Efficacy of Platelet Gel in Children with Stomatitis during Chemotherapy

A prospective, open-label study of the efficacy of platelet gel (PG) in children with stomatitis during chemotherapy.

The study included children (0–18 years old) who developed stomatitis during cancer therapy in the Department of Pediatrics, Hematology, and Oncology at the Medical University of Warsaw from July 2018 to March 2019. Diagnosis of stomatitis was based on clinical examination. The degree of inflammation was assessed according to a World Health Organization (WHO) scale (Table 1). Inclusion criteria were stomatitis Grades II and III. Patients with Grade IV stomatitis did not qualify due to severe pain and an inability to open the mouth sufficiently, and those with Grade I did not qualify because the pathology was mild, with no indication for a more powerful intervention.

Allogeneic PG was prepared at the Institute of Hematology and Transfusion Medicine from PCs collected at the Regional Blood Transfusion Center in Warsaw. PCs were obtained using a cell separator (AMICUS®, Fresenius Kabi AG, Bad Homburg vor der Höhe, Germany) according to Polish regulations, and were subjected to a pathogen-inactivation procedure (Mirasol® PRT, Terumo BCT, Japan; and the Intercept Blood System®, Cerus Corporation, Concord, USA). All procedures were performed in a closed system using a sterile connection device (TSCD®, Terumo BCT, Japan). PG was immediately frozen for on-site storage, or transported frozen (-18°C). PG was prepared for patient application immediately before use. Freezing and thawing activated platelet cells and released growth factors. Simple preparation of the platelet gel was carried out in a closed system, which additionally increased the microbiological safety of PG.

In the study group, ABO group-compatible PG was applied in 2 ml doses (with cotton swabs) to mucosal lesions four times per day. All patients also received topical agents such as Mix No. 1 (3% hydrogen peroxide, 0.1% lidocaine, nystatin, and dolomite), nystatin, miconazole, and an herbal mouthwash containing panthenol and allantoin. Analgesics (e.g., acetaminophen, tramadol, and morphine) were administered to patients who developed pain, dysphagia, and severe stomatitis. Additionally, most patients received intravenous antifungal agents (e.g., fluconazole, micafungin, or amphotericin B) due to agranulocytosis and the risk of developing a fungal infection.

The primary endpoint of the study was stomatitis regression by at least one degree on the WHO classification scale. Regression time was assessed with an accuracy of one day. Secondary endpoints included relief from pain, degree of pain reduction, and PG safety. Assessment of pain intensity was dependent on patient age and developmental level using analog or numeric scales, or subjective opinions of caregivers for infants and younger children. Safety was assessed by the incidence of adverse reactions reported by patients and/or caregivers.

Chemotherapeutics trigger an inflammatory cascade, have direct and destructive effects on the epithelium and its DNA, and may also cause the formation of free radicals. This inflammation process not only applies to the epithelium, but also to the submucosal layer and the intercellular matrix [4, 12]. Moreover, mucosal lesions are constantly exposed to irritation associated with food intake, which explains why the mucosa healing process in stomatitis is prolonged. Based on the literature, regression of stomatitis takes approximately two weeks [4, 12, 13]. We conducted a retrospective analysis of stomatitis cases in pediatric patients treated with chemotherapy (similar protocols to those used in our study group) at our center during the two years preceding this study (data not published). The average duration of Grade II and III stomatitis before regression by one grade was 7-10 days. Progression to a higher grade of stomatitis was also observed in many of those patients. In the present study, no cases of progression were seen, and 89% of patients experienced a reduction in stomatitis severity within 4-5 days. Therefore, the use of PG shortened the time of mucosal-lesion treatment by 3-5 days and may have prevented stomatitis progression. These results are consistent with previously published data [1, 10, 11].

Previous studies have shown an improvement in the quality of life after PG treatment in adult patients with stomatitis during anticancer therapy [10]. Here, PG was effective in reducing pain in the vast majority (93%) of patients after the first day of use. Only in two patients did the therapy not bring pain relief, and these individuals complained of additional discomfort which resulted in termination of the therapy after three attempts. During the assessment of pain, by definition a subjective feeling, the possibility of a placebo effect cannot be excluded. In addition, the intensity of pain in the youngest patients was assessed by caregivers based only on observations, and their knowledge of the patients’ reactions. These assessments may not have fully reflected actual feelings of discomfort. However, such a high percentage of pain relief is a cause for optimism, even taking into account a possible placebo effect. The specific use of placebo controls should be adopted in future studies.

The use of PG appears to be very safe. Only two patients reported repeated adverse reactions in the form of a burning sensation, which resulted in the termination of PG treatment for them. No serious adverse events were reported, and PG was assessed as easy to use, even in very young children.

This was the first study to evaluate the efficacy of PG in pediatric patients with stomatitis during chemotherapy. Its main disadvantages were the lack of any real-time controls, and the lack of a comparison to a placebo control, both of which can be incorporated into future research on PG usability.