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Cancer Treatment Reviews (2006) 32, 541– 547

available at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/ctrv

COMPLICATIONS OF TREATMENT

Radiotherapy-induced taste impairment


Maria Grazia Ruo Redda *, Simona Allis

Department of Radiation Oncology and Diagnostic Imaging, University of Turin, S. Luigi Hospital Regione Gonzole 10,
10043 Orbassano, Turin, Italy

Received 3 October 2005; revised 12 June 2006; accepted 14 June 2006

KEYWORDS Summary Changes in taste perception occur in a significant proportion of cancer patients.
Head and neck cancer; Among cancer patients treated with radiotherapy (RT) in head and neck area, the vast majority
Radiotherapy; reports an altered taste sense during and after treatments. Taste impairment starts a few
Oral side effects; weeks after the beginning of irradiation, and almost all such patients experienced loss of taste
Taste impairment acuity at a dose of 60 Gy. Some studies investigated the four basic taste intensities (sweet,
salty, sour and bitter) and the umami taste, and several of these reports identified diminished
threshold sensitivity for at least one taste quality. Six months to one year after RT, taste acuity
recovers to its previous level in many patients, but some patients show incomplete or no recov-
ery even several years later.
Taste impairment has profound effects on patients’ quality of life because is associated with
weight loss through reduced appetite and altered patterns of food intake.
Damage to the major salivary glands during head and neck RT leads to disturbance in taste
acuity. With the implementation of new radiation techniques, such as conformal and intensity-
modulated RT in head and neck irradiation, the late-radiation effects can probably be reduced,
but the remaining sequelae are still bothersome to the patients.
c 2006 Elsevier Ltd. All rights reserved.

Introduction associated discomfort are normal tissue complications


accompanying almost all cancer patients who receive RT
Radiation damage to normal tissues is the most important in head and neck area. Taste impairments have a great im-
dose-limiting factor in radiotherapy (RT). A reduction in pact on the patients’ quality of life because, coupled with
taste sensitivity (hypogeusia), an absence of taste sensation radiation-induced mucositis, xerostomia and dysphagia, re-
(ageusia), or a distortion of normal taste (dysgeusia) and the duce food enjoyment and affect the nutritional status of the
patients.1–5
Acute taste complication due to irradiation has been
* Corresponding author. Tel.: +39 0 11 678947; fax: +39 0 11 investigated in several studies and is encountered in daily
6638680. clinical practice. However, late taste complication has not
E-mail addresses: mariagrazia.ruoredda@unito.it (M.G. Ruo been well investigated, although it is sometimes encoun-
Redda), simona.allis@virgilio.it (S. Allis). tered in daily clinical practice.6


0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2006.06.003
542 M.G. Ruo Redda, S. Allis

References for this review were identified by a compre- for taste perception, with modulating effects on the four
hensive search of MEDLINE for the years 1980–2005, with basic taste modalities. Saliva strongly influences salt taste
no language restriction. References were supplemented threshold levels and provides the ionic environment for
with relevant citations from older literature and from the taste cells through signal transduction. The type of taste
reference list of retrieved papers. Papers were selected stimuli can influence salivary flow rate and composition.
on the basis of their relevance to the topic. Sour taste induces the highest flow rate and sodium concen-
trations, whereas salt gives rise to high protein and calcium
concentrations.5,9
Definition, anatomy and physiology of taste
‘‘. . .exteriori vero parte (papillare corpus) inaequale est, Risk factors
papillas enim nerveas insignes miro ordine dispositas pro-
mit; hae in bove, capra, ove et ipso etiam homine, ex con- Taste disorders are wide-spread and associated with a vari-
figuratione et magnitudine sunt in triplice discrimine. . .’’. ety of illnesses. Taste loss occurs as a natural phenomenon
Marcello Malpighi, professor of Medicine at the Messina Uni- of aging and also in response to normal changes such as
versity described in this way his anatomical discovery in a pregnancy and menopause.11 Poor dentition and hygiene,
letter dated 31st October 1664.7 alcoholism and/or excessive smoking are common condi-
Taste could be defined as a chemical sensation related to tions that affect taste. Patients with xerostomia, Sjögren
specialized receptors, selectively stimulated by molecules syndrome, vitamin and zinc deficiency may also experience
and ions of solutions in contact with them. taste loss. Other conditions in which taste loss may occur in-
Taste buds are the anatomical structures which contain clude liver and kidney disorders, endocrine disorders, diabe-
the receptor cells that mediate the sense of taste. These tes mellitus, psychological disorders, central nervous
pear-shaped organs are found on the tongue, soft palate, system disorders, and surgical procedures around the chor-
pharynx, larynx, uvula, the upper third of the esophagus, da tympani or glossopharyngeal nerve. Various types of
lips and cheeks. Taste buds on the tongue are contained drugs and antineoplastic agents are associated with taste
in small specialized structures called papillae (fungiform, impairment and usually induced a temporary effect which
circumvallate, and foliate papillae). Each taste buds consist diminishes after the drug is discontinued.12,13
of 50–100 taste receptor cells that have a life span of The finding of dysgeusia and taste threshold abnormality,
approximately 10–11 days.8 Taste impulses are carried to anorexia and weight loss is common among patients with
the brain by parasympathetic nerves, many of which travel head and neck cancer as well as those with malignancies in
with branches of trigeminal nerve. The sensory nerves, other sites (i.e. esophagus, lung, lymphomas, breast, central
which carry signals in response to stimulation of taste nervous system). In particular, in patients with head and
receptors are, with regards to the tongue, the facial nerve, neck tumours abnormal taste acuity and associated discom-
whereas the glossopharyngeal nerve innervates the circum- fort are present even before the beginning of RT or chemo-
vallate papillae, the back of the tongue and the palate. Fi- therapy for one (88.9%) or more taste qualities (66.7%).14–16
bers of the vagal nerve innervate taste buds in the tonsillar Alteration in taste is an early response to RT and often
region, the epiglottis, the pharynx and esophagus. The taste precedes mucositis.3,17 Damage to oral mucosa and taste
pathway activated by inputs from the facial, glossopharyn- buds is strongly related to radiation dose, fraction size, vol-
geal and vagal nerves have ipsilateral reflex connections ume of irradiated tissue and technique.
to salivatory center in the brain stem. Taste information is During a course of conventional curative RT of 60–70 Gy
transmitted to the postcentral gyrus-facial area via the nu- over 6–8 weeks, taste function becomes measurably im-
cleus of the solitary tract and thalamus, and there are also paired by the first week of treatment for bitter flavour
projections to the olfactory cortex. and becomes worse during the second week of treatment.18
Four main taste modalities can be distinguished: sweet, The greatest degree of compromise is reached during the
sour, salty and bitter. Each modality is based on distinct third and fourth weeks of treatment and lasts throughout
transductional systems in the single receptor cell leading the entire radiation cycle.14,18 Taste loss is not observed un-
to depolarization of the receptor potential and generation til radiation doses of 20 Gy have been administrated to head
of action potentials. This facilitates the release of neuro- and neck regions and is reported to be exponential up to an
transmitters, stimulating gustatory afferent nerve fibers accumulated dose of 30 Gy and involves all taste qualities;
that then carry the taste signal onto higher-order systems. however, a dose of 60 Gy causes a relative taste loss in over
Each taste receptor cell responds in varying degrees to sub- 90% of patients.10,16,19,20 Regarding taste thresholds, the
stances that fall into more than one taste category.9 bitter and salt qualities show the earliest and the greatest
In addition to the four taste qualities, a novel taste, that impairment, the sweet quality the least. The preservation
is referred by the Japanese word umami, which means deli- of the sweet taste quality may be related to the observation
cious, has come to be recognized as a ‘‘fifth taste’’. Umami that the greatest number of taste buds in the oral cavity are
taste is found in a diversity of foods (e.g. fish, meat, milk, devoted to the sensitive perception of sweet taste.18 Unlike
tomato and some vegetables) and is elicited by monosodium the four basic tastes, umami taste showed a distinctive pat-
glutamate and certain ribonucleotides.10 tern of impairment with an increased threshold after irradi-
The sense of taste is activated during the initial stage of ation at 15 Gy, a significant impairment at 30 Gy and a peak
ingestion of food particles and is the main stimulant for for- of mean threshold at 45 Gy. This suggests that the modality
mation of saliva. On the other hand, the presence and the of damage caused by RT may be different between umami
composition of saliva in the oral cavity are also essential receptor and that of the other four basic tastes.10
Radiotherapy-induced taste impairment 543

Fernando et al. observed that both objective and subjec- acids for acid, quinine sulfate for bitter, mono-sodium L-glu-
tive taste loss was significantly associated with the portion tamate for umami taste.27 The solution could be applied di-
of tongue, but not parotid, contained within the high dose rectly on the tongue by a drop, or by paper disks or cotton
of the radiation treatment field. This study suggests that swabs on different sectors of the tongue to verify different
the volume of tongue should be kept to a minimum, provid- taste sites.
ing that steps to do this do not risk compromising adequate Chemical gustometry is used by different authors to study
local control.21,22 This can often be achieved by using spe- taste disorders in patients receiving head and neck RT.
cific positioning techniques, field arrangements (e.g. tongue Conger used conventional taste-testing procedures to
depressor or a pair wedge technique) and certain blocks to determine patients’ recognition thresholds for sweet, acid,
avoid a part of the tongue and thus to reduce number of and bitter.19 Test solutions were made up with reagent
taste buds irradiated. grade sucrose and hydrochloric acid, and pharmaceutical
Furthermore, radiation-induced changes in quantity and grade quinine hydrochloride in boiled distilled water in a
composition of saliva occur shortly after RT and modify concentration series, each taste solution being one-half
taste acuity. Saliva acts as a solvent for taste substances the concentration of its predecessor in the series. These re-
and protects the taste receptor from damage brought about agents are so-called ‘‘pure tastes’’ and are odourless.28
by dryness and bacterial infection and, as such, might play a Mossman measured the detection and recognition thresholds
role in taste sensitivity; however, the role of salivary flow in using a forced choice-three stimulus drop technique for rep-
affecting taste sensitivity is not completely understood. Sal- resentatives of each of four taste qualities (salt, sweet, sour
ivary glands were damaged permanently by RT, while taste and bitter). The technique consisted of introducing se-
sensitivity only suffered a temporary impairment. Salivary quences of three drops of solutions into the oral cavity,
secretions reached the minimum after 6 months after irradi- two of these were water, and one a solute dissolved in
ation, but taste sensitivity did not show further deteriorate water. For threshold determinations the patient was re-
after RT.5,23–25 quired to taste each drop and make two responses: which
The relationship between salivary flow and taste distur- of the three drops tasted different from the other two and
bance had been reviewed recently by Inokuchi, who con- what was the characteristic taste of the dissimilar drop
cluded that salivary dysfunction was not likely the major (i.e. was the drop salty, sweet, sour or bitter). Taste loss
factor in affecting taste disturbance.26 for detection and recognition for each taste quality was de-
fined as the increase in threshold above the upper limit of
normal.16,18,22 Some authors used the method of gustatory
Measurement of taste acuity test by filter-paper disc, previously described by Okuda,
for detection of threshold for sweet, salt, sour and bitter.29
Taste, where only specialized taste receptors are stimu- Each stimulating solutes was diluted to five steps and each of
lated, should be distinguish from ‘‘flavour’’ where other these reagent concentrations correspond to five scores for
receptors such us tactile, thermal, pain and smell receptors taste thresholds. Gustometry was done on both sides of
are stimulated. This difference should be kept in mind in the tongue dorsum surface: the mean value of the estimated
taste acuity evaluation in order to avoid interference with thresholds on both sides was considered as the threshold.30
other senses particularly that of smell. While the sectorial exploration is the most precise
Taste acuity evaluation relies on both subjective and method in the common clinical practice, full/mouth or
objective. Subjective evaluation, such as chemical gustom- whole/mouth techniques exploring the whole taste area
etry and electrogustometry, are rather old and to date not are more easily executed. Yamauchi et al. had used four
replaced by newer techniques. tastes in progressive solutions in 13 steps with the whole-
mouth technique. The threshold was measured spraying
1 ml of solution starting with the lower dilution with dis-
Subjective evaluation tilled water mouth rinse between applications. The test
could be randomised and repeated several times to avoid
Chemical gustometry simulation phenomenon.10,31
Chemical gustometry could also be executed with supra-
Chemical gustometry consists on measurement of detection threshold stimuli.2 Two tests are employed to evaluate the
and recognition thresholds and taste-intensity responsive- degree of taste impairment. In the first test the patient
ness. A threshold is defined as the concentration of a stim- should compare increasing concentrations of a solution to
ulus detected or recognized by a patient in more than 50% a sound in a 1 to 9 scale, where 9 corresponds to the highest
of the performed tests. The detection threshold corre- sound and 1 to the lowest. The second test allows the iden-
sponds to the lowest concentration of the stimulus distin- tification of non sensitive areas resulted from nerve damage
guished by a patient as different from water (‘‘yes, I and is also useful for the evaluation of dysgeusia and focal
detect a taste’’). The recognition threshold is the lowest small areas of taste loss, that could be important to identify
concentration or the quality and/or the type of the stimulus the cause of taste disorder.
that has been correctly recognized by a patient (‘‘this taste
is salt, sweet. . .’’).22
There are four test qualities tested in chemical gustom- Electrogustometry
etry, with the recent introduction of umami taste. The most
used taste solutions are sodium chloride for salt, sucrose, The electrogustrometry is a physical method based on the
glucose, glycerol and fructose for sweet, citric and chloride determination of the recognition threshold of an electrical
544 M.G. Ruo Redda, S. Allis

stimulus such as a continuous wave from a cathode to an an- of these methods with the measurement of gustatory-
ode placed on the tongue while another electrode closes the evoked potentials could be useful for evaluating gustatory
circuit on the pulse. In these conditions, the saliva is hydro- function objectively.32–34
lyzed and a wave of chemical stimulation by ionophoresis is
applied. The recognition threshold is expressed in lA, in Scoring systems
electrogustometric unit or in decibel. The normal values
scale relates to the surface of electrode in contact with Multiple systems have been developed for grading the ad-
the tongue and varies from 5 to 50 lA. The hypogeusia verse effects of cancer treatment and several classifications
threshold is in general placed between 50 and 100 lA and have been used for describing the radiation-induced altera-
ageusia is considered for threshold values above 300– tions. Obviously, such situation has created difficulties in
500 lA, depending of the different authors and devices used. routine clinical trials applications and in comparing results
The advantage of this method is the easy and precise indi- between studies and institutions.
vidualization of the stimulus area limited in general to the The Radiation Therapy Oncology Group (RTOG) criteria
tongue dorsum surface. However, the electrogustrometry and the Late Effects of Normal Tissue/Somatic Objective
does not allow the identification of different test qualities Management Analytic (LENT/SOMA) scoring system include
and has the limitation of not using a physiological stimulus. taste disturbances in the salivary gland morbidity and in
Nevertheless, a good correlation exists among chemical gus- the oral and pharyngeal mucosa morbidity, respec-
tometry and electrogustrometry. Given the quantitative tively.35,36 Also in the Common Toxicity Criteria of the Na-
characteristic of the electrogustrometry, it is considered tional Cancer Institute (NCI-CTC v2.0), modifications of
the ideal for the assessment of taste disturbances.6,14 taste associated with RT are graded under salivary gland
changes in the gastrointestinal category and are focused
Taste questionnaires on acute effects.37 However, these classification systems
are not appropriate for scoring taste disturbances, although
Taste questionnaires are used to assess subjective aware- taste alterations are mentioned.
ness of taste impairment or taste loss and the presence of The NCI Common Terminology Criteria for Adverse Events
any distress caused by changes in taste acuity (e.g. de- (CTCAE v3.0), implemented in 2003 as a multimodality grad-
creased enjoyment of food and appetite). Self-reports of ing system for reporting both acute and late effects of can-
various degree of oral dryness are also evaluated in most cer treatment, recognize, within the gastrointestinal
of these questionnaires.2,10,16,18,21,22 category, an additional subcategory of taste alterations as
a distinctive adverse event, accompanied by a scoring scale
of severity (Table 1).38,39
Objective evaluation Furthermore, a Subjective Total Taste Acuity (STTA)
scale, modified from the LENT/SOMA scoring system, is used
Subjective evaluation is characterized by evident limita- to evaluate, in a specific way, the subjective total taste
tions in both medical and juridical extent, because of sub- acuity (Table 2).6
jective response of the patient. Therefore, an objective
evaluation should exceed the previously described subjec-
Studies on radiation-induced taste impairment
tive tests. Of the objective modalities that have been inves-
tigated, the measurement of gustatory-evoked potentials
Impairment of taste and correlated discomforts have been
has been the most widely studied because it does not re-
investigated by several and heterogeneous studies in pa-
quire expensive equipment. Evoked potentials are the ac-
tients who receive radiation for treatment of tumors of
tion potentials that occur in response to stimulation of
the head and neck region.2,10,16,18,19,21,22,40–45
sensory receptors or nerves. To obtain gustatory-evoked
Several of these reports identified diminished threshold
potentials that are useful for evaluating taste function, test
sensitivity for at least one taste quality; however, the sever-
subjects need to receive appropriate taste stimuli (electri-
ity and pattern of taste impairments were still in contro-
cal stimulation or application of a chemical solution), the
versy. Some studies reported that the ability to detect
system for presenting stimuli and recording responses must
sweet solutions diminished while sensitivity for bitter ones
provide reproducible results and there must be a consensus
increased,44,45 but others argued that the bitter and the
concerning how to interpret the results. The techniques
developed to date are not yet clinically useful and are still
under scientific evaluation for improving stimulation meth-
ods and recording equipment. Table 1 Taste alteration (dysgeusia) according to the
Other methods that have been considered for objective CTCAE v3.0 criteria
evaluation of gustatory function include imaging techniques Score Taste alteration (dysgeusia)
such as Positron Emission Tomography and Functional Mag- Grade 0 None
netic Resonance scans, used in the study of brain tissue’s Grade 1 Altered taste but no change in diet
modifications induced by changes in perfusion and oxygena- Grade 2 Altered taste with change in diet
tion after the presentation of appropriate taste stimuli. It (e.g. oral supplements);
would be difficult to evaluate gustatory function using one noxious or unpleasant taste; loss of taste
of these modalities alone, because it would be difficult to Grade 3 –
discriminate the informations related to gustatory or to Grade 4 –
other sensory functions. However, the combination of one
Radiotherapy-induced taste impairment 545

Table 2 Scale of Subjective Total Taste Acuity (STTA) Prevention and treatment
Grade 0 Same taste acuity as before treatment
Head and neck RT induces damage in normal tissues that may
Grade 1 Mild loss of taste acuity, but not
result in oral sequelae such as mucositis, hyposalivation,
inconvenient in daily life
radiation caries, taste loss, trismus, soft-tissue necrosis,
Grade 2 Moderate loss of taste acuity, and sometimes
and osteoradionecrosis. These sequelae may be dose-limit-
inconvenient in daily life
ing and may cause substantial problems during and after
Grade 3 Severe loss of taste acuity, and frequently
RT and are major factors in determining the patient’s quality
inconvenient in daily life
of life. Acute exacerbation of focal infection, e.g., periapi-
Grade 4 Almost complete or complete loss of taste
cal and periodontal infection, and severe mucositis occa-
acuity
sionally may necessitate an adjustment or an interruption
of the radiation treatment schedule. For these reasons, oral
complications should be prevented or reduced to a minimum
salty qualities showed the earliest and greatest impairment using protocols before, during and after RT. Generally, the
while the sweet quality showed the least.16,18,22 Schwartz primary issues of patient care before radiation exposure
et al., however, reported near normal suprathreshold inten- are screening, consequential treatment, explication, pa-
sity perception of the four basic tastes in patients following tient motivation, and initiation of preventive measures.
head and neck irradiation.2 Management during RT is characterized by prevention and
In addition to the four basic tastes, Shi et al. investigated treatment of acute complications induced by radiation expo-
the recognition threshold of umami taste at different irradi- sure and comprehensive counselling. After RT, the preven-
ation dose intervals during RT in 30 patients with neoplasm tion and treatment of chronic and late complications in
of head and neck. Sweet, sour, salty, and bitter tastes conjunction with close follow-up are the main issues of pa-
showed temporarily and slightly increased thresholds during tient care.3,46
treatment, but no statistical difference was found between In particular, inadvertent damage to the major salivary
the threshold at pre-RT and that at 15, 30, 45 and 60 Gy in glands, during irradiation of head and neck malignancies,
any taste quality. Significantly impaired threshold of umami results in severe reduction of salivary flow and altered sali-
taste was revealed at 30 Gy and remained throughout the vary composition, leading to disturbance in taste acuity.
following treatment. The authors concluded that the clini- The maximum dose delivered to the tumor is generally lim-
cal impairment pattern of umami taste is different from ited by the tolerance dose of healthy normal tissues. Radia-
that of the other four basic tastes in head and neck cancer tion dose-response curves have been studied by Mossman
patients during RT, and plays an important role in impacting et al.20,22 The maximum tolerance doses resulting in a
the quality of life of the patients.10 50% complication rate 5 years after treatment (TD 50/5)
Maes et al. evaluated the prevalence and distress of are estimated to be 40–65 Gy for xerostomia and 50–
taste loss at different intervals after RT for head and neck 65 Gy for taste loss. One of the means of limiting radiation
cancer, in order to quantify the magnitude of the problem, damage to healthy tissues is to reduce the irradiated volume
the impact on the patients’ quality of life and to detect by posing constraints on the dose-volume histogram (DVH).
recovery in time after treatment. Loss of taste after RT The effect of volume reduction mainly depends on the ana-
was found to be most pronounced after 2 months. A gradual tomic structure of the organ. When independent units of
improvement of taste function was seen for all four taste function in an organ (e.g., acini in salivary gland) have a
qualities 6 and 12–24 months after RT and further recovery parallel organization, irradiation of a small part of the organ
in the period after 24 months may be possible, even if par- has less effect in terms of function loss when the organ has a
tial taste loss still persisted 1–2 years after treatment.16 serial anatomic organization. At present, prevention of radi-
Barbieri et al. reported the maximum compromise for all ation damage to salivary glands is best accomplished by new
four taste categories at 30 days after RT, with complete radiation techniques, including conformal and intensity-
recovery of taste function at three months after treat- modulated radiation therapy, designed to spare as much
ment.14 However, some authors suggest that total recovery of major salivary glands as possible.47 However, Konings
is usually not achieved even in later years after treatment. et al. found, in rat model studies, regional differences in
Mossman et al. observed objective taste loss in 69% of the radiosensitivity of the parotid gland and suggested that late
patients up to 7 years after RT, but, in spite of the measur- radiation damage after partial irradiation of the gland
able taste loss, only 15% of the patients complained of taste showed region-dependent volume effects. This finding is ex-
loss. The discrepancy between measurable taste loss and pected to be relevant to the radiosensitivity of human sali-
subjective awareness of taste loss was explained by a possi- vary glands and may theoretically have some unexpected
ble adaptation of the patient to the sensory loss.22 consequences for the clinical outcome of the conformal
In order to evaluate the impact of treatment fields and and intensity-modulated RT.48
volumes, Fernando et al. reported a significant correlation Furthermore, gaining in-depth-knowledge on the mecha-
between the proportion of tongue contained within the nism of radiosensitivity will provide informations on the pos-
radiation fields and both objective and subjective taste sibilities of amelioration of acute and late radiation damage
loss.21 However, Maes et al. could not show any correlation to the salivary glands. Classical ways of protecting salivary
between tumor site or radiation dose and the prevalence of cells from radical-induced DNA damage as well as stimula-
taste loss, because the studied group was too small and all tion of cell proliferation by suitable drugs seem to be the
treated patients received radiation doses over 50 Gy.16 approach to pursue. Radical scavenging and treatment with
546 M.G. Ruo Redda, S. Allis

transition metal chelators will protect against early as well to prevent most of the clinical complaints resulting from
as against late radiation damage.49 hyposalivation. Furthermore, gaining in-depth knowledge
A cytoprotection against the loss of taste was reported on the mechanism of radiosensitivity may provide means
by the administration of amifostine during a course of radio- on protecting salivary glands during the course of RT, and
chemotherapy. However, the design of the latter is ques- ultimately will result in less reduction of oral function and
tionable, because a wide variety of treatment protocols a higher quality of life in head and neck cancer patients.
was used.47,50
Since taste loss can result in weight loss, the importance
of dietary counselling should be stressed. Indeed, patients References
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