Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by early metastatic spread and responsiveness to initial therapy. The incidence of SCLC has been declining in the United States in parallel with the decreasing prevalence of cigarette smoking. Limited stage disease is potentially curable with chemoradiotherapy followed by cranial irradiation. Extensive stage disease is incurable, but systemic chemotherapy can improve quality of life and prolong survival. Nearly all patients relapse with chemoresistant disease. Molecularly targeted therapy has failed to yield convincing clinical benefits. Nevertheless, many biologically rational strategies, including immune checkpoint inhibition, show promise in ongoing clinical trials.
Key points
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Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with rapid growth, early metastatic spread and initial responsiveness to therapy.
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Limited stage (LS)-SCLC is curable, with long-term survival of 20% to 25% when treated with platinum-based chemotherapy plus thoracic radiation and prophylactic cranial irradiation.
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Extensive stage (ES)-SCLC is incurable, but combination chemotherapy can prolong survival and improve quality of life.
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Although many potential molecular targets have been identified, targeted therapy has not demonstrated consistent clinical activity in SCLC.
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Future advances will depend on therapeutic strategies that target the pathways driving cancer cell survival and immunologic avoidance.
Introduction
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with clinical and pathologic characteristics distinct from those of non-SCLC. The primary cause of SCLC is tobacco use, with more than 95% of patients being current or former smokers. In the United States, the decreasing prevalence of cigarette smoking has resulted in a decrease in the incidence of SCLC. The frequency of SCLC as a proportion of all lung cancer cases peaked at 17% to 20% in the late 1980s, but is now 13% to 15%. Despite the decrease in incidence, SCLC remains the seventh most common cause of cancer-related death in the United States. From 1973 to 2002, the 5-year overall survival rate only increased from 4.3% to 6.3%.
Introduction
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with clinical and pathologic characteristics distinct from those of non-SCLC. The primary cause of SCLC is tobacco use, with more than 95% of patients being current or former smokers. In the United States, the decreasing prevalence of cigarette smoking has resulted in a decrease in the incidence of SCLC. The frequency of SCLC as a proportion of all lung cancer cases peaked at 17% to 20% in the late 1980s, but is now 13% to 15%. Despite the decrease in incidence, SCLC remains the seventh most common cause of cancer-related death in the United States. From 1973 to 2002, the 5-year overall survival rate only increased from 4.3% to 6.3%.
Staging systems
The Veterans’ Administration Lung Study Group (VALSG) 2-stage classification has been the standard system for staging SCLC for decades. This system defines limited stage (LS) as disease confined to 1 hemithorax, including contralateral mediastinal and ipsilateral supraclavicular lymph nodes, if all disease can be safely encompassed in a radiation port. Extensive stage (ES) is defined as disease that cannot be classified as limited, including malignant pleural or pericardial effusions and hematogenous metastases. The classification of metastases to contralateral supraclavicular or hilar lymph nodes is debatable, with individualized treatment based on the ability to safely treat all areas of disease with radiotherapy (RT).
It has been suggested that the TNM staging classification should replace the VALSG system for SCLC. This recommendation is based on the finding that the individual tumor (T), node (N), and metastasis (M) classifiers, and the stage I through IV groupings are predictive of overall survival in SCLC. However, the degree of prognostic discrimination with the TNM system is less impressive in SCLC than in non-SCLC. In addition, nearly all of the clinical trials that guide the treatment of patients with SCLC have used the VALSG staging system, so the immediate application of TNM staging may confuse clinical decision making. Nonetheless, TNM staging is useful in the selection of patients for surgical resection (ie, T1-2 N0), and should be incorporated into clinical trial design and tumor registries.
Initial assessment and staging
LS-SCLC is a curable disease, but ES-SCLC is not, so the primary goal of staging is to look for distant metastases. The initial evaluation of patients with newly diagnosed SCLC is highlighted in Box 1 . An MRI scan will detect brain metastases in 10% to 15% of newly diagnosed patients without neurologic symptoms. Fewer than 5% of patients will have bone marrow involvement as the only site of metastatic disease, so bone marrow aspiration/biopsy should only be considered in patients with significant hematological abnormalities.
Complete medical history and physical examination
Pathologic review of biopsy with immunohistochemical analysis
Laboratory studies
Complete blood count (white blood cells, hemoglobin/hematocrit, platelets)
Serum electrolytes (Na, K, Cl, HCO 3 , Ca)
Renal function tests (blood urea nitrogen, creatinine)
Liver function tests (AST, ALT, bilirubin, alkaline phosphatase)
Serum lactate dehydrogenase (lactate dehydrogenase)
Nutritional status (total protein, albumin)
CT of the chest and upper abdomen (liver, adrenal glands) with intravenous contrast
18 F-fluorodeoxyglucose-PET/CT (whole body)
MRI or CT of brain with intravenous contrast
Bone scan (optional if PET obtained)
Performance status assessment
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.
Recently, 18 F-fluorodeoxyglucose (FDG)-PET has been incorporated into the staging evaluation of SCLC. If PET is obtained, then bone scan is not necessary because FDG-PET imaging is as sensitive as bone scan for the detection of bone metastases. The sensitivity of FDG-PET imaging is 100% for the detection of SCLC. A systematic review of studies comparing FDG-PET imaging with conventional imaging procedures reported that 16% of patients with LS-SCLC by conventional imaging were upstaged to ES by FDG-PET imaging, whereas 11% of patients with ES-SCLC by conventional imaging were downstaged to LS. A metaanalysis of studies defined the sensitivity and specificity of FDG-PET for the detection of ES-SCLC as 97.5% and 98.2%, respectively. However, FDG-PET is inferior to MRI and CT scanning for the detection of brain metastases. A review of 7 studies found that FDG-PET led to a change in the initial management in 28% of patients, with one-third owing to a change in stage and the rest owing to adjustment of RT fields in patients with LS-SCLC, which may result in better locoregional disease control.
The addition of FDG-PET imaging to conventional imaging studies improves the accuracy of staging and RT planning in patients with SCLC, and is recommended in the initial workup. Owing to the potential for false-positive findings, pathologic confirmation is recommended for any PET-detected lesion that results in a change in treatment.
Treatment of small cell lung cancer
The management of SCLC is often complicated by the fact that many patients present with debilitating symptoms of disease. The high prevalence of cigarette smoking also results in comorbidities that further impair performance status.
Stage-Specific Therapy
LS-SCLC is a potentially curable disease. Surgical resection followed by adjuvant chemotherapy is indicated for the few patients (<5%) who present with true stage I (T1-2 N0) disease. The standard of care for most patients with LS-SCLC consists of 4 to 6 cycles of cisplatin/carboplatin and etoposide plus early, concurrent thoracic RT. Prophylactic cranial irradiation (PCI) is recommended for patients with good performance status who achieve a robust response to initial therapy. Standard therapy yields an objective tumor response in 90% of patients and a 5-year survival rate of 20% to 25%.
ES-SCLC is an incurable disease in which platinum-based chemotherapy is given with palliative intent. Combination chemotherapy results in an objective response in 60% to 70% of patients. Patients with a good response to chemotherapy and a good performance status should be considered for PCI and/or thoracic RT, which may improve survival. Although chemotherapy improves quality of life and prolongs survival, relapse with relatively chemoresistant disease is inevitable, and fewer than 10% of patients with ES-SCLC remain alive 2 years after diagnosis. The stage-specific treatment of patients with SCLC is outlined in Box 2 .
Limited stage
Cisplatin/carboplatin + etoposide × 4 to 6 cycles
Early, concurrent thoracic radiotherapy
Prophylactic cranial irradiation for responders
Surgical resection followed by adjuvant chemotherapy (stage I only)
Extensive stage
Platinum-based chemotherapy (eg, carboplatin + etoposide) × 4 to 6 cycles
Prophylactic cranial irradiation for responders
Thoracic radiation for responders
Recurrent disease
Single-agent chemotherapy (eg, topotecan, paclitaxel)
Palliative radiotherapy, as needed for symptoms
Clinical trials of investigational therapeutic agents
Thoracic Radiotherapy in Limited Stage Small Cell Lung Cancer
The expanded use of RT has yielded modest improvements in outcomes for patients with both LS-SCLC and ES-SCLC. In LS-SCLC, metaanalyses demonstrated that the addition of definitive thoracic RT to chemotherapy significantly improved the 2- to 3-year overall survival rate by 5.4%. Subsequently, a metaanalysis reported that early thoracic RT (initiated before the third cycle of chemotherapy) resulted in a 5% improvement in 2-year overall survival when compared with late RT. Another metaanalysis of 4 trials reported that patients with a shorter interval between the start of any treatment and the end of RT had a better 5-year survival rate (relative risk, 0.62; P = .0003). Based on these findings, early concurrent chemoradiotherapy is the standard approach for patients with LS-SCLC.
The role of hyperfractionated thoracic RT remains controversial. Turrisi and colleagues reported a phase III trial in which 417 patients with LS-SCLC were randomized to receive cisplatin plus etoposide (PE) with 45 Gy of early, concurrent thoracic RT given either once daily or twice daily. Twice-daily RT resulted in a significant improvement in overall survival (5 years, 26% vs 16%; P = .04). However, patients on the once-daily RT arm received a relatively low dose of radiation that was not biologically equivalent to the dose delivered on the twice-daily RT arm. Bonner and colleagues reported another randomized trial of hyperfractionated RT in which 262 patients with LS-SCLC were assigned to receive PE plus either once-daily thoracic RT to 50.4 Gy or twice-daily RT to 48 Gy in a split course. RT was started with the third cycle of chemotherapy in both arms. There were no differences in survival between the arms. The late initiation of RT and the use of a split course of RT in the twice-daily arm are both considered suboptimal therapy. Therefore, the potential benefit of hyperfractionated RT in LS-SCLC remains unclear.
Thoracic Radiotherapy in Extensive Stage Small Cell Lung Cancer
The role of thoracic RT in patients with ES-SCLC is also controversial. Jeremic and colleagues reported a study in which patients who had an excellent response to initial PE were randomized to receive either hyperfractionated thoracic RT (54 Gy) plus concurrent chemotherapy or further PE without RT. Overall survival was significantly better in patients on the RT arm (median, 17 vs 11 months; P = .041). A recent phase III study by Slotman and colleagues randomized 495 patients with ES-SCLC who responded to first-line chemotherapy to either thoracic RT (30 Gy) or no RT. Thoracic RT did not significantly improve the primary endpoint of 1-year overall survival (33% vs 28%; P = .07), but did improve 2-year overall survival (13% vs 3%; P = .004). These trials suggest that patients with ES-SCLC who have responded well to chemotherapy may benefit from RT to residual thoracic disease.
Prophylactic Cranial Irradiation
Approximately 60% of patients with SCLC develop brain metastases. A metaanalysis of randomized trials of PCI in mostly LS-SCLC reported a 25% decrease in the incidence of brain metastases (58% vs 33%; P <.001) and a 5.4% improvement in the 3-year survival rate (15.3% vs 20.7%; P = .01) with PCI. To evaluate the effects of PCI in ES-SCLC, the European Organization for Research and Treatment of Cancer randomized 286 patients with ES-SCLC who had responded to first-line chemotherapy to either PCI or no PCI, and found that PCI decreased the incidence of brain metastases (14.6% vs 40.4%; P <.001) and improved the 1-year survival rate (27.1% vs 13.3%; P = .003). Despite a short-term decline in quality of life, PCI did not have a lasting effect on global quality-of-life scores. However, preliminary data from Japan have cast doubt on these findings, with a randomized trial of PCI versus no PCI in patients with ES-SCLC that demonstrated a trend toward better survival in the no PCI arm (median, 15 vs 10 months; P = .09). Pending the final results of this study, PCI (25 Gy in 10 fractions) is recommended for patients with LS-SCLC or ES-SCLC and good performance status who have had a robust response to initial therapy.
First-Line Chemotherapy
SCLC usually responds well to initial chemotherapy and RT, with relatively rapid improvement in symptoms. Many cytotoxic drugs have activity in SCLC, but the duration of response with single-agents is short ( Box 3 ). Alkylator-based regimens, such as cyclophosphamide, doxorubicin, and vincristine, improved response rates to 60% to 80% and median survival to 7 to 10 months. In LS-SCLC, up to 25% of patients remained disease free at 2 years. Subsequently, PE was found to have efficacy similar to that of alkylator-based regimens, with more tolerable toxicity. One phase III study comparing PE to cyclophosphamide, epirubicin, and vincristine reported significantly better overall survival with PE (10.2 vs 7.8 months; P = .0004). In addition, metaanalyses reported a modest survival benefit for patients treated with cisplatin-based therapy. Therefore, PE became the primary regimen for both ES-SCLC and LS-SCLC.
DNA-intercalating agents: cisplatin, carboplatin
Alkylating agents: cyclophosphamide, ifosfamide, temozolomide, bendamustine
Microtubule inhibitors: vincristine, vinblastine, vinorelbine
Microtubule stabilizers: paclitaxel, docetaxel
Topoisomerase I inhibitors: irinotecan, topotecan
Topoisomerase II inhibitors: etoposide, teniposide
Anthracyclines: doxorubicin, epirubicin, amrubicin
Antimetabolites: methotrexate, gemcitabine
Many other systemic approaches have been assessed, but none have proven superior to PE. Many studies have evaluated combinations of cisplatin/carboplatin plus a topoisomerase 1 inhibitor ( Table 1 ). In Japan, a phase III study randomized 154 patients with previously untreated ES-SCLC to PE or cisplatin plus irinotecan (PI) and reported that PI significantly improved response rate, progression-free survival, and overall survival. However, randomized trials in Western countries have failed to confirm the superiority of PI over PE with no differences in efficacy outcomes, but less toxicity with PE.
| Trial | Arm | N | Response Rate | Overall Survival | ||||
|---|---|---|---|---|---|---|---|---|
| % | P | Median | 1 y (%) | 2 y (%) | P | |||
| Noda et al, 2002 | IP | 77 | 84 | .02 | 12.8 mo | 58.4 | 19.5 | .002 |
| EP | 77 | 68 | 9.4 mo | 37.7 | 5.2 | |||
| Hanna et al, 2006 | IP | 221 | 48 | NS | 9.3 mo | 35 | 8 | .74 |
| EP | 110 | 44 | 10.2 mo | 35 | 8 | |||
| Lara et al, 2009 | IP | 324 | 60 | .56 | 9.9 mo | 41 | NR | .71 |
| EP | 327 | 57 | 9.1 mo | 34 | NR | |||
| Zatloukal et al, 2010 | IP | 202 | 39 | NS | 10.2 mo | 42 | 16 | .06 |
| EP | 203 | 47 | 9.7 mo | 39 | 8 | |||
| Hermes et al, 2008 | IC | 105 | 17 a | .02 | 8.5 mo | NR | NR | .02 |
| EC | 104 | 7 a | 7.1 mo | NR | NR | |||
| Schmittel et al, 2006 | IC | 35 | 67 | .24 | 9.0 mo b | 27 b | NR | .03 |
| EC | 35 | 59 | 6.0 mo b | 11 b | NR | |||
| Eckardt et al, 2006 | TP | 389 | 63 | NS | 9.0 mo | 31 | NR | .48 |
| EP | 395 | 69 | 9.2 mo | 31 | NR | |||
| Fink et al, 2012 | TP | 358 | 56 | .01 | 45 wk | 40 | NR | .30 |
| EP | 345 | 46 | 41 wk | 36 | NR | |||
Related posts:
Evolving Treatment Options for Lung Cancer
Treatment of Locally Advanced Non–Small Cell Lung Cancer
Second-Line Chemotherapy and Beyond for Non–Small Cell Lung Cancer
First-Line Systemic Therapy for Non–Small Cell Lung Cancer
New Targets in Non–Small Cell Lung Cancer
Systemic Treatment of Brain Metastases
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