Elsevier

Oral Oncology

Volume 90, March 2019, Pages 67-73
Oral Oncology

The effects of checkpoint inhibition on head and neck squamous cell carcinoma: A systematic review

https://doi.org/10.1016/j.oraloncology.2019.01.018Get rights and content

Highlights

  • The OS in HNSCC treated with checkpoint inhibition range from 5.5  to 13.0 months.

  • PD-L1 positive responded with greater antitumor activity compared to PD-L1 negative.

  • Checkpoint inhibition resulted fewer and less severe AE compared tostandard-therapy.

Abstract

Background

Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent malignancy worldwide. Immunotherapy with checkpoint inhibitors such as anti-CTLA-4 anti-PD-l and anti-PD-L1 has shown promising results in treating patients with recurrent/metastatic HNSCC. We aimed to systematically review the literature on immunotherapy with checkpoint inhibitors as treatment for advanced HNSCC.

Methods

PubMed, EMBASE, Google Scholar, and the Cochrane Library were systematically searched with the purpose of identifying all studies addressing the effects of checkpoint inhibitors as treatment for HNSCC in human clinical trials. We assessed effects of the treatment with checkpoint inhibitors on overall survival (OS), progression-free survival (PFS), HPV-status, PD-L1-status, and adverse events.

Results

We identified eight studies (n = 1431 patients) with an OS ranging from 7.5 to 14.9 months in PD-1 checkpoint inhibition. Two studies (n = 541 patients) observed a significantly (p = 0.01) and (p = 0.007) longer OS with checkpoint inhibition compared to standard-treatment, platinum-based chemotherapy (7.5 versus 5.1 months and 14.9 months versus 10.7 months). Two studies (n = 411 patients) found an increased OS associated with PD-L1-postive patients compared to PD-L1-negative patients. The eight studies have heterogenous design with only three being randomized.

Conclusion

Few clinical trials have investigated the treatment with checkpoint inhibition for HNSCC. Solely, two randomized studies comprising 240 patients treated with nivolumab (anti-PD-L) and 301 patients treated with pembrolizumab (anti-PD-L) showed a significantly prolonged survival in patients with recurrent/metastatic HNSCC compared with standard-treatment. There is a further need for randomized clinical trials investigating a putative role of checkpoint inhibition in the treatment of advanced HNSCC.

Introduction

Head and neck cancer is the sixth most frequent malignancy worldwide, with more than 650,000 reported cases annually [1] and with a continued increase in incidence [2]. The far majority of head and neck cancers are squamous cell carcinomas (HNSCC) accounting for more than 90% of the cancers located in the upper aerodigestive tract [3]. Several standard treatment modalities for HNSCC exist including surgery, chemotherapy, radiation-therapy, and epidermal growth factor receptor inhibitor (Cetuximab) [4]. Despite the development in chemotherapy, targeted radiotherapy, and surgery the estimated 5-year survival of HNSCC remains approximately 50% [5]. A potentially new therapeutic option in the treatment of HNSCC is immunotherapy targeting checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) [6]. The basic principle of immunotherapy is to activate and allow the endogenous immune system to attack the tumor cells.

PD-1 and CTLA-4 downregulate and inhibit T-cells by binding with its ligands programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) or CD80/CD86. Unlike the ligands of CTLA-4, which are only expressed on antigen presenting cell (APC), PD-1’s ligands are more widely expressed on leukocytes, nonlymphoid tissues, and some tumors including HNSCC [7]. Under normal conditions the immune system uses the inhibitory checkpoint pathways with CTLA-4 and PD-1 to regulate targeted activation and immune response against pathogens, while preventing the immune system from attacking itself and inducing autoimmune activity. Tumor cells take advantage of these pathways to create an immunosuppressive microenvironment in which they can hide themselves from the immune system [8]. Some tumors including HNSCC have showed an increased expression of PD-L1, the ligands for PD-1, which is thought to help create the immunosuppressive microenvironment around the tumor [9]. Blockage of the immunosuppressive effect of PD-1, PD-L1, and CTLA-4 has shown promising results as antitumor immunity, allowing T-cells to be upregulated and attack tumor cells, leading to a potentially reduction of the tumor. This has been seen in the treatment of solid tumors including HNSCC [10].

This study systematically evaluated the literature on the effects of checkpoint inhibitors on HNSCC patients. We aimed to clarify the potential benefits and harms in the use of immunotherapy targeting checkpoint inhibitors in patients with advanced HNSCC.

Section snippets

Materials and methods

This systematic review was conducted with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11].

Results

The electronic literature search generated 670 potentially eligible studies of which four studies met the inclusion criteria. Four additional study was found through reference list (Fig. 1).

Eight clinical trials (n = 1431 patients) evaluated the safety and effects of checkpoint inhibitors as a treatment for HNSCC (Table 1, Table 2). All clinical trials included patients that had been diagnosed with recurrent HNSCC and whose previous standard treatment had failed, or primary HNSCC with

Discussion

This study is the first systematic review to evaluate the effect of immunotherapy with checkpoint inhibitors for HNSCC.

We found that treating recurrent/metastatic HNSCC patients with PD-1 checkpoint inhibitors resulted in an OS ranging from 7.5 months to 14.9 months. There is a clear interval-difference of 7.4 months between the highest reported OS and the lowest. Furthermore, in patients treated with a combination of PD-L1/CTLA-4 checkpoint inhibitors resulted in an OS of 7.6 months. PD-L1 and

Conflicts of interest

The authors declare no conflicts of interest.

Funding

None.

References (21)

There are more references available in the full text version of this article.

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