Salivary gland adenoid cystic carcinoma: A review of chemotherapy and molecular therapies

Summary

Adenoid cystic carcinoma (ACC) accounts for about 1% of all head and neck malignancies. It has a tendency for a prolonged clinical course, with local recurrences and distant metastases sometimes occurring many years after presentation. Standard treatment for salivary gland ACC is surgery and post-operative radiotherapy. The aim of this review was to examine the reported efficacy of various chemotherapy regimens and molecular therapies on recurrent/metastatic salivary gland ACC. One hundred and fourteen publications were reviewed on chemotherapy as well as possible molecular targets of therapy, including KIT, epidermal growth factor receptor (EGFR), human epidermal growth receptor-2 (HER-2), oestrogen and progesterone receptors, proliferating cell nuclear antigen (PCNA), Ki-67 and the p53, bcl-2 and SOX-4 genes. Reported response rates to combination chemotherapy are low and response duration generally short lived. The response to molecular therapies is low also. More research into novel molecular targets is needed.

Introduction

Adenoid cystic carcinoma (ACC) is an uncommon malignancy that arises in secretory glands particularly the major and minor salivary glands. Other sites include the tracheobronchial tree, breast, skin, lacrimal gland, female genital tract and prostate. In all these sites it has a relatively indolent course. Adenoid cystic carcinoma accounts for around 10% of all salivary gland neoplasms,1, 2, 3, 4, 5, 6 22% of all salivary gland malignancies⁷ and about 1% of all head and neck malignancies.2, 3 The majority of these tumours occur in the minor salivary glands and the oral cavity is the most frequent site.1, 3, 6, 8 The median/mean age at presentation is 47–56.1, 2, 3, 4, 5, 8, 10, 11, 12 There are three histological sub-types, solid, cribriform and tubular, but grading is difficult as a tumour may show evidence of more than one sub-type.12, 13, 14 Patients with tumours of predominantly solid characteristics are claimed to have a worse prognosis,2, 6, 10, 11, 12, 13, 15 but stage is more important than histological type in determining outcome.5, 14

ACC has the propensity for a protracted clinical course; even if there is local or distant spread, survival may be prolonged. However, overall the clinical pattern of behaviour is extremely variable. The tumour has a predilection for perineural infiltration, which partially explains the tendency for local recurrence. Having positive surgical margins, major nerve involvement and a minor salivary gland primary make it more likely for ACC to recur locally.3, 14, 16 Unlike squamous cell head and neck cancer, ACC often spreads systemically. Distant metastases are more likely to occur if the tumour is of solid histology, primary size >3 cm, origin in the nasal cavity/paranasal sinuses, positive lymph nodes or if there is local recurrence.2, 9, 11, 14 The commonest metastatic site is the lung and spread is rarely solitary.2, 3, 4, 5, 6, 9, 10, 11, 14, 17 Another site commonly affected is bone and once this has occurred the disease generally progresses rapidly.6, 11, 14 At least 30% of patients with systemic metastases will be disease-free at the primary site.9, 16

Primary site in the nasal cavity/paranasal sinuses, advanced primary tumour stage, major nerve involvement, solid histology, positive lymph nodes and positive surgical margins have all been shown in some series to affect survival.1, 2, 6, 8, 10, 11, 12, 13, 14, 17 ACC in the major salivary glands has been shown to have a more favourable outcome than if the primary is in a minor salivary gland, mainly due to earlier presentation and feasibility of complete removal.1, 8, 12, 17 Some important statistics for ACC are shown in Table 1.

The primary treatment of ACC is surgery, which is usually followed by post-operative radiotherapy. There is considerable uncertainty about the systemic management of recurrent or metastatic ACC and indeed whether systemic therapy impacts on the course of the disease. The aim of this review is to comprehensively explore the role of cytotoxic chemotherapy, as well as examine current trials and potential novel approaches for the management of recurrent and metastatic ACC.