# Cold Atmospheric Plasma Cancer Treatment, a Critical Review
## 6 An Outlook of CAP Cancer Treatment  
Recently, clinical tests have been performed by various organizations in which CAP treatment was incorporated into patient treatment plans. US Medical Innovation, LLC performed a clinical test where a CAP jet was used to treat stage 4 colon cancer remnants at Baton Rouge General Medical Center in Baton Rouge, Louisiana, after initial surgery to remove a tumor [101]. Another test in Germany was performed by treating six patients with a locally advanced (pT4) squamous cell carcinoma of the oropharynx, and who were suffering from open infected ulcerations [102]. CAP treatment noticeably inhibited the growth of tumors in some patients and caused a reduction in odor and the use of pain medication [102]. Partial remission was achieved for at least 9 months in two patients after CAP treatment. Incisional biopsies found a moderate amount of apoptotic tumor cells and a desmoplastic reaction of connective tissue. CAP has also been used to treat oral cancer with very mild side effects, such as a bad taste during and after treatment and minimal discomfort during treatment. None of these side effects were life threatening and most were transient with full recovery of normalcy [103]. These clinical tests have a common feature: bulk CAP directly touches tumorous tissues without the cover of a bulk medium or an aqueous layer with a macroscale. Such a working condition is essentially different from the experimental conditions that are used in in vitro studies. Due to the absence of a bulk aqueous layer, it is highly probable that the physical factors in CAP play an important role in clinical application. Based on the discussion above, the following predictions for possible approaches of CAP-based cancer treatment can be made (Figure 5). For subcutaneous tumors, a direct treatment strategy just above the skin of the tumor site is recommended. Based on the observation from physical-based CAP treatment in vitro, we speculate that even an air gap, such as several mm between bulk CAP and the skin, will not fully weaken the treatment's efficacy. In contrast, the efficacy of treatment may be fully inhibited when bulk CAP completely touches the skin too closely. For intraperitoneal tumor or tumors residing in deeper tissues, simply treating the skin is a questionable approach based on the current evidence and conclusions. If considering the anti-cancer capacity due to physical factors, the effective penetration depth remains unknown. PAS or PAM may be used to treat the tumor in such cases by administering subcutaneous or intraperitoneal injections. It is important to mention that CAP may be synergistically used with endoscopic technology to treat deep tissue tumors by a minimally invasive surgery [104]. In addition to these cases, CAP can also be used as an adjunct to current surgical methods. Bulk CAP can come in direct contact with the exposed tumor tissue or the remnants of tumor tissue during surgery. This direction may be another promising candidate. One unique feature of CAP is its ability to quickly change its composition and key parameters on demand and subject to specific requirements [105]. An illustration of the adaptive CAP concept is presented in Figure 6a. This concept is based on the capacity to read the cellular response to CAP in real time and to modify plasma composition and power in real time via a feedback mechanism [106; 107]. Direct treatment is the prerequisite to realize such adaptive plasma sources. Adaptive CAP enables the modification of plasma conditions in real time to optimize the effect on cancer and normal cells. An adaptive plasma therapeutic system can adjust its interaction with cells and tissues by responding to the boundary conditions at the cold plasma-cell interface [108]. Furthermore, due to the different effects of CAP on cancer cells and normal cells, an adaptive CAP system can achieve an enhanced selective anti-cancer effect by controlling the dose of reactive species or other possible interactions between cells and CAP.