# Medical Gas Plasma Treatment in Head and Neck Cancer--Challenges and Opportunities
## 2 Head and Neck Cancer  
Head and neck cancer accounts for roughly 4% of all cancers worldwide and is the sixth most common type of cancer with over 800,000 new cases annually [43]. This type of cancer occurs more than twice as often among men than women [44], and the average age of diagnosis is approximately 50 years old [45]. Head and neck cancer arises at several anatomical sites of the upper aerodigestive tract, such as the oral cavity, pharynx, and larynx, whereby the most common histologic type (90%) is the head and neck squamous cell carcinoma (HNSCC) [46]. It is widely accepted that alcohol and tobacco over-use is associated with the majority (72%) [47; 48] of this malignancy, partly through the formation of free radicals leading to DNA damage and mutation [49; 50]. Another high-risk factor is infection with specific serotypes of human papilloma virus (HPV), especially HSP16 and HSP18. These were established to have an etiological role in the development of HNSCC, primarily of the oropharynx. HPV-associated HNSCC arises in younger patients more often than tobacco- and alcohol-driven HNSCC, and are associated with prolonged survival and better treatment outcomes [51]. Despite the ongoing discovery of new therapies and the optimization of existing therapies, head and neck cancer remains challenging to treat due to resistance development and high genetic heterogeneity [52; 53]. Conventional treatment approaches are surgical excision, chemotherapy, and radiotherapy, and therapeutic decisions are based on the tumor location and stage. Approximately one-third of patients display an early-stage disease, while two-thirds suffer from advanced head and neck cancer with lymph node metastases [19]. Early-stage malignancies are predominantly treated using radiation therapy, either alone or in combination with surgery. Chemotherapy in combination with radiation is used as a primary treatment strategy or following surgical resection for patients with advanced disease stages. Treatment options for recurrent disease or distant metastasis are more limited [45], leading to poor survival outcomes and high morbidity [19]. Some of the existing chemotherapeutic agents are poorly selective and associated with toxicities. The surgical removal of oral cancer can result in a facial distortion with physical and psychological consequences [54], and it is sometimes not possible because of the cancer tissue being in close vicinity to vital nerves or vasculature. In addition, patients often develop loco-regional recurrences, distant metastases, and second primary tumors [55]. The emergence of immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided significant clinical improvements, but only about 20% of the patients respond to this kind of cancer therapy [56]. The prognosis for patients with head and neck cancer is mainly determined by the stage at diagnosis. It is devastating to note that survival has not markedly improved in recent decades, with there being an average 5-year survival rate of only 40-50%, and even as poor as 25% for hypopharyngeal cancer [55; 56; 57]. This highlights the urgent need for new treatment strategies, experimental investigations, and discoveries of new therapeutic targets in HNSCC.