Elsevier

The Lancet Oncology

Volume 15, Issue 11, October 2014, Pages 1254-1262
The Lancet Oncology

Articles
Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data

https://doi.org/10.1016/S1470-2045(14)70402-4Get rights and content

Summary

Background

Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy.

Methods

All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics.

Findings

Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients—568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98–10·69] in patients assigned to six cycles vs 8·68 months [8·03–9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83–1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I2=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82–6·87) in patients assigned to six cycles and 5·33 months (4·90–5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68–0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia.

Interpretation

Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients.

Funding

None.

Introduction

The number of new cases of lung cancer diagnosed annually worldwide is about 1·5 million, roughly 85% of which are non-small-cell lung cancers. Unfortunately, more than 70% of cases are diagnosed at an advanced stage of the disease so these patients are only candidates for palliative systemic therapy.1

Standard first-line chemotherapy includes platinum-based regimens, four cycles of which are recommended for patients with stable disease with possibly two additional cycles for those who respond to treatment.2, 3, 4, 5 On the basis of these recommendations, all randomised trials, both published or ongoing, investigating maintenance approaches in advanced non-small-cell lung cancer include four cycles of induction platinum-based chemotherapy.6, 7, 8, 9, 10

Randomised phase 3 trials comparing six versus three or four planned cycles of platinum-based chemotherapy reported no significant differences in any outcomes, except increased toxicity with the more prolonged treatment.11, 12, 13 However, these trials were underpowered and judged to be inconclusive.4 A systematic review and meta-analysis14 based on abstracted data showed that more than four cycles of chemotherapy was associated with a longer progression-free survival compared with fewer cycles (hazard ratio [HR] 0·75, 95% CI 0·60–0·85; p<0·0001), without statistically significant differences in overall survival (HR 0·97, 95% CI 0·84–1·11; p=0·65) and with increased haematological toxicity.14 Another meta-analysis15 of abstracted data of randomised trials comparing different durations of treatment also showed that longer treatment was associated with a prolongation of progression-free survival (HR 0·75, 95% CI 0·69–0·81; p<0·00001) and a small increase in overall survival (0·92, 0·86–0·99; p=0·03).15 However, these meta-analyses included trials with varying study designs and studies that did not involve platinum-based chemotherapy, which makes the specific effect of the different number of cycles difficult to discern. Moreover, analyses of other outcomes and description of how effects vary by disease and patient characteristics were not possible without individual patient data.

Therefore, in view of this conflicting scenario and the new maintenance treatment approach for patients with advanced non-small-cell lung cancer without disease progression after the first cycles of treatment,2, 3, 4, 5 we did a systematic review and meta-analysis of individual patient data from trials that compared six versus fewer planned cycles of platinum-based chemotherapy. Our aims were to provide more conclusive clinical evidence about the outcome of six versus fewer planned cycles of platinum-based induction chemotherapy, and to explore whether this outcome might vary by patient and tumour characteristics.

Section snippets

Identification of eligible trials

On June 1, 2012, we did a search to identify all randomised trials (both published and unpublished) comparing six versus fewer planned cycles of platinum-based chemotherapy as the first-line treatment of patients with advanced non-small-cell lung cancer. Trials in which chemotherapy treatment was continued for more than six cycles or for an undefined number of cycles were not eligible for inclusion. We searched PubMed, Embase, Medline, and the Cochrane Library for papers published from 1966

Results

Our initial database search identified 679 potential full-text trials. Of these papers, 675 were excluded because they did not meet the inclusion criteria (eg, they were not randomised controlled trials) and four full-text studies were judged to be eligible for inclusion11, 12, 13, 20 (figure 1). We found another eligible trial in the proceedings of the 2007 World Conference on Lung Cancer.16 The trials were done by Tourani and colleagues in France,20 by Smith and colleagues in the UK,11 by von

Discussion

We did an individual patient data meta-analysis of four randomised trials comparing two different planned numbers of cycles of platinum-based regimens (panel).11, 12, 13, 16 Individual data from one further eligible trial were not available, but the data we collected represent 93·4% of all patients who were randomised in potentially eligible trials. We have recorded no evidence of additional benefit for six versus fewer cycles of platinum-based chemotherapy on overall survival. This result did

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