Reply to Watkins and Rukazenkov (J Cell Mol Med 2010), re-Letter of Response to manuscript entitled ‘Clinical outcomes in NSCLC patients with EGFR mutations: pooled analysis’ (Paz-Ares et al., J Cell Mol Med. 2010; 14(1–2): 51–69)

Abstract

To the Editor: In the Letter of Response from Watkins and Rukazenkov (J Cell Mol Med 2010), the paragraph starting with ‘It is important to note…’ summarizes potential sources of error in our pooled analysis. We were aware of the points correctly raised by Watkins and Rukazenkov when conducting our analysis and we agree that it is important to see the limitations of the performed study; these have been carefully detailed in the discussion part of the paper. The pooled analysis strived for a concise summary of the published data and we acknowledge that simplifying assumptions like the exponential distribution were indispensible to accomplish this. We would like to point out that the simplifications were applied to all treatments in an identical way and that a weighted pooled analysis was performed to adjust for different sample sizes. That this process would favour only one treatment and/or be detrimental to another treatment can therefore be ruled out. In many places within the paper we point to the need to exercise caution when interpreting the presented data, for example, it is repeatedly noted that the conclusions from the pooled analysis only apply to the considered patient pool and may not be readily extrapolated to an unseen patient population. Similarly, the reported P values gained from permutation runs are statistically valid, but apply as any conditional test to the considered patient pool only. Watkins and Rukazenkov refer correctly to randomized clinical trials (RCTs) as the gold standard to evaluate treatments; however, the pooled analysis of published studies provides a relevant view of the accumulated treatment experience in its own right. We consider this summary as a worthwhile contribution to the scientific/medical discussion in the area. Finally, we note that new RCT data have recently become available. The OPTIMAL study, a randomized phase III trial conducted only in patients with epidermal growth factor receptor (EGFR) activating mutation-positive non small cell lung cancer (NSCLC), evaluated first-line platinum doublet chemotherapy versus erlotinib. This study (n = 165) was reported at the ESMO congress in October 2010 and showed a hazard ratio for progression-free survival of 0.16 in favour of the erlotinib-treated patients. The median progression free survival (PFS) of 13.1 months in the erlotinib-treated group and 4.6 in the chemotherapy-treated group further support the results of our pooled analyses.