.

Are you sure your patient has small-cell lung cancer? What should you expect to find?

Signs and symptoms of SCLC relate to the physical bulk of the tumor and its anatomic location, as SCLC commonly presents with a central mass. Cough, weight loss, dyspnea, and chest pain are present in approximately 30 percent of patients with SCLC. Hemoptysis and hoarseness are also common presenting symptoms.

Superior vena cava obstruction (SVCO) is commonly seen in SCLC. Patients with SVCO present with facial and neck swelling, dilated veins over the upper torso and shoulders, and symptoms of headache, lightheadedness, blurry vision, cough, and dysphagia.

Patients with ES-SCLC may present with symptoms related to metastatic disease such as bone pain and neurologic symptoms. SCLC is associated with a variety of paraneoplastic syndromes, and about 10 percent of all patients with SCLC will present with symptoms related to a paraneoplastic syndrome, including syndrome of inappropriate antidiuretic hormone secretion (SIADH), leading to hyponatremia; secretion of adrenocorticotropic hormone (ACTH) leading to Cushing syndrome; Lambert-Eaton syndrome, leading to muscular weakness, autonomic dysfunction, and cranial nerve involvement; sensory neuropathy; and limbic encephalitis (anti-Hu antibodies), leading to cognitive dysfunction, memory impairment, seizures, depression, anxiety, and hallucinations.

Beware: there are other diseases that can mimic small-cell lung cancer:

SCLC can mimic non-small-cell lung cancer (NSCLC) and lymphoma.

How and/or why did the patient develop small-cell lung cancer?

Smoking remains the predominant risk factor for the development of SCLC. Development of SCLC in a nonsmoker is extremely rare (0% to 3%), so if a lifelong nonsmoker is diagnosed with SCLC, one must question this diagnosis. Additional risk factors include exposure to asbestos, radon, uranium mining, and bis-chloromethyl ether.

Which individuals are at greatest risk of developing small-cell lung cancer?

Smokers are at greatest risk for developing SCLC.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Laboratory studies obtained in the evaluation of a patient suspected or known to have SCLC include CBC, LDH (a helpful prognostic indicator in ES-SCLC), chemistry panel (hyponatremia that is due to SIADH syndrome may be present), and liver function tests. One can also screen for paraneoplastic syndromes, including anti-Hu antibodies in patients with unexplained neurologic symptoms.

What imaging studies will be helpful in making or excluding the diagnosis of small-cell lung cancer? 

Computed tomography (CT) of the chest with intravenous (IV) contrast that includes the liver and the adrenal glands, or a CT of the chest and abdomen with IV contrast are the recommended modalities. SCLC usually presents with a central, bulky mass or hilar mass that invades the mediastinum. Supraclavicular lymph adenopathy, pleural effusion, liver and adrenal metastasis may be seen on the CT scan of the chest and abdomen. Occasionally, SCLC presents as a solitary lung nodule/mass. (Figure 1)

Figure 1.

Central mass with mediastinal invasion

Although the radiographic findings usually raise a strong suspicion of SCLC, histologic or cytologic confirmation must be obtained.

Given the high incidence of metastatic disease in SCLC, CT with contrast or MRI of the brain and a bone scan should be performed. Routine bone marrow biopsies are no longer recommended.

SCLC is fluorodeoxyglucose avid on positron emission tomography (PET). Overall, the use of PET scans, in addition to CT scans of the chest and abdomen and MRI or CT scans of the brain, appears to improve the accuracy of initial staging in LS-SCLC and The American College of Chest Physicians (ACCP) Lung Cancer Guidelines suggest PET imaging in patients with LS-SCLC. If a PET is obtained, then bone scan may be omitted.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of small-cell lung cancer?

There are none.

What diagnostic procedures will be helpful in making or excluding the diagnosis of small-cell lung cancer?

In a patient with evidence of metastatic disease, the site of metastasis should be biopsied (i.e., percutaneous biopsy of liver lesion, bone lesion, percutaneous needle aspiration, or biopsy of adrenal mass) in order to establish the diagnosis and confirm the stage.

In patients with a pleural effusion, a thoracentesis should be performed to evaluate for metastatic pleural effusion.

In patients with supraclavicular lymph node involvement, fine needle aspiration or biopsy of the node should be performed. 

In patients with disease limited to the chest, bronchoscopy with transbronchial needle aspiration (TBNA) or endobronchial ultrasound-guided-needle aspiration (EBUS-NA) is usually the diagnostic test of choice in LS-SCLC, given the central presentation of this cancer.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of small-cell lung cancer?

Cytologic or histologic confirmation is needed. Immunohistochemical stains to confirm SCLC include neuroendocrine markers (chromogranin and synaptophysin) and antibodies to thyroid transcription factor 1 (TTF-1). Immunohistochemical stains are particularly important in differentiating SCLC from non-Hodgkin's lymphoma. 

If you decide the patient has small-cell lung cancer, how should the patient be managed?

Patients diagnosed with LS-SCLC should be encouraged to stop smoking before combined modality therapy because continued smoking may compromise cure rates.

LS-SCLC is treated with combined modality therapy. The current standard of care is chemotherapy (etoposide and cisplatin [EP]) with concurrent radiotherapy. Hyperfractionated radiotherapy (45Gy given twice a day over 3 weeks) has been shown to improve survival rates.

Surgery is the standard of care for patients who present with a solitary SCLC tumor. Patients who are to undergo surgery require staging of the mediastinum with EBUS-fine needle aspiration and/or mediastinoscopy and extrathoracic staging (CT abdomen, CT/MRI of brain, bone scan or PET scan, and brain MRI) before resection. Following surgical resection, platin-based adjuvant chemotherapy is recommended.

Prophylactic cranial irradiation (PCI) should be offered to patients with LD-SCLC who achieve complete response after treatment with concurrent chemoradiation or who have undergone surgical resection, as it improves the 3-year survival rate.

ES-SCLC is treated with chemotherapy. In the United States, the standard regimen is etoposide combined with cisplatin (EP). Irinotecan and cisplatin (IP) have been reported to be more effective than the standard regimen in a large randomized Japanese trial, but a large North American trial failed to show superiority for IP over EP in a western population. Evidence suggests that adding thoracic radiotherapy to chemotherapy improves the survival of patients with ES-SCLC who have had a complete response outside the thorax and at least partial response in the thorax after chemotherapy.

PCI is recommended for patients with ES-SCLC who achieve a complete response after treatment, as it improves the 1-year survival rate.

Complications of treatment include esophagitis, radiation pneumonitis, leukopenia, hair loss, fatigue, renal impairment, and parasthesias. Delayed neurologic complications from PCI include weakness, hearing loss, transient hemiparesis, visual disturbances, and progressive dementia, although this last is rare.

What is the prognosis for patients managed in the recommended ways?

LS-SCLC treated with concurrent chemotherapy and hyperfractionated radiotherapy has a 5-year survival rate of 26 percent and a local failure rate of 36 percent.

ES-SCLC has a median survival of 7 to 12 months; only 1 percent of these patients survive to 5 years.

What other considerations exist for patients with small-cell lung cancer?

Most patients who present with LS-SCLC and nearly all with ES-SCLC will develop recurrent disease. Patients who do not respond to first-line therapy or who relapse within 3 months after treatment with first-line therapy have chemoresistant disease and a worse prognosis.

Patients with residual disease after first-line therapy or who relapse after first-line therapy should be offered second-line treatment with chemotherapy. Topotecan has been approved for the treatment of relapsed SCLC and has been shown to improve symptom control, slow the decline in quality of life, and improve survival rates when compared with best-supportive care. 

There is no role for maintenance therapy in SCLC.

The addition of targeted agents, such as angiogenesis inhibitors (bevacizumab) and tyrosine kinase inhibitors (cediranib, vandetanib), has not yet translated into better outcomes for patients with SCLC.

Long-term survivors of SCLC are at risk for new primary cancers; the risk is estimated at 5 to 10 percent per year and about 30 percent at 5 years. New lung cancers account for half of second malignancies, leukemia accounts for about 8 percent, and an average of 11 percent of second cancers involve the genitourinary system. Close follow-up is warranted in patients with SCLC who respond to treatment.

What’s the evidence?

Govindan, R, Page, N, Morgensztern, D, Read, W, Tierney, R, Vlahiotis, A. "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.". J Clin Oncol . vol. 24. 2006. pp. 4539-4544.

(An up-to-date assessment of the changing profile of small-cell lung cancer in the United States with implications for diagnosis.)

Parkin, DM, Sankaranarayanan, R. "Overview on small-cell lung cancer in the world. Industrialized countries, Third World, Eastern Europe.". Anticancer Res. vol. 14. 1994. pp. 277-282.

A classic review of the varied clinical expressions of small-cell lung cancer formulated from cancer registries in 20 countries.

Shepherd, PA, Crowley, J, Van Houtte, P. "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. vol. 2. 2007. pp. 1067-1077.

Barbone, F, Bovenzi, M, Cavallieri, F, Stanta, G. "Cigarette smoking and histologic type of lung cancer in men". Chest. vol. 112. 1997. pp. 1474-1479.

(The relationship between cigarette smoking and lung cancer cell type is reviewed.)

Morbia, A, Wynder, EL. "Cigarette smoking and lung cancer cell types". Cancer. vol. 68. 1991. pp. 2074-2078.

Another perspective on cell type and smoking history.

Steenland, K, Loomis, D, Shy, C, Simonsen, N. "Review of occupational lung carcinogens". Am J Int Med.. vol. 29. 1996. pp. 474-490.

The authors review the relationship between occupational carcinogens and lung cancer.

Chute, CG, Greenberg, ER, Baron, J, Korson, R, Baker, J, Yates, J. "Presenting conditions of 1539 population-based lung cancer patients by cell type and stage in New Hampshire and Vermont". Cancer. vol. 56. 1985. pp. 2107-2111.

This comprehensive review of modes of presentations of a large sample of patients with different lung cancer cell types and stages assists clinicians who evaluate patients for the possibility of lung cancer.

Ost, DE, Yeung, SCJ, Tanoue, LT, Gould, MK. "Clinical and organizational factors in the initial evaluation of patients with lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines". Chest. vol. 143 (5 Suppl). 2013. pp. e121S-e141S.

This recent guideline presents evidence-based approaches to diagnosing lung cancer based on clinical presentation.

Fischer, BM, Mortensen, J, Langer, SW. "Fischer BM, Mortensen J, Langer SW, et al. A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis.". Ann Oncol. vol. 18. 2007. pp. 338-345.

Bradley, JD, Dehdashti, F, Mintun, MA, Govindan, R, Trinkaus, K, Siegel, BA. "Positron emission tomography in limited-stage small-cell lung cancer: a prospective study.". J Clin Oncol. vol. 22. 2004. pp. 3248-3254.

PET scanning has emerged as an important staging tool for lung cancer patients. These two reports review the approach to imaging.

Turrisi, AT, Kim, K, Blum, R, Sause, WT, Livingston, RB, Komaki, R. "Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.". N Engl J Med . vol. 340. 1999. pp. 265-271.

This study reports the relative value of different regimens for delivering radiotherapy in patients with small-cell lung cancer.

Auperin, A, Arriagada, R, Pignon, JP, Le Pechoux, C, Gregor, A, Stephens, RJ. "Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission: Prophylactic Cranial Irradiation Overview Collaborative Group.". N Engl J Med . vol. 341. 1999. pp. 476-484.

The role of prophylactic cranial irradiation for small-cell lung cancer has been controversial. This study provides data on its appropriate role.

Jett, JR, Schild, SE, Kesler, KA, Kalemkerian, GP. "Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.". Chest. vol. 143 (5 Suppl). 2013. pp. e400S-e419S.

This guideline represents a highly respected evidence-based approach for managing patients with small-cell lung cancer.

Noda, K, Nishiwaki, Y, Kawahara, M, Negoro, S, Sugiura, T, Yokoyama, A. "Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer.". N Engl J Med . vol. 346. 2002. pp. 85-91.

A clinical trial of two regimens for small-cell lung cancer.

Lara, PN, Natale, R, Crowley, J, Lenz, HJ, Redman, MW, Carleton, JE. "Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124.". J Clin Oncol . vol. 27. 2009. pp. 2530-2535.

Slotman, B, Faivre-Finn, C, Kramer, G, Rankin, E, Snee, M, Hatton, M. "Prophylactic cranial irradiation in extensive small-cell lung cancer.". N Engl J Med . vol. 357. 2007. pp. 664-672.

Jeremic, B, Shibamoto, Y, Nikolic, N, Milicic, B, Milisavljevic, S, Dagovic, A. "Role of radiation therapy in the combined-modality treatment of patients with extensive-stage small-cell lung cancer: a randomized study.". J Clin Oncol . vol. 17. 1999. pp. 2092-2099.

Rodriguez Estelamari, Lilenbaum, RC. "Small cell lung cancer: past, present, and future". Curr Oncol Rep. vol. 12. 2010. pp. 327-334.

This recent review provides a comprehensive overview of the state of the art for managing patients with small-cell lung cancer.

Socinski, MA, Bogart, JA. "Limited-stage small-cell lung cancer: the current status of combined-modality therapy". J Clin Oncol. vol. 25. 2007. pp. 4137-4145.

Demedts, IK, Vermaelen, KY, van Meerbeeck, JP. "Treatment of extensive-stage small cell lung carcinoma: current status and future prospects". Eur Respir J. vol. 35. 2010. pp. 202-215.

Videtic, GM, Stitt, LW, Dar, AR, Kocha, WI, Tomiak, AT, Truong, PT. "Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival.". J Clin Oncol . vol. 21. 2003. pp. 1544-1549.

Tucker, MA, Murray, N, Shaw, EG, Ettinger, DS, Mabry, M, Huber, MH. "Second primary cancers related to smoking and treatment of small-cell lung cancer.". J Clin Oncol . vol. 89. 1997. pp. 1782-1788.

Sagman, U, Lishner, M, Maki, E, Shepherd, FA, Haddad, R, Evans, WK. "Second primary malignancies following diagnosis of small-cell lung cancer.". J Clin Oncol . vol. 10. 1992. pp. 1525-1533.

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