Cold Atmospheric Pressure Plasma (CAP) as a New Tool for the Management of Vulva Cancer and Vulvar Premalignant Lesions in Gynaecological Oncology

Abstract

Vulvar cancer (VC) is a specific form of malignancy accounting for 5-6% of all gynaecologic malignancies. Although VC occurs most commonly in women after 60 years of age, disease incidence has risen progressively in premenopausal women in recent decades. VC demonstrates particular features requiring well-adapted therapeutic approaches to avoid potential treatment-related complications. Significant improvements in disease-free survival and overall survival rates for patients diagnosed with post-stage I disease have been achieved by implementing a combination therapy consisting of radical surgical resection, systemic chemotherapy and/or radiotherapy. Achieving local control remains challenging. However, mostly due to specific anatomical conditions, the need for comprehensive surgical reconstruction and frequent post-operative healing complications. Novel therapeutic tools better adapted to VC particularities are essential for improving individual outcomes. To this end, cold atmospheric plasma (CAP) treatment is a promising option for VC, and is particularly appropriate for the local treatment of dysplastic lesions, early intraepithelial cancer, and invasive tumours. In addition, CAP also helps reduce inflammatory complications and improve wound healing. The application of CAP may realise either directly or indirectly utilising nanoparticle technologies. CAP has demonstrated remarkable treatment benefits for several malignant conditions, and has created new medical fields, such as "plasma medicine" and "plasma oncology". This article highlights the benefits of CAP for the treatment of VC, VC pre-stages, and postsurgical wound complications. There has not yet been a published report of CAP on vulvar cancer cells, and so this review summarises the progress made in gynaecological oncology and in other cancers, and promotes an important, understudied area for future research. The paradigm shift from reactive to predictive, preventive and personalised medical approaches in overall VC management is also considered.

Keywords: cancer development; cold atmospheric plasma; gynaecological oncology; individualised profiling; patient stratification; plasma tissue interaction; predictive preventive personalised medicine (PPPM/3PM); premalignant lesions; risk factors; treatment; vulva cancer.

Figure 1

The mechanism of cold atmospheric plasma (CAP) in cancer treatment. Formation of plasma starts in high electric field across the region of gas (pure helium or argon, and/or their mixtures with oxygen) that accelerates electrons. These processes lead to the initiation of a cascade of chemical reactions associated with the generation of various chemical species. CAP is a source of highly reactive species (ROS, RNS, atomic oxygen, hydroxyl radical, superoxide, nitrogen oxides, and singlet delta oxygen), neutral particles (photons and neutrons), electrons, and physical factors (electromagnetic field and UV radiation) [199]. Reactive species produced by CAP have the ability to directly induce DNA damage and cell cycle arrest resulting in the apoptotic signalling of tumour cells. The production of reactive species can activate macrophages leading to higher elevation of TNF-α–mediated NF-κB activation and the expression of proinflammatory genes associated with tumourigenesis. On the other hand, CAP seems to be an effective inhibitor of TNF-α–mediated NF-κB activation with a potential role in anticancer strategies. CAP can also induce the immunogenic cell death (ICD) of tumour cells that lead to systematic immune response. ICD can also be achieved by the regulation of various cytokines, including TNF, that play a crucial role in the creation of immunogenic microenvironment [200]. Abbreviations: ROS, reactive oxygen species; RNS, reactive nitrogen species; AQP, aquaporin; TNFR, tumour necrosis factor receptor; Nox, NADPH oxidases; ATM, ataxia-telangiectasia mutated kinase; JNK, c-Jun N-terminal kinase; ASK, apoptosis signal-regulating kinase; APC, antigen-presenting cell; TNF-α, tumour necrosis factor alpha; Bax, Bcl-2-associated protein X; UV, ultraviolet radiation; APC, antigen-presenting cell.