Correspondence

Authors Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their 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 ASCOs conflict of interest
policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Authors

Employment

Leadership

Consultant

Stock

T.G. Eisen
P.G. Harper

Eli Lilly (A)

Honoraria

Research Funds

Eli Lilly (A)

Eli Lilly (A)

Testimony

Other

Eli Lilly (A)

W.M.C. Martin

Lilly (A)
Dollar Amount Codes

(A) $10,000

(B) $10,000-99,999

REFERENCES
1. Rudd RM, Gower NH, Spiro SG, et al: Gemcitabine plus carboplatin
versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV
non-small-cell lung cancer: A phase III randomized study of the London Lung
Cancer Group. J Clin Oncol 23:142-153, 2005
2. Cullen MH, Joshi R, Chetiyawardana AD, et al: Mitomycin, ifosfamide
and cisplatin in non-small cell lung cancer: Treatment good enough to
compare. Br J Cancer 58:359-361, 1988
3. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: Effects on
survival and quality of life. J Clin Oncol 17:3188-3194, 1999
4. Sculier JP, Paesmans M, Lafitte JJ, et al: A randomised phase III trial
comparing consolidation treatment with further chemotherapy to chest
irradiation in patients with initially unresectable locoregional non-small-cell
lung cancer responding to induction chemotherapy: European Lung Cancer
Working Party. Ann Oncol 10:295-303, 1999
5. Sculier JP, Lafitte JJ, Paesmans M, et al: Phase III randomized trial
comparing moderate-dose cisplatin to combined cisplatin and carboplatin in
addition to mitomycin and ifosfamide in patients with stage IV non-small-cell
lung cancer. Br J Cancer 83:1128-1135, 2000
6. Sculier JP, Lafitte JJ, Berghmans T, et al: A phase III randomised study
comparing two different dose-intensity regimens as induction chemotherapy followed by thoracic irradiation in patients with advanced locoregional
non-small-cell lung cancer. Ann Oncol 15:399-409, 2004

DOI: 10.1200/JCO.2005.01.7640

Imatinib Mesylate Can Induce

Objective Response in Progressing,
Highly Expressing KIT Adenoid
Cystic Carcinoma of the
Salivary Glands
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 im-

(C) $100,000

(N/R) Not Required

munohistochemistry (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 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.
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

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Correspondence

Fig 1. Baseline (A)-(C) and evidence of

objective response (B)-(D) in a patient with
multiple pulmonary metastasis of an adenoid cystic carcinoma after 3 months of
daily oral 800 mg imatinib mesylate.

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
6272

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 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.6 Thus, the median duration of treatment in the
study by Hotte et al might be regarded as insufficient to
JOURNAL OF CLINICAL ONCOLOGY

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of Clinical Oncology. All rights reserved.
67.99.175.226

Correspondence

draw definitive conclusions on imatinib mesylate efficacy in

adenoid cystic carcinoma.
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.
Sandrine Faivre, Eric Raymond, Odile Casiraghi,
Stphane Temam, and Patrice Berthaud
Beaujon University Hospital, Clichy; Institut Gustave-Roussy, Villejuif;
Novartis Pharma; France

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 ASCOs conflict of interest
policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Authors
Patrice Berthaud

Employment

Leadership

Consultant

Stock

Honoraria

Research Funds

Testimony

Other

Novartis Pharma
Dollar Amount Codes

(A) $10,000

(B) $10,000-99,999

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
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
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
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 23:585590, 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
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)

DOI: 10.1200/JCO.2005.01.6055

IN REPLY: 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

(C) $100,000

(N/R) Not Required

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

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