Chemotherapy for Salivary Gland Malignant Carcinoma : Meta-analysis and Systemic Review

Abstract

 The primary form of treatment for salivary gland cancer is surgical resection. Radiation therapy is used as adjuvant therapy in cases of aggressive tumours, currently patients with recurrent or metastatic cancer who are not suitable for surgery or radiation are most often treated with chemotherapy. PRISMA guidelines for systematic reviews were followed to evaluate salivary gland malignancies involving cytotoxic chemotherapy and biologic agents. An electronic literature search of Medline, PubMed, Scopus, etc. was performed and relevant articles were selected based on the inclusion criteria. Cytotoxic chemotherapies and biologic drugs such as anti HER − 2, anti-EGFR and anti-C-Kit are used to treat salivary gland cancer. Although most trials have respond poorly to standard chemotherapy with short durability and significant toxicity. Most of the research has focused on ACC and the use of combination therapy with cisplastin in conjunction with other treatments has been found to improve overall survival rate. Due to the limited patient population it was difficult to assess the efficacy of chemotherapy, which achieved very modest results. There are potential molecular targets such as HER2,NTRK and targeted treatments are becoming more popular. However to further explore potential treatment alternatives SGC patients should be enrolled in clinical trials.

Introduction

Malignant salivary gland tumours are a diverse collection of neoplasms that vary according to histology and anatomic location. It is a rare tumour, accounting for only 6% of head and neck malignancies, and according to the WHO classification, there are 24 malignant histologic subtypes [1–3]. The most common are mucoepidermoid carcinoma (MEC), which accounts for about one-third of SGC cases, and adenoid cystic carcinoma (ACC), which has a prevalence of 23.8%. Salivary gland tumours occur most commonly in the parotid gland, but only 25% of these lesions are malignant. For salivary gland cancer, surgical resection is the main treatment option [4, 5] When surgical resection is not an option, radiation therapy is often used as the final treatment or as adjuvant therapy for tumours that are thought to be at high risk of recurrence. Currently, chemotherapy or systemic therapy is used primarily in patients with recurrent or metastatic disease for whom surgery or radiotherapy is not an option [5, 6].

Due to the rarity and diversity of these tumours, rigorous testing or standardisation of systemic therapies for metastatic or recurrent salivary gland carcinoma is challenging. Although many invasive salivary gland malignancies can be effectively treated with surgery alone, adenoid cystic carcinoma (ACC), adenocarcinoma ( NOS), expleomorphic adenoma, mucoepidermoid carcinoma (MEC), and salivary duct carcinoma (SDC) have recurring and metastatic nature. Standardisation of therapy is difficult for these tumours because the clinical features of the numerous forms of salivary tumours vary from aggressive to indolent, with variation even within a given subtype. Regardless of the form of salivary gland cancer, most patients who develop metastatic salivary gland cancer succumb from it, and the disease is usually incurable [7, 8].

With an emphasis on cytotoxic chemotherapy, biologic agents that have been tested over the past 20 years, and an outlook on potential future treatments, this paper reviews and meta-analyses the current state of knowledge on therapeutic options for recurrent and metastatic salivary gland cancer.

Materials and Methods

For a methodical approach and reliable outcome, this review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. PubMed, Medline, Scopus, and Web of Science databases were all searched electronically. Chemotherapy, Mucoepidermoid Carcinoma, and Salivary Gland Malignancy, adenocarcinoma were utilised as search terms.

Inclusion criteria: The PICOS components were used to establish the inclusion criteria for this review. Population (P) – Patients with proven SGM. Intervention (I) – Studies that reported on the use of one or more drug combination therapies in the management. Comparison (C) – Patients that were managed only with biological agent. Outcome (O) – overall survival rate with adequate follow up time for at least 12 months. Study design (S) – Prospective randomised controlled trials, cohort studies, cross-sectional studies and case series. In addition, studies should be published in English. Exclusion criteria: Non-human studies, review articles, letters to the editor, studies without comprehensive descriptions of the treatments utilised, adequate information of follow-up periods or recurrence, and studies not published in are publications that are excluded from studies. Study selection and data extraction: We read the titles and abstracts of every report found through our computerised and manual searches. The following information was taken from the articles that met the criteria: authors, date of publication, study design, number of patients, total number of salivary gland malignancies, recurrences, range of follow-up or mean follow-up period, response rate, survival rate, clinical benefit rate, and treatment regimen.

Results

The search strategy resulted in 106 articles from all databases. After screening for duplication, 68 articles were eliminated resulting in 38 articles that were screened for eligibility. After eligibility screening from reading the titles and abstracts, 31 articles were selected for full text reviews, 06 studies were excluded as they did not meet the inclusion criteria. The remaining 25 studies (Table 1) were included in the review. Using the Newcastle-Ottawa scale, authors independently assessed the risk of bias for each of the selected studies. According to the guidelines, a study can receive one point in each of the categories and a maximum of two points in the comparability category. The highest possible score is 9, indicating a low probability of bias. Any research that receives 7 or more points in this review is considered high quality.

Table 1.

Studies using either cytotoxic chemotherapy or only biologic medicines along with adjuvant treatments 5FU 5-florouracil, ACC adenoid cystic carcinoma; Ad adenocarcinoma, Bor bortezomib, Cis cisplatin, Dox Doxorubicin, MEC mucoepidermoid carcinoma, Plat platinum, Vino vinorelbine, NR not reported

Author	No of patients	Pharmocotherapy	Malignancy type	Response rate ( in %)	Clinical benfical rate (in %)	Survival rate ( in months )
Laurie et al.	33	Plat + Gemcitabine	Ad (8), ACC (10), MEC (4), others (11)	24	82	13
Hitre et al.	12	Cetuximab + Cis + 5FU	ACC (12)	42	92	24
Airoldi et al.	60	Cis + Vino	Ad (16), ACC (34), MEC( 10)	23	57	10
Gedlicka et al.	14	Mitoxantrone + Cis	ACC (4), MEC (10),	14	79	27
Agulnik et al.	39	Lapatinib	Ad (7), ACC (20), MEC (2), others (11)	0	78	13( NON ACC)
Haddad et al.	14	Trastuzumab	Ad (7), ACC (2), MEC (3), others (2)	8	8	NR
Hotte et al.	16	Imatinib	ACC (16)	0	56	7
Airoldi et al.	20VS 16	Vino vs. Cis + Vino	Ad (9), ACC (22), MEC (1), others (4)	20 VS 44	65 VS 81	8.5VS 10
Gilbert et al.	45	Paclitaxel	Ad (17), ACC (14), MEC (14)	18	51	12.5
Ross et al.	8	Epirubicin + Plat + 5FU	ACC(8)	12	75	27
Ghosal et al.	28	Cis + Imatinib	ACC(28)	11	79	35
Pfeffer et al.	10	Imatinib	ACC(10)	0	20	NR
Locati et al.	37	Sorafenib	ACC (19), others (18)	17	73	NR
Kim et al.	34	Everolimus	ACC(34)	0	79	23
Hoover et al.	15	Nelfinavir	ACC(15)	0	47	NR
Wong et al.	54	Dasatinib	ACC (40), others (14)	2	50	14.5 (ACC), NR (non-ACC)
Jakob et al.	36	Gefitinib	Ad (9), ACC (18), MEC (2), others (6)	0	59	25.9 (ACC); 16 (non-ACC)
Dillon et al.	35	Dovitinib	ACC(35)	6	71	22
Argiris et al.	24	Bor→Bor + Dox	ACC (24)	0%and8%	63% and 58%	21
Keam et al.	32	Dovitinib	ACC(32)	3	94	NR
Thomson	23	Sorafenib	ACC(23)	11	79	19.6
Guigay et al.	17	Imatinib	ACC(17)	13	47	NR
Goncalves et al.	30	Vorinostat	ACC(30)	3	87	NR
van Herpen et al.	21	Gemcitabine	ACC (21)	0	52	NR
Jaspers et al.	10	Bicalutamide	SDC(10)	20	50	12

Role of Combination Therapy with Platinum

For all salivary gland cancers, including ACC, adenocarcinoma NOS, and MEC, we analysed research that used cytotoxic chemotherapy. Most of these studies used chemotherapy combinations that included either cisplatin or carboplatin. Nearly half of the studies examined only ACC, while the other half also examined other histologic subtypes, but to a lesser extent. Platinum-doublet therapy appears to be supported by four studies in particular; all four studies included a mixed sample of individuals with salivary cancer, with ACC and adenocarcinoma predominating [8, 9]. A study by Airoldi et al., significant as one of the few studies with randomised data, showed a better overall response with the combination of cisplatin and vinorelbine over vinorelbine alone (44 and 20%, respectively). In another study, an ORR( overall survival rate) of 23% was achieved in a large cohort of 60 patients treated with cisplatin and vinorelbine, with better results with first-line treatment producing higher results (31% first-line versus 5% second-line) [10–12]. A brief study by Ross et al. evaluated the combination of cisplatin/carboplatin, epirubicin, and 5-fluorouracil (5 FU) in eight patients with ACC, seven of whom were treated as first-line, and reported triple therapy with platinum. The ORR was only 12% despite the inclusion of a third cytotoxic drug, providing further evidence that cytotoxic triple therapies have no clinical benefit in metastatic salivary cancers. The fact that the median OS was still 27 months despite the low ORR highlights the fact that metastatic ACC often has a lax clinical response and highlights the difficulties in understanding how transient disease responses translate into a significant survival benefit [13].

The role of Biologic Agents

The ineffectiveness and limited value of cytotoxic chemotherapy has necessitated a comprehensive review of alternative treatment options for advanced salivary gland carcinoma. Numerous studies have been conducted with biologic agents because salivary gland carcinomas are known to express a variety of potential targets, including epidermal growth factor receptor (EGFR), c-kit, and human epidermal growth factor receptor-2 (HER − 2) [14, 15].

It was found that salivary gland carcinomas that are HER − 2 positive are extremely rare and the efficacy of HER − 2 targeted treatment of patients with metastatic or recurrent salivary gland cancer was low, with the significant exception of patients with HER − 2-positive SDC ( Salivary duct carcinoma) [16, 17].

Imatinib and dasatinib, C-kit-directed drugs, are used in clinical trials. The use of the single drug imatinib in ACC has been studied in three different studies, one of which, by Guigay et al., showed a 13% ORR to imatinib, while the other two failed to produce any objective responses. Dasatinib, a second-generation c-kit inhibitor, also showed no objective results in a sizable phase 2 research [18, 19].

EGFR-targeted Treatment

It is observed that ACC salivary gland carcinomas overexpress EGFR, two unsuccessful phase 2 trials evaluated single-agent cetuximab and gefitinib. With cetuximab as the only treatment, Locati et al. included 30 patients (23 ACC) but found no objective results. Similarly, a study by Jakob et al. found no objective response to gefitinib in a non-selected group of patients with advanced salivary cancer. Further investigation of EGFR-targeted single-agent treatment is not needed given the complete lack of response to these drugs [19, 20].

Combination Therapy with Cytotoxic Chemotherapy and Biologics

After initial excitement about the potential responses with c-kit overexpression ACC, cisplatin and imatinib have been explored. Imatinib was administered as induction therapy at 800 mg per day for 8 weeks, then at 400 mg per day with 80 mg/m2 cisplatin intravenously every 4 weeks. In stable or responding disease, imatinib was continued as maintenance therapy. Only three patients responded to therapy, but the median OS was 35 months. As noted earlier, ACC typically over-expresses EGFR. In a group of 12 metastatic patients, Hitre et al. found a 42% response rate to a regimen comparable to EXTREME in patients with ACC. Finally, a study evaluating the combination of bortezomib, a proteasome inhibitor, and doxorubicin found no improvement in ACC patients, although the clinical benefit of the combination is estimated at 58%. Currently, there are no biologic treatments or chemotherapy regimens that have been shown to benefit patients with advanced salivary cancer [21–23].

Hormonal Therapy

Abiraterone, a CYP17 inhibitor, has recently been shown to be beneficial in second-line hormone treatment, according to case studies. An remarkable ORR of 65% was found in retrospective data where patients received consistent treatment with triptorelin and bicalutamide. A randomised trial is now being conducted to examine the effectiveness of androgen deprivation treatment in androgen receptor-positive salivary malignancies (NCT01969578) [24, 25].

Tyrosine Kinase Inhibitors

A number of multi-target tyrosine kinase inhibitors (TKIs) have been studied in advanced malignancies of the salivary gland, with most studies conducted in patients with ACC. Thomson et al. studied sorafenib in two trials, one in patients with ACC only and the other in a mixed population, with the possibility that non- ACC patients would benefit more. In patients with ACC, he reported an ORR of 11% and a median of 19.6 months OS. Similarly, Locati et al. found an overall response rate of 16%, with ACC and non- ACC responding differently (11 and 22%, respectively) [26, 27]. With response rates ranging from 11 to 22%, sorafenib is the most promising among antiangiogenic TKIs. Sunitinib has generally demonstrated unsatisfactory outcomes in patients with recurrent or metastatic salivary gland malignancies. Sunitinib did not show an objective responses in patients with ACC.

Although several TKIs have been studied in ACC patients only, the condition is still incredibly resistant to therapy. In a single-centre study at ACC, axitinib, a small-molecule inhibitor of VEGF, c-kit, and the platelet derived growth factor receptor (PDGFR), resulted in three partial responses (9% ORR). Dovitinib, an oral tyrosine kinase inhibitor that blocks VEGF and fibroblast growth factor receptors (FGFR), showed poor tolerability and low efficacy in two studies (ORR 3% and 6%). The proteosome inhibitor nelfinavir also showed no discernible effects in ACC patients, although it effectively inhibits AKT [28–30].

Discussion

There is no accepted standard of care for salivary gland carcinoma, especially for ACC. When chemotherapy is administered, platinum-based chemotherapy is still the best option, but it is not effective enough to be considered the standard of care. Due to the rarity of these malignancies, behavioural variability, and the composition of participants in each experiment, it is very difficult to methodically explore potential new drugs and evaluate outcomes between trials and over time [31]. In recent years, it has been possible to conduct more subtype-specific studies, at least for ACC. It is noteworthy that over the past decade, the number of published studies on salivary cancer has steadily increased. Considering the rarity of this cancer, this is a remarkable achievement and an important first step in the search for novel therapeutic approaches[32, 33]. To date, there is no broadly applicable targeted treatment for salivary gland carcinoma. A new wave of clinical trials was triggered by publications showing the expression of multiple potential targets in salivary gland cancers, such as c-kit, EGFR and HER − 2. Despite a good scientific basis, imatinib and dasatinib failed to show a therapeutic advantage. The heterogeneous criteria for c-kit staining and the inability to relate the degree of positive staining to response were two complicating factors. No information is available on whether response rates are related to any c-kit mutations. Although the genetic landscape of ACC is known, the overall future of salivary gland malignancies is unclear. The ability to screen for driving mutations in specific individuals and customise therapy to the patient’s tumour, both clinically and molecularly, may make individualised medicine most beneficial to patients [34, 35] There are some promising signs for the treatment of advanced malignant salivary gland tumours, although the results of recent trials of chemotherapeutic and biologic treatments are generally underwhelming. Salivary gland adenocarcinoma appears to be more receptive to treatment, with a higher chance of benefit from cytotoxic chemotherapy and a possible response to immune checkpoint inhibitors. In salivary gland carcinomas or AR +/HER2 + adenocarcinomas, the use of hormonal therapy and anti-HER2 therapy should be further developed and investigated [36, 37].

Developing a standard treatment approach for patients with recurrent or metastatic salivary cancer is challenging because of the paucity of high-quality data for therapy and the heterogeneity of tumours. If the patient has a low disease burden with isolated or oligometastatic disease favourable for local therapies, local therapy with stereotactic body irradiation or cryoablation is usually used. In patients with slow-growing, indolent disease such as classic ACC, observation is recommended. For aggressive growth, systemic treatment with either standard chemotherapy or targeted therapy is preferred [38]. In patients for whom chemotherapy is recommended, a platinum doublet is often used. All patients with recurrent or metastatic salivary cancer should undergo genetic testing to determine if targeted treatment can be used off-label or as part of a phase 1 clinical trial. It is recommended that patients with adenocarcinoma and SDC undergo androgen receptor staining and HER − 2 testing. If they test significantly positive for the androgen receptor, they should be treated with combined androgen deprivation treatment with bicalutamide and leuprolide, leuprolide alone, or anti HER − 2 therapy if HER − 2 is positive [38, 39].

Immunotherapy

It is reasonable to speculate if individuals with salivary cancer may benefit from immunotherapy considering the current trend in cancer therapies. There are also ongoing trials looking at combination immunotherapy or immunotherapy combined with additional treatments for salivary cancer, such as ipilimumab combined with nivolumab (NCT02834013), oncolytic adenovirus combined with pembrolizumab (NCT02576431), and histone deacetylase (HDAC) inhibitors combined with pembrolizumab (NCT02538510) [39, 40].

The medical community will eagerly await the results of the upcoming immunotherapeutic treatment trials, which will theoretically advance clinical practise and break the therapeutic plateau that cytotoxic agents have likely reached. Patients with advanced salivary cancers should be given the opportunity to participate in trials specifically designed for salivary cancers and/or have access to genetic testing to facilitate participation in the relevant phase 1 clinical trials or in tailored treatment plans that involve the use of already approved drugs [41].

Conclusion

Finding successful treatments for salivary malignancies has proven to be difficult, but we must keep looking for new research. In order to promote coordination, prevent duplication, and boost interest in clinical trials, Laurie and colleagues have made several guidelines for evaluating medicines in uncommon cancers including salivary gland malignancies. The trials discussed here do not provide a standard of care for the treatment of malignancies of the salivary glands, but rather they point to a future where individuals with salivary cancer will get a variety of personalised treatments. Hope for novel therapeutic possibilities and cross-disciplinary research collaboration is provided by the development of immunotherapy and the rise in clinical trials for salivary cancer in recent years.

Funding

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Declarations

Conflict of interest

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