EDITORIAL

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

Janessa Laskin, Alan Sandler, David H. Johnson

Affiliations of authors: J. Laskin, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada; A. Sandler, D. H. Johnson, Vanderbilt-Ingram Cancer Center, Nashville, TN.

Correspondence to: David H. Johnson, MD, Division of Hematology and Oncology, Vanderbilt-Ingram Comprehensive Cancer Center, 2220 Pierce Ave., Nashville, TN 37232–6307 (e-mail: david.h.johnson{at}vanderbilt.edu).

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 (912). 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 (2022). 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.

REFERENCES

1 Travis WD, Lubin J, Ries L, Devesa S. United States lung carcinoma incidence trends: declining for most histologic types among males, increasing among females. Cancer 1996;77:2464–70.[CrossRef][ISI][Medline]

2 Page NC, Read WL, Tierney RM, Arquette MA, Piccirillo JF, Govindan R. The epidemiology of small cell lung carcinoma [abstract]. Proc ASCO 2002;21:305a.

3 Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 1999;17:1794–801.[Abstract/Free Full Text]

4 Janne PA, Freidlin B, Saxman S, Johnson DH, Livingston RB, Shepherd FA, et al. Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 2002;95:1528–38.[CrossRef][ISI][Medline]

5 Johnson DH. Management of small cell lung cancer: current state of the art. Chest 1999;116:525S–30S.[Abstract/Free Full Text]

6 Turrisi AT 3rd. Limited stage small cell lung cancer: treatment and therapy. Curr Treat Options Oncol 2003;4:61–4.[Medline]

7 Sambrook RJ, Girling DJ. A national survey of the chemotherapy regimens used to treat small cell lung cancer (SCLC) in the United Kingdom. Br J Cancer 2001;84:1447–52.[CrossRef][ISI][Medline]

8 Sundstrom S, Bremnes RM, Kaasa S, Aasebo U, Hatlevoll R, Dahle R, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol 2002;20:4665–72.[Abstract/Free Full Text]

9 Ettinger DS, Finkelstein DM, Sarma RP, Johnson DH. Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 1995;13:1430–5.[Abstract]

10 Schiller JH, Kim K, Hutson P, DeVore R, Glick J, Stewart J, et al. Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial. J Clin Oncol 1996;14:2345–52.[Abstract]

11 Fukuoka M, Masuda N. Clinical studies of irinotecan alone and in combination with cisplatin. Cancer Chemother Pharmacol 1994;34 Suppl: S105–11.[ISI][Medline]

12 Kirschling RJ, Grill JP, Marks RS, Kugler JW, Gerstner JB, Kuross SA, et al. Paclitaxel and G-CSF in previously untreated patients with extensive stage small-cell lung cancer: a phase II study of the North Central Cancer Treatment Group. Am J Clin Oncol 1999;22:517–22.[CrossRef][ISI][Medline]

13 Reck M, von Pawel J, Macha HN, Kaukel E, Deppermann KM, Bonnet R, et al. Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst 2003:95;1118–27.[Abstract/Free Full Text]

14 Murray N, Sheehan F. Limited stage small cell lung cancer. Curr Treat Options Oncol 2001;2:63–70.[Medline]

15 Niell HB, Herndon JE, Miller AA, Watson DM, Sandier AB, Kelly K, et al. Randomized phase III Integroup trial (CALGB 9732) of etoposide (VP-16) and cisplatin (DDP) with or without paclitaxel (TAX) in patients with extensive stage small cell lung cancer (ED-SCLC) [abstract]. Proc ASCO 2002;21:293a.

16 Mavroudis D, Papadakis E, Veslemes M, Tsiafaki X, Stavrakakis J, Kouroussis C, et al. A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 2001;12:463–70.[Abstract]

17 Kelly K, Pan Z, Wood ME, Murphy J, Bunn PA Jr. A phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small cell lung cancer. Clin Cancer Res 1999;5:3419–24.[Abstract/Free Full Text]

18 Glisson BS, Kurie JM, Perez-Soler R, Fox NJ, Murphy WK, Fossella FV, et al. Cisplatin, etoposide, and paclitaxel in the treatment of patients with extensive small-cell lung carcinoma. J Clin Oncol 1999;17:2309–15.[Abstract/Free Full Text]

19 Skarlos DV, Samantas E, Kosmidis P, Fountzilas G, Angelidou M, Palamidas P, et al. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994;5:601–7.[Abstract]

20 Bajorin DF, Sarosdy MF, Pfister DG, Mazumdar M, Motzer RJ, Scher HI, et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. J Clin Oncol 1993;11:598–606.[Abstract]

21 Bokemeyer C, Kohrmann O, Tischler J, Weissbach L, Rath U, Haupt A, et al. A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with ‘good-risk’ metastatic non-seminomatous germ cell tumors. Ann Oncol 1996;7:1015–21.[Abstract]

22 Horwich A, Sleijfer DT, Fossa SD, Kaye SB, Oliver RT, Cullen MH, et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997;15:1844–52.[Abstract]

23 Turrisi AT, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265–71.[Abstract/Free Full Text]

24 Goodman G, Crowley J, Blasko J, Livingston R, Beck T, Demattia M, et al. Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol 1990;8:39–47.[Abstract]

25 Ettinger DS. The role of carboplatin in the treatment of small-cell lung cancer. Oncology (Huntingt) 1998;12(1 Suppl 2):36–43.

26 Schiller JH, Adak S, Cella D, DeVore RF, Johnson DH. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:2114–22.[Abstract/Free Full Text]

27 Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346:85–91.[Abstract/Free Full Text]

28 Bunn PA Jr. Treatment of advanced non-small-cell lung cancer with two-drug combinations. J Clin Oncol 2002;20:3565–7.[Free Full Text]

29 Shepherd FA, Giaccone G, Seymour L, Debruyne C, Bezjak A, Hirsh V, et al. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol 2002;20:4434–9.[Abstract/Free Full Text]

30 Dy GK, Adjei AA. Novel targets for lung cancer therapy: part I. J Clin Oncol 2002;20:2881–94.[Abstract/Free Full Text]

31 Dy GK, Adjei AA. Novel targets for lung cancer therapy: part II. J Clin Oncol 2002;20:3016–28.[Abstract/Free Full Text]

32 Salven P, Ruotsalainen T, Mattson K, Joensuu H. High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer 1998;79:144–6.[CrossRef][ISI][Medline]


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2003 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement