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Originally published as JCO Early Release 10.1200/JCO.2008.19.5164 on October 20 2008 © 2008 American Society of Clinical Oncology.
Personalized Medicine in Advanced Non–Small-Cell Lung Cancer: Reality or Wishful Thinking?
University College Cork, Bon Secours Hospital, College Road, Cork, Ireland
University College Cork, Bon Secours Hospital, College Road, Cork, Ireland 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. NOTES published online ahead of print at www.jco.org on October 20, 2008 REFERENCES
1. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol 26:3543-3551, 2008 2. Ceppi P, Volante M, Saviozzi S, et al: Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107:1589-1596, 2006[CrossRef][Medline] 3. Peng G, Zinner R, Wang Y, et al: Comparison of patient outcomes stratified by histology among pemetrexed (P)-treated patients (pts) with stage IIIB/IV non–small-cell lung cancer (NSCLC) in two phase II trials. J Clin Oncol 26:447s, 2008 (suppl; abstr 8096)[CrossRef] 4. Peterson P, Park K, Fossella F, et al: Is pemetrexed more effective in adenocarcinoma and large cell carcinoma than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non–small-cell lung cancer (NSCLC). J Thorac Oncol 2:S851, 2008 (suppl 4)[CrossRef] 5. Ohe Y, Ichinose Y, Nakagawa K, et al: Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 14:4206-4212, 2008 6. Ciuleanu TE, Brodowicz T, Belani CP, et al: Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: A phase III study. J Clin Oncol 26;426s, 2008 (suppl; abstr 8011)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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