To the Editor:

We read with interest the recent manuscript of Scagliotti et al¹ reporting results of a noninferiority study comparing cisplatin plus gemcitabine to cisplatin and pemetrexed in advanced stage non–small-cell lung cancer (NSCLC). The authors are to be congratulated for completing the largest ever reported randomized trial in advanced NSCLC with more than twice as many patients assigned to treatment arms compared with other pivotal phase III trials.

We have some reservations in relation to the conclusion recommending cisplatin plus pemetrexed as a reference regimen for future studies in nonsquamous NSCLC testing molecular-targeted therapies. While the prespecified analysis demonstrated the superiority of cisplatin plus pemetrexed over cisplatin and gemcitabine in terms of response rate, progression-free survival (PFS) and overall survival in nonsquamous histology, this trial was neither designed nor powered to answer this question. Rather, it should be considered hypothesis generating. The preclinical rationale derives from a study showing high expression of thymidylate synthase (therapeutic target of pemetrexed) in squamous carcinoma, indicating resistance to pemetrexed.² However, the clinical evidence currently available is not overwhelming. The majority of published studies of chemotherapy in NSCLC have not shown any significant difference with respect to histology.

Recently Pang et al³ reported a combined analysis of two phase II trials. Patients with adenocarcinoma had better response rates to pemetrexed-based first-line chemotherapy but this did not transform to any significant differences in PFS and overall survival. It appears that response rates were not independently reviewed. A retrospective analysis of a phase III study of second-line therapy comparing docetaxel with pemetrexed suggested worse survival in pemetrexed arm with squamous histology and, conversely, a benefit in nonsquamous histology.⁴ Another study comparing standard- and low-dose of pemetrexed in second and third line showed on retrospective analysis that patients with nonsquamous histology did remarkably better.⁵ Finally Ciuleanu et al⁶ presented better PFS with pemetrexed maintenance after first-line therapy in comparison to placebo in nonsquamous histology.

This data could be interpreted in various ways. It may mean that pemetrexed is less effective in squamous histology with similar efficacy in nonsquamous in comparison with other platinum doublets. Therefore, we believe the definite answer can only be provided by a specifically designed prospective randomized trial.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.