Abstract
Objective: To observe the efficacy of Kangfuxin liquid on radiotherapy-induced oral mucositis for patients with head and neck squamous cell carcinoma and its effects on salivary glands and immune function. Methods: A total of 97 patients with head and neck squamous cell carcinoma receiving radiotherapy in Guigang City People’s Hospital from January 2019 to June 2021 were retrospectively analyzed and divided into a control group and a test group according to different treatment plans. The two groups received the same radiation therapy. Patients in the control group (n=46) were given borax-containing gargles, while those in the test group (n=51) were treated with Kangfuxin liquid. We observed the incidences and grades of oral mucositis and oral pain, changes in saliva flow rate, pH of saliva, levels of epidermal growth factor (EGF) and amylase, levels of CD4+/CD8+, CD19+/CD69+ and natural killer (NK) cells, and serum cytokine (TGF-β1, IL-6 and C-reactive protein (CRP)) levels in the two groups before radiotherapy, and after 21 d and 42 d of radiotherapy. Quality of Life Instruments for Cancer Patients-Head and Neck Cancer (QLICP-HN) scores were compared in both groups before radiotherapy, and after 42 d of radiotherapy. Results: No oral mucositis or oral pain was found before radiotherapy in both groups. The incidences of oral mucositis and oral pain after 21 d and 42 d of radiotherapy in the test group were not significantly different from those in the control group (all P>0.05). The grades of oral mucositis and oral pain in the test group after 21 d and 42 d of radiotherapy were lower than those in the control group (all P<0.05). The test group had higher saliva flow rate, pH of saliva, levels of EGF and amylase, and levels of CD4+/CD8+, CD19+/CD69+ and NK cells. The test group had lower serum levels of TGF-β1, IL-6, and CRP than the control group after 21 d and 42 d of radiotherapy (all P<0.05). The scores of each item of the QLICP-HN scale and total scores in the test group were higher than those of the control group after 42 d of radiotherapy (all P<0.05). Conclusion: Kangfuxin liquid effectively prevents the occurrence of radiotherapy-induced oral mucositis for patients with head and neck squamous cell carcinoma, reduces oral mucosal reactions and oral pain, improves salivary gland function, reduces inflammatory response, promotes cellular immune function, improves quality of life, and improves prognosis.
Keywords: Kangfuxin liquid, head and neck squamous cell carcinoma, radiotherapy, oral mucositis, salivary glands, immune function
Introduction
Radiation therapy is the major approach to treat head and neck cancer. Although radiation effectively kills tumor cells, it causes damage, necrosis, or apoptosis of mucosal epithelial cells, increases oral mucosal fragility, reduces saliva secretion, and lowers oral immune function, resulting in oral mucositis to varying degrees [1,2]. Edema, mucosal hyperemia, ulceration, erosion, pain and secondary infection are the main clinical manifestations of oral mucositis, which not only seriously affects the normal eating of patients, causes weight loss and reduces quality of life, but also easily reduces the tolerance of normal tissues to radiation, finally affecting its efficacy [3,4]. In 2010, the Clinical Guidelines for Oral Mucositis from the European Society of Medical Oncology stated that patients with head and neck squamous cell carcinoma had a high risk (85%) of developing moderate to severe oral mucositis during radiotherapy, 15% of whom need hospitalization [5]. Therefore, exploring a reasonable and efficient treatment for the prevention and cure of radiation-induced oral mucositis is crucial to alleviating the patients’ discomfort from radiotherapy and improving radiotherapy efficacy. Kangfuxin liquid is a dried insect extract of American cockroach, with mucinine, epidermal growth factor, polyols and other active substances, that can enhance cellular immunity, activate immune system, eliminate inflammatory edema, improve wound microcirculation, repair ulcer wounds, and accelerate wound granulation tissue production [6,7]. At present, it has been confirmed that Kangfuxin liquid effectively prevents and treats radiation-induced oral mucositis in patients with malignant tumors and alleviates oral mucosal responses, but its effects on salivary gland function, immune function, and inflammatory response of patients with head and neck squamous cell carcinoma after radiation have been rarely reported [8]. In order to further prevent and treat radiation-induced oral mucositis, this study retrospectively analyzed the effects of Kangfuxin liquid on the occurrence of oral mucositis, salivary gland function, and immune function in head and neck squamous cell carcinoma patients.
Materials and methods
General data
A total of 97 patients with head and neck squamous cell carcinoma receiving radiotherapy in Guigang City People’s Hospital from January 2019 to June 2021 were retrospectively analyzed in this study. Among them, there were 68 men and 29 women from 29 to 78 years old, with an average age of 59.94±2.89 years old. As for primary site, there were 32 cases in the oral cavity, 12 cases in oropharynx, 11 cases in hypopharynx, and 42 cases in larynx. According to the American Joint Committee Cancer (AJCC) staging system, 44 and 53 cases were at stage III and IV, respectively. This clinical study had been approved by the Ethics Committee of Guigang City People’s Hospital (approval number: GYLLPJ-20210626-08). Patients or their family members voluntarily signed an informed consent form.
Inclusion criteria: (1) Patients met the diagnostic criteria for head and neck squamous cell carcinoma in the Expert Consensus on Comprehensive Treatment of Head and Neck Tumors [9]. (2) Patients were at stage III or IV in the AJCC staging system [10]. (3) Patients were undergoing radiation therapy for the first time. (4) Patients’ Karnofsky scores were ≥70 points [11].
Exclusion criteria: (1) Patients had oral mucositis, mouth ulcers, oral pain, periodontitis, Sjögren’s syndrome, and infectious diseases before radiation therapy. (2) Patients had contraindications associated with radiation therapy to head and neck tumors. (3) Patients suffered from autoimmune diseases, severe organic diseases, abnormal bone marrow hematopoietic function, or other malignant tumors. (4) Patients were allergic to medications used in this study. (5) Patients had coagulation disorders. (6) Patients had cardiovascular and cerebrovascular diseases. (7) Patients had a previous history of salivary gland disease. (8) Pregnant or breast-feeding women. (9) Patients had poor compliance.
Methods
Radiotherapy regimen [12]: Intensity-modulated radiation therapy was carried out. 6 MV-X-rays were used, and a 7-9 wild IMRT radiotherapy plan was designed. The gross tumor volume included positive lymph nodes, primary lesions, 2 Gy/time, 5 times/week, with the prescribed dose of 66-74 Gy. The radiation doses for temporal lobe, temporomandibular joint, mandible, cervical cord, inner or middle ear and cartilagines larynges were limited to a dose of 60 Gy, 65 Gy, 65 Gy, 45 Gy, 50 Gy and 45 Gy, respectively. 50% volume of the bilateral parotid gland should be limited to a dose of 30 Gy. The radiation dose for oral mucosa without PTV was limited to 55 Gy. The radiation doses for optic nerve, optic chiasm and brainstem were all limited to 54 Gy.
Chemotherapy regimen: Intravenous infusion of cisplatin of 100 mg/m2 was administered on the 1st day, 22nd day, and 43rd day of radiotherapy.
Treatment protocols: During radiotherapy and chemotherapy, gargle containing vitamin C, normal saline, lidocaine, vitamin B6, and dexamethasone was applied in both groups, 3 times/day. Gargle use was stopped after radiotherapy.
1) The control group was treated with borax-containing gargle (Shanghai Yunjia Huangpu Pharmaceutical Co., Ltd., 250 mL/bottle, H31022772), 15 mL/time. Patients were guided to rinse the mouth with water first, and then rinse with borax-containing gargle diluting with 5 times the amount of warm water. Patients were instructed to give the liquid as much exposure as possible to the oral mucosa, 3-4 times/day.
2) The test group was given 10 mL/time of Kangfuxin liquid from the 1st day to the end of radiotherapy (Kunming Sainuo Pharmaceutical Co., Ltd., 50 mL/bottle, Z53020054). Patients should rinse mouth with water first, and then rinse mouth with kangfuxin liquid and take it. Patients were instructed to give the liquid as much exposure as possible to the oral mucosa, and swallow slowly after about 3 minutes, 3 times/day.
Outcome measures
Oral mucositis and oral pain were observed and recorded before radiotherapy, and after 21 d and 42 d of radiotherapy. Based on CTCAE v3.0 criteria, 0 points was assigned for asymptomatic, 1 point for mucosal erythema, 2 points for plaque ulcers or pseudomembrane, 3 points for continuous ulcers or pseudomembrane, bleeding caused by small abrasions, and 4 points for tissue necrosis, obvious spontaneous bleeding, or life-threatening condition [13]. Verbal Rating Scale was used to describe pain intensity. “No pain” =0; “Mild pain which can be tolerated and had no effect on sleep or life” =1; “Moderate pain which can’t be tolerated and had an effect on sleep and life” =2; “Severe pain which can’t be tolerated and had serious effects on sleep and life, with postural or autonomic disturbances” =3.
Saliva flow rate and pH of saliva were evaluated before radiotherapy, and after 21 d and 42 d of radiotherapy [14]. A certain weight of yarn cotton was put in the patient’s mouth and removed after 30 s. Saliva flow rate = increased weight of yarn cotton/0.5. The precision pH test strip (5.5-9.0; Beijing Kaishiyuan Biotechnology Co., Ltd.) was placed under the patient’s tongue. After the front end of the test strip was soaked by patient’s saliva, the value was read within 3-5 seconds.
The morning saliva of patients before radiotherapy, after 21 d and 42 d of radiotherapy was collected, and placed in a refrigerator (Guangzhou Kezhilan Instrument Co., Ltd.) at -4°C to precipitate [15]. After 24 h, the saliva was taken out and centrifuged on a high-speed centrifuge (415D, Eppendorf Company of Germany) for 10 min at a speed of 3,000 r/min with a centrifugal radius of 6 cm. The mucin and residue were removed, and 2-3 mL of filtrate was obtained. The levels of saliva epidermal growth factor (EGF, PC1828, Pufei Biotechnology Co., Ltd.) and amylase (YT6040, Beijing Ita Biotechnology Co., Ltd.) were determined by enzyme linked immunosorbent assay (ELISA), and the model 680 microplate reader (Bio Rad Company, USA) was used.
Fasting peripheral venous blood (3 mL) was collected from patients before radiotherapy, and after 21 d and 42 d of radiotherapy. The blood was centrifuged for 5 min, at 2,500 r/min, with the centrifugal radius of 6 cm. The supernatant was taken. A high-throughput flow cytometer (MACSQuant® Analyzer 16, Meitenbitech Co., Ltd., Germany) was used to determine the levels of CD4+, CD8+, CD19+, CD69+, and natural killer (NK) cells (M2704, Shanghai Mingjin Biological Technology Co., Ltd.). The CD4+/CD8+ values, and CD19+/CD69+ values were calculated. Serum levels of IL-6 (IB-E10049, Jiangxi Aiboin Biotechnology Co., Ltd.), TGF-β1 (EK-H12176, Shanghai Enzyme Research Biotechnology Co., Ltd.), and C-reactive protein (CRP, SEKH-0138, Beijing Solarbio Science & Technology Co., Ltd.) were determined by ELISA.
Quality of Life Instruments for Cancer Patients-Head and Neck Cancer scale was used to evaluate patients’ quality of life before radiotherapy, and after 42 d of radiotherapy [16]. The scale includes 5 dimensions and 46 items, using a 5-point scale ranging from 1 to 5, with total scores of 230. There are 9 items for mental function, 8 items for physical function, 15 items for social function, 7 items for head and neck cancer specific modules, and 7 items for common symptoms and side effects. A higher score reveals higher quality of life.
Three months after radiotherapy, the recurrence of stomatitis was evaluated.
Statistical analysis
Statistical analyses were conducted using SPSS 23.0 software. Measured data with a normal distribution were expressed as mean ± standard deviation (x̅ ± sd). Independent sample t-test was adopted for the comparison between groups. Paired t-test was used for the comparison in the same group. Wilcoxon signed-rank test was used to analyze measurement data with non-normal distribution. Counted data were represented as case/percentage (n/%) and tested by Pearson’s chi-square test. Ordinal data were analyzed by Rank-sum test. P<0.05 was considered a significant difference.
Results
Comparison of general data
There was no significant difference in general data between both groups (P>0.05). See Table 1.
Table 1.
Comparison of general data (n, x̅ ± sd)
| Group | Male/Female | Age (years) | Course of disease (years) | Body mass index (kg/m2) | Primary site | AJCC staging |
|---|---|---|---|---|---|---|
|
| ||||||
| Oral cavity/oropharynx/hypopharynx/larynx | III/IV | |||||
| Control group (n=46) | 30/16 | 59.6±3.3 | 5.84±1.02 | 22.84±1.65 | 15/6/5/20 | 20/26 |
| Test group (n=51) | 38/13 | 60.2±2.7 | 5.97±1.35 | 22.98±1.52 | 17/6/6/22 | 24/27 |
| χ2/t | 0.996 | 0.890 | 0.531 | 0.435 | 0.003 | 0.125 |
| P | 0.318 | 0.376 | 0.597 | 0.665 | 0.956 | 0.724 |
Note: The incidence of radiotherapy-reduced oral mucositis among male/female, primary site, and AJCC staging ratio was compared between the two groups, using Pearson’s chi-square test. The averages of age, disease course, and body mass index of the two groups were compared with independent samples t-test. AJCC: American Joint Committee on Cancer.
Comparison of oral mucositis
No oral mucositis was found before radiotherapy in both groups. The incidences of oral mucositis (98.04%, 92.16%) after 21 d and 42 d of radiotherapy in the test group were not significantly different from those of the control group (100.00%, 100.00%; both P>0.05). The grades of oral mucositis in the test group after 21 d and 42 d of radiotherapy were lower than those of the control group (both P<0.05). See Table 2.
Table 2.
Comparison of oral mucositis before radiotherapy, after 21 d and 42 d of radiotherapy (n, %)
| Group | Grade 0 | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Total incidence |
|---|---|---|---|---|---|---|
| Before radiotherapy | ||||||
| Control group (n=46) | 46 (100.00) | 0 | 0 | 0 | 0 | 0 (0.00) |
| Test group (n=51) | 51 (100.00) | 0 | 0 | 0 | 0 | 0 (0.00) |
| χ2/Z | Z=0.000 | χ2=0.000 | ||||
| P | 1.000 | 1.000 | ||||
| After 21 d of radiotherapy | ||||||
| Control group (n=46) | 0 | 5 | 15 | 26 | 0 | 46 (100.00) |
| Test group (n=51) | 1 | 12 | 18 | 20 | 0 | 50 (98.04) |
| χ2/Z | Z=2.023 | χ2=0.000 | ||||
| P | 0.043 | 1.000 | ||||
| After 42 d of radiotherapy | ||||||
| Control group (n=46) | 0 | 6 | 14 | 26 | 0 | 46 (100.00) |
| Test group (n=51) | 4 | 13 | 15 | 19 | 0 | 47 (92.16) |
| χ2/Z | Z=2.422 | χ2=2.041 | ||||
| P | 0.016 | 0.153 | ||||
Note: Pearson’s chi-square test was used for comparison of oral mucositis between the two groups. Z-test was adopted to test the grades of oral mucositis between the two groups.
Comparison of oral pain
There was no oral pain before radiotherapy in both groups. The incidences of oral pain (96.08%, 88.24%) after 21 d and 42 d of radiotherapy in the test group were not significantly different from those of the control group (100.00%, 97.83%; both P>0.05). The grades of oral pain in the test group after 21 d and 42 d of radiotherapy were lower than those of the control group (P<0.05). See Table 3.
Table 3.
Comparison of oral pain before radiotherapy, and after 21 d and 42 d of radiotherapy (n, %)
| Time | Group | Grade 0 | Grade 1 | Grade 2 | Grade 3 | Total incidence |
|---|---|---|---|---|---|---|
| Before radiotherapy | Control group (n=46) | 46 (100.00) | 0 | 0 | 0 | 0 (0.00) |
| Test group (n=51) | 51 (100.00) | 0 | 0 | 0 | 0 (0.00) | |
| χ2/Z | 0.000 | 0.000 | ||||
| P | 1.000 | 1.000 | ||||
| After 21 d of radiotherapy | Control group (n=46) | 0 | 11 | 30 | 5 | 46 (100.00) |
| Test group (n=51) | 2 | 24 | 24 | 1 | 49 (96.08) | |
| χ2/Z | 3.055 | 0.005 | ||||
| P | 0.002 | 0.943 | ||||
| After 42 d of radiotherapy | Control group (n=46) | 1 | 12 | 31 | 2 | 45 (97.83) |
| Test group (n=51) | 6 | 21 | 23 | 1 | 45 (88.24) | |
| χ2/Z | 2.625 | 2.045 | ||||
| P | 0.009 | 0.153 | ||||
Note: Pearson’s chi-square test was used for comparison of oral pain between the two groups. Z-test was adopted to test the grades of oral pain between the two groups.
Comparison of saliva flow rate and pH of saliva
Before radiotherapy, compared to the control group, there were no significant differences in saliva flow rate or pH of saliva in the test group (both P>0.05). Compared to before radiotherapy, the saliva flow rate and pH of saliva were higher in both groups after 21 d and 42 d of radiotherapy (both P<0.05). The test group had a higher saliva flow rate and pH of saliva than the control group (both P<0.05). See Table 4.
Table 4.
Comparison of saliva flow rate and pH of saliva before radiotherapy, and after 21 d and 42 d of radiotherapy (x̅ ± sd)
| Time | Group | Saliva flow rate (mg/min) | pH of saliva |
|---|---|---|---|
| Before radiotherapy | Control group (n=46) | 229.65±21.54 | 5.96±0.74 |
| Test group (n=51) | 231.05±22.49 | 6.02±0.84 | |
| t | 0.312 | 0.372 | |
| P | 0.756 | 0.711 | |
| After 21 d of radiotherapy | Control group (n=46) | 302.45±28.96*** | 6.48±0.87*** |
| Test group (n=51) | 349.67±31.78*** | 6.89±0.82*** | |
| t | 7.620 | 2.389 | |
| P | <0.001 | 0.019 | |
| After 42 d of radiotherapy | Control group (n=46) | 396.74±33.75***,### | 6.96±0.76***,## |
| Test group (n=51) | 493.87±48.52***,### | 7.35±0.69***,### | |
| t | 11.326 | 2.649 | |
| P | <0.001 | 0.001 |
Note: Paired t-test was used for the comparison in the same group before radiotherapy;
P<0.001.
Paired t-test was used for the comparison in the same group after 21 d of radiotherapy;
P<0.01;
P<0.001.
Comparison of levels of EGF and amylase
Compared to the control group, there was no significant difference between levels of EGF and amylase before radiotherapy in the test group (both P>0.05). The levels of EGF and amylase were increased in the two groups after 21 d and 42 d of radiotherapy (both P<0.05). The levels of EGF and amylase were higher in the test group than in the control group (both P<0.05). See Table 5.
Table 5.
Comparison of levels of EGF and amylase before radiotherapy, and after 21 d and 42 d of radiotherapy (x̅ ± sd)
| Time | Group | Amylase (ng/mL) | EGF (ng/L) |
|---|---|---|---|
| Before radiotherapy | Control group (n=46) | 211.36±46.84 | 69.63±10.35 |
| Test group (n=51) | 213.94±44.76 | 70.16±9.68 | |
| t | 0.277 | 0.261 | |
| P | 0.782 | 0.795 | |
| After 21 d of radiotherapy | Control group (n=46) | 273.95±36.98*** | 99.63±12.74*** |
| Test group (n=51) | 328.74±40.09*** | 143.86±20.47*** | |
| t | 6.974 | 12.613 | |
| P | <0.001 | <0.001 | |
| After 42 d of radiotherapy | Control group (n=46) | 342.74±51.29***,### | 186.63±20.41***,### |
| Test group (n=51) | 417.96±58.62***,### | 257.83±31.48***,### | |
| t | 6.693 | 13.060 | |
| P | <0.001 | <0.001 |
Note: Paired t-test was used for the comparison in the same group before radiotherapy;
P<0.001.
Paired t-test was used for the comparison in the same group after 21 d of radiotherapy;
P<0.001.
EGF: epidermal growth factor.
Comparison of cellular immune function
No significant differences between the levels of CD4+/CD8+, CD19+/CD69+, or NK cells were found in the test group compared to the control group before radiotherapy (all P>0.05). The levels of CD4+/CD8+, CD19+/CD69+, and NK cell counts after 21 d of radiotherapy were decreased in the two groups, and then were increased after 42 d of radiotherapy (all P<0.05). The levels of CD4+/CD8+, CD19+/CD69+, and NK cells in the test group after 21 d and 42 d of radiotherapy were higher than those of the control group (all P<0.05). See Table 6.
Table 6.
Comparison of cellular immune function before radiotherapy, and after 21 d and 42 d of radiotherapy (x̅ ± sd)
| Time | Group | CD4+/CD8+ | CD19+/CD69+ | NK cell (%) |
|---|---|---|---|---|
| Before radiotherapy | Control group (n=46) | 1.95±0.24 | 15.68±2.28 | 59.63±6.25 |
| Test group (n=51) | 1.93±0.35 | 16.15±3.34 | 58.49±7.72 | |
| t | 0.325 | 0.801 | 0.794 | |
| P | 0.746 | 0.425 | 0.429 | |
| After 21 d of radiotherapy | Control group (n=46) | 0.80±0.22*** | 5.86±1.28*** | 31.02±4.15*** |
| Test group (n=51) | 0.99±0.35*** | 8.96±1.37*** | 39.64±6.02*** | |
| t | 3.161 | 11.479 | 8.124 | |
| P | 0.002 | <0.001 | <0.001 | |
| After 42 d of radiotherapy | Control group (n=46) | 1.19±0.19***,### | 9.36±2.02***,### | 39.63±5.52***,### |
| Test group (n=51) | 1.76±0.38***,### | 13.38±3.38***,### | 45.96±6.32***,### | |
| t | 9.187 | 7.014 | 5.228 | |
| P | <0.001 | <0.001 | <0.001 |
Note: Paired t-test was used for the comparison in the same group before radiotherapy;
P<0.001.
Paired t-test was used for the comparison in the same group after 21 d of radiotherapy;
P<0.001.
NK: natural killer.
Comparison of serum cytokine levels
Serum cytokine (TGF-β1, IL-6 and CRP) levels before radiotherapy in the test group were not significantly different from those in the control group (all P>0.05). Serum cytokine levels were reduced after 21 d and 42 d of radiotherapy in the two groups (all P<0.05). The serum levels of TGF-β1, IL-6, and CRP in the test group after 21 d and 42 d of radiotherapy were lower than those of the control group (all P<0.05). See Table 7 and Figure 1.
Table 7.
Comparison of serum cytokine levels before radiotherapy, and after 21 d and 42 d of radiotherapy (x̅ ± sd)
| Time | Group | TGF-β1 (ng/mL) | IL-6 (ng/L) | CRP (ng/L) |
|---|---|---|---|---|
| Before radiotherapy | Control group (n=46) | 15.65±3.32 | 18.63±3.12 | 21.69±5.25 |
| Test group (n=51) | 14.49±2.98 | 19.68±2.96 | 22.39±4.15 | |
| t | 1.814 | 1.700 | 0.732 | |
| P | 0.073 | 0.092 | 0.466 | |
| After 21 d of radiotherapy | Control group (n=46) | 11.25±2.74*** | 15.98±2.18*** | 17.11±4.36*** |
| Test group (n=51) | 9.02±2.19*** | 12.02±3.32*** | 13.39±5.28*** | |
| t | 4.448 | 6.863 | 3.760 | |
| P | <0.001 | <0.001 | <0.001 | |
| After 42 d of radiotherapy | Control group (n=46) | 8.19±1.65***,### | 11.98±2.38***,### | 13.84±5.84***,### |
| Test group (n=51) | 6.63±1.02***,### | 9.02±1.74***,### | 9.63±3.38***,### | |
| t | 5.660 | 7.039 | 4.440 | |
| P | <0.001 | <0.001 | <0.001 |
Note: Paired t-test was used for the comparison in the same group before radiotherapy;
P<0.001.
Paired t-test was used for the comparison in the same group after 21 d of radiotherapy;
P<0.001.
CRP: C-reactive protein.
Figure 1.
Comparison of serum cytokine levels before radiotherapy, after 21 d of radiotherapy, and after 42 d of radiotherapy. A: TGF-β1; B: IL-6; C: CRP. Compared to before radiotherapy in the same group, ***P<0.001; compared to after 21 d of radiotherapy in the same group, ###P<0.001; compared to the control group at the same time, ΔΔΔP<0.001. CRP: C-reactive protein.
Comparison of quality of life
Before radiotherapy, there was no significant difference in the QLICP-HN scores in the test group compared to the control group (P>0.05). The scores of each dimension of the QLICP-HN scale and total scores after 42 d of radiotherapy were increased in both groups (all P<0.05). All the scores of the test group were higher than those of the control group after 42 d of radiotherapy (all P<0.05). See Table 8 and Figure 2.
Table 8.
Comparison of quality of life before radiotherapy, and after 42 d of radiotherapy (x̅ ± sd)
| Time | Group | Mental function | Physical function | Social function | Head and neck cancer specific module | Common symptoms and side effects | Total score |
|---|---|---|---|---|---|---|---|
| Before radiotherapy | Control group (n=46) | 21.03±4.58 | 20.65±3.98 | 45.63±6.32 | 20.22±4.15 | 23.65±4.11 | 131.18±28.65 |
| Test group (n=51) | 22.16±4.96 | 19.65±4.02 | 46.18±5.52 | 19.68±3.95 | 22.98±3.96 | 130.62±29.32 | |
| t | 1.162 | 1.229 | 0.458 | 0.656 | 0.817 | 0.095 | |
| P | 0.248 | 0.222 | 0.648 | 0.513 | 0.416 | 0.925 | |
| After 42 d of radiotherapy | Control group (n=46) | 28.96±5.52*** | 27.69±4.42*** | 51.16±4.96*** | 23.86±5.52*** | 26.48±3.02*** | 158.15±31.05*** |
| Test group (n=51) | 34.96±6.32*** | 32.35±5.52*** | 56.39±3.25*** | 27.15±2.52*** | 31.15±2.14*** | 182.00±35.78*** | |
| t | 4.956 | 4.557 | 6.200 | 3.838 | 8.853 | 3.489 | |
| P | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
Note: Paired t-test was used for the comparison in the same group before radiotherapy;
P<0.001.
Figure 2.
Comparison of quality of life before radiotherapy and after 42 d of radiotherapy. A: Mental function; B: Physical function; C: Social function; D: Head and neck cancer specific module; E: Common symptoms and side effects; F: Total score. Compared to before radiotherapy in the same group, ***P<0.001; compared to control group, ###P<0.001.
Comparison of prognosis
Three months after radiotherapy, a recurrence of stomatitis was observed in both groups. The recurrence rates of the two groups were both 0, indicating a good prognosis in both.
Discussion
Currently, the pathogenesis of radiotherapy-induced oral mucositis has not been fully elucidated. It is generally believed to be related to inhibition of mucosal epithelial cell division and proliferation, an oral microflora disorder, weakened immune function, and activation of inflammatory factors due to radiation [17]. At this stage, the main prevention and control measures include cell protective agents, laser therapy, and cryotherapy, but the prevention and treatment effects vary greatly with no unified treatment standard. Borax-containing gargles are commonly applied in the treatment of oral mucositis, which protect the oral mucosa, have antibacterial and anti-inflammatory effects, but cannot promote mucosal repair. Additionally, long-term use of them may induce adverse reactions such as dry mouth and oral pigmentation [18].
Kangfuxin liquid, as an ethanol extract of American cockroach with polyols, mucous acids, peptides, a variety of growth factors and 18 kinds of amino acids, has the pharmacological effect of enhancing immunity, promoting blood circulation, nourishing yin and promoting granulation. It is widely used in the treatment of nasal diseases, digestive system diseases, and mouth ulcers. [19]. Qu et al. reported in a meta-systematic review that Kangfuxin liquid can effectively prevent diabetic foot ulcers and shorten treatment time [20]. Tang et al. have found that Kangfuxin liquid can alleviate acute ulcerative colitis in mice by inhibiting the inflammatory response and regulating the immune response [21]. However, there are few reports on the use of Kangfuxin liquid in the prevention and treatment of radiotherapy-reduced oral mucositis. In this study, the test group had a lower incidence of oral mucositis and oral pain than the control group after 21 d and 42 d of radiotherapy. The test group had increased scores of each dimension of the QLICP-HN scale and total scores in comparison to the control group after 42 d of radiotherapy. This result was similar to some Chinese reports. For example, Bai et al. have reported that Kangfuxin liquid can significantly reduce the incidence of oral mucositis and oral pain in patients with nasopharyngeal cancer during radiotherapy [22]. Possible mechanisms of the Kangfuxin fluid are as follows. (1) The peptides in Kangfuxin fluid promote the synthesis and secretion of nucleic acids in the oral mucosa cells, thereby accelerating the growth of the new granulation tissue and promoting the repair of ulcer wounds. (2) The polyols in Kangfuxin liquid promote angiogenesis, granulation tissue proliferation, and epidermal cell proliferation, regulate the blood microcirculation of the wound, and accelerate the shedding of necrotic tissue, thereby repairing the wound [23]. (3) EGF is a stimulator of cellular mitosis. It plays an important role in promoting ulcer healing and extracellular matrix formation by influencing the proliferation and metabolism of epithelial cells and fibroblasts, regulating the inflammatory response, and changing the synthesis and secretion of extracellular matrix. Kangfuxin liquid is rich in epidermal growth factors that promote tissue regeneration and cell growth, which can enhance the production, differentiation, and proliferation of epidermal cells, promote the shedding of wound necrotic tissues, and then accelerate the healing of oral mucosa.
The main function of the salivary gland is to secrete saliva to maintain the normality and stability of digestive function, feeding, and speech. Excessive radiation exposure can cause apoptosis of glandular cells, a decrease in the total number of cells, and a weakening of secretory function, leading to a decrease in the amount of glandular secretion [24]. EGF is a single-chain polypeptide composed of 53 amino acids, which can aggregate many growth factors in wounds, stimulate epidermal growth and keratinization, promote the growth of epithelium and interstitial matter, and maintain the stability of the oral mucosa. Thereby, EGF plays a key role in promoting the healing of damaged mucosa and maintaining the integrity of the epithelium. When the content of EGF in saliva decreases, this may indicate a decrease in the thickness of mucus on the surface of the oral epithelium and the loss of the first protective barrier function of the epithelial tissue, thereby increasing the risk of oral ulcers and oral mucositis. Amylase is an indicator of the synthesis of proteins in the serous acinar cells of the salivary glands, which reflects sympathetic activity and glandular cell damage. Kawahara et al. found that baseline amylase levels were inversely correlated with the amount of stimulated saliva 1 month after chemoradiotherapy and positively correlated with EGF levels, indicating a decrease in amylase levels may increase the risk of oral mucositis during chemoradiotherapy [25]. When buffer systems such as phosphate and bicarbonate are intact, the pH of saliva is generally maintained within a neutral range. After the saliva buffer system is affected by external factors such as radiotherapy, it leads to abnormal oral pH and disrupts the homeostasis of oral flora. In this study, the saliva flow rate, pH of saliva, and levels of EGF and amylase were higher in the test group than in the control group after 21 d and 42 d of radiotherapy. This suggests that Kangfuxin liquid may improve salivary gland function in patients with head and neck squamous cell carcinoma undergoing radiotherapy by increasing salivary amylase and EGF levels, and maintaining oral pH, to prevent oral mucositis.
Immunosuppression is another important mechanism for the occurrence of radiotherapy-reduced oral mucositis. While killing tumor cells, radiation also damages normal cells and tissues to a certain extent, inhibits the immune system, causes neutropenia, leads to lymphocyte and B cell functional activity disorders, weakens the proliferation of immune cells, and thus promotes oral mucositis [26]. Under normal circumstances, CD4+/CD8+ is in a relatively balanced state, which helps maintain the body’s immune function. When the CD4+/CD8+ value decreases, the body’s anti-tumor ability is reduced, indicating disturbed immune function. NK cells, whose activity is closely related to patient prognosis, play an important role in immune regulation, immune surveillance, and killing target cells. CD19+ is a totally specific antigen for B lymphocytes, which is closely involved in the physiological processes of B lymphocyte activation and signaling. CD69+ is the earliest surface antigen expressed by T lymphocytes after activation, and can be used as a co-stimulation signal to promote further proliferation and activation of T cells. Yang et al. point out that kangfuxin liquid increases the levels of CD4+/CD8+, and CD19+/CD69+ cells after radiotherapy and chemotherapy for nasopharyngeal cancer, and improves patients’ cellular immune function [27]. In this study, the levels of CD4+/CD8+, CD19+/CD69+, and NK cells after 21 d of radiotherapy were decreased in the two groups, and then were increased after 42 d of radiotherapy. The levels of CD4+/CD8+, CD19+/CD69+, and NK cells in the test group after 21 d and 42 d of radiotherapy were higher than those of the control group, which was consistent with the above finding. In addition, in this study, after 21 d and 42 d of radiotherapy, the serum levels of TGF-β1, IL-6, and CRP in the test group were lower than those in the control group. It could be seen that Kangfuxin liquid improved the cellular immune function during radiotherapy and chemotherapy in patients with head and neck squamous cell carcinoma, reduced the inflammatory response, improved the tolerance, and reduced radiation injury and infection. The reasons are related to the following points. (1) The mucosulline contained in Kangfuxin liquid has the effect of activating non-specific immune function cells, which can enhance the direct phagocytosis of pathogens by NK cells, macrophages, and polymorphonuclear leukocytes, thereby enhancing serum lysozyme activity and lymphocyte activity, releasing free radicals, and killing microorganisms [28,29]. (2) Kangfuxin liquid can reduce the effect of effector T cells on local accumulation of tissue by regulating the cytokine network and cytokine secretion, and enhance wound immunity. (3) Kangfuxin liquid increases the number of neutrophils in the wound and improves the function of neutrophil actin, thereby enhancing the body’s immune function. (4) In addition, kangfuxin liquid promotes the body to produce leukotrienes, interleukins, and prostaglandins, accelerates the elimination of edema, and weakens the inflammatory response [30].
However, some limitations existed in this study. This was a single-center study with small sample size, and short observation time. A multi-center study should be further carried out, the number of cases should be expanded, and the observation time should be extended in the future.
To sum up, Kangfuxin liquid effectively prevents the occurrence of radiotherapy-induced oral mucositis for patients with head and neck squamous cell carcinoma, reduces oral mucosal reactions and oral pain, improves salivary gland function, reduces inflammatory response, promotes cellular immune function, improves quality of life, and improves prognosis.
Disclosure of conflict of interest
None.
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