For all patients with SCLC, chemotherapy is an essential component of appropriate treatment.7
Adjuvant chemotherapy is recommended for those who have undergone surgical resection. For patients with extensive-stage disease, chemotherapy alone is the recommended treatment, although radiotherapy may be used in select patients for palliation of symptoms (see pages 81 and 85 for recommended regimens). In patients with extensive disease and brain metastases, chemotherapy can be given either before or after whole-brain radiotherapy, depending on whether the patient has neurologic symptoms (see page 81).8,51
Single-agent and combination chemotherapy regimens have been shown to be active in SCLC.52–54
Etoposide and cisplatin (EP) is the most commonly used initial combination chemotherapy regimen (see page 85).7,55,56
This combination replaced alkylator/anthracycline-based regimens based on its superiority in both efficacy and toxicity in the limited-stage setting.57
In clinical practice, carboplatin is frequently substituted for cisplatin to reduce the risk of emesis, neuropathy, and nephropathy. However, the use of carboplatin carries a greater risk of myelosuppression.58
Small randomized trials have suggested similar efficacy of cisplatin and carboplatin in patients with SCLC.59,60
A meta-analysis of 4 randomized studies compared cisplatin-based versus carboplatin-based regimens in patients with SCLC.61
Of 663 patients included in this meta-analysis, 32% had limited-stage and 68% had extensive-stage disease. No significant difference was observed in response rate (67% vs. 66%), progression-free survival (5.5 vs. 5.3 months), or overall survival (9.6 vs. 9.4 months) in patients receiving cisplatin-containing versus carboplatin-containing regimens, suggesting equivalent efficacy in patients with SCLC.
Many other combinations have been evaluated in patients with extensive-stage disease, with little consistent evidence of benefit when compared with EP. The panel recommends etoposide plus platinum as the standard regimen for patients with SCLC. Recently, the combination of irinotecan and a platinum agent has provided the greatest challenge to EP. Initially, a small phase III trial performed in Japan reported that patients with extensive-stage SCLC who were treated with irinotecan plus cisplatin experienced a median survival of 12.8 months compared with 9.4 months for patients treated with EP (P
In addition, the 2-year survival was 19.5% in the irinotecan plus cisplatin group versus 5.2% in the EP group.62
However, 2 subsequent large phase III trials performed in the United States comparing irinotecan plus cisplatin versus EP failed to show a significant difference in response rate or overall survival between the regimens.63,64
A randomized phase II trial (n=70) comparing carboplatin and irinotecan versus carboplatin and etoposide showed a modest improvement in progression-free survival with the irinotecan combination.65
A phase III randomized trial (n=220) found that median overall survival was slightly improved with irino-tecan and carboplatin compared with carboplatin and oral etoposide (8.5 vs. 7.1 months; P
Based on these findings, the carboplatin and irinotecan regimen has been added to these guidelines as an option for patients with extensive-stage disease. A recent meta-analysis suggests an improvement in progression-free survival and overall survival with irinotecan plus platinum regimens compared with etoposide plus platinum regimens.67
However, this meta-analysis was not performed using individual patient data. In addition, the relatively small absolute survival benefit must be balanced against the toxicity profile of irinotecan-based regimens. Therefore, the panel continues to recommend etoposide plus platinum as the standard regimen for patients with SCLC.
In patients with extensive-stage disease, response rates of 60% to 70% can be achieved with combination chemotherapy alone.52
Unfortunately, median survival rates are only 9 to 11 months for patients with extensive-stage disease. After appropriate treatment, the 2-year survival rate is less than 5% in those with extensive-stage disease.68
Many strategies have been evaluated in an effort to improve on the results that have been achieved with standard treatment for extensive-stage SCLC, including the addition of a third agent to standard 2-drug regimens. In 2 trials, the addition of ifosfamide (or cyclophosphamide plus an anthracycline) to EP showed a modest survival advantage for patients with extensive disease.69,70
However, these findings have not been uniformly observed, and the addition of an alkylating agent, with or without an anthracycline, significantly increases hematologic toxicity compared with EP alone.71
Similarly, the addition of paclitaxel to either cisplatin or carboplatin plus etoposide yielded promising results in phase II trials but did not improve survival, and was associated with unacceptable toxicity in a subsequent phase III study.72
The use of maintenance or consolidation chemotherapy beyond 4 to 6 cycles of standard treatment produces a minor prolongation of duration of response without improving survival and carries a greater risk of cumulative toxicity.73
The inability to destroy residual cells, despite the initial chemosensitivity of SCLC, suggests the existence of cancer stem cells that are relatively resistant to cytotoxic therapy. To overcome drug resistance, alternating or sequential combination therapies have been designed to expose the tumor to as many active cytotoxic agents as possible during initial treatment.74
However, randomized trials have failed to show improved progression-free or overall survival with this approach.75,76
Multidrug cyclic weekly therapy was designed to increase dose intensity. Early phase II results of this approach were promising, although favorable patient selection was of some concern.77,78
Nevertheless, no survival benefits were documented in randomized trials, and excessive treatment-related mortality was noted with multidrug cyclic weekly regimens.79–82
The role of higher-dose therapy for patients with SCLC remains controversial.83
Higher complete and partial response rates, and modestly longer median survival times, have been observed in patients receiving high doses compared with those given conventional doses of the same agents.84
In general, however, randomized trials comparing conventional doses with an incrementally increased dose intensity up to 2 times the conventional dose have not consistently shown an increase in response rate or survival.85–88
In addition, a meta-analysis of trials that compared standard versus dose-intense variations of the CAV (cyclophosphamide, doxorubicin [Adriamycin], and vincristine) and EP regimens found that increased relative dose intensity resulted in only a small, clinically insignificant enhancement of median survival in patients with extensive-stage disease.89
Currently available cytokines (eg, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor) can ameliorate chemotherapy-induced myelosuppression and reduce the incidence of febrile neutropenia, but cumulative thrombocytopenia remains dose-limiting. Although trials involving patients with SCLC were instrumental in obtaining FDA approval for the clinical use of cytokines,90
little evidence suggests that maintenance of dose intensity with growth factors prolongs disease-free or overall survival, and the routine use of growth factors at the initiation of chemotherapy is not recommended.
The potential benefits of antiangiogenic therapy have begun to be evaluated in SCLC. In extensive-stage SCLC, 2 phase II trials of platinum-based chemotherapy plus bevacizumab have yielded promising response and survival data.91–93
Randomized phase III trials are ongoing to determine if the addition of bevacizumab to chemotherapy improves survival in patients with extensive-stage SCLC. Currently, the panel does not recommend use of bevacizumab in patients with SCLC.
Overall, attempts to improve long-term survival rates in patients with SCLC through the addition of more agents or the use of dose-intense chemotherapy regimens, maintenance therapy, or alternating non–cross-resistant chemotherapy regimens have failed to yield significant advantages compared with standard approaches.