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An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists


 
  Table of Contents    
ORIGINAL ARTICLE  
Year : 2017  |  Volume : 21  |  Issue : 3  |  Page : 459-460
 

A study on Evaluation of efficacy of bethanechol in the management of chemoradiation-induced xerostomia in oral cancer patients


1 Department of Oral Medicine and Radiology, Madha Dental College and Hospital, Chennai, Tamil Nadu, India
2 Department of Oral Medicine and Radiology, Government Dental College and Research Institute, Bengaluru, Karnataka, India

Date of Submission17-Apr-2016
Date of Acceptance12-Aug-2017
Date of Web Publication15-Dec-2017

Correspondence Address:
Dr. M Kavitha
Department of Oral Medicine and Radiology, Madha Dental College and Hospital, Kundrathur, Chennai - 600 069, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jomfp.JOMFP_72_16

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   Abstract 

Objectives: Squamous cell carcinoma is the most common oral cancer. Radiotherapy with concomitant chemotherapy is an ideal treatment modality largely used for oral cancers, which precipitates many side effects, of which the most challenging and debilitating side effect is xerostomia. This study aimed to evaluate the efficacy of bethanechol in patients with xerostomia following chemoradiation therapy for oral cancer.
Materials and Methods: Fifty patients with xerostomia postchemoradiation therapy, aged between 30 and 65 years, were selected based on selection criteria. Thirty patients in the study group were administered 25 mg bethanechol three times daily (TDS) and 20 patients in the control group with placebo capsules. The subjective symptoms of oral dryness were periodically evaluated at baseline, at the end of 1st, 2nd and 3rd weeks using a self-reported questionnaire. Salivary analysis such as whole resting saliva and whole stimulated saliva (WSS) volumes, amylase, pH and sodium potassium ratio were evaluated before and 3 weeks after bethanechol and placebo therapy.
Results: Twenty-four (80%) patients in bethanechol group and only 2 (10%) patients in control group showed subjective improvement in oral dryness at the end of 3rd week. A significant difference was found between two groups in whole resting and stimulated saliva volume, pH and amylase. However, there was no statistically significant difference in sodium potassium ratio with insignificant adverse effects after 3 weeks of bethanechol therapy.
Conclusions: 25 mg bethanechol (TDS) has shown subjective improvement in oral dryness in 24 (80%) patients with significant improvement in whole resting and WSS volumes, pH and salivary amylase with insignificant adverse effects.


Keywords: Bethanechol, oral cancer, radiotherapy, saliva, xerostomia


How to cite this article:
Kavitha M, Mubeen K, Vijayalakshmi K R. A study on Evaluation of efficacy of bethanechol in the management of chemoradiation-induced xerostomia in oral cancer patients. J Oral Maxillofac Pathol 2017;21:459-60

How to cite this URL:
Kavitha M, Mubeen K, Vijayalakshmi K R. A study on Evaluation of efficacy of bethanechol in the management of chemoradiation-induced xerostomia in oral cancer patients. J Oral Maxillofac Pathol [serial online] 2017 [cited 2019 Sep 18];21:459-60. Available from: http://www.jomfp.in/text.asp?2017/21/3/459/220919



   Introduction Top


Squamous cell carcinoma is the most common cancer in the oral cavity, accounting for >90% of all oral cancers.[1] It is estimated that annually 70,000–80,000 new cases are reported in India. The high incidence of oral cancer in India is attributed to chronic use of tobacco in smoking and smokeless forms.[2]

The mainstay of treatment for oral cancers is surgery, radiotherapy and chemotherapy. However, radiotherapy with concomitant chemotherapy is an ideal nonsurgical treatment modality largely used for oral cancers.[3] Radiation of the head and neck precipitates many side effects such as mucositis, dysgeusia, candidiasis and radiation caries. However, the most challenging and debilitating side effect is xerostomia.[4],[5]

Various treatment strategies such as topical lubricants, coating agents, salivary substitutes, or lozenges have been tried which all provide only a transient relief from xerostomia. However, the most accepted treatment is use of systemic sialogogs, which acts by the stimulation of residual functional salivary gland tissue.[4],[6]

Recently, clinical trials on bethanechol, an acetylcholine analog possessing muscarinic cholinergic activity, have reported increase in whole resting and stimulated saliva with minimum side effects in xerostomia patients.[7],[8] However, at present, there are no studies in India for evaluating the efficacy of bethanechol in patients with xerostomia following chemoradiation therapy. Hence, the need is felt for the study.

Aims and objectives

  1. Quantification of whole resting saliva (WRS) and whole stimulated saliva (WSS) volumes and to assess the levels of salivary alpha amylase, sodium potassium ratio and pH in patients with chemoradiation-induced xerostomia in oral cancer before and after bethanechol therapy
  2. To assess the role of bethanechol in the management of xerostomia postchemoradiation therapy in oral cancer patients.



   Materials and Methods Top


The study was conducted in the Department of Oral Medicine and Radiology and consists of fifty xerostomia patients, who underwent chemoradiation therapy for oral cancer. The study was conducted in full accordance with ethical principles and was approved by an institutional ethical board.

Method of collection of data

Fifty patients with xerostomia, aged between 30 and 65 years, were selected for the study based on set inclusion and exclusion criteria.

Inclusion criteria

  1. Patients with histopathologically diagnosed as carcinoma of buccal mucosa, gingivo-buccal sulcus, anterior 2/3rd of the tongue, floor of the mouth, gingiva and hard palate [Figure 1]
  2. Patients who received external beam radiation therapy with Tele-Cobalt 60 to a mean dose of 60–70 Gy, over 30–35 fractions, 2 Gy/day, 5 fractions a week for 6–7 weeks with concurrent chemotherapy, a single agent cisplatin, 40 mg/m2 intravenous at weekly intervals
  3. Patients with major salivary glands within the radiation portals
  4. Patients with xerostomia immediately following chemoradiation therapy (i.e., WRS <0.1–0.2 ml/min and WSS <0.5–0.7 ml/min) based on set criteria by Epstein et al.[7]
  5. Patients with normal liver and renal function.
Figure 1: Carcinoma involving anterior alveolus extending into floor of the mouth (ulcero-proliferative type)

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Exclusion criteria

  1. Patients with carcinomas other than oral cavity
  2. Patients with known allergy to many drugs
  3. Patients with systemic diseases influencing salivary gland and its secretions such as diabetes and renal disease
  4. Patients taking medications such as tri-cyclic anti-depressants, anti-anxiety drugs, anti hypertensives, antihistamines with anti-cholinergic effects
  5. Patients suffering from salivary gland diseases
  6. Patients aged over 65 years.


The details of the study were explained to the patients and written informed consents were obtained. A detailed case history was collected and thorough clinical examination was carried out and recorded in specially prepared case history pro forma.

Patients with xerostomia were divided into two groups:

  1. Study group: Thirty patients with xerostomia were subjected to liver and renal function test. Patients with normal liver and renal function were prescribed with bethanechol tablets 25 mg (available with a trade name of URIVOID), orally 3 times daily on empty stomach, 1 h before or 2 h after food to prevent nausea and vomiting for 3 weeks
  2. Control group: Twenty patients with xerostomia were prescribed with placebo capsules containing wheat flour, orally three times daily 1 h before or 2 h after food for 3 weeks.


Method of collection of salivary sample

  1. Patients were called in the morning session between 9 a. m and 11.00 a. m and were made to sit in a comfortable position
  2. Patients were instructed not to drink (except water) or eat 1 h before saliva collection
  3. WRS was collected for 5 min by expectoration into sterile graduated container every 1 min and saliva volumes collected were expressed as ml/min. Patients were instructed not to swallow any saliva during the 5 min collection periods
  4. Stimulated whole saliva was collected after the patient chewed on a standard piece of preweighed paraffin wax (1 g). Collection of saliva was started 1 min after chewing. Patients were asked to spit into a sterile graduated container, once per minute for 5 min and the saliva volumes collected were expressed as ml/min.[7],[9]


The patients in the study were followed up for 3 weeks, and subjective symptoms of oral dryness were periodically evaluated at baseline, at the end of 1st, 2nd and 3rd weeks using a self-reported questionnaire designed by Eisbruch et al. and Meirovitz et al.[10],[11] Salivary analysis such as whole resting and stimulated saliva volumes, salivary amylase, sodium potassium ratio and pH were evaluated before and 3 weeks after bethanechol and placebo therapy using standard kit and procedure. Any adverse effects during the treatment period were recorded.

Self-reported questionnaire for evaluation of xerostomia (from baseline to 3 weeks after bethanechol and placebo therapy)

  • Rate your difficulty in chewing due to dryness
  • Rate your difficulty in swallowing solid foods due to dryness
  • Rate your mouth or throat dryness while not eating
  • Rate your difficulty in talking due to dryness
  • Rate the frequency of your sleeping problems due to dryness
  • Rate the frequency of sipping liquids to aid swallowing food and for oral comfort.[10],[11]


Method of estimation of salivary amylase

Enzymatic colorimetric assay

Procedure

The samples and the reagent were brought to room temperature prior to use. 1 in 10 diluted saliva sample (450 μl of distilled water and 50 μl of WRS sample) was added to CoBAS cup. Reagent casettee and CoBAS cup containing saliva sample were inserted in the respective racks in fully automated analyzer (CoBAS Integra 400). The values displayed on monitor were recorded.[12],[13]

Estimation of salivary sodium

Method (colorimetric method): Sodium estimation comprising two steps

Step 1: Precipitation of sodium

  • Clean dry test tubes were labeled as standard (S) and test (T)
  • 1 ml of precipitating reagent and 0.02 ml of standard were added to test tube (S)
  • 1 ml of precipitating reagent and 0.02 ml of WRS sample were added to test tube (T)
  • Tubes were mixed well and incubated at room temperature for 5 min and then centrifuged at 2000–3000 rpm for 2 min to obtain a clear supernatant.[14],[15]


Step 2: Color development

  • Clean dry test tubes were labeled as blank (B), standard (S) and test (T)
  • 1 ml of acid reagent, 0.02 ml of precipitating reagent and 0.1 ml of color reagent were added into the blank tube
  • 1 ml of acid reagent, 0.02 ml of supernatant from step 1 (standard reagent) and 0.1 ml of color reagent were added into the standard tube
  • 1 ml of acid reagent, 0.02 ml of supernatant from step 1 (saliva sample) and 0.1 ml of color reagent were added into the test tube
  • Test tubes were mixed well and incubated at room temperature for 5 min. Measurement of the absorbance of the blank (Abs. B), standard (Abs. S) and test sample (Abs. T) against distilled water was done within 15 min at 530 nm using colorimeter.[14],[15]


Calculations



Estimation of salivary potassium

Procedure: Clean dry test tubes were labeled as blank (B), standard (S) and test (T).

  • 1 ml of potassium reagent and 0.02 ml of deionized water were added in the blank tube
  • 1 ml of potassium reagent and 0.02 ml of standard reagent were added in the standard tube
  • 1 ml of potassium reagent and 0.02 ml of WRS sample were added in the test tube
  • Test tubes were mixed well and incubated at room temperature for 5 min. Measurement of the absorbance of the standard (Abs. S) and test sample (Abs. T) against blank was done within 15 min at 630 nm using colorimeter.[14],[15]


Calculations



Estimation of salivary pH

The saliva pH was measured using pH indicator strips with a range of 3.5–6.0 and 6.5–9.0 against the standards assigned by the manufacturer before and 3 weeks after administration of bethanechol and placebo capsules.[16]

The results of the study were statistically analyzed.


   Results Top


Age distribution

The overall mean age in the study sample was found to be 47.74 years.

Gender distribution

In the study group, 63% of patients were males and 37% of patients were females, whereas in the control group, 60% of patients were males and 40% of were females.

The subjective symptoms due to oral dryness were evaluated with planned questionnaire designed by Eisbruch et al. and Meirovitz et al. [Table 1] and [Table 2].
Table 1: Evaluation of symptoms of oral dryness in bethanechol group from baseline to 3 weeks assessed using self-reported questionnaire

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Table 2: Evaluation of symptoms of oral dryness in control group from baseline to 3 weeks assessed using self-reported questionnaire

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Whole resting and whole stimulated saliva volume in the study and control groups

The difference in mean whole resting and WSS volume between the two groups was found to be statistically significant at 3 weeks (P< 0.001) [Table 3] and [Graph 1] and [Graph 2].
Table 3: Salivary analysis at baseline and after 3 weeks in bethanechol and control groups

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Salivary amylase level in the study and control groups

The difference in mean salivary amylase level between the two groups was found to be statistically significant at 3 weeks (P< 0.001)[9] [Table 3].

Sodium and potassium concentration in the study and control groups

The difference in mean salivary sodium potassium ratio between the two groups was not found to be statistically significant at 3 weeks (P > 0.05) [Table 3].

Salivary pH in study and control groups

The difference in mean salivary pH between the two groups was found to be statistically significant at 3 weeks (P< 0.001) [Table 3].

Side effects of bethanechol

In the study group, three patients reported frequent urination as adverse effect (10%) and only one patient had sweating (3.3%), with overall percentage of adverse reactions of about 13.3% in patients treated with bethanechol.


   Discussion Top


Bethanechol, a centrally acting parasympathomimetic drug, is currently indicated for the treatment of postoperative and postpartum nonobstructive urinary retention and neurogenic atony of the urinary bladder with retention, which brings about wonderful results with less adverse reactions.[7],[17]

Xerostomia associated with radiotherapy for head and neck cancer has its onset during the first 2 weeks, progresses and reaches maximum at the end of 6 weeks.[18],[19] The salivary quantity drops from the usual normal values of WRS volume of 0.3–0.4 ml/min and WSS volume of 1–3 ml/min.[20] The composition of saliva also shows alterations such as decreased alpha amylase,[21],[22] increased sodium potassium ratio,[23] and decreased salivary pH,[21],[22] against normal values (normal levels of salivary amylase = 27 ± 3.8–1440 ± 160 U/ml,[12] sodium potassium ratio = 0.5,[24] and pH = 6–7).[24] There are several ways to clinically assess the signs and symptoms of xerostomia, but the most accepted is self-reported questionnaire designed by Eisbruch et al. and Meirovitz et al.[10],[11] Hence, we have used the same in our study.

The statistically significant increase in WRS and WSS volume in the study group could be explained based on the fact that, after oral administration of bethanechol, it is rapidly absorbed from gastrointestinal tract and pharmacologic effects appear in 30 min, reaching maximum effectiveness in 60–90 min and it stimulates functional residual salivary tissues outside the radiation field, chiefly minor glands rather than those glands that were included in the radiation portals, with a duration of action of 6–8 h.[8]

The results of our study are similar to results of studies by Epstein et al.,[7] Gorsky et al.,[8] Jham et al.[17] and Chainani-Wu et al.[25] who also reported significant increases in whole resting and WSS volumes.

The time taken for acinar regeneration after radiotherapy of oral cancer is found to be 6–12 months and hence there was no significant improvement in WRS and WSS after 3 weeks in the control group.[18]

Salivary amylase is an enzyme synthesized primarily in the acinar cells and less consistently in the proximal cells of the intercalated ducts and is a good indicator of the function of salivary glands.[26]

The significant increase in the level of amylase is reported and substantiated by Turner and Sugiya [27] by the fact that bethanechol acts on residual acinar cells, causing stimulation of muscarinic receptors, which activates phosphatidylinositide metabolism and induces an increase in intracellular Ca2+ concentration resulting in Ca2+-dependent amylase secretion.

In our study, increased sodium potassium ratio was observed after radiotherapy (0.78) similar to studies by Ben-Aryeh et al.[28] and could be due to effect of ionizing radiation on the reabsorption ability of the tubuli. The level of sodium ions in resting saliva did not show significant alteration after bethanechol therapy. The sodium and potassium levels in the saliva depend on the reabsorption ability of the tubuli and tubular secretion, respectively,[24],[29] and are proportionate to the flow rate.[29] Since bethanechol acts on muscarinic cholinergic receptors and increases salivary flow rate, there may be time lapse in reabsorption of sodium from intercalated duct as explained by Case et al.[29]

There is an increase in pH values after bethanechol therapy (5.5–5.7) which is statistically significant (P< 0.001) and may be explained based on increased flow rate and bicarbonate secretion.[30] However, there is no significant change in the control group.

In our study, side effects reported in the bethanechol group were insignificant and only three patients had urinary emergency (10%) and one patient had sweating (3.3%); however, no patient discontinued the drug during 3 weeks of therapy.


   Conclusions Top


This is a preliminary study for evaluating the efficacy of bethanechol in the management of xerostomia in patients treated for oral cancer. The following observations were noted in the study.

  1. There was a significant improvement in subjective symptoms of xerostomia in 80% of patients treated with bethanechol
  2. There was a significant increase in the whole resting and stimulated saliva volumes, salivary amylase level and salivary pH in the bethanechol group compared to control group. However, there was no significant change in sodium potassium ratio in patients treated with bethanechol and control groups
  3. There was an insignificant adverse effect in the bethanechol group.


Thus, 25 mg bethanechol (TDS) administration in patients undergoing chemo-radiation therapy for oral cancer has shown significant improvement in salivary secretion [Figure 2] and [Figure 3]. The results of our study encourage for further studies on large sample size with a follow-up of more than 3 weeks.
Figure 2: Appearance of oral mucosa in postirradiated xerostomia patient before bethanechol therapy

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Figure 3: Intraoral photograph showing moist mucosa after bethanechol therapy

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Acknowledgment

We would like to express our heartful thanks and acknowledge staffs of Department of Radiotherapy and Biochemistry, Bangalore Medical College and Research Institute, and Victoria Hospital, Bangalore, Karnataka, for extending their help during the conduction of the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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