© 2004 European Society for Medical Oncology
Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials
1 Department of Medicine II, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama, 700-8558; 2 Department of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
* Correspondence to: Dr K. Hotta, Department of Medicine II, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama, 700-8558, Japan. Tel: +81-86-235-7227; Fax: +81-86-232-8226; Email: khotta{at}md.okayama-u.ac.jp
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Abstract |
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Background: Single new agents reportedly produce promising response and survival effects, but platinum-based doublets remain the standard chemotherapy for advanced non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the effectiveness of platinum for advanced NSCLC by carrying out a meta-analysis of trials that compared platinum-based doublets with single new agent therapy alone.
Methods: We carried out a literature search to identify trials, conducted between 1994 and 2003, comparing a doublet of platinum plus a new agent with a new agent alone in previously untreated patients with advanced NSCLC. Outcomes analysed were response, survival and toxicity.
Results: Eight trials encompassing 2374 patients were identified. Platinum-based doublets produced an approximately two-fold higher overall (complete and partial) response rate than the new agent alone [odds ratio = 2.32; 95% confidence interval (CI)=1.68–3.20]. Platinum-based doublet therapy was also associated with a 13% prolongation of survival (hazard ratio = 0.87; 95% CI = 0.80–0.94, P <0.001). Despite significant increases in the frequencies of various toxic effects in patients receiving platinum-based doublets, no significant difference in treatment-related mortality was observed.
Conclusion: This is the first published meta-analysis demonstrating the importance of combining platinum with single new agents in the treatment of advanced NSCLC.
Key words: doublets, non-small-cell lung cancer, platinum, single-agent therapy
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Introduction |
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Lung cancer is the leading cause of cancer-related deaths within the United States and throughout the world, with a median survival time of 16.8 months in 2001, and non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases [1
]. A previous meta-analysis showed a 10% absolute improvement in the 1-year survival rate in patients with advanced NSCLC treated with cisplatin (CDDP)-based chemotherapy over best supportive care alone [2].
Recently, new agents with novel mechanisms [paclitaxel (Taxol), docetaxel (Taxotere), irinotecan, gemcitabine and vinorelbine] have been developed and some of them have already been reported to produce a significant survival advantage as a single-agent over the best supportive care alone in patients with advanced NSCLC [3, 4]. Furthermore, doublets consisting of CDDP plus one of these new agents have been shown to improve survival compared to CDDP plus existing agents such as vindesine or etoposide in patients with advanced NSCLC [5, 6].
Several randomised trials have thus compared single new agent treatment with doublets consisting of platinum plus one of the new agents [7–16]. However, these trials have yielded conflicting survival results. Accordingly, we carried out a meta-analysis to compare the effects of platinum plus a single new agent with single new agent therapy alone on overall survival as well as on overall (complete and partial) response rate and toxicity in patients with advanced NSCLC.
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Materials and methods |
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Search for trials
Both published and unpublished trials reported between January 1994 and February 2003 were identified through a computer-based search of the PubMed database and Ichushi, a Japanese journal database, and a manual search of abstracts from the past 10 conferences of the American Society of Clinical Oncology and the past three conferences of the International Association for the Study of Lung Cancer. We searched using the following terms: ‘lung cancer’, ‘chemotherapy’ and ‘randomised controlled trial’. We also examined reference lists of original articles, review articles, relevant books and the Physician Data Query registry of clinical trials.
Selection of trials
If at least one platinum-based doublet and one single new agent therapy were included in a randomised trial, it was considered to be eligible. A platinum-based doublet included one platinum agent and one new agent (paclitaxel, docetaxel, irinotecan, gemcitabine, or vinorelbine), and the single agent had to be one of these new agents. Trials were excluded from our analysis if the new agents used in the platinum-based doublet were different from the single-agent therapies. Patients with pathologically confirmed advanced NSCLC who had not previously received chemotherapy were enrolled in these trials.
Validity assessment
We carried out an open assessment of the trials and used the instrument reported by Jadad et al. [17]. However, no evident differences were observed among the trials. Therefore, the result of the validity assessment was not considered in the meta-analysis.
Data abstraction
To avoid bias in the data abstraction process, two observers (K.H. and H.U.) independently abstracted the data from the trials and subsequently compared the results. All data were checked for internal consistency, and disagreements were resolved by discussion among the investigators. We tried to contact principal investigators of the trials to confirm or update both published and unpublished data.
Quantitative data synthesis
We applied odds ratios (ORs) to assess objective response rate and toxic events. We constructed 2 x 2 tables from abstracted data for responses and for each toxic event. ORs and their variances for the subjects who received a platinum-based doublet relative to those receiving single new agent therapy alone were calculated from the tables. For OR calculations, we excluded ineligible subjects from each evaluation.
Hazard ratios (HR) were applied to assess the survival advantage of platinum-based doublets compared with that of single-agent therapy alone. Crude log HR and its variance for each trial were calculated using the abstracted survival probabilities at each time point according to the methods proposed by Parmar et al. [18]. Minimum and maximum follow-up times were used to estimate censored subjects under the assumption that censoring happens constantly throughout follow-up. If the minimum follow-up time was not available, time zero was substituted for it. As we assumed a constant hazard for the two types of therapy within an individual trial, all of the survival probabilities available in each trial were used to obtain a representative HR for each trial instead of limiting time points to specified times. HRs were calculated to represent how many times higher the probability of death was from any cause in patients receiving a platinum-based doublet compared with those receiving single-agent therapy. Therefore, a HR below unity indicates that the platinum-based doublet is better than single-agent therapy.
A general variance-based method was used to estimate the summary HR, ORs and their 95% confidence intervals (CIs). We looked for heterogeneity among the trials based on standard methods [19]. We also calculated the between-study variation (
2) from the Q statistic according to the method described by DerSimonian and Laird [20]. Regardless of the statistical significance of the Q test, we applied a random effect model which allows meta-analyses to take between-study variation into consideration. We also used Begg's funnel plots [21] and Egger's test [22] to detect possible publication bias. Meta-regression analysis was applied to detect the source of heterogeneity in the survival analysis. The factors examined in meta-regression analysis were study quality score [17], starting year of the trial, proportion of patients with performance status (PS) 0–1, using the World Health Organization criteria or others proportion of stage IV patients, proportion of male patients, and inclusion of carboplatin. A cumulative meta-analysis was planned in order to take trial quality into consideration when the trial showed quality score heterogeneity [17].
All statistical analyses were conducted with STATA ver. 8 software (College Station, TX, USA). We defined a statistical test with a P value less than 0.05 as significant.
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Results |
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Trial flow
The flow chart of our study is shown in Figure 1. Ultimately, eight trials involving 2374 patients with advanced NSCLC were analysed in this meta-analysis [7
–14]. There were no trials that were excluded from our study only because they were published in languages other than English. One of the remaining 10 potentially appropriate trials that compared CDDP and gemcitabine with gemcitabine alone in 72 patients was excluded from our analysis because we were unable to obtain the relevant data [16].
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Characteristics of the eight trials
Baseline characteristics of the eight trials are listed in Table 1. In total, 2351 patients were randomised to a platinum-based doublet (1191 patients) or a single new agent therapy (1160 patients); 23 patients enrolled in one trial were excluded before randomisation [12
]. Further information about one published trial [8] and three unpublished trials [11–13] were obtained by contacting the principal authors. Other potential sources of heterogeneity, including platinum type (CDDP versus carboplatin), were examined by meta-regression analysis. However, none of these factors were associated with significant differences in outcomes with a few exceptions as described below.
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Response rate and overall survival
Data on objective response rates were available for all eight trials (Table 2). Based on intention-to-treat analysis using all randomised patients, the objective response rate to a platinum-based doublet was more than two-fold higher than to single-agent therapy (OR = 2.32; 95% CI = 1.68–3.20 Figure 2). Neither a funnel plot nor a rank correlation test regarding response rate indicated the existence of publication bias (Z=1.24, P=0.22). The heterogeneity test yielded a significant result (P=0.017). Meta-regression analysis showed that a higher percentage of stage IV patients had a reduced response (P=0.01).
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Data on overall survival were available for all eight trials (2331 patients, Table 3). Survival analyses were carried out based on intention-to-treat analysis in five trials and seven, six and seven patients in the trials reported by Lorusso et al. [9
], Deza et al. [11] and Negoro et al. [10], respectively, were excluded from the survival analysis after randomisation. Since none of the trials gave the HR required for meta-analysis, we applied HRs calculated from KM curves in all trials, based on the method of Parmar et al. [18]. Platinum-based doublet therapy was associated with a 13% improvement in overall survival compared with single-agent therapy (HR = 0.87; 95% CI = 0.80–0.94, P <0.001, Figure 3). Similarly, a funnel plot and rank correlation test regarding survival confirmed the absence of publication bias (Z=0.83, P=0.40).
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Toxicity
Eight trials encompassing 2251 patients provided toxicity profile results (Table 4). Complete data for neutropenia were not obtained in three trials [9
, 11, 13]; data for thrombocytopenia and nausea/vomiting were not available in two trials each [9, 11]; and data for nephrotoxicity were not available in one trial [11]. The heterogeneity test was statistically significant for neutropenia and nausea/vomiting. Further meta-regression analysis failed to show any significant source of heterogeneity from examined factors for neutropenia. Regarding nausea/vomiting, male subjects had an increased chance of experiencing a nausea/vomiting event and use of carboplatin reduced it. Platinum-based doublet therapy significantly increased the frequency of all toxic effects over single-agent therapy, whereas no significant difference in treatment-related mortality was observed between the two treatment modalities (1.4% versus 1.2%, OR = 0.97; 95% CI = 0.41–2.26, P=0.94).
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Discussion |
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Lilenbaum et al. [12
] previously carried out a meta-analysis to compare the effect of combination chemotherapy with that of single-agent chemotherapy on overall survival in patients with advanced NSCLC [23]. They concluded that overall survival was modestly improved with combination chemotherapy. However, in the majority of trials analysed, outdated chemotherapy regimens were used, and only small numbers of patients were included. Thus, the impact of platinum plus one of the new agents on the survival of advanced NSCLC patients compared with that of single new agent therapy remained undetermined.
In this study, we used data from trials comparing platinum plus one of the new agents with the new agent alone; three trials evaluated in our study were also included in Lilenbaum's study [7, 8, 11]. Our results indicate that the addition of platinum to single new agents is important, if they have adequate organ function and good performance status. However, it remains unclear which new drug should be combined with platinum in a platinum-based doublet and further investigation is necessary.
Two meta-analyses on the addition of a second drug for recently advanced NSCLC have been presented [24, 25]. Both were based on literature data. Using 33 trials with 7872 patients, Delbaldo et al. [24] demonstrated a significant increase in response rate and survival in favour of two drugs (OR = 0.39; 95% CI = 0.35–0.45, P <0.001 and HR = 0.79; 95%CI = 0.75–0.83, P <0.001). Baggstrom et al. [25] identified 17 trials randomising 4421 patients with advanced NSCLC to one drug or two drugs, and demonstrated that the doublet chemotherapy is superior in terms of overall survival as well as response. Although the eligible trials and patient populations were different among the studies, all three studies including our study indicate that a one-drug regimen is inferior in terms of response and survival.
We included the two trials in which the effect of carboplatin was investigated [12, 13]. Recently, we carried out another meta-analysis of the trials that compared CDDP-based chemotherapy with carboplatin-based chemotherapy, which revealed that combination chemotherapy consisting of CDDP plus a new agent yields a substantial survival advantage compared with carboplatin plus a new agent in patients with advanced NSCLC [26]. Thus, inclusion of trials using carboplatin will give conservative P values for summary statistics. However, the highly significant association found in the current analysis indicates that CDDP is important in the treatment of advanced NSCLC. In addition, meta-regression analysis in this study showed that inclusion of trials using carboplatin did not change the results in our study, which suggests that the inclusion of the two trials using carboplatin did not alter our main conclusion. Further investigation will be needed to clarify the role of carboplatin in the treatment of advanced NSCLC.
Our study has several limitations. First, one major problem is that our analyses were based on abstracted data, since an individual patient data based meta-analysis would give a more robust estimate of the association [27]. Therefore, physicians should interpret our results carefully. Second, some of the trials we identified were reported in abstract form only, which made it difficult to extract complete data for our meta-analysis. However, additional updated data fully adequate for this meta-analysis were obtained in several cases by contacting the principal investigators. Third, as is often the case with meta-analysis, one must still be cautious in interpreting our results because of the substantial effect of heterogeneity, although we applied a random-effect model to obtain summary statistics. The significant results from the heterogeneity tests for response rate, neutropenia and nausea/vomiting represent potential heterogeneity and may modify the association we found in our study. Possible publication bias is also a potential harm in our study, though we did not detect it statistically. Finally, the dose of new agent used in the platinum-based doublet was different from that in the single-agent therapy in Negoro's trial [10]. Irinotecan was administered at a dose of 100 mg/m2 in the single-agent therapy, whereas 60 mg/m2 of irinotecan was combined with cisplatin in the combination arm. It might be problematic to analyse the importance of platinum in our study. However, we considered that the effect would be very small, if any, because it occurred in only one of the eight trials and because the same administration schedule for irinotecan was used in both arms.
In conclusion, this is the first published meta-analysis, to our knowledge, of randomised trials of platinum-based doublet versus single new agent therapy alone. Although modest, the survival improvement obtained with the platinum-based doublet in comparison to a single new agent therapy indicates the importance of platinum in the treatment of advanced NSCLC.
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Acknowledgements |
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We wish to thank Dr Alain Depierre, Dr Ernesto Gil Deza, Dr Rogerio C Lilenbaum and Dr Christer Sederholm for their valuable comments and for providing data.
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Notes |
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These authors contributed equally to this work. 
Received for publication April 11, 2004. Revision received July 6, 2004. Accepted for publication July 19, 2004.
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