|Year : 2020 | Volume
| Issue : 3 | Page : 458-462
The efficacy of an ayurvedic preparation of yashtimadhu (Glycyrrhiza glabra) on radiation-induced mucositis in head-and-neck cancer patients: A pilot study
Ravindra Kumar Mamgain1, Meenu Gupta2, Pratibha Mamgain1, Sanjeev Kumar Verma3, Deep Shankar Pruthi2, Abhishek Kandwal4, Sunil Saini5
1 Department of Ayurvedic Medicine, Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
2 Department of Radiation Oncology, Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
3 Department of Medicine, Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
4 Department of Dental Surgery, Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
5 Department of Surgery, Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
|Date of Submission||29-Jul-2016|
|Date of Decision||13-Aug-2017|
|Date of Acceptance||24-Feb-2018|
|Date of Web Publication||24-Oct-2018|
Department of Radiation Oncology, Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Jolly Grant, Doiwala, Dehradun, Uttarakhand
Source of Support: None, Conflict of Interest: None
Background: Oral mucositis is a common and debilitating painful side effect of many forms of chemotherapy and radiation therapy. Mucositis may lead to dose reductions and unplanned interruptions of chemotherapy and/or radiotherapy (RT) and often affects patients' quality of life.
Aim: The objective of the study was to assess the efficacy of the ayurvedic preparation in decreasing the severity of mucositis in head-and-neck cancer patients receiving concomitant chemoradiotherapy.
Materials and Methods: In this prospective randomized study, the patients were divided into three groups. Group 1 patients received conventional mucositis treatment, whereas Group 2 patients received ayurvedic preparation Yashtimadhu in addition to conventional treatment. Group 3 patients received honey for local application in oral cavity as well as one tea spoon of honey twice daily orally in addition to routine conventional treatment. All the patients were assessed for mucositis at the end of every week during the RT for a period of 6 weeks.
Results: A significant difference was observed between the groups at each time point. Nearly 42.85% of patients in conventional treatment arm developed Grade 3 mucositis, 20% of patients developed Grade 3 mucositis in group where honey was given, and only 15.5% of patients developed Grade 3 mucositis in Yastimadhu group. Unplanned treatment breaks and hospitalization of patients were reduced with the use of yashtimadhu as compared to other two groups.
Conclusion: Yashtimadhu was observed to be effective and delayed the development of severe form of mucositis. The drug appeared to be more efficient in the management of radiation-induced mucositis.
Keywords: Chemoradiation, honey, mucositis, yashtimadhu
|How to cite this article:|
Mamgain RK, Gupta M, Mamgain P, Verma SK, Pruthi DS, Kandwal A, Saini S. The efficacy of an ayurvedic preparation of yashtimadhu (Glycyrrhiza glabra) on radiation-induced mucositis in head-and-neck cancer patients: A pilot study. J Can Res Ther 2020;16:458-62
|How to cite this URL:|
Mamgain RK, Gupta M, Mamgain P, Verma SK, Pruthi DS, Kandwal A, Saini S. The efficacy of an ayurvedic preparation of yashtimadhu (Glycyrrhiza glabra) on radiation-induced mucositis in head-and-neck cancer patients: A pilot study. J Can Res Ther [serial online] 2020 [cited 2020 Aug 4];16:458-62. Available from: http://www.cancerjournal.net/text.asp?2020/16/3/458/243495
| > Introduction|| |
The multimodality management of head-neck cancer (HNC) is to maximize treatment efficacy without increasing the toxicity. Head-and-neck squamous cell cancer management involves newer approaches such as induction chemotherapy, altered fractionation radiation with chemotherapy, intensity-modulated radiation therapy, and the use of biologically targeted drugs to achieve this goal. Due to the location of the primary tumors, the target volume invariably includes the salivary glands, oral cavity, and mandible in the treatment portals. As a result, changes induced by exposure to radiation occur in these critical tissues, leading to mucositis, which is one of the major causes of decreased quality of life. Incidence of mucositis in such groups is almost 85%–100%. Traditional allopathic treatments have limited role in mucositis as far as patient's quality of life is concerned.
An integrated approach is needed for the management of cancer as well as for minimizing the radiotherapy (RT)/chemotherapy-induced side effects. Many herbal preparations are being screened worldwide to validate their use as anticancerous drugs, and Ayurveda is supposed to step up the prophylactic, palliative, supportive, and curative aspects of cancer. Glycyrrhiza glabra which commonly known as Yashtimadhu is one of the most widely used herbs in traditional ayurvedic and Chinese medicine for its multifaceted therapeutic efficacy. It is a very sweet, moist, and soothing herb that is used in Ayurveda for treating cough, congestion, sore throat, hoarseness of voice, enhancing memory, chronic fatigue, rejuvenation, sexual debility, liver disorders, constipation, hyperacidity, peptic ulceration, and mouth ulcers. This plant has also been pharmacologically studied for its antiulcerogenic, antioxidant, antimicrobial, and anti-inflammatory properties., This study attempts to evaluate the efficacy of the ayurvedic preparation in decreasing the severity of mucositis in HNC patients receiving concomitant chemoradiotherapy.
| > Materials and Methods|| |
This prospective randomized study was undertaken in a tertiary care hospital setup with the aim to assess the efficacy of the ayurvedic preparation in decreasing the severity of mucositis in HNC patients receiving concomitant chemoradiotherapy. The study was approved by the Institutional Ethics Committee. Written and informed consent was obtained from all participants.
HNC patients attending Radiation Oncology Clinic at Cancer Research Institute from June 2012 to June 2014 participated in the study.
Patients having age ≥18 years, Eastern Cooperative Oncology Group Performance Status ≤3, diagnosed case of carcinoma oral cavity, oropharynx, hypopharynx, or larynx (supraglottis) planned to receive radical chemoradiation using conventional technique with directly visible oral or oropharyngeal mucosa in radiation field, normal hematological investigations, renal function test, liver function test, and chest X-ray were included in the study.
Patients having open mouth ulcers at the onset of study, known cases of diabetes mellitus, planned to receive external beam RT (EBRT) by altered fractionation schedules or with intensity-modulated RT, planned to receive total dose <45 Gy, history of previous treatment of head-and-neck malignancy with any of the following modalities – surgery, RT, or chemotherapy were excluded from the study. Patients who required the use of any form of treatment/medicaments such as antibiotics during the course of RT because of exacerbation of symptoms were not included in the study.
Eligible patients were randomly selected using random number table. A total of 150 participants were enrolled and subsequently randomly assigned to either of the groups. Group 1 patients received conventional mucositis treatment, whereas Group 2 patients were given ayurvedic protocol in addition to conventional treatment. Group 3 patients received honey for local application in oral cavity as well as one teaspoon of honey twice daily orally in addition to routine conventional treatment. Due to lost to follow-up and some patients left the treatment, finally, 42 participants in the Group 1, 45 participants in the Group 2, and 40 patients in Group 3 were analyzed.
Yastimadhu powder and honey for local application within the oral cavity was procured from the good manufacturing practice certified ayurvedic pharmacy of Dehradun, Uttarakhand, India. Capsules of yastimadhu were prescribed twice daily to be taken per orally, supplied by a national ayurvedic drug company. All patients who participated in this study received EBRT to oral cavity and neck on 6MV LlINAC by conventional fractionation. All the study participants received 2 Gy of therapeutic radiation daily, up to a total median dose of 60 Gy; the doses were given 5 days a week over a period of 6 weeks. Concurrent cisplatin 35mg/m2 was given in these patients.
After explaining about the study to the patients, an informed consent was obtained, and detailed case history with relevant clinical findings was recorded. Group 1 was treated with conventional modern medications such as antacid and local/oral anesthetic preparations.
In Group 2, after rinsing the mouth with warm salt water, the patients were advised to use the paste of 5 g of yashtimadhu powder mixed in honey for local application within the oral cavity twice daily along with 500 mg of yashtimadhu capsule twice daily per orally. Ayurvedic protocol was strictly followed and prescribed under the supervision of an ayurvedic physician. Group 3 patients were prescribed with local application of honey in the oral cavity as well as one teaspoon of honey twice daily per orally.
Conventional mucositis was managed and assessed by the radiation oncologists participating as investigators in this study. All the patients were examined at the end of every week for 6-week period till the end of RT. Mucositis was recorded at the end of every week and graded as recommended by radiation therapy oncology group (RTOG). The Grading is shown in [Table 1].
Pain was recorded at the end of every week and was graded as recommended by the Lindquist/Hickey scale. Scale indicated 0 – no pain, 1 – slight burning (mild), 2 - oral pain but able to eat (moderate), and 3 – severe pain and unable to eat (severe).
The primary end point of the study was to assess mucositis at the end of the 6th week, after the conclusion of RT. The data were compiled in software SPSS version 20 IBM, USA. The data were presented in percentages, and statistical tests used for comparing qualitative and quantitative data were Chi-square and ANOVA, respectively. P < 0.05 was considered statistically significant.
| > Results|| |
A total of 127 patients were analyzed at the end of the study. Baseline characteristics were similar between the groups in terms of gender and age allocation, history of smoking, site stage of cancer, and modality of chemoradiotherapy [Table 2]. As majority of patients received concurrent chemotherapy from day 1 of treatment, so all the patients were clinically examined from day 1 of RT, throughout the RT regimen for the development of oral mucositis.
|Table 2: Distribution of patient characteristics in three groups based on age, sex, location, and stage of cancer|
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[Figure 1] shows the distribution of patients among the three groups based on the onset of mucositis. It was observed that, at the end of the 3rd week of RT, there were more patients (68.8%) with absent/no mucositis in the Group 2, as compared to the Group 1 (9.5%) and Group 3 (45%). However, mucositis was present in mild forms in all three groups. Hence, it appears that Yastimadhu and honey did not absolutely control the cascade of inflammatory events associated with RT. Mild pain had developed in more number of patients in Group 1 (88%) as compared to the Group 2 (52%) and Group 3 (68%).
|Figure 1: Distribution of patients among the three groups based on the onset of mucositis through the treatment period (weeks). Onset of mucositis was early with conventional treatment as compared to other two groups|
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Onset of mucositis was defined in the present trial as the time when the patient showed first evidence of mucositis. Among the eight patients who had mucositis onset at the end of 1st week, 6 belonged to Group 1, while only 2 belonged to Group 3 and no patient was from Group 2. The day of onset of mucositis was evaluated in all the three groups [Table 3]. The onset of Grade 1 mucositis was early in conventional group (mean = 15th day) as compared to Groups 2 and 3. At the end of treatment, Grade 3 mucositis was observed in 15.5% of patients in Yashtimadhu group, whereas it was 42.85% and 20% in Groups 1 and 3, respectively. None of the patients developed Grade 4 mucositis in Yastimadhu group.
[Table 4] shows various grades of mucositis among three groups.
For intergroup comparison, post hoc analysis showed significant differences in terms of mucositis of Group 1 compared with Groups 2 and 3. The results revealed that there were fewer patients suffering from mucositis in group where Yastimadhu was given in addition to conventional treatment as compared to Groups 1 and 3 [Table 5] and the difference was statistically significant.
| > Discussion|| |
Oral mucositis varies greatly in severity ranging from mild erythema, which produces burning mucosal discomfort, to large areas of deep, coalescing ulcers that require high doses of opioids for effective intervention. The oral mucosa has an environment rich in microbes such as bacteria, fungi, and viruses. The presence of disruptions provides an important portal of entry for these infectious organisms within the mucosal lining, especially in cancer patients suffering from neutropenia. The importance of mucositis as a risk factor for bacteremia and sepsis is also well established. These factors lead to break from radiochemotherapy causing under treatment, resulting in suboptimal cancer therapy. Studies conducted on modern scientific parameters have proved the healing, antiulcer, anti-inflammatory, and skin regeneration activity of Yashtimadhu. Sodium glycyrrhizate possesses antiulcer activity and also stimulates regeneration of skin.
Yashtimadhu contains carbenoxolone derived from glycyrrhetinic acid, and it is reported that carbenoxolone can increase mucous production, which can inhibit vagus irritation in the gastrointestinal tract and accelerate the antiemetic effect. Psychogenic stress causes vagal stimulation, leading to nausea and vomiting. The anticholinergic effect of Yastimadhu reduces gastric irritation. The hydroalcoholic extract, as Ocimum sanctum, provides a radioprotective effect when given intraperitoneally before a whole-body exposure to 11 Gy of Co-60.
In the present study, exposure to ionizing radiation caused mucositis in all three study groups. However, in the participants using Yashtimadhu, the clinical appearance of mucositis was delayed, and the intolerable Grade 3 mucositis was reduced, indicating that Yashtimadhu is effective in preventing mucositis. Our results are similar to that of previous studies with Yashtimadhu, where various investigators have observed it to be effective in preventing against radiation-induced mucositis. We compared Yashtimadhu with comparable natural antibiotic honey. In our study, use of Yashtimadhu was started on day 1 of treatment as majority of patients had poor oro-dental hygiene. The prophylactic use of such products such as bee products such as honey, royal jelly, and propolis for oral mucositis have been reported by many authors.
Mucositis at the end of the 1st week which was seen in eight patients was attributed to the use of concurrent chemotherapy. All locally advanced laryngeal carcinoma cases had received concurrent chemotherapy and mucositis was scored as per RTOG criteria.
Kohnoet al. reported the prophylactic use of honey extract along with concurrent chemoradiotherapy for HNC patients. Sonis et al. described that analgesic and anti-inflammatory activity of honey is due to inhibition of the signal amplification by pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1 (IL-1), and IL-6. Choet al. performed meta-analysis of the efficacy of honey in the management of oral mucositis during RT in patients with HNC. Nine studies comprising 476 patients were included and they concluded that oral administration of honey with RT could prevent moderate-to-severe mucositis and associated weight loss.
In our study, 5% of our patients developed Grade 4 mucositis in Group 3 where honey was given along with conventional mucositis treatment as compared to 9.52% in Group 1 where conventional mucositis treatment was given. Although none of the participants had Grade 4 mucositis in Yastimadhu group, 7 (15.5%) patients developed Grade 3 mucositis. In the present study, 22 (52.3%) of patients in Group 1 were hospitalized due to severe mucositis. In Yastimadhu group, none of the patients were hospitalized due to severe mucositis.
Six (15%) patients in Group 3 were hospitalized and managed with intravenous antibiotic support. A study conducted by Jayalekshmi et al. also reported hospitalization in 16% of patients who received RT with conventional mucositis treatment due to severe mucositis. Glycyrrhizin in Yashtimadhu decreases plasma clearance and increases the plasma concentration of certain drugs such as prednisolone, and thus its action is enhanced. It also causes hypertension, edema, and hypokalemia when simultaneously used with oral contraceptives. It is reported that oral contraceptive use may increase sensitivity to glycyrrhizin. Women are reportedly more sensitive than men to adverse effects of Yashtimadhu. It should not be administered for prolonged time with thiazide and loop diuretics because it increases potassium loss. However, none of the patients in our study experienced any side effects of this drug.
| > Conclusion|| |
Yashtimadhu (G. glabra) is effective in providing a significant and clinically meaningful alleviation of mucositis, thus accelerating resolution of mucositis and pain. Unplanned treatment breaks and hospitalization of patients were reduced with the use of yashtimadhu as compared to conventional mucositis treatment of HNC patients, thus leading to better radiocurability of tumors on the radiobiological basis.
Financial support and sponsorship
This study was financially supported by Research Committee Himalayan Institute of Medical Sciences, Dehradun, India.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]