Management of Extensive-Stage Small Cell Lung Cancer | 11 |
INTRODUCTION
Small cell lung cancer (SCLC) is an aggressive, poorly differentiated neuroendocrine carcinoma with clinical, pathological, and molecular characteristics that are distinct from those of non–small-cell lung cancer (NSCLC). Clinically, SCLC is characterized by rapid growth, early lymphatic and hematogenous metastatic spread, initial responsiveness to chemotherapy and radiation, relapse with relatively chemoresistant disease, and poor overall prognosis.
STAGE CLASSIFICATION
The Veterans’ Administration Lung Group classification is routinely used to stage SCLC. Limited-stage (LS) is defined as tumor confined to one hemithorax, with or without regional lymph node involvement, which can be safely encompassed in a tolerable radiation therapy (RT) port. Extensive-stage (ES) is defined as disease that has spread beyond this point, including malignant pleural or pericardial effusion, tumor nodules in different ipsilateral lung lobes, contralateral lung nodules, and other hematogenous metastases. Involvement of contralateral mediastinal and ipsilateral supraclavicular lymph nodes is usually considered LS, while involvement of contralateral supraclavicular and hilar lymph nodes is frequently deemed ES due to the toxicity associated with an extended radiation field. However, the decision on how to treat such patients needs to be individualized based on the potential risks and benefits as assessed by the managing care team. At least two-thirds of patients are found to have ES-SCLC at initial diagnosis.
The TNM staging system that is used for NSCLC could also be applied to SCLC since these T and N descriptors and the overall stage I to IV groupings, also predict prognosis in patients with SCLC (1) (Appendix A.1). In the TNM system, ES-SCLC can be defined as T1-4 N0-3 M1a/b or T3-4 due to multiple lung nodules that are too extensive or dispersed to be encompassed in a tolerable radiation port.
OVERVIEW OF CLINICAL MANAGEMENT
The management of ES-SCLC is frequently complicated by both the aggressiveness of the disease and the underlying health status of the patient. Many patients present with rapidly progressive, debilitating symptoms due to bulky intrathoracic disease, widespread metastases, and/or paraneoplastic syndromes. Due to long-term tobacco use, many patients also have comorbidities that contribute to their impaired performance status and limit the delivery of optimal therapy. These factors also complicate the enrollment of patients with SCLC onto clinical trials.
ES-SCLC is an incurable disease in which the goals of care are to palliate symptoms, optimize quality of life, and prolong survival. The mainstay of treatment is platinum-based, two-drug chemotherapy which yields an objective response rate of 60% to 70% and a complete response rate of up to 10%. Patients who attain a good response and maintain a good performance status are candidates for prophylactic cranial irradiation (PCI) and consolidative thoracic RT, based on clinical trials demonstrating improved survival. Although chemotherapy improves quality of life and prolongs survival in patients with ES-SCLC, nearly all relapse with relatively chemoresistant disease.
Single-agent chemotherapy is the standard treatment for patients with relapsed SCLC based on the demonstration of improvement in survival versus supportive care alone. Palliative RT is usually very useful for control of localizable symptoms, such as shortness of breath due to bronchial obstruction, superior vena cava syndrome, bone pain, or neurologic dysfunction due to brain metastases. The prognosis of patients with ES-SCLC has changed little since the 1970s, with 2-year overall survival improving only from 3.4% to 5.6% (2).
FIRST-LINE CHEMOTHERAPY
Historical Development
Historically, patients with ES-SCLC who did not receive therapy had a very poor prognosis, with a median survival of less than 2 months. Clinical trials with single-agent therapy revealed surprisingly high-response rates, resulting in an extensive list of active agents (Table 11.1). However, single-agent therapy yields few complete responses and a relatively short duration of response. In the 1970s, alkylator-based combination chemotherapy regimens, such as cyclophosphamide, doxorubicin, and vincristine (CAV), resulted in significant improvements in overall survival when compared to single-agent therapy (3). In patients with ES-SCLC, these regimens resulted in response rates of 60% to 80%, complete response rates of 15% to 25%, and median survival times of 7 to 10 months.
Table 11.1 Clinically active agents in small cell lung cancer | |
DNA intercalating agents | Cisplatin |
| Carboplatin |
Alkylating agents | Cyclophosphamide |
| Ifosfamide |
| Temozolomide |
| Bendamustine |
Topoisomerase 2 inhibitors | Etoposide |
| Teniposide |
Anthracyclines | Doxorubicin |
| Epirubicin |
| Amrubicin |
Topoisomerase 1 inhibitors | Irinotecan |
| Topotecan |
Microtubule inhibitors | Vincristine |
| Vinblastine |
| Vinorelbine |
Microtubule stabilizers | Paclitaxel |
| Docetaxel |
Antimetabolites | Methotrexate |
| Gemcitabine |
Immune checkpoint inhibitors | Pembrolizumab |
| Nivolumab |
Cisplatin Plus Etoposide
In the 1980s, the combination of etoposide and cisplatin (EP) was found to have response and survival rates similar to those of older alkylator-based regimens with a relatively favorable toxicity profile (4). Subsequently, randomized trials directly comparing CAV to EP failed to demonstrate the superiority of either regimen (5). Recently, a phase III study comparing EP to cyclophosphamide, epirubicin, and vincristine (CEV) in patients with both LS- and ES-SCLC reported that overall survival was significantly better with EP (10.2 vs. 7.8 months, P = .0004), although there was little difference noted in those with ES-SCLC (6). Meta-analyses have also demonstrated a modest survival advantage for cisplatin-based therapy (7). Therefore, EP has become the standard regimen for SCLC based on efficacy that is at least as good as other regimens, a reasonable toxicity profile, and the ease with which it can be combined with thoracic RT in patients with LS-SCLC.
Cisplatin Versus Carboplatin
Cisplatin is a relatively difficult drug, particularly in the palliative setting, due to its cumbersome administration and unpleasant side effects, including nausea/vomiting, ototoxicity, nephrotoxicity, and peripheral neuropathy. Due to these limitations, many oncologists freely substitute carboplatin in light of its ease of administration and more favorable nonhematologic toxicity profile. Thus far, only one trial has directly compared EP to etoposide plus carboplatin (EC). Sklaros et al. randomized 147 patients with LS- or ES-SCLC to six cycles of EP or EC, adding concurrent thoracic RT in those with LS (8). There was no difference in response rate (57% vs. 58%), time to progression (TTP; median, 8.4 vs. 8.6 months), or overall survival (median, 12.5 vs. 11.8 months) between EP and EC, respectively.
Recently, the COCIS meta-analysis of 663 patients from four trials compared cisplatin-based to carboplatin-based therapy for first-line treatment of both LS- and ES-SCLC (9). Two-thirds of patients had ES disease. This meta-analysis found no significant difference between cisplatin and carboplatin in any efficacy endpoint, including response rate (67% vs. 66%, P = .83), progression-free survival (PFS; median, 5.5 vs. 5.3 months, P = .25), and overall survival (median, 9.6 vs. 9.4 months, P = .37)(9). Carboplatin-based regimens were associated with more grade 3 to 4 cytopenia, while cisplatin predictably caused more nausea/vomiting, neurotoxicity, and nephrotoxicity. Based on these data demonstrating equivalent efficacy, it is most reasonable to use carboplatin-based regimens in patients with ES-SCLC given the palliative nature of therapy and the focus on maintenance of good quality of life.
Alternative First-Line Regimens
Topoisomerase I Inhibitors + Platinum
Irinotecan and topotecan are topoisomerase I inhibitors with single-agent activity against SCLC. Several regimens combining these agents with platinum analogs have been compared to platinum plus etoposide in patients with ES-SCLC (Table 11.2). In the first phase III trial of irinotecan plus cisplatin (IP), Noda et al. from the Japanese Cooperative Oncology Group (JCOG) randomized 154 patients with previously untreated ES-SCLC to either EP or IP and reported that IP resulted in a significantly better response rate, PFS, and overall survival (Table 11.2) (10). IP resulted in significantly more diarrhea, while EP caused greater hematologic toxicity. Subsequent randomized trials in Western patients have failed to confirm the superiority of IP over EP. Hanna et al. compared a modified IP regimen to EP in 331 patients with previously untreated ES-SCLC and reported no difference in overall efficacy (Table 11.2) (11). As in the JCOG trial, EP resulted in more myelosuppression and febrile neutropenia, while IP caused more diarrhea. In a Southwest Oncology Group (SWOG) study from the United States, Lara et al. randomized 651 patients with previously untreated ES-SCLC to receive IP or EP using the same regimens and schedules as the initial JCOG trial (12). Again, there was no significant difference in response rate or survival between the two arms (Table 11.2). A European study by Zatloukal et al. randomized 405 patients with previously untreated ES-SCLC to receive IP or EP and reported noninferiority of IP, with the response rate and TTP favoring EP, but overall survival favoring IP (Table 11.2) (13).
The combination of irinotecan plus carboplatin (IC) has also been studied in patients with ES-SCLC. In a phase III trial, Hermes et al. randomized 209 patients with untreated ES-SCLC to receive IC or EC and reported a significant improvement in overall survival with IC, with similar quality of life outcomes in both arms (Table 11.2) (14).
Topotecan is generally considered to be more tolerable than irinotecan. Eckardt et al. randomized 784 patients with previously untreated ES-SCLC to receive either oral topotecan plus cisplatin (TP) or EP. Once again, efficacy was similar in both arms (Table 11.2) (15). As in the prior trials of IP versus EP, there was more neutropenia and febrile neutropenia in patients receiving EP and more diarrhea in those treated with TP. Quality of life analysis slightly favored EP (P = .049). A similar study by Fink et al. compared TP to EP in 703 patients with untreated ES-SCLC and reported a significant improvement in response rate and TTP with TP, but no difference in overall survival (Table 11.2) (16).
Meta-analyses of studies comparing platinum analogs plus either topoisomerase 1 inhibitors or etoposide have reported modest improvements in overall survival with platinum plus irinotecan or topotecan combinations (17). However, when balancing toxicity profiles and efficacy endpoints, it is clear that these regimens are not a significant advance, and EP or EC remain the standard-of-care for patients with ES-SCLC.
Other Chemotherapy Regimens
Phase II trials utilizing a variety of regimens, including carboplatin plus paclitaxel and paclitaxel plus topotecan, in patients with ES-SCLC have reported response and survival outcomes that appear similar to those achieved with standard regimens (18,19). Although these empiric combinations have not been evaluated in randomized trials, it is unlikely that they would result in significant improvements in survival.
Recent studies have demonstrated that amrubicin, a novel anthracycline, has clinically relevant activity in patients with SCLC. Early phase studies in previously untreated patients with ES-SCLC showed high response rates for both single-agent amrubicin and the combination of amrubicin plus cisplatin (AP). However, a phase III trial comparing AP to IP in 284 previously untreated patients with ES-SCLC was stopped early due to futility with similar response rates for AP and IP (78% vs. 72%, P = .33), but with PFS (median, 5.6 vs. 5.1 months; HR1.42, 95% CI 1.16–1.73) and overall survival (median, 17.7 vs. 15.0 months; HR 1.43, 95% CI 1.10–1.85) significantly favoring IP (20).
Other Chemotherapy-Based Strategies
Numerous chemotherapy-based strategies, including dose-intensification, dose-dense regimens, weekly administration, triplet therapy, high-dose consolidation, alternating or sequential non–cross-resistant regimens, maintenance therapy, and consolidation therapy, have failed to demonstrate consistent improvements in survival, and many of these more aggressive approaches have resulted in unacceptable toxicity.
As an example of three-drug therapy, CALGB 9732 randomized 587 patients with untreated ES-SCLC to receive six cycles of EP or EP plus paclitaxel (PET) (21). The response rates were 68% and 75% for EP and PET, respectively, with overlapping 95% confidence intervals. Similarly, there were no significant differences in failure-free survival (median, 5.9 vs. 6.4 months, P = .18) or overall survival (median, 9.9 vs. 10.6 months, P = .17) between EP and PET, respectively. However, PET was associated with an unacceptable increase in treatment-related deaths, primarily due to neutropenic sepsis (2.4% vs. 6.5%) despite the planned use of G-CSF.
In regard to consolidation therapy, ECOG 7593 evaluated EP for four cycles versus EP for four cycles followed by four cycles of topotecan in 402 patients with ES-SCLC (22). Although PFS was modestly but statistically significantly improved with the addition of topotecan (median, 3.6 vs. 2.3 months, P < .001), there was no difference in overall survival (median, 9.3 vs. 8.9 months, P = .43). As expected, consolidation topotecan did increase toxicity, but there was no significant difference in reported quality of life between the two arms. In addition to refuting the notion of consolidation topotecan (or early second-line therapy), this study indirectly supports the use of four, rather than six or more, cycles of initial chemotherapy.
Recommendations for First-Line Chemotherapy
Based on the available data and the palliative goals of care, four to six cycles of carboplatin AUC 5 on day 1 plus etoposide 100 mg/m2 days 1 to 3 every 21 days should be considered the preferred first-line chemotherapy regimen for patients with ES-SCLC. Cisplatin 75 mg/m2 plus etoposide 100 mg/m2 days 1 to 3 every 21 days for four to six cycles is an option for younger patients with good performance status and normal organ function.
RADIATION THERAPY
General Principles
Since ES-SCLC is an incurable, systemic disease, RT has traditionally been used only to prevent or palliate symptoms. However, building on improvements in outcomes for patients with LS-SCLC with the addition of RT, several studies have been published over the past decade that have demonstrated improvement in survival with the addition of RT in patients with ES-SCLC, thereby expanding the role of RT in this setting.
Prophylactic Cranial Irradiation
SCLC has an extraordinarily high propensity to metastasize to the brain. PCI has been shown in a meta-analysis to improve survival in patients with SCLC who have had a complete response to initial treatment (23). Of note, approximately 85% of the patients included in this meta-analysis had LS disease and 75% received thoracic RT, raising questions as to the applicability of these findings to patients with ES-SCLC. To address the question of PCI in ES-SCLC, the European Organization for Research and Treatment of Cancer (EORTC) undertook a trial in which 286 patients with ES-SCLC and any response to chemotherapy were randomized to PCI or no further therapy (24). This study allowed four to six cycles of any type of chemotherapy and used a variety of different PCI schedules (e.g., 20 Gy in 5 or 8 fractions, 24 Gy in 12 fractions, 25 Gy in 10 fractions, 30 Gy in 10 or 12 fractions). In addition, repeat negative brain imaging after chemotherapy was not required for study entry. PCI decreased the incidence of symptomatic brain metastases from 40% to 15% at 1 year (P < .001) and increased the 1-year survival rate from 13% to 27% (P = .003) without a large decrement in quality of life (25). However, a more recent study from Japan, which has only been reported as an abstract, has questioned the use of PCI in ES-SCLC (26). This study required a negative brain MRI prior to enrollment and randomized patients with any response to platinum-based doublet chemotherapy to PCI of 25 Gy in 10 fractions or no further therapy. After enrolling 163 of a planned 330 patients, an interim analysis led to early termination of the study due to futility with patients in the PCI arm demonstrating a lower median overall survival than those on observation without PCI (10 vs. 15 months, P = .09).
Recommendations for PCI
At this time, PCI is still recommended for patients with ES-SCLC with a response to chemotherapy, good performance status, and no evidence of brain metastases on repeat brain imaging. Considering the poor prognosis and comorbidities of patients with ES-SCLC, the potential benefits and risks of PCI need to be carefully weighed for every patient. It is generally agreed that if PCI is planned it should be started soon after restaging. Most patients in the EORTC study received 20 Gy in 5 fractions or 30 Gy in 10 fractions. However, due to concerns about neurocognitive toxicity and data from a PCI trial in LS-SCLC that demonstrated better outcomes with 25 Gy than with 36 Gy, the use of 25 Gy in 10 fractions is favored (27). Data in patients with LS-SCLC also demonstrated that age is the most significant predictor of chronic neurotoxicity following PCI (28). Although long-term toxicity may be less relevant in patients with ES-SCLC due to their relatively poor prognosis, it is reasonable to withhold PCI in elderly patients and those with impaired baseline neurocognitive function.
Thoracic Radiation Therapy
Based on data demonstrating an improvement in survival with the addition of thoracic RT in patients with LS-SCLC and the fact that most patients with ES-SCLC will have symptomatic progression of thoracic disease after response to initial therapy, there has been increasing interest in adding thoracic RT in patients with ES disease. In a single institution study, Jeremic et al. reported on a subgroup of 109 patients with ES-SCLC who had at least a partial response in the chest and a complete response at distant sites following three cycles of EP who were randomized to accelerated hyperfractionated RT of 54 Gy in twice daily 1.5 Gy fractions with concurrent low-dose daily EP versus two more cycles of EP without RT (29). Patients in both arms then received PCI and two more cycles of EP. Patients on the RT arm had significantly better overall survival (median, 17 vs. 11 months; 5-year, 9.1% vs. 3.7%; P = .041). However, because these data came from a single institution study with a small sample size, required a complete response in all distant sites, and employed aggressive thoracic RT with concurrent chemotherapy, these results were generally viewed as hypothesis generating rather than practice changing.
Encouraging data from this trial and other smaller studies served as justification for the phase III European CREST trial in which 495 patients with ES-SCLC who had responded to initial chemotherapy were randomized to receive either thoracic RT (30 Gy in 10 fractions) or no thoracic RT (30). All patients received PCI and 88% of those on the thoracic RT arm underwent concurrent RT to both sites. While the addition of thoracic RT did not achieve a statistically significant improvement in the primary endpoint of 1-year overall survival (33% vs. 28%, P = .066), a secondary analysis did find significant improvement in 2-year overall survival (13% vs. 3%, P = .004).
Recommendation for Thoracic RT
Results from the CREST trial have led to the use of thoracic RT in patients with ES-SCLC who have had a response to chemotherapy and good performance status. As with PCI, the potential benefits and risks of thoracic RT must be carefully evaluated for each individual patient. Based on the design of this pivotal trial, thoracic RT and PCI are typically initiated concurrently within 2 to 7 weeks after chemotherapy. The standard dose of thoracic RT is 30 Gy in 10 fractions although some data support the use of doses up to 45 Gy in 15 fractions.
Radiation Therapy to Oligometastatic Sites
Approximately 60% of patients with ES-SCLC treated with chemotherapy, PCI, and thoracic RT progress at sites other than the chest and brain (30). This finding raises the question of whether there is a role for using RT to treat limited metastatic sites. In a randomized phase II Radiation Therapy Oncology Group (RTOG)/NRG trial, patients with one to four metastatic lesions with a response to four to six cycles of platinum-based chemotherapy and no brain metastases received PCI or PCI plus RT of 45 Gy in 15 fractions to the chest and to sites of metastatic disease. After enrolling 86 eligible patients, a preplanned interim analysis led to early termination of the study due to futility with no statistical difference in 1-year overall survival between the PCI only arm and the PCI plus thoracic and metastatic site RT arm (60% vs. 51%; P = .21) (31).
Recommendation for RT to Oligometastatic Sites
Given the lack of benefit in the RTOG/NRG trial, treating even a limited number of asymptomatic metastatic sites with RT in patients with ES-SCLC is not recommended.
Palliative Radiation Therapy
In patients with symptomatic metastatic lesions, RT can be highly effective in achieving symptom relief. For example, RT can relieve neurologic symptoms due to brain metastases or vertebral metastases causing spinal cord, cauda equina, or nerve root compression, pain from bone metastases, and respiratory symptoms due to bronchial obstruction from lung tumors or lymph node metastases. In addition, due to the fact that SCLC is generally very responsive to RT, patients with SCLC typically experience more rapid palliation of their symptoms with RT than patients with NSCLC.
In light of the high degree of responsiveness of SCLC to first-line chemotherapy, many focal symptoms in newly diagnosed patients, such as superior vena cava syndrome, airway obstruction, or bone pain, can be managed with prompt initiation of systemic chemotherapy, with RT held in reserve. However, in patients with spinal cord compression RT should be initiated urgently. For patients with asymptomatic brain metastases identified on initial staging evaluation, brain RT can be delayed in favor of early initiation of systemic first-line chemotherapy, which is frequently needed to control rapidly progressive systemic symptoms and declining performance status. In such situations, brain metastases usually respond to systemic therapy and brain scans should be repeated every two cycles with initiation of brain RT for any evidence of progressive CNS disease.
Recommendations for Palliative RT
The approach used for treating patients with symptomatic SCLC metastases is similar to that for treating patients with other primary cancers. For example, 30 Gy in 10 fractions is commonly used for symptomatic brain, bone, and thoracic metastases. However, there are several caveats. Because SCLC is so radiation-responsive, lower doses of RT are frequently employed (e.g., 20 Gy in 5 fractions). In addition, even in patients with a limited number of small brain metastases that may be amenable to stereotactic radiosurgery, its use is not recommended due to the responsiveness of the disease and the high likelihood of subclinical disease elsewhere in the brain. Instead, whole brain RT is recommended as initial treatment with radiosurgery reserved for salvage therapy in patients with progression in a limited number of lesions after whole brain RT.
CHEMOTHERAPY FOR RECURRENT DISEASE
Virtually all patients with ES-SCLC will relapse with relatively chemoresistant disease. Recurrent SCLC has traditionally been divided into two categories based on responsiveness to further therapy: (a) refractory/resistant disease is defined as primary progression or recurrence within 3 months of initial therapy, and (b) relapsed/sensitive disease is defined as recurrence more than 3 months after initial therapy. Response rates for subsequent therapy are substantially lower in patients with a shorter duration of response to initial treatment (i.e., refractory/resistant).
Topotecan
Topotecan is the only drug currently approved by the U.S. Food and Drug Administration (FDA) for use in patients with relapsed SCLC. The benefit of second-line therapy in patients with recurrent SCLC was demonstrated by O’Brien et al. in a randomized trial comparing oral topotecan to best supportive care in 141 patients with both sensitive and resistant relapse (32). Despite a response rate of only 7%, overall survival was significantly better in patients receiving oral topotecan (median, 26 vs. 14 weeks; 6-month, 49% vs. 26%; P = .01) (Table 11.3).
Phase II trials evaluating single-agents and combination regimens in patients with relapsed SCLC have generally demonstrated higher response rates with combination therapy, but no apparent improvement in overall survival. In addition, the toxicity of combination regimens is difficult for many patients with recurrent SCLC due to impaired performance status and significant comorbidities. A randomized phase III trial compared single-agent topotecan 1.5 mg/m2 IV on days one to five every 21 days to CAV in 211 patients with SCLC who had relapsed more than 60 days after initial therapy (33). This trial reported no significant difference in response rate (24% vs. 18%, P = .29), TTP (median, 13 vs. 12 weeks, P = .55), or overall survival (median, 25 weeks both arms, P = .79) between topotecan and CAV, respectively (Table 11.3). However, hematologic toxicity was significantly greater with the combination regimen. In addition, patients receiving topotecan noted greater improvement in symptoms, such as dyspnea, anorexia, and fatigue, and a delay in eventual symptom progression. Based on these findings, single-agent chemotherapy became the standard treatment approach for patients with relapsed SCLC who have a good performance status.
A phase III randomized study compared oral versus intravenous (IV) topotecan in patients with recurrent SCLC and reported no statistically significant or clinically meaningful differences in response rate, PFS, or overall survival (Table 11.3) (34). Quality of life measures were also similar, but oral topotecan did result in less severe neutropenia.
The standard regimen of topotecan 1.5 mg/m2 IV on days one to five of a 21 day cycle induces severe myelotoxicity and fatigue. An attenuated dose regimen of topotecan 1.25 mg/m2 IV on days one to five of a 21 day cycle adjusted for toxicity on subsequent cycles may be equally efficacious with lower toxicity (35). Weekly topotecan 4 mg/m2 IV also appears to have lower toxicity than the standard regimen, but efficacy may be compromised (36). Pooled analyses have suggested that standard-dose topotecan is tolerable and effective in patients with relapsed SCLC and an ECOG performance status of two, but the high rate of treatment delays (46% for cycle 2), low dose-intensity (1.59 mg/m2/week), and short overall survival (median, 16 weeks) raise serious questions about the utility of this regimen in this impaired patient population (37).
Other Chemotherapy Agents
Several other standard drugs have demonstrated modest activity in phase II studies in patients with relapsed SCLC, including irinotecan, oral etoposide, paclitaxel, docetaxel, vinorelbine, and gemcitabine (38). For example, oral etoposide has shown response rates of 23% to 45%, but little activity is noted in patients with resistant relapse (39). In contrast, paclitaxel had a response rate of 29% in patients who had received at least two prior lines of chemotherapy, suggesting that it is a reasonable option for patients with refractory/resistant disease (40).
The most recent additions to the list of active agents in relapsed SCLC are temozolomide and bendamustine. In a phase II trial, 64 patients who had one to two prior regimens received temozolomide 75 mg/m2 for 21 days of a 28-day cycle. The overall response rate was around 20% in both the second- and third-line settings, and 38% in patients with brain metastases (41). A subsequent study with temozolomide 200 mg/m2 on days 1–5 of a 28-day cycle reported a response rate of 12% with a more tolerable toxicity profile (42). Bendamustine, an alkylating agent used routinely in chronic lymphocytic leukemia, has demonstrated response rates of 26% and 29%, along with tolerable toxicity in two phase II trials in patients with relapsed SCLC (43,44).
A randomized phase II trial compared amrubicin to topotecan in 76 patients with recurrent SCLC and reported a significantly better response rate (44% vs. 15%, P = .02) with modest improvements in PFS and overall survival with amrubicin (45). However, a phase III trial in which 637 patients with recurrent SCLC were randomized to receive either amrubicin or topotecan reported a significant improvement in response rate (31% vs. 17%, P = .0002) with amrubicin, but no difference in median PFS (4.1 vs. 4.0 months, P = .98) or overall survival (7.5 vs. 7.8 months, P = .17) (Table 11.3) (46). The disappointing survival outcomes in phase III trials with amrubicin in both the first-line and relapsed settings have dimmed enthusiasm for this agent.
Combination Chemotherapy
Recently, a phase III trial from Japan has challenged the standard of single-agent therapy for relapsed SCLC. In this study, 180 patients with SCLC that had relapsed more than 90 days after initial therapy were randomized to single-agent topotecan 1.0 mg/m2 IV on days 1 to 5 every 21 days for four cycles or the combination of cisplatin 25 mg/m2 in days 1 and 8, etoposide 60 mg/m2 on days 1 to 3, and irinotecan 90 mg/m2 on day 8 every 2 weeks for five cycles (PEI). (47). The PEI regimen significantly improved response rate (84% vs. 27%; P < .0001), PFS (median, 5.7 vs. 3.6 months; HR 0.50; P < .001), and overall survival (median, 18.2 vs. 12.5 months; HR 0.67; P = .008). However, 50% of patients receiving PEI required dose reductions and 31% developed febrile neutropenia despite routine use of G-CSF. Severe diarrhea and hematologic toxicity also occurred more frequently with PEI. While the efficacy of PEI is notable, the toxicity raises concerns as to the tolerability and generalizability of this regimen, and confirmatory trials with modified dosing are needed before adopting PEI as a standard treatment option.
Reinduction Chemotherapy
Reinitiation of the first-line chemotherapy regimen is recommended for patients with an initial response duration of greater than 6 months based on studies demonstrating response rates of 50% to 60% with this approach (48,49).
Recommendations for Subsequent Chemotherapy
Reinduction with the initial chemotherapy regimen is preferred for patients who relapse more than 6 months from first-line therapy. For patients relapsing within 6 months of initial treatment who have good performance status, single-agent chemotherapy is considered the standard-of-care, with topotecan or paclitaxel being the most commonly used agents. Close attention to toxicity is essential, with appropriate use of dose-modifications and treatment holds in order to maintain quality of life. Although the optimal duration of subsequent chemotherapy for SCLC has not been studied, cumulative toxicity is often limiting. Therefore, it is reasonable to continue subsequent chemotherapy until two cycles beyond best response, progression of disease, or development of unacceptable toxicity. Treatment beyond second-line chemotherapy remains an option for patients with a good performance status, but the low response rate associated with such treatment makes enrollment on a clinical trial a more attractive alternative.
MOLECULARLY TARGETED THERAPY
Future advances in the treatment of SCLC will rely on continued research into the biology of the disease and the identification of molecular targets that drive survival, proliferation, and metastasis. Although many rational, targeted therapies have already been evaluated in clinical trials in patients with SCLC, these approaches have demonstrated little clinical activity. Thus far, strategies demonstrating limited promise include antiangiogenic agents, metalloproteinase inhibitors, growth factor pathway inhibitors, retinoids, proapoptotic agents, therapeutic vaccines, and oncolytic tumor viruses (50). Despite these setbacks, an unprecedented number of novel molecular strategies are now being evaluated in preclinical and clinical studies in SCLC.
Identification of Molecular Targets
Several reports have recently been published on the application of advanced, next-generation molecular techniques for the identification of therapeutic targets and predictive biomarkers in SCLC. A consistent finding of these studies is the very high frequency of protein-altering mutations in SCLC, likely due to prolonged exposure to tobacco carcinogens (51–53). Another common finding is that the TP53 and RB1 tumor suppressor genes are mutated and inactivated in nearly all SCLCs. Many other candidates for targeted therapeutic strategies have been identified in genomic and proteomic studies in SCLC, including: MYC-family gene amplification; histone-modifiers (CREBBP, MLL, EP300); the PI3K–PTEN pathway; FGFR1; the neural cell migration mediator SLIT2; DNA repair mediators (PARP1); cell cycle checkpoint regulators (EZH2); and mediators of “stem-cell” characteristics (Notch, Hedgehog, SOX2) (51–54).
The most promising recent approach targets delta-like protein 3 (DLL3), a Notch ligand that is overexpressed in SCLC tumor-initiating cells. Rovalpituzumab tesirine (Rova-T) consists of a humanized monoclonal antibody targeting DLL3 linked to a DNA damaging toxin. A phase I study of Rova-T in patients with relapsed SCLC reported a response rate of 23% in all patients and 44% in those with high DLL3 tumor expression treated at the recommended phase II dose (55).
The technology now exists for rapid and broad characterization of molecular drivers in cancer cells. In SCLC and other cancers with high mutational burdens, the clinical validation of relevant therapeutic targets remains challenging. In such tumors, it is likely that tumor cell heterogeneity and the dysregulation of numerous pathways will limit the activity of any single molecularly targeted intervention and more complex approaches with combinations of agents will be needed to attain adequate tumor control or eradication.
Immunotherapy
Immune checkpoint inhibitors have shown promise in many tumor types, including SCLC. Ipilimumab is a human monoclonal antibody that binds to CTLA-4 and enhances T-cell activation in tumors. A randomized phase II trial enrolled 164 patients with ES-SCLC who received carboplatin and paclitaxel plus either concurrent or phased ipilumumab or placebo (56). Phased ipilumumab given after two cycles of chemotherapy resulted in a higher response rate and better overall survival than placebo (median, 13 vs. 10 months; HR, 0.75; P = .13), suggesting that chemotherapy may sensitize SCLC to immunotherapy.
Activated T-cells also express PD-1, another immune checkpoint receptor, and binding of PD-1 to its ligand PD-L1 inactivates T-cells. Many cancer cells produce PD-L1, resulting in localized immunosuppression that protects tumors from immune surveillance. A phase Ib trial of pembrolizumab, an anti-PD1 monoclonal antibody, yielded a response rate of 35% in 20 patients with PD-L1-positive SCLC (57). Another phase I/II study of patients with relapsed SCLC evaluated nivolumab, another anti-PD1 monoclonal antibody, and the combination of nivolumab plus ipilumumab (58). Response rates were 10% in 98 patients treated with single-agent nivolumab, and 21% in 115 patients treated with the combination. Further trials of immune checkpoint inhibitors in SCLC are currently under way.
CONCLUSION
ES-SCLC remains an incurable disease. Cytotoxic chemotherapy does improve survival and quality of life, but nearly all patients relapse within 1 to 2 years with relatively chemoresistant disease. Platinum-based chemotherapy has been the standard first-line therapy for the past 30 years, with cisplatin or carboplatin plus etoposide being favored worldwide. While many other chemotherapeutic strategies have been evaluated to improve outcomes, none have shown a clear benefit over standard platinum-based therapy. The use of PCI and sequential thoracic RT in patients with ES-SCLC is now part of routine care based on supportive data from randomized trials. However, the benefits of these interventions are modest. Given the disseminated nature of SCLC, more effective systemic therapy is clearly needed to have a greater impact on this disease. Advanced molecular analyses are now allowing the definition of many candidate driver mutations in SCLC. Future gains in treatment will depend on the development of strategies to successfully target the genetic and immunologic drivers of tumor growth and survival.
