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National Cancer Institute
Ultima Vez Modificado: 20 de enero del 2012
Small cell lung cancer (SCLC) accounts for approximately 15% of bronchogenic carcinomas.
At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD). 1 Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED).
SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.
The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades. 2
Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2012: 3
Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough, shortness of breath, and dyspnea. Other presenting symptoms include the following:
Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases.
Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease.
Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.
Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC. 4 Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.
Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. About 10% of the total population of SCLC patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types). 5 The overall survival at 5 years is 5% to 10%. 1 5 6 7
An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported. 1 6 8 9 Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival. 10
Improved long-term survival in patients with LD has been shown with combined-modality therapy. 9 11[Level of evidence: 1iiA] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care. 12 Adding TRT increases absolute survival by approximately 5% over chemotherapy alone. 11 13 The optimal timing of TRT relative to chemotherapy has been evaluated in multiple trials and meta-analyses with the weight of evidence suggesting a small benefit to early TRT. 1 14 15[Level of evidence: 1iiA]
In patients with ED, median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.
All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI Web site.
Before initiating treatment of a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathologic material.
The current classification of subtypes of SCLC includes the following: 1
SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.
Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now described with only one variant, SCLC combined, when at least 10% of the tumor bulk is made of an associated non-small cell component.
SCLC presents as a proliferation of small cells with the following morphological features: 2
Combined small cell carcinoma includes a mixture of small cell and large cell or any other non-small cell component. Any cases showing at least 10% of SCLC are diagnosed as combined SCLC, and SCLC is limited to tumors with pure SCLC histology. SCLC associated with LCNEC is diagnosed as SCLC combined with LCNEC.
Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC. 3
Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC. 4
No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.
Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.
Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED. 3 4
The AJCC TNM defines LD as any T, except for T3-4, due to multiple lung nodals that do not fit in a tolerable radiation field, any N, and M0. 1 This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1) including malignant pleural effusions. 3 4
The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survivals for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement. 3 Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important. 3
Staging procedures for SCLC are important in distinguishing patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.
Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include the following:
The role of positron emission tomography (PET) is still under study. SCLC is fluorodeoxyglucose (FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields due to the identification of additional sites of nodal metastases.
Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).
Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a minority of patients. 1 2 Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival. 3 With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.
The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen. 4 5 6[Level of evidence: 1iiA] No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy. 7 8 9 10 11 12[Level of evidence: 1iiA]
SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors. 13 14 15[Level of evidence: 1iiA] Prophylactic cranial radiation prevents central nervous system recurrence and may improve the long-term survival of patients who have responded to chemoradiation therapy 16 17 18[Level of evidence: 1iiA] and offers palliation of symptomatic metastatic disease.
|Stage||Standard Treatment Options|
|Limited-stage disease||Chemotherapy and radiation therapy|
|Combination chemotherapy alone|
|Surgery followed by chemotherapy or chemoradiotherapy|
|Prophylactic cranial irradiation|
|Extensive-stage disease||Combination chemotherapy|
|Prophylactic cranial irradiation|
Despite treatment advances, the majority of patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.
Information about ongoing clinical trials is available from the NCI Web site.
Standard treatment options for patients with limited-stage SCLC include the following:
Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.
Patients with a contraindication to radiation therapy could be treated with chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation. 21 22 (Refer to the PDQ® summary on Cardiopulmonary Syndromes for more information.)
The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy. 23 24 25 26 27[Level of evidence: 3iiiDii] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery. 27[Level of evidence: 3iiiDii] Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and risk from the surgical procedure.
Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment. 27 29 30 The majority of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% by the administration of PCI. 29
Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment. 27 30 32 33 34 Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated. 34 The majority of patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI. 34 Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment. 32 33 34 Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.
The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity. 35 Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.
No specific phase III trial in older patients with LD SCLC has been reported; however, three secondary analyses of two cooperative group trials have been published evaluating outcomes in patients aged 70 years or older. 36 37 38 The survival outcomes for the older patients were identical to their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the EST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged 70 years; P = .01). 37 Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with limited stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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