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). 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.

Incidence and Mortality

The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.

Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer combined) in the United States in 2024:

• New cases: 234,580.
• Deaths: 125,070.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:

• History of or current tobacco use: cigarettes, pipes, and cigars.
• Exposure to cancer-causing substances in secondhand smoke.
• Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.
• Radiation exposure from any of the following:
  • Radiation therapy to the breast or chest.
  • Radon exposure in the home or workplace.
  • Medical imaging tests, such as computed tomography (CT) scans.
  • Atomic bomb radiation.
• Living in an area with air pollution.
• Family history of lung cancer.
• Human immunodeficiency virus infection.
• Beta carotene supplements in heavy smokers.

Clinical Features

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:

• Chest pain.
• Hoarseness.
• Malaise.
• Anorexia.
• Weight loss.
• Hemoptysis.

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:

• Inappropriate antidiuretic hormone secretion.
• Cushing syndrome from secretion of adrenocorticotropic hormone.
• Paraneoplastic cerebellar degeneration.
• Lambert-Eaton myasthenic syndrome.

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.

Diagnosis

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:

• History.
• Physical examination.
• Routine laboratory evaluations.
• Chest x-ray.
• Chest CT scan with infusion of contrast material.
• Biopsy.

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. 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.

Prognosis and Survival

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). The overall survival rate at 5 years is 5% to 10%.

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. Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.

Patients with LD have improved long-term survival with combined-modality therapy. 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. Adding TRT increases absolute survival by approximately 5% over chemotherapy alone. 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.

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.

Thoracic radiation may also improve long-term outcomes for these patients.

All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis.

Before initiating treatment for a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathological material.

Pathological Classification

The current classification of subtypes of SCLC includes the following:

• Small cell carcinoma.
• Combined small cell carcinoma (i.e., SCLC combined with additional components from any of the non-small cell lung carcinoma histological types).

SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.

Neuroendocrine tumors include the following:

• Low-grade typical carcinoid.
• Intermediate-grade atypical carcinoid.
• High-grade neuroendocrine tumors, including large-cell neuroendocrine carcinoma (LCNEC) and SCLC.

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. 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.

SCLC presents as a proliferation of small cells with the following morphological features:

• Scant cytoplasm.
• Ill-defined borders.
• Finely granular salt and pepper chromatin.
• Absent or inconspicuous nucleoli.
• Frequent nuclear molding.
• A high mitotic count.

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.

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.

Staging Systems

Several staging systems have been proposed for small cell lung cancer (SCLC). These staging systems include the following:

• American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM). The 8th edition of the AJCC Cancer Staging Manual recommends the use of the TNM to classify SCLC. For more information, see the AJCC Stage Groupings and TNM Definitions section in Non-Small Cell Lung Cancer Treatment.
• Veterans Administration Lung Study Group (VALG).
• International Association for the Study of Lung Cancer (IASLC).

Limited-Stage Disease

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

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.

IASLC-AJCC TNM Staging System

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. This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1), including malignant pleural effusions. 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. 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.

Staging Evaluation

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:

• A thorough physical examination.
• Routine blood counts and serum chemistries.
• Chest and upper abdominal computed tomography (CT) scanning.
• A radionuclide bone scan.
• A brain magnetic resonance imaging scan or CT scan.
• Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results.

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):

1. In a study of 120 patients with LD SCLC or ED SCLC, FDG-PET led to restaging of ten patients to a higher stage and three patients to a lower stage. FDG-PET was more sensitive and specific than CT scans for nonbrain distant metastases.
2. In a small series of 24 patients with LD by conventional staging, two patients were restaged to ED. Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain.

Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).

Chemotherapy

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. 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. 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. 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.

Radiation Therapy

SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors. 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. 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.

Table 1. Treatment Options for Patients With SCLC

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.

Treatment Options for Patients With Limited-Stage SCLC

Treatment options for patients with limited-stage small-cell lung cancer (SCLC) include the following:

1. Chemotherapy and radiation therapy.
2. Combination chemotherapy alone.
3. Surgery followed by chemotherapy or chemoradiation therapy.
4. Prophylactic cranial irradiation (PCI).
5. 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).

Chemotherapy and radiation therapy

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):

1. Survival. The following results have been reported in clinical trials:
   1. Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.
   2. Clinical trials have consistently achieved median survivals of 18 to 24 months and 2-year survival rates of 40% to 50%, with a treatment-related mortality rate of less than 3%.
   3. No consistent survival benefit has resulted from the following:
      • Increased dose intensity.
      • Increased dose density.
      • Administration of additional drugs or other (non–etoposide-containing) platinum-based combination regimens.
      • Altered modes of administration of various chemotherapeutic agents.
      • Maintenance chemotherapy.
2. Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.
3. Dose and timing. The optimal dose and timing of TRT remain controversial.
   1. Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).
   2. The amount of time from start to completion of TRT in LD SCLC may also affect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval , 0.49–0.80; P = .0003).
   3. Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin.
      • One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks, compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04). Esophagitis was increased with twice-daily treatment.
      • The phase III CONVERT study (NCT00433563) randomly assigned patients to receive either 45 Gy radiation therapy in 30 twice-daily fractions of 1.5 Gy over 19 days or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The primary end point was OS, defined as time from randomization until death from any cause, analyzed by modified intention-to-treat. A 12% higher OS at 2 years in the once-daily group versus the twice-daily group was considered clinically significant to show superiority of the once-daily regimen.
        • At a median follow-up of 45 months (interquartile range , 35–58), median OS was 30 months (95% CI, 24–34) in the twice-daily group versus 25 months (95% CI, 21–31) in the once-daily group (hazard ratio for death in the once-daily group, 1.18 ; P = .14).
        • The two-year OS rate was 56% (95% CI, 50%–62%) in the twice-daily group and 51% (45%–57%) in the once-daily group (absolute difference between the treatment groups, 5.3% ).
        • Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiation therapy (129 vs. 101 ; P = .05). In contrast to the earlier study, there was no difference between the groups in terms of rates of grade 3 to 4 esophagitis or pneumonitis.
      • Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to doses higher than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.

Combination chemotherapy alone

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. For more information, see Cardiopulmonary Syndromes.

Surgery followed by chemotherapy or chemoradiation therapy

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. 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. 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):

1. A randomized study evaluated the role of surgery in addition to chemoradiation therapy for 328 patients with LD SCLC. The study found no OS benefit with the addition of pulmonary resection.

PCI

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. 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.

Evidence (role of PCI):

1. A meta-analysis of seven randomized trials evaluated the value of PCI for patients in complete remission. The addition of PCI improved the rates of brain recurrence, disease-free survival, and OS. The 3-year OS rate increased from 15% to 21% with PCI.
2. The randomized RTOG-0212 study (NCT00005062) included 720 patients with LD SCLC in complete remission after chemoradiation therapy. The trial demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as, and less toxic than, higher doses of brain radiation.
3. Randomized trials such as RTOG-0212 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.

Neurological sequelae

Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment. Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated with PCI. 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. Patients treated for SCLC continue to have declining neuropsychological function after 2 years from the start of treatment. 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.

Treatment options for older patients

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. 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. 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). 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.

Treatment Options for Patients With Extensive-Stage SCLC

Treatment options for patients with extensive-stage disease (ED) small-cell lung cancer (SCLC) include the following:

1. Immune checkpoint modulation and combination chemotherapy.
   • Atezolizumab.
   • Durvalumab.
2. Combination chemotherapy.
3. Radiation therapy.
   • Thoracic radiation therapy for patients who respond to chemotherapy.
   • Prophylactic cranial irradiation (PCI).
4. Clinical trials evaluating new drug regimens or alternative drug doses and schedules.

Immune checkpoint modulation and combination chemotherapy

Studies have evaluated the role of immune checkpoint inhibitors (programmed cell death-1 or programmed death-ligand 1 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.

Evidence (immune checkpoint modulation and combination chemotherapy):

1. Atezolizumab. IMpower133 (NCT02763579), a double-blind, placebo-controlled, randomized, phase III trial, compared four cycles of carboplatin and etoposide with either atezolizumab (n = 201) or placebo (n = 202), followed by maintenance with either atezolizumab or placebo (as per the original randomization) until unacceptable toxic effects, disease progression, or no additional benefit.
   • At the planned interim analysis for OS, with a median follow-up of 22.9 months, the median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.76; 95% confidence interval , 0.60−0.95; descriptive P = .0154).
   • The median progression-free survival (PFS) was 5.2 months for the atezolizumab group and 4.3 months for the placebo group (HR for disease progression or death, 0.77; 95% CI, 0.63−0.95; P = .02).
   • The toxicity event rate was similar for both arms, consistent with known adverse events of the individual agents. Grade 3 or 4 adverse events occurred in 56.6% of patients in the atezolizumab group and 56.1% of patients in the placebo group.
2. Durvalumab. CASPIAN (NCT03043872) was a randomized, open-label, phase III trial that assigned patients to durvalumab plus platinum-etoposide (n = 268), durvalumab plus tremelimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) plus platinum-etoposide (n = 268), or platinum-etoposide alone (n = 269). In the immunotherapy arms, patients received four cycles of platinum-etoposide plus durvalumab with or without tremelimumab, followed by durvalumab maintenance until intolerance or disease progression or until other discontinuation criteria were met. In the chemotherapy-alone arm, up to six cycles of chemotherapy could be given, as well as PCI, at the investigator’s discretion. At the time of planned interim OS analysis, the durvalumab plus platinum-etoposide group met the predefined threshold for statistical significance.
   • The median OS was 12.9 months in the durvalumab plus platinum-etoposide group versus 10.5 months in the platinum-etoposide group (HR for OS, 0.75; 95% CI, 0.62−0.91; nominal P = .0032).
   • The toxicity event rate was similar in both arms, consistent with known adverse events of the individual agents. Grade 3 or 4 events occurred in 62% of patients in both study arms.

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 SCLC). 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.

Table 2. Combination Chemotherapy for Extensive-Stage SCLC

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.

Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.

Evidence (standard regimens):

1. Two meta-analyses evaluated the role of platinum combinations versus nonplatinum combinations.
   • A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.
   • A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those receiving a nonplatinum agent.
2. The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide. The median survival was 11.8 months in the cisplatin arm and 12.5 months in the carboplatin arm. Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED.

Evidence (other combination chemotherapy regimens):

1. Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan-and-cisplatin combination. Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles. Irinotecan-and-cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide-and-cisplatin regimens. Treatment-related deaths were comparable between the two groups.
2. Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not superior to etoposide and cisplatin. The 1-year survival rate was 31% (95% CI, 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.
3. Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.

Evidence (duration of treatment):

1. The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.
2. Reported data from randomized trials show no clear evidence that maintenance chemotherapy improves survival duration. However, a meta-analysis of 14 published randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year OS (95% CI, 0.56–0.79; P < .001 for 1-year OS and 0.53–0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.

Evidence (dose intensification):

1. The role of dose intensification in patients with SCLC remains unclear. Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival. A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC. These studies have yielded conflicting results.
   • Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival, with no compromise in quality of life (QOL).
   • Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.
   • The European Organisation for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support. The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival.
   • A randomized phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support. Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment. Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection.
   • A randomized phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05). However, given the small study size (only 70 patients), these results should be viewed with caution.

Factors influencing treatment with chemotherapy

1. Performance status.

   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.

   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.

   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. 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. 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.

2. Age.

   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. 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

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.

Thoracic radiation therapy for patients who respond to chemotherapy

Patients with ED SCLC treated with chemotherapy who have achieved a response may receive thoracic radiation therapy.

Evidence (thoracic radiation therapy):

1. A randomized trial of 498 patients who responded after receiving four to six cycles of chemotherapy compared thoracic radiation therapy with 30 Gy in 10 fractions versus no radiation therapy. All patients received PCI.
   • OS was the primary study end point and not statistically different between the two groups at 1 year (33% for the thoracic radiation therapy group vs. 28% for the control group, P = .066).
   • However, in a secondary analysis, the 2-year OS rate was 13% in the thoracic radiation group (95% CI, 9%–19%) versus 3% in the control group (95% CI, 2%–8%; P = .004). The OS during the entire course of follow-up was not reported.
   • Thoracic radiation therapy resulted in a 6-month PFS rate of 24% in the thoracic radiation group (95% CI, 19%–30%) versus 7% in the control group (95% CI, 4%–11%; P = .001).
   • Intrathoracic recurrences, both isolated (19.8% vs. 46.0%) and in combination with recurrences at other sites (43.7% vs. 79.8%), were reduced by approximately 50%.
   • Thoracic radiation therapy was well tolerated.

PCI

Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.

Evidence (PCI):

1. A randomized trial of 286 patients who responded after four to six cycles of chemotherapy compared PCI with no further therapy.
2. Radiation had side effects but did not have a clinically significant effect on global health status.
3. Only 29% of the randomly assigned patients had brain imaging at diagnosis.

Combination chemotherapy and radiation therapy

Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC.

Treatment Options for Patients With Recurrent SCLC

Treatment options for patients with recurrent small-cell lung cancer (SCLC) include the following:

1. Chemotherapy.
   • Topotecan.
   • Lurbinectedin.
   • Other chemotherapy agents.
2. Immune checkpoint modulation.
3. Palliative therapy.
4. Phase I and II clinical trials evaluating new drugs. New bispecific T-cell engager (BiTE) immunotherapies are being developed and early results are encouraging. BiTE technology is a targeted immuno-oncology platform designed to direct a patient’s own T cells to any tumor-specific antigen. BiTE therapy activates the cytotoxic potential of T cells to eliminate detectable cancer.

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.

Chemotherapy

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. 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. Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy. 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.

Topotecan is a standard chemotherapy for recurrent SCLC. Lurbinectedin, a selective inhibitor of oncogenic transcription, is another option. Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine. Response rates for combination agents are generally higher than those reported for single agents, 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.

Topotecan

Evidence (topotecan and other chemotherapy agents):

1. A randomized comparison of second-line treatment with either cyclophosphamide, doxorubicin, and vincristine or topotecan in patients with sensitive disease reported no significant difference in response rates or survival. However, palliation of common lung cancer symptoms was better with topotecan.
2. A phase III trial comparing chemotherapy with best supportive care (BSC) in patients with relapsed SCLC demonstrated that the addition of oral topotecan to BSC significantly increased overall survival (OS) and resulted in better symptom control compared with BSC alone. The study enrolled 141 patients with chemosensitive or chemoresistant relapsed SCLC who were unsuitable for further standard intravenous chemotherapy. The median survivals for patients receiving topotecan plus BSC were 25.9 weeks versus 13.9 weeks for BSC alone (P = .01).
3. A randomized phase III trial (CWRU-SKF-1598 ) of 304 patients assessed the use of oral topotecan (2.3 mg/m2/day for 5 days every 21 days) or intravenous topotecan (1.5 mg/m2/day for 5 days every 21 days). Confirmed response rates were 18.3% and 21.9%, respectively. Secondary end points of median survival and 1-year survival rates were also similar (33 weeks vs. 35 weeks and 33% vs. 29%, respectively). Patients receiving oral topotecan experienced less grade 4 neutropenia (47% vs. 64.2%) but more diarrhea of all grades (35.9% vs. 19.9%) than with intravenous topotecan. Quality-of-life (QOL) analysis (using a nonvalidated QOL questionnaire) demonstrated no significant difference between the two arms.

Lurbinectedin

Evidence (lurbinectedin):

1. A single-arm, open-label, phase II basket trial (NCT02454972) enrolled 105 patients with SCLC who had been previously treated with one line of a chemotherapy-containing regimen.
   • The overall response rate after treatment with lurbinectedin was 35% (95% confidence interval , 26%−45%), with a median response duration of 5.3 months (95% CI, 4.1−6.4).
   • The overall response rate was 45% (95% CI, 32%−58%) for patients with chemosensitive disease and 22% (95% CI, 11%−37%) for patients with chemoresistant disease.
   • The median duration of response was 6.2 months (95% CI, 3.5−7.3) for patients with chemosensitive disease and 4.7 months (95% CI, 2.6−5.6) for patients with chemoresistant disease.

Other chemotherapy agents

Evidence (other chemotherapy agents):

1. A phase III trial (University Hospital Medical Information Network Clinical Trials Registry ) in Japan included 180 patients with extensive-stage SCLC, who had responded to first-line platinum-doublet chemotherapy but had their disease progress more than 90 days after completion of chemotherapy. Patients were randomly assigned 1:1 to receive intravenous topotecan for four cycles, which is the standard of care, or five 2-week cycles of cisplatin, etoposide, and irinotecan.
   • The primary end point of OS was significantly prolonged with the combination of cisplatin, etoposide, and irinotecan (18.2 months; 95% CI, 15.7–20.6) compared with topotecan alone (12.5 months; 95% CI, 10.8–14.9; hazard ratio, 0.67; 90% CI, 0.51–0.88; P = .0079).
   • Rates of grade 3 to 4 toxicities were higher in patients treated with the combination regimen. Toxicities included febrile neutropenia (31% for the combination arm vs. 7% for topotecan alone) and thrombocytopenia (41% for the combination arm vs. 28% for topotecan alone).

Immune checkpoint modulation

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.

Palliative therapy

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. Most patients treated with radiation therapy obtain objective responses and improvement after radiation therapy.

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. 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.

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.