Elsevier

Lung Cancer

Volume 30, Issue 1, October 2000, Pages 23-36
Lung Cancer

A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis

https://doi.org/10.1016/S0169-5002(00)00127-6Get rights and content

Abstract

Purpose: Cisplatin (CDDP) and etoposide (VP16) are considered major standard cytotoxic drugs for small cell lung cancer (SCLC). The present systematic review had as its objective the evaluation of their role, as components of chemotherapy regimens, on survival. Methods: Published randomised clinical trials (from 1980 to 1998) were selected comparing, in SCLC patients, chemotherapy regimens, given as first-line therapy. One arm (the experimental arm) had to include CDDP and/or VP16, while another had to omit the same drug(s). Trials quality was assessed by two published scores (Chalmers and European Lung Cancer Working Party (ELCWP)). For each individual trial, the hazard ratio (HR) of the survival distributions was estimated on the basis of reported statistics or, if not available, by extracting, from the survival graphical representations, the data required to construct the difference between expected and observed numbers of events as calculated in the log-rank statistic. A combined hazard ratio was obtained by the Peto method (a value <1 meaning a benefit for CDDP and/or VP16). Results: Thirty-six trials eligible for our systematic review were identified, classified into four groups (I–IV): group I, 1 trial testing a CDDP-based regimen (without VP16) against another arm not including either CDDP or VP16; group II, 17 trials testing a VP16-based regimen (without CDDP) against a regimen without VP16 and CDDP; group III, nine trials comparing a regimen including CDDP and VP16 with a regimen using neither drug; and, finally, group IV, nine trials comparing a regimen based on both drugs with a regimen based on VP16 only. Overall, Chalmers and ELCWP scores correlated well (rS=0.76, P<0.001) and had respective median scores of 50.3 and 63.7%. The number of eligible patients did not have a significant impact on the scores as well as the trials group, the trial positivity (a positive trial defined as showing itself a statistically significant survival benefit for the experimental regimen), overall or in categories, and the year of publication. Combined hazard ratios with 95% confidence intervals were: 0.70 (0.41–1.21) for group I, 0.72 (0.67–0.78) for II, 0.57 (0.51–0.64) for III, and 0.74 (0.66–0.83) for IV, showing a survival benefit in favour of regimens including etoposide alone or in combination with cisplatin, justifying with high significance levels the use of each of these drugs. Overall survival benefits could also be shown for regimens including CDDP (HR=0.61; confidence interval (CI), 0.57–0.66), as well as for those including VP16 (HR=0.65; CI, 0.61–0.69). Robustness of these results has to be confirmed with appropriate randomised trials.

Introduction

Polychemotherapy has been a main progress in the curative treatment of small cell lung cancer (SCLC). The first used regimens included cyclophosphamide (CPA), methotrexate, vincristine (VCR) and/or lomustine (CCNU). In the 1970s, a new combination was developed, called VAC and containing VCR, adriamycine (ADR) and CPA. Later, etoposide (VP16) and cisplatin (CDDP) were shown to be major active agents and their combination (EP) is today considered by most authors as the standard induction chemotherapy regimen for SCLC [1]. However, the randomised studies testing these drugs have given contradictory results, preventing, up to now, recommendation of the cisplatin–etoposide regimen with a high level of evidence.

The purpose of the present study was to assess the role of CDDP and VP16 in the medical treatment of SCLC by performing a systematic review of the randomised trials published in the literature with a qualitative evaluation of their methodology and an aggregation (meta-analysis) of the survival results.

Section snippets

Materials and methods

Criteria for eligibility of a trial to the present systematic review were the following: to deal only with small cell lung cancer, to be randomised, to have been published as a full paper between 1980 and 1998 in two major languages and one minor language, as those languages were those understandable by all the readers (English and French, and Dutch), to include at least 15 eligible patients per arm, and to compare first-line chemotherapy regimens, with an experimental arm containing CDDP

Results

Thirty-six studies, corresponding to a total of 40 publications [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49] and of 7173 randomised patients, were selected. Their main characteristics are shown in Table 1. The median number of eligible patients per study was 153 (range, 59–577). Ten trials dealt with

Discussion

This systematic review, by pooling all randomised trials comparing chemotherapy regimens with or without etoposide and/or cisplatin, revealed a positive effect on survival of the administration of these drugs in small cell lung cancer. As shown by the meta-analysis, in each of the four groups (Table 4), survival improvement is achieved by the use of regimens with etoposide but without cisplatin or of regimens with both drugs. It was not possible to analyse the role of cisplatin in regimens

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