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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1325-1326 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.118
Trastuzumab in the Treatment of Advanced Non–Small-Cell Lung Cancer: Is There a Role?University of Michigan, Ann Arbor, MI To the Editor: Recently, Langer et al1 published the results of a phase II trial of trastuzumab in combination with carboplatin and paclitaxel in patients with advanced non–small-cell lung cancer (NSCLC). One of the authors' conclusions, which appears in both the Abstract and the Results sections of this article, is that the subset of patients whose tumors exhibited 3+ immunohistochemical expression of HER-2/neu experienced a survival exceeding that of historical controls. This interpretation of the study's data is not justifiable for several reasons. First, there were no significant differences in overall or progression-free survival between any of the HER-2/neu expression level subsets (log-rank P = .77 and P = .34, respectively). Median and 1-year overall survival and median progression-free survival are actually better in the subset of patients with 1+ HER-2/neu expression than in those with 3+ expression. The only parameter that appears to favor the 3+ HER-2/neu subset is 2-year overall survival (25%), which is based on the relative longevity of two of the eight patients in the 3+ HER-2/neu subset, both of whom appear to have died shortly thereafter. Basing a major conclusion in the Abstract of an article on two patients does not seem appropriate. Second, the historical controls used for comparison derive from a prior phase III Eastern Cooperative Oncology Group trial in which one of the experimental arms was carboplatin plus paclitaxel.2 Although the response rate and survival reported in the current trial by Langer et al1 do appear slightly higher than those in the prior Eastern Cooperative Oncology Group trial, a comparison between phase II and phase III data is highly suspect, even if the phase II trial is multi-institutional. As a case in point, the first phase II trial of carboplatin plus paclitaxel in advanced NSCLC reported a response rate of 62% with median and 1-year overall survivals of 53 weeks and 54%, respectively3—results that have never been approached in any randomized trial of this regimen and are also far better than those in the current phase II trial of trastuzumab, carboplatin, and paclitaxel. Finally, the comparison of a small, selected subset of patients from one study (eg, those with 3+ HER-2/neu expression) with the overall population of another study is invalid. In such a comparison, it is impossible to tell if any differences in outcome are due to the specific treatment or to the biology of the tumor in the selected subset. Perhaps patients with 3+ HER-2/neu expression respond better to carboplatin and paclitaxel, even without trastuzumab, than those with low or no expression of HER-2/neu. Answering this question would require a trial in which patients are randomly assigned to chemotherapy with or without trastuzumab. Thus far, only one such trial has been reported in patients with NSCLC, with no overall outcome differences noted with the addition of trastuzumab to chemotherapy.4 As noted by Langer et al, the six patients in the fluorescence in situ hybridization–positive or 3+ HER-2/neu subset treated with chemotherapy plus trastuzumab in this trial had a promising progression-free survival. However, because there were only two such patients in the chemotherapy-alone arm, a valid comparison of patients in this subset enrolled in each arm could not be presented. Langer et al1 appropriately conclude that the role of trastuzumab in the treatment of NSCLC remains unclear. However, their secondary conclusion regarding patients with 3+ HER-2/neu expression appears to be an overly enthusiastic interpretation of the data that should not have been prominently reported. Oncologists, even those not enrolling patients onto clinical trials, tend to be an experimental lot, and this conclusion, as presented, could inadvertently encourage the use of an expensive and toxic therapy for an unproven indication. On the basis of this article and the results of other available studies, the clear answer to the question posed in the title of the article is that, at this time, there is no role for trastuzumab in the treatment of patients with NSCLC outside of the clinical trial setting, regardless of the level of HER-2/neu expression. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Langer CJ, Stephenson P, Thor A, et al: Trastuzumab in the treatment of advanced non-small-cell lung cancer: Is there a role? Focus on Eastern Cooperative Oncology Group study 2598. J Clin Oncol 22:1180-1187, 2004
2. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346:92-98, 2002
3. Langer CJ, Leighton JC, Comis R, et al: Paclitaxel and carboplatin in combination in the treatment of advanced non-small cell lung cancer: A phase II toxicity, response, and survival analysis. J Clin Oncol 13:1860-1870, 1995
4. Gatzenmeier U, Groth G, Butts C, et al: Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small cell lung cancer. Ann Oncol 15:19-27, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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