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.

7

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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