Case Report, Clin Oncol Case Rep Vol: 5 Issue: 2

Pembrolizumab as a First Line Therapy in a Patient with Extensive Mucoepidermoid Salivary Gland Carcinoma: A Complete Clinical, Radiological And Pathological Response: A Very Specific Case

Raed Farhat^1*, Noam Asna², Yaniv Avraham¹, Ashraf Khater¹, Majd Asakla¹, Alaa Safia¹, Nidal Elkhatib¹, and Shlomo Merchavy¹

¹Otolaryngology, Head & Neck Surgery Unit, Ziv Medical Center, Safed, Israel

²Director, Oncology Institute, Ziv Medical Center, Zefat, Israel

*Corresponding Author:

Raed Farhat
Department of Otolaryngology Head and Neck Surgery, Ziv Medical Center,
Postal Code-1028, Golan Heights, Buqata, Israel
E-mail:  raed.frhat88@gmail.com

Received: January 16, 2022, Manuscript No: COCR-22-51739;
Editor Assigned: January 19, 2022, PreQC No: P-51739;
Reviewed: February 14, 2022, QC No: Q-51739;
Revised: February 20, 2022, Manuscript No: R-51739;
Published: February 27, 2022, DOI: 10.4172/cocr.5(2).218

Citation: Farhat R, Asna N, Avraham Y, Khater A, Asakla M, Safia A, Elkhatib N, Merchavy S (2022) Pembrolizumab as a First Line Therapy in a Patient with Extensive Mucoepidermoid Salivary Gland Carcinoma: A Complete Clinical, Radiological And Pathological Response: A Very Specific Case. Clin Oncol Case Rep 5:2.

Abstract

Keywords: Pembrolizumab; Salivary Gland Cancers (SGCs) Immunotherapy; Complete Response (CR)

Introduction

Salivary Gland Carcinoma (SGC) is a rare tumor and represents ∼6% of head and neck cancers [1]. Regardless of its histological subtype, curative treatment consists of a surgical resection with or without postoperative adjuvant radiation therapy [2-4] .

Mucoepidermoid Carcinoma (MEC) is a malignant tumor predominantly arising from the salivary glands; the minor glands preferentially give rise to MEC [5,6]. MEC is the most frequent malignant salivary gland tumor in children and adults6.

Although adjuvant treatment options like chemotherapy or radiation do not have a detectable impact on survival in highly aggressive subtypes like salivary duct carcinomas [7]. There is also no standard treatment or proven efficacy for patients with unresectable primaries/recurrences or patients with distant metastasis [8]. The benefit of chemotherapies like combinations of cisplatin, doxorubicin and cyclophosphamide was reported to be minimal with a prognosis that remains poor [2,9,10].

Immunotherapies have shown remarkable success in various entities not limited to non-small cell lung cancer and malignant melanoma. All these therapies share a similar mode of action directing the body’s own immune system to dispose of tumor cells [11,12] .

Pembrolizumab is a fully humanized immunoglobulin G4/κ anti-PD-1 monoclonal antibody. Pembrolizumab has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types and is currently approved in over 60 countries for 1 or more advanced malignancies, including in the United States for recurrent or metastatic head and neck squamous cell carcinoma that progressed on or after platinum containing chemotherapy [13-15].

The recently published keynote-048 trial established a new standard in this setting with the introduction of immunotherapy, either alone or in combination with chemotherapy [16].

This article reports a unique case of unresectable advanced high grade mucoepidermoid carcinoma of the salivary gland with complete response after Pembrolizumab treatment as a first line therapy. A similar strategy has never been tried in high grade salivary gland tumors, and complete radiological and pathological responses have never been reported before in this kind of tumors. This treatment resulted in downstaging of the tumor and led to its successful surgical resection.

Case Presentation

A 68-year-old male, diabetic with a forty pack-year smoking history presented with an enlarging left, slightly tender, rapidly progressive swelling of the left parotid gland during the previous 6 months before our first examination. The patient was referred to head and neck clinic, Department of Otolaryngology Head and Neck Surgery, Ziv Medical Center in Safed, in the north of Israel.

Physical examination showed a firm, immobile, slightly tender, 3 cm × 3 cm left parotid mass with overlying skin change (Figure 1), with multiple hard, immobile lymph nodes, 3 cm × 2 cm, at level II,III,V of the left neck, the remainder of the head and neck examination was unremarkable. Flexible nasendoscopy findings of the nasopharynx, oropharynx, and larynx were unremarkable.

Fine Needle Aspiration (FNA) of the left parotid mass was consistent with positive malignant cells for high grade mucoepidermoid carcinoma with mitosis.

Contrast-enhanced Magnetic Resonance Imaging (MRI) revealed a lobulated, irregular mass, 37 mm × 39 mm × 47 mm located in the posteroinferior segment of the superficial and deep lobe in the left parotid gland, with areas of extensive central necrosis, septation, and peripheral wall enhancement contiguous with the anterior portion of external auditory canal and SCM muscle with subcutaneous tissue and skin involvement, several nodules in the left infraparotid area and level II were calcified (Figure 2).

The 18F-FDG PET/CT revealed hypermetabolic activity within the mass in the left parotid gland with involvement of the skin, SCM muscle and several nodules in the left infraparotid area and level II,III in the left neck (Figure 3). The final diagnosis was clinical stage IV (T4aN2bM0).

The patient was considered as high-grade MECs which progressed rapidly and caused pain, soft tissue invasion; these MECs are associated with poor overall survival, which approaches 40% to 50% at 5 years, and with an increased risk for locoregional and distant failures [17-19].

The recommended therapy for high-grade MECs includes surgical resection with selective neck dissection followed by adjuvant radiotherapy [20].

In our case, the high morbidity and mortality associated with the need of extensive surgical resection with free flap reconstruction and the massive loss of tissue with possible facial nerve sacrifice, in addition to increased risk for locoregional and distant failures led us to think about neoadjuvant treatment.

Pembrolizumab monotherapy was generally well tolerated in advanced Salivary Gland Carcinoma (SGC), with a safety profile that reflects previous experience of pembrolizumab in patients with advanced cancers [21].

Treatment plan was made by a multidisciplinary team and after multiple discussions with the goal of maximizing survival with preservation of form and function. The patient received pembrolizumab intravenously at 200 mg every 2 weeks, with a good compliance. From September 2021 to November 2021, he underwent 2 cycles of pembrolizumab with no side effects.

The MRI scan after 3 cycles revealed a significant decrease in the tumor or even its disappearance, and on examination WHEN? The patient had attained a complete remission in the clinic examination (Figure 4, Figure 5).

Restaging with 18FDG PET-CT at 6 weeks after completion of immunologic treatment demonstrated a full resolution of the parotid gland metabolic activity. In the left neck, the nodal status had generally improved with no signs of hypermetabolic activity. High metabolic uptake was not seen elsewhere (Figure 6 ).

As a precaution, left parotidectomy and unilateral neck dissection levels I, II, III, IV were recommended for locoregional control and because of remaining morphological masses on CT (Figure 7). All the 18 FDG PET-CT scans performed are summarized in (Figure 8).

Final pathological results showed no evidence of carcinoma neither in the parotid gland nor in the neck lymph nodes and had free margins.The patient has continued to be supervised with CT scans and serum tumor marker measurements every 3 or 4 months and is still in complete remission at this time.

Discussion

This is the first report that describes complete resolution of high grade malignant salivary gland mucoepidermoid carcinoma with Pembrolizumab as a “first line” therapy treatment.

Cohen et al. [21] reported the phase Ib KEYNOTE-28 experience using single-agent pembrolizumab 10 mg/kg once every 2 weeks in 38 PDL1 expressing recurrent-metastatic salivary gland carcinomas. This study did not report evidence of progression before participation, and the majority of enrolled participants had adenocarcinomas. Among 38 patients enrolled, three had a Partial Response (PR) with an overall response rate of 12% with a 3-month median duration of response. There were no complete remission responses.

There is no gold standard for management of advanced SGC, and existing therapies generally lack significant clinical benefits. Available data supporting use of traditional cytotoxic chemotherapy are based on small studies, many of which were conducted before contemporary analytical concepts (e.g, RECIST) [22].

The prospective experience with the anti PD1 checkpoint inhibitors in salivary gland carcinoma consists of small phase I and II clinical trials, again with heterogenous histologies and variations in design and eligibility for such treatment.

Although pembrolizumab carries a primary site agnostic US Food and Drug Administration approval for mismatch repair–deficient tumors, it is important to note that this was based on a nine-patient cohort of non-colorectal cancer patients, none of whom had salivary gland malignancies [23].

The role of Tumor Mutation Burden (TMB) is unclear in SGCs. The subgroup analysis by TMB from the KEYNOTE-158 trial led to the approval of pembrolizumab for patients with TMB >10 mut/Mb as an agnostic treatment. There were three patients with salivary histology and high TMB, one of whom achieved partial response [23].

Although the current data from salivary gland malignancies trials are limited, our result in using Pembrolizumab as a first line agent in advanced high grade mucoepidermoid carcinoma suggests that this treatment remains a promising cancer therapy .

Further research studies which will evaluate the treatment of Pembrolizumab to front-line, maintenance settings, and trials of combinations with chemotherapy, radiotherapy or other immune checkpoints are very necessary.

Conclusion

In conclusion, Pembrolizumab has demonstrated a promising antitumor activity in pre-treated patients with high grade salivary gland mucoepidermoid carcinoma, and offered a clinically, radiological and pathological response with a meaningful therapeutic option.

Further studies that move the treatment of Pembrolizumab to front-line, maintenance settings and combinations with other treatment methods are necessary. These studies should include the time and duration of the pharmacotherapy in relation to the needed time of surgery. Side effects of the drugs should also be followed as well as patient compliance.

Acknowledgment

We would like to thank the entire department of Otolaryngology head and neck surgery and Oncology Department for their help and support.

Conflicts of interest statement and funding: None

References

1. Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP (2005) Trends in incidence and prognosis for head and neck cancer in the United States: A sitespecific analysis of the SEER database. Int J Cancer 114: 806-816.
   Google Scholar   CrossRef
2. Mukaigawa T, Hayashi R, Hashimoto K, Ugumori T, Hato N, et al. (2016) Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas. J Surg Oncol 114: 36-43.
   Google Scholar   CrossRef
3. Garden AS, Naggar AKE, Morrison WH, Callender DL, Ang KK, et al. (1997) Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37: 79-85.
   Google Scholar   CrossRef
4. Terhaard CH, Lubsen H, Rasch CRN, van Den Ende PLA, Burlage F (2005) The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys 61: 103-111.
   Google Scholar   CrossRef
5. Strutz J, Mann WJ (2009) Praxis der HNO-Heilkunde. Thieme, Stuttgart.
6. Goode RK, El-Naggar AK (2005) Mucoepidermoid carcinoma (Head and Neck). World Health Organization Classification of Tumours, IARC Press, Lyon.
7. Osborn V, Givi B, Lee A, Sheth N, Roden D, et al (2017) Characterization, treatment and outcomes of salivary ductal carcinoma using the National Cancer Database. Oral Oncol 71: 41-46.
   Google Scholar   CrossRef
8. Sridharan V, Gjini E, Liao X, Chau NG, Haddad RI, et al (2016) Immune profiling of adenoid cystic carcinoma: PD-L2 expression and associations with tumor-infiltrating lymphocytes. Cancer Immunol Res 4: 679-687.
   Google Scholar   CrossRef
9. Laurie SA, Ho AL, Fury MG, Sherman E, Pfister DG (2011) Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol 12: 815-824.
   Google Scholar   CrossRef
10. Alberts DS, Manning MR, Coulthard SW, Koopmann CF, Herman TS (1981) Adriamycin/cis-platinum/cyclophosphamide combination chemotherapy for advanced carcinoma of the parotid gland. Cancer 47: 6450-648.
    Google Scholar   CrossRef
11. Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16: 275-287.
    Google Scholar   CrossRef
12. Dolan DE, Gupta S (2014) PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control 21: 231-237.
    Google Scholar   CrossRef
13. Sharp M, Corp D (2017) Keytrudas (Pembrolizumab) injection, for Intravenous Use. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.
14. Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, et al (2016) Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 2016;34: 3838-3845.
    Google Scholar   CrossRef
15. Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, et al (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an openlabel, multicentre, phase 1b trial. Lancet Oncol 17: 956-965.
    Google Scholar   CrossRef
16. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, et al (2019) Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or meta-static squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 394: 1915-1928.
    Google Scholar   CrossRef
17. McHugh CH, Roberts DB, El-Naggar AK, Hanna EY, Garden AS, et al (2012) Prognostic factors in mucoepidermoid carcinoma of the salivary glands. Cancer 118: 3928-3936.
    Google Scholar   CrossRef
18. Chen AM, Lau VH, Farwell DG, Luu Q, Donald PJ (2013) Mucoepidermoid carcinoma of the parotid gland treated by surgery and postoperative radiation therapy: Clinicopathologic correlates of outcome. Laryngoscope 123: 3049-3055.
    Google Scholar   CrossRef
19. Brandwein MS, Ivanov K, Wallace DI, Hille JJ, Wang B, et al (2001) Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25: 835-845.
    Google Scholar   CrossRef
20. National Comprehensive Cancer Network (2021) NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers.
21. Cohen R, Delord J, Doi T, Piha-Paul S, Liu S, et al (2018) Pembrolizumab for the treatment of advanced salivary gland carcinoma. Am J Clin Oncol 41: 1083-1088.
    Google Scholar   CrossRef
22. Laurie SA, Licitra L (2006) Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol 24: 2673-2678.
    Google Scholar   CrossRef
23. Marabelle A, Fakih M, Lopez J, Shah M, Nakagawa K, et al (2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21:1353-1365.
    Google Scholar   CrossRef