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© 2002 American Society for Clinical Oncology
"The Guard Dies, It Does Not Surrender!" Progress in the Management of Small-Cell Lung Cancer?Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical School, Nashville, TN FOR SEVERAL DECADES now, small-cell lung cancer (SCLC) has been characterized as a "chemosensitive" and potentially "curable" neoplasm.1,2 Indeed, there are a number of chemotherapy agents capable of effecting high objective response rates in this disease. Among the many available drug combinations used to treat SCLC, cisplatin and etoposide (PE) combination tends to be the preferred regimen in North America and Japan, whereas anthracycline-based regimens tend to predominate in Europe.3 Both types of regimens are active against SCLC and both are conveniently administered in the outpatient setting. However, given the extant differences in national health care financing and practice patterns around the globe, it is not surprising that neither regimen has emerged as the international consensus best treatment for SCLC. In this issue of the Journal of Clinical Oncology, Sundstrøm et al4 present the results of a randomized trial in which they prospectively compared the activity of cyclophosphamide, epirubicin, and vincristine (CEV) with that of PE in patients with SCLC. Epirubicin is the preferred anthracycline in Europe due in part to its decreased cardiac toxicity relative to doxorubicin.5 Thus, CEV can be viewed as a European version of cyclophosphamide, doxorubicin, and vincristine (CAV), an anthracycline-based drug combination commonly used in North America throughout the 1970s and 1980s.2,6 Although the comparability of the single-agent activities of epirubicin and doxorubicin has not been fully established in SCLC, it is reasonable to believe that these anthracyclines possess essentially identical efficacy. The trial conducted by Sundstrøm et al4 enrolled 440 SCLC patients with both limited-stage (LS) and extensive-stage (ES) disease. LS patients also received thoracic radiotherapy (TRT) between the third and fourth cycles of chemotherapy. Overall survival was significantly better among the group randomized to PE compared with CEV (10.2 months v 7.8 months; P = .0004). There were no meaningful differences noted in the quality of life between the two arms. The authors, therefore, concluded that PE is superior to CEV in the treatment of SCLC. In a subset analysis, the superiority of the PE regimen seemed to be restricted to patients with LS disease (14.5 v 9.7 months), with no survival improvement noted in patients with ES disease (8.4 v 6.5 months). Do these data now firmly establish PE as a regimen superior to anthracycline-based therapy for SCLC? The results of the Sundstrøm et al trial will come as no great surprise to most lung cancer experts. Over the past two decades, several groups have prospectively compared anthracycline-based chemotherapy regimens to PE.7-10 Most of these trials failed to demonstrate a survival advantage for PE, possibly because many of the trials were conducted exclusively in ES SCLC patients.8-11 However, in a recent overview of United States (U.S.) National Cancer Institute–sponsored ES SCLC trials conducted between 1972 and 1990, Chute et al11 demonstrated that platinum-containing chemotherapy does impart a relatively modest median survival benefit of approximately 2 months compared with nonplatinum regimens. Perhaps more importantly (at least to patients), the platinum-based regimens are generally better tolerated than the anthracycline-containing regimens.9,10 This is particularly true if one substitutes carboplatin for cisplatin.12 In fact, on the basis of these clinical observations, oncologists in North America have long accepted that platinum-based therapy is at least as good as anthracycline-based regimens for the treatment of ES SCLC and probably better. However, the real "advantage" for platinum-based therapy comes from the ease with which these regimens can be delivered concomitantly with TRT, an absolute necessity if one is to achieve maximum survival outcome in LS patients with good performance.13 Efforts to combine anthracycline-based regimens concurrently with TRT have proved difficult and, in some cases, even life-threatening.14,15 Thus, when PE is included in the induction regimen of LS SCLC treatment programs, one frequently observes a modest survival benefit (albeit not always a statistically significant improvement).9,16,17 Like previous investigators, Sundstrøm et al4 also noted a survival benefit in LS SCLC with the use of PE. There are several interesting aspects to the Sundstrøm trial. First, the median survival times of the ES SCLC patients (CEV, 6.5 months v 8.4 months) nearly perfectly mirror those reported by Chute et al11 in their review of the 1972 to 1990 U.S. cooperative group ES SCLC experience. For example, the median of the median survival times of the patients treated in the U.S. between 1972 and 1981 on the control arms was 7.0 months. These patients were treated primarily with cyclophosphamide- or anthracycline-based chemotherapy regimens. By contrast, patients treated in the U.S. between 1982 and 1990 enjoyed a median survival time of 8.9 months (P = .001) and these patients were treated using platinum-based regimens. Although it may be tempting to invoke the specter of "stage shifting" to account for this improvement in survival,18 an analysis of the Surveillance, Epidemiology, and End-Results database over the same time period shows a similar 2-month prolongation in median survival time of ES SCLC patients.11 This suggests that stage shifting alone is not the explanation for the improved survival observed in U.S. cooperative group studies. Second, the median survival times of the LS SCLC patients enrolled onto the Norwegian study were rather poor (PE, 14.5 months; CEV, 9.7 months). By comparison, in North American cooperative group trials median survival typically exceeds 17 to 18 months and was more than 20 months in the most recent intergroup LS SCLC study.19,20 In fact, similar good results were being reported over a decade ago, around the time cisplatin was first introduced into the indication regimens of LS SCLC.21 Because the characteristics of the patients enrolled onto the Sundstrøm trial more or less mirror those recorded for participants in recent U.S. cooperative group studies, one has to wonder what additional factors played a role in the relatively poor outcome observed in the Norwegian study. One possible explanation for the disappointing results observed in LS SCLC in the Sundstrøm trial relates to the TRT dose and schedule used (42 Gy in 15 2.8-Gy fractions). Although medical oncologists might be loath to admit it, refinements in radiation therapy delivery and technique have made a greater contribution to survival prolongation of LS SCLC in recent years than have improvements in chemotherapy. This was borne out in a recent review conducted by Janne et al.19 Among LS SCLC patients treated within the context of U.S. cooperative group trials, some modification in radiotherapy accounted for the improved survival noted in all of the positive trials. In other words, in none of the National Cancer Institute–sponsored randomized trials carried out between 1972 and 1992 did a change in chemotherapy alone account for an obvious survival improvement. In the Sundstrøm trial, the TRT dose and fractionation differed from those commonly used in North American trials. Was the dose and fractionation schedule optimal radiotherapy circa 1990? Possibly. Was the TRT adequate to maximize local tumor control? Doubtful. This is a critical issue since we know that improved local control is a prerequisite for improved survival.20 How to achieve improved local control is the subject of ongoing investigations, but some possible options include increasing the total dose of radiotherapy or changing fractionation.22 Although one could debate some of the particulars of the Sundstrøm trial design, in general, it was a well-designed randomized study seeking to address a straightforward question. This was not simply a Sisyphean exercise, and the results should alter practice patterns, at least in countries where anthracycline-based therapy still predominates. These findings are particularly relevant to the treatment of LS SCLC where maintaining maximum dose-intensity of both radiotherapy and chemotherapy is critical. Indeed, one should also avoid ad hoc changes in established and well-tested treatments plans. The consequences of such changes are unknown and could prove disastrous. Finally, in most cancers, the best outcome is usually obtained when a team of highly experienced experts cares for the patient. This means that SCLC patients, and especially those with LS disease, should be treated by highly qualified medical and radiation oncologists using an integrated, multidisciplinary approach with appropriate chemotherapy regimens. Patient volume and overall physician experience do matter.23 When approached in this manner, optimal outcome will be realized in the highest possible number of cancer cases.24 The results of this trial may be viewed as further validation of practice patterns in North America and Japan. By contrast, physicians unalterably opposed to the use of platinum-based therapy in SCLC may attempt to find fatal flaws in the Sundstrøm trial design to justify their refusal to include cisplatin in their treatment programs. Perhaps General Count Etienne Cambronne said it best at the Battle of Waterloo: "La Garde meurt, elle ne se rend pas!" "The Guard dies, it does not surrender!" REFERENCES 1. Karnofsky DA, Abelmann WH, Craver LF, et al: The use of the nitrogen mustards in the palliative treatment of carcinoma. Cancer 1: 634-656, 1948[CrossRef] 2. Johnson BE: Management of small cell lung cancer. Clin Chest Med 23: 225-239, 2002[CrossRef][Medline] 3. 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 84: 1447-1452, 2001[CrossRef][Medline]
4. Sundstrøm S, Bremnes RM, Kaasa S, 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 20: 4665-4672, 2002 5. Launchbury AP, Habboubi N: Epirubicin and doxorubicin: A comparison of their characteristics, therapeutic activity and toxicity. Cancer Treat Rev 19: 197-228, 1993[CrossRef][Medline]
6. Johnson DH: Management of small cell lung cancer: Current state of the art. Chest 116: 525S-530S, 1999
7. Feld R, Evans WK, Coy P, et al: Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small cell carcinoma of the lung. J Clin Oncol 5: 1401-1409, 1987
8. Evans WK, Feld R, Murray N, et al: Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: A multicenter, randomized clinical trial by the National Cancer Institute of Canada. Ann Intern Med 107: 451-458, 1987
9. Fukuoka M, Furuse K, Saijo N, et al: Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83: 855-861, 1991 10. Roth BJ, Johnson DH, Einhorn LH, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10: 282-291, 1992[Abstract]
11. Chute JP, Chen T, Feigal E, et al: Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: Perceptible progress. J Clin Oncol 17: 1794-1801, 1999 12. Ettinger DS: The role of carboplatin in the treatment of small-cell lung cancer. Oncology (Huntingt) 12: 36-43, 1998[CrossRef] 13. Murray N, Sheehan F: Limited stage small cell lung cancer. Curr Treat Options Oncol 2: 63-70, 2001[Medline] 14. Johnson RE, Brereton HD, Kent CH: "Total" therapy for small cell carcinoma of the lung. Ann Thorac Surg 25: 510-515, 1978[Abstract] 15. Perez CA, Einhorn L, Oldham RK, et al: Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 2: 1200-1208, 1984[Abstract] 16. Einhorn LH, Crawford J, Birch R, et al: Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. J Clin Oncol 6: 451-456, 1988[Abstract]
17. Johnson DH, Bass D, Einhorn LH, et al: Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: A randomized trial of the Southeastern Cancer Study Group. J Clin Oncol 11: 1223-1229, 1993 18. Feinstein A, Sosin D, Wells C: The Will Rogers phenomenon: Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 312: 1604-1608, 1985[Abstract] 19. Janne PA, Freidlin B, Saxman S, et al: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95: 1528-1538, 2002[CrossRef][Medline]
20. Turrisi AT, Kim K, Blum 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 340: 265-271, 1999
21. Goodman G, Crowley J, Blasko J, 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 8: 39-47, 1990 22. Choi NC, Herndon JE 2nd, Rosenman J, et al: Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 16: 3528-3536, 1998[Abstract]
23. Begg CB, Cramer LD, Hoskins WJ, et al: Impact of hospital volume on operative mortality for major cancer surgery. JAMA 280: 1747-1751, 1998
24. Hillner BE, Smith TJ: Hospital volume and patient outcomes in major cancer surgery: A catalyst for quality assessment and concentration of cancer services. JAMA 280: 1783-1784, 1998
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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