Abstract
Background/Aim: Radiation-induced stomatitis is one of the main acute disorders in patients with head and neck cancer. Since its treatment is often delayed or discontinued, the control of perioperative oral function is necessary. It has been reported that Hangeshashinto (Japanese traditional herbal medicine) and cryotherapy (known as frozen therapy) alleviate oral stomatitis and the accompanying pain. In the present study, the combination effect of Hangeshashinto and cryotherapy on radiation-induced stomatitis in patients with head and neck cancers was investigated for the first time. Patients and Methods: Fifty patients with head and neck cancer were subjected to radiation therapy with concomitant administration of anticancer drugs. They were separated into two groups, matched according to age, stage of cancer progression, total radiation dose, and type of concomitant anticancer drugs. One group was orally administrated frozen Hangeshashinto, while another group was not. Oral mucosal damage was assessed by the grade classification CTCAE v4.0 of the National Cancer Institute of the United States (Japanese JCOG version). Duration time of radiation-induced stomatitis was determined by the appearance of grade 1 redness to its disappearance. Results: Frozen Hangeshashinto significantly alleviated, delayed the onset, and reduced the duration time of the radiation-induced stomatitis. Conclusion: Cryotherapy in combination with Hangeshashinto can be used for the treatment of radiation-induced oral stomatitis.
Head and neck cancer is one of the most common cancer types with an incidence of more than 5 million cases per year, approximately 90% of which are accounted by oral, pharyngeal, and laryngeal squamous cell carcinoma (SCC). As treatments, surgical resection, and radiation therapy, alone or combined, have been used over the past few decades (1, 2).
Radiation therapy improves clinical, morphological, and functional outcomes in cancer patients. Currently, nearly 75% of head and neck cancer patients benefit from radiation therapy, regardless of getting primary or adjuvant therapy after surgical resection. In the early stages of cancer, radiation therapy can replace surgical resection (3-5). Cancer patients can be treated with chemoradiotherapy for locally advanced cancer or surgical resection followed by adjuvant radiation therapy (6). Therefore, it is important to complete the treatment of radiation therapy. Stomatitis caused by radiation therapy is one of the main acute disorders, and treatment is often delayed or discontinued (6). Since radiation-induced stomatitis is inevitable, it is important to control the perioperative oral function in cancer therapy (7). However, despite many approaches tried so far, it has been difficult to control oral function in most cases.
Hangeshashinto is a traditional Japanese medicine composed of seven herbal crude extracts: pinelliae tuber, Scutellariae Radix, Glycyrrhizae Radix, Zizyphi fructus, Ginseng Radix, Zingiberis Processum Rhizoma, and Coptidis Rhizoma. Hangeshashinto has been reported to show potent anti-inflammatory activity in vitro (8-10), and significantly reduce the duration of ≥ grade 2 oral mucositis (11). Among 150 Kampo medicines, only Hangeshashinto, Ourento, and Inchinkouto are used for the treatment of stomatitis (12). Two ingredients of Hangeshashinto, gingerol and shogaol, alleviated oral ulcer-induced pain via inhibition of voltage-activated sodium channels in rat experimentally-induced oral ulcerative mucositis model (13). On the other hand, cryotherapy, known as local cold (low temperature) therapy, reduced the development and duration of chemotherapy and radiotherapy-induced oral stomatitis (14, 15) and as well as the associated severity and pain (16). As far as we know, there is no report on the combination therapy of Hangeshashinto and cryotherapy. In the present study, we evaluated for the first time the possible therapeutic effects of frozen Hangeshashinto in combination with cryotherapy on radiation-induced stomatitis in head and neck cancer patients.
Patients and Methods
Subjects. Among the outpatients in the Department of Oral and Maxillofacial Surgery, Kanazawa Medical University Hospital from August 2014 to December 2022 (8 years and 4 months), 25 patients (20 males and 5 females) (treated group) underwent radiation therapy in the head and neck and perioperative oral function control using frozen Hangeshashinto, after obtaining consent. An untreated (control) group of 25 patients (20 males and 5 females) underwent perioperative oral function management without frozen Hangeshashinto (Table I). This study was approved by the Kanazawa Medical University Clinical Research Ethics Review Committee (approval number: #I456).
Treatment outcome of frozen Hangeshashinto and control groups.
Preparation of frozen Hangeshashinto. Tsumura Hangeshashinto (TJ-14), which contains negligible amounts of endotoxin contamination (8.7 ng/g) (8), was kindly provided by Tsumura & Co. Tokyo, Japan. Hangeshashinto (2.5 g) was dissolved in 100 ml of hot water (to make a final concentration of 86.8 mg/ml) and then frozen into 24 (1.2 cm×1 cm×1 cm) ice blocks (referred to as frozen “Hangeshashinto”).
Application of frozen Hangeshashinto to cancer patients. Fifty cancer patients (with several types of cancer at the indicated stages of cancer progression, total radiation dose, concomitant medication) were subjected to radiation therapy (CLINAC iX, Varian Medical Systems, Inc., Palo Alto, CA, USA) (Table I). Six pieces of Hangeshashinto were placed in the mouth of administrated in each of the 25 patients (treated group), but not to another 25 patients (control group), once a day from Monday to Friday (except for holidays) just after radiation. After 10 min, when the complete dissolution of all six pieces of frozen Hangeshashinto was confirmed, they swallowed them. During treatment, onset of stomatitis from the start date of radiation therapy and duration of stomatitis were checked. Oral mucosal damage was evaluated according to the grade classification CTCAE v4.0 of the National Cancer Institute of the United States (Japanese JCOG version). The duration time of radiation-induced stomatitis was defined as the period (days) from the appearance of grade 1 redness to its disappearance.
Statistical treatments. Wilcoxon signed-rank test was applied to evaluate significant differences between two groups regarding the grade, latent periods, and duration of radiation-induced oral mucositis, using IBM SPSS 27.0 (IBM Corp., Armonk, NY, USA). The significance level was set at p<0.01.
Results
Under the control of perioperative oral function, twenty-five patients (20 males and 5 females) (treated group), but not another 25 patients (20 males and 5 females) (control group), were treated with frozen Hangeshashinto (Table I). This treatment did not affect the stage of tumor progression (Table I).
Age. The ages of patients were classified into 40s, 50s, 60s, 70s, and 80s. The 25 patients of the treated group were distributed into the following age groups: 1 in 40s, 6 in 50s, 8 in 60s, 9 in 70s and 1 in 80s, yielding the mean age of 66.7 years (upper panel, Figure 1A). Twenty-five patients of the control group were distributed into: 3 in 50s, 4 in 60s, 15 in 70s and 3 in 80s, yielding the mean age of 69.3 years old (lower panel, Figure 1A).
Age distribution (A), male-to-female ratio (B) and total radiation dose (C) of frozen Hangeshashinto-treated group (25 patients) (upper panel) and untreated (control) group (25 patients) (lower panel).
Male-to-female ratio. The male-to-female ratio was the same (20:5) in both treated (upper panel, Figure 1B) and control groups (lower panel in Figure 1B).
Total radiation dose. The distribution of the total radiation dose of patients of the treated group was 70-79 Gy in 13 patients, followed by 60-69 Gy in 5 patients, 50-59 Gy in 4 patients, and 40-49 Gy in 3 patients, yielding the mean of 61.92 Gy (upper panel, Figure 1C). The distribution of the total radiation dose of the control group was 60-68 Gy for 13 patients and 70-79 Gy for 12 patients, yielding a mean of 67.04 Gy (lower panel, Figure 1C).
Alleviation of radiation-stomatitis. The extent of radiation-induced stomatitis was quantified according to grade, which reflects the progression of stomatitis. In the treated group (25 patients), 20, 4, and 1 patients had grade 2, grade 1, and grade 3, respectively, yielding a mean grade of 1.9. In the control group (25 patients), 14, and 11 patients had grade 2, and grade 3, respectively, yielding a mean grade of 2.4, a slightly higher score of stomatitis (Figure 2A). This demonstrates that frozen Hangeshashinto significantly (p<0.01) alleviated radiation-induced stomatitis (Table I).
Grade distribution (A), average latent period (days from the start of radiation therapy to the appearance of oral mucositis) (B) and average duration time of radiation-induced stomatitis (C) in frozen Hangeshashinto-treated and control groups. Each value represents mean±SD of 25 patients. *p<0.01 by Wilcoxon signed-rank test.
Delay of onset of oral mucositis. Oral stomatitis was detected 16.1±10.1 and 9.5±4.9 days after the start of radiation in the treated and control groups, respectively (Figure 2B). Frozen Hangeshashinto significantly (p<0.01) delayed the onset of oral mucositis.
Diminished duration time of radiation stomatitis. The average duration time of radiation-induced stomatitis in the treated and control groups was 33.3±14.6 and 49.2±11.1 days, respectively. Frozen Hangeshashinto significantly (p<0.01) diminished the duration time of radiation-induced stomatitis (Figure 2C).
Discussion
Radiation therapy for head and neck cancer is often performed when tumor cells are found in the resection stumps during the post-surgery pathological examination, or when surgical therapy is judged to be unsuitable (5, 17). Therefore, it is important to complete the treatment of radiation therapy. Radiation-induced stomatitis is one of the main acute disorders, and when treatment is delayed or discontinued (6, 18), stomatitis is inevitably generated (7, 19-21). Therefore, the control of perioperative oral function is very important in cancer chemotherapy (7, 22). However, effective modalities for its prevention have not yet been established (9). We have previously reported that Hangeshashinto (62.5∼250 μg/ml) significantly inhibited prostaglandin E2 production by interleukin-1β-stimulated human gingival and periodontal ligament fibroblasts via suppression of cyclooxygenase-2 protein expression (8). This provides the basis for clinical application of Hangeshashinto for the treatment of stomatitis. Although ice has been used as cryotherapy for oral stomatitis (14, 15), no report is available on the combination of Hangeshashinto and cryotherapy. This study was conducted based on the hypothesis that radiation stomatitis will be reduced even further by the combination of Hangeshashinto and cryotherapy.
At the initial stage of the present study, it was necessary to check whether there are significant bias in the age distribution, male to female ratio, total radiation dose, and stage of tumor progression between the frozen Hangeshashinto-treated and control groups. We found that the former group had a relatively higher proportion of younger patients (Figure 1A), but the mean age of the two groups was 65.7 and 69.3 years old, respectively; only a 3.6-year differences was found (Table I). The male to female ratio was the same (80%/20%=4) in both cases (Figure 1B). This is consistent with the fact that oral cancer is more common in men than women, which is largely attributable to more tobacco use, heavier use of alcohol, and longer sun exposure of men (23). As for the total radiation dose, the treated group was exposed to a wider range of doses with a peak at 70-79 Gy, compared to the control group (Figure 1C). However, the average total radiation dose was 61.9 and 67.0 Gy; there was only a small difference between the two groups (Table I). Finally, no significant difference was found between the two groups regarding the stage of cancer progression (Table I). Based on these data, we conclude that there was no bias in age distribution, male to female ratio, total radiation dose, and stage of tumor progression between treated and control groups.
The present study demonstrated that frozen Hangeshashinto treatment significantly (p<0.01) alleviated radiation-induced stomatitis (Figure 2A). Frozen Hangeshashinto suppressed the aggravation of radiation-induced stomatitis, possibly due to the anti-inflammation activity of Hangeshashinto (8, 10, 11) and vasoconstriction induced by cooling (1, 15). Frozen Hangeshashinto significantly prolonged the expression time of oral mucositis by 41% (from 9.5 to 16.1 days) (Figure 2B), indicating that it delayed the onset of radiation stomatitis. Furthermore, frozen Hangeshashinto reduced the duration time of stomatitis by 32% (from 49.2 to 33.3 days) (Figure 2C). The combination of Hangeshashinto and cryotherapy reduced the severity, delayed the onset, and shortened the duration of the radiation-induced oral stomatitis, suggesting its possible application as a therapy for radiation-induced oral stomatitis. Since Hangeshashinto can be easily obtained via the internet at a low price, the present study can be reproduced at many medical institutions without any special equipment.
Further study on a higher number of patients is necessary to confirm whether cryotherapy and Hangeshashinto show synergistic effects on oral stomatitis and associated pain.
Acknowledgements
The Authors would like to express their deepest gratitude to TSUMURA & CO. (Tokyo, Japan) for providing Hangeshashinto (JT-14). This work was partially supported by Miyata Research Fund E of Meikai University School of Dentistry (HS), Saitama, Japan.
Footnotes
Authors’ Contributions
TK performed the present study and wrote the manuscript. HS reviewed the manuscript and edited the manuscript. All Authors read and approved the final version of the manuscript.
Conflicts of Interest
The Authors wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
- Received January 5, 2023.
- Revision received January 19, 2023.
- Accepted January 20, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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