Treatment of oral mucositis from chemotherapy and radiotherapy with sericin

Oral mucositis follows a five-phase course: initiation, driven by DNA damage and the production of reactive oxygen species; upregulation of NF-kB and of cytokines such as TNF-alpha, IL-1beta and IL-6; signal amplification; ulceration with bacterial colonization; and finally healing. Pain and dysphagia lead to treatment interruptions, enteral nutrition and hospital admissions, with an impact that weighs on both oncological outcome and costs. Few interventions have consolidated evidence behind them, among them palifermin in specific settings, oral cryotherapy for particular regimens and photobiomodulation, and management remains largely symptomatic.

Incidence is very high in some settings. In head and neck cancers treated with radiotherapy, severe-grade mucositis affects the majority of patients, and in conditioning regimens for hematopoietic stem cell transplantation the proportion is just as significant. In these situations the pain often requires systemic opioids, and the loss of mucosal barrier integrity increases the risk of bacteremia in neutropenic patients, turning a local complication into a systemic problem.

Sericin brings together, in a single material, several useful properties. Its antioxidant activity, linked to its hydroxylated residues and its capacity to scavenge radicals, may limit the initial phase of damage. The anti-inflammatory effects reported on cytokine production in cellular and animal models fit with the involvement of NF-kB. Its film-forming and mucoadhesive behavior makes it possible to create a protective barrier over the ulcerated surface, reducing irritation from mechanical and chemical stimuli, while its effect on the migration of keratinocytes and fibroblasts, described in wound studies, may speed up re-epithelialization.

Formulation plays a central role. A mouthwash has a very short residence time because of salivary clearance, which is why mucoadhesive gels, applicable films or in situ gelling systems appear preferable. The choice of molecular weight and concentration also affects viscosity, adhesion and tolerability.

Fibroin and sericin differ significantly in the properties that matter on the mucosa. Sericin, which is more soluble and has a higher density of polar groups, forms viscous solutions and flexible films that adhere to moist tissues, whereas fibroin usually requires a more stable structure. A formulation that combines sericin, for its biological and barrier effect, with a mucoadhesive polymer such as chitosan, hyaluronic acid or carbomers can exploit synergies, provided that compatibility is verified.

The standard model is the hamster with mucositis induced by localized irradiation of the cheek pouch, which allows macroscopic severity to be assessed with validated scales, together with histology and inflammatory markers. For chemotherapy-induced forms, 5-fluorouracil is frequently used. In humans, the sensitive endpoints are the incidence of severe mucositis, grade 3 or higher according to the WHO or CTCAE criteria, its duration, pain on a numerical scale and the need for opioid analgesics, along with the maintenance of the planned oncological schedule.

From a mechanistic standpoint, one indication of interest is the modulation of the amplification phase, in which the production of proinflammatory cytokines sustains the damage. Measurements of TNF-alpha, IL-1beta and IL-6 in tissue, of myeloperoxidase as an indicator of neutrophil infiltrate and of malondialdehyde as a marker of lipid peroxidation provide a biochemical reading that complements the clinical assessment, and make it possible to understand at which level of the process the effect of the formulation lies.

A product intended for immunocompromised patients must guarantee rigorous control of bioburden and endotoxins, together with a characterization of its potential immunogenicity, even though the tolerability profile of purified sericin is generally favorable. The realistic positioning is as an adjunctive supportive therapy, and clinical evidence will need to demonstrate an added benefit over standard measures, not merely a symptomatic effect.

Clinical research on mucositis poses well-known methodological challenges. Severity is assessed with scales that include both objective and subjective components, there is variability between operators, and the response is influenced by the oncological regimen, the dose, oral hygiene and nutritional status. A randomized, double-blind, placebo-controlled design, with stratification by type of treatment, reduces these confounding factors, and the use of trained assessors and standardized photographs improves reproducibility.

The endpoint most relevant to the clinician is the reduction in the incidence and duration of severe mucositis, because it affects treatment interruptions, hospitalizations and artificial nutrition. A benefit on pain, measured with numerical scales and with analgesic consumption, is a supporting endpoint. Safety must include the assessment of any hypersensitivity reactions, given that this is a protein material, and of possible interactions with the oncological therapy, which in principle must not reduce its efficacy, a point that needs to be demonstrated above all for formulations with antioxidant activity.