|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 6271-6273 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.6055
Imatinib Mesylate Can Induce Objective Response in Progressing, Highly Expressing KIT Adenoid Cystic Carcinoma of the Salivary GlandsBeaujon University Hospital, Clichy; Institut Gustave-Roussy, Villejuif; Novartis Pharma; France To the Editor: KIT expression appears as a common feature in 80% to 100% of adenoid cystic carcinoma of the salivary glands arising from the head and neck.1-3 Imatinib mesylate to prevent the activation of KIT has been recently reported by Hotte et al as having limited or no activity in a multicenter phase II trial in 15 patients with unresectable or metastatic salivary adenoid cystic carcinoma.4
We are currently conducting a multicenter phase II trial in patients with recurrent or metastatic adenoid cystic carcinoma strongly overexpressing KIT using CD117 immunohistochemistry (50% to 100% staining in tumor cells). In our study, patients were required to display documented tumor progression on two consecutive computed tomography and/or magnetic resonance imaging scans performed 3 to 4 months apart before study entry and to have at least one measurable target lesion To date, eight patients (one male, seven females) have entered the study. Target lesions were pulmonary metastasis in all patients, with one patient also displaying locoregional recurrence. Median age was 45 years (range, 37 to 71), performance status was 0 in seven patients and 1 in one patient. Previous treatment with chemotherapy was reported in four patients. Toxicity was mild to moderate in all but one patient, who presented grade 3 neutropenia and anemia requiring transfusion and dose reduction, and another who experienced severe fatigue requiring treatment discontinuation. The latter patient, who was withdrawn early on for toxicity, was not assessable for efficacy. Among six assessable patients, three patients were stable after 3 months of treatment and one patient displayed a partial response of 42% according to the Response Evaluation Criteria in Solid Tumors Group criteria. This response was observed in a 41-year old woman who previously received cisplatin-FU combination with no objective response. Baseline grade 1 dyspnea completely resolved within the first two months of treatment. This clinical benefit correlated with a significant improvement in imaging as measured by a computed tomography scan performed after 3 months of treatment showing objective response on multiple pulmonary target lesions (Fig 1). The patient is still under treatment at 800 mg/d.
Results of the study by Hotte et al recently published in the Journal of Clinical Oncology have appeared rather disappointing with no evidence of objective response among 15 treated patients.4 Based on their results, the authors conclude that evaluation of imatinib mesylate is no longer warranted in this population. However, based on encouraging preliminary results in our phase II trial and other recent case reports,5 we would like to modulate this statement and suggest that imatimib mesylate may have, at least in a limited subset of patients, antitumor activity in adenoid cystic carcinoma. Interestingly, responses have been reported both in irradiated areas and in patients failing prior therapy with platinum.5 The natural history of this disease appears to be associated with a prolonged chronic phase during which the proliferation index as measured by flow cytometry in our experience was lower than 1%. A switch phase with acceleration of tumor progression is known to occur in most advanced disease. As physicians involved in early drug development trials, we usually require documented tumor progression as an essential eligibility criteria. Hence, in our trial and few case reports of objective responses,5 patients had clear documented tumor progression at study entry. Antitumor activity was preceded by early evidence of clinical benefit (disappearance of trismus, dysphagia or bleeding for locoregional relapse,5 complete resolution of dyspnea for pulmonary metastasis in our experience) after a few weeks of treatment. Therefore, discrepancies in results by Hotte et al and others might be, at least in part, explained by the nonrequirement for documented tumor progression at baseline in the Hotte et al study, suggesting that most of their patients might have been treated during nonacceleration phases of the disease. Therefore, the absence of cellular proliferation might have limited the potential of imatinib mesylate to induce tumor regression.
In addition, treatment parameters may also have impacted the likelihood of efficacy. In the study by Hotte et al the median duration of treatment was Finally, the level of KIT overexpression might play a role in imatinib mesylate sensitivity. Interestingly, a strong overexpression of KIT by tumor cells was a prerequisite to enter our study. The above-described patient who responded exhibited strong CD117 immunostaining. Conversely, only four of 16 patients were reported to display strong KIT expression in the study by Hotte et al. In the absence of overexpression and/or KIT mutations, response to imatinib mesylate is likely to be low and might account for the absence of drug activity in the study by Hotte et al. We are currently investigating the type of KIT mutation harbored by our responding patient. In summary, considering the few possible alternatives given to patients with recurrent or metastatic progressive adenoid cystic carcinoma, we consider that, although sporadic, evidence of antitumor activity deserves further clinical investigation. Translational research that could help to identify patients who would respond to imatinib mesylate is warranted before rejecting this drug for the treatment of patients with adenoid cystic carcinoma. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES 1. Holst VA, Marshall CE, Moskaluk CA, et al: KIT protein expression and analysis of c-kit gene mutation in adenoid cystic carcinoma. Mod Pathol 12:956-960, 1999[Medline] 2. Jeng YM, Lin CY, Hsu HC: Expression of the c-kit protein is associated with certain subtypes of salivary gland carcinoma. Cancer Lett 154:107-111, 2000[CrossRef][Medline] 3. Edwards PC, Bhuiya T, Kelsch RD: C-kit expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and monomorphic adenoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 95:586-593, 2003[Medline]
4. Hotte SJ, Winquist EW, Lamont E, et al: Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: A Princess Margaret Hospital phase II consortium Study. J Clin Oncol 23:585-590, 2005 5. 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] 6. Raymond E, Brandes A, Van Oosterom A, et al. Multicentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: An EORTC: NDDG/BTG Intergroup Study. Proc Am Assoc Clin Oncol 22:107s, 2004 (abstr (1501)
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
2 cm. Imatinib mesylate was administered at 400 mg orally bid (800 mg/d). The primary end point of our study is the assessment of time to tumor progression given the low proliferative fraction characterizing this disease making the observation of objective tumor shrinkage with any previously used anticancer agent unusual. 
2 months, which in a nonaccelerated phase might have been insufficient to maximize the duration of exposure and optimize the potential benefit of treatment. In our study, the first tumor evaluation was performed only after 3 months of treatment that was further maintained in the absence of tumor progression. Response to imatinib mesylate is known to sometimes occur only after several months of treatment and be preceded by sustained tumor stabilization. This has been observed in gastrointestinal stromal tumors, and slow responses according to Response Evaluation Criteria in Solid Tumors Group criteria have been supported by the use of positron emission tomography scans showing evidence of metabolic inactivation of the tumor. Similar observations were reported in patients with glioblastoma in whom responses occurred sometime after 6 months of tumor stabilization.
