ARD is often defined to occur within the first 90 days of RT, typically starting to occur after a moderately high dose (e.g., 35–40 Gy in 2 Gy per fraction) has been delivered to the skin. Different patient characteristics and treatment techniques may lead to different degrees of ARD. A variety of ARD severity exists in the literature and our cohort for NPC patients treated with PBT or XRT. The proportion of patients with grade 1, 2 and 3 ARD after treatment with PBT was 0-64.3%, 25-67.4%, and 3.6–42.0%, respectively[3, 4, 14, 20]. For XRT, it varies from 6.4–51.0% for grade 1, 31–69% for grade 2, and 8.8–23.6% for grade3 in selected reports [21–24]. In a clinical setting, the comparison of ARD between PBT and XRT remains inconsistent. After matching between groups, a higher probability of grade 3 ARD was observed in the PBT group reported by Chou et al. (35% versus 7.5%)[3] and Holliday et al. (40% versus 25%)[25] but was not observed by Li et al. (3.6% versus 2.0%) [4].
The severity of ARD is related to numerous risk factors that have been classified as being patient-related or treatment-related. Patient-related risk factors may include age, gender, smoking, nutritional status, body mass index, comorbidity, or genetic factors. Treatment-related factors include the total radiation dose, the dose fractionation schedule, RT technique, combination with chemotherapy, and the volume and surface area of irradiated tissue [9, 26, 27]. For NPC patients, in a large cohort study treated with XRT (including intensity modulated RT or three-dimensional conformal RT), treatment with intensity modulated RT, lower performance status and multicycle chemotherapy were observed to be predictors of severe ARD [28]. In our patients uniformly treated with PBT with standardized protocols including total dose and dose per fraction, chemotherapy regimens, and skin care, the variables of smoking habit and advanced nodal status were observed to be significant predictors for grade 2 and 3 ARD.
The correlation of habitual smoking with ARD remains inconsistent in the literature for patients treated with XRT [26, 29, 30]. For PBT, very limited data are available. The association between habitual smoking and the severity of ARD after PBT has been previously reported in patients with breast cancer [12] but was reported for the first time in patients with NPC in the present study. The mechanism of the effect of smoking on ARD is unknown. However, strong evidence has demonstrated that smoking adversely impacts the wound healing process [31]. Tissue hypoxia is viewed as a fundamental mechanism through which cigarette smoking disrupts acute wound healing [32]. Cigarette smoking impairs the function of several cell types such as neutrophils and macrophages important to inflammatory and bactericidal activity and also compromises oxygen delivery to tissues [33].
Patients with advanced nodal status often receive a higher radiation dose to the neck skin, putting them at a higher risk of severe ARD. The identification of neck skin as a sensitive structure for dose optimization during the process of treatment planning of RT could significantly reduce the skin dose to a tolerable level [34]. The volume of skin at 2mm receiving a dose above 56Gy was observed to be predictive of grade 2 and 3 ARD for head and neck cancer patients treated with XRT [35]. The dosimetric parameters related to the severity of ARD were not explored in current study. As far as we know, a validated dosimetric constraint for neck skin used to mitigate the severity of ARD for patients treated with PBT at head and neck area is still lacking, though, some dosimetric parameters related to severe ARD in chest skin or scalp have been reported in patients treated with PBT [12, 15].
The differential biologic effects on normal tissue induced by PBT compared to XRT are not well established [36, 37]. The pathogenesis of ARD involves a combination of direct radiation injury and a subsequent inflammatory response, affecting cellular elements in the epidermis, dermis, and vasculature. Direct radiation injury causes changes in skin pigmentation through the migration of melanosomes, interrupted hair growth, and damage to the deeper dermis, which disrupts the normal process of skin cell repopulation, resulting in erythema due to dermal vessel dilation and release of a histamine-like substance [38]. The mechanism of radiation-induced inflammation is not yet completely understood, but keratinocytes, fibroblasts, and endothelial cells stimulate immune cells in the epidermal and dermal layers, as well as those in circulation [39].
Some degree of chronic radiodermatitis was observed in our cases with grade 3 ARD after longer follow-up. Grade 3 ARD at the end of XRT has been observed to be associated with neck fibrosis at 6 months in head and neck cancer patients [40]. Chronic radiodermatitis often presents several months to years after RT has been completed. Post-inflammatory hypo- and hyperpigmentation are common chronic changes seen in patients as a result of the dermo-epithelial junction being disrupted, which depends on patient- and treatment-related factors and may persist or normalize with time [9]. Telangiectasia and fibrosis are also common in chronic radiodermatitis in NPC patients. The incidence of symptomatic neck fibrosis varies from 2.3–38% in NPC patients treated with XRT [23, 41]. The consequential effect of ARD induced by PBT on chronic skin injury warrants further investigation.
General management of ARD begins with basic preventive measures, including self-care and the use of prophylactic topical corticosteroids and/or antibiotics. It is difficult to establish strong evidence-based clinical practice guidelines in the approach to self-care for ARD. The medication for ARD induced by PBT generally follows the clinical practice used for patients treated with XRT. Several clinical trials have demonstrated a favorable effect for the use of prophylactic topical corticosteroids [42–44] or silver sulfadiazine [45] to reduce ARD. In our cohort, topical corticosteroid was prescribed for patients with grade 1 ARD and silver sulfadiazine was added if the ARD progressed to grade 2 or more. The regimens were observed to be effective in the treatment of ARD induced by PBT.
Admittedly, there are several limitations to the study. First, the cases were limited to a single institute and it is therefore vulnerable to selection bias. Second, a dosimetric evaluation of the effects of PBT on the skin surface was not conducted due to the limited sample size. Third, the effect of ARD induced by PBT on chronic skin injury needs long-term studies.