**1.2 Acute radiation dermatitis (ARD)**

Acute radiation dermatitis (ARD) is a skin reaction with a high incidence that affects cancer patients undergoing RT for up to 3 months after the end of the treatment [13, 14]. Approximately 95–100% of cancer patients have some degree of ARD during RT, which is very common in patients treated for breast and head and neck cancer [15–17]. The first effects of ionizing radiation on the skin are expected to appear 2–4 weeks after the first dose of RT [15].

ARD usually starts with hyperpigmentation of the irradiated area, followed by mild or transient erythema, intense erythema, dry desquamation, and moist desquamation, and in more severe cases, leads to hemorrhage, necrosis, and ulceration (**Figure 1**) [15]. Generally, RT is interrupted when patients present with disseminated moist desquamation and the skin tissue does not progress to more severe reactions.

## *1.2.1 Pathophysiology*

The pathophysiological mechanism underlying ARD development is similar to that of the mechanism of ionizing radiation on the tumor, i.e. through direct and indirect DNA damage mechanisms. The effects of RT on skin tissue are cumulative and add up to each fraction of the ionizing radiation received [15, 18].

Tissue injury occurs through alterations in the double-stranded DNA of epithelial cells or through an increase in the concentration of reactive oxygen species in the intracellular environment [15, 16]. These lesions primarily affect the basal cells of the epidermis, which cannot self-renew in sufficient time to reconstitute the tissue [15]. Furthermore, ionizing radiation promotes the activation of the inflammatory cascade in the skin tissue [15, 16, 18].

#### **Figure 1.**

*Signs of ARD in head and neck cancer patients: A) hyperpigmentation; B) erythema; C) dry desquamation; D) moist desquamation. Source: Digital collection of the interdisciplinary Laboratory for Applied Research to clinical practice in oncology (LIONCO).*

Skin hyperpigmentation occurs due to excessive stimulation of melanin production triggered by exposure to ionizing radiation [14, 15].

Local erythema starts soon after the first fraction dose of RT and is more intense around the second week due to vasodilation and increased vascular permeability [13–15]. This then initiates an inflammatory reaction with the release of chemokines and cytokines (primarily interleukins and TNF-α), which control endothelial cell adhesion and recruit immune cells [15]. This process can be observed as the manifestation of intense erythema [15].

Dry desquamation usually appears at an accumulated dose of approximately 30 Gy [14], between the third and fourth week [13]. This occurs as a result of a rapid compensatory attempt to renew epidermal basal cells, which occurs faster than the elimination of damaged epidermal cells [15]. In addition, RT promotes lesions in the cells of the sebaceous glands and hair follicles, which causes increased dryness of the skin and loss of hair in the treated area [15]. When the entire basal layer is destroyed, moist desquamation occurs after approximately 4–5 weeks of treatment [13] with barrier disruption and exudate production [15].

It is important to emphasize that these cellular reactions will be observed in the skin corresponding to the irradiated area and do not necessarily need to occur gradually. In addition, the time to the onset of each degree of reaction may vary among patients. Scales are generally used to measure and monitor the evolution of ARD during treatment. The Common Toxicity Criteria for Adverse Events (CTCAE) scale [19] and the Radiation Therapy Oncology Group (RTOG) scale [20] are widely used.
