Planning systemic therapy for salivary gland cancers has been a persistent problem for medical oncologists, but salivary duct carcinomas are good candidates for systemic therapy. Here, Dr. Akhil Kapoor discusses the algorithm for planning systemic therapy for patients with a brief discussion on next generation sequencing (NGS).

The natural history of advanced salivary gland cancers (SGC) is highly variable with few patients requiring no treatment for protracted time while some progressing rapidly. Slow disease growth is common in adenoid cystic carcinomas (ACC) besides acinic cell, and myoepithelial carcinomas. Thus, it is very difficult to make firm conclusions from single arm studies with limited sample sizes, since disease stabilisation or even a response may be the result of the natural history of the disease rather than a result of the therapy.

Salivary duct carcinoma (SDC) constitutes an aggressive subtype of SGC, and the patients usually present in advanced stage. The combination chemotherapy leads to responses in around 40% of the patients, but the major problem is early relapse. While deciding the systemic therapy, the following algorithm can be considered.

The first thing that should be looked into while deciding the treatment of unresectable or metastatic salivary gland cancer is to identify whether the patient is symptomatic or has high disease burden especially in critical areas such as close to spinal canal or bile ducts. If there is no such feature, the patient can be kept under surveillance. It is preferable to send next generation sequencing (NGS) besides AR, HER2, MMR testing by immunohistochemistry at the baseline.

Patients with adenoid cystic carcinomas

In symptomatic patients, the histology helps in decision making, for example, in patients with ACC, combination chemotherapy in the form of paclitaxel and carboplatin is preferred, while in the second line treatment of ACC, targeted therapy with lenvatinib is preferred, other options being axitinib and sorafenib.

The use of paclitaxel carboplatin is associated with neuropathy and myelosupression, the usual adverse effects of this combination and should be specifically looked for in patients who are diabetic as neuropathy can be accentuated in these patients. The use of tyrosine kinase inhibitors (TKIs) are associated with the class adverse effects leading to mucositis, palmo-plantar erythrodysesthesia, hypertension, and protienuria. Other adverse effects that should be kept in mind include trasnaminitis and lipid profile derangements. Thus, monitoring of these adverse effects should be done periodically while the patient is on TKI.

Patients with non-adenoid cystic carcinomas

In patients with non-ACC, the first thing that should be looked is if the disease has secretory histology, in which case NTRK fusion incidence is close to 100%. If this genomic aberration is detected, the patient is a candidate of NTRK inhibitors like larotrectinib and entrectinib. Larotrectinib is preferred over the latter as it has stronger data with better toxicity profile. In case these are not available or feasible by compassionate access programme, combination chemotherapy should be considered. The main adverse effects associated with these agents include transaminitis, anaemia, neutropenia, diarrhoea, and hypoalbuminemia.

If HER2 amplification or overexpression is confirmed, chemotherapy in combination with trastuzumab appears to be the best option. Patients with HER2 alteration progressing on trastuzumab based chemotherapy can be offered ado trastuzumab emtansine (TDM1) in view of recent data showing high response rates with the same. The recommended dose is similar to that of breast cancer, 3.6 mg/kg intravenous given 3-weekly. It should be noted that this drug is associated with thrombocytopenia, transaminitis, neuropathy, and myalgia.

In case HER2 is negative but AR expression is present, combined androgen blockade with leuprolide and bicalutamide is the usual choice especially when rapid response is not warranted. There are few studies supporting the use of leuprolide and enzalutamide as well and this can be considered in patients who can afford it. These drugs have typical adverse effects of blocking the testosterone pathway, that include hot flashes, anemia, low mood, constipation, and weight gain. Besides, enzalutamide is known to cause hyponatremia, hyperkalaemia, hyperglycaemia, and lower the seizure threshold.

Immunotherapy

Immunotherapy with pembrolizumab or nivolumab has resulted in only modest response rates of 12-15% and these can be considered down the line when limited systemic options are feasible. These can be considered as an option in early lines when mismatch repair-deficiency is established by testing for the same. These drugs are associated with class adverse effects which are immune mediated and include fatigue, pneumonitis, hepatitis, colitis, and hypophysitis.

To conclude, SGC are rare tumors with poor prognosis and limited systemic therapy options. The use of NGS is increasing day-by-day and this might help in improving outcomes by detecting rare mutations which are potentially targetable.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Akhil Kapoor, MD, DM, ECMO is working as an Assistant Professor in the Department of Medical Oncology, Mumbai. He has more than 100 publications in national and international peer-reviewed journals. He also has a keen interest in clinical research and in contributing to the advancement of patient care in Oncology.