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© 2001 American Society for Clinical Oncology Twenty-Two Years of Phase III Trials for Patients With Advanced Non–Small-Cell Lung Cancer: Sobering ResultsFrom the Lowe Center for Thoracic Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute, and Departments of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; Biometric Research Branch, Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; Cancer and Leukemia Group B, Chicago, IL; Eastern Cooperative Oncology Group, Pittsburgh, PA; Southwest Oncology Group, San Antonio, TX; North Central Cancer Treatment Group Philadelphia, PA; and National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada. Address reprint requests to Oscar S. Breathnach, MD, Thoracic Oncology Program, Dana-Farber Cancer Institute, Ste 1234, 44 Binney St, Boston, MA 02115.
PURPOSE: To determine the changes in clinical trials and outcomes of patients with advanced-stage non–small-cell lung cancer (NSCLC) treated on phase III randomized trials initiated in North America from 1973 to 1994. PATIENTS AND METHODS: Phase III trials for patients with advanced-stage NSCLC were identified through a search of the National Cancer Institute’s Cancer Therapy Evaluation Program database from 1973 to 1994, contact with Cooperative Groups, and by literature search of MEDLINE. Patients with advanced NSCLC treated during a similar time interval were also examined in the SEER database. Trends were tested in the number of trials, in the number and sex of patients entered on the trials, and in survival over time. RESULTS: Thirty-three phase III trials were initiated between 1973 and 1994. Twenty-four trials (73%) were initiated within the first half of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434 eligible patients. The median number of patients treated per arm of the trials rose from 77 (1973 to 1983) to 121 (1984 to 1994) (P < .001). Five trials (15%) showed a statistically significant difference in survival between treatment arms, with a median prolongation of the median survival of 2 months (range, 0.7 to 2.7 months). CONCLUSION: Analysis of past trials in North America shows that the prolongation in median survival between two arms of a randomized study was rarely in excess of 2 months. Techniques for improved use of patient resources and appropriate trial design for phase III randomized therapeutic trials with patients with advanced NSCLC need to be developed.
SYSTEMIC CHEMOTHERAPY for patients with advanced-stage non–small-cell lung cancer (NSCLC) prolongs survival and palliates symptoms compared with best supportive care alone.1,2 Meta-analysis of patients with advanced NSCLC who were treated with cisplatin-based therapy shows a modest improvement in survival.1 Despite systemic chemotherapy, lung cancer remains the greatest cause of cancer-related mortality within the United States.3 The 5-year survival of patients with advanced-stage NSCLC is less than 5%. Prior analysis of phase III trials for patients with extensive-stage small-cell lung cancer (SCLC) revealed that the median of median survival of patients treated on phase III trials and of patients recorded within the SEER database increased by 2 months between 1972 and 1990.4 We therefore chose to review all the published North American Cooperative Groups and institutional phase III randomized therapeutic trials for patients with advanced-stage NSCLC initiated during the time period of 1973 to 1994 in order to assess the impact of systemic chemotherapy on survival over time. As platinum-based regimens were used throughout the period under review, we divided the analyzed trials for comparison purposes according to two equivalent time periods: 1973 through 1983 and 1984 through 1994. Trials assessing combined-modality therapy of chemotherapy plus chest irradiation were not included in the analysis. We investigated whether the number of trials initiated had changed, whether the number of patients enrolled on the trials had increased or decreased over time, and whether survival of patients treated on these trials had improved. The median and 5-year survival information on patients with advanced-stage NSCLC from the last 25 years is available on the SEER database. This database provides the data with which to compare the outcomes of patients with advanced-stage NSCLC in both cooperative groups and in a population database.
Phase III Trials Phase III trials initiated for patients with advanced (inoperable stage III and IV) NSCLC were identified through a search of the National Cancer Institute’s Cancer Therapy Evaluation Program database from 1973 to 1994, by computer-based search of MEDLINE, and by direct contact with the Eastern Cooperative Oncology, Southwest Oncology, North Central Cancer Treatment, and National Cancer Institute of Canada-Clinical Trials cooperative groups, and Cancer and Leukemia Group B. We evaluated phase III trials initiated between 1973 and 1994, because this allowed adequate time for patient entry on study, follow-up, and publication of the mature results of the therapeutic trials. This period also included the interval examined in the meta-analysis by the Non-Small Cell Lung Cancer Collaborative Group, which compared systemic chemotherapy and best supportive care with best supportive care alone (11 trials; 1970 to 1985).1 The lung cancer committee chairs from each cooperative group in North America were contacted to notify them of this analysis and to inquire whether additional trials had been performed that were not known to the authors. Information was obtained about each trial regarding the years of enrollment within the trials, the number of patients enrolled on study, the sex of the patients, treatment regimens used, response rates, median survivals, the number of patient deaths at the time of the analysis, and differences in overall survival. The median of the median survival times was computed without adjusting for the sample size of the control group, and the median survival time of patients before and after 1983 was not adjusted for trial size. Each study median was entered as a data point. Trials included both patients with unresectable locally advanced-stage III disease and/or metastatic disease, in which chemotherapy was the primary therapeutic modality used in all patients. The inclusion criteria were similar to those of the preceding meta-analysis.1 The control arms were identified in each of the phase III trials on the basis of the statements of the authors in the published reports. A minority of the phase III trials did not have all of this information available in published articles. In these cases, the author of the study and the cooperative group statistician were contacted and additional data were obtained if available and permitted by the author. The SEER database was also examined to compare the median and 5-year survival information for patients with advanced-stage NSCLC versus our analysis of patients treated on phase III trials over the same time period. The time period from 1973 to 1995 was examined because the starting year corresponded most closely with the start of the cooperative studies, and 1995 corresponded most closely with the year that the cooperative group trials finished their accrual. In the SEER database, patients with metastatic disease are categorized as "distant disease." The SEER definition of distant disease is a neoplasm that has spread to parts of the body remote from the primary tumor either by direct extension or by discontinuous metastasis. In this analysis, patients from the SEER database with distant disease are termed "advanced stage" to be consistent with the terminology used in the cooperative group studies.
Statistical Method
Phase III Trials Forty-three randomized, controlled phase III trials initiated between 1973 and 1994 in North America involving 9,215 patients with advanced non–small-cell lung cancer were identified.5-47 Ten trials were found to be ineligible for the purpose of this analysis. Seven trials with 637 patients did not report the dates of initiation of the trials,13,14,17,33,36,45 two trials with 333 patients were reported as subgroup analyses, reporting only on their patients with squamous cell lung cancer and epidermoid lung cancers, respectively;23,31 and one trial with 109 patients included patients with small-cell lung cancer.8 Several attempts were made to contact the authors of the seven trials that had no reported date of initiation, but we were unsuccessful in gaining this information. The exclusion of this data did not appreciably alter the outcome of the study. We analyzed the treatment arms from the remaining 33 published phase-III trials that were initiated from 1973 to 1994. The results of these 33 trials are listed in Table 1.
A total of 8,434 patients with advanced-stage NSCLC were treated on these 33 phase III trials. Twenty-four trials (73%) were initiated within the first half of the period under analysis (1973 to 1983) and accounted for 64% of treated patients (n = 5,359). The percentage of women treated did not change significantly between the 1973-to-1983 and 1984-to-1994 time periods (40% and 39%, respectively). Eight of the nine trials (89%) initiated between 1984 and 1994 included only patients with performance status 0-2, compared with 50% of trials initiated between 1973 and 1983. Patients with brain metastases were included in three of the trials initiated between 1984 and 1994, which compares to 14 of the trials initiated between 1973 to 1983. In six trials initiated between 1973 and 1983, the authors do not specify whether the presence of brain metastases was considered in the eligibility criteria.10,11,15,21,26,29 The vast majority of trials (97%) included only patients not previously treated with chemotherapy. Seventeen percent of patients in a single trial had received prior chemotherapy.15 A median of 94 patients were treated per regimen in the 33 phase III trials initiated from 1973 to 1994 (range, 19 to 209). The median number of patients treated per arm of the trials increased from 77 (time period, 1973 to 1983) to 121 (time period, 1984 to 1994) (P < .001). Twenty-three trials (70%) included a platinum-based regimen in at least one arm of the trial. Eight of the nine (89%) trials in the 1984-to-1994 time period included a platinum-based regimen, compared with 15 of the 24 (63%) in the 1973-to-1983 time period. The overall response rate with chemotherapy ranged from 1% (vindesine alone) to 46% (vindesine and cisplatin), with a median of 17% over all therapeutic regimens.20,32 Three trials compared the response rate of low dose versus higher dose cisplatin. No significant difference was detected in the overall response rates between patients treated with low (50 mg/m2 to 60 mg/m2) or high doses (100 mg/m2 to 120 mg/m2) of cisplatin.11,18,20 The overall response rates in the 128 patients treated on the two trials with single-agent cisplatin at 50 mg/m2 were 4% (n = 1/23) and 12% (n = 13/105) compared with 7% (n = 2/27) and 14% (n = 15/108) in the 135 patients treated with single-agent cisplatin at 100 mg/m2, respectively.11,18 The third trial compared cisplatin at two dose levels (60 mg/m2 v 120 mg/m2) in association with a fixed dose of vindesine (3 mg/m2). The overall response rate in the 41 patients who received the 60-mg/m2 dose of cisplatin and vindesine was 46% compared with 40% in the 40 patients who received a 120-mg/m2 dose of cisplatin plus vindesine.20
Survival Time of Patients
A multivariate regression analysis that included the year of study initiation, platinum-based regimen indicator, treatment group indicator, brain metastases indicator, and the maximum performance status showed that platinum-based regimen and the year of study initiation (more recent years) were significantly related to median survival (P = .0318 and P = .0214, respectively). Five (15%) of the 33 phase III trials showed a statistically significant difference in survival time, and all were in favor of the patient cohort that received the experimental therapy compared with the control group (median, 2 months; range, 0.9 to 2.7).5,9,34,37,47 These five studies5,9,34,37,47 included a significantly larger number of patients per treatment arm (median, 149 patients per arm; range, 50 to 209) than did the studies that did not show a significant difference in median survival time (median, 88 patients per arm; range, 19 to 197; Wilcoxon test P = .026). Four of the five trials involved platinum-based regimens. Wozniak et al compared cisplatin versus cisplatin and vinorelbine (median survival, 6 v 8 months, respectively).47 Bonomi et al compared etoposide and cisplatin to 24-hour infusional paclitaxel at two dose levels in association with bolus cisplatin (median survival, 7.6 v 9.9 months, respectively).5 Crawford et al compared fluorouracil and leucovorin versus vinorelbine (median survival, 5.1 v 6.9 months, respectively).9 Rapp et al compared cyclophosphamide, doxorubicin, and cisplatin (CAP) versus vindesine and cisplatin (median survival, 5.2 v 7.9, respectively).37 The study also included an arm that evaluated patients treated with best supportive care alone (median survival, 3.9 months), which was not included in this current analysis; however, for the sake of completeness, the results of the best supportive care arm are included in Table 1. Miller et al compared fluorouracil, vincristine, and mitomycin C (FOMi) versus CAP versus alternating FOMi/CAP (median survival, 4.6 v 5.5 v 5.3 months, respectively).34 Nineteen of the other 28 trials that showed no significant difference in survival included platinum-based regimens.
SEER Database
The survival of all patients with non–small-cell lung cancer in the SEER database was also examined to determine potential change. There was a statistically significant linear trend in 5-year survival of all patients with non–small-cell lung cancer evaluated over 2-year intervals in 1973 to 1974 through 1991 to 1992 (P = .012). The median survival time for all patients with non–small-cell lung cancer in the SEER database increased from 9.1 months in the 1973-to-1974 time period to 10 months in the 1993-to-1994 time period, respectively. The corresponding 3-year and 5-year survival data increased by 2% to 4% (P < .0001) ( Table 2).
Analyses of phase III trials of systemic chemotherapy for advanced-stage non–small-cell lung cancer during the past 25 years show perceptible but modest advances in patient outcome. The increase in median survival in the phase III trials from the early time period (1973 to 1983) to the latter period (1984 to 1994) was 2.6 weeks. This closely matches the increase in median survival of 2 weeks in the SEER data over a similar period. During the late 1970s there was a shift from alkylating agent–based therapy to platinum-based regimens, with more recently available agents such as vinorelbine and paclitaxel included in trials only since 1990. However, other agents such as gemcitabine or docetaxel were only included in phase III trials starting after 1994 and so are not included in this analysis. Of the 33 phase III trials evaluated, only 5 (15%) trials showed a statistically significant prolongation in survival.5,9,34,37,47 In two of these five trials the control arm consisted of single-agent therapy. The choice of the control arm of fluorouracil in the trial by Crawford et al and the choice of a cisplatin-alone control arm in the trial by Wozniak et al might be perceived as attempts to maximize the potential for statistically significant differences in survival in these respective trials.9,47 Data from a meta-analysis that compared single agent versus combination chemotherapy in patients with advanced-stage NSCLC reported increased objective response rates and toxicity with combination therapy; however, when a platinum analog or vinorelbine was used as a single agent (10 trials), survival was not significantly increased with combination therapy.48 More recent phase III trials that compare the single-agent therapy of cisplatin with a combination therapy of cisplatin plus new agents, such as vinorelbine or gemcitabine, have favored the combination regimens, with statistically significant prolongation of survival being reported.47,49 The therapeutic potential of these newer agents in isolation continues to be evaluated. The analyses of the phase III therapeutic trials for patients with advanced lung cancer show some similarities as well as some differences between patients with NSCLC (8,436 patients on 33 trials) and those with SCLC (5,746 patients on 21 trials).4 Fifteen percent of the phase III trials in patients with advanced-stage NSCLC had statistically significant differences in survival compared with 5 (24%) of 21 phase III trials in patients with extensive-stage SCLC during a similar time period.4 The difference in median survival between patients treated with the control and experimental arm was 2 months or longer in only 11% of the phase III trials for both patients with NSCLC (8 of 33 trials) and SCLC (2 of 21 trials). Only one phase III trial (3%) in patients with advanced-stage NSCLC demonstrated a median survival in excess of 11 months,25 compared with four (19%) of the 21 trials in patients with extensive-stage SCLC.4 This finding may relate to the fact that SCLC is a more chemoresponsive disease, and that prolongation of survival is, therefore, more likely in its patients compared to those with NSCLC.
The number of phase III trials for patients with advanced-stage NSCLC in North America initiated between 1973 and 1994 decreased nearly three-fold over the latter half of the period assessed. In patients with extensive-stage SCLC a similar decrease in the number of phase III trials performed was not noted, with 11 trials that included 2,578 patients initiated from 1972 to 1981 and another 10 trials with 3,168 patients from 1982 to 1990.4 Potential explanations for the decrease in the number of phase III trials in patients with NSCLC may be the lack of innovative treatments introduced during this time period, and/or a declining interest on the part of physicians in the design and initiation of clinical trials in these patients. Despite the decrease in the number of phase III trials, the average number of patients per trial rose from 223 (5,359 patients on 24 trials) to 342 (3,075 patients on 9 trials) between the two time periods. Women with advanced-stage NSCLC represented
A comparison of the median survival time of patients with advanced-stage NSCLC in the SEER database shows a prolongation of median survival times of slightly less than 2 weeks in the group treated between 1973 and 1974 (6.9 months) compared with the group treated between 1993 and 1994 (7.3 months). This result is significantly less than the The quality of the trials performed during the time period under analysis also needs to be considered. Given that we propose that phase III trials should include at least 200 patients per treatment arm to detect a statistically significant differences in survival of 2 months between control and experimental arms, only one of the 33 trials that we included was actually eligible.47 Comorbid conditions of included patients are not included in the descriptions of patient characteristics in the individual trials, though exclusion criteria are fully detailed in all the 33 trials included. On the other hand, these eligibility criteria have become more strict, particularly since 1990, with the inclusion of only patients with a performance status of 0-1 and no evidence of brain metastases. Patients with performance status of either 0-3 (4 trials)7,10,11,26 or 0-4 (4 trials)21,22,28,29 were included on trials initiated before 1978. Of the patients included on these trials, 29% to 63% had a performance status of 0-1 (median, 39%). In comparison, from 1990 to 1994, three of the four trials performed included only patients with a performance status of 0-1, with all three trials showing statistically significant differences in survival.5,9,47 Trials initiated since 1988 have excluded patients with brain metastases. Fifteen of the 33 trials included patients with unresectable stage-III disease; more recent approaches include concurrent chemoradiation for patients with stage IIIB disease in the absence of malignant effusions. Only one of the 33 trials was blinded to treatment.30 The trials do not report on non–small-cell lung cancer–related mortality, so we are unable to provide that particular information. Only 18 of the 33 trials report on the number of patients alive at the time of study publication.5,6,15,16,18,21,24,26,27,29,30,34,35,41-43,46,47 Whether patients received further additional chemotherapy following completion of the phase III study–assigned chemotherapy is not reported, so we are unable to comment on its potential role. Multivariate regression analysis demonstrated that cisplatin-based chemotherapy and the year of treatment were significantly associated with improved median survival over the years in this study. Platinum-based regimens were more commonly used in the latter time period (1984 to 1994), which probably reflected the growing awareness of the impact of platinum-based regimens on survival.1 The improvement in survival over time was independently associated with both platinum-based therapy as well as with the passage of time. These findings were also identified as contributing to the increase in survival of the 5,746 patients with extensive-stage SCLC treated on 21 phase III trials.4 We speculate that the increase in survival time observed in patients with advanced-stage NSCLC with the passage of time may be, in part, owing to factors other than the transition to platinum-based therapy and the adoption of prior experimental regimens as both control and experimental treatment arms in subsequent trials. Additional factors that may also have contributed to prolonged survival include improvements in supportive care and general medical management of these patients, in addition to more selective inclusion criteria for trials in more recent years. Improved surgical and imaging staging techniques may have also resulted in the identification and treatment of patients with less extensively "advanced-stage" disease in more recent years; however, the increase in both the 3-year and 5-year survival of patients with all stages of non–small-cell lung cancer combined infers that stage migration alone doesn’t explain the modest improvement in survival in those patients with advanced-stage disease. In conclusion, the difference in median survival times between patients with advanced-stage non–small-cell lung cancer treated on experimental versus control arms has been modest, even in the five studies that show a significant difference in survival times between the treatment arms. Experimental regimens that investigators believe are promising in pilot or phase II trials rarely show prolonged survival beyond 2 months when these regimens are compared with standard treatments for patients with advanced-stage non–small-cell lung cancer. As a consequence, the majority of phase III trials have been underpowered in terms of the ability to detect realistic differences in survival between treatment arms. Future phase III clinical trials should be sized appropriately, with at least 200 patients per treatment arm, in order to detect an expected 2-month prolongation in survival between the therapeutic regimens. As promising results from phase II trials are often disappointing when assessed in phase III trials, they should not be regarded as adequate to change standard practice. In addition to the necessary development of therapeutic agents that act along novel pathways, techniques need to be developed for both the improved use of patient resources and a more appropriate trial design for phase III randomized trials of systemic chemotherapy in patients with advanced-stage NSCLC.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40% of persons entered on the phase III trials. This percentage remained constant between the periods 1973 to 1983 and 1984 to 1994. In the SEER database, women represent 34.5% of patients diagnosed with advanced-stage non–small-cell lung cancer between 1973 and 1994, with an increase in incidence from 29% to 37% for the time periods 1973 to 1983 and 1984 to 1994, respectively. This indicates a proportional representation of women in phase III trials of chemotherapy in persons with advanced-stage NSCLC. 
