Limited-stage small cell lung cancer: Initial management

INTRODUCTION — Small cell lung cancer (SCLC) is a poorly differentiated neuroendocrine tumor that represents approximately 15 percent of all lung cancers. Nearly all patients with SCLC are current or former smokers. (See "Cigarette smoking and other possible risk factors for lung cancer".)

SCLC is distinguished from non-small cell lung cancer (NSCLC) by its pathologic features. Clinically, it is distinguished by its rapid doubling time and high growth fraction, and the early development of metastases. SCLC usually presents with disseminated disease, and treatment strategies have been largely focused on systemic therapy. For patients with limited-stage (LS) disease, treatment usually also includes radiation therapy (RT) directed toward thoracic disease, as well as prophylactic treatment of the brain. In the uncommon circumstance that SCLC presents as a single pulmonary nodule, surgery may be a component of multimodality treatment.

For patients with extensive-stage disease, the mainstay of treatment is chemotherapy plus immunotherapy. RT to the chest and brain may be offered in select circumstances. (See "Extensive-stage small cell lung cancer: Initial management".)

The initial management of patients with LS-SCLC is reviewed here. Related topics include:

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

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

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

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

DEFINITION OF LIMITED-STAGE DISEASE — 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. Most patients with LS-SCLC will have clinical or pathologic evidence of mediastinal lymph node involvement.

STAGING

Staging system — Patients with SCLC are typically divided into those with limited-stage (LS) versus extensive-stage (ES) disease. However, both the American Joint Committee on Cancer and the International Association for the Study of Lung Cancer recommend Tumor, Node, Metastasis staging for SCLC as well as non-small cell lung cancer (NSCLC; (table 1)). (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'.)

Components of staging — Thorough staging is indicated for all patients. Necessary components of staging include:

●Computed tomography (CT) of chest, abdomen, and pelvis with intravenous contrast.

●Positron emission tomography-computed tomography (PET-CT).

●Magnetic resonance imaging (MRI) of the brain (CT brain with contrast if MRI is contraindicated).

●Bone scan (only if PET-CT is not available).

●For patients with clinical stage I (T1 to 2, N0) disease, invasive staging of mediastinal lymph nodes is also indicated to identify the small fraction of patients who do not have lymph node involvement or other metastatic disease.

●Patients who have pleural effusions but otherwise LS disease should undergo thoracentesis with cytologic analysis to confirm LS disease.

OVERVIEW OF TREATMENT AND BENEFITS — The general approach for managing patients with SCLC is summarized in the algorithm (algorithm 1). The current standard of care for patients with LS-SCLC that involves the lymph nodes consists of four cycles of combination chemotherapy (typically cisplatin plus etoposide [EP]) along with concurrent thoracic radiotherapy during the early part of the chemotherapy treatment (starting with the first or second cycle of chemotherapy). Prophylactic cranial irradiation (PCI) is generally recommended for patients with a complete response or significant tumor regression at the completion of chemotherapy.

Although carboplatin can be substituted for cisplatin in combination with etoposide with statistically similar outcomes, EP is preferred in patients with LS-SCLC due to the paucity of directly comparative data in this setting. However, carboplatin can be substituted if cisplatin is contraindicated for reasons such as pre-existing neuropathy, hearing loss, renal insufficiency, or congestive heart failure.

Patients with SCLC rarely survive more than a few months without treatment, even when disease appears to be localized. However, SCLC is highly responsive to both chemotherapy and radiation therapy. The results with treatment vary significantly depending upon the extent of disease.

For patients with LS-SCLC treated with contemporary chemoradiotherapy and PCI, overall response rates of 80 to 90 percent, including 50 to 60 percent complete response rates, are typically reported. Median survival is approximately 17 months, and the five-year survival rate is approximately 20 percent [1,2]. The impact of treatment on patients with extensive-stage SCLC is discussed separately. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Overview of treatment of extensive-stage disease'.)

STAGE I DISEASE (T1 TO T2, N0) — For patients with stage I (T1 to 2, N0) LS-SCLC who have no evidence of distant metastases, histologic confirmation that the hilar and mediastinal lymph nodes are not involved, and no contraindications to surgery, we suggest resection of the primary tumor with lobectomy, plus mediastinal lymph node sampling or dissection. If performed, this should then be followed by adjuvant chemotherapy with four cycles of cisplatin-based therapy, extrapolating from benefits observed largely in patients with node-positive disease (although not typically administered with radiation). (See 'Chemotherapy' below.)

Components of treatment

Surgery — We suggest surgical resection for patients who present with a solitary pulmonary nodule that has been diagnosed as SCLC and who have no evidence of hilar or mediastinal nodal involvement, no distant metastases, and no contraindications to surgery. There are no clinical trials that directly compare a combined-modality approach including surgery with chemoradiotherapy alone. Retrospective data cannot exclude the possibility of selection bias. Specifically, the observed survival outcomes in resected SCLC may be due to reduced tumor burden among patients in whom resection is possible, or that these patients have biologically less aggressive disease.

Data suggesting a benefit from surgery in patients with LS-SCLC come from the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Study Project [3]. The IASLC database of over 8000 cases of SCLC included 349 cases (4 percent) in which the cancer was resected and staged pathologically. The five-year survival rates for patients with pathologic stage I, II, and III SCLC were 48, 39, and 15 percent, respectively. By contrast, evidence from multiple clinical trials indicates that a nonsurgical (chemoradiotherapy) approach in patients with LS-SCLC results in a five-year survival rate of 26 to 34 percent in primarily stage III SCLC.

Similar results were observed in a subsequent propensity- and stage-matched analysis of survival of patients with early-stage and locally advanced SCLC in the National Cancer Database. From a dataset of 29,994 clinical stages I to III SCLC, 2089 patients who had surgery were matched to nonsurgically treated patients. This analysis suggested nearly a doubling of median overall survival (OS) for N0 patients treated with surgery: 38 versus 22 months. Their analysis also showed that the benefits of surgery were only seen when an R0 resection was achieved, that lobectomy was superior to sublobar resections and to pneumonectomies, and that adjuvant chemotherapy should be considered after these R0 resections [4].

Postoperative chemotherapy — We suggest adjuvant chemotherapy for patients who have undergone a complete resection for SCLC. Regimen selection is the same as for patients who do not undergo surgery. (See 'Chemotherapy' below.)

There are no randomized clinical trials that have compared surgery alone versus surgery followed by adjuvant chemotherapy or chemoradiotherapy. However, observational studies have suggested improved outcomes with adjuvant chemotherapy. In a study of over 1500 patients with pT1-2N0M0 SCLC in the National Cancer Database, patients receiving adjuvant chemotherapy (with or without radiation) experienced an improved five-year survival compared with those undergoing surgery alone (53 versus 40 percent, respectively) [5]. In another series of 119 patients who underwent surgical resection for SCLC, 112 of whom also received adjuvant chemotherapy, the five-year survival rates for those with pathologic stage I, II, or III disease were 51, 28, and 19 percent, respectively [6]. This is in contrast to results from earlier studies that demonstrated a five-year survival rate of 1 percent among patients treated with surgery alone [7].

Adjuvant RT, if nodal involvement identified at surgery — A retrospective review of 3017 patients with LS-SCLC enrolled in the National Cancer Database suggested that postoperative thoracic radiation therapy (RT) was associated with a five-year OS benefit among those with pathologic N2 disease (29 versus 19 percent), but not among those with lesser degrees of nodal involvement [8]. Patients with pathologic N0 disease had decreased five-year OS with RT (39 versus 46 percent, respectively), while there were no differences in survival among patients with pathologic N1 disease.

STAGE II TO III DISEASE

Components of treatment

Chemotherapy

Preferred regimen: Etoposide plus cisplatin — Etoposide plus cisplatin (EP) is the standard regimen for chemotherapy in patients with LS-SCLC along with early, concurrent thoracic radiation therapy (RT) (table 2).

Initial studies of combined-modality therapy in patients with LS-SCLC used chemotherapy regimens such as cyclophosphamide, doxorubicin, and vincristine (CAV), followed sequentially by thoracic RT. Subsequent studies used EP in a similar sequential approach and demonstrated favorable response and survival rates with relatively tolerable toxicity [9].

These regimens were compared in a trial in which patients with either LS- or extensive-stage (ES)-SCLC were randomly assigned to CAV, EP, or CAV alternating with EP [10]. The 146 patients with LS-SCLC received thoracic RT (40 to 50 Gy) after four cycles of chemotherapy. For patients with LS-SCLC, response rates to initial chemotherapy were significantly higher with EP (77 percent) and CAV/EP (88 percent) compared with CAV (51 percent); overall survival (OS) was similar in all three treatment arms (EP 11.7 months, CAV/EP 11.8 months, CAV 12.4 months). Based on these early studies, many oncologists adopted EP as the standard of care since it resulted in less myelotoxicity and was easier to combine with thoracic RT in patients with LS-SCLC due to a lower risk of mucosal and pulmonary toxicity.

EP was compared with another alkylator-based regimen, cyclophosphamide, epirubicin, and vincristine (CEV), in 214 patients with LS-SCLC; thoracic RT (42 Gy) was given between the third and fourth cycles of chemotherapy [11]. OS was significantly better in patients assigned to EP, with a median survival of 14.5 months versus 9.7 months and two-year survival rates of 25 versus 8 percent in the EP and CEV arms, respectively. There was no difference between arms in the number of patients who received definitive thoracic RT, prophylactic cranial irradiation, or second-line chemotherapy for relapse. These results in favor of EP are consistent with the findings of two meta-analyses that demonstrated a modest survival advantage in studies evaluating etoposide-based or cisplatin-based therapy in patients with both LS- and ES-SCLC [12,13].

Overall, these studies confirm EP as the preferred regimen for the treatment of patients with LS-SCLC.

Alternatives

●Substitution of carboplatin for cisplatin – Carboplatin is frequently substituted for cisplatin to reduce the risk of nonhematologic toxicities, such as nausea, vomiting, ototoxicity, neuropathy, and nephropathy. However, due to the potential curability of LS-SCLC and the relatively small number of LS-SCLC patients evaluated thus far, cisplatin remains the standard agent, with carboplatin restricted to patients with contraindications to or poor tolerance of cisplatin.

A meta-analysis that included 663 patients in four trials compared the efficacy of cisplatin-based versus carboplatin-based regimens in SCLC [14]. Only 32 percent of patients in the meta-analysis had LS-SCLC, since only two of the trials enrolled patients with LS disease [15,16]. Overall, response rate, progression-free survival (PFS), and OS were similar with cisplatin-based and carboplatin-based regimens in patients with both LS- and ES-SCLC [14]. As expected, hematologic toxicity was greater with carboplatin, while nonhematologic toxicity was greater with cisplatin. These data suggest that, if necessary, carboplatin can be safely substituted for cisplatin without compromising therapeutic efficacy.

●Irinotecan-containing regimens – Etoposide plus cisplatin (or carboplatin) is the standard regimen for patients with LS- and ES-SCLC, although the combination of irinotecan plus cisplatin has been extensively studied in both settings. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Cisplatin plus irinotecan'.)

The most extensive data on irinotecan in patients with LS-SCLC come from a phase III trial (JCOG0202), in which 281 patients were initially treated with induction etoposide plus cisplatin in conjunction with accelerated hyperfractionated RT [17]. After induction, 256 patients without progression were randomly assigned to consolidation with either irinotecan plus cisplatin or etoposide plus cisplatin. There was no statistically significant difference in OS, the primary endpoint of the trial, between the two treatment arms (median, 2.8 years with irinotecan plus cisplatin versus 3.2 years with EP; hazard ratio [HR] 1.09, 95% CI 0.80-1.46).

Similarly, in a separate trial conducted in Japan in 221 patients with completely resected stage I to IIIA high-grade neuroendocrine carcinoma of the lung, irinotecan and cisplatin resulted in a similar three-year recurrence-free survival rate as EP in the overall trial, as well as in the subset of 117 patients with SCLC or mixed SCLC (67 versus 65 percent; HR 1.03, 95% CI 0.54-1.94) [18]. In the overall group, grade 3 to 4 adverse events were more frequent in the EP arm, with febrile neutropenia (20 versus 4 percent) and neutropenia (97 versus 36 percent) being the most common. By contrast, grade 3 to 4 anorexia (6 versus 11 percent) and diarrhea (1 versus 8 percent) were more frequent in the irinotecan-plus-cisplatin group.

Despite certain higher toxicities of EP in this study, other trials in Western populations have not demonstrated such high rates of febrile neutropenia with this regimen [19,20]. In our experience, the gastrointestinal toxicity associated with irinotecan is more bothersome for patients than the hematologic toxicity observed with etoposide. As such, we typically use EP.

Investigational approaches — Variations on the EP regimen have included the use of other agents such as paclitaxel in addition to EP. A number of novel agents are also being investigated. These approaches are considered investigational.

●Paclitaxel-containing regimens – Paclitaxel-containing regimens have been studied in sequential approaches prior to thoracic RT, given concurrently with RT, and in more complex regimens. The use of approaches incorporating paclitaxel remains experimental.

An initial study that directly compared the three-drug combination paclitaxel plus EP (TEP) with EP alone suggested that the addition of paclitaxel improved outcomes [21]. However, two larger phase II studies that evaluated TEP with concurrent thoracic RT in patients with LS-SCLC concluded that this approach did not demonstrate any improvement in efficacy over standard EP plus early, concurrent RT, but did result in grade 3 to 4 esophagitis in 32 to 36 percent of patients [22,23].

Other trials have examined other paclitaxel-containing regimens, but data are insufficient to recommend them. In a trial of 608 SCLC patients, one-half of whom had LS disease, paclitaxel, etoposide, plus carboplatin (TEC) resulted in similar efficacy but less hematologic toxicity compared with carboplatin, etoposide, and vincristine [24]. However, TEC has not been compared with EP. TEC with concurrent thoracic RT has been evaluated in two phase II trials, which yielded favorable overall and complete response rates, but relatively unexceptional survivals and substantial toxicity [25,26].

●Novel agents – Many novel agents have been evaluated in patients with SCLC. Most of these agents have been tested in patients with ES disease, although several have been incorporated into combined-modality regimens for LS-SCLC. Examples of agents that have been incorporated into trials of patients with LS-SCLC include tirapazamine [27], thalidomide [28], vandetanib [29], bevacizumab [30], matrix metalloproteinase inhibitors [31,32], tamoxifen [33], and the Bec2/BCG vaccine [34]. None of these approaches has a role in LS disease outside of a clinical trial.

Of note, two trials (one in LS-SCLC, one in stage III non-small cell lung cancer [NSCLC]) of bevacizumab in combination with concurrent chemoradiotherapy were stopped early due to the excessive incidence of tracheoesophageal fistulae [30]. Antiangiogenic agents, including bevacizumab, should not be used in combination with chemoradiotherapy in patients with lung cancer.

Many studies evaluating immunotherapy in SCLC are underway. The addition of either atezolizumab or durvalumab, programmed cell death ligand 1 inhibitors, to carboplatin and etoposide has been shown to improve survival for patients with ES-SCLC, but, thus far, such a benefit has not been demonstrated in the setting of LS-SCLC [19,35].

Thoracic RT — The key parameters that influence the effectiveness of radiation therapy (RT) are the dose of radiation, the treatment volume, and the fractionation schedule, as well as its integration with chemotherapy. (See 'Integration of chemotherapy with RT' below.)

Benefit of RT — The addition of thoracic radiation therapy (RT) to chemotherapy results in a small, statistically significant improvement in survival compared with the use of chemotherapy alone, although the combined-modality approach is associated with an increase in toxicity.

Two large meta-analyses have reported benefit to the use of combined chemotherapy and thoracic RT.

●One meta-analysis, which included 11 randomized studies, found that the addition of thoracic RT was associated with an absolute improvement in local control of 23 percent (two-year local control rate, 47 versus 24 percent) [36]. The chemotherapy regimens differed among the studies, as did the thoracic RT doses and delivery schedules.

●Another meta-analysis of 13 randomized trials (including the same 11 studies evaluated in the previously noted meta-analysis) found that the use of combined chemotherapy and thoracic RT resulted in an absolute survival benefit of 5.4 percent at three years [37].

The survival benefit associated with the use of thoracic RT outside of clinical trials was also suggested in a subsequent review from the National Cancer Database [1]. For patients with LS-SCLC, the five-year survival rate for the 6752 patients diagnosed in 2000 was significantly higher in patients treated with thoracic RT plus chemotherapy compared with chemotherapy alone (13.3 versus 5.7 percent).

While the benefit of RT in one of the meta-analyses was greatest for patients younger than 55 years old, with a trend towards detriment in patients age 70 years and older [37], modern RT techniques and supportive care have improved such that the benefits may outweigh toxicities for the older population as well. A retrospective analysis of approximately 8600 patients age 70 years and older treated between 2003 and 2011 found that the addition of RT to chemotherapy was associated with improved OS rates (15.7 percent absolute OS benefit at three years) [38].

Treatment volume — Despite some uncertainty, the use of limited-field thoracic RT is the current standard of care. Specifically, the treatment volume should include all gross disease present at the time of RT planning (postchemotherapy volume), and all nodal regions involved at the time of initial diagnosis (prechemotherapy volume). Positron emission tomography scans should be obtained for staging if RT is planned for patients with suspected LS-SCLC. (See 'Components of staging' above.)

Treatment with these smaller fields is associated with a reduction in the severity of toxicity from combined-modality therapy, and it does not appear to jeopardize local control rates. Such toxicity issues will have increasing importance as both RT and chemotherapy doses are intensified and agents with potential lung toxicity are added to chemotherapy regimens.

Historically, thoracic RT treatment volumes included all gross disease present at the time of initial diagnosis (prechemotherapy volume), as well as prophylactic inclusion of adjacent uninvolved nodal regions. Several reports support the use of more limited thoracic RT fields to include only the postchemotherapy tumor volume and prechemotherapy nodal volume [39-41]. As an example, in a trial by SWOG, including 191 patients with a partial response or stable disease following induction chemotherapy, those assigned to RT fields including either the prechemotherapy versus the postchemotherapy tumor volumes experienced similar patterns of failure and median survival [39]. Although there was no apparent difference in severe drug-related toxicity or radiation pneumonitis between the two groups, those assigned to the larger RT fields experienced more frequent severe complications related to myelosuppression than the reduced-field group (18 versus 7 percent).

Dose fractionation schedule — Either conventional fractionation (total dose of 60 to 70 Gy in fractions of 2 Gy) or accelerated hyperfractionated schedules are appropriate options in LS-SCLC. When administering accelerated hyperfractionation, we suggest 45 Gy in twice-daily fractions over three weeks, but note that 60 Gy in twice-daily fractions may be an acceptable alternative in select patients with good performance status and in whom dose constraints to the normal tissues can be met. Definitions and supporting data are discussed below.

●Accelerated hyperfractionation schedules administer RT over a shorter total treatment time (acceleration) and with a greater number of treatment fractions (hyperfractionation). The preferred accelerated dose fractionation schedule for LS-SCLC is 45 Gy given in 1.5 Gy fractions twice daily over three weeks. Accelerated hyperfractionated RT potentially reduces the opportunity for tumor cell regeneration during treatment by shortening the overall treatment time. However, acute toxicities to normal tissues may be greater compared with conventional schedules (especially esophagitis). Late toxicities should be similar, given that late effects of RT are more dependent on dose per fraction and total dose than overall treatment time.

●Conventional RT fractionation schedules employ single daily treatments of 1.8 to 2 Gy, five times per week, over a continuous course for about six weeks. For once-daily fractionation using 1.8 or 2 Gy fractions, a dose of 60 to 70 Gy is appropriate [42].

Several randomized trials comparing once- and twice-daily thoracic RT have been performed, with mixed results [43-49], suggesting that the survival of patients after higher-dose once-daily thoracic RT (66 to 70 Gy) is not statistically different from the standard-dose (45 Gy) twice-daily regimen.

●In the phase III CONVERT trial, 547 patients with LS-SCLC were randomly assigned to twice-daily concurrent chemoradiotherapy (45 Gy in 30 fractions) versus once-daily concurrent RT (66 Gy in 33 fractions) [43]. At a median follow-up of 45 months, the median survival in the twice-daily versus once-daily group was 30 versus 25 months, respectively, a difference that was not statistically significant (HR 1.18, 95% CI 0.95-1.45). In patients assessed for RT toxicity, there was no difference in grade 3 to 4 esophagitis (19 percent in both groups) or radiation pneumonitis (3 versus 2 percent in the twice- versus once-daily treatment groups). Eleven patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group).

●Similarly, in the phase III CALGB 30610 trial, 638 patients with LS-SCLC were randomly assigned to concurrent chemoradiation with either 45 Gy twice daily or 70 Gy once daily. Results presented in abstract form show both PFS (median, 13.5 versus 14.2 months) and OS (median, 29 versus 31 months; HR 0.94, p = 0.59) were similar between patients in the two study arms [50]. Rates of grade 3 or higher adverse events were also similar between the arms.

●Twice-daily RT was supported by another phase III trial in which 417 patients with LS-SCLC were randomized to receive concurrent chemoradiotherapy with 45 Gy of total radiation either twice daily or once daily. Those in the twice-daily arm experienced improvement in five-year OS (26 versus 16 percent), but with more frequent severe esophagitis (27 versus 11 percent). Severe hematologic and pulmonary toxicities did not differ significantly between study arms. Although this study showed that 45 Gy given twice daily was more efficacious than 45 Gy given once daily, it should be noted that the more appropriate once-daily dose is now considered to be 60 to 70 Gy [44].

●By contrast, in a randomized phase II trial in which 182 patients were assigned to concurrent chemoradiotherapy at either 45 Gy twice daily in 30 fractions or 65 Gy once daily in 26 fractions, the once-daily group experienced improved PFS (median, 13.4 versus 17.2 months; HR 0.67, 95% CI 0.46-0.96) [51]. Median OS was 34 months in the twice-daily group versus 39 months in the once-daily group, a difference that was not statistically significant. The incidence of ≥grade 3 esophagitis and pneumonitis, and the treatment-related death rates were similar between the groups.

Subsequent randomized trials evaluated whether dose escalation, among patients receiving accelerated hyperfractionation, improved outcomes. In an open-label, phase II trial from Norway including 170 patients, those assigned to dose-escalated thoracic RT of 60 Gy in 40 fractions versus 45 Gy in 30 fractions experienced improved two-year OS rates (75 versus 48 percent; odds ratio 3.09, 95% CI 1.62-5.89) [52]. However, it is puzzling that this study showed no statistically significant differences for local control, PFS, or distant metastasis endpoints, nor were there significant differences in toxicity rates. Separately, in a trial presented in an oral abstract, among 224 patients receiving thoracic radiation for LS-SCLC, 54 Gy in 30 fractions improved OS relative to 45 Gy in 30 fractions (62 compared with 43 months), without increasing toxicities [53].

In conclusion, the data support both 60 to 70 Gy daily RT or 45 Gy twice daily, with the possibility of escalating the dose to 60 Gy twice daily, in select patients.

Integration of chemotherapy with RT — For patients with LS-SCLC, we recommend the addition of thoracic radiation therapy (RT) to EP chemotherapy.

Preference for concurrent rather than sequential treatment — We suggest that treatment start concurrently with chemotherapy during cycle 1 or 2. However, initiation of chemotherapy should not be delayed to accommodate delivery of RT with cycle 1.

Sequential, concurrent, and alternating approaches integrating chemotherapy and thoracic RT have all been studied in trials demonstrating a survival benefit for chemoradiation over chemotherapy [54-57]. Sequential therapy refers to treatment with one modality at a time, while concurrent therapy indicates that chemotherapy and thoracic RT are delivered simultaneously. Alternating therapy refers to delivery of thoracic RT on days when chemotherapy is not given, in such a fashion that the timing of the next chemotherapy cycle is not altered. In this treatment scheme, thoracic RT is necessarily delivered as a split course.

The concurrent and alternating approaches are intuitively appealing because they enable delivery of multiple chemotherapy cycles without interruption. Insofar as SCLC is a systemic disease, the optimal delivery of systemic treatment is crucial. However, concurrent or alternating regimens have been associated with more toxicity (myelosuppression, esophagitis, pneumonitis) when compared with sequential treatment [36]. This increased toxicity is considered acceptable based on improved outcomes with concurrent regimens [58].

●In the Japanese Clinical Oncology Group Study 9104, 231 patients with LS-SCLC were randomly assigned to four cycles of EP every three or four weeks with either sequential or concurrent thoracic RT (45 Gy twice daily over three weeks in both groups) [58]. The concurrent group experienced a median OS of 27 months versus 20 months in the sequential group, but the difference was not statistically significant (p = 0.10). Severe esophagitis was infrequent, but was more common in the concurrently treated group (9 versus 4 percent) [58]. Rates of pulmonary toxicity and treatment-related death were similar.

●Trials including alternating therapy have been less convincing. In an earlier meta-analysis of 13 randomized trials, thoracic RT outcomes in SCLC indirectly compared sequential versus alternating or concurrent and found no differences between the two approaches [37]. In a separate trial, there was no survival benefit with alternating versus sequential therapy [59].

Overall, the available data suggest that concurrent treatment may be more efficacious than sequential therapy. Furthermore, studies suggest that early integration of thoracic RT concurrently with chemotherapy as compared with delayed thoracic RT is associated with a significant survival benefit. (See 'Early versus late thoracic RT' below.)

Early versus late thoracic RT — We suggest that thoracic radiation therapy (RT) be integrated early (in cycle 1 or 2) with chemotherapy rather than later in the treatment course.

There have been eight randomized trials [54,58-65] and three meta-analyses [66-68] that have attempted to address the timing of the delivery of thoracic RT relative to chemotherapy. All the studies that employed standard cisplatin-based chemotherapy without significant dose reductions convincingly showed that early (starting with cycle 1 or 2 of chemotherapy) rather than late integration of thoracic RT is associated with a better outcome.

As an example, a meta-analysis reported in 2004, which included seven randomized trials published after 1985, showed a significant improvement in two-year OS for early versus late thoracic RT [68]. A subsequent meta-analysis showed that the most important factor associated with improved five-year survival was a short interval between the start of any treatment and the completion of thoracic RT (relative risk, 0.62) [67].

Importance of receiving all planned chemotherapy — Overall, in trials that have demonstrated a survival advantage for early thoracic RT, patients received cisplatin-based chemotherapy and both the early and late treatment arms had similar high rates of patients receiving full doses of chemotherapy [58,60,62]. By contrast, the randomized trials that did not demonstrate an advantage for early thoracic RT either did not use cisplatin-based chemotherapy and/or a lower percentage of patients in the early thoracic RT arms received full-dose chemotherapy compared with those in the late thoracic RT arms [54,59,61,63,65]. These deficits may suffice to explain the lack of an observed benefit for early thoracic RT in some studies. The importance of receiving all planned chemotherapy has been further supported in another meta-analysis of eight trials [63].

Delivery of concurrent thoracic RT integrated early (in cycle 1 or 2) with chemotherapy is the current standard of care.

Is there a role for surgery in patients with a good response to treatment? — The potential role of surgical resection following induction chemotherapy remains uncertain. In the setting of limited data, we do not pursue surgery in patients with stage II or III disease, irrespective of response to chemoradiotherapy, although we acknowledge that other experts may adopt this approach in select instances.

Although some observational data suggest possible benefit in select populations [69,70], a randomized trial suggested that this approach did not improve outcomes [71]. Among 146 patients with LS-SCLC judged to be suitable for resection after induction chemotherapy (with CAV), those assigned to surgery versus observation experienced the same two-year survival (20 percent). These results do not support the addition of pulmonary resection to chemoradiation for SCLC.

PROPHYLACTIC CRANIAL IRRADIATION — Prophylactic cranial irradiation (PCI) following chemotherapy has been demonstrated to decrease the incidence of symptomatic brain metastases (BM) and increase overall survival in patients with LS-SCLC [72,73]. As such, PCI is the standard of care for most patients with LS-SCLC who achieve a complete or good partial response following treatment [42]. However, for patients with stage I disease, the risk of BM is low and the relative benefits of PCI are less clear [74,75]. The use of PCI for this group should therefore be discussed with the patient and decided on an individual basis [42]. The role of PCI following initial treatment for LS-SCLC is discussed separately. (See "Prophylactic cranial irradiation for patients with small cell lung cancer", section on 'Limited-stage SCLC'.)

SPECIAL CONSIDERATIONS

Patients with progressive disease — The approach to patients with progression after initial treatment is discussed elsewhere. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Patients with relapse within 6 months of treatment'.)

Patients with SVC obstruction — For patients with LS-SCLC and symptoms of superior vena cava (SVC) obstruction, standard treatment should consist of concurrent chemotherapy plus definitive thoracic radiation therapy (RT) with curative intent. If there is any potential delay in planning of RT, then the first cycle of chemotherapy should be initiated as soon as possible, with definitive RT added in once planning has been completed.

Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high 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 other 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.)

●Beyond the Basics topics (see "Patient education: Small cell lung cancer treatment (Beyond the Basics)" and "Patient education: Lung cancer risks, symptoms, and diagnosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction and treatment algorithm – A combined-modality approach is indicated for the management of patients with limited-stage small cell lung cancer (LS-SCLC), following careful staging to rule out distant metastases (algorithm 1).

●Staging – Necessary components of staging include:

•Computed tomography (CT) of chest, abdomen and pelvis with intravenous contrast.

•Positron emission tomography-computed tomography (PET-CT).

•Magnetic resonance imaging (MRI) of the brain (CT brain with contrast if MRI is contraindicated).

•Bone scan (only if PET-CT is not available).

•For patients with clinical stage I (T1 to 2, N0) disease, invasive staging of mediastinal lymph nodes is also indicated to identify the small fraction of patients who do not have lymph node involvement or other metastatic disease.

●Stage I disease

•For patients with clinical stage I (cT1 to 2, N0) LS-SCLC we suggest initial surgery followed by adjuvant treatment, rather than chemotherapy or chemoradiotherapy alone (Grade 2C). If patients are not surgical candidates, chemoradiotherapy is an appropriate alternative. (See 'Stage I disease (T1 to T2, N0)' above.)

•After surgery, if no nodal involvement has been identified, we suggest adjuvant chemotherapy rather than chemoradiotherapy (Grade 2C).

•If nodal involvement has been identified, we suggest sequential adjuvant chemotherapy followed by radiation therapy (RT) rather than chemotherapy alone or observation (Grade 2C).

•Regimen selection for adjuvant treatment is the same as for patients with higher-stage disease, as discussed below.

●Stage II to III patients

•Chemotherapy – For patients with LS-SCLC, we recommend two-drug platinum-based chemotherapy (Grade 1B).

-Preferred regimen – When choosing a regimen, we suggest four cycles of cisplatin plus etoposide (EP; (table 2)) (Grade 2C). The use of this combination is compatible with concurrent RT.

-Alternatives – Carboplatin may be substituted for cisplatin in patients with contraindications to or poor tolerance of cisplatin. Irinotecan plus cisplatin is another acceptable regimen, but may cause more significant gastrointestinal side effects than EP. (See 'Chemotherapy' above.)

•Thoracic RT – For patients with LS-SCLC, we recommend thoracic RT rather than no radiation (Grade 1B).

-Treatment volume – We suggest limited thoracic RT fields that include postchemotherapy gross disease and prechemotherapy nodal volumes, rather than larger fields including the pretreatment tumor volume and/or elective nodal sites (Grade 2C). Baseline PET scans at diagnosis should be obtained for RT planning whenever possible. (See 'Treatment volume' above.)

-Fractionation schedule and dose – Either conventional fractionation (total dose of 60 to 70 Gy in fractions of 2 Gy) or accelerated hyperfractionated schedules are appropriate options. When administering accelerated hyperfractionation, we administer 45 Gy in twice-daily fractions over three weeks, but note that 60 Gy in twice-daily fractions may be an acceptable alternative in select patients with good performance status and in whom dose constraints to the normal tissues can be met. (See 'Dose fractionation schedule' above.)

-Treatment timing – We suggest that thoracic RT be started concurrently with the first or second cycle of chemotherapy rather than with later cycles of chemotherapy or sequentially with chemotherapy (Grade 2B). (See 'Early versus late thoracic RT' above.)

●Prophylactic cranial irradiation – Prophylactic cranial irradiation is offered to most patients with LS-SCLC who achieve a complete or very good partial response to their initial chemotherapy treatment. Supporting data are discussed elsewhere. (See "Prophylactic cranial irradiation for patients with small cell lung cancer".)