ArticlesSix 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
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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These authors contributed equally