1
ABSTRACT
Taste and smell changes, otherwise known as chemosensory changes, are frequently
reported symptoms in cancer. Research to date has mainly focused on patients undergoing
treatment i.e. chemotherapy (CT) or head and neck radiotherapy (RT). However, it has been
suggested that taste and smell changes may also occur pre-treatment with diverse primary
cancer sites. There is a paucity of research on this issue and mechanisms for these findings
are poorly understood.
Both subjective and objective methods can be used to measure taste and smell changes.
Increased and decreased taste and/or smell sensitivity has been observed pre- and post-
treatment. Bitter is reported to be most disturbed by cancer and its treatment. Distorted
smell perception is frequently described as rancid. Given that taste and smell function is
positively correlated with dietary intake, alterations may affect nutritional status. Adequate
dietary intake is imperative with cancer, since 20% of patients die from malnutrition, rather
than malignancy.
Previous research and clinical experience suggest that many cancer symptoms e.g. anorexia,
dry mouth, taste changes and weight loss occur together in groups or clusters. Correct
categorisation of symptom clusters is likely to be therapeutically important because
treatment of one symptom may influence another in the same cluster.
This review aims to summarize the prevalence, pathophysiology and clinical sequelae of
taste and smell changes in cancer, with an emphasis on the treatment-naive population. A
greater understanding of these abnormalities may help to identify and promote earlier
interventions, prevent weight loss complications and enhance quality of life.
Keywords: taste and smell changes; chemosensory changes; cancer; oncology; clinical
review
2
1. INTRODUCTION
The chemical senses of taste and smell are essential to life. They alert us to danger (e.g. gas,
fire), prevent us ingesting toxic substances and support oral nutrition1. Together, taste and
smell drive flavour perception, i.e. the sensory impression of food2 and support digestion.
They increase salivary flow, trigger the release of gastrointestinal enzymes and hormones,
and stimulate gut motilty3. Brain reward pathways (which involve the hedonic aspects of
eating) are also affected4. Disturbance of these senses is termed chemosensory
dysfunction5. Food preferences may change and food aversions can develop6, 7. These can
significantly impair food intake, reduce enjoyment of meals and lead to poor nutritional
status and weight loss1, 8. Adequate dietary intake is imperative at all stages of cancer, since
20% of cancer patients die from malnutrition, rather than the malignancy9.
1.1 Normal Physiology of Taste and Smell
Taste
Taste perception is mediated by receptor cells in taste buds on the dorsal and posterio-
lateral tongue surfaces and the epithelial surface of the oropharynx and larynx. These cells
detect chemical signals which produce taste and stimulate neurotransmitter release onto
first-order afferent nerve fibres, which then convey signals to the brainstem10. Second-order
neurons travel through the thalamus and project to the insular cortex, operculum, and other
areas such as the caudal orbital cortex. The latter is responsible for conscious perception of
taste10.
Smell
Odour perception is also stimulated by chemical signalling. Odour molecules bind to
neuroepithelium receptors in the cilia of olfactory receptor neurons11. This depolarizes the
receptor cell and propagates an olfactory nerve action potential, which terminates in the
nasal olfactory bulb. Convergence of olfactory bulb action potentials generates signals to
the primary olfactory cortex. Olfactory information then passes to adjacent areas such as
the caudal orbital cortex, where the combination of odour and taste creates the perception
of flavour11 (Figure 1).
Olfaction can be further classified as orthonasal or retronasal12. The former refers to odours
which pass through the external nares or nostrils when one sniffs, the latter to odours which
3
pass through the mouth and the internal nares during eating and drinking. Retronasal
stimulation improves gustation. Of taste perception, 80-90% may in fact be smell13.
Figure A1: Normal Physiology of Taste and Smell. Source: Kibiuk and Stuart14
.
1.2 Prevalence and Pathophysiology of Taste and Smell Changes in Cancer
Research into taste and smell changes in cancer has primarily focused on patients
undergoing chemotherapy (CT) or head and neck radiotherapy (RT). Alterations of taste and
smell function can be classified into three major types15:
1. Transport losses: Failure of stimuli to reach taste or smell receptors, e.g. blocked
taste buds or nasal passages, dry mouth.
2. Sensory losses: Damage to sensory organs by, e.g. age-related decline, anti-cancer
treatments, medication, tumour obstruction.
3. Neural losses: Damage to peripheral or central nervous system, e.g. head trauma,
tumour invasion, neurological diseases, surgery, toxins.
Chemotherapy
Taste changes have been reported in 48-80%16-18 and smell changes in 14-46%16, 19. The
lower smell changes prevalence may be due to less CT damage to olfactory receptors, since
they have a slower turnover (mean 30 days) than gustatory receptors (mean 10 days)20. The
olfactory epithelium is also more robust21. Most studies have included heterogeneous
populations of varying disease severity, and multiple treatment regimens of varied
duration16. There is no consensus on the relative prevalence of chemosensory changes post
CT in one cancer type versus another16, 22 or for different drugs. Taxane-based CT22 and
irinotecan23 may have the greatest effect on taste changes, but changes have also been
4
noted with cyclophosphamide, folinic acid antagonists, methotrexate and platinum agents16.
Recent studies suggest that the nucleoside analogue, gemcitabine, has the least effect on
taste16, 23. There is no difference between CT agents’ effect on olfaction22, 24.
CT causes taste and smell changes via cytotoxic damage to rapidly dividing gustatory and
olfactory receptors8. Cytotoxic drugs themselves can also have an independent effect on
gustatory function. They can cause a bitter taste by entering the mouth through gingival
sulcus fluid (a serous transudate or exudate) or diffusing from capillaries to receptor cells25.
Saliva and mucous production can also be disrupted causing oral mucositis, dry mouth and
dental caries, which in turn affect taste26.
Radiotherapy
Most research about RT-induced chemosensory changes has focused on head and neck
cancer. To date, there is very limited research on taste and smell changes post RT in other
cancers. Of those given RT to the head and neck, taste changes occur in 92-100%27, 28 and
smell changes in 50%29.
RT can damage sensory receptors, dependant on the field of administration21. Salivary
glands can also be affected. This can cause hyposalivation and dry mouth, which may reduce
taste due to limited delivery of chemical stimulants to receptors30. The minimum radiation
dose capable of reducing taste ranges from 15 to 30Gy depending on treatment conditions
and disease state31. Olfactory loss can also occur secondary to the direct toxic effects of
RT26.
Treatment-Naive
Of people not in active treatment, the prevalence of chemosensory changes range from 10-
86%. Most literature is relatively old and contradictory (Table 1). Yavuzsen et al.32 found no
relationship between taste changes and anti-cancer therapy and propose that the cancer
itself may be responsible. Sandow et al.33, on the other hand, did not corroborate this. They
found no differences in taste and smell acuity between oropharyngeal cancer pre-treatment
and controls. Mechanisms for altered sensory perception in the treatment-naive are poorly
understood5, 34 and understudied35, 36. Several explanations have been proposed (Table 2).
However, most studies did not characterise chemosensory changes pre-treatment1.
5
Table 2: Possible Mechanisms that may affect Chemosensory Function in Cancer Patients Naive to CT/RT.
Classification Possible Mechanisms
Mechanical
Tumour obstruction to chemoreceptor sites26
.
Surgical resection of the oral or nasal cavity37
.
Neurological
Tumour interference with neural transmission and sensory processing26
.
Tumour damage to cranial nerves I, VII, IX or X8.
Increased salivary sodium concentration due to neural stimulation of salivary acinar cells
(elevating salt taste threshold)38
.
Centrally mediated phantom tastes/smells26
.
Conditioned aversion to food secondary to post-prandial pain/vomiting8.
Metabolic
Tumour secretion of amino-acid-like substances39
.
Increased salivary urea concentration due to tissue catabolism (bitter taste)40
.
Immune-cell derived by-products such as TNF-α, IL-1β, IL-6, which stimulate the
gustatory nerve system41
.
Lipid peroxidation of oral epithelial cells due to tumour-related oxidative stress, leading
to the production of carbonyls (causing a metallic taste)42
.
Non-tumour
related
Smoking Status
Significant relationship with olfactory impairment only43
.
Can occur due to structural and functional changes in the olfactory neuroepithelium44
.
No relationship with former smoking status7, 43
.
Age
Age-related decline due to delayed cell renewal45
.
Mediated by reduced levels of oestrogen and testosterone or alterations in
neurotransmitter levels 45, 46
.
Medication
Side-effects e.g. antibiotics and analgesics47
.
Can induce their own taste change or affect the CNS and/or PNS46
.
Micronutrient Deficiencies
Zinc and/or vitamin B1245
due to increased catabolism, malnutrition and cachexia8.
Oral complications of cancer
Infections, ulcers, dry mouth48
.
CNS, Central Nervous System; IL-1β, Interleukin-1 Beta; IL-6, Interleukin-6; PNS, Peripheral Nervous System;
TNF-α, Tumour Necrosis Factor-Alpha.
Despite study discrepancies, there is a consensus that the prevalence of chemosensory
changes in cancer is underestimated49. A study in 1998 found that taste changes were
under-recognised by medical oncologists in 36% of cases50 and the situation is unchanged23.
6
Patients may be unaware of chemosensory changes51, deem them to be trivial or cannot
articulate their sensations52, and they may go unnoticed. Staff and patients may
communicate less about symptoms they believe untreatable52, as few, if any, effective
interventions are available8.
2. IDENTIFYING TASTE AND SMELL CHANGES
Taste and smell changes can be measured by both subjective and objective means34, 53
(Table 3). Objective measures of altered clinical thresholds are not the sole determinant of
sensory perception and food intake. This involves more complex concepts, e.g. flavour as
described above. Patients may be burdened by chemosensory changes not identified in
objective testing54. Consequently, sensory evaluation is more accurately represented by
self-report measures that avoid these limitations5, 16, 34, 35. This is reflected in the US Food
and Drug Administration’s 2006 approval of patient-reported outcomes as a criterion in
admissions to all trials55. Self-report measures are, therefore, applicable for investigating a
wide range of problems. Moreover, food and mealtimes have important symbolic, cultural
and religious values beyond nutrition and thus chemosensory changes may also be expected
to cause psychosocial issues5. Patient-reported data rather than clinical measures have,
consequently, been suggested to be a more suitable predictor of dietary behaviour16.
3. CHARACTERISATION OF TASTE AND SMELL CHANGES
Taste and smell changes can be broadly classified into three categories: loss of sensitivity,
distorted perception, and hallucination (Table 4). Dysfunction of both taste and smell
commonly co-occur1, 5, 35. Increased and decreased objective clinical thresholds for basic
tastes (sweet, sour, salty, bitter and umami (the savouriness of protein-rich foods)) have
been reported pre- and post-treatment5, 22, 56. It is uncertain whether this lack of consensus
about clinical thresholds is due to varied measurement techniques or other reasons like
tumour type or treatment regimens57. Bitterness is the basic taste reported to be most
distorted by cancer and its treatment, in terms of both frequency and magnitude58. Metallic
or ‘nauseating’ tastes are common59, the former being present in 32% with breast,
colorectal, head and neck, lung, stomach, and other cancers50 and in 16% with lung cancer60.
Elevated salt thresholds have also been documented, both objectively and subjectively2, 61.
Phantogeusia (Table 4) has not been reported in cancer patients53.
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Table 4: Definitions of Taste and Odour Disorders62
.
There is little literature on smell changes, as noted above, but higher odour thresholds
(reduced sensation)63 and stronger olfactory sensations1 have been observed, both
subjectively and objectively. Distorted smell perception is often described as rancid64. In
cancer, regardless of tumour site, qualitative changes in smell perception like altered
discrimination predominate8. Hallucinations may also occur during strong emotional
experiences, such as receiving CT; someone may experience a chemical odour due to
treatment anxiety65. Odour signals are processed in the limbic system, which also handles
memories and emotions66.
There are discrepancies between experimental data on the characterisation of
chemosensory changes and patient reports26. This may reflect the link between retronasal
olfaction and improved taste13. In particular, Henkin et al.67 recently demonstrated that
hyposmia was associated with increased salt intake.
4. CHEMOSENSORY DYSFUNCTION AND SYMPTOM CLUSTERS
Clinical experience and research suggest that many cancer symptoms e.g. anorexia, dry
mouth, taste changes and weight loss are interrelated and occur together in groups or
clusters68, 69. Various descriptions of a symptom cluster exist, yet a consensus definition has
not been established70. In addition, there is no agreement as to what constitutes a symptom
cluster71, whether they share a common pathophysiology69, or whether one symptom
Disorder Definition
Taste-related abnormality
Ageusia
Hypogeusia
Dysgeusia
Phantogeusia
Heterogeusia
Absence.
Decreased sensitivity.
Distortion.
Perception without an external stimulus.
Inability to differentiate between tastes.
Odour-related abnormality
Anosmia
Hyposmia
Dysosmia
-Parosmia
-Agnosia
Phantosmia
Absence.
Decreased sensitivity.
Distorted ability to identify odours.
Inability to identify an odour’s ‘natural’ smell.
Inability to discriminate perceived odours.
Odour perception without any odour.
8
cluster can potentiate another. In particular, Honea et al.72 found that when CT stimulates
chemoreceptor trigger zones, it causes nausea and vomiting, which is associated with
reduced appetite, altered taste and fatigue.
Nevertheless, one research group has recently described a symptom cluster as “a stable
group of two or more symptoms that predictably co-occur and are independent of other
clusters”73. Seven clusters have been identified69, with taste change featuring as part of the
fatigue/anorexia-cachexia cluster (Table 5). The relationship between these changes,
particularly in the absence of therapy, requires greater scrutiny5, since symptom clusters
may not correlate with tumour burden71. Correct categorisation of clusters is likely to be
therapeutically important because management of one symptom may be influenced by
another in the cluster74, e.g. taste changes and anorexia.
Table 5: Characterisation of Cancer Symptom Clusters69
.
4.1 Fatigue/Anorexia-Cachexia Symptom Cluster and Nutritional Status
Symptom clusters can interfere with appetite and ability to eat5, 75, and may be one
determinant of the cancer anorexia-cachexia syndrome32. This significantly affects
nutritional status76. Malnutrition has been identified in 40% of hospitalized cancer patients,
regardless of disease stage77, and up to 90% of those with advanced cancer78, 79.
Interestingly, Khalid et al.80 noted that people who do not have a mechanical cause for
malnutrition e.g. in colorectal cancer, experience symptoms which could negatively affect
nutritional status. This highlights the importance of identifying and managing these
symptoms, such as taste and smell changes.
Cluster Symptoms
1. Aerodigestive Cough, dysphagia, dyspnoea, hoarseness.
2. Debility Confusion, oedema.
3. Fatigue/anorexia-cachexia Anorexia, dry mouth, early satiety, easy fatigue, taste
change, weakness, weight loss (>10 %).
4. Nausea and vomiting Nausea, vomiting.
5. Neuropsychological Anxiety, depression, sleep problems.
6. Pain Constipation, pain.
7. Upper gastrointestinal Belching, bloating, dizzy spells, dyspepsia.
9
Altered chemosensation can interfere with the hedonic value and normal physiological
responses to food and cause food aversion8. This may occur pre-treatment, inhibiting food
intake81. A substantial decrease in calorie intake (430-1100 kcal/day) associated with severe
taste and smell changes has been reported in advanced cancer1, 5, 7. Average energy intake
in this population subgroup (19 kcal/kg BW/day)5 was significantly below typical basal
metabolic rates (22-24 kcal/kg/day)82.
Not only is energy intake reduced, but a decreased diversity of foods is consumed. In
another study, up to 55% experienced an unpleasant bitter taste and odour of high-protein
foods, especially red meat, and so avoided them81. People with advanced cancer with
altered taste had a significantly lower mean percentage energy contribution from protein
compared with those without taste changes83. Protein metabolism is also dysregulated in
cancer and correlated with muscle wasting84. However, Ovesen et al.85 showed that in
breast, lung and ovarian cancer, pre-treatment taste and smell changes did not reduce
energy and protein intake. They hypothesised that patients may have increased their food
intake to achieve a certain level of sensory stimulation85.
Understanding and addressing the association between irregular chemosensory function,
related symptoms and dietary intake may improve nutritional status in cancer patients. In
the elderly, sensory enhancement of food increased dietary intake86 and improved
functional status87. This is particularly important since malnutrition significantly reduces
cancer survival rates. In addition, it predicts poor tolerance of treatment88. There is an
increased frequency and severity of CT89,89 and RT toxicity90, 91 and post-operative
complications92. Furthermore, economic burden may be greater due to increased length of
stay and treatment costs93. Finally, malnutrition in cancer has been associated with
irreversible muscle and weight loss94. Early recognition is, therefore, vital.
4.2 Impact on Quality of Life
Chemosensory alterations can induce stress, anxiety and depression and contribute to a
poor quality of life for patients and caregivers5, 19. Patients may feel guilty when unable to
participate in meal preparation or attend social events, for example, due to intolerable food
odours1. A caregiver may become anxious and frustrated after a carefully prepared meal is
rejected, generating conflict. Thus, chemosensory changes can affect patients
physiologically, psychologically and socially, and reduce overall quality of life1.
10
5. CONCLUSIONS
Most research about taste and smell changes in cancer involves patients undergoing CT or
RT. Prevalence estimates of chemosensory changes range from 14-80% in the former and
50-100% of the latter. Probable mechanisms for such therapy-induced changes have been
identified. However, there is little literature on taste and smell changes in treatment-naive
cancer patients, and variation exists in published studies. The pathophysiology and
characteristics of such changes in this patient group are unknown, despite research which
shows an association between chemosensory dysfunction, malnutrition and poor
psychosocial wellbeing.
Chemosensory dysfunction can be part of a cluster of symptoms, the categorisation of which
may affect treatment options. However, the relationship between symptoms has not been
clearly defined. Management of taste and smell changes in cancer remains a challenge,
particularly given the lack of experimental research. Given the heterogeneity of
chemosensory changes in cancer, a greater understanding of these abnormalities may allow
earlier intervention, prevent weight loss complications, enhance quality of life, and
ultimately increase survival time.
11
Ca, Cancer; CT, Chemotherapy; FAACT, Functional Assessment of Anorexia/Cachexia Therapy; GI, Gastrointestinal; NA, Not Assessed; NS, Not Significant; PG-SGA, Patient
Generated Subjective Global Assessment; RT, Radiotherapy; SC, Smell Changes; TC, Taste Changes; TSCs, Taste and Smell Changes.
References Patient Population
Instruments Prevalence of TSCs Characterisation of TSCs
Subjective Objective
DeWys and Walters, 1975
95
-N=50 metastatic Ca (mixed). -N=23 controls.
Semi-structured interviews.
Henkin’s 3-drop forced-choice test
96.
TCs: 50% (patients).
Taste: Ca vs. controls: -Elevated sweet threshold. -Lowered bitter threshold. -Meat aversion: 32%. -Bitter taste with coffee or chocolate: 20%.
Williams and Cohen, 1978
56
-N=30 lung Ca. -N=30 controls.
NA Henkin’s 3-drop forced-choice test
96.
NA Taste: Ca vs. controls: -Significant reduction in sour acuity. -Elevated sweet recognition threshold (NS).
Kamath et al., 198340
-N=12 oesophageal Ca. -N=14 controls.
NA Henkin’s 3-drop forced-choice test
96.
NA Taste: Ca vs. controls: NS differences in detection and recognition thresholds between groups.
Ovesen et al., 199185
-N=31 Ca (mixed).
NA -Electrogustometry. -Odour thresholds for dilutions of pyridine in mineral oil.
TCs: 16%. SCs: 10%.
NA
Harris et al., 200397
-N=99 Ca post upper GI surgery.
Questionnaire. NA TCs and/or SCs: 45%. TSCs: 18%.
NA
Hutton et al., 20075 -N=66 advanced
Ca (mixed). -3-day food record. -FAACT Questionnaire. -Taste and Smell Survey
6
NA TCs and/or SCs: 86%. TSCs: 52%. TCs only: 30%. SCs only: 5%.
Taste: Increased bitter (23%) and sour (27%) sensitivity. -11% reported TCs as ‘severe’ or ‘incapacitating’. Smell: Increased sensitivity (20%). -5% reported SCs as ‘severe’ or ‘incapacitating’.
Steinbach et al., 2010
98
-N=69 breast Ca. NA ‘Taste Strips’. ‘Sniffin’ Sticks’.
NA Compared to normative data: Taste: Significantly lower sour sensitivity. Smell: NS difference in thresholds.
Mahmoud et al., 2011
34
-N=15 advanced Ca (mixed).
-Questionnaire. -TC checklist.
Modified Henkin’s 3-drop forced-choice test
96.
TCs: 80%.
Taste: All food tasteless: 53%. -All food bitter: 20%. -Persistent chocolate taste: 13%. -Meat aversion: 33%. -Alcohol aversion: 33%. -Dislike for sweet food: 67%.
Belqaid et al., 201435
-N=117 lung Ca. -N=98 controls.
-Taste and Smell Survey
6.
-PG-SGA.
NA TSCs: 38% (patients and controls).
NA
Table 1: Studies of Taste and Smell Changes in Treatment-Naive Cancer Patients.
12
Table 3: Objective Measures of Chemosensory Function.
TASTE: Test Description Advantages Disadvantages
Application of dilutions of basic taste substances of
varied strengths18, 99, 100
Assesses whole mouth or localized
sensitivity and recognition of taste of
exponentially increasing strength101
.
Reproducible56
. Reliability and validity not established102
.
Time consuming and laborious103
.
Electrogustometry103, 104
Electrical current (microampere range)
applied to receptors by an electrode to
assess taste detection53
.
Reliable104
.
Reproducible104
.
Limited clinical use due to poor
correlation between electrically and
chemically induced taste perception105
.
Does not measure recognition53
.
‘Taste Strips’22
Filter paper impregnated with taste
solution applied to receptors to measure
detection and recognition53
.
Reproducible104
.
Normative data available106
.
Time and cost-effective53
.
Thresholds may differ depending where
on the tongue the stimulus is applied103
.
SMELL:
Inhalation of solutions of phenyl methyl-ethyl-
carbinol85, 100
or phenethyl and menthol100
Administered via nasal spray to assess
odour detection107
.
Reliable107
.
Reproducible107
Significant within- and across-subject
variability108
.
Significant day-to-day variability109
.
Sniffin’ Sticks22, 110
Pen-like odour dispensing devices for
identification, recognition and
discrimination thresholds22
.
Validated in various
populations111, 112
.
Normative data available113
.
Cost-effective114
.
Needs cultural adaptation111, 112
.
May be prone to learning effects22
.
University of Pennsylvania Smell Identification
Test115
Impregnated odour cards, scratched to
determine odour identification116
.
Normative data available116
. Does not measure detection
thresholds115
.
13
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