Elsevier

Lung Cancer

Volume 63, Issue 1, January 2009, Pages 50-57
Lung Cancer

Magnitude of benefit of adjuvant chemotherapy for non-small cell lung cancer: Meta-analysis of randomized clinical trials

https://doi.org/10.1016/j.lungcan.2008.05.002Get rights and content

Summary

Several randomized trials investigating the benefit of adjuvant chemotherapy after surgery in non-small cell lung cancer (NSCLC) have provided conflicting results. With over 7000 patients included, we analyzed results of 13 reports over the past 10 years in which patients received either platinum-containing chemotherapy or not. The major endpoint was to assess the magnitude of the benefit of adjuvant chemotherapy in terms of the absolute benefit. All phase III randomized trials and meta-analyses published as peer-reviewed papers or as abstracts from 1994 to 2007 were eligible. A literature-based meta-analysis was performed; event-based overall- and disease-free survival (OS/DFS) and Relative Risks (RRs) with 95% confidence intervals (CIs) were derived. Magnitudes of benefit were evaluated with: absolute benefit and the number of patients treated for one patient to benefit. Seven sub-populations were examined. Combined effect estimation was computed with fixed- and random-effect models; a heterogeneity test was also applied. Twelve trials plus an individual patient meta-analysis (7334 patients) were gathered; the trials were designed to determine if cisplatin- or carboplatin-based chemotherapy improves survival over surgery. When data were pooled and plotted, significant differences in favor of chemotherapy were seen in OS in all seven sub-population, with a relative benefit of 7–12% and an absolute benefit ranging from 2.5% to 4.1%. A more significant trend for chemotherapy was found in DFS. No significant heterogeneity was observed for all outcomes and sub-populations. The absolute benefit of adjuvant chemotherapy remains essentially the same regardless of how data are screened. While significant differences are clearly found in this analysis, the small magnitude of benefit seen with this large population, especially when considering the number of patients needed for one to benefit, raises important issues when weighing risks and benefits of treatment for individual patients.

Introduction

Lung cancer is the leading cause of cancer death for both men and women in the US. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers [1], [2]. Despite progress in imaging and diagnostic procedures, patients with NSCLC usually present as advanced (locally or more frequently disseminated), and a small proportion (around 30%) as early stage [2]. Even for patients presenting with early stage disease and are completely surgically resected, about half will die due to lung cancer.

In order to improve survival and to delay recurrence, randomized phase III trials have been conducted to examine whether adjuvant radiotherapy and/or chemotherapy add any benefit over surgery alone. A recently updated meta-analysis of more than 2000 patients showed that radiotherapy does not add any benefit over surgery alone, and should not be considered as standard treatment [3], [4], [5]. The adoption of older techniques and the extra-thoracic relapse can explain this effect and suggests a role for adjuvant chemotherapy [2].

The landmark meta-analysis published by the NSCLC Collaborative Group (NSCLC-CG-MA) showed a significant benefit of chemotherapy over supportive care in advanced NSCLC; a further part of the meta-analysis demonstrated no statistically significant survival benefit for chemotherapy over surgery alone, although a positive trend was seen [6].

Eleven randomized clinical trials (RCTs) addressing the adjuvant chemotherapy question have recently been completed and published with conflicting results [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. One further phase III trial has been presented, without providing any significant benefit for platinum-based chemotherapy over surgery alone in stage IB patients [19]. Since more than 7000 patients have been enrolled in these trials without unanimity about the role of adjuvant chemotherapy for early NSCLC, a meta-analysis, seems appropriate to define the role and quantify any benefit.

In the field of evidence-based medicine, common standard of medical practice is built on levels of evidence [20]; the strongest contribution to care changes is provided by level-one-recommendations, arising from large RCTs or meta-analyses. A meta-analysis is particularly needed in those clinical situations in which RCTs produce conflicting results or have small sample sizes [21].

Although a consensus regarding adjuvant chemotherapy after surgical treatment has been reached nowadays [22], we performed a meta-analysis to quantify the survival outcome benefit, by comparing death and recurrence events in adjuvant cisplatin-based chemotherapy treated and untreated population.

Section snippets

Methods

Our comprehensive literature-based meta-analysis was conducted following four steps: the definition of the outcomes (definition of the question which the analysis was designed to answer), the definition of the criteria applied for the selection of the eligible trials, the definition of the search strategy, and the detailed description of the used statistical method [21], [23].

Selected trials

Trials selected for the analysis are summarized in Table 1. Twelve phase III prospective randomized trials published as original papers in peer-review journals or presented at major meetings from 2000 to 2007 and one individual patient meta-analysis published in 1995 addressing our pre-specified question were collected. At the time of our examination, all trials were closed for final analyses. The primary end-point of all trials was OS. All arms within each of the RCTs were well balanced for

Discussion

Although a consensus has been recently reached, there are still several controversies about the magnitude of the benefit of adjuvant chemotherapy in early NSCLC, due to different results provided by the large RCTs available in the literature [22], [32]. These RCTs were designed to confirm the trend in favor of chemotherapy after surgery that has been demonstrated by the NSCLC Collaborative Group Meta-analysis published in 1995 [6].

In general, a quantitative combined analysis should always be

Conclusions

This literature-based meta-analysis of all randomized phase III adjuvant cisplatin-based chemotherapy trials indicates that a significant benefit on both overall and disease-free survival is consistent across all subgroups examined at the sensitivity analysis, performed to decrease heterogeneity and biases. While a consistent benefit was observed, the magnitude of the benefit was not large. Overall, about a 3–4% absolute benefit in survival is found. The data indicate that approximately 24–39

Conflict of interest

None.

Acknowledgement

Supported by Italian Ministry of Health grant.

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