The eligibility criteria for inclusion in the study were as follows: Male and female patients who had signed an informed consent, aged 45–75 years, with malignant neoplasms and who had been prescribed radiotherapy, chemotherapy or a combination of the two, with an Eastern Cooperative Oncology Group performance status score of ≤3, with grade 2–3 OM according to the World Health Organization (WHO) Oral Toxicity Scale. The exclusion criteria were as follows: Severe concomitant diseases or conditions that may complicate or make impossible the patient's participation in the study, or make it difficult to interpret the clinical data (including mental disorders, severe infectious and parasitic diseases and intolerability to any of the ONCX components), the patient's family or official relations with a member of staff of the study center, the patient's failure to assess his/her physical and/or emotional condition, the patient's failure to comply with the study requirements, the patient's refusal to participate in the study and pregnancy or lactation.

The present study was approved by the Ethics Committee of The Loginov Moscow Clinical Scientific Centre, protocol 3/2017 4.17.17. The inclusion period was between November 2017 and March 2018. In accordance with the Declaration of Helsinki, all patients provided written informed consent to participate in the study and to publish the results and anonymized photos. The study was retrospectively registered under the study registration number NCT03577535.

The present study was a pilot study conducted to verify the hypothesis that ONCX can improve the symptoms of OM. The primary objective of the study was to evaluate the efficacy of ONCX in patients with grade 2–3 OM based on the WHO Oral Toxicity Scale. The following outcome measures were used: Mean WHO Oral Toxicity Scale grade (primary endpoint), body mass, days with regular food intake, days with normal appetite, adverse events and the Common Toxicity Criteria (ver. 2) of the National Cancer Institute (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf) using the blood, hepatic and infection scales. The study regimen is shown in Fig. 1. This study was a single-center, open-label, randomized trial in two parallel groups with a 20-day treatment period. No follow-up period was intended. The study was conducted at a stomatological clinic (Medical Scientific Centre of Professor Shumsky, Samara, Russian Federation). Patients were randomly allocated in 2:1 comparison groups for the ONCX and control groups, respectively. A total of 15 patients were enrolled in the study; 10 in the ONCX group and 5 as controls. Sequentially numbered opaque sealed envelopes were used as the method for randomization. The study center was provided with excess amount of ONCX and excess number of envelopes.

Patients from both groups were allowed to use any anticancer treatment and any OM care prior to the present study. In addition to their current treatment, patients in the ONCX group used 25 ml of the ONCX nutritional supplement twice daily for 20 days. ONCX contains microelements, vitamins, amino acids and certain naturally occurring, biologically active substances; the composition of ONCX is presented in Table I. The next course of chemotherapy or chemoradiotherapy was withheld until the full resolution of OM symptoms. Oral cavity and dental treatment were provided to all patients as the standard procedure before the start of chemotherapy. Caries and dental deposits were treated if necessary during the study. As a part of oral care, patients used oral washes containing antiseptics including octenidine dihydrochloride and phenoxyethanol or myramistin. To accelerate the regeneration process, Solcoseryl dental adhesive paste and Actovegin tablets were used. Patients were advised to use soft or very soft toothbrushes and non-abrasive toothpaste with a foaming effect. In case of moderate or severe pain, patients were advised to use nimesulide tablets and local application of lidocaine gel.

Statistical analysis was performed using StatSoft Statistica 10.0 software (http://statsoft.ru/). Baseline characteristics are presented as mean ± standard deviation; when comparisons between groups or within a group were made, the data were presented as mean (95% confidence interval). The differences between the ONCX and control groups were compared using Mann-Whitney U test and the differences within each group were compared using sign test; P<0.05 was considered to indicate a statistically significant difference.

The baseline characteristic of the patients are presented in Table II. There were no statistically significant differences between the groups at the baseline. It should be noted that no underweight patients were included in the present study. No patients required administration of opioid analgesics throughout the study.

The changes in efficacy outcomes during the study are listed in Table III. The WHO Oral Toxicity Scale grade had decreased by 41% in the ONCX group at ~7 days from the start of the study (Visit 2) compared with a minimal change in the control group. At the end of the study, the difference was even more prominent, with a 73 and 20% decrease from the baseline in the ONCX and control groups, respectively (Figs. 2 and 3).

A significant difference in number of days with regular food intake was observed. Over the entire testing period, patients in the ONCX group were able to eat normally during 65% of the days, in contrast to only 29% of the days in the control group (Fig. 4).

There were no statistically significant changes in absolute body mass between groups or even within each group, although there were clear positive and negative tendencies in the ONCX and control groups, respectively. Thus, mean change from the body mass baseline was calculated and it was found that ONCX caused a weight gain of 2.5 kg (−1.86 to 6.86) over 20 days, whereas the control group exhibited loss of 2.8 kg (−4.96 to −0.55) (P=0.03). No statistically relevant differences in the number of days with normal appetite were observed. In the control group there were no days with normal appetite throughout the whole study, while in the ONCX group there were 4.80 (0.59–9.01) days with normal appetite between Visits 2 and 3 (P=0.13 vs. controls).

In addition to efficacy outcomes, some differences in treatment toxicity were also observed (Table IV). The decrease of liver toxicity is of a special interest. The alanine aminotransferase and aspartate aminotransferase levels had decreased 4- to 7-fold at the end of the treatment in the ONCX group, whereas no changes were observed in the control group. The leukocyte count and incidence of infections were also in favour of the ONCX group. Therefore, ONCX was found to be well-tolerated, without associated adverse events.