Open Questions in Cold Atmospheric Plasma Treatment in Head and Neck Cancer: A Systematic Review

Abstract

Over the past decade, we witnessed a promising application of cold atmospheric plasma (CAP) in cancer therapy. The aim of this systematic review was to provide an exhaustive state of the art of CAP employed for the treatment of head and neck cancer (HNC), a tumor whose late diagnosis, local recurrence, distant metastases, and treatment failure are the main causes of patients' death. Specifically, the characteristics and settings of the CAP devices and the in vitro and in vivo treatment protocols were summarized to meet the urgent need for standardization. Its molecular mechanisms of action, as well as the successes and pitfalls of current CAP applications in HNC, were discussed. Finally, the interesting emerging preclinical hypotheses that warrant further clinical investigation have risen. A total of 24 studies were included. Most studies used a plasma jet device (54.2%). Argon resulted as the mostly employed working gas (33.32%). Direct and indirect plasma application was reported in 87.5% and 20.8% of studies, respectively. In vitro investigations were 79.17%, most of them concerned with direct treatment (78.94%). Only eight (33.32%) in vivo studies were found; three were conducted in mice, and five on human beings. CAP showed pro-apoptotic effects more efficiently in tumor cells than in normal cells by altering redox balance in a way that oxidative distress leads to cell death. In preclinical studies, it exhibited efficacy and tolerability. Results from this systematic review pointed out the current limitations of translational application of CAP in the urge of standardization of the current protocols while highlighting promising effects as supporting treatment in HNC.

Keywords: RONS; apoptosis; cold atmospheric plasma; head and neck cancer.

Figure 1

Schematic representation of two basic strategies to use cold atmospheric plasma. Direct cold atmospheric plasma treatment on cancer cells in vitro or on subcutaneous xenograft tumors in vivo (left). Indirect cold atmospheric plasma treatment on solutions, mostly medium. Plasma Activated Medium is used to treat cancer cells seeded in dish or tumor tissues in mice (right).

Figure 2

PRISMA 2020 Flow Diagram of the screening process. In total, 24 studies were included in the present systematic review.

Figure 3

Schematic representation of the most relevant cold atmospheric plasma studies [5,6,15,23,36,37,38,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87] published in various countries.

Figure 4

Molecular mechanisms induced by direct and indirect application of cold atmospheric plasma included in the present systematic review.

Figure 5

Mechanism and pathways induced by plasma-activated media treatment in head and neck cancer. (A) Top relevant canonical pathways associated with plasma activated media treatment by core analysis. (B) The proposed mechanism of plasma activated media based anti-cancer effects on head and neck cancer cells [77].

Figure 6

Yearly distribution of the 23 articles (Dai et al. [84] has been excluded because the carrier gas was not specified in the articles) in the present systematic review according to the type of carrier gas.