xerostomia: selected treatments
TRANSCRIPT
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 1 of 36
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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).
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 2 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 3 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 4 of 36
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.
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 5 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 6 of 36
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.
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 7 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 8 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 9 of 36
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,
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 10 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 11 of 36
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.
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 12 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 13 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 14 of 36
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 15 of 36
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-
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 16 of 36
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
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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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 18 of 36
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
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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,
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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
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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
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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
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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
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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
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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
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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
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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
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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
complications of head and neck cancer and its
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".
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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):
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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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 30 of 36
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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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 31 of 36
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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.
4/27/2021 https://aetnet.aetna.com/mpa/cpb/300_399/0302.html
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 32 of 36
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
complications of head and neck cancer and its
treatment. UpToDate [online serial]. Waltham, MA:
UpToDate; reviewed January 2016.
20.
Galloway T, Amdur RJ. Management of late
complications of head and neck cancer and its
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
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 33 of 36
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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.
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 34 of 36
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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.
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Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 35 of 36
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.
Xerostomia: Selected Treatments - Medical Clinical Policy Bulletins | Aetna Page 36 of 36
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