Elsevier

Oral Oncology

Volume 43, Issue 1, January 2007, Pages 33-36
Oral Oncology

A phase II study of Imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands

https://doi.org/10.1016/j.oraloncology.2005.12.026Get rights and content

Summary

Adenoid cystic carcinoma of the salivary glands is characterized by a poor response to chemotherapy. Most cases of adenoid cystic carcinoma express the c-kit protein. Imatinib mesylate (Gleevec) inhibits several protein-tyrosine kinases, including c-kit. We therefore hypothesized that Imatinib may be an effective drug in patients with locally advanced or metastatic adenoid cystic carcinoma and conducted a phase 2 trial in order to study this. Patients with locally advanced or metastatic adenoid cystic carcinoma and c-kit positive tumours were eligible. Fourteen patients were screened and 10 patients (71%) with c-kit positive tumours entered the study. Treatment was begun at a dose of Imatinib of 400 mg/day. Dose escalation was allowed in the absence of toxicity. The dose was increased to 600 mg/d in three patients and 800 mg/d in one patient. Three patients required dose reduction to 300 mg/d, due to grade 3 toxicity. No grade 4 toxicity was seen. No objective responses were seen. Two patients (20%) exhibited stable disease for 11 and 14 months, respectively. All other patients stopped treatment after 2–14 (median 6) months due to progressive disease. Imatinib has no major effect on advanced adenoid cystic carcinoma of the head and neck.

Introduction

Adenoid cystic carcinoma of the salivary glands (ACC) is an uncommon tumour which presents most often in the minor salivary glands. ACC have a tendency for infiltrating surrounding tissues and for perineural spread particularly towards the skull base. These tumours often develop loco-regional recurrence and tend to metastasize to the lungs. ACC are characterized by slow growth and it is not unusual for patients with lung metastases from ACC to survive for many years until the metastases reach a size that compromises respiratory function. These tumours usually respond poorly to chemotherapy. Most cases of adenoid cystic carcinoma of the salivary glands express the c-kit protein, often with very high levels of expression. 1, 2, 3

Imatinib mesylate (Glivec or Gleevec) is an inhibitor of several protein-tyrosine kinases, including those associated with BcrAbl, the PDGF-R and c-kit.4 These protein-tyrosine kinases are believed to play a role in tumour cell proliferation and are either uniquely or preferentially expressed in tumour cells. Inhibitors of these kinases may therefore be expected to show anti-tumour effect, possibly with fewer side effects than those associated with conventional anticancer chemotherapy.

Following the early reports that patients with gastrointestinal stromal sarcoma (GIST), which is characterized by high level of c-kit expression, showed important clinical responses to Imatinib, we decided to study this drug in patients with locally advanced and metastatic adenoid cystic carcinoma. The starting dose of 400 mg/day was chosen since in the initial phase 1 study of Imatinib in patients with GIST only 65% of patients receiving an initial dose of Imatinib greater than 400 mg/day were able to maintain that dose after 8 weeks treatment.5 In addition 400 mg/day was the dose selected for phase 3 study in patients with newly diagnosed chronic myeloid leukemia (CML).6 In our study dose escalation of Imatinib was allowed in patients who had no drug induced toxicity, following reports of a prolonged effect of Imatinib in patients with GIST receiving a higher dose of Imatinib.7

Section snippets

Patients and methods

Patients with histologically proven adenoid cystic carcinoma arising in the head and neck area who had metastatic disease or who had loco-regional disease which was judged by our head and neck cancer tumour board not to be amenable to curative therapy, were eligible for this study. Patients were required to have at least one site of measurable disease. Inclusion criteria included ECOG performance status 0–3, normal bone marrow (neutrophils >1500/μl; thrombocytes >100000/μl) and normal renal and

Results

Fourteen eligible patients who consented to participate in the study were screened. The tumours from 10 patients were considered to stain positively for c-kit and these patients received treatment with Imatinib. Patient characteristics are summarized in Table 1.

All patients began treatment with a dose of Imatinib of 400 mg/day. The dose of Imatinib was increased to 600 mg/day in three patients and to 800 mg in one patient. No grade 4 toxicity was seen. Three patients had dose reduction to 300 mg/d,

Discussion

Adenoid cystic carcinoma is a relatively rare tumour of the major and minor salivary glands. Surgical resection is the mainstay of treatment. The use of radiotherapy is controversial with some authors reporting long-term control after high dose radiotherapy,8 and others reporting little anti-tumour effect. Systemic chemotherapy has modest effect on adenoid cystic carcinoma.9 Thirty percent of patients in one study responded to 5FU-based chemotherapy10 although in another study no objective

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