Radiotherapy (RT) is a cornerstone in the management of cancers that affect the head and neck region, typically using ionizing radiation doses ranging from 60 Grays (Gy) to 70 Gy (1). Despite its efficacy, RT is associated with a significant incidence of acute toxicities that can substantially impair patients’ quality of life (2). In this context, acute radiodermatitis (ARD) is a common cutaneous adverse event characterized by an inflammatory response to ionizing radiation (3–5).

Early manifestations of ARD include transient erythema within the first 24 hours after RT initiation, followed by hyperpigmentation, pain, itching, edema, and desquamation (6, 7). In severe cases, ARD may progress to moist desquamation, ulceration, or even necrosis (6, 8, 9).

Pathophysiologically, ARD results from radiation-induced depletion of basal keratinocytes, which compromises epidermal regeneration (5, 10). Repeated radiation fractions exacerbate these effects, leading to increased transepidermal water loss, disruption of the cutaneous microbiome, and a greater susceptibility to colonization by opportunistic pathogens, particularly in areas affected by moist desquamation (9, 11–14).

A critical independent risk factor for the development of severe ARD is colonization and infection by Staphylococcus aureus (12). Furthermore, depletion of commensal bacteria such as S. hominis and S. epidermidis often precedes this dysbiosis (12). This observation is complemented by recent microbiome evidence demonstrating that RT, particularly hypofractionated regimens, induces dysbiosis by increasing the abundance of potentially pathogenic genera, including Finegoldia and Dermacoccus (15). At the same time, a relative increase in Staphylococcus is associated with worsening clinician-reported pruritus and dermatitis (15). Given that head and neck RT protocols are particularly aggressive, patients may be more vulnerable to these opportunistic infections. Thus, targeting S. aureus and restoring microbial homeostasis represent a key therapeutic strategy.

Despite the clinical burden of ARD, there is currently no standardized management protocol, largely due to heterogeneity across studies and interventions, including topical agents, corticosteroids, barrier dressings, and natural therapies such as chamomile (3, 4, 16). In this context, antimicrobial photodynamic therapy (aPDT) has emerged as a promising adjunct approach (17–19). By activating photosensitizers with visible light (from lasers or LEDs) to generate reactive oxygen species (ROS), aPDT induces microbial cell death through oxidative stress (17, 20). This therapy has demonstrated efficacy against a broad spectrum of pathogens, including resistant S. aureus strains frequently associated with severe cases of ARD (12).

Among the available photosensitizers, methylene blue (MB) is a cationic phenothiazine dye widely used in aPDT due to its strong absorption in the red-light spectrum (630–680 nm), which favors effective tissue penetration, and its photochemical properties (21, 22). The clinical advantages of MB include its excellent safety profile, widespread availability, relatively low cost, and practical application features such as a short incubation period and generally painless irradiation, making it a suitable agent for managing superficial infections in a clinical setting (17, 22).

Given the multifactorial nature of severe ARD, which involves skin barrier dysfunction, inflammation, and secondary infection, aPDT offers a multimodal mechanism to support local healing and tissue repair. This study reports a case series describing the clinical effects of aPDT in patients with severe ARD undergoing head and neck RT.

We conducted a case series over an eight-month period from 2024 to 2025 involving five patients with severe ARD (GRA-L scale ≥ 5) who received aPDT following a standardized protocol. Clinical assessments were performed every 72 hours, including photographic documentation and severity scoring with the GRA-L scale. This study complies with the Declaration of Helsinki, and it has already been approved by the Research Ethics Committee of the University Hospital of Brasília, Brazil. The case description was conducted according to the CARE Statement Guideline (23).

The sociodemographic and clinical characteristics of the five patients are summarized in Table 1. All patients developed severe ARD (GRA-L grade ≥ 5) during or after RT and were subsequently treated with aPDT.

The clinical progression of the severe ARD lesions, the appearance during aPDT intervention, and the final healing outcomes for all five patients are presented in Figure 1.

This case series highlights the potential of aPDT as an effective and safe adjuvant therapy for managing severe ARD in cancer patients undergoing head and neck RT. Despite presenting advanced lesions (GRA-L ≥ 5), including necrosis, all patients showed rapid clinical improvement and complete healing of moist desquamation with minimal adverse effects. In this study, “complete healing” referred to full re-epithelialization and clinical resolution of moist desquamation. Mild residual erythema persisted in some patients, corresponding to GRA-L 1 rather than GRA-L 0. These outcomes are clinically relevant, given that severe ARD affects approximately 25% of this population and often leads to interruptions in curative-intent RT (26).

The head and neck region are highly susceptible to severe ARD due to anatomical factors, such as skin folds and the use of aggressive RT protocols (12, 28, 29). Disruption of the skin barrier facilitates microbial colonization, especially by S. aureus, which exacerbates ARD severity (12, 13). In addition, patient-related risk factors, including smoking history and actinic elastosis, may impair microvascular function, reduce skin regenerative capacity, and intensify inflammatory responses, thereby increasing vulnerability to more radiation-induced toxicity (30–33). Within this multifactorial context, the dual therapeutic action of aPDT offers a distinct advantage by simultaneously reducing microbial burden and promoting tissue repair (34–36).

aPDT exerts a direct antimicrobial effect and a pro-healing photobiomodulatory effect. Upon activation of methylene blue by red light, ROS are generated and induce oxidative damage to microbial membranes and essential biomolecules, leading to rapid microbial inactivation, an effect consistently demonstrated in in vitro and in vivo aPDT studies (34, 35). In parallel, sublethal ROS modulate local inflammation and stimulate angiogenesis, fibroblast proliferation, extracellular matrix deposition, and re-epithelialization (36), thereby promoting tissue repair (37). These biological effects are aligned with previous evidence demonstrating aPDT-mediated modulation of matrix remodeling and restoration of tissue integrity (37, 38).

The energy density applied in our protocol (91.836 J/cm²) is consistent with the therapeutic range reported in aPDT studies targeting infected tissues (22, 35, 38). We recognize that clinical trials in superficial infections typically utilize lower energy densities (6–18 J/cm²) in combination with very low MB concentrations (0.0003–0.06 molar) (22). However, higher dosimetric values have proven effective and necessary in deeper or heavily colonized wounds (35, 38). For instance, aPDT delivered at 60 J/cm² using 0.01% MB resulted in clinical improvement of infected diabetic foot ulcers (38), while preclinical murine models of S. aureus skin infection demonstrated significant bacterial reduction and accelerated healing at 74 J/cm² (35). Importantly, our protocol employed a substantially higher MB concentration (1%), and higher photosensitizer loads require proportionally greater radiant exposure to ensure adequate photoactivation across the full thickness of inflamed, exudative, and partially necrotic tissue, features that characterize severe ARD.

Importantly, the mechanistic rationale described above was directly reflected in the clinical evolution observed in our case series. The rapid reduction of purulent exudate, foul odor, and necrotic tissue after the first aPDT session mirrors the established antimicrobial and antibiofilm effects of MB (22, 34, 35). Likewise, the marked improvement in erythema, pain, and moist desquamation within 48–72 hours is consistent with the anti-inflammatory and pro-repair roles of sublethal ROS, including modulation of angiogenesis, fibroblast activation, and extracellular matrix remodeling (35, 37).

Beyond clinical healing, the shortened repair time contributed to improved patient satisfaction and quality of life. Severe ARD not only compromises RT delivery but also impacts psychosocial well-being due to body image changes resulting from skin toxicity (39). By accelerating tissue recovery and reducing radiotoxicity, aPDT may serve as a valuable adjunct to standard supportive care in this vulnerable population.

Nevertheless, certain limitations must be acknowledged. Microbiological confirmation of infection was not performed, and the diagnosis relied instead on clinical signs such as foul odor and necrotic appearance. The sample size limits the extrapolation of the findings to broader populations, and the case series design, lacking a control group, precludes robust causal inferences. Future controlled trials with larger cohorts are necessary to validate these promising results and establish evidence-based protocols.

The primary “take-away” lessons from this case series are that long-term effects of head and neck RT contribute significantly to the overall cost of survivorship care. Thus, aPDT can substantially mitigate the clinical and cost-of-care impact for patients, also it would reduce costs associated with utilization of health care resources.

This case series provides preliminary evidence that aPDT may assist in the management of severe ARD in patients undergoing head and neck RT. While the observed improvements were encouraging, these findings are exploratory and require confirmation in larger, controlled studies before aPDT can be considered within standardized supportive care approaches.