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Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 6273-6274 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.6592
In Reply:Princess Margaret Hospital Phase II Consortium, Canada National Cancer Institute, Bethesda, MD We would first like to congratulate Dr Faivre and colleagues for conducting their innovative and interesting study, and we thank them for sharing their preliminary data. We will address their concerns related to our study1 and its conclusions.
Faivre et al state that one objective response has been seen on their study, and that at least two other responses have been observed by others and published as a case report.2 Although promising, the response seen in the study of Faivre et al has not yet been confirmed to our knowledge. Furthermore, the anecdotal responses observed in the case report were not part of a study protocol and should be interpreted with caution. Slevin et al recently published in abstract form their preliminary results of a phase II study with imatinib mesylate and cisplatin in patients with adenoid cystic carcinoma (ACC).3 One of 12 assessable patients had a documented partial response, which may be attributable to the combination of agents, but may also have been secondary to cisplatin alone. Our conclusion that imatinib mesylate did not warrant further evaluation in this patient population was not based on the premise that the agent had no activity whatsoever. It was based on the finding that, at the end of the first stage, the observed level of activity was lower than our predetermined assumption that imatinib mesylate would be worthy of further evaluation if the response rate was at least 5%.4 This was not observed in our study, and early termination occurred after completion of the first stage. Faivre et al also postulate that the patients enrolled in our study might have had limited potential to respond to imatinib mesylate because some of them may have been entered during a nonacceleration phase. Although interesting, we do not believe that this hypothesis has been supported by published scientific observations. In actuality, studies have suggested that patients in an accelerated phase of any type of cancer may not respond as well to these agents because of the development of multiple alternative mechanisms of progression. An example of this is the relative resistance of chronic myelogenous leukemia to imatinib mesylate in patients in an accelerated phase of the disease.5 In our study, median survival duration was 30 weeks, and 6-month survival proportion was 61.4%,1 suggesting that most patients were likely in an accelerated phase, given that ACC is a relatively indolent disease for the majority of its natural history. Faivre et al also suggest that because the median duration of treatment was Faivre et al suggest that the level of KIT overexpression may have played a role in the sensitivity of imatinib mesylate in our study. Certainly, from the literature on epidermal growth factor receptor (EGFR) inhibitors, data suggest a lack of correlation between intensity of EGFR overexpression by immunohistochemistry and clinical outcome.6,7 In our study, two of the four patients who had strong or moderate-to-strong staining had progressive disease, and the other two patients had stable disease, while at least one of the two patients who had prolonged stable disease status had weak immunohistochemical staining for KIT. Although these numbers are too small to make any definitive conclusions, they do suggest a lack of correlation. Finally, Faivre et al state that they are currently investigating the type of KIT mutations harbored by their responding patient. We await with interest their results, which may provide a molecular basis of the observed presumed response. We wholeheartedly agree that patients with recurrent or metastatic progressive ACC have very few possible therapeutic alternatives. It is for that reason that we must continue to study promising agents that will hopefully someday benefit patients afflicted with this disease. We are encouraged that, despite the fact that ACC is a rare disease, the investigators involved in this study were able to rapidly enter the necessary number of patients and look forward to further collaborations. Finally, we feel that the optimal first-line therapy for patients with advanced ACC should be administered within the realms of a clinical trial. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Hotte SJ, Winquist EW, Lamont E, et al: Imatinib mesylate in patients with C-KIT expressing adenoid cystic cancers of the salivary glands: A Princess Margaret Hospital Phase II Consortium study. J Clin Oncol 23:585-590, 2005 2. Alcedo JC, Fabrega JM, Arosemena JR, et al: Imatinib mesylate as treatment for adenoid cystic carcinoma of the salivary glands: Report of two successfully treated cases. Head Neck 26:829-831, 2004[CrossRef][Medline] 3. Slevin NJ, Mais KL, Bruce I, et al: Imatinib with cisplatin in recurrent and/or metastatic salivary adenoidcystic carcinoma –response assessed by FDG-PET scanning. J Clin Oncol 22:514s, 2004 (abstr 5604) 4. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline] 5. Hochhaus A, La Rosee P: Imatinib therapy in chronic myelogenous leukemia: Strategies to avoid and overcome resistance. Leukemia 18:1321-1331, 2004[CrossRef][Medline] 6. Parra HS, Cavina R, Latteri F, et al: Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1830) in non-small-cell lung cancer. Br J Cancer 91:208-212, 2004[Medline]
7. Soulieres D, Senzer NN, Vokes EE, et al: Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22:77-85, 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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2 months, patients were not on imatinib mesylate for a sufficient duration to benefit from the treatment. We disagree with this assumption. The vast majority of patients were taken off study because of disease progression, and the median progression-free survival was 10 weeks. Although we agree that imatinib mesylate may induce responses only after prolonged exposure, responding patients usually have stable disease before responding, and not disease progression, as observed in the patients treated in our study. 
