Xerostomia: Selected Treatments

Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna of 36

(https://www.aetna.com/)

Xerostomia: Selected Treatments

Policy History

Last Review

04/02/2021

Effective: 02/06/2004

Next

Review: 03/10/2022

Review History

Definitions

Additional Information

Clinical Policy Bulletin

Notes

Number: 0302

Policy *Please see amendment forPennsylvaniaMedicaid

at the end of this CPB.

Aetna considers electrical stimulation (e.g., the Salitron

System and the Saliwell Crown device) experimental and

investigational for the prevention or treatment of xerostomia

(dry mouth) or for any other indications because its

effectiveness has not been established.

Aetna considers the following interventions experimental and

investigational for the treatment of xerostomia because their

effectiveness for this indication has not been established (not

an all-inclusive list):

▪ Acupuncture

▪ Acupuncture-like transcutaneous electrical nerve

stimulation (ALTENS)

▪ Adipose tissue-derived mesenchymal stem cell therapy

▪ Fat grafting to salivary glands

▪ Hyperbaric oxygen,

▪ Low-level laser therapy

▪ Transcutaneous electrical nerve stimulation (TENS)

▪ Venalot Depot (coumarin plus troxerutin).

https://www.aetna.com/


Background

Chronic xerostomia can be caused by Sjogren's syndrome,

certain medications or therapeutic irradiation. It can cause

difficulty in eating dry foods, swallowing and wearing dentures;

and susceptibility to dental caries, oral pain and frequent

infections. Proponents of electrostimulation as a treatment

option postulate that stimulating the tongue and the roof of the

mouth simultaneously will result in impulses to all residual

salivary tissues, major and minor, in the oral and pharyngeal

regions, thus causing salivation.

Electrical Stimulation

Although the Food and Drug Administration (FDA) approved

the Salitron System in 1988 to treat xerostomia secondary to

Sjogren's syndrome, the Agency for Health Care Policy and

Research (AHCPR) advised in a 1991 assessment that there

were "insufficient data to determine the clinical effectiveness of

this modality of salivary production, or to identify those

xerostomic patients who would benefit from the

procedure" (Erlichman, 1991). One published study (Weiss et

al, 1986) reported some degree of response after 3 stimulation

sessions of 3 minutes each in 24 patients with xerostomia

related to Sjogren's, radiation therapy, drugs or unknown

etiology. However, there was no control group, information on

the duration of response, quantitative assessment of salivary

response, or intermediate or long-term assessment of

effectiveness.

Another report, a double-blind study (Steller et al, 1988) noted

a statistically significant mean increase in post-stimulation

whole saliva flow between subjects (n = 29) using active and

placebo stimulators. However, this was due mainly to the

responses of 3 subjects who showed marked increases in their

whole saliva flow rate during the study. Of the active study

arm, only 1 subject showed evidence of a cumulative response


over the 4 weeks of the study. Further research of electrical

stimulation of salivary flow is needed to ascertain its role in the

treatment of Sjogren's patients with xerostomia.

Talal and colleagues (1992) reported that electrical stimulation

improves salivary function of patients with Sjogren's syndrome.

In this placebo controlled study, patients received three

treatments (2 weeks apart, over a 4-week period) with an

active device (n = 34) or a placebo device (n = 37). Patients

using active devices showed a statistically greater increase in

salivary production than patients using placebo devices.

Moreover, patients demonstrated significant improvement in

other symptoms such as difficulty in swallowing as well as

burning tongue. The major shortcomings of this study were (i)

it is unclear whether the control group was age-matched,

(ii) lack of long-term assessment of effectiveness, and (iii)

the number of patients in the active device group who did

not respond to treatment was not disclosed, and the range

or standard deviation for pre- and post-stimulation whole

salivary flow rates was not given.

The role of electrical stimulation in the management of patients

with xerostomia awaits the outcomes of randomized, double-

blind, controlled clinical studies with large sample sizes and

long-term follow-up. In many reviews on the management of

patients with xerostomia (Cooke, 1996; Fox, 1997; Davies,

1997; Mariette, 2002; Fox, 2003), salivary electrostimulation

was not mentioned as a method to manage patients with this

condition.

Strietzel et al (2007) evaluated the safety and effectiveness of

a recently developed electro-stimulating device mounted on an

individualized intra-oral removable appliance. The device,

containing electrodes, a wetness sensor, an electronic circuit

and a power source, was tested on patients with xerostomia in

a cross-over, randomized, sham-controlled, double-blinded,

multi-center study (n = 23; 10 with primary Sjogren's


syndrome, 7 with medication-induced xerostomia, and 6 with

idiopathic xerostomia). Electrical stimulation and also sham

were delivered for 10 mins to the oral mucosa, in the

mandibular third molar region. Oral dryness was measured by

the sensor. As the primary outcome, sensor dryness and

xerostomia symptom changes as a result of device wearing

were assessed, and compared between active and sham

modes. In addition, side-effects were recorded. Electro-

stimulation resulted in a significant decrease in sensor

dryness, leading to a beneficial effect on patients' subjective

condition. No significant adverse events were observed.

However, 30.4 % patients reported the sham mode to be

more effective than the activ e mode. The authors stated that

these findings are encouraging enough to continue developing

and investigating the miniature electrostimulating device

mounted on a dental implant.

In a preliminary study, Ami and Wolff (2010) evaluated the

effect on xerostomia of the Saliwell Crown (Saliwell Ltd.,

Harutzim, Israel), an innovative saliva electrostimulation device

fixed on an implant, placed in the lower third molar area. A

Saliwell Crown was placed in the lower third molar area of an

81-year old female patient with complaints of dry and burning

mouth. Salivary secretion was measured, and the patient was

asked to fill in written satisfaction questionnaires. The patient

was monitored for 1 year, comparing her salivary secretion

rates and the written questionnaires. The results showed a

constant slight but significant increase in the salivary secretion

and in the patient's personal feelings as presented in the

questionnaires. The authors concluded that the saliva

stimulation device Saliwell Crown, placed on an implant in an

81-year old patient with dry and burning mouth complaints,

presented promising results when both the salivary secretion

tests and the self-assessment questionnaires were examined

and compared. The findings of this case study need to be

validated by well-designed studies.


Strietzel and colleagues (2011) evaluated the safety and

effectiveness of an intra-oral electrostimulation device,

consisting of stimulating electrodes, an electronic circuit, and a

power source, in treating xerostomia. The device delivers

electrostimulation through the oral mucosa to the lingual nerve

in order to enhance the salivary reflex. The device was tested

on a sample of patients with xerostomia due to Sjogren's

syndrome and other sicca conditions in a 2-stage prospective,

randomized, multi-center trial. Stage I was a double-blind,

cross-over stage designed to compare the effects of the

electrically active device with the sham device, each used for 1

month, and stage II was a 3-month open-label stage designed

to assess the long-term effects of the active device.

Improvement in xerostomia severity from baseline was the

primary outcome measure. A total of 114 patients were

randomized. In stage I, the active device performed better

than the sham device for patient-reported xerostomia severity

(p < 0.002), xerostomia frequency (p < 0.05), quality of life

impairment (p < 0.01), and swallowing difficulty (p < 0.02). At

the end of stage II, statistically significant improvements were

verified for patient-reported xerostomia severity (p < 0.0001),

xerostomia frequency (p < 0.0001), oral discomfort (p < 0.001),

speech difficulty (p < 0.02), sleeping difficulty (p < 0.001), and

resting salivary flow rate (p < 0.01). The authors concluded

that the results indicated that daily use of the device alleviated

oral dryness, discomfort, and some complications of

xerostomia, such as speech and sleeping difficulties, and

increased salivary output. These findings need to be verified

by additional research.

Fedele et al (2010) noted that xerostomia is a very common

condition, which not only involves dry mouth feeling, but can

also lead to psychosocial distress, impaired quality of life, and

complications, such as dental caries and oral candidiasis. It is

generally induced by hypofunction of salivary glands, which

has a wide variety of etiologies, such as Sjogren's syndrome,

radiotherapy to the head and neck and side effects of

medications. Current therapies rely on saliva substitutes and


pharmacological stimulation of the parasympathetic system.

These treatment modalities are somewhat limited by their

short-term efficacy, high cost and drug interactions or other

adverse effects. Local transcutaneous or per-mucosal

electrostimulation in areas close to the nerves participating in

the salivary autonomic reflex has been found to increase

salivary secretion in animal and clinical experiments and to

relieve symptoms of dry mouth in patients with salivary gland

hypofunction. These investigators reviewed the current status

and potential of intra-oral miniature electrostimulating devices.

The authors stated that these intra-oral electrostimulating

devices offer promise as an optional safe and non-chemical

treatment of xerostomia.

In a phase II randomized, controlled study, Wong et al (2010)

examined the potential effectiveness of xerostomia prevention

using acupuncture-like transcutaneous electrical nerve

stimulation (ALTENS) delivered concomitantly with

radiotherapy administered to head and neck cancer patients.

A total of 60 patients were randomized to either the treatment

group (n = 30) that received ALTENS daily with radiotherapy

or the control group (n = 26) that had standard mouth care

only. Stimulated and basal unstimulated whole saliva

production (WSP) plus radiation-induced xerostomia (RIX)

symptoms visual analog score (RIXVAS) were assessed at

specific time points. Generalized linear models and

generalized estimating equations were used for analysis.

RIXVAS at 3 months follow-up after therapy completion was

used as the primary study endpoint. The mean RIXVAS for

the ALTENS intervention at 3 months was 39.8, which was not

significantly different from the control arm value of 40.5. There

were no statistically significant differences between the 2

groups for their mean RIXVAS and WSP at all assessment

time points. The authors concluded that there was no

significant difference in mean WSP and RIXVAS between

the 2 groups, so ALTENS is not recommended as a

prophylactic intervention.


In a phase II component of a multi-institutional, phase II/III,

randomized trial, Wong et al (2012) evaluated the feasibility

and preliminary effectiveness of ALTENS in reducing radiation-

induced xerostomia. Patients with cancer of the head and

neck who were 3 to 24 months from completing radiotherapy

with or without chemotherapy (RT +/- C) and who were

experiencing xerostomia symptoms with basal whole saliva

production greater than or equal to 0.1 ml/min and were

without recurrence were eligible. Patients received twice-

weekly ALTENS sessions (24 sessions over 12 weeks) using a

proprietary electrical stimulation unit. The primary study

objective was to assess the feasibility of ALTENS treatment.

Patients were considered compliant if 19 of 24 ALTENS

sessions were delivered, and the targeted compliance rate

was 85 %. Secondary objectives measured treatment-related

toxicities and the effect of ALTENS on overall radiation-

induced xerostomia burden using the University of Michigan

Xerostomia-Related Quality of Life Scale (XeQOLS). Of 48

accrued patients, 47 were evaluable. The median age was 60

years, 84 % of patients were men, 70 % completed RT +/- C

for greater than 12 months, and 21 % had previously received

pilocarpine. Thirty-four patients completed all 24 ALTENS

sessions, 9 patients completed 20 to 23 sessions, and 1

patient completed 19 sessions, representing a 94 % total

compliance rate. Six-month XeQOLS sco res were available

for 35 patients and indicated that 30 patients (86 %) achieved

a positive treatment response with a mean +/- standard

deviation reduction of 35.9 % +/- 36.1 %. Five patients

developed grade 1 or 2 gastro-intestinal toxicity, and 1 had a

grade 1 pain event. The authors concluded that the current

results indicated that ALTENS treatment for radiation-induced

xerostomia can be delivered uniformly in a cooperative, multi-

center setting and produced possible beneficial treatment

response. They noted that given these results, the phase III

component of this study was initiated.

In a Cochrane review, Furness et al (2013) evaluated the

effects of non-pharmacological interventions administered to


stimulate saliva production for the relief of dry

mouth/xerostomia. These investigators searched the

Cochrane Oral Health Group's Trials Register (to April 16,

2013), the Cochrane Central Register of Controlled Trials

(CENTRAL) (The Cochrane Library 2013, Issue 3), MEDLINE

via OVID (1948 to April 16, 2013), EMBASE via OVID (1980 to

April 16, 2013), AMED via OVID (1985 to April 16, 2013),

CINAHL via EBSCO (1981 to April 16, 2013), and

CANCERLIT via PubMed (1950 to April 16, 2013). The

metaRegister of Controlled Clinical Trials and

ClinicalTrials.gov were also searched to identify ongoing and

completed trials. References lists of included studies and

relevant reviews were also searched. There were no

restrictions on the language of publication or publication

status. These researchers included parallel group randomized

controlled trials of non-pharmacological interventions to treat

dry mouth, where participants had dry mouth symptoms at

baseline. At least 2 review authors assessed each of the

included studies to confirm eligibility, assess risk of bias and

extract data using a piloted data extraction form. They

calculated mean difference (MD) and 95 % confidence

intervals (CI) for continuous outcomes or where different

scales were used to assess outcome, they calculated

standardized mean differences (SMD) together with 95 % CIs.

These investigators attempted to extract data on adverse

effects of interventions. Where data were missing or unclear,

they attempted to contact study authors to obtain further

information. There were 9 studies (total 366 participants

randomized) included in this review of non-pharmacological

interventions for dry mouth, which were divided into 3

comparisons: (i) 8 studies were assessed at high-risk of bias

in at least one domain and the remaining study was at

unclear risk of bias, (ii) 5 small studies (total 153

participants, with dry mouth following radiotherapy

treatment) compared acupuncture with placebo, and 4

were assessed at high-risk and 1 at unclear risk of bias, (iii)

2 trials reported outcome data for dry mouth in a form

http://ClinicalTrials.gov


suitable for meta-analysis. The pooled estimate of these 2

trials (70 participants, low-quality evidence) showed no

difference between acupuncture and control in dry mouth

symptoms (SMD -0.34, 95 % CI: -0.81 to 0.14, p value 0.17, I

(2) = 39 %) with the CIs including both a possible reduction or

a possible increase in dry mouth symptoms. Acupuncture was

associated with more adverse effects (tiny bruises and

tiredness that were mild and temporary). There was a very

small increase in unstimulated whole saliva (UWS) at the end

of 4 to 6 weeks of treatment (3 trials, 71 participants, low-

quality evidence) (MD 0.02 ml/min, 95 % CI: 0 to 0.04, p value

0.04, I(2) = 57 %), and this benefit persisted at the 12-month

follow-up evaluation (2 trials, 54 participants, low-quality

evidence) (UWS, MD 0.06 ml/min, 95 % CI: 0.01 to 0.11, p

value 0.03, I(2) = 10 %). For the outcome of stimulated whole

saliva (SWS, 3 trials, 71 participants, low-quality evidence)

there was a benefit favoring acupuncture (MD 0.19 ml/min, 95

% CI: 0.07 to 0.31, p value 0.002, I(2) = 1 %) an effect which

also persisted at the 12-month follow-up evaluation (SWS MD

0.28 ml/min, 95 % CI: 0.09 to 0.47, p value 0.004, I(2) = 0 %)

(2 trials, 54 participants, low-quality evidence). Two small

studies, both at high-risk of bias, compared the use of an

electro-stimulation device with a placebo device in participants

with Sjogren's syndrome (total 101 participants). A further

study, also at high-risk of bias, compared acupuncture-like

electro-stimulation of different sets of points in participants who

had previously been treated with radiotherapy. None of these

studies reported the outcome of dry mouth. There was no

difference between electro-stimulation and placebo in the

outcomes of UWS or SWS at the end of the 4-week treatment

period in the 1 study (very low that provided data for these

outcomes). No adverse effects were reported. A single study

at high-risk of bias, compared the stimulatory effect of powered

versus manual tooth-brushing and found no difference for the

outcomes of UWS or SWS. The authors concluded that there

is low-quality evidence that acupuncture is no different from

placebo acupuncture with regard to dry mouth symptoms,


which is the most important outcome. This may be because

there were insufficient participants included in the 2 trials to

show a possible effect or it may be that there was some

benefit due to "placebo" acupuncture that could have biased

the effect to the null. There is insufficient evidence to

determine the effects of electro-stimulation devices on dry

mouth symptoms. It is well-known that dry mouth symptoms

may be problematic even when saliva production is increased,

yet only 2 of the trials that evaluated acupuncture reported dry

mouth symptoms, a worrying reporting bias. There is some

low-quality evidence that acupuncture results in a small

increase in saliva production in patients with dry mouth

following radiotherapy. There is insufficient evidence to

determine the effects of electro-stimulation devices on dry

mouth symptoms or saliva production in patients with

Sjogren's syndrome. Reported adverse effects of acupuncture

are mild and of short duration, and there were no reported

adverse effects from electro-stimulation.

In a phase II clinical trial, Vijayan et al (2014) evaluated the

effectiveness of TENS delivered using an extra-oral device in

patients with radiation-induced xerostomia. A total of 30 oral

cavity and oropharyngeal cancer patients post-adjuvant (n =

26) or definitive radiotherapy (n = 4) were enrolled in this

study. The TENS electrode pads were placed externally on

the skin overlying the parotid glands. Un-stimulated whole

saliva was collected for 5 mins into graduated tubes using the

low forced spitting method. The TENS unit was then activated

and stimulated saliva was collected for an additional 5 mins.

The difference between un-stimulated and stimulated saliva

output was measured using the paired t-test. Linear

regression was used to determine factors significantly

influencing the improvement in salivary output. Twenty-nine

(96.7 %) of 30 patients showed increased saliva flow during

stimulation. A statistically significant improvement in saliva

production (p < 0.05) during stimulation was noted. The mean

un-stimulated saliva flow was 0.056 ml/min and the mean

stimulated saliva flow was 0.12 ml/min with a median increase


of 0.06 ml/min. The interval to the application of TENS after

radiotherapy significantly influenced the improvement in

salivary flow. The authors concluded that extra-oral

application of TENS is effective in increasing the whole

salivary flow in most of the post-radiated oral

cavity/oropharyngeal cancer patients with xerostomia. They

stated that TENS therapy may be useful as an effective

supportive treatment modality in post-radiated oral cancer

patients. These preliminary findings from a small (n = 30)

phase II study need to be validated by well-designed studies.

In a case-series study, Zadik et al (2014) investigated the

safety of an intra-oral electrostimulator (GenNarino) in

symptomatic chronic graft-versus-host disease (cGVHD)

patients. The secondary objective was to study the impact on

the salivary gland involvement of cGVHD patients. The study

included patients treated for 4 weeks, randomly assigned to

the active device and then crossed-over to a sham-device or

vice versa. The patients and clinicians were blind to the

treatment delivered. Data regarding oral mucosal and salivary

gland involvement were collected. A total of 6 patients were

included in this study. Most of the intra-oral areas with

manifestations of cGVHD were not in contact with the

GenNarino device. Two patients developed mild mucosal

lesions in areas in contact with the GenNarino during the

study. However, only 1 of them had a change in the National

Institutes of Health (NIH) score for oral cGVHD. The un-

stimulated and stimulated salivary flow rate increased in 4 out

of the 5 patients included in this analysis. Symptoms of dry

mouth and general oral comfort improved. The authors

concluded that the findings of this study suggested that

GenNarino is safe in cGVHD patients with respect to oral

tissues. Furthermore the use of GenNarino resulted in

subjective and objective improvements in dry mouth

symptoms. Moreover, they stated that a large scale study is

needed to confirm the impact and safety of GenNarino on

systemic cGVHD.


Bakarman and Keenan (2014) examined the evidence of non-

pharmacological treatments for patients with dry mouth. Study

assessment and data extraction were carried out

independently by at least 2 reviewers. Mean difference and

SMD together with 95 % CIs were calculated where

appropriate. A total of 9 studies (366 participants) were

included in this review, 8 were assessed at high risk of bias

and 1 at unclear risk of bias. Five small studies (153

participants), with dry mouth following radiotherapy treatment

compared acupuncture with placebo. Four were at high risk

and 1 at unclear risk of bias. Two trials reported outcome data

for dry mouth in a form suitable for meta- analysis. The pooled

estimate of these 2 trials (70 participants, low quality ev idence)

showed no difference between acupuncture and control in dry

mouth symptoms (SMD -0.34, 95 % CI: -0.81 to 0.14, p value

0.17, I2 = 39 %) with the CIs including a possible reduction or

a possible increase in dry mouth symptoms. Acupuncture was

associated with more adverse effects (tiny bruises and

tiredness which were mild and temporary). There was a very

small increase in unstimulated whole saliva (UWS) at the end

of 4 to 6 weeks of treatment (3 trials, 71 participants, low

quality evidence) (MD 0.02 ml/minute, 95 % CI: 0 to 0.04, p

value 0.04, I2 = 57 %), and this benefit persisted at the 12-

month follow-up evaluation (2 trials, 54 participants, low quality

evidence) (UWS, MD 0.06 ml/minute, 95 % CI: 0.01 to 0.11, p

value 0.03, I2 = 10 %). For the outcome of stimulated whole

saliva (SWS, 3 trials, 71 participants, low quality evidence)

there was a benefit favoring acupuncture (MD 0.19 ml/minute,

95 % CI: 0.07 to 0.31, p value 0.002, I2 = 1 %) an effect which

also persisted at the 12-month follow-up evaluation (SWS MD

0.28 ml/minute, 95 % CI: 0.09 to 0.47, p value 0.004, I2 = 0 %)

(2 trials, 54 participants, low quality evidence). Two small

studies, both at high risk of bias, compared the use of an

electrostimulation device with a placebo device in participants

with Sjogren's syndrome (total 101 participants). A further

study, also at high risk of bias, compared acupuncture-like

electrostimulation. None of these studies reported the

outcome of dry mouth. A single study at high risk of bias


compared the stimulatory effect of powered versus manual

tooth-brushing and found no difference for the outcomes of

UWS or SWS. The authors concluded that there is low quality

evidence that acupuncture is no different from placebo

acupuncture with regard to dry mouth symptoms, which is the

most important outcome. This may be because there were

insufficient participants included in the 2 trials to show a

possible effect or it may be that there was some benefit due to

"placebo" acupuncture, which could have biased the effect to

the null. There is insufficient evidence to determine the effects

of electrostimulation devices on dry mouth symptoms. It is well-

known that dry mouth symptoms may be problematic even

when saliva production is increased, yet only 2 of the trials that

evaluated acupuncture reported dry mouth symptoms, a

worrying reporting bias. There is some low quality evidence

that acupuncture results in a small increase in saliva production

in patients with dry mouth following radiotherapy. There is

insufficient evidence to determine the effects of

electrostimulation devices on dry mouth symptoms or saliva

production in patients with Sjogren's syndrome.

Reported adverse effects of acupuncture are mild and of short

duration, and there were no reported adverse effects from

electrostimulation.

In a pilot study, Lakshman et al (2015) evaluated the

effectiveness of a TENS unit in stimulating the whole salivary

flow rate in radiation-induced xerostomia patients. A total of

40 subjects were included in the study. The study group

consisted of 30 individuals and was divided into Group S1 (n =

20), which was further subdivided into Group S1A (n = 10)

subjects complaining of dry mouth who were undergoing head

and neck radiotherapy with TENS stimulation during the

commencement of radiotherapy, on the third week, sixth week

and after a month of completion of radiotherapy and Group

S1B (n = 10) with TENS stimulation daily during the full course

of radiotherapy and Group S2 (n = 10) subjects complaining of

dry mouth who had undergone head and neck radiotherapy

that ended 1 month prior to their entry into the study. The


control group (n = 10) consisted of healthy individuals not

complaining of dry mouth and who have not undergone head

and neck radiotherapy. Whole saliva was collected without

stimulation for 10 mins and after electrostimulation with TENS

unit for additional 10 mins in a graduated test tube. The

results were statistically analyzed using Mann-Whitney U-test

and Kruskal-Wallis's test. The data analysis revealed that

control and S1B group showed increased salivary flow rate

after stimulation by TENS therapy compared with the

unstimulated salivary flow, whereas in S1A and S2 group it

was found to be statistically non-significant. The authors

concluded that the findings of this study provided an insight

about the effectiveness of TENS therapy in stimulating salivary

flow in healthy subjects and it is very effective when used in

conjunction with radiation therapy by reducing the side-effects

of radiation therapy. They stated that TENS therapy can be

used as an adjunctive method for the treatment of xerostomia

along with other treatment modalities. These preliminary

findings need to be validated by well-designed studies.

Wong et al (2015) presented the results of the phase III clinical

trial, RTOG 0537, which compared ALTENS with pilocarpine

(PC) for relieving radiation-induced xerostomia. Eligible

patients were randomized to twice-weekly 20-min ALTENS

sessions for 24 sessions during 12 weeks or PC (5 mg 3 times

daily for 12 weeks). The primary end-point was the change in

the University of Michigan Xerostomia-Related Quality of Life

Scale (XeQOLS) scores from baseline to 9 months from

randomization (MFR). Secondary end-points included basal

and citric acid primed whole salivary production (WSP), ratios

of positive responders (defined as patients with greater than

or equal to 20 % reduction in overall radiation-induced

xerostomia symptom burden), and the presence of adverse

events based on the Common Terminology Criteria for

Adverse Events version 3. An intention-to-treat analysis was

conducted. A total of 148 patients were randomized. Only 96

patients completed the required XeQOLS and were evaluable

at 9 MFR (representing merely 68.6 % statistical power); 76


patients were evaluable at 15 MFR. The median change in

the overall XeQOLS in ALTENS and PC groups at 9 and 15

MFR were -0.53 and -0.27 (p = 0.45) and -0.6 and -0.47 (p =

0.21). The corresponding percentages of positive responders

were 81 % and 72 % (p = 0.34) and 83 % and 63 % (p =

0.04). Changes in WSP were not significantly different

between the groups. Grade 3 or less adverse events, mostly

consisting of grade 1, developed in 20.8 % of patients in the

ALTENS group and in 61.6 % of the PC group. The authors

concluded that the observed effect size was smaller than

hypothesized, and statistical power was limited because only

64.8 % (96 of 148) of the recruited were evaluable. The

primary end-point -- the change in radiation-induced

xerostomia symptom burden at 9 MFR-was not significantly

different between the ALTENS and PC groups. There was

significantly less toxicity in patients receiving ALTENS.

Patient (a medical information and support organization from

England and Wales)’s webpage on "Dry Mouth

(Xerostomia)" (last updated 12/23/2015) stated that "A

technique called acupuncture-like transelectrical nerve

stimulation is currently being investigated".

Furthermore, an UpToDate review on "Management of late

complications of head and neck cancer and its

treatment" (Galloway and Amdur, 2016) states that

"Neuromuscular electrical stimulation (NMSE) is a potentially

promising improvement to traditional therapy (for dysphagia)".

It does not mention electrical stimulation as a therapeutic

option for xerostomia.

Fat Grafting to Salivary Glands

Kawakami and colleagues (2016) stated that atrophy or hypo-

function of the salivary gland because of aging or disease

leads to hypo-salivation that affects patient quality of life by

causing dry mouth, deterioration of mastication/deglutition, and

poor oral hygiene status. Current therapy for atrophy or hypo-


function of the salivary gland in clinical practice focuses on

symptom relief using drugs and artificial saliva; therefore, there

is still a need to develop new therapies. To investigate

potential novel therapeutic targets, these researchers induced

the differentiation of salivary gland cells by co-culturing human

adipose-derived stem cells isolated from buccal fat pads (hBFP-

ASCs) with human salivary-gland-derived fibroblasts (hSG

fibros). They examined their potential for transplantation and

tissue neogenesis. Following the culture of hBFP-ASCs and

hSG-fibros, differentiated cells were transplanted into the

submandibular glands of SCID mice, and their degree of

differentiation in tissues was determined. These investigators

also examined their potential for functional tissue

reconstitution using a three-dimensional (3D) culture system.

Co-cultured cells expressed salivary gland-related markers

and generated new tissues following transplantation in-vivo.

Moreover, cell reconstituted glandular structures in the 3D

culture system. The authors concluded that co-culture of hSG-

fibros with hBFP-ASCs led to successful differentiation into

salivary gland cells that could be transplanted to generate new

tissues.

Furthermore, a systematic review on "Treatment of xerostomia

and hyposalivation in the elderly" (Gil-Montoya et al, 2016) and

an UpToDate review on "Treatment of dry mouth and other

non-ocular sicca symptoms in Sjogren's syndrome" (Baer,

2016) does not mention fat grafting as a therapeutic option.

Acupuncture

Assy and Brand (2018) noted that several studies have

suggested a positive effect of acupuncture on oral dryness.

These investigators carried out a systematic review of the

effects of acupuncture on xerostomia and hypo-salivation.

PubMed and Web of Science were electronically searched.

Reference lists of the included studies and relevant reviews

were manually searched. Studies that met the inclusion

criteria were systematically evaluated; 2 reviewers assessed


each of the included studies to confirm eligibility and assessing

the risk of bias. A total of 10 randomized controlled trials

(RCTs) investigating the effect of acupuncture were included;

5 trials compared acupuncture to sham/placebo acupuncture;

4 trials compared acupuncture to oral hygiene/usual care.

Only 1 clinical trial used oral care sessions as control group.

For all the included studies, the quality for all the main

outcomes had been rated as low. Although some publications

suggested a positive effect of acupuncture on either salivary

flow rate or subjective dry mouth feeling, the studies were

inconclusive about the potential effects of acupuncture. The

authors concluded that insufficient evidence was available to

conclude whether acupuncture is an evidence-based

therapeutic option for xerostomia/hypo-salivation. They stated

that further well-designed, larger, double-blinded trials are

needed to determine the potential benefit of acupuncture.

Sample size calculations should be performed before initiating

these studies.

In a 2-center, phase-III, randomized clinical trial, Garcia and

colleagues (2019) examined if acupuncture can prevent RIX in

patients with head and neck cancer undergoing radiation

therapy. This trial compared a standard care control (SCC)

with true acupuncture (TA) and sham acupuncture (SA) among

patients with oropharyngeal or nasopharyngeal carcinoma who

were undergoing radiation therapy in comprehensive cancer

centers in the U.S. and China. Patients were enrolled

between December 16, 2011, and July 7, 2015. Final follow-

up was August 15, 2016. Analyses were conducted February

1 through 28, 2019. Either TA or SA using a validated

acupuncture placebo device was performed 3 times per week

during a 6- to 7-week course of radiation therapy. The primary

end-point was RIX, as determined by the Xerostomia

Questionnaire in which a higher score indicates worse RIX, for

combined institutions 1 year after radiation therapy ended.

Secondary outcomes included incidence of clinically

significant xerostomia (score of greater than 30), salivary flow,

QOL, salivary constituents, and role of baseline expectancy


related to acupuncture on outcomes. Of 399 patients

randomized, 339 were included in the final analysis (mean

[SD] age of 51.3 [11.7] years; age range of 21 to 79 years; 258

[77.6 %] men), including 112 patients in the TA group, 115

patients in the SA group, and 112 patients in the SCC group.

For the primary aim, the adjusted least square mean (SD)

xerostomia score in the TA group (26.6 [17.7]) was

significantly lower than in the SCC group (34.8 [18.7]) (p  =  0.001;

effect size  =  -0.44) and marginally lower but not

statistically significant different from the SA group (31.3 [18.6])

(p  =  0.06; effect size  =  -0.26). Incidence of clinically significant

xerostomia 1 year after radiation therapy ended followed a

similar pattern, with 38 patients in the TA group (34.6 %), 54

patients in the SA group (47.8 %), and 60 patients in the SCC

group (55.1 %) experiencing clinically significant xerostomia (p  

=  0.009). Post-hoc comparisons revealed a significant

difference between the TA and SCC groups at both

institutions, but TA was significantly different from SA only at

Fudan University Cancer Center, Shanghai, China (estimated

difference [SE]: TA versus SCC, -9.9 [2.5]; p  <  0.001; SA

versus SCC, -1.7 [2.5]; p =  0.50; TA versus SA, -8.2 [2.5]; p  =  0.001),

and SA was significantly different from SCC only at the

University of Texas MD Anderson Cancer Center, Houston,

Texas (estimated difference [SE]: TA versus SCC, -8.1 [3.4]; p  

=  0.016; SA versus SCC, -10.5 [3.3]; p  =  0.002; TA versus SA,

2.4 [3.2]; p  =  0.45). The authors concluded that this

randomized clinical trial found that TA resulted in significantly

fewer and less severe RIX symptoms 1 year following

treatment vs SCC. However, these researchers stated that

further studies are needed to confirm clinical relevance and

generalizability of this finding and to evaluate inconsistencies

in response to sham acupuncture between patients in the U.S.

and China.

Artificial Saliva


Apperley and co-workers (2017) noted that researchers have

recently developed a novel oily formulation for potential use as

a saliva substitute for the treatment of dry mouth. In a

randomized, cross-over study, these researchers compared

this new formulation to a currently available saliva substitute

and a control of water on measures of mastication, subjective

feeling of oral dryness and product acceptability. A total of 40

participants treated with radiotherapy to the head and neck

and experiencing xerostomia were invited to participate in the

trial. Each participant tried all 3 products in a randomized

order. The effect of each product was measured using the

Test of Masticating and Swallowing Solids (TOMASS), the

Shortened Xerostomia Inventory (SXI) and a questionnaire

designed to test patient acceptability of each product.

Outcome data were gathered in a single session after the first

administration of each product to evaluate immediate effects

and after 7 days of use to evaluate longer-term effects.

Statistical analyses consisted of repeated-measures analysis

of variance and mixed models. There was no evidence that

application of the 3 formulations had an effect on any of the

TOMASS measures, either immediately or after 1 week of use

(p > 0ꞏ05). There was a significant main effect of formulation

on the SXI score (p = 0ꞏ02). Application of the novel emulsion

resulted in a clinically small but significant improvement in SXI

score (p < 0ꞏ01); however, application of methylcellulose (p =

0ꞏ21) and water (p = 0ꞏ81) resulted in no significant

difference. There was no difference in participant acceptability

between the 3 products (p = 0ꞏ32). The novel oily emulsion

showed no clinically significant benefit over 2 existing products

for relief of xerostomia; in fact, none of the 3e products

demonstrated significant change in patient outcomes.

In a double-blind, randomized, controlled study, Cifuentes and

colleagues (2018) compared the efficacy of pilocarpine and

artificial saliva as symptomatic treatments for xerostomia and

xerophthalmia in patients with Sjogren's Syndrome (SS). A

total of 72 patients with SS were assigned randomly to receive

10 drops of pilocarpine (5 mg) or 10 drops of artificial saliva,


4/27/2021 https://aetnet.aetna.com/mpa/cpb/300_399/0302.html

orally, t.i.d. for 12 weeks. Patients were evaluated at baseline

and periodically throughout the study by whole saliva and tear

flow for global assessment of their dryness as well as for any

adverse effects. Patients receiving pilocarpine had a

statistically significant improvement in their salivary flow (p <

0.0001), lachrymal flow (p < 0.0001), and their subjective

global assessment (p < 0.0001), compared with patients on

artificial saliva. The most common side effects were sialorrhea

and nausea. The authors concluded that pilocarpine was

more effective than artificial saliva for enhancing salivary and

lachrymal secretion in patients with SS. They noted that this

was the first study comparing the efficacy of pilocarpine and

artificial saliva as treatments for xerostomia and xerophthalmia

in SS.

In a systematic review, Assery (2019) provided an update on

artificial saliva used to maintain the health of the oral cavity of

patients with severe hypo-salivation. A literature search was

conducted in April 2018 in 3 electronic databases (the

Cochrane Central Register of Controlled Trials [CENTRAL],

PubMed, and Embase) by combining key words and terms

related to the population and intervention of the topic. The

databases search resulted in 455 titles and abstracts. Of

these, 21 were judged to meet inclusion criteria and full texts

were read. Finally, 10 clinical trials were included for

qualitative synthesis. The author concluded that published

evidence suggested that all the artificial saliva products tested

in included studies reduced symptoms of xerostomia. These

products should specifically be selected according to the

patients' concerns and needs. However, the included studies

presented a wide range of products and suffered from high risk

of bias. Thus, the author stated that long-term RCTs on

effects of various products conducted according to

Consolidated Standards of Reporting Trials (CONSORT)

statements with large sample size are needed to reach an

unbiased conclusion.

Low-Level Laser Therapy

https://aetnet.aetna.com/mpa/cpb/300_399/0302.html



In a randomized trial, Fidelix and associates (2018) evaluated

the effectiveness of low-level laser therapy (LLLT) in the

treatment of xerostomia in primary SS. Patients with dry

mouth symptoms associated with primary SS receiving care at

a university hospital were eligible for enrollment in the study.

A total of 66 patients were randomly assigned with a 1:1

allocation ratio to receive LLLT (laser group, n = 33) or

placebo treatment (placebo group, n = 33). Patients in the

laser group received LLLT twice-weekly for 6 weeks, for a total

of 12 treatment sessions. Laser irradiation was performed with

an aluminum-gallium-arsenide laser diode at a wavelength of

808 nm, 100-mW output power, and energy density of 4.0

J/cm2 per irradiation point per session. Placebo treatment

was performed following the same protocol used for irradiated

patients and using the same laser device to mimic a real

irradiation, but with no active laser emission and the tip of the

laser probe covered with aluminum foil. The outcomes of

interest were xerostomia inventory scores, salivary flow rate,

salivary beta-2 microglobulin levels, and salivary sodium and

chlorine concentrations. Patients in both groups showed no

improvement in xerostomia. Likewise, there was no significant

improvement in xerostomia inventory scores (p = 0.301) or

salivary flow rate (p = 0.643) in either group. There was no

difference in salivary beta-2 microglobulin levels, sodium

concentration, and chlorine concentration before and after

intervention or between the 2 groups. The authors concluded

that the LLLT protocol used in this study effected no

improvement in xerostomia or salivary flow rate in patients with

primary SS.

Transcutaneous Electrical Nerve Stimulation (TENS)

Sivaramakrishnan and Sridharan (2017) stated that the use of

transcutaneous electrical nerve stimulation (TENS) has been

contemplated on by various researchers for treatment of

xerostomia. These researchers performed a systematic

compilation and quantitative synthesis of the existing evidence

related to the utility of TENS in patients with xerostomia. A




total of 6 RCTs were identified from databases for inclusion

and analyzed using non-Cochrane mode in RevMan 5.0

software. The heterogeneity between the studies were

assessed using Forest plot, I2 statistics wherein more than 50

% was considered to have moderate-to-severe heterogeneity

and Chi-square test with a statistical p-value of less than 0.10

to indicate statistical significance. Results show that the effect

of TENS on salivary flow rate in 369 participants with SMD [95

% CI] was 0.63 [-0.03 to 1.29] and was not statistically

significant. The authors concluded that the available evidence

did not support the use of TENS in patients with xerostomia

and may be considered as a salivary substitute for

symptomatic improvement. However the type, frequency and

amplitude of current used needs to be studied in detail. They

stated that high quality RCTs with adequate power are

needed, either to support or refute the use of TENS in

xerostomia.

Experimental and Investigational Interventions for the Treatment of Xerostomia

Ferraiolo and Veitz-Keenan (2018) reviewed the evidence

regarding various interventions to prevent dry mouth and

salivary gland dysfunction following head and neck

radiotherapy. Data sources included Cochrane Oral Health's

Trials Register, the Cochrane Central Register of Controlled

Trials (CENTRAL), Medline, Embase, CINAHL, EBSCO

(Cumulative Index to Nursing and Allied Health Literature,

LILACS, BIREME, Virtual Health Library (Latin American and

Caribbean Health Science Information database), Zetoc

Conference Proceedings, the US National Institutes of Health

(NIH) Ongoing Trials Register, (ClinicalTrials.gov) and the

World Health Organization (WHO) International Clinical Trials

Registry Platform for ongoing trials. No restrictions were

placed on the language or date of publication when searching

the electronic databases. The review included RCTs,

irrespective of their language of publication or publication

status. Subjects could be out-patients or in-patients. The


http://ClinicalTrials.gov



review included trials comparing any pharmacological agent

regimen, prescribed prophylactically for salivary gland

dysfunction before or during radiotherapy, with placebo, no

intervention or an alternative pharmacological intervention.

Comparisons of radiation techniques were excluded.

Standard Cochrane methodological processes were followed.

A total of 39 studies that randomized 3,520 participants were

included; the number of participants analyzed varied by

outcome and time-point. The studies were ordered into 14

separate comparisons with meta-analysis only being possible

in 3 of these. These investigators found low-quality evidence

to show that amifostine, when compared to a placebo or no

treatment control, might reduce the risk of moderate-to-severe

xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of

radiotherapy (risk ratio (RR) 0.35, 95 % CI: 0.19 to 0.67; p =

0.001, 3 studies, 119 participants), and up to 3 months after

radiotherapy (RR 0.66, 95 % CI: 0.48 to 0.92; p = 0.01, 5

studies, 687 participants), but there was insufficient evidence

that the effect was sustained up to 12 months following

radiotherapy (RR 0.70, 95 % CI: 0.40 to 1.23; p = 0.21, 7

studies, 682 participants). These researchers found very low-

quality evidence that amifostine increased unstimulated

salivary flow rate up to 12 months after radiotherapy, both in

terms of mg of saliva/5 mins (MD 0.32, 95 % CI: 0.09 to 0.55;

p = 0.006, 1 study, 27 participants), and incidence of

producing greater than 0.1 g of saliva over 5 mins (RR 1.45,

95 % CI: 1.13 to 1.86; p = 0.004, 1 study, 175 participants).

However, there was insufficient evidence to show a difference

when looking at stimulated salivary flow rates. There was

insufficient (very low-quality) evidence to show that amifostine

compromised the effects of cancer treatment when looking at

survival measures. There was some very low-quality evidence

of a small benefit for amifostine in terms of QOL (10-point

scale) at 12 months after radiotherapy (MD 0.70, 95 % CI: 0.20

to 1.20; p = 0.006, 1 study, 180 participants), but insufficient

evidence at the end of and up to 3-month post-radiotherapy. A

further study showed no evidence of a difference at 6-, 12-,

18- and 24-month post-radiotherapy. There was low-quality




evidence that amifostine was associated with increases in:

vomiting (RR 4.90, 95 % CI: 2.87 to 8.38; p < 0.00001, 5

studies, 601 participants); hypotension (RR 9.20, 95 % CI:

2.84 to 29.83; p = 0.0002, 3 studies, 376 participants); nausea

(RR 2.60, 95 % CI: 1.81 to 3.74; p < 0.00001, 4 studies, 556

participants); and allergic response (RR 7.51, 95 % CI: 1.40 to

40.39; p = 0.02, 3 studies, 524 participants). The authors

founded insufficient evidence (that was of very low-quality) to

determine whether or not pilocarpine performed better or

worse than a placebo or no treatment control for the

outcomes: xerostomia, salivary flow rate, survival and QOL.

There was some low-quality evidence that pilocarpine was

associated with an increase in sweating (RR 2.98, 95 % CI:

1.43 to 6.22; p = 0.004, 5 studies, 389 participants). The

authors found insufficient evidence to determine whether or

not palifermin performed better or worse than placebo for:

xerostomia (low-quality); survival (moderate-quality); and any

adverse events (AEs). There was also insufficient evidence to

determine the effects of the following interventions: biperiden

plus pilocarpine, Chinese medicines, bethanechol, artificial

saliva, selenium, antiseptic mouth rinse, anti-microbial

lozenge, polaprezinc, azulene rinse and Venalot Depot

(coumarin plus troxerutin). The authors concluded that there

was some low-quality evidence to suggest that amifostine

prevented the feeling of dry mouth in individuals receiving

radiotherapy to the head and neck (with or without

chemotherapy) in the short- (end of radiotherapy) to medium-

term (3-month post-radiotherapy). However, it was less clear

whether or not this effect is sustained to 12-month post-

radiotherapy. The benefits of amifostine should be weighed

against its high cost and side effects. There was insufficient

evidence to show that any other intervention is beneficial.

In a randomized, placebo-controlled, phase-I/Ii clinical trial,

Gronhoj and co-workers (2018) examined the safety and

efficacy of adipose tissue-derived mesenchymal stem cell

(ASC) therapy for radiation-induced xerostomia. This trial

included 30 patients, randomized in a 1:1 ratio to receive




ultrasound (US)-guided transplantation of ASCs or placebo to

the submandibular glands. Patients had previously received

radiotherapy for a T1-2, N0-2A, human papillomavirus (HPV)

-positive, oropharyngeal squamous cell carcinoma (SCC). The

primary outcome was the change in unstimulated whole

salivary flow rate, measured before and after the intervention.

All assessments were performed 1 month prior (baseline) and

1 and 4 months following ASC or placebo administration. No

AEs were detected. Unstimulated whole salivary flow rates

significantly increased in the ASC-arm at 1 month (33 %; p =

0.048) and 4 months (50 %; p = 0.003), but not in the placebo-

arm (p = 0.6, and p = 0.8), compared to baseline. The ASC-

arm symptom scores significantly decreased on the

xerostomia and VAS questionnaires, in the domains of thirst

(-22 %, p = 0.035) and difficulties in eating solid foods (-2 %, p

= 0.008) after 4 months compared to baseline. The ASC-arm

showed significantly improved salivary gland functions of

inorganic element secretion and absorption, at baseline and 4

months, compared to the placebo-arm. Core-needle biopsies

showed increases in serous gland tissue and decreases in

adipose and connective tissues in the ASC-arm compared to

the placebo-arm (p = 0.04 and p = 0.02, respectively); MRIs

showed no significant differences between groups in gland

size or intensity (p < 0.05). The authors concluded that ASC

therapy for radiation-induced hypofunction and xerostomia

was safe and significantly improved salivary gland functions

and patient-reported outcomes. They stated that these

findings should encourage further exploratory and confirmatory

trials.

In a randomized, double-blind clinical trial, Lee and associates

(2019) examined if pre-treatment with amifostine reduced the

incidence of RTOG grade greater than or equal to 2 acute and

late xerostomia in patients receiving definitive or adjuvant

radiotherapy for head and neck squamous cell carcinoma

(HNSCC), without reducing tumor control or survival. Between

September 14, 2001 and November 8, 2004, a total of 44

Royal Adelaide Hospital patients were randomized to receive




amifostine (200 mg/m2 IV) or placebo (normal saline IV) for 5

days/week, prior to standard radiotherapy (60 to 70 Gy), each

having greater than or equal to 75 % of the parotids treated to

greater than or equal to 40 Gy. Side effects were assessed

weekly during treatment, at 3 and 5 months after radiotherapy,

then every 6 months until disease progression or death. The

accrual target was 200 patients over 4 to 5 years, but the trial

closed prematurely when only 44 patients had been

randomized after 3 years. Of 41 evaluable patients, 80 %

(16/20) in the amifostine arm had grade greater than or equal

to 2 acute radiation salivary toxicity versus 76 % (16/21) in the

placebo arm (p = 1.00). The rate of grade greater than or

equal to 2 late radiation salivary toxicity at 12 months was 66

% in the amifostine arm and 82 % in the placebo arm

(estimated hazard ratio [HR] 1.61, 95 % CI: 0.74 to 3.49, p =

0.22). Other toxicities tended to be worse in the amifostine

arm: acute grade 3 to 4 skin 35 % versus 5 % and mucous

membrane 40 % versus 5 %; grade greater than or equal to 2

vomiting 35 % versus 5 %, hypocalcaemia 25 % versus 5 %

and fatigue 85 % versus 33 %, with only the latter retaining

statistical significance after adjusting for multiple comparisons.

There were no significant differences in failure-free (p = 0.70)

or overall survival (OS) (p = 0.86), with estimated 4-year rates

of 48 % versus 54 % and 49 % versus 59 % for the amifostine

versus placebo arms, respectively. The authors concluded

that there was no clear evidence that pre-treatment with

amifostine made any difference to the incidence of grade

greater than or equal to 2 acute or late xerostomia. Other

toxicity tended to be more severe with amifostine. There was

no effect on failure-free or OS. These researchers noted that

acknowledging the low statistical power, these results did not

support the use of intravenous amifostine pre-radiotherapy in

HNSCC.

Ma and colleagues (2019) noted that xerostomia is a

significant problem affecting QOL in patients treated with

radiation therapy for head and neck cancer. Strategies for

reduction of xerostomia burden vary widely, with options




including: sialagogue medications, saliva substitutes,

acupuncture, vitamins, hyperbaric oxygen, submandibular

gland transfer, and acupuncture or associated treatments.

These investigators evaluated long-term outcomes of patients

treated with various interventions for radiation-induced

xerostomia. They carried out a literature search using the

terms "xerostomia" and "radiation" or "radiotherapy"; all

prospective clinical trials were evaluated, and only studies that

reported 1 year follow-up were included. The search results

yielded 2,193 studies, 1,977 of which were in English. Of

those, 304 were clinical trials or clinical studies. After abstract

review, a total of 23 trials were included in the review

evaluating the following treatment modalities: pilocarpine (n =

3); cevimeline (n= 1); amifostine (n = 11); submandibular gland

transfer (n = 5); acupuncture like transcutaneous electrical

nerve stimulation (ALTENS) (n = 1); hyperbaric oxygen (n = 1);

and acupuncture (n = 1). Pilocarpine, cevimeline, and

amifostine had been shown in some studies to improve

xerostomia outcomes, at the cost of toxicity; ALTENS had

similar efficacy with fewer side effects. Submandibular gland

transfer was effective but needed an elective surgery, and thus

may not always be appropriate or practical. The authors

stated that the use of intensity-modulated radiation therapy

(OMRT), in addition to dose de-escalation in select patients,

may result in fewer patients with late xerostomia, reducing the

need for additional interventions.

An UpToDate review on "Management and prevention of

complications during initial treatment of head and neck

cancer" (Galloway and Amdur, 2019a) states that "Amifostine

is an organic thiophosphate that is thought to act by donating a

protective thiol group that is a scavenger of free radicals

generated in tissues exposed to radiation. Amifostine is the

only pharmacologic agent with established efficacy in the

prevention of xerostomia. Its role in patient management is

uncertain ... Currently, the routine use of amifostine in patients

receiving modern combined modality chemoradiation is not

justified … Surgical transfer of the submandibular salivary




gland from an uninvolved hemi-neck to the submental space

prior to radiation can be useful to maintain saliva production in

carefully selected patients. Although a small prospective multi-

institutional trial has demonstrated the reproducibility of this

technique, it is currently practiced only at select centers. The

reasons for the limited use of this technique seem to be

3- fold: It requires an elective operation on the contralateral

neck that includes a level I-III dissection that could be

construed as an intensification of therapy. It has never been

tested against modern (i.e., submandibular and oral cavity

sparing) IMRT, an intervention that does not require an

additional operation. There is no billing code for the

procedure, potentially discouraging head and neck surgeons".

Furthermore, an UpToDate review on "Management of late


treatment" (Galloway and Amdur, 2019b) states that

"Commercially available salivary substitutes or artificial saliva

(oral rinses containing hyetellose, hyprolose, or carmellose)

relieve the discomfort of xerostomia by wetting the oral

mucosa. Although these agents may provide temporary relief,

many patients need frequent sips of water to remain

comfortable. In addition to being inconvenient, this can lead to

secondary problems, such as nocturia from late night fluid

intake in men with prostatic hypertrophy and in men and

women with small bladder capacity … Preliminary evidence

suggests that hyperbaric oxygen may have a beneficial effect

on xerostomia, but these results must be confirmed on a larger

scale before such therapy can be recommended. As an

example, a pilot study evaluated the salivary effects of

hyperbaric oxygen in a group of 80 patients, 45 of whom had

hypo-salivation. Patient self-assessment of xerostomia, and

unstimulated and stimulated whole saliva flow rates all

increased after 30 sessions of hyperbaric oxygen".



CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

CPT codes not covered for indications listed in the CPB:

15769 Grafting of autologous soft tissue, other,

harvested by direct excision (eg, fat, dermis,

fascia)

15773 Grafting of autologous fat harvested by

liposuction technique to face, eyelids, mouth,

neck, ears, orbits, genitalia, hands, and/or feet;

25 cc or less injectate

+15774 each additional 25 cc injectate, or part

thereof (List separately in addition to code for

primary procedure)

97810 -

97814

Acupuncture

99183 Physician or other qualified health care

professional attendance and supervision of

hyperbaric oxygen therapy, per session

HCPCS codes not covered for indications listed in the CPB:

E0755 Electronic salivary reflex stimulator

(intraoral/noninvasive)

G0277 Hyperbaric oxygen under pressure, full body

chamber, per 30 minute interval

S8948 Application of a modality (requiring constant

provider attendance) to one or more areas; low-

level laser; each 15 minutes

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):



Code Code Description

K02.3 -

K02.9

K03.89

Dental caries and other specified diseases of

hard tissues of teeth

K11.7 Disturbance of salivary secretion (xerostomia)

K12.1

K13.1

K13.4

K13.6 -

K13.79

Other and unspecified diseases of oral soft

tissues

M35.00 -

M35.09

Sicca syndrome [Sjögren]

R13.10 -

R13.19

Dysphagia

R68.2 Dry mouth, unspecified

T66.xx+ Effects of radiation, unspecified [radiation-

induced xerostomia]

Z92.3 Personal history of irradiation



The above policy is based on the following references:

1. Abughanam G, Elkashty OA, Liu Y, et al. Mesenchymal

stem cells extract (MSCsE)-based therapy alleviates

xerostomia and keratoconjunctivitis sicca in Sjogren's

syndrome-like disease. Int J Mol Sci. 2019;20(19).

2. Ami S, Wolff A. Implant-supported electrostimulating

device to treat xerostomia: A preliminary study. Clin

Implant Dent Relat Res. 2010;12(1):62-71.

3. Apperley O, Medlicott N, Rich A, et al. A clinical trial of

a novel emulsion for potential use as a saliva




substitute in patients with radiation-induced

xerostomia. J Oral Rehabil. 2017;44(11):889-895.

4. Assery MKA. Efficacy of Artificial salivary substitutes in

treatment of xerostomia: A systematic review. J Pharm

Bioallied Sci. 2019;11(Suppl 1):S1-S12.

5. Assy Z, Brand HS. A systematic review of the effects of

acupuncture on xerostomia and hyposalivation. BMC

Complement Altern Med. 2018;18(1):57.

6. Baer AN. Treatment of dry mouth and other non-

ocular sicca symptoms in Sjögren's syndrome.

UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed December 2016.

7. Bakarman EO, Keenan AV. Limited evidence for non-

pharmacological interventions for the relief of dry

mouth. Evid Based Dent. 2014;15(1):25-26.

8. Cifuentes M, Del Barrio-Díaz P, Vera-Kellet C.

Pilocarpine and artificial saliva for the treatment of

xerostomia and xerophthalmia of Sjogren's syndrome:

A double blind control trial. Br J Dermatol. 2018;179

(5):1056-1061.

9. Cooke C. Xerostomia -- A review. Palliative Med.

1996;10(4):284-292.

10. Davies AN. The management of xerostomia: A review.

Eur J Cancer Care. 1997;6(3):209-214.

11. Erlichman M. Salivary electrostimulation in Sjogren's

syndrome. AHCPR Health Technology Assessment

Report No. 8. AHCPR Pub. No. 91-0009. Rockville, MD:

Agency for Health Care Policy and Research (AHCPR);

March 1991.

12. Fedele S, Wolff A, Strietzel FP, et al. Electrostimulation

for the treatment of dry mouth. Harefuah. 2010;149

(2):99-103, 123.

13. Ferraiolo DM, Veitz-Keenan A. Insufficient evidence for

interventions to prevent dry mouth and salivary gland

dysfunction post head and neck radiotherapy. Evid

Based Dent. 2018;19(1):30-31.




14. Fidelix T, Czapkowski A, Azjen S, et al. Low-level laser

therapy for xerostomia in primary Sjögren's syndrome:

A randomized trial. Clin Rheumatol. 2018;37(3):729-

736.

15. Fox PC. Management of dry mouth. Dent Clin North

Am. 1997;41(4):863-875.

16. Fox RI. Sjogren's syndrome: Evolving therapies. Expert

Opin Investig Drugs. 2003;12(2):247-254.

17. Furness S, Bryan G, McMillan R, et al. Interventions for

the management of dry mouth: Non-pharmacological

interventions. Cochrane Database Syst Rev.

2013;9:CD009603.

18.

Galloway T, Amdur RJ. Management and prevention of

complications during initial treatment of head and

neck cancer. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed January 2019a.

19. Galloway T, Amdur RJ. Management of late


treatment. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed January 2016.

20.

Galloway T, Amdur RJ. Management of late


treatment. UpToDate [online serial]. Waltham, MA:

UpToDate; reviewed January 2019b.

21. Garcia MK, Meng Z, Rosenthal DI, et al. Effect of true

and sham acupuncture on radiation-induced

xerostomia among patients with head and neck

cancer: A randomized clinical trial. JAMA Netw Open.

2019;2(12):e1916910.

22. Gil-Montoya JA, Silvestre FJ, Barrios R, Silvestre-Rangil J.

Treatment of xerostomia and hyposalivation in the

elderly: A systematic review. Med Oral Patol Oral Cir

Bucal. 2016;21(3):e355-e366.

23. Gronhoj C, Jensen DH, Vester-Glowinski P, et al. Safety

and efficacy of mesenchymal stem cells for radiation-

induced xerostomia: A randomized, placebo-controlled




phase 1/2 trial (MESRIX). Int J Radiat Oncol Biol Phys.

2018;101(3):581-592.

24. Kawakami M, Ishikawa H, Tanaka A, Mataga I.

Induction and differentiation of adipose-derived stem

cells from human buccal fat pads into salivary gland

cells. Hum Cell. 2016;29(3):101-110.

25. Lakshman AR, Babu GS, Rao S. Evaluation of effect of

transcutaneous electrical nerve stimulation on salivary

flow rate in radiation induced xerostomia patients: A

pilot study. J Cancer Res Ther. 2015;11(1):229-233.

26. Lee MG, Freeman AR, Roos DE, et al. Randomized

double-blind trial of amifostine versus placebo for

radiation-induced xerostomia in patients with head

and neck cancer. J Med Imaging Radiat Oncol. 2019;63

(1):142-150.

27. Lopez-Pintor RM, Ramírez L, Serrano J, et al. Effects of

Xerostom® products on xerostomia in primary

Sjögren's syndrome: A randomized clinical trial. Oral

Dis. 2019;25(3):772-780.

28. Ma SJ, Rivers CI, Serra LM, Singh AK. "Management of

late complications of head and neck cancer and its

treatment;" Long-term outcomes of interventions for

radiation-induced xerostomia: A review. World J Clin

Oncol. 2019;10(1):1-13.

29. Mariette X. Current and potential treatments for

primary Sjogren's syndrome. Joint Bone Spine. 2002;69

(4):363-366.

30. Riley P, Glenny AM, Hua F, Worthington HV.

Pharmacological interventions for preventing dry

mouth and salivary gland dysfunction following

radiotherapy. Cochrane Database Syst Rev.

2017;7:CD012744.

31. Sivaramakrishnan G, Sridharan K. Electrical nerve

stimulation for xerostomia: A meta-analysis of

randomised controlled trials. J Tradit Complement

Med. 2017;7(4):409-413.




32. Steller M, Chou L, Daniels TE. Electrical stimulation of

salivary flow in patients with Sjogren's syndrome. J

Dental Res. 1988;67(10):1334-1337.

33. Strietzel FP, Lafaurie GI, Mendoza GR, et al. Efficacy

and safety of an intraoral electrostimulation device for

xerostomia relief: A multicenter, randomized trial.

Arthritis Rheum. 2011;63(1):180-190.

34. Strietzel FP, Martín-Granizo R, Fedele S, et al.

Electrostimulating device in the management of

xerostomia. Oral Dis. 2007;13(2):206-213.

35. Talal N, Quinn JH, Daniels TE. The clinical effects of

electrostimulation on salivary function of Sjogren's

syndrome patients. Rheumatol Int. 1992;12(2):43-45.

36. Vijayan A, Asha ML, Babu S, Chakraborty S. Prospective

phase II study of the efficacy of transcutaneous

electrical nerve stimulation in post-radiation patients.

Clin Oncol (R Coll Radiol). 2014;26(12):743-747.

37. Weiss WW Jr, Brenman HS, Katz P, Bennett JA. Use of

electronic stimulation for the treatment of dry mouth.

J Oral Maxillofacial Surg. 1986;44(11):845-850.

38. Wong RK, Deshmukh S, Wyatt G, et al. Acupuncture-

like transcutaneous electrical nerve stimulation versus

pilocarpine in treating radiation-induced xerostomia:

Results of RTOG 0537 Phase 3 Study. Int J Radiat Oncol

Biol Phys. 2015;92(2):220-227.

39. Wong RK, James JL, Sagar S, et al. Phase 2 results from

Radiation Therapy Oncology Group Study 0537: A

phase 2/3 study comparing acupuncture-like

transcutaneous electrical nerve stimulation versus

pilocarpine in treating early radiation-induced

xerostomia. Cancer. 2012;118(17):4244-4252.

40. Wong RK, Sagar SM, Chen BJ, et al. Phase II

randomized trial of acupuncture-like transcutaneous

electrical nerve stimulation to prevent radiation-

induced xerostomia in head and neck cancer patients.

J Soc Integr Oncol. 2010;8(2):35-42.




41. Wu X, Chung VCh, Hui EP, et al. Effectiveness of

acupuncture and related therapies for palliative care

of cancer: Overview of systematic reviews. Sci Rep.

2015;5:16776.

42. Zadik Y, Zeevi I, Luboshitz-Shon N, et al. Safety and

efficacy of an intra-oral electrostimulator for the relief

of dry mouth in patients with chronic graft versus host

disease: Case series. Med Oral Patol Oral Cir Bucal.

2014;19(3):e212-e219.



Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors

in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely

responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is

subject to change.

Copyright © 2001-2021 Aetna Inc.

https://aetnet.aetna.com/mpa/cpb/300_399/0302.html 4/27/2021


AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0302 Xerostomia:

Selected Treatments

There are no amendments for Medicaid.

annual 05/01/2021

Xerostomia: Selected Treatments

Documents

Transcript of Xerostomia: Selected Treatments