Extensive-stage small cell lung cancer: Initial management

INTRODUCTION — Small cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 15 percent of all lung cancers. SCLC occurs predominantly in smokers. (See "Cigarette smoking and other possible risk factors for lung cancer".)

SCLC is distinguished clinically from most types of non-small cell lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and the early development of metastases. Large cell neuroendocrine carcinoma, a rare form of lung cancer, and extrapulmonary small cell carcinomas are generally treated with the same chemotherapy regimens used for SCLC. (See "Extrapulmonary small cell cancer" and "Pathology of lung malignancies", section on 'Large cell neuroendocrine carcinoma'.)

SCLC usually presents with disseminated disease, and treatment strategies have focused on systemic therapy. Although SCLC is highly responsive to both chemotherapy and radiotherapy (RT), it commonly relapses within months despite treatment.

The initial management of patients with extensive-stage (ES)-SCLC will be reviewed here. Related topics include:

●(See "Pathobiology and staging of small cell carcinoma of the lung".)

●(See "Limited-stage small cell lung cancer: Initial management".)

●(See "Prophylactic cranial irradiation for patients with small cell lung cancer".)

●(See "Treatment of refractory and relapsed small cell lung cancer".)

●(See "Large cell neuroendocrine carcinoma of the lung".)

STAGING — Patients with SCLC are typically divided into those with limited-stage (LS) versus extensive-stage (ES) disease, although the International Association for the Study of Lung Cancer (IASCLC) has recommended that patients should be staged using the Tumor, Node, Metastasis (TNM) classification. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'.)

LS-SCLC is defined as disease that is limited to the ipsilateral hemithorax and regional lymph nodes and can be encompassed in a safe radiotherapy field. ES-SCLC is disease that has spread beyond this and may include distant metastases, malignant pericardial or pleural effusions, and/or contralateral supraclavicular and contralateral hilar lymph node involvement.

OVERVIEW OF TREATMENT OF EXTENSIVE-STAGE DISEASE — Patients with SCLC rarely survive more than a couple of months without treatment. However, SCLC is highly responsive to multiple chemotherapeutic drugs, and chemotherapy is the mainstay of initial treatment, prolonging survival compared with best supportive care [1]. These benefits may be seen even in patients with advanced disease, poor performance status, and severe organ dysfunction [2]. The addition of immunotherapy to a chemotherapy backbone adds further benefit (algorithm 1).

For those with residual disease in the thorax following systemic chemotherapy, thoracic radiation therapy improves survival. Additionally, prophylactic cranial irradiation (PCI) decreases the incidence of symptomatic brain metastases in patients who have responded to systemic chemotherapy, although its impact on overall survival is uncertain. In this modern imaging era, surveillance magnetic resonance imaging (MRI) scans may be considered as an alternative to PCI. (see "Prophylactic cranial irradiation for patients with small cell lung cancer", section on 'Extensive-stage SCLC' and 'Prophylactic cranial irradiation' below).

INITIAL TREATMENT

Preferred option: Immunotherapy plus platinum-etoposide

Rationale for platinum-etoposide as choice of chemotherapy — Randomized trials have shown a survival benefit for combination regimens compared with single agent chemotherapy, and for simultaneous administration of multiple agents as compared with sequential administration of the same agents [3]. The use of maintenance chemotherapy, three- or four-drug combinations, and alternating or sequential non-cross-resistant regimens have not been shown to offer substantial benefits compared with a two-drug combination; thus, these approaches should not be utilized.

No specific combination has established superiority in the treatment of SCLC. However, platinum-based combinations are the standard of care for the initial systemic therapy in patients with SCLC, based upon their clinical activity and toxicity profile. In multiple randomized trials, the cisplatin-etoposide (PE) regimen appears to be at least as effective as older regimens such as cyclophosphamide, doxorubicin, and vincristine (CAV) or cyclophosphamide, epirubicin, and vincristine (CEV), and has less toxicity [4-6].

Although PE is associated with comparable response rates to carboplatin-etoposide (CE), most clinicians in the United States use CE to treat patients with ES-SCLC based upon its better toxicity profile (table 1). CE poses less risk for nephrotoxicity, neuropathy, and ototoxicity than PE, and is associated with lesser risk of emesis. PE, however, has less hematologic toxicity, risk of mucosal toxicity, and interstitial pneumonitis.

Cisplatin-based regimens have been compared with carboplatin-based combinations in four randomized trials [7-10]. A meta-analysis that included individual patient data from these four trials found no statistically significant difference between cisplatin and carboplatin-based combinations in terms of overall survival (OS), progression-free survival (PFS), or objective response rate (median OS 9.6 versus 9.4 months, 5.5 versus 5.3 months, and 67 versus 66 percent, respectively) [11].

Other efforts to improve on the results with PE have substituted etoposide with a camptothecin analogue (irinotecan or topotecan) or epirubicin. These results are discussed below. (See 'Less preferred options' below.)

Rationale for addition of immune checkpoint inhibitors to chemotherapy — Atezolizumab and durvalumab are humanized monoclonal anti-programmed death-ligand 1 (PD-L1) antibodies that have improved survival, when combined with a platinum agent and etoposide during induction and continued as maintenance [12,13]. The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab has been shown to improve PFS with a favorable but nonsignificant survival advantage [14]. The addition of an anti-CTLA4 inhibitor to durvalumab and PE also showed a trend towards improved survival compared with PE alone, but this was not statistically significant. These randomized trial data are summarized in the sections below.

Cross-trial comparisons suggest similar efficacy and toxicities between durvalumab and atezolizumab when paired with chemotherapy, and a choice between them should depend on provider preference and insurance coverage. If atezolizumab is chosen, we use CE as the accompanying chemotherapy regimen, as atezolizumab has not been evaluated in combination with PE. Durvalumab may be paired with either PE or CE [15].

Despite the improvements observed with the addition of immunotherapy to chemotherapy in induction, maintenance immunotherapy has not demonstrated benefits among those induced with chemotherapy alone. In CHECKMATE 451, which evaluated maintenance therapy in patients with stable disease or response after initial chemotherapy, neither of the two immunotherapy arms (nivolumab alone or nivolumab in combination with ipilimumab) improved survival relative to placebo [16].

The available data collectively support chemoimmunotherapy as induction (followed by immunotherapy maintenance), rather than chemotherapy alone as induction followed by maintenance immunotherapy.

Atezolizumab plus carboplatin and etoposide — Atezolizumab in combination with carboplatin and etoposide (table 2) was the first therapeutic advance in the treatment of SCLC since approximately the 1990s.

In a randomized trial of 403 patients with treatment-naïve ES-SCLC, patients were assigned to receive carboplatin and etoposide with either atezolizumab or placebo for four cycles, followed by maintenance with either atezolizumab or placebo (according to the previous assignment) (table 2) [12,17]. At a median follow-up of 23 months, the median OS for the atezolizumab versus placebo group was 12.3 and 10.3 months (hazard ratio [HR] 0.76, 95% CI 0.60-0.95). Median PFS was also improved among those receiving atezolizumab (5.2 versus 4.3 months; HR for disease progression or death 0.77, 95% CI 0.62-0.96). Rates of toxicity of any grade were similar between the two groups, as were grade ≥3 toxicities, which occurred in 58 percent of patients in each group. Neither PD-L1 immunohistochemistry nor blood-based (circulating tumor DNA) tumor mutational burden was shown to be a predictive biomarker.

Durvalumab plus platinum-etoposide — The addition of the anti-PD-L1 antibody durvalumab to platinum-etoposide has also shown improved survival outcomes relative to chemotherapy alone as front-line treatment for ES-SCLC.

In updated results from the phase III CASPIAN trial that included 537 treatment-naïve patients with ES-SCLC, those randomly assigned to durvalumab plus four cycles of platinum-etoposide followed by maintenance durvalumab had improved OS relative to those assigned to four to six cycles of platinum-etoposide (12.9 versus 10.5 months; HR 0.75, 95% CI 0.62-0.9) [13,18]. Updated PFS demonstrated an HR of 0.80 (95% CI 0.66-0.96), but this was not formally tested for significance. Landmark PFS rates at 24 months were 11 percent for durvalumab plus PE versus 2.9 percent for PE. The objective response rate (ORR) was 68 and 58 percent, respectively. Responses were durable with durvalumab (13.5 versus 3.9 percent in the control arm, at two years). Approximately three-quarters of the patients in this trial received carboplatin, while the remaining received cisplatin. Any-cause grade 3 or 4 adverse events occurred in 62 percent of each group. Adverse events leading to death occurred in 13 (5 percent) and 15 (6 percent) patients.

Other combinations

●Pembrolizumab and platinum-etoposide – The addition of the anti-PD-1 antibody pembrolizumab has demonstrated improved PFS, but not OS, outcomes, when added to platinum and etoposide.

In a randomized, placebo-controlled trial of 453 treatment-naïve patients with ES-SCLC, the addition of pembrolizumab to four cycles of platinum-etoposide, with continuation of pembrolizumab for up to 35 cycles, improved PFS (12-month PFS rates of 13.6 versus 3.1 percent, with and without pembrolizumab; HR 0.75, 95% CI 0.61-0.91) [14]. Although pembrolizumab plus chemotherapy numerically improved OS, the statistical significance threshold was not met (24-month OS rates of 23 versus 11 percent, respectively; HR 0.80, 95% CI 0.64-0.98). In the pembrolizumab plus chemotherapy versus placebo plus chemotherapy arms, any-cause grade 3 to 4 adverse events occurred in 75 and 77 percent, and grade 5 events occurred in 6.3 and 5.4 percent, respectively.

●Durvalumab, tremelimumab, and platinum-etoposide – The CASPIAN trial discussed above also evaluated the addition of tremelimumab (an anti-CTLA4 inhibitor) and durvalumab to PE versus PE alone. Although not directly compared, the addition of tremelimumab to durvalumab did not appear to increase antitumor activity and may have increased toxicity.

This part of the study enrolled 268 patients. Patients received the immune combination every three weeks for four cycles with chemotherapy, followed by durvalumab every four weeks until progression. Improvements in OS with the addition of the immunotherapy combination were not statistically significant, although the threshold for significance was narrowly missed (HR 0.82, 95% CI 0.68-1.00) [18]. Similarly, there was a trend for favorable PFS that did not reach statistical significance (HR 0.84, 95% CI 0.70-1.01). The ORR rates were identical at 58 percent, but the duration of response was more durable (17 percent for durvalumab/tremelimumab/PE versus 3.9 percent for PE at two years). Adverse events leading to treatment discontinuation and death were higher in the quadruplet arm (21 and 4.5 percent compared with 9.4 and 0.8 percent in the doublet arm).

Other investigational agents are showing promise, for example the novel anti-PD-1 antibodies serplulimab and adebrelimab, each of which has shown benefits when combined with chemotherapy [19,20]. In a randomized trial including 585 patients with treatment naïve, extensive-stage SCLC, the addition of serplulimab to chemotherapy improved overall survival relative to chemotherapy alone (15.4 versus 10.9 months, HR 0.63, 95% CI 0.49-0.82), with modestly higher incidence of grade ≥3 adverse events (33 versus 28 percent) [20]. Similarly, adding adebrelimab to chemotherapy improved overall survival in a randomized trial in patients with extensive-stage SCLC (15.3 versus 12.8 months, HR 0.72, 95% CI 0.58-0.90), with an acceptable safety profile [19]. Further data or regulatory approval are required.

Less preferred options — For patients who are not eligible for immunotherapy, chemotherapy alone is appropriate, and platinum-etoposide may be offered. Contraindications for treatment with immunotherapy may include active autoimmune disease, such as a neurologic paraneoplastic syndrome, or concurrent use of immunosuppressives.

However, in addition to platinum compounds (cisplatin, carboplatin) and podophyllotoxins (etoposide), the camptothecins (irinotecan, topotecan) also have significant activity against SCLC either in the first- or second-line setting. Either cisplatin/irinotecan or carboplatin/irinotecan may be used for those who are not candidates for immunotherapy plus platinum-etoposide. (See 'Preferred option: Immunotherapy plus platinum-etoposide' above.)

Further discussion on platinum-irinotecan combinations is provided in the sections below. (See 'Cisplatin plus irinotecan' below and 'Carboplatin plus irinotecan' below.)

Cisplatin plus irinotecan — Multiple clinical trials have evaluated whether the substitution of a camptothecin analogue for etoposide in combination with a platinum compound can improve survival in patients with ES-SCLC [21-25]. However, the bulk of evidence suggests that this strategy does not improve upon the results with a platinum plus etoposide regimen.

In the Japanese Cooperative Oncology Group trial (JCOG 9511), 154 patients were randomly assigned to cisplatin (80 mg/m² on day 1) plus etoposide (100 mg/m² intravenous [IV] on days 1 to 3) every three weeks or cisplatin (60 mg/m² on day 1) plus irinotecan (60 mg/m² on days 1, 8, and 15) every four weeks [21]. Enrollment was stopped prematurely based upon the results of an interim analysis. Patients treated with irinotecan plus cisplatin had a significantly higher response rate compared with the etoposide-based regimen (84 versus 68 percent), longer median survival (12.8 versus 9.4 months), and a higher two-year survival rate (19.5 versus 5.2 percent). Although hematologic toxicity was less pronounced (grade 3 or 4 neutropenia in 65 versus 92 percent), irinotecan caused more grade 3 or 4 diarrhea (17 versus 0 percent).

However, three larger trials conducted outside Japan have failed to confirm this observation [22,23,25]. In the largest of these (the Southwest Oncology Group trial S0124), 671 patients with ES-SCLC were randomly assigned to the identical regimens used in JCOG 9511 [23]. There were no statistically significant differences in the median PFS, median OS, or objective response rates (5.8 versus 5.2 months, 9.9 versus 9.1 months, and 60 versus 57 percent, for the irinotecan plus cisplatin and etoposide plus cisplatin regimens, respectively). The patterns of toxicity were similar to that in JCOG 9511.

Similarly, a phase III trial comparing these two regimens in patients with LS disease failed to demonstrate any improvement with the irinotecan-based regimen [26]. (See "Limited-stage small cell lung cancer: Initial management", section on 'Alternatives'.)

The differences between JCOG 9511 and the three other trials may reflect pharmacogenomic differences between the Japanese and American/Western patient populations. Alternatively, the early termination of the JCOG 9511 may have contributed to a false positive result.

Carboplatin plus irinotecan — Two randomized European phase III trials have compared the combination of carboplatin plus irinotecan with carboplatin plus etoposide for patients with extended-stage SCLC:

●One trial found a slight prolongation in OS with the irinotecan combination compared with the etoposide regimen (median survival 8.5 versus 7.1 months) [24]. However, that trial used a relatively low dose of carboplatin (area under the curve [AUC] 4) and oral rather than intravenous etoposide, which may have contributed to the relatively short survival on both treatment arms.

●By contrast, the other trial used a higher dose of carboplatin (AUC 5) and intravenous etoposide [27]. The difference in survival was not statistically significant (10 versus 9 months for the irinotecan and etoposide-based regimens).

Duration of treatment — The optimal duration of induction chemotherapy for patients with SCLC is not well defined; our general approach is to give four to six cycles. When atezolizumab or durvalumab are administered, they are continued until progression of disease or unacceptable toxicity.

Adjunctive treatments — For patients receiving chemotherapy for ES-SCLC, trilaciclib, an intravenous inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6), has been found to decrease myelosuppression, and it is approved by the US Food and Drug Administration for this indication [28]. However, it is not our typical practice to use this agent, given that it has not been found to decrease rates of febrile neutropenia or hospitalizations, or to improve PFS or OS. Trilaciclib is associated with fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increase, headache, and pneumonia.

ASSESSMENT OF RESPONSE AND NEXT STEPS — Following initial therapy (or earlier, if clinically indicated), we assess response with computed tomography (CT) of the chest, abdomen, and pelvis, with intravenous (IV) contrast (algorithm 1). We also obtain a brain magnetic resonance imaging (MRI) to determine the role for prophylactic cranial radiation. Subsequent treatment depends on clinical response.

Subsequent treatment for those with primary progressive disease — Patients with primary progressive disease may be appropriate candidates for salvage treatments. This approach is described in detail elsewhere. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Patients with relapse within 6 months of treatment'.)

Subsequent treatment for those with stable disease or response

Radiation therapy options for those with disease response — Both thoracic radiation therapy (RT) and prophylactic cranial irradiation (PCI) may have roles in patients with ES-SCLC and a good response to initial systemic chemotherapy. There are no clinical trials defining the optimal sequencing of these approaches.

Thoracic radiation for those with residual disease in the chest — The presence or absence of thoracic disease is a factor that should be considered in deciding whether or not to give thoracic RT. There is no evidence that thoracic RT improves survival in those without residual thoracic disease by CT. However, we suggest thoracic radiation for those with response to initial systemic therapy who have residual disease limited to the chest. The rationale for our recommendation is improved overall survival (OS) observed with thoracic RT after induction chemotherapy in this subset; however, we recognize that the trials evaluating front-line chemoimmunotherapy induction did not permit thoracic radiation.

The following two randomized trials are illustrative:

●In a European multicenter trial, patients with ES-SCLC were initially treated with four to six cycles of platinum-based chemotherapy [29]. Following this, 498 patients with at least some response to chemotherapy (complete, partial, or less than partial in 5, 70, and 24 percent, respectively) were randomly assigned to thoracic RT (30 Gy in 10 fractions) plus PCI or PCI without thoracic RT. For those randomized to both PCI and thoracic RT, the two approaches were combined in 88 percent of cases. The primary endpoint of the trial was OS.

For the entire cohort, improvements in OS were not statistically significant in those given thoracic RT compared with chemotherapy alone (33 versus 28 percent; hazard ratio [HR] 0.84, 95% CI 0.69-1.01). However, in a secondary analysis, the survival curves diverged after longer follow-up, and subsequent survival was better for those receiving thoracic RT (two-year OS rate 13 versus 3 percent). Progression-free survival (PFS) was better for patients receiving thoracic RT (24 versus 7 percent at six months; HR 0.73, 95% CI 0.61-0.87).

In a subsequent brief communication, the benefits were limited to the 434 patients (87 percent) who had residual intrathoracic disease based upon CT following chemotherapy, and not in those with a complete response [30]. The survival benefit with thoracic RT was statistically significant (HR 0.81, 95% CI 0.66-1.00); the one-year survival was 33 percent versus 26 percent in those not receiving RT, and the two-year survival was 12 versus 3 percent. PFS was also longer (HR 0.70, 95% CI 0.57-0.85).

●Another trial treated 206 patients with ES-SCLC with three cycles of cisplatin-etoposide (PE) [31]. The 109 patients with a complete response at distant sites and at least a partial response in the chest were randomly assigned to thoracic RT (54 Gy in 36 fractions over 18 days) plus daily low-dose chemotherapy or to four additional cycles of PE without RT. Thoracic RT significantly increased OS compared with chemotherapy (median 17 versus 11 months, five-year survival rate 9 versus 4 percent).

Prophylactic cranial irradiation — PCI following chemotherapy has been demonstrated to decrease the incidence of symptomatic brain metastases, although the impact on OS is uncertain in the era of modern imaging. A Japanese phase III trial in ES-SCLC patients comparing PCI plus MRI surveillance versus MRI surveillance failed to demonstrate a difference in PFS or OS between the two strategies [32]. Hence, MRI surveillance may be considered as an alternative to PCI in ES disease, but no data have been generated for patients with limited-stage (LS) disease, and, moreover, it is unknown how these results would translate to a non-Asian patient population. SWOG is conducting a phase III study of PCI versus MRI in both LS- and ES-SCLC patients (S1827, the MAVERICK trial) to confirm the Japanese data in ES disease and provide data in LS disease. A key secondary endpoint is cognitive preservation.

The role of PCI following initial treatment for ES-SCLC is discussed separately. (See "Prophylactic cranial irradiation for patients with small cell lung cancer", section on 'Extensive-stage SCLC'.)

Disease surveillance — For those with stable disease or response after initial treatment, we typically follow up initially every three months during years 1 and 2, and every six months during year 3. At each visit, we obtain history and physical exam, and computed tomography (CT) scans of the chest abdomen and pelvis. We also assess brain MRI every three to four months during year 1, and every six months during year 2 [32]. The approach to treatment for patient who experience progression is discussed elsewhere.

INVESTIGATIONAL APPROACHES — Although the anti-programmed death-ligand 1 (PD-L1) antibodies atezolizumab and durvalumab have improved outcomes when added to chemotherapy, other novel immunotherapy agents, drug antibody conjugates, cytotoxic agents, and targeted agents such as poly(ADP-ribose) polymerase (PARP) inhibitors are being integrated into the first-line chemoimmunotherapy regimen.

PROGNOSIS — From the time of original diagnosis, the median survival for patients with ES-SCLC is about 8 to 13 months. In most series, less than 5 percent of those with ES-SCLC survive beyond two years. However, with new treatment paradigms, including incorporation of immunotherapy into front-line and subsequent line treatment, prognosis for this condition may improve with more research.

SPECIAL CONSIDERATIONS

Tumor lysis syndrome in those with bulky disease — Although tumor lysis syndrome is rare in SCLC, patients with bulky or advanced-stage disease, or those with pretreatment renal insufficiency, elevated serum lactate dehydrogenase, and hyperuricemia, may be classified as being at intermediate risk, and prophylaxis against the complications of tumor lysis syndrome may be considered [33,34]. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Patients with superior vena cava syndrome — For most patients with SCLC and symptoms of superior vena cava (SVC) obstruction, initial chemotherapy plus immunotherapy is the treatment of choice, rather than radiation therapy (RT). The clinical response to chemotherapy alone is usually rapid. However, endovascular therapy or RT may be required for patients with potentially life-threatening SVC obstruction or in those who do not respond to systemic therapy. (See "Malignancy-related superior vena cava syndrome".)

Older adult patients or those with poor performance status — Approximately one-half of patients with SCLC are 70 years of age or older. Older adult patients are eligible for clinical trials, but very few trials report the percentage of older adult patients enrolled or their outcomes. In general, good performance older adult patients should receive the same doses as younger patients. Dose attenuation and carboplatin-based regimens are preferred if there are competing risks. There are no data that define the role of treatment in poor performance status patients (PS3 or PS4) (table 3). Our approach is to offer standard first-line treatment to all such patients if their poor performance status is due to SCLC rather than comorbidity because of the potential for a clinically significant response.

There has been one phase III trial that randomly assigned patients 70 years or older or younger patients with a performance status of 3 to etoposide (80 mg/m² days 1 to 3) plus split-dose cisplatin (25 mg/m² days 1 to 3) or the standard regimen of etoposide (80 mg/m² days 1 to 3) and carboplatin (area under the curve [AUC] 5 on day 1) [9]. Ninety-two percent of the 220 enrolled patients were 70 years of age or older. Response rates and overall survival (OS) were similar with the cisplatin and carboplatin regimens (response rate, 73 with both regimens; median survival, 9.8 versus 10.6 months; and one-year survival rates 35 versus 41 percent, respectively). Toxicity was similar except for increased incidence of asymptomatic grade 3 to 4 thrombocytopenia with carboplatin compared with cisplatin (56 versus 16 percent).

A small phase II trial of irinotecan (50 mg/m² day 1 and 8) plus carboplatin AUC 5 conducted in 30 older adult patients (8 with limited stage and 22 with extensive stage) revealed acceptable survival outcomes of 24 and 11 months, respectively. Toxicities were manageable and there were no toxic deaths. Half of the patients were 75 years old or greater and 27 percent were 80 years old or greater [35]. Based on these data, there is an ongoing randomized phase II/III trial versus the standard carboplatin plus etoposide regimen described above.

Similarly, observational data have also suggested benefit with chemotherapy in older adults. In a retrospective study of 146 patients ≥80 years with SCLC (one-third with limited stage and two thirds with extensive stage), 30 percent received no therapy, 10 percent received local therapy only, 45 percent received chemotherapy alone, and 19 percent received chemotherapy plus local therapy [36]. For those receiving no therapy, the median OS was 1.3 months; 6 months for local therapy alone; 7.2 months for chemotherapy alone; and 14.4 months with chemotherapy and local therapy. Similar findings were observed when the limited- and extensive-stage cohorts were separately analyzed.

Special considerations for the use of chemotherapy in the older adult population are discussed elsewhere. (See "Systemic chemotherapy for cancer in older adults" and "Comprehensive geriatric assessment for patients with cancer".)

Patients who present with brain metastases — Patients who present with ES-SCLC with brain metastases may be treated with initial systemic therapy if their intracranial disease is asymptomatic and with whole-brain RT (WBRT) upon completion of induction therapy. However, those with symptomatic brain metastases are usually managed initially with WBRT, followed by induction systemic therapy. Although stereotactic radiation surgery (SRS) is often chosen for tumors of other histologies with a small and limited number of brain metastases, WBRT is typically preferred for those with SCLC and any degree of intracranial disease, due to the propensity for SCLC to recur intracranially. (See "Overview of the treatment of brain metastases".)

There is, however, interest in evaluating SRS as an efficacious alternative [37,38]. This is due in part to the recognition that WBRT results in greater cognitive decline without an improvement in survival compared with SRS. This is because SRS is focused on the lesions themselves, sparing the normal brain tissue between the lesions. For example, in a cohort study of 710 patients with SCLC brain metastases who received first-line SRS, the median OS was 8.5 months, and the median time to central nervous system progression was 8.1 months [39]. After controlling for multiple prognostic factors, WBRT versus SRS was associated with superior time to central nervous system progression (hazard ratio [HR] 0.38, 95% CI 0.26-0.55), but offered no OS advantage (median OS for WBRT of 5.2 months versus 6.5 months for SRS; 95% CI 5.5-8.0). Another group analyzed the National Cancer Database for patients with SCLC and brain metastases at diagnosis and stratified by upfront SRS compared with upfront WBRT, with or without SRS. This study included 5952 patients (200 of whom received SRS, and the rest receiving WBRT) with a median follow-up of 40 months. Patients who got SRS were a highly selected subset in this retrospective analysis. Upfront SRS was associated with superior survival (median 10.8 versus 7.1 months), which persisted on multivariate analysis controlling for comorbidities, extracranial metastases, age, race/ethnicity, and gender (HR 0.70, 95% CI 0.60-0.81) [38].

The reported response rates of brain metastases to systemic chemotherapy in previously untreated patients have varied between 27 and 85 percent, with some studies suggesting that brain metastases are as sensitive to systemic chemotherapy as extracranial disease [40-42]. The likelihood of intracranial response may be higher for certain regimens, particularly those containing a platinum. In one small study of patients who received first-line cyclophosphamide, doxorubicin, and etoposide, the objective intracranial response rate was only 27 percent, compared with a 73 percent systemic response rate [43].

Patients with treatment-refractory disease who develop brain metastases is discussed elsewhere. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Patients with brain metastases'.)

Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Small cell lung cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Small cell lung cancer treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction – Small cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 15 percent of all lung cancers. SCLC occurs predominantly in smokers. SCLC is distinguished clinically from most types of non-small cell lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and the early development of metastases. (See 'Introduction' above.)

●Initial treatment

•Approach to treatment is summarized in the algorithm (algorithm 1).

•For patients with extensive-stage (ES)-SCLC, we recommend addition of an immune checkpoint inhibitor to platinum-etoposide rather than chemotherapy alone (Grade 1B).

•In choosing between immunotherapy options, we suggest atezolizumab or durvalumab rather than pembrolizumab (table 2) (Grade 2C), although the agents have never been compared directly, and pembrolizumab is a reasonable alternative. (See 'Preferred option: Immunotherapy plus platinum-etoposide' above.)

•In regards to choice of chemotherapy, we suggest carboplatin-etoposide (CE) over cisplatin-etoposide (PE) (Grade 2C), based on its better toxicity profile and comparable outcomes, although PE is an acceptable alternative (table 4 and table 1). (See 'Rationale for platinum-etoposide as choice of chemotherapy' above.)

•The use of maintenance chemotherapy, three- or four-drug combinations, and alternating or sequential non-cross-resistant regimens have not been shown to offer substantial benefits compared with a two-drug combination; thus, these approaches should not be utilized.

•For patients who are not candidates for immunotherapy, platinum-etoposide chemotherapy alone is appropriate. Additional alternatives include regimens substituting irinotecan instead of etoposide, in combination with a platinum agent. (See 'Less preferred options' above.)

•Initial chemotherapy is usually limited to four to six cycles, with the immune checkpoint inhibitor continuing until progression of disease or unacceptable toxicity. (See 'Duration of treatment' above.)

●Special considerations

•Patients with brain metastases – Patients who present with ES-SCLC with brain metastases may be treated with initial systemic therapy if their intracranial disease is asymptomatic, followed by radiation therapy (RT) upon completion of induction therapy. However, those with symptomatic brain metastases are usually managed initially with radiation, followed by induction systemic therapy. In regards to type of radiation, we suggest whole-brain RT (WBRT) (Grade 2C). Stereotactic radiation surgery is a reasonable alternative to WBRT, although we recognize that randomized trial data are lacking. (See 'Patients who present with brain metastases' above.)

•Older patients – Only limited data are available from randomized trials to guide treatment in older adult patients. We suggest that older adult patients be treated with the same doses and regimens as younger patients, if their overall medical condition is satisfactory (Grade 2B). Otherwise, modified doses are reasonable. A comprehensive geriatric assessment prior to initiating treatment may be useful in assessing whether or not an individual patient is a candidate for chemotherapy. (See 'Older adult patients or those with poor performance status' above and "Comprehensive geriatric assessment for patients with cancer".)

●Assessment of response and next steps – Following initial therapy (or earlier, if clinically indicated), we assess response with computed tomography (CT) of the chest, abdomen, and pelvis, with intravenous (IV) contrast. We also obtain a brain magnetic resonance imaging (MRI). Subsequent treatment depends on clinical response. (See 'Assessment of response and next steps' above.)

•For patients with ES-SCLC who have had a favorable response to chemotherapy but in whom there is evidence of residual disease within the chest identified on CT, we suggest thoracic RT (Grade 2C). However, we acknowledge the limitations in available data, given that trials evaluating chemoimmunotherapy induction did not permit thoracic RT. (See 'Thoracic radiation for those with residual disease in the chest' above.)

•For patients with ES-SCLC with favorable tumor response or better at the completion of chemotherapy and a good performance status, we suggest prophylactic cranial irradiation (Grade 2C), but recognize that surveillance with MRI is also acceptable and may be preferred by some patients. PCI following chemotherapy decreases the incidence of symptomatic brain metastases, although the impact on overall survival is uncertain in the era of modern imaging. (See "Prophylactic cranial irradiation for patients with small cell lung cancer", section on 'Extensive-stage SCLC'.)

●Disease surveillance – For those with stable disease or response after initial treatment, we typically follow up initially every two months with history and physical exam, and CT scans of the chest abdomen and pelvis, with brain MRI every two to four months. (See 'Disease surveillance' above.)

●Prognosis – From the time of original diagnosis, the median survival for patients with ES-SCLC is about 8 to 13 months. In most series, less than 5 percent of those with ES-SCLC survive beyond two years. (See 'Prognosis' above.)