SCLC accounts for approximately 15% of bronchogenic carcinomas.
At the time of diagnosis, approximately 30% of patients with SCLC have tumors confined to the hemithorax of origin, mediastinum, or supraclavicular lymph nodes. These patients have limited-stage disease (LD).[1] Patients with tumors that have spread beyond the supraclavicular areas 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 2024:[3]
Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:
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 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 defects or personality changes from brain metastases and pain from bone metastases.
Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:
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.
The procedures used to determine the presence of cancer include the following:
Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathological 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.[19] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.
For more information, see the Staging Evaluation section.
Regardless of stage, the prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with a median survival from diagnosis of only 2 to 4 months. About 10% of people with SCLC remain free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. However, even these patients are at risk of dying of lung cancer (both small and non-small cell types).[20] The overall survival rate at 5 years is 5% to 10%.[1,20-22]
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, the median survival is 16 to 24 months and the 5-year survival rates is 14% with current forms of treatment.[1,21,23,24] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.[25]
Patients with LD have improved long-term survival with combined-modality therapy.[24,26][Level of evidence A1] 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.[27] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[26,28] Multiple trials and meta-analyses have evaluated the optimal timing of TRT relative to chemotherapy, with the weight of evidence suggesting a small benefit to early TRT.[1,29,30][Level of evidence A1]
In patients with ED, the median survival 6 to 12 months with currently available therapy, but long-term disease-free survival is rare.
Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or a very good partial response to chemoradiation in LD or chemotherapy in ED.[31,32][Level of evidence A1]
Thoracic radiation may also improve long-term outcomes for these patients.[33]
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 website.
Before initiating treatment for a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathological 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.
Neuroendocrine tumors include the following:
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 divided into SCLC and combined SCLC.[2] No minimum percentage of the additional component is required for a combined SCLC diagnosis with the exception of mixed LCNEC and SCLC, in which a 10% minimum LCNEC component is required.[3]
SCLC presents as a proliferation of small cells with the following morphological features:[4]
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.[5]
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.[6]
Several staging systems have been proposed for small cell lung cancer (SCLC). These staging systems include the following:
No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, mediastinum, or 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 in 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 nodules 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] For more information, see the AJCC Stage Groupings and TNM Definitions section in Non-Small Cell Lung Cancer Treatment.
The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survival rates 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 to distinguish 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 fluorine F 18-fludeoxyglucose (18F-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 resulting from the identification of additional sites of nodal metastases.
Evidence (18F-FDG PET):
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 few 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] Incorporating current chemotherapy regimens into the treatment program prolongs survival, 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.[4-6][Level of evidence A1] 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.[7-12][Level of evidence A1]
SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[13-16][Level of evidence A1] Prophylactic cranial irradiation prevents central nervous system recurrence and may improve the long-term survival of patients with good performance status who have responded to chemoradiation therapy.[17-19][Level of evidence A1] This type of irradiation also offers palliation of symptomatic metastatic disease.
Treatment options for patients with LD, ED, or recurrent SCLC are summarized in Table 1.
Stage | Treatment Options |
---|---|
ED = extensive-stage disease; LD = limited-stage disease. | |
LD | Chemotherapy and radiation therapy |
Adjuvant treatment after chemoradiation therapy | |
Combination chemotherapy alone | |
Surgery followed by chemotherapy or chemoradiation therapy | |
Prophylactic cranial irradiation | |
Clinical trials evaluating new drug regimens, surgical resection of the primary tumor, or new radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation) | |
ED | Immune checkpoint modulation and combination chemotherapy |
Combination chemotherapy | |
Radiation therapy | |
Clinical trials evaluating new drug regimens or alternative drug doses and schedules | |
Recurrent disease | Chemotherapy |
Immunotherapy | |
Immune checkpoint modulation | |
Palliative therapy | |
Phase I and II clinical trials evaluating new drugs |
Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in 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 website.
Treatment options for patients with limited-stage small cell lung cancer (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.
Evidence (combined-modality treatment):
Evidence (adjuvant treatment after chemoradiation therapy):
This is the first new treatment option for patients with LD SCLC in over 35 years.
Patients with a contraindication to radiation therapy may receive 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.[23,24] For more information, see Cardiopulmonary Syndromes.
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.[25-29][Level of evidence C2] 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.[29][Level of evidence C2] Given the absence of data from randomized trials, the potential benefits and risks of surgery in the management of individual patients with SCLC must be considered.
Evidence (role of surgery):
Patients who have achieved a complete remission may receive 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.[29,31,32] Most of these patients have disease that relapses only in the brain, and nearly all of those with CNS relapse die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% with the administration of PCI.[31]
Evidence (role of PCI):
Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[29,32,36-38] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated with PCI.[38] Most patients with SCLC have neuropsychological abnormalities before the start of PCI and have no detectable neurological decline for as long as 2 years after the start of PCI.[38] Patients treated for SCLC continue to have declining neuropsychological function after 2 years from the start of treatment.[36-38] Additional neuropsychological testing of patients beyond 2 years from the start of treatment is 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 decreased performance status and increased comorbidity.[39] 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 these findings were 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 evaluating outcomes in patients aged 70 years or older have been published.[40-42] The survival outcomes for the older patients were identical to those of their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematological, 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).[41] 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.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for patients with extensive-stage disease (ED) small cell lung cancer (SCLC) include the following:
Studies have evaluated the role of immune checkpoint inhibitors (programmed cell death-1 [PD-1] or programmed death-ligand 1 [PD-L1] inhibitors) in frontline treatment of patients with ED SCLC. Two PD-L1 inhibitors, atezolizumab and durvalumab, prolonged overall survival (OS) when combined with platinum and etoposide, compared with the same combination chemotherapy regimen alone. For more information, see the Combination chemotherapy section. Treatment with a PD-1 inhibitor, pembrolizumab, in combination with chemotherapy, did not meet statistical significance for the prespecified end point of OS in the KEYNOTE-604 (NCT03066778) phase III trial.[1][Level of evidence B1]
Evidence (immune checkpoint modulation and combination chemotherapy):
Chemotherapy for patients with ED SCLC is commonly given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC).[4] Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects.
Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use.
Standard treatment | Etoposide + cisplatin |
Etoposide + carboplatin | |
Other regimens | Cisplatin + irinotecan |
Ifosfamide + cisplatin + etoposide | |
Cyclophosphamide + doxorubicin + etoposide | |
Cyclophosphamide + doxorubicin + etoposide + vincristine | |
Cyclophosphamide + etoposide + vincristine | |
Cyclophosphamide + doxorubicin + vincristine |
Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED SCLC.[5,6][Level of evidence A1]
Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.[7,8]
Evidence (standard regimens):
Evidence (other combination chemotherapy regimens):
Evidence (duration of treatment):
Evidence (dose intensification):
More patients with ED SCLC have greatly impaired performance status at the time of diagnosis than patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined-modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.[33,38-44]
Prospective randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with single-agent, low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in patients receiving regular treatment.[41][Level of evidence B1]
Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide-plus-vincristine regimen and a four-drug regimen.[42] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[42][Level of evidence A3] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[38,43][Level of evidence A1]
Subgroup analyses of phase II and III trials of patients with SCLC by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in older patients than in younger patients, and that the incidence of treatment-related death tended to be higher in older patients.[44] About 80% of older patients, however, received optimal treatment, and their survival was comparable with that of younger patients. The standard chemotherapy regimens for the general population could be applied to older patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, disease-free survival (DFS), or OS in older patients compared with younger patients.
Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases, is a standard treatment option for patients with ED SCLC. Brain metastases are treated with whole-brain radiation therapy.
Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. For more information, see Cardiopulmonary Syndromes.
Patients with ED SCLC treated with chemotherapy who have achieved a response may receive thoracic radiation therapy.
Evidence (thoracic radiation therapy):
Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.
Evidence (PCI):
Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for patients with recurrent small cell lung cancer (SCLC) include the following:
At the time of recurrence, many patients with SCLC are potential candidates for further therapy.
For patients with recurrent SCLC, immune checkpoint modulation with anti–programmed death-ligand 1 (anti–PD-L1) antibodies may lead to durable responses either as single agents or in combination with cytotoxic T lymphocyte antigen-4 (anti–CTLA-4). Impacts on long-term survival from these approaches are being assessed in randomized trials.
Although second-line chemotherapy has produced tumor regression, responses are usually short lived. The median survival is rarely more than 12 months and usually less than 6 months after second-line therapy.[1] Response to first-line chemotherapy predicts subsequent response to second-line therapy.
As in other chemosensitive tumors (e.g., Hodgkin lymphoma and ovarian epithelial cancer), two main categories of patients receiving second-line chemotherapy have been described: sensitive and resistant. Sensitive patients have a first-line response that lasted more than 90 days after treatment was completed. These patients have the greatest benefit from second-line chemotherapy. Patients with sensitive disease respond to the same initial regimen in approximately 50% of cases; however, cumulative toxic effects may ensue.[2] Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy.[3] Results from phase II studies of drugs such as topotecan, irinotecan, and gemcitabine indicate that response rates to agents vary depending on whether patients have sensitive, resistant, or refractory disease.[4-8][Level of evidence C2]
Topotecan is a standard chemotherapy for recurrent SCLC.[9,10] Lurbinectedin, a selective inhibitor of oncogenic transcription, is another option.[11] Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine.[4-8,12-14][Level of evidence C2] Response rates for combination agents are generally higher than those reported for single agents,[15,16] and one phase III study reported improved survival for patients with sensitive disease treated with combination cisplatin, etoposide, and irinotecan. However, higher rates of toxicity have been seen.[17]
Evidence (topotecan and other chemotherapy agents):
Evidence (lurbinectedin):
Evidence (other chemotherapy agents):
Tarlatamab is a BiTE immunotherapy drug that targets delta-like ligand 3 (DLL3) and CD3. BiTE technology is a targeted immuno-oncology platform designed to engage a patient's own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer.
Evidence (tarlatamab):
Early phase Ib and II trials showed objective response rates of 10% to 33% with nivolumab or pembrolizumab treatment in patients with disease progression after one or more lines of chemotherapy, resulting in accelerated approval from the U.S. Food and Drug Administration. However, both agents were voluntarily withdrawn after subsequent trials failed to confirm benefit.[19,20]
Patients with central nervous system (CNS) recurrences can often obtain palliation of symptoms with additional chemotherapy and/or radiation therapy. A retrospective review showed that 43% of patients had disease response when treated with additional chemotherapy at the time of CNS relapse.[21] Most patients treated with radiation therapy obtain objective responses and improvement after radiation therapy.[22]
Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression caused by the tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy.[23] Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, which results in improved symptoms and pulmonary function in patients with malignant airways obstruction.[24]
Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and short-term local control with external-beam radiation therapy. Only the rare patient, however, will experience long-term survival after receiving salvage radiation therapy.[25]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment Option Overview for Small Cell Lung Cancer (SCLC)
Revised Table 1, Treatment Options for Patients With SCLC, to include adjuvant treatment after chemoradiation therapy as an option for patients with limited-stage SCLC.
Treatment of Limited-Stage SCLC
Added Adjuvant treatment after chemoradiation therapy as a new subsection.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of small cell lung cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Adult Treatment Editorial Board. PDQ Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389347]
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