# Medical Gas Plasma Treatment in Head and Neck Cancer--Challenges and Opportunities
## 5 Clinical Studies  
All clinical studies that investigated the impact of physical plasma on head and neck cancer (Table 2) were performed with the kINPen MED (Neoplas tools GmbH, Greifswald, Germany), which is licensed for the treatment of infected wounds, as well as infective skin diseases, and has been described in detail before [1]. Except for one trial, the application of plasma was used for the treatment of locally advanced squamous cell carcinoma of the head and neck region, with the primary aim of tumor tissue decontamination as part of the palliative concept. The most apparent plasma-induced effects were a visible change of the tumor surface similar to partial local regression, wound healing of infected ulcerations, and the reduction of the typical fetid odor that is caused by microbial contamination of the tumor. Regarding cancer patient palliation, a decline of requested pain medication was observed, along with an improvement in social interaction, positive emotional effects, and weight gain. These effects led to an overall increase in patients' quality of life [21; 39; 41]. In a few patients, an 80% reduction of the tumor surface was even observed [21]. The reduction of the tumor mass and inhibition of tumor growth was not only apparent through visible changes, but was also confirmed on a molecular level using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining indicative of apoptosis within the plasma-treated tissue [21; 39]. This was confirmed in ex vivo plasma-treated tumor tissue samples, showing increased apoptosis within the tumor tissue [6]. Molecular analysis of the liquid environment that harbored the tissues after plasma treatment moreover revealed elevated cytochrome c levels in malignant over non-malignant samples. This was concomitant with changes in the inflammatory signatures, as seen in elevated levels of tumor necrosis factor-\(\alpha\) (TNF\(\alpha\)), interleukin-10 (IL-10), and interferon-\(\gamma\) (IFN\(\gamma\)) in plasma-treated head and neck cancer when compared to plasma-treated non-malignant tissue. Another trial utilized hyperspectral-imaging technology to investigate the impact of plasma on tissue microcirculation parameters in head and neck cancer. An increase of superficial and deeper cutaneous oxygen saturation was demonstrated that correlated with elevated hemoglobin concentration and distribution within the plasma-treated region compared to the non-treated area. Around the spot of plasma treatment, this effect extended locally to the adjacent region not directly being exposed to plasma treatment. Interestingly, the effect also lasted well beyond the time when plasma treatment was stopped. Such a plasma-mediated impact on the microcirculation may not only promote wound healing, but may also reduce microbial contamination through an increased influx of leukocytes [40]. It is essential to mention that plasma-mediated tumor regress was only effective in some patients (responders), while others showed no response (non-responders) [21; 41]. One particular case showed a dramatic tumor shrinkage with plasma treatment over 7 months before tumor growth relapsed, despite the continuation of the plasma treatment further. This loss of physical plasma efficacy with long-term treatment reveals one of the challenges in the medical application of this innovative tool since the success seems to depend on various parameters ranging from the general genetics of the tumor to the tumor microenvironment and possibly adaption [21]. Clonal evolution and tissue conductivity also contribute to potential therapeutic resistance in head and neck tumors [39]. Theoretically, tissue conductivity may influence the production of plasma-derived ROS, thereby altering the plasma composition itself and, as a result, its downstream effects in the tumor tissue [21]. In light of the current literature, it is difficult to assess whether gas plasma treatment of HNSCC might be more promising in this type of tumor than other tumor types.