The diversity and complexity, combined with the rarity of salivary gland malignancies, lead to definite and distinct challenges in their study, and consequently in advancing treatment options for affected patients.
Salivary gland malignancies represent one of the most diverse groups of human tumors. The current World Health Organization (WHO) classification lists more than 20 different histologic types of malignancies that can arise from the salivary glands, each with its own biology and underlying molecular pathogenesis. This diversity and complexity, combined with the rarity of these cancers, lead to definite and distinct challenges in their study, and consequently in advancing treatment options for affected patients. This is evident when comparing the current review by Goyal et al with one published almost a decade ago; despite a few additional trials (mostly in adenoid cystic carcinoma [ACC]), no clearly meaningful advances in treatment have been made.
The major factor accounting for this lack of significant advances is of course the rarity of these tumors. Salivary gland cancers account for no more than 5% of all head and neck cancers. Of these, the majority are low-grade, are cured with surgical resection, and thankfully never require systemic therapies. Some, however-such as ACC, high-grade mucoepidermoid carcinoma (MEC), salivary duct carcinoma, and high-grade adenocarcinoma-have a tendency to recur and metastasize. Of these, MEC, salivary duct carcinoma, and high-grade adenocarcinoma are particularly uncommon; it is possible that oncologists practicing outside a major academic institution might see one such patient in their entire career. ACC is a little easier to study because it is often indolent, leading to a prevalence higher than its incidence.
The rarity of salivary gland tumors often leads, in clinical trials, to the grouping of patients into those with ACC and those with non-ACC histologies. While more recently there have been clinical trials specifically for ACC, even these often involve considerable heterogeneity, particularly with respect to the number of prior therapies. To conduct even a single-arm phase II clinical trial limited to one of the other subtypes would require a large number of sites and a great deal of time. All of this adds to cost, and finding the financial support to conduct a trial in such a niche population is challenging. Furthermore, trials in such small subgroups run the risk of never coming to completion, as was the case, for example, with the trial of trastuzumab in human epidermal growth factor 2 (HER2)-overexpressing salivary gland cancers (most commonly, salivary duct carcinomas), which had to close because only 14 patients were enrolled, due to a low incidence of HER2 positivity and slow accrual.
The complexity of the pathology of salivary gland cancers raises questions about the interpretation of older clinical trials, and also has a direct impact on patient care. It is important to ensure that patients have an accurate histologic diagnosis; consideration should be given to having the pathology reviewed by an experienced specialized head and neck pathologist. It is possible that in older trials, tumors may have been misclassified, using older versions of the WHO system. This may make the results of these trials an unreliable basis for predicting the efficacy of a regimen in some of the rare subtypes. Older publications are often retrospective series, rather than prospective clinical trials, reporting on heterogeneous groups of patients treated with regimens that varied in dose and schedule. Case reports of patients responding to a therapy are inherently biased towards positive outcomes, overestimating the true efficacy of regimens. Thus the quality of available evidence for the optimal chemotherapeutic regimen in salivary gland cancers is poor.
How do we move forward? Patients with salivary gland cancers should be enrolled in clinical trials whenever possible. Recent cooperative group studies have shown that, at least for ACC, clinical trials can be accomplished in a timely manner. Trials in salivary gland cancers should have at the very least separate ACC cohorts, and if others are lumped together in a non-ACC cohort, results for each histologic subtype should be presented separately. Multicenter, international cooperation is required to advance the science. Under the auspices of the International Rare Cancers Initiative (www.irci.info), the European Organisation for Research and Treatment of Cancer (EORTC) has recently launched a randomized phase II trial comparing platinum-based chemotherapy with total androgen blockade in androgen receptor–expressing salivary gland cancers. International databases and registries of outcomes with various treatments used outside of a clinical trial would be a big step forward in increasing the amount of data available for determining the true efficacy of commonly used regimens. Finally, in conjunction with a concerted effort to determine the underlying molecular phenotypes of the different salivary gland cancer subtypes, “window-of-opportunity” trials of potential targeted agents in early-stage resectable disease would be very informative.
Patients with rare cancers don’t suffer any less than those with more common tumors, and the lack of research into their illness can lead to its own kind of frustration for many of them. Those with salivary gland cancers deserve equal attention.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization classification of tumors. Pathology and genetics of head and neck tumours. Lyon, France: IARC Press; 2005.
2. Goyal G, Mehdi SA, Ganti AP. Salivary gland cancers: biology and systemic therapy. Oncology (Williston Park). 2015;29:773-80.
3. Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 2006;24:2673-8.
4. Haddad R, Colevas AD, Krane JF, et al. Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study. Oral Oncol. 2003;39:724-7.