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© 1999 American Society for Clinical Oncology Twenty Years of Phase III Trials for Patients With Extensive-Stage Small-Cell Lung Cancer: Perceptible ProgressFrom the Naval Medical Research Institute and Division of Hematology/Oncology, National Naval Medical Center; and the Biometric Research Branch, Clinical Investigations Branch, and Medicine Branch, National Cancer Institute, Bethesda, MD. Address reprint requests to Bruce E. Johnson, MD, Lung Cancer Biology Section, Medicine Branch, National Cancer Institute, Building 8, Room 5101, National Naval Medical Center, Bethesda, MD 20889-5105; email bejohnson{at}partners.org
PURPOSE: All cooperative group studies performed in North America for patients with extensive-stage small-cell lung cancer (SCLC) were evaluated to determine the pattern of the clinical trials and the outcome of patients over the past 20 years. PATIENTS AND METHODS: Phase III trials for patients with extensive-stage SCLC were identified through a search of the National Cancer Institute Cancer Therapy Evaluation Program database from 1972 to 1993. Patients with extensive-stage SCLC treated during a similar time interval listed in the Surveillance, Epidemiology, and End Results (SEER) database were also examined. Trends were tested in the number of trials over time, the number and sex of patients entered onto the trials, and the survival time of patients treated over time. RESULTS: Twenty-one phase III trials for patients with extensive-stage SCLC were initiated between 1972 and1990. The median of the median survival times of patients treated on the control arms of the phase III trials initiated between 1972 and 1981 was 7.0 months; for those patients enrolled onto control arms between 1982 and 1990, the median survival time was 8.9 months (P = .001). Analysis of the SEER database of patients with extensive-stage SCLC over the same time period shows a similar 2-month prolongation in median survival time. CONCLUSION: Analysis of 21 phase III trials initiated in North America and the SEER database from 1972 to 1994 demonstrates that there has been a modest improvement in the survival time of patients with extensive-stage SCLC.
COMBINATION CHEMOTHERAPY became the mainstay of treatment for patients with extensive-stage small-cell lung cancer (SCLC) in the 1970s.1 Combination chemotherapy regimens achieve initial response rates of 50% to 60% and median survival times of 7 to 11 months in patients with extensive-stage disease.2,3 Despite this, less than 3% of patients with extensive-stage SCLC achieve a 3-year survival time with currently available regimens.4 A review of patients with extensive-stage SCLC treated at the National Cancer Institute, Bethesda, MD, over the last 20 years has recently been reported.5 Despite diverse strategies for the treatment of these patients, the median survival time ranged from 6.3 to 11.3 months in different trials, and there has been no significant trend toward longer survival times for patients with extensive-stage SCLC who were treated more recently. These results are in contrast to the recent analysis by Aisner,6 who reported in a selected review that patients with extensive-stage SCLC who were treated with higher doses of combination chemotherapy over the past 10 years have prolonged survival times compared with selected historical controls. In light of these analyses of patients with extensive-stage SCLC,5,6 we chose to review all of the cooperative group North American phase III randomized therapeutic trials for patients with extensive-stage SCLC that have been performed during the same time period. The focus on this study is on patients with extensive-stage SCLC because this isolates the effects (benefits) of chemotherapy. Patients with limited-stage SCLC were not included because their treatment can include chest radiotherapy or surgery, which makes analyses more complicated. We evaluated the cooperative group trials because the trial information was readily retrievable from the Cancer Therapy Evaluation Program database, and information from pharmaceutical industry–sponsored trials was not available from a central source. We examined whether the number of trials being initiated had changed, whether the number of patients enrolled onto the trials had increased or decreased over time, and whether changes had occurred in the survival time of patients treated on these trials. We also examined whether patients treated with newer experimental regimens lived significantly longer compared with patients treated with standard chemotherapy regimens. The median and 5-year survival time information on patients with extensive-stage SCLC from the past 25 years is available on the Surveillance, Epidemiology, and End Results (SEER) database.7 This database provided the data to compare the outcome of patients with extensive-stage SCLC in both cooperative groups and a population database. We also evaluated potential changes in patient survival time with the passage of time reported in our single-institution experience,5 cooperative group studies, and the population database during the same time period.
Phase III Trials The phase III trials initiated for patients with extensive-stage SCLC were identified through a search of the National Cancer Institute Cancer Therapy Evaluation Program database for the time period between 1972 and 1990. We evaluated the trials initiated between 1972 and 1990 because this corresponded closely with the interval examined in our previous report5 and because this time period allowed adequate time for patient enrollment onto a study, follow-up, and publication of the mature results of the therapeutic trials. The lung cancer committee chairs from each cooperative group in North America were contacted to inform them of this analysis and to determine whether additional trials had been performed that were not known to us. Information about each trial was obtained regarding the years of the trial, the number of patients enrolled onto the study, sex of the patients, treatment regimens used, response rates, median survival times, and the number patients deaths at the time of the analysis. The median of the median survival times was computed without adjusting for the sample size of the control arm, and the median survival time of patients before and after 1981 was not adjusted for trial size. Each study median was treated as a data point. Some phase III trials incorporated patients with both limited- and extensive-stage disease. Only patients with extensive-stage SCLC were included in this analysis. We acknowledge that the definitions of limited- and extensive-stage SCLC vary somewhat in the different cooperative groups. However, we did not attempt to reallocate patients based on these differences because of the difficulty of identifying which patients would be reallocated and then obtaining information on their characteristics and survival time. The control arms in each of the phase III trials were identified based on the statement of the authors in the published reports and were verified by contacting the group chair. A small minority of the phase III trials did not have all of this information available in the published article. In these cases, the author of the study and cooperative group statistician were contacted and additional data were obtained if available and the author permitted its use. The SEER database was also examined to compare the median and 5-year survival time information for all patients with SCLC and those with extensive-stage SCLC versus our analysis of patients treated on phase III trials over the same time period. The time period from 1973 to 1994 was examined because the starting year corresponded most closely with the start of the cooperative group studies and 1994 corresponded most closely with the year the cooperative group trials finished their accrual.7 In the SEER database, patients with metastatic disease are categorized as "distant," which is roughly equivalent to extensive-stage disease. In this analysis, patients from the SEER database with distant disease are termed extensive-stage to be consistent with the terminology used in the cooperative group studies.
Statistical Methods
Phase III Trials Twenty-two North American cooperative group phase III trials that were initiated between 1972 and 1990 were identified. One study, performed between 1980 and 1984 by the Northern California Oncology Group, has yet to be published in either abstract or manuscript form. The data from this study cannot be referenced, so we did not include it in this analysis. The exclusion of this data did not appreciably alter the outcome of the study. We analyzed the treatment arms from the 21 published phase III trials.9-29 The results of these 21 cooperative group trials are listed in Table 1. A total of 5,746 patients with extensive-stage SCLC were treated on 21 different studies initiated from 1972 to 1990. The number of different studies initiated and number of patients participating on the control and experimental arms of the phase III trials did not significantly change with the passage of time. Eleven studies were initiated between 1972 and 1981, and 10 studies were initiated from 1982 to 1990. A median of 86 patients were treated with each regimen in the 21 phase III trials initiated from 1972 to 1990 (range, 12 to 342). The median number of patients enrolled onto phase III trials was greater between 1982 and 1990 than from 1972 to 1981 (295.5 patients per trial v 168 patients per trial, respectively) but did not reach statistical significance (Wilcoxon test, P = .072). The number of patients enrolled onto the trials over the entire period of the analysis did not have a significant trend (P = .66). If we analyze the patients on the control arm only, then the medians are 132.5 patients per trial (1982 to 1990) versus 76 patients (1972 to 1981; Wilcoxon test, P = .072 and trend test, P = .84).
Survival Time of Patients
Five (24%) of the 21 phase III trials showed a statistically significant difference in survival time in the group of patients who received experimental therapy compared with the control group (Table 1). Loehrer et al27 compared etoposide and cisplatin (EP) treatment with the same drugs plus ifosfamide. Evans et al21 compared one combination (cyclophosphamide, doxorubicin, and vincristine [CAV]) to an alternating regimen (CAV/EP). Daniels et al13 compared procarbazine, vincristine, cyclophosphamide, and lomustine followed by etoposide, doxorubicin, and methotrexate with an alternating regimen of these same drugs. Ettinger et al22 compared standard-dose CAV with a regimen alternating the use of CAV and hexamethylmelamine, etoposide, and methotrexate. Hong et al18 compared CAV versus cyclophosphamide, etoposide, and vincristine versus high-dose cisplatin and vincristine. The five phase III trials that demonstrated a difference between the experimental arm and standard treatment showed a modest prolongation in median survival time (median, 1.8 months; range, 0.8 to 3.0 months). Sixteen (76%) of the 21 phase III cooperative group trials showed no difference in the survival time of patients treated on the experimental versus the standard arms. Twelve (57%) of these trials examined different methods of delivering cyclophosphamide-based chemotherapy (Table 1). Three recently completed trials compared different methods of combining EP chemotherapy26,28,29 and an additional phase III study by Roth et al24 examined alternating EP with CAV versus CAV or EP alone. The five studies that showed a significant difference in survival time13,18,21,22,27 did not have a significantly larger number of patients enrolled (median, 84 patients per arm; range, 50 to 294) than the studies that did not show a difference in survival time (median, 88.5 patients per arm; range, 12 to 342; P = .83). The study by Ettinger et al had the greatest number of patients enrolled (n = 577) compared with all other studies. Despite only 0.8 months difference in median survival time of patients treated on the control arm compared with patients treated on the experimental arm, this trial showed a statistically significant difference in survival time.
SEER Database
Analysis of North American cooperative group phase III trials for patients with extensive-stage SCLC initiated between 1972 and 1990 demonstrated that there was no significant change in the number of trials instituted or the number of patients enrolled onto phase III trials over time. In addition, our review of the North American cooperative group trials for patients with extensive-stage SCLC revealed that only six phase III trials were initiated in North America between 1984 and 1990 and none between 1990 and 1993. These results may be consistent with a declining interest on the part of physicians in the enrollment of patients with extensive-stage SCLC onto phase III trials. It also may reflect a paucity of ideas regarding innovative treatments for patients with extensive-stage SCLC. The advent of etoposide and cisplatin as standard therapy in the early 1980s may also have caused a decline in the number of trials being initiated and the number of patients being referred for phase III trials. Since the combination of etoposide and cisplatin was introduced in the treatment of this disease, there has been a significant lack of new drugs to use until recently. In this study, a least squares regression analysis demonstrated that cisplatin-based chemotherapy and the year of treatment were significantly associated with improved median survival time over the years (P = .04 and P = .002, respectively). The improvement in survival time was independently associated with both cisplatin-based therapy as well as the passage of time. Therefore, the increase in survival time observed with the passage of time was contributed to by factors other than the transition to etoposide and cisplatin therapy. We speculate that the other factor that most likely has contributed to the prolongation of patient survival over time is the improvement in the supportive care and general medical management of these patients. The association between cisplatin-based treatment and prolonged survival has also been observed in a recent meta-analysis of trials for patients with metastatic non-SCLC.30 Sixteen (76%) of the 21 phase III cooperative group therapeutic trials for patients with extensive-stage SCLC showed no difference in the survival time of patients between the experimental and standard arms regardless of the treatment regimens used. Three of the five studies13,18,27 that showed a significant difference between the experimental and control arms had median survival times in the control arms that were lower than the median survival time of patients in the SEER database treated during the same time period (7.0, 7.1, and 7.3 months in the phase III trials v 7.2, 7.3, and 7.9 months in the SEER database). The relatively poor outcome of patients in the control arm of these three phase III studies may have contributed to the significant differences in survival times that were observed in these trials. Despite diverse treatment strategies, the longest median survival time achieved in any of the experimental arms of the cooperative group studies was 12.3 months, and only four (19%) of the 21 phase III trials that we reviewed demonstrated a median survival time in the experimental arm of greater than 11 months. These results demonstrate that experimental regimens that investigators believe are promising in pilot or phase II studies rarely show prolonged survival when these regimens are compared with standard treatments for patients with extensive-stage SCLC. Although we observed a significant trend (P = .0001) toward a 2-month prolongation in patient median survival time over the 22 years of this analysis, there was no significant improvement in median survival time over the past 10 years (P = .27). The early phase III studies (between 1972 and 1981) had relatively short median survival times on the control arms, which included two studies that used single-agent cyclophosphamide as control treatment.9,11 The lack of change in patient survival time over the past 10 years contrasts with the conclusions presented recently by another investigator who reviewed selected aggressive chemotherapy regimens for patients with extensive-stage SCLC over the past 30 years and concluded that survival time of these patients was improving over the years.6 The lack of change in patient survival time that we observed over the past 10 years may reflect the consistent use of CAV or etoposide and cisplatin in the control arms of trials for patients with extensive-stage SCLC during that time period. These regimens have been shown in randomized studies to achieve similar survival times for patients with extensive-stage SCLC.24,31 In light of our observations that 22 years of clinical research has achieved only a 2-month improvement in the survival time of patients with extensive-stage SCLC, one must consider the economic impact and quality-of-life issues that surround the treatment of this disease. Studies of the quality of life of patients with extensive-stage SCLC have produced conflicting results. A study by Earl et al32 demonstrated that patients who received standard chemotherapy on schedule had a significantly improved quality of life compared with patients who received chemotherapy only as symptoms dictated. Another study found that weekly dose-intensive chemotherapy was associated with a significant decline in patient quality of life, whereas patients receiving the same chemotherapy given every 3 weeks had significantly less change in their quality-of-life parameters.33 Similar studies of quality of life in patients with non-SCLC receiving chemotherapy indicate that most patients report improvements in quality-of-life parameters once treatment is initiated.34 Although we were unable to retrieve information on patient quality of life in this study, the limited changes we observed in patient survival time suggest that a greater effort to apply new, experimental agents is indicated for patients with this disease. A comparison of the median survival time of patients with extensive-stage SCLC in the SEER database showed significantly prolonged median survival times of slightly less than 2 months in the group treated between 1993 and 1994 compared with the group treated between 1973 and 1974. The trend toward prolongation in survival has continued from 1977 to 1989 (Fig 2A). The SEER data corresponded with the modest trend for a prolongation of survival for patients with extensive-stage SCLC treated in cooperative group therapeutic trials over the past 20 years. This prolongation in the survival of patients with extensive-stage SCLC could have been caused by stage migration because of improved technology for imaging metastatic sites developed during the last 20 years, a phenomena referred to as the Will Rogers effect.35 If this were the case, we would expect there to be a prolongation in survival for each stage without an overall improvement. However, the SEER data suggest that there has been a prolongation in the survival of all patients with SCLC as well as those with extensive-stage SCLC over the 1973-to-1994 time period (Fig 2B). Our analysis and the results of these other studies show that many of the phase III trials that have been completed over the past 25 years have been small (< 100 patients per arm) and have insufficient power to detect modest differences (> 2 months) in survival times between the patients treated with the different regimens being tested. In this analysis, only seven (33%) of the 21 phase III trials enrolled at least 100 patients with extensive-stage SCLC onto each treatment arm and two (29%) of these seven showed a significant difference between the control and experimental arm (Table 1). In contrast, 14 (67%) of the 21 studies had fewer than 100 patients on at least one study arm and only three (21%) of the 14 showed a significant difference in the treatment outcomes. The differences in median survival times between patients with extensive-stage SCLC treated on experimental versus control arms have been small, even in the five studies that had a significant difference in survival times between the two arms. Only one of five trials had a difference of more than 2 months in median survival time between those patients treated with an experimental regimen and those treated with a control regimen.13 We believe that future trials designed for patients with extensive-stage SCLC should incorporate this information. Differences in median survival times in excess of 2 months are unlikely, so the trials should be sized appropriately. For example, for patients with extensive-stage SCLC, if one assumes a median survival time of 9 months in the control arm, a 2-month improvement is a 22% improvement. To detect a 22% improvement, the total sample size requirement is 840 patients for a power of 0.80.36 The new regimens brought forth in pilot and phase II studies have rarely led to significant prolongation in survival for patients with extensive-stage SCLC in phase III studies. We are currently developing a statistical model based on the results of the phase III trials for extensive-stage SCLC reported here that may assist investigators in deciding which pilot/phase II regimens are likely to prolong survival when tested in a phase III trial.37
The views and opinions expressed herein are those of the authors and are not to be construed as the official opinion of the United States Navy or the Department of Defense.
1. Ihde DC: Chemotherapy of lung cancer. N Engl J Med 327:1434-1441, 1992[Medline] 2. Albain KS, Crowley JJ, LeBlanc M, et al: Determinants of improved outcome in small-cell lung cancer: An analysis of the 2,580-patient Southwest Oncology Group data base. J Clin Oncol 8:1563-1574, 1990[Abstract] 3. Spiegelman D, Maurer LH, Ware JH, et al: Prognostic factors in small-cell carcinoma of the lung: An analysis of 1,521 patients. J Clin Oncol 7:344-354, 1989[Abstract] 4. Ihde DC, Glatstein EJ, Pass HI: Small-cell lung cancer, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott-Raven, 1997, pp 911-950 5. Chute JP, Venzon D, Hankins L, et al: Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute. Mayo Clin Proc 72:901-912, 1997[Abstract]
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Aisner J: Extensive-disease small-cell lung cancer: The thrill of victory; the agony of defeat. J Clin Oncol 14:658-665, 1996 7. The SEER 1973-1994 Public Use Data, SEER*Stat [computer database]. Version 1.0 for Windows 95/NT. Bethesda, MD, National Cancer Institute, 1997 8. Snedecor GW, Cochran WG: Statistical Methods (ed 6). Ames, IA, Iowa State University Press, 1967 9. Maurer LH, Tulloh M, Weiss RB, et al: A randomized combined modality trial in small cell carcinoma of the lung: Comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer 45:30-39, 1980[Medline] 10. Ettinger DS, Lagakos S: Phase III study of CCNU, cyclophosphamide, adriamycin, vincristine, and VP-16 in small-cell carcinoma of the lung. Cancer 49:1544-1554, 1982[Medline] 11. Lowenbraun S, Bartolucci A, Smalley RV, et al: The superiority of combination chemotherapy over single agent chemotherapy in small cell lung carcinoma. Cancer 44:406-413, 1979[Medline] 12. McCracken JD, Heilbrun L, White J, et al: Combination chemotherapy, radiotherapy, and BCG immunotherapy in extensive(metastatic) small cell carcinoma of the lung: A Southwest Oncology Group study. Cancer 46:2335-2340, 1980[Medline] 13. Daniels JR, Chak LY, Sikic BI, et al: Chemotherapy of small-cell carcinoma of lung: A randomized comparison of alternating and sequential combination chemotherapy programs. J Clin Oncol 2:1192-1199, 1984[Abstract] 14. Livingston RB, Mira JG, Chen TT, et al: Combined modality treatment of extensive small cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 2:585-590, 1984[Abstract] 15. Sandler A, Jirotek M, Vogl S, et al: A comparison of standard with intensive combination chemotherapy in small-cell lung cancer, mature results: An Eastern Cooperative Oncology Group Trial (ECOG). Proc Am Soc Clin Oncol 16:418a, 1997 (abstr 1730)
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Jackson DV Jr, Case LD, Zekan PJ, et al: Improvement of long-term survival in extensive small-cell lung cancer. J Clin Oncol 6:1161-1169, 1988 17. Everson LK, Jett JR, O'Fallon JR, et al: Alternating chemotherapy with or without VP-16 in extensive-stage small-cell lung cancer. Am J Clin Oncol 12:339-344, 1989[Medline] 18. Hong WK, Nicaise C, Lawson R, et al: Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: A randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol 7:450-456, 1989[Abstract] 19. Chahinian AP, Propert KJ, Ware JH, et al: A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 7:993-1002, 1989[Abstract]
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Johnson DH, Einhorn LH, Birch R, et al: A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 5:1731-1738, 1987 21. 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 [published erratum appears in Ann Intern Med 108:496, 1988]. Ann Intern Med 107:451-458, 1987 22. Ettinger DS, Finkelstein DM, Abeloff MD, et al: A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: A phase III study of the Eastern Cooperative Oncology Group. J Clin Oncol 8:230-240, 1990[Abstract] 23. Livingston RB, Schulman S, Mira JG, et al: Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: A Southwest Oncology Group study. Cancer Treat Rep 70:1395-1401, 1986[Medline] 24. 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]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
