An Advance in Small-Cell Lung Cancer Treatment--More or Less

Although small-cell lung cancer (SCLC) once constituted 20%–25% of all newly diagnosed lung cancers in North America, in recent years the incidence has decreased to less than 15% (1,2). Nonetheless, deaths resulting from SCLC remain substantial and represent a major public health concern both in the United States and abroad. Fortunately, SCLC is a moderately chemo-sensitive neoplasm and, over the past three decades, considerable progress has been made in the management of this disease (3,4). In fact, even though cure remains elusive for most patients, median survival now approaches 2 years for patients with limited-stage disease and averages 9–10 months for patients with extensive-stage disease (5). In North America, SCLC is most commonly treated with a two-drug chemotherapy regimen consisting of cisplatin (or carboplatin) and etoposide (PE). Patients with limited-stage disease also receive thoracic radiotherapy, usually administered concurrently with the first or second cycle of chemotherapy (6). In Europe, the situation is somewhat different. Induction chemotherapy regimens tend to be more varied, with a higher percentage of oncologists using anthracycline-based drug combinations (7). However, this practice pattern may change in light of a recently reported randomized trial demonstrating the superiority of platinum-based therapy compared with a standard anthracycline-based regimen (8). Although these improvements in SCLC treatment are gratifying, there is clearly more work to do. Over the last decade, several new drugs have been identified with excellent activity against SCLC in the first- and second-line settings, including irinotecan, topotecan, and paclitaxel (9–12). Given the biology of SCLC, with its proclivity toward early relapse and subsequent refractoriness to therapy, the desire to incorporate these newer agents into front-line therapy is obvious. In this issue of the Journal, Reck et al. (13) report the results of a randomized phase III trial comparison of carboplatin, etoposide, and vincristine (CEV)—the standard arm—versus carboplatin, etoposide, and paclitaxel (TEC)—the experimental arm. Their attempt to improve upon an existing chemotherapy regimen followed a time-honored and traditional strategy of adding (or substituting) an active drug to an active regimen. Their choice of paclitaxel as a substitute for vincristine is logical on the basis of its novel mechanism of action and the extant phase II data (9,12). Their study included patients with both limited- and extensive-stage disease. Notably, patients with limited-stage disease were treated with sequential thoracic radiotherapy upon completion of induction chemotherapy, which some experts believe is not the optimal method of delivering radiotherapy (6,14). Patients who progressed or failed to respond to treatment after the initial two cycles of induction therapy were switched to cyclophosphamide, doxorubicin, and vincristine. A total of 614 patients were enrolled over a 2-year period. Median survival for patients in the TEC arm was superior to that achieved by patients in the CEV arm (12.7 versus 11.7 months), and the hazard ratio of death was statistically significantly higher for patients in the CEV arm (hazard ratio = 1.22, 95% confidence interval = 1.03 to 1.45; P = .024). When analyzed by stage, the apparent survival advantage was seemingly confined to limited-stage patients (17.6 versus 16.6 months) and was not apparent for those with extensive-stage disease (9.8 versus 10.0 months), a pattern reminiscent of the European trial in which less-than-optimal thoracic radiotherapy was used (8). Myelosuppression was the principal toxicity in both treatment groups (13). Grade 3 or 4 neurotoxicity and thrombocytopenia, however, were more common for patients in the CEV arm. The authors concluded that TEC is preferable to CEV in the treatment of patients with SCLC. What can we make of these data? Should TEC supplant PE as the regimen of choice in SCLC? The U.S. Intergroup recently reported the results of a randomized study in which cisplatin, etoposide, and paclitaxel (TEP) were compared with PE alone (15). The study enrolled nearly 600 patients, all of whom had extensive-stage disease. Although failure-free survival favored patients in the TEP arm, similar to the study by Reck et al. (13), median survival was not statistically significantly different between the two arms (10.35 versus 9.86 months; P = .27) in contrast to median survival in the German study (13). There were more treatment-related deaths in the TEP-treated group (15). The Greek Lung Cancer Cooperative Group also conducted a prospective randomized trial of TEP versus PE (16). However, the trial enrolled only 133 patients with limited- and extensive-stage disease and was closed before meeting the intended accrual goal because of excessive toxicity and mortality in the TEP arm. There were no differences in objective response rates or median survival times between the two regimens (16). However, eight patients in the TEP arm died from toxicity whereas none of the patients in the EP arm died (P = .001). Moreover, the TEP regimen was associated with statistically significantly more grade 4 neutropenia, grade 3–4 thrombocytopenia, febrile neutropenia, grade 3–4 diarrhea, grade 3–4 asthenia, and grade 3 neurotoxicity. Similar high levels of toxicity have been reported in various phase I/II trials using this three-drug regimen (17,18). Reck et al. (13) do not report such excessive toxicities in their trial, possibly because carboplatin was substituted for cisplatin. However, a note of caution is warranted. Although these two drugs are likely to be comparable, their comparability has never been established in SCLC in an adequately designed randomized trial (19). It is also worth remembering that in testicular cancer, another chemo-sensitive and potentially curable neoplasm, carboplatin has consistently proved to be inferior to cisplatin (20–22). If a similar difference in efficacy exists for these agents in SCLC, it could be particularly important for patients with limited-stage disease where cure is the goal. In fact, the studies that yield the best overall survival rates in limited-stage SCLC have typically used cisplatin-based chemotherapy (23,24). Therefore, to simply assume that carboplatin is equivalent in this setting could be problematic. By contrast, carboplatin might be perfectly appropriate for patients with extensive-stage disease when the intention of the chemotherapy is mainly palliation (25). Collectively, the data from the Reck et al. (13) and the aforementioned U.S. and Greek trials (15,16) lessen our enthusiasm for adopting this three-drug TEC or TEP induction regimen for SCLC. By and large, the addition of a third drug to a PE regimen has not substantially improved outcome in patients with SCLC, irrespective of how the third drug is incorporated (26). Indeed, with rare exception (27), no contemporary randomized trial has yielded a survival rate superior to that of PE alone in SCLC. The lack of clinically significant survival benefit using three-drug therapy versus two-drug therapy is not unique to SCLC and has been observed in non–small-cell lung cancer (NSCLC) (28). In fact, over the past 10–15 years, the treatment strategies for these biologically different cancers have tended to merge. For example, the combined chemotherapy–thoracic radiotherapy commonly used in locally advanced NSCLC closely resembles the program used in limited-stage SCLC, and the two-drug combination chemotherapy used for advanced, metastatic NSCLC is similar to the strategy currently used in extensive-stage SCLC. Of equal interest, there is remarkable similarity in the survival outcomes of these two diseases (5,28). Where are we headed in the treatment of SCLC? No one knows for sure, but a good bet would be into the realm of so-called “targeted therapy.” The initial foray into this world was unsuccessful (29)—perhaps not too surprisingly, given the aggressive behavior of SCLC. Nonetheless, we believe this is the future of SCLC therapeutic research. Drugs that target components of the Ras–mitogen-activated protein kinase pathway or angiogenesis are but a few of the many therapeutic possibilities (30,31). Indeed, the recent success with bevacizumab in colon cancer is encouraging. Patients with highly vascular tumors are known to have a poor outcome when serum vascular endothelial growth factor levels are elevated (32); thus, there is a compelling rationale for studying antiangiogenic agents in SCLC because these tumors are highly vascular. Strategies that take advantage of our admittedly limited knowledge of tumor biology are in progress. It is hoped that one or several of these approaches will prove successful and further enhance our ability to treat this still-too-common and deadly disease.

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