Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study

doi:10.1016/S1368-8375(03)00097-6

Oral Oncology

Volume 39, Issue 7, October 2003, Pages 724-727

https://doi.org/10.1016/S1368-8375(03)00097-6 Get rights and content

Abstract

Phase II study of Herceptin® (Trastuzumab) in patients with advanced salivary gland tumors overexpressing Her2/neu. Patients with advanced, incurable salivary gland tumors and 2+ or 3+ Her2/neu expression in their tumors were enrolled in the study. After an initial dose of 4 mg/kg, patients received 2 mg/kg weekly. Patients were treated until they experienced progression of disease or unacceptable toxicity. The study was closed early when it has become clear that the majority of tumors screened did not overexpress Her2/neu. Fourteen patients were enrolled in the study. A total of 86 cycles of Herceptin were delivered with a median of three cycles per patient (range 1–40). Median time to progression was 4.2 months. One patient with metastatic mucoepidermoid carcinoma has received 40 cycles of Herceptin to date with a documented partial response. Herceptin given as a single agent has a low activity in salivary gland tumors overexpressing Her2/neu. New agents are still needed.

Introduction

Salivary gland neoplasms account for approximately 5% of all head and neck cancers. The majority arise in the parotid gland, and of these 25% are malignant. Of those tumors which arise in the other salivary glands, 50% are malignant.¹ Malignant epithelial tumors of the salivary glands can be classified histologically as mucopeidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), carcinoma ex pleomorphic adenoma, acinic cell carcinoma, polymorphous low grade adenocarcinomas and a collection of other rare tumor types.² Acinic cell carcinoma, adenoid cystic carcinoma and carcinoma ex pleomorphic adenoma are thought to arise from the intercalated duct of the salivary gland, whereas salivary duct carcinoma, squamous cell carcinoma and mucoepidermoid carcinoma are thought to arise from the salivary excretory duct.³

Surgical resection is the primary treatment of these neoplasms at initial diagnosis. Radiation therapy is usually reserved for patients with advanced disease with inadequate margins or with poor prognostic features such as perineural invasion or anaplastic histology.⁴

Chemotherapy, in general, has been reserved for patients with incurable salivary neoplasms. Typical response rates are in the order of 15–30% and are usually short lived. The most active single agents include cisplatin, cyclophosphamide, doxorubicin and 5-fluorouracil. Therefore, there is a definite need to look for more active agents in this disease.

Her2/neu is a protooncogene that is located on chromosome 17q. Amplification of Her2/neu or overexpression of its protein exists in a number of human carcinomas including breast, ovary, endometrial, thyroid and salivary neoplasms and has been associated with a poor prognosis in these patients.5, 6, 7, 8 Salivary carcinoma overexpression of Her2/neu assayed by immunostaining techniques has been reported prior to this study in mucoepidermoid carcinoma (30–38%), adenoid cystic carcinoma (56%) and terminal duct carcinoma (24%), suggesting that dysregulation of Her2/neu as a contributing factor is not histology specific.5, 9

Herceptin® (Trastuzumab), a humanized murine monoclonal antibody directed against Her2/neu protein has been studied extensively in breast cancer. There are no prior trials of Herceptin in patients with advanced salivary gland neoplasms. We report here the first such trial in these patients.

Section snippets

Patients and methods

Patients with locally advanced or metastatic salivary gland tumors were enrolled in an institutional review board (IRB) approved phase II study of Herceptin used as a single agent. All patients signed IRB approved consents prior to enrollment. Entry criteria included a histological diagnosis of salivary gland tumor, incurable disease on the basis of unresectable local disease or distant metastasis, maximum of two regimens of cytotoxic chemotherapy, ECOG performance status of 0 or 1,

Results

Patient characteristics are listed in Table 1. Fourteen patients were enrolled between October 1999 and August 2001. The study was closed early when it became clear that the majority of patients screened did not overexpress Her2/neu suggesting a very limited role for Herceptin in salivary gland tumors.¹⁰ There were 10 males and 4 females with a mean age of 60 (range 44–80). The majority of the tumors were of parotid origin (9/14) with the predominant histology being adenocarcinoma (7/14). Five

Discussion

Malignant tumors of salivary gland origin are rare neoplasms. There are approximately 2000 cases reported annually in the USA. Many pathologic subtypes have been defined as distinct clinicopathologic and biologic entities. Salivary duct carcinoma, intermediate and high grade mucoepidermoid carcinoma, undifferentiated carcinoma and carcinoma ex pleomorphic adenoma are clinically aggressive and may recur or metastasize quickly. Adenoid cystic carcinoma is often controlled locally, however

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Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study☆

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Otolaryngol Head Neck Surg

Malignant salivary tumors—analysis of prognostic factors and survival

Head Neck Surg

Salivary neoplasmsoverview of a 35-year experience with 2,807 patients

Head Neck Surg

Malignant tumors of the salivary glands

Management of malignant tumors of the salivary glands

Oncology (Huntingt)

Amplification and overexpression of HER-2/neu in carcinomas of the salivary glandcorrelation with poor prognosis

Cancer Res.

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes

Br J Cancer