Hangeshashinto for prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized phase II study

Purpose Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). Methods Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. Results Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2–3: P = 0.027, G3: P = 0.047). Conclusions The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. Trial registration This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).


Introduction
Oral mucositis (OM) is a side effect associated with cancer treatment.The incidence of OM is 20% to 40% in patients undergoing conventional chemotherapy, 60% to 85% in those undergoing hematopoietic stem cell transplantation (HSCT), and almost 100% in those undergoing chemoradiation therapy for head and neck cancer [1][2][3].OM can reduce patients' quality of life because of pain-induced difficulty in eating, swallowing, talking, or brushing teeth.It sometimes causes discontinuation of cancer treatment.Patients with OM may also be susceptible to infection through the mucous membranes, and some outcomes are fatal [4][5][6].
Numerous reports focusing on prevention or treatment of OM secondary to cancer therapy have been published [7,8].Basic oral care by patients themselves or care providers is important for inhibition of OM.Educational interventions that underwent oral examinations and continuously received professional oral care interventions during data collection.They were randomly assigned to 2 groups of 15 patients each.Patients using HST were instructed to wash their mouth three times a day with 2.5 g HST (TJ-14; Tsumura, Tokyo, Japan) dissolved in 40 mL saline solution after brushing after meals.Patients assigned to the control group were instructed to wash their mouth using only saline solution.The duration of HST use was from initiation of the conditioning regimen of HSCT to the date of engraftment.Concomitant drugs were not restricted.If engraftment failure occurred more than 28 days after transplantation, data collection was finished.

Data collection
The following patient characteristics were collected: age, sex, smoking history, drinking history, body mass index, performance status, diagnosis, conditioning regimen, donor, and duration from pretreatment to engraftment.The following oral findings and dental treatments prior to HSCT were also collected: number of remaining teeth, simplified debris index, state of alveolar bone loss, periodontal pocket depth, bleeding on probing, periapical periodontitis, high-grade caries, tooth extraction, and apicoectomy.

Outcomes
The endpoint of this study was the incidence of OM.Oral assessment of each patient was performed by a single evaluator (M.Y.).The severity of OM was determined with reference to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 as follows: Grade (G)1, asymptomatic or mild symptoms, intervention not indicated; G2, moderate pain or ulcer that does not interfere with oral intake, modified diet indicated; G3, severe pain interfering with oral intake; G4, life-threatening consequences, urgent intervention indicated; and G5, death.Adverse events were recorded regardless of whether they had a causal link to the mouthwash used during the study period.

Statistical analysis
Data are expressed as number of patients or median [25 th -75 th percentile].The cumulative incidence of OM was depicted using a Kaplan-Meier curve and analyzed with a log-rank test.The Mann-Whitney U test, Fisher's exact test, the Kruskal-Wallis test, or Spearman's rank correlation coefficient was used to evaluate the patient characteristics, and the occurrence and duration of OM.SPSS software version 27.0 (Japan IBM Co., Tokyo, Japan) was used for statistical analysis.All P values were based on a two-sided hypothesis, and P < 0.05 was considered statistically significant.

Patient characteristics
The patients' characteristics are summarized in Table 1.The median age was 56.0 years in the HST group and 58.0 years in the control group.Nineteen patients were male and 11 were female.The patients' diagnoses were acute myeloid leukemia (n = 11), adult T-cell leukemia/lymphoma (n = 5), myelodysplastic syndromes (n = 4), acute lymphoid leukemia (n = 2), and other hematological diseases.The types of conditioning regimens were myeloablative conditioning (MAC) (n = 12) and reduced-intensity conditioning (RIC) (n = 18).Twenty-two patients received grafts from related donors, and eight received grafts from unrelated donors.The median duration from pretreatment to engraftment was 20.0 days in the HST group and 21.0 days in the control group.The median number of remaining teeth was 28.0 in the HST group and 26.0 in the control group, and 13 patients underwent tooth extraction or apicoectomy to prevent infection prior to the starting day of pretreatment.There was no significant difference in background factors between two groups.

Cumulative incidence of OM
Eight patients in the HST group and 10 patients in the control group developed OM.No patients developed G4 or G5 OM. Figure 1 shows the cumulative incidence of OM.There was no significant difference between the two groups (P = 0.406).

Factors related to occurrence of OM
Table 2 shows the relationship of each factor with the occurrence of OM.The incidence of G1, G2, and G3 OM was significantly higher in patients who received the MAC regimen than in those who received the RIC regimen (G1 P < 0.001, G2 P = 0.001, G3 P = 0.002).There was no significant difference in the duration of HST use between patients with and without OM.

Relationship between each variable and duration of OM
Tables 3, 4, and 5 show the relationship of each variable with the duration of OM.The durations of G1-G3, G2-G3, and G3 OM were significantly longer in patients who received the MAC regimen than in those who received the RIC regimen (G1-G3 P = 0.001, G2-G3 P = 0.003, G3 P = 0.022).Moreover, there was a tendency toward a negative correlation between the duration of HST use and the duration of G2-G3 and G3 OM (G2-G3 correlation coefficient (rho) = − 0.404, P = 0.027; G3 rho = − 0.365, P = 0.047) (Tables 4 and 5; Fig. 2).

Discussion
In this single-center study, the effects of HST for prevention of OM were investigated in patients undergoing HSCT.The incidence of OM was not significantly different between the HST group and control group.However, the duration of HST use showed a tendency toward a negative correlation with the duration of ≥ G2 OM.OM is a common adverse event in patients with cancer.Vagliano et al. [16] reported that 71.4% of patients undergoing HSCT developed OM and that 21.6% had ≥ G3 OM.Guberti et al. [17] found that 78.0% of patients who underwent HSCT developed OM.In a systematic review, the incidence of OM in patients undergoing HSCT was 83.5% among seven studies [2].In the present study, 60.0% of patients developed OM.Although not definitive because of the small number of patients, this incidence is likely lower than that in previous reports.In this study, the use of concomitant drugs or combination therapies was not limited.Moreover, oral care education and professional oral care interventions by dentists and dental hygienists were given to all patients throughout the study period.These factors may have contributed to better oral health and reduction of OM in this study.
Symptoms of OM were recognized from 0 to 19 days after starting the conditioning regimen and continued from 1 to 23 days during the study period (data not shown).Onset and progression of OM are related to various factors, such as the presence of other disorders, the patient's general condition, and oral health [18].Pathobiologically, onset of the first phase of OM occurs immediately after starting chemotherapy, and the healing phase usually occurs approximately 2 to 4 weeks after the final day of chemotherapy [18][19][20].Clinically, the mean onset of OM was 9.1 days after initiation of the conditioning regimen and that the duration was 10.4 days in patients undergoing HSCT [17].Onset and healing of OM in this study indicated in accordance with these reports.
OM was recognized in all patients who received the MAC regimen in this study.By contrast, 33.3% of patients who received the RIC regimen developed OM.In addition, no patient who received the RIC regimen developed G3 OM.There was a significant difference in the incidence of G1, G2, and G3 OM between the MAC and RIC regimens.Moreover, the duration of G1-3, G2-3, and G3 OM was significantly longer in the MAC than RIC regimen.One systematic review showed that the RIC regimen was associated with a high incidence of OM similar to that associated with the MAC regimen [21].The authors of the review also noted that various definitions were used to categorize patients into the MAC and RIC regimens.In the Nagasaki Transplant Group, the conditioning intensity is determined by the consensus of the Center for International Blood and Marrow Transplant Research criteria [22,23].Several reports have shown that the appearance of OM with chemotherapy depends on the dose and type of chemotherapy and that the incidence of OM is higher with MAC than RIC regimens in patients undergoing HSCT [24,25].These findings are in agreement with our results.In this study, the duration of HST use showed a negative correlation with the duration of both G2-3 and G3.Kono et al. [13] demonstrated that use of HST had therapeutic effects on chemotherapy-induced OM in patients with advanced colorectal cancer.Matsuda et al. [14] reported that the duration of ≥ G2 OM was significantly reduced when HST was used in patients who received chemotherapy for colorectal cancer.Biologically, chemotherapy induces DNA damage of stem cells in the basal layer of the submucosa; consequently, mucosal tissues are broken down and become ulcerated [9,10,12].Reactive oxygen species are formed in response to mucosal damage, and release of proinflammatory cytokines is induced.Furthermore, chemotherapy reduces immunity; accordingly, oral bacteria colonize the ulcerated mucosal surface, the injury is potentiated, and infection develops.The components of HST have effective anti-oxidation, anti-inflammatory, and anti-bacterial effects [11,12].Although damage of mucosal tissue is considered unavoidable during chemotherapy, our study data suggest that the ingredients in HST contributed to suppression of OM deterioration.
No patients in the control group dropped out of this study.However, six patients in the HST group withdrew from the study because of nausea (n = 4), fever (n = 1), or  by the period of HST use than by whether HST was used (Tables 2, 3, 4 and 5; Fig. 2).This study had three main limitations.First, the sample size was small, and all participants who withdrew from the study were in the HST group.Second, we may not have been able to completely prevent placebo effects and bias because the study was not double-blinded.Third, we did not restrict the use of concomitant medications for stomatitis, such as steroid treatments and anti-inflammatory gargle solutions.HST has a known tendency to inhibit OM exacerbation, but further clinical and biological studies are necessary for a full understanding of inhibition of OM in patients undergoing HSCT.

Fig. 2
Fig. 2 Correlation between duration of HST use and duration of oral mucositis.(a) Correlation between duration of HST use and duration of G2-3 oral mucositis.(b) Correlation between duration of HST use and duration of G3 oral mucositis.G, grade; HST, Hangeshashinto

Table 1 Patient characteristics Data are presented as number of patients or median [25-75% tale]
HST Hangeshashinto, AML acute myeloid leukemia, ATL adult T-cell leukemia/lymphoma, MDS myelodysplastic syndromes, ALL acute lymphoid leukemia, MPAL mixed phenotype acute leukemia, CMML chronic myelomonocytic leukemia, DLBCL diffuse large B-cell lymphoma, MAC myeloablative conditioning, RIC reduced-intensity conditioning § Mann-Whitney U test, † Fisher's exact test