Head and neck
carcinoma (HNC) is the sixth most common
cancer worldwide, accounting for 2.8% of all
malignancies. In 2006, an estimated 39,250
Americans will develop HNC, and 11,090
deaths will occur. Radiotherapy (RT) and
surgery are the main treatment modalities,
although there is an increasing role for
chemotherapy. The choice of modality depends
on patient factors, primary site, clinical
stage, and resectability of the tumor.
Approximately 30% to 40% of patients present
with early-stage disease that is amendable
to curative surgery or RT. More than 50% of
patients present with locoregionally
advanced disease at diagnosis. These
patients can be treated with complete
surgical excision followed by postoperative
RT or with concomitant chemoradiotherapy.
Despite this aggressive bimodality treatment
approach, patients have a poor prognosis,
with 5-year survival rates of 30% to 40%.
RT for
definitive treatment of HNC is
conventionally given in daily fractions of
1.8 grays (Gy) to 2.0 Gy, up to total doses
of 66 Gy to 70 Gy over 6 or 7 weeks. Recent
evidence suggests that alterations in the
fractionation schedule as well as
concomitant chemotherapy may improve results
significantly.RT of the head and neck region
causes
both
acute and long-term complications
because of adverse effects on normal tissue.
Frequently seen acute side-effects are
mucositis, dysphagia, hoarseness, erythema,
and desquamation of the skin. Effective
management of these complications is
important, because they may interfere with
compliance or cause treatment delays,
resulting in loss of tumor control. Late
complications are chiefly the results of
chronic injury to vasculature, salivary
glands, mucosa, connective tissue, and bone.
The type and severity of these changes are
related directly to radiation dosimetry,
including total dose, fraction size, and
duration of the treatment. Possible late
sequelae include osteonecrosis, subcutaneous
fibrosis, trismus, taste loss, thyroid
dysfunction, esophageal stenosis,
hoarseness, dental decay, and damage to the
middle or inner ear.
Xerostomia is the most prominent
complication in patients with HNC,
because RT usually involves administering a
high radiation dose to the salivary glands
bilaterally. In 1 survey, investigators
observed that
64%
of long-term survivors (at least 3
years after conventional RT) experienced a
moderate to severe degree of xerostomia.
Radiation-induced damage to the salivary
glands alters the volume, consistency, and
pH of secreted saliva. Saliva changes from
thin secretions with a neutral pH to thick,
tenacious secretions with increased acidity.
Patients suffer from oral discomfort or
pain; find it difficult to speak, chew, or
swallow; and run an increased risk of dental
caries or oral infection. Ultimately, this
can lead to decreased nutritional intake and
weight loss. Xerostomia not only
significantly reduces quality of life (QoL)
for many patients who are potentially cured
from their cancer but also poses a major new
health problem for them.
Radiation-induced xerostomia
starts early during treatment: in the first
week, a 50% to 60% decrease in salivary flow
occurs; and, after 7 weeks of conventional
RT, salivary flow diminishes to
approximately 20%. In 1911, the
French radiobiologist Jean Bergonie
described this apparent radiosensitivity of
the salivary glands as an enigma. This is
because the functional (ie, excretory,
acinar) cells of the salivary glands are
highly differentiated and have a slow
turnover, but they behave like acute
responding tissues to radiation.
Classically, of course, tissues with a slow
mitotic rate should not be particularly
radiosensitive.
The first
explicatory concept that was suggested was
the so-called granulation hypothesis: the
membranes of secreting granules in acinar
cells become damaged by radiation-induced
lipid peroxidation, and, consequently,
proteolytic enzymes begin to leak from these
granules, causing immediate lysis of the
cells. However, a clinical study using
salivary gland scintigraphy (SGS) early
after RT showed that trapping of technetium-pertechnetate
was not affected, although saliva excretion
was reduced severely. This finding
seemed to indicate that the gland volume
remains intact, while the excretory function
is impaired, which brings into question
whether massive cell loss is the cause of
early loss of function.
Apparently,
saliva-producing cells do not disappear but
lose their function during the first days
after irradiation. Konings et al proposed 2
separate mechanisms to explain
radiation-induced salivary gland
dysfunction. First, there is a defect in
cellular functioning because of selective
membrane damage, confounding the
receptor-mediated signaling pathways of
water excretion. No immediate cell death or
lysis takes place. Late damage is explained
by classical cell killing of progenitor
cells and stem cells, thus inhibiting proper
cell renewal, and by damage to the cellular
environment, causing a shortage of properly
functioning secretory cells.
Salivary function continues to decline for
up to several months after RT.
Thereafter, some recovery is possible until
12 to 18 months after RT, depending on the
dose received by the salivary glands and the
volume of the gland tissue included
in the irradiation fields; however,
generally, xerostomia develops into an
irreversible, life-long problem.
Recently, Braam and colleagues reported that
salivary output could still recover many
years after RT, with an approximately 32%
increase in salivary flow from 1 year to 5
years after treatment. This is by no
means generally accepted, and most
longitudinal studies found very little
recovery over time in patients who did not
receive some sort of salivary gland-sparing
radiation technique.Although altered
fractionation schedules are increasingly
used, it is not yet clear what impact this
will have on the incidence of xerostomia.
There is evidence to suggest that, when
multiple daily treatments are given in small
fractions (<1.8-2 Gy), this does not
increase the incidence of xerostomia,
although more aggressive regimens can
exacerbate late toxicity, including
xerostomia.
Measuring and
reporting the severity of xerostomia are not
straightforward. However, standardized
measurements are necessary to compare the
efficacy of preventive or curative
interventions. Generally, both objective
methods, such as salivary flow measurements,
SGS, or magnetic resonance imaging (MRI),
and subjective measurements with
observer-based toxicity grading or patient
self-reported scoring are used. It is not
clear which method reflects most accurately
the impact of xerostomia on patient well
being and health.
Measurements
of salivary flow rate are currently the most
commonly applied objective measures of
salivary gland function. In healthy
individuals, the salivary glands produce
between 1 L and 1.5 L of saliva per day.
The
major glands (parotid, submandibular, and
sublingual) produce up to 90% of saliva.
Typically, approximately 60% to 65% of the
total salivary volume is produced by the
parotid glands, from 20% to 30% is produced
by the submandibular glands, and from 2% to
5% by the sublingual glands. The
minor glands are distributed throughout the
oral cavity and pharynx, and their number is
variable.
Usually,
saliva is collected selectively from each
major gland: the output from the parotid
gland is measured by placing a suction cup (Lashley
cup) at the orifice of the Stensen duct; for
the submandibular and sublingual glands,
gentle suction with a micropipette at the
orifices of the Wharton duct is necessary.
Collection can be either unstimulated or
stimulated (eg, with 2% citric acid or by
chewing). Saliva production by all of the
glands collectively can be measured by
spitting, drainage, or weighing cotton rolls
inserted into the mouth. However,
results are not always comparable between
studies because of differences in the nature
and length of application of stimulants,
differences in the method and duration of
collection, and neglect of other factors
that may affect salivary output. There is
also a weak correlation between salivary
flow measurements and xerostomia symptom
scores, probably caused by the variation in
normal salivary flow rates and discrepancies
between the salivary output and the
hydration status of the mucosa. This
seriously impedes the definition of a
threshold of saliva output with which to
characterize xerostomia. Arbitrarily, a
reduction of salivary flow to
25% of the pre-RT
flow is considered a relevant threshold.
Several imaging techniques, such as SGS,
also can be used to evaluate the effect of
radiation on salivary gland function.
Scintigraphy is especially useful when
combined with single photon emission
computed tomography (SPECT) because of the
additional spatial information it provides.
The ability of MRI sialography to depict
radiation-induced changes to the salivary
glands and ducts was recently demonstrated.
Another valuable technique is
diffusion-weighted MRI, which can be used to
noninvasively demonstrate functional changes
in the salivary glands and is under
investigation in the post-RT setting at the
Leuven University Hospital.
Observer-based toxicity scoring is generally
based on the Radiation Therapy Oncology
Group (RTOG)/European Organization for
Research and Treatment of Cancer (EORTC)
grading scale. However, because
xerostomia is defined as a symptom, it is
equally important to estimate the subjective
appreciation of oral dryness by the patient.
Several xerostomia questionnaires have been
developed to permit patient self-reporting,
most notably by the University of Michigan.
It has been suggested that this
questionnaire is more accurate in estimating
the severity of xerostomia compared with the
RTOG/EORTC grading system. More recently,
the Late Effects Normal Tissue
(LENT)-Subjective, Objective, Management,
Analytic (SOMA) scoring system offers a
detailed evaluation of xerostomia. The
system is a combination of observer-based
grading of patient-reported degree of mouth
dryness, oral moisture, necessary frequency
of saliva substitutes, and objective
measurement of the salivary flow rate. It
correlates well with patient-reported
xerostomia and may prove to be a valuable
tool for the correct assessment of
xerostomia. The National Cancer Institute
recently developed the Common Toxicity
Criteria (version 3.0) to replace the RTOG
grading system. Its use in the estimation of
RT-induced xerostomia has not yet been
reported.
QoL in
patients who are treated for HNC is
influenced strongly by xerostomia and all of
its ramifications. A survey of 65 patients
who survived for longer than 6 months after
RT found that 91.8% complained of a dry
mouth, 43% had difficulty chewing, 63.1% had
dysphagia, 75.4% had taste loss, 50.8% had
altered speech, 48.5% had difficulty with
dentures, and 38.5% reported increased tooth
decay. Pain was common (58.4%) and
interfered with daily activities in 30.8% of
patients. More than half of the patients
(58.3%) had mood complaints, and 60% had
interference by their physical condition on
their social activities.
Most patients
with xerostomia experience difficulty eating
dry or hard food, which forces them to
adjust their diet, albeit sometimes
unconsciously. Mastication and oral
manipulation of food becomes uncomfortable
or even painful, most patients need frequent
sips of water while they eat, and food gets
stuck in their mouth or throat.
Not only
chewing but also swallowing of food becomes
a problem. A generalized decrease in the
mobility of pharyngeal structures is
demonstrated after RT, with prolonged
pharyngeal transit and a delay of laryngeal
closure. In a study that compared swallowing
function between patients (1 year after they
received RT) and healthy volunteers,
patients showed a significant degree of
abnormality in the bolus transport.
Elevation of the hyoid bone began too late,
and it was held in an elevated position for
too long. Consequently, the upper esophageal
sphincter opened too early relative to the
arrival of the bolus. Other changes included
reduced contact of the base of the tongue to
the pharyngeal wall, restricted laryngeal
motion, and impaired closure of the
laryngeal vestibule and true vocal folds,
resulting in aspiration.
When oral and
pharyngeal mucosa is exposed to radiation,
taste receptors become damaged, and taste
discrimination increasingly becomes
compromised. Decreased saliva output may
affect taste, often contributing to the slow
return of taste perception after RT. This is
most pronounced after 2 months, when bitter
and salt qualities generally are impaired
the most. Although gradual recovery of taste
is observed during the first year, partial
loss still persists from 1 to 2 years after
treatment.
Difficulty
with speech is another common complaint of
patients who have radiation-induced
xerostomia. Even after 5 years, patients
still report self-perceived speech problems,
difficulty being understood, and diminished
intelligibility.
The risk of
dental caries increases secondary to a
number of factors, including shifts to a
cariogenic flora (eg, increased colonization
with Streptococcus mutans and
Lactobacillus), reduction of the salivary
pH, altered immunoglobulin composition, and
loss of mineralizing components.
The reduction
in salivary flow may also contribute to the
risk of osteonecrosis of the mandible and to
esophageal injury by decreasing acid
clearance by salivary bicarbonate. Dryness
of the oral mucosa creates a predisposition
to mucosal fissures and ulcerations.
These
secondary effects contribute to the
so-called
xerostomia syndrome. In the end, this
combination of factors can result in
decreased nutritional intake and weight
loss, posing a major health problem for some
patients.
Several
agents have been developed to protect normal
tissue against the toxic effect of
radiotherapy and/or chemotherapy. Amifostine
(WR-2721, Ethyol®), which is a spin-off of
the nuclear warfare program, has long been
recognized as a potential radioprotector.
When amifostine enters the bloodstream, it
is rapidly hydrolyzed by alkaline
phosphatases of the endothelium and is
converted to its active form, WR-1065. This
active form enters cells and nuclei, where
it acts as a potent scavenger against free
radicals, thus preventing radiation damage
to DNA. It has been suggested that both the
lack of alkaline phosphatases in the
endothelium and the acidic conditions in the
microenvironment prevent the activation of
amifostine in the tumor, assuring a
selective protection of normal tissues.
However, various preclinical data are
conflicting, and the issue continues to
divide the scientific community.
Conversely,
there is clinical evidence to support the
use of amifostine. The largest study to
date, a Phase III trial by Brizel et al,
randomized 303 patients who received
conventional RT for HNC (both postoperative
and as primary treatment) to receive
amifostine daily before each fraction (200
mg/m[2] intravenously).
Amifostine significantly reduced the
incidence of grade
2 acute
xerostomia from 78% to 51% and reduced the
incidence of grade
2 chronic
xerostomia from 57% to 34% without altering
disease control or survival. The use of
amifostine consequently was approved by the
U.S. Food and Drug Administration (FDA).
Recently, a follow-up to that study was
published, and the results suggested that
the administration of amifostine during RT
reduces the severity of xerostomia until 2
years after treatment. No difference after 2
years was observed in locoregional control
or survival.
To date,
however, no trial has been powered
sufficiently to detect small differences in
survival. A recent meta-analysis tried to
overcome this problem. In that analysis, the
investigators observed that amifostine
significantly reduced the risk of developing
acute grade 2
xerostomia by 76% and the risk of developing
late grade 2
xerostomia by 67% in patients who received
RT. There was no evidence from that
trial that amifostine would weaken the
effectiveness of treatment in any way.
The
use
of amifostine during concomitant chemo-RT is
controversial. No randomized
controlled trial to date has shown that this
may be an indication for the use of
amifostine, so it probably should not be
used outside of a clinical study.
Another
important issue is the toxicity of
amifostine. Nausea and emesis are common
side effects, but they generally are mild
and can be controlled effectively with
standard antiemetic medication. There is a
risk of transient hypotension when
amifostine is administered intravenously
administered, but not when it is
administered subcutaneously.
The extent of
the damage caused by RT depends both on the
volume of tissue that is irradiated and on
the dose of radiation that is delivered.
Therefore, a sound approach to the
prevention of radiation-induced xerostomia
is to focus the radiation beams better to
the target volume and to avoid unnecessary
irradiation of salivary gland tissue.
It has
recently become possible to spare a portion
of the parotid gland by the implementation
of 3-dimensional (3D) conformal RT (3D-CRT)
and intensity-modulated RT (IMRT) techniques
in clinical practice. A high dose is
administered to a small part of the parotid
and is positioned close to the tumor, while
the rest of the gland receives a low dose or
no dose at all. Several centers have started
to use parotid-sparing protocols to prevent
permanent xerostomia. At the Leuven
University Hospital Department of
Radiotherapy, for example, a comparatively
straightforward 3D-CRT technique (without
intensity modulation) has been implemented
in clinical practice since September 1999
with the objective of sparing the parotid
gland contralateral to the tumor. Patients
who received that treatment have gained
partial sparing of the salivary output from
the parotid gland. It is not always possible
to use such techniques: Patients who have
tumors that originate from the midline or
that cross the midline are excluded along
with patients who have evidence of
contralateral neck lymph node metastasis. If
those limitations are respected, then the
use of 3D-CRT or IMRT does not seem to be
associated with an increased risk of tumor
recurrence in the spared area.
The ability
of 3D-CRT and IMRT to produce dose
distributions that allow preservation of
parotid gland tissue and reduction of
xerostomia has been demonstrated abundantly.
There also is evidence that reduction of
xerostomia results in improved QoL. Lin and
colleagues reported that both xerostomia and
QoL scores improved significantly over time
during the first year after IMRT. In a
matched case-control study by Jabbari et al
from the same institution, both xerostomia
and QoL improved over time after IMRT, but
not after conventional RT. The potential
benefits gained from IMRT were reflected
best late after therapy (>6 months).
Data
regarding the doses and irradiated volumes
that permit preservation of the salivary
flow after RT are emerging slowly. Usually,
3D dose distributions in parotid glands are
compared with residual saliva production.
Correlation of dose with salivary flow
measurements allows the production of
dose/volume-response relations for parotid
gland function. It became clear that there
is an exponential relation between saliva
flow reduction and mean parotid dose for
each gland, suggesting that it is essential
to respect a certain threshold for mean
parotid dose to preserve gland function.
A mean gland
dose of 26 Gy
was initially proposed as a planning
objective for substantial sparing of the
gland function by Eisbruch and colleagues
from the University of Michigan. Researchers
from Washington University reported very
similar results: In their analysis, a mean
parotid dose of >25.8 Gy was likely to
reduce salivary flow to 25% of its
pretreatment value, and the incidence of
xerostomia was decreased significantly when
the mean parotid dose of at least 1 gland
was kept 25.8
Gy.Investigators who used SGS to evaluate
parotid function after RT reported similar
results: a mean parotid dose <26 Gy to 30 Gy
allowed preservation of the salivary gland
function.
Gradually, a consensus was formed that a
significant reduction of xerostomia can be
achieved by using a mean parotid dose of <26
Gy to 30 Gy as a planning criterion.
However, the use of a mean dose as a
threshold for the control of normal tissue
tolerance is helpful only when an organ
consists of independent functional units
that are organized in parallel. In such an
organ, irradiation of a small part results
in less loss of function than in an organ
that has a serial anatomic organization. In
the latter case, damage to 1 substructure
disables the entire organ (eg, the spinal
cord). For the healthy parotid gland, it is
generally assumed that a homogenous
distribution of saliva production takes
place over the entire volume.
Some
interesting data with rats, however, show
that late radiation damage after partial
irradiation of the parotid glands may be
region-dependent. This means that partial
irradiation leads to varying late radiation
damage, depending on the region that has
been exposed: Irradiation of the cranial
half resulted in more late damage than
irradiation of the caudal half. It was
suggested that spatial information should be
included in the comparison of different
plans and that the mean dose concept has
limited use for the prediction of late
radiation damage. However thought-provoking
these results may be, the delineation of
anatomic regions within the parotid is
highly theoretical and without a firm
anatomic basis. Similarly, it remains to be
determined whether regional differences in
gland radiosensitivity will prove to be
equally important in humans as they appear
to be in rats.
At the Leuven
University Hospital, a combination of SGS
with SPECT was used to determine the
salivary function of different regions
within the gland after parotid-sparing RT.
Each of the 8 to 12 transverse slices within
the parotid gland was considered as a
functional subunit, and a salivary excretion
fraction (SEF) was measured for each slice.
Before RT, all slices contributed equally; 7
months after an average dose of 22.5 Gy
(D50), the subunit had lost 50% of its SEF.
There was high interpatient variability in
D50, and low doses (10-15 Gy) also could
induce serious loss of function, casting
doubt on the utility of a general, standard,
mean gland dose threshold. Probably, the
mean parotid dose should be kept as low as
possible.
Recently,
Saarilathi et al were the first to
demonstrate that sparing of the
contralateral submandibular gland (doses <25
Gy) is feasible with IMRT and results in
prevention of xerostomia. Perhaps the mean
dose to the oral cavity, representing RT
effect on the minor salivary glands, is
equally important, although data on possible
thresholds are currently lacking.
Another,
although less wide-spread approach is
salivary gland transfer. Colleagues Jha et
al and Seikaly et al were the first to
propose surgical transfer of 1 submandibular
gland to the submental space, outside the
proposed radiation field.This is only
practicable in patients who are planned to
receive postoperative RT, because the
transfer is done as part of the surgical
intervention. Obviously, it is not always
straightforward to predict which patients
will need postoperative RT, and some
patients may refuse further treatment. Then
again, in some patients, the submental space
cannot be shielded because of its proximity
to the disease. These are important
limitations, and, in the largest study to
date, 17 of 60 patients (28.3%) underwent
salivary gland transfer without subsequent
RT or without sparing of the relocated
gland.
However, all
of the glands survived transfer and
functioned well; the surgical technique had
no complications and added an average of 45
minutes to the surgical protocol. The
results in preventing xerostomia are
convincing: 81% of patients had no or
minimal xerostomia, and 19% had moderate to
severe xerostomia. Long-term follow-up data
recently have been published, and 83% of
patients reported normal amounts of saliva 2
years after RT. Other centers attained
similar results; however, salivary gland
transfer should not be considered a standard
procedure. Institutional experience with
this technique is essential, and it is
probably inevitable that a substantial
percentage of patients will undergo the
procedure without gaining a real benefit.
Current
therapies for the management of
radiation-induced xerostomia include
stringent oral hygiene with fluoride agents
and antimicrobials to prevent dental caries
and oral infection, saliva substitutes to
relieve symptoms, and sialogogic agents to
stimulate saliva production from remaining
intact gland tissue. A variety of artificial
saliva substitutes have been developed to
supplement the reduced production of saliva,
although very few have been evaluated
appropriately. Obviously, because saliva is
a complex substance with many functions, it
is difficult to replace; therefore, saliva
substitutes rarely are effective, and some
patients find regular sips of water equally
useful. Moreover, artificial
substitutes do not replace the antibacterial
and immunologic protection of saliva and,
thus, do not exclude the need for regular
dental care and appropriate oral hygiene.
Antimicrobial mouthwashes, such as
chlorhexidine and hexitidine, play a central
role in reducing the bacterial load and
inhibiting cariogenesis. Studies have shown
that, when there still is some residual
salivary function, saliva stimulants produce
greater relief than saliva substitutes.
Pilocarpine is currently the sole sialogogic
agent approved by the FDA for
radiation-induced xerostomia. Pilocarpine is
a naturally occurring alkaloid that
functions primarily as a muscarinic-cholinergic
agonist with mild
-adrenergic
activity; as a parasympathomimetic agent, it
causes stimulation of cholinergic receptors
on the surface of exocrine glands, resulting
in diaphoresis, salivation, lacrimation, and
pancreatic secretion.
The first
trials with pilocarpine in radiation-induced
xerostomia were performed in the early 1990s
and showed significant improvement of oral
dryness in approximately half of patients.
For optimal results, it is necessary to
treat the patient during 8 to 12 weeks with
doses >2.5 mg 3 times daily.
Pilocarpine also may be used safely as
maintenance therapy during longer treatment
periods.
Pilocarpine
obviously is contraindicated in patients who
have asthma, acute iritis, or glaucoma and
should be used with extreme caution in
patients who have chronic obstructive
pulmonary disease and cardiovascular
disease. The side effects of pilocarpine are
caused by a generalized parasympathetic
stimulation, which causes mild-to-moderate
sweating in almost half of patients and,
less frequently, urinary frequency,
lacrimation, and rhinitis. Some work has
been done with topical (ie, oral)
application of pilocarpine, which seemed to
produce results similar to those achieved
with systemic delivery methods but with
improved patient tolerance. It has
been suggested that pilocarpine given during
RT in some way may salvage salivary gland
function and prevent xerostomia: However,
results were disappointing, and this
indication warrants further investigation.
Cevimeline is a newer muscarinic agonist
that has been found safe and effective in
treating xerostomia in patients with Sjogren
disease and that also may have merit for the
treatment of radiation-induced xerostomia.
Other drugs, including bethanechol,
metacholine, and carbachol, also have been
investigated, although the results generally
have been poor.
Some
promising preclinical results have been
obtained by gene transfer, although clinical
studies have yet to be initiated. Recently,
it was suggested that the expanding field of
stem cell research also may yield results in
the treatment of radiation-induced
xerostomia. Apparently, mobilized bone
marrow cells may home to salivary glands and
induce repair by secreting stimulatory
factors, causing improved salivary gland
function.
Xerostomia is
an almost ubiquitous, long-term complication
of RT for HNC. Recently, significant
progress has been made in the prevention of
xerostomia through salivary gland-sparing
radiation techniques, such as 3D-CRT and
IMRT, and, more controversially, by the use
of concomitant pilocarpine or surgical
transfer of a submandibular gland to the
submental space. However, to date, it still
is impossible to successfully prevent
radiation-induced xerostomia in all
patients, and a large percentage of HNC
survivors continue to suffer from xerostomia.
Therefore, further research, particularly
regarding treatment, is urgently warranted.