|Year : 2018 | Volume
| Issue : 1 | Page : 10-18
Novel therapeutic options for recurrent metastatic salivary gland tumors: Review of ongoing clinical trials
Avinash Pandey1, Manish Kumar2, Heena Shahi1, Aishwarya Kumari1, Shivkant Singh1
1 Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
2 Department of Surgical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
|Date of Web Publication||12-Dec-2018|
Department of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar
Source of Support: None, Conflict of Interest: None
The clinical behavior and biology of recurrent malignant salivary gland tumors are myriad with slow-growing indolent disease at the one end of spectrum and aggressive symptomatic illness with metastases to bone, lung, and liver at the other end. Several different agents and combination chemotherapy regimens have been explored in patients whose disease is symptomatic with response rates between 15% and 40%. Recently, molecular studies have evolved to reveal targetable biomarkers which can be further explored in the therapeutic landscape with specific targeted therapies. A subset of tumors also expresses hormone receptors and hence is amenable to conventional antihormonal agents to obtain a possibly meaningful benefit. We searched for all ongoing and completed clinical trials involving chemotherapy, targeted therapy, hormonal therapy, and immunotherapy valid for patients with recurrent metastatic salivary gland tumors. We present the current viable therapeutic options for such a cohort of patients in routine clinical practice.
Keywords: Chemotherapy; clinical trials; malignant salivary gland tumors
|How to cite this article:|
Pandey A, Kumar M, Shahi H, Kumari A, Singh S. Novel therapeutic options for recurrent metastatic salivary gland tumors: Review of ongoing clinical trials. Cancer Res Stat Treat 2018;1:10-8
|How to cite this URL:|
Pandey A, Kumar M, Shahi H, Kumari A, Singh S. Novel therapeutic options for recurrent metastatic salivary gland tumors: Review of ongoing clinical trials. Cancer Res Stat Treat [serial online] 2018 [cited 2019 Apr 26];1:10-8. Available from: http://www.crstonline.com/text.asp?2018/1/1/10/247324
| Introduction|| |
Salivary gland tumors are a rare, heterogeneous group of tumors with varied pathology, biology, clinical behavior, and outcomes. Adenoid cystic, mucoepidermoid carcinoma, acinic cell carcinoma, and low-grade polymorphous adenocarcinoma are often treated alike and grouped into one cohort of salivary gland tumors, despite having a varied natural history., Malignant salivary gland tumors often have a wide spectrum of presentations ranging from indolent asymptomatic disease which does not require any intervention to florid metastatic disease involving the lung, bones, and liver requiring systemic therapy.,
Chemotherapy is often used for symptomatic metastatic salivary gland tumors; chemotherapy leads to a modest but meaningful response ranging from 15% to 40% depending upon the agent used and whether single or multidrug combination is used. Due to a paucity of randomized controlled trials evaluating the role and choices of chemotherapy regimens in salivary gland tumors, there is no clear consensus regarding the degree of benefit, the specific drugs and doses, and the best combination therapies. We searched through all available ongoing registered clinical trials evaluating the question of choice of chemotherapeutic, targeted, hormonal, and immunotherapeutic regimens in recurrent metastatic salivary gland tumors. We summarize the results with regard to their use in the current oncology practice.
| Materials and Methods|| |
We accessed the online available database of privately funded and public-funded clinical studies conducted around the world at https://clinicaltrials.gov/, which is maintained by the National Library of Medicine at the National Institute of Health. This website contains summary information on study participants and study outcomes including adverse events for clinical trials registered in its database. We used the search terms 'salivary gland tumors' and 'salivary gland cancer' under disease or condition, without any filters. The studies selected for the current review included Phase III, Phase II, and Phase I with Phase II extension trials, including chemotherapy, hormonal therapy, targeted therapy, and immunotherapy in recurrent metastatic salivary gland tumors. All trials registered but withdrawn, prematurely terminated, or trials with unknown status were excluded from the final analysis. We included in the final list all these ongoing, completed, active (nonrecruiting and recruiting) clinical trials except for the pure Phase I dose finding/maximum tolerated dose (MTD) trials that had been excluded.
| Results|| |
The above search using 'salivary gland tumors' and 'salivary gland cancer' as the search terms yielded 189 clinical studies. Among these, 83 clinical trials were evaluating the use of chemotherapy, hormonal therapy, targeted therapy, or immunotherapy in recurrent metastatic salivary gland tumors. We excluded 30 trials due to status unknown (5), withdrawn (6), prematurely terminated (9), and pure dose finding/MTD Phase I trials (10). The final list included 53 clinical Phase III, Phase II, and Phase I with Phase II extension studies evaluating chemotherapy (18), targeted therapy (26), immunotherapy (7), and hormonal therapy (2) in recurrent malignant salivary gland tumors [Table 1], [Table 2], [Table 3], [Table 4].
|Table 1: Ongoing clinical trials of chemotherapy in recurrent metastatic salivary gland tumors|
Click here to view
|Table 2: Ongoing clinical trials of targeted therapy in recurrent metastatic salivary gland tumors|
Click here to view
|Table 3: Clinical trials exploring role of immunotherapy in recurrent metastatic salivary gland tumors|
Click here to view
|Table 4: Undergoing clinical trials with hormonal agents in recurrent metastatic salivary gland tumors|
Click here to view
| Discussion|| |
Recurrent/metastatic salivary gland tumors are one of the orphan diseases where, due to a paucity of cases, a large prospective randomized data are unavailable. Routine clinical therapeutic decisions often include single or double chemotherapy with modest responses and remissions which are seldom durable. Several ongoing and few completed clinical trials suggest differential benefit of therapy depending upon histology and biomarker expression. As being a consortium of different histology, patients with salivary gland tumor need much better biomarkers to target molecular drivers by several novel drugs including targeted therapy, androgen blockage, and immunotherapy for improved outcomes.
The goal of treatment for recurrent/metastatic salivary gland tumors is palliation. Except for slow-growing asymptomatic disease, majority of patients with symptomatic metastatic disease receive chemotherapy for symptomatic relief although their benefit in survival is equivocal. In the absence of robust Level I evidence, choice of therapy depends on individual physician and institute practice. Despite metastatic disease, majority of patients enjoy better survival as compared to conventional metastatic head and neck squamous cell carcinoma., Hence, it is prudent to use intermittent chemotherapy for palliation of symptomatic progression and interim observation to avoid potential adverse effects.
Several chemotherapy agents such as cisplatin, paclitaxel, doxorubicin, methotrexate, epirubicin, gemcitabine, doxorubicin, fluorouracil, cyclophosphamide, mitoxantrone, and vinorelbine have been tried as single agents in recurrent metastatic salivary gland tumors, producing response rates in the range of 15%–20%.,,, Paclitaxel produces better responses in adenocarcinoma and mucoepidermoid carcinoma compared to adenoid cystic carcinoma. Combination chemotherapy such as vinorelbine–cisplatin or cyclophosphamide–adriamycin–cisplatin produces superior response rates in the range of 40%–50% and hence is worth trying in patients with aggressive or high symptom disease for early and effective palliation., When combination of irinotecan and cisplatin was explored in recurrent metastatic head and neck cancer, including salivary gland tumors, it produced overall response rate of 30% with disease control rates of 53%., Ispinesib, a novel spindle protein inhibitor which prevents binding of microtubules, thus inhibiting microtubule assembly leading to cell cycle arrest in M phase, failed to produce any responses in a Phase II clinical trial.
Research has recently illustrated certain molecular changes driven by gene mutation and translocations which help to select available targeted agents for symptomatic palliation. Larotrectinib, a specific inhibitor of neurotrophic tropomyosin receptor kinase (NTRK) gene, seen commonly in secretory carcinoma variants, produces an overall response rate of 25% with 86% of responders continuing to benefit at a median follow-up of 9 months. Another set of Phase II trials of larotrectinib and entrectinib in tumors harboring NTRK 1/2/3 mutation is currently recruiting patients. Overexpression of Her2neu or gene amplification by fluorescence in situ hybridization is seen in one-third of mucoepidermoid carcinomas. Patients overexpressing Her2neu did well on trastuzumab with one-third showing durable responses extending beyond 2 years, while the remaining two-third showed disease stabilization beyond 10 months. Several Phase II trials of trastuzumab and lapatinib in Her2neu-overexpressing salivary gland tumors have been completed with results awaited.,,
As compared to mucoepidermoid tumors, adenoid cystic carcinomas express more c-kit in 90% of cases. However, neither imatinib nor dasatinib has led to significant responses in this cohort of patients., A Phase II trial of dasatinib in patients expressing c-kit failed to produce any objective responses but achieved disease control rate of 50% with median progression-free survival (PFS) of 4.8 months. Contrary to this, in a similar cohort of patients, dasatinib led to dismal PFS of 6.6% at 12 weeks without any responses. Oral anti-vascular endothelial growth factor (VEGF) agents such as sunitinib, sorafenib, and axitinib have failed to provide complete responses. Partial responses were achieved in <10% of patients with median PFS between 6 and 8 months, while overall survival ranged between 22 and 26 months.,, Anti-epithelial growth factor receptor (EGFR) antibody, cetuximab, did not produce any objective responses, but 12 of 30 patients with adenoid cystic carcinomas achieved disease stabilization for 6 months. Addition of cetuximab to mammalian target of rapamycin inhibitor temsirolimus or anti-VEGF sorafenib failed to improve median PFS.,
Among the several histological subtypes, salivary duct carcinomas exclusively express androgen receptors., When combined androgen blockage, comprising leuprolide and bicalutamide, was used in patients with androgen expressing salivary duct carcinomas, an impressive objective response rate of 41% with median PFS of 9 months and overall survival of 30 months was noted. Further clinical trials with abiraterone and comparison between chemotherapy and combined androgen blockage are currently ongoing.,, Immune checkpoint inhibitors are currently still in clinical trials and hence investigational, with several Phase II trials using PD1/anti-PD-L1 inhibitors, nivolumab and pembrolizumab, and CTLA-4 inhibitors, ipilimumab, actively recruiting patients.,,,,,
| Conclusion|| |
Chemotherapeutic and targeted therapy options exist and selection criteria differ depending upon histology and molecular biomarkers in recurrent/metastatic salivary gland tumors. In symptomatic metastatic disease, combination or single-agent chemotherapy provides effective and durable palliation. Targeted therapy in mucoepidermoid and secretory carcinomas with trastuzumab and NTRK inhibitors are potentially effective in selected cohort of patients. C-kit, anti-VEGF, and anti-EGFR agents have failed to elicit major responses. Complete androgen blockade may be effective for androgen receptor expressing salivary duct carcinomas. Further results of ongoing Phase II studies with chemotherapy, hormonal therapy, immunotherapy, and targeted therapy are awaited. 
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Guzzo M, Locati LD, Prott FJ, Gatta G, McGurk M, Licitra L, et al.
Major and minor salivary gland tumors. Crit Rev Oncol Hematol 2010;74:134-48.
Sur RK, Donde B, Levin V, Pacella J, Kotzen J, Cooper K, et al.
Adenoid cystic carcinoma of the salivary glands: A review of 10 years. Laryngoscope 1997;107:1276-80.
Yu T, Gao QH, Wang XY, Wen YM, Li LJ. Malignant sublingual gland tumors: A retrospective clinicopathologic study of 28 cases. Oncology 2007;72:39-44.
Sung MW, Kim KH, Kim JW, Min YG, Seong WJ, Roh JL, et al.
Clinicopathologic predictors and impact of distant metastasis from adenoid cystic carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 2003;129:1193-7.
Hill ME, Constenla DO, A'Hern RP, Henk JM, Rhys-Evans P, Breach N, et al.
Cisplatin and 5-fluorouracil for symptom control in advanced salivary adenoid cystic carcinoma. Oral Oncol 1997;33:275-8.
Laurie SA, Ho AL, Fury MG, Sherman E, Pfister DG. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: A systematic review. Lancet Oncol 2011;12:815-24.
Spiro RH. Distant metastasis in adenoid cystic carcinoma of salivary origin. Am J Surg 1997;174:495-8.
van der Wal JE, Becking AG, Snow GB, van der Waal I. Distant metastases of adenoid cystic carcinoma of the salivary glands and the value of diagnostic examinations during follow-up. Head Neck 2002;24:779-83.
Verweij J, de Mulder PH, de Graeff A, Vermorken JB, Wildiers J, Kerger J, et al.
Phase II study on mitoxantrone in adenoid cystic carcinomas of the head and neck. EORTC head and neck cancer cooperative group. Ann Oncol 1996;7:867-9.
Licitra L, Marchini S, Spinazzè S, Rossi A, Rocca A, Grandi C, et al.
Cisplatin in advanced salivary gland carcinoma. A phase II study of 25 patients. Cancer 1991;68:1874-7.
Vermorken JB, Verweij J, de Mulder PH, Cognetti F, Clavel M, Rodenhuis S, et al.
Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: A phase II study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1993;4:785-8.
Airoldi M, Pedani F, Succo G, Gabriele AM, Ragona R, Marchionatti S, et al.
Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer 2001;91:541-7.
Dreyfuss AI, Clark JR, Fallon BG, Posner MR, Norris CM Jr., Miller D, et al.
Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin. Cancer 1987;60:2869-72.
Gilbert J, Cmelak A, Shyr Y, Netterville J, Burkey BB, Sinard RJ, et al.
Phase II trial of irinotecan plus cisplatin in patients with recurrent or metastatic squamous carcinoma of the head and neck. Cancer 2008;113:186-92.
Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al.
Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731-9.
Glisson B, Colevas AD, Haddad R, Krane J, El-Naggar A, Kies M, et al.
HER2 expression in salivary gland carcinomas: Dependence on histological subtype. Clin Cancer Res 2004;10:944-6.
Haddad R, Colevas AD, Krane JF, Cooper D, Glisson B, Amrein PC, et al.
Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study. Oral Oncol 2003;39:724-7.
Mino M, Pilch BZ, Faquin WC. Expression of KIT (CD117) in neoplasms of the head and neck: An ancillary marker for adenoid cystic carcinoma. Mod Pathol 2003;16:1224-31.
Pfeffer MR, Talmi Y, Catane R, Symon Z, Yosepovitch A, Levitt M, et al.
A phase II study of imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands. Oral Oncol 2007;43:33-6.
Wong SJ, Karrison T, Hayes DN, Kies MS, Cullen KJ, Tanvetyanon T, et al.
Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors. Ann Oncol 2016;27:318-23.
Chau NG, Hotte SJ, Chen EX, Chin SF, Turner S, Wang L, et al.
A phase II study of sunitinib in recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the salivary glands: Current progress and challenges in evaluating molecularly targeted agents in ACC. Ann Oncol 2012;23:1562-70.
Locati LD, Perrone F, Cortelazzi B, Bergamini C, Bossi P, Civelli E, et al.
A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact. Eur J Cancer 2016;69:158-65.
Ho AL, Dunn L, Sherman EJ, Fury MG, Baxi SS, Chandramohan R, et al.
A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma. Ann Oncol 2016;27:1902-8.
Locati LD, Bossi P, Perrone F, Potepan P, Crippa F, Mariani L, et al.
Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study. Oral Oncol 2009;45:574-8.
Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol 2014;25:2101-15.
Fan CY, Melhem MF, Hosal AS, Grandis JR, Barnes EL. Expression of androgen receptor, epidermal growth factor receptor, and transforming growth factor alpha in salivary duct carcinoma. Arch Otolaryngol Head Neck Surg 2001;127:1075-9.
Fushimi C, Tada Y, Takahashi H, Nagao T, Ojiri H, Masubuchi T, et al.
A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma. Ann Oncol 2018;29:979-84.
Jakob JA, Kies MS, Glisson BS, Kupferman ME, Liu DD, Lee JJ, et al.
Phase II study of gefitinib in patients with advanced salivary gland cancers. Head Neck 2015;37:644-9.
[Table 1], [Table 2], [Table 3], [Table 4]