Elsevier

Lung Cancer

Volume 47, Issue 1, January 2005, Pages 69-80
Lung Cancer

Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes

https://doi.org/10.1016/j.lungcan.2004.10.014Get rights and content

Abstract

Purpose:

Gemcitabine–platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally.

Design:

Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes.

Results:

A significant reduction in overall mortality in favor of gemcitabine–platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84–0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine–platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine–platinum regimens, HR 0.84 (CI: 0.71–0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine–platinum regimens, HR 0.93 (CI: 0.86–1.01).

There was a significant decrease in the risk of disease progression in favor of gemcitabine–platinum regimens, HR 0.88 (CI: 0.82–0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine–platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine–platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77–0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82–0.96).

Introduction

Lung cancer is one of the most common forms of cancer in the world, in terms of incidence and mortality, with over one million new cases annually [1]. Non-small-cell lung cancer (NSCLC) accounts for at least 80% of all lung cancer cases, presenting as locally advanced disease in approximately 25–30% of cases and as metastatic disease in approximately 40–50% of cases [2]. The use of chemotherapy in patients with NSCLC has been under investigation for several decades. Conceptually, it has evolved from administration in the palliative care setting to integration into combined-modality curative therapy settings in patients with loco-regionally advanced disease, and more recently, data from the International Adjuvant Lung Trial suggest that chemotherapy plus surgery in early-stage disease provides benefit [3], [4], [5].

Incremental advances in the treatment of advanced NSCLC have occurred during the last two decades. Platinum-based combination therapies emerged as the standard treatment for advanced NSCLC [6], [7]. Randomized studies from the 1980s reported survival gains with cisplatin-based chemotherapy over best supportive care, which was confirmed by a large meta-analysis of cisplatin-based chemotherapy that estimated significant increases in median survival of 1.5 months and 1-year survival rate of 10% [8]. The 1995 meta-analysis evaluated the first- and second-generation platinum-based regimens (developed in the 1980s) before the third-generation cytotoxic agents (developed in the 1990s) including vinorelbine, docetaxel, paclitaxel and gemcitabine established their efficacy in advanced NSCLC in combination with cisplatin and carboplatin. Comparable efficacy was demonstrated by the third-generation agent platinum doublets when compared to each other in randomized trials [9], [10].

Consequently, a meaningful question may concern the potential survival advantage of these third-generation doublet combinations over those included in the previous NSCLC meta-analysis. The meta-analysis is the more appropriate methodological tool to look at small, but statistically significant, survival differences considering that a single randomized trial sized specifically to detect such small difference would not be feasible.

Gemcitabine is a novel nucleoside analogue exercising a wide spectrum of anti-tumoral activity, and in combination with cisplatin has shown activity in NSCLC. Several phase II studies of gemcitabine plus cisplatin reported median survival times of 11–15 months and response rates of 40% to above 50% [11], [12], while phase III studies showed superiority of gemcitabine plus cisplatin in advanced NSCLC in terms of both survival and quality of life benefits when compared with platinum alone or in combination with older chemotherapy agents [13], [14]. Gemcitabine plus cisplatin is widely used in clinical practice throughout the world, and in several European countries has become a common doublet combination for the treatment of advanced NSCLC. Replacement of cisplatin with carboplatin is attractive because it avoids cisplatin side effects and administration requirements. The combination of gemcitabine and carboplatin has been shown to be feasible and active in recent clinical trials [15], [16], [17].

The present meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent, cisplatin or carboplatin, in the treatment of advanced NSCLC using randomized clinical trials because gemcitabine plus platinum is a commonly used regimen and there is a large amount of published clinical trial data. The primary comparator was any regimen containing a platinum agent, alone or in combination, given the standard use of platinum-containing chemotherapy in the treatment of advanced NSCLC. The main outcome of interest was overall survival.

Section snippets

Identification of trials

The focus for the analysis was on randomized trials comparing gemcitabine doublets, containing either cisplatin or carboplatin, with any non-gemcitabine platinum-containing regimen (single agent, doublet or triplet) for the treatment of advanced NSCLC, reporting survival data using appropriate statistics. The search of all randomized trials was conducted through the major indexed literature databases, CancerLit, Current Contents, EMBASE, MEDLINE, PreMEDLINE, over the period of 1980 to December

Patient characteristics

A total of 4556 and 4249 patients were included in the meta-analysis of overall survival and progression-free survival, respectively. Main patient characteristics are given for each trial in Table 2. The median patient age across all trials was between 57 and 64 years, with an age range of 23–84 years. Of the enrolled population, the proportion of males ranged from 45 to 95%. All patients had histologically or cytologically confirmed non-small-cell lung cancer (NSCLC) as the primary diagnosis.

Discussion

Treatment of NSCLC has been a major challenge for oncologists in the past 15 years due to its high incidence and the large proportion of patients presenting with advanced or metastatic disease. A wide-reaching meta-analysis conducted last decade determined that cisplatin-based chemotherapy prolonged survival in advanced NSCLC [8]. Since then the combinations of third-generation agents, gemcitabine, docetaxel, paclitaxel, and vinorelbine, with either cisplatin or carboplatin, have made

Acknowledgements

The authors would like to thank Jean Pierre Pignon from the Institut Gustave-Roussy, France, for his guidance in carrying out the meta-analysis and support in the preparation of this manuscript. An unrestricted educational grant was provided to the contract research organization, M-TAG, to gather data, conduct the analysis and interpret the results in coordination with the authors. No grants were paid to the authors for participation in this meta-analysis. Three clinical investigators, Thierry

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