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University of Groningen
Taste and smell changes in cancer patients
IJpma, Irene
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1
General introduction
1
Taste and smell
Taste and smell are two of the five senses of the human body, next to vision, hearing, and
touch. All senses play a role in the pleasure of eating. Taste and smell are chemosensory
senses. These senses respond to binding of molecules that are dissolved in fluid on
receptors. Patients with cancer often experience taste and smell changes. In order to
improve our understanding of these chemosensory changes, this introduction starts with
a short overview of the general function and mechanism of taste and smell. This will
be followed by a description of taste and smell changes in patients with cancer. Next,
attention will be given to oral nutritional supplements (ONS) and to the study population
of testicular cancer patients in relation to taste and smell research. At last, the aim and
thesis outline are described.
Taste function
Taste is also known as gustation. The function of taste is to determine whether or not
to eat something. The sensation of taste consists of five primary qualities: sweet, sour,
salty, bitter, and umami (savoury). Each taste quality is associated with a particular
physiological function. Sweet taste is tuned to detect the energy content of foods. Sour
taste is used to guard the acid-base balance in the body. The function of salty taste is to
maintain the electrolyte balance in the body. Bitter taste is a sign for toxins and umami
taste drives the protein intake [1,2].
The sense of taste is stimulated when nutrients or other chemical compounds
enter the mouth and activate taste receptor cells. Taste receptor cells are clustered in
taste buds. A taste bud contains approximately 50-100 taste receptor cells, representing
all five primary tastes [2,3]. The tongue contains the highest density of taste buds, but
taste buds are also found on the soft palate (back on the roof of the mouth), pharynx,
larynx, and epiglottis [3]. Taste buds are located in structures called ‘papillae’. The human
tongue contains four types of papillae: fungiform, circumvallate, foliate, and filiform
papillae [1]. The papillae increase the area of contact between the tongue and food. All
papillae, except the filiform papillae, contain taste buds. The filiform papillae serve a
tactile function. The lifespan of taste receptor cells is short, varying from a couple of
days to a month, and they are continuously replaced [1,4].
Salty and sour chemicals are detected by ion channel receptors. Sweet, bitter,
10
General introduction
and umami qualities are detected by G-protein-coupled receptors (sweet: T1R2 + T1R3;
bitter: T2Rs; umami: T1R1 + T1R3). When taste receptor cells are stimulated, these
cells become depolarized, produce action potentials, and release neurotransmitters
that stimulate nearby sensory neurons associated with taste buds. Taste buds of the
anterior two-thirds of the tongue are innervated by the facial nerve (central nerve (CN)
VII), the posterior one third of the tongue is innervated by the glossopharyngeal nerve
(CN IX), and the pharynx and larynx are innervated by the vagus nerve (CN X). The taste
signals are sent to the solitary tract in the brainstem, next to the insular cortex and
subsequently to the orbitofrontal cortex [1,3,5,6].
Smell function
Smell is also known as olfaction. Compared to the five tastes, the number of odorants is
almost unlimited. Approximately 80% of what we perceive as taste is actually due to the
sense of smell. Therefore, both senses are important in the acceptance of foods. The
sense of smell is stimulated in two ways: orthonasal and retronasal. Orthonasal smell
refers to the perception of odours through the nose during sniffing. Retronasal smell
is the perception of odours through the mouth during eating and drinking. When food
enters the mouth, the primary tastes are merged with the smell of foods [1]. The term
‘flavour’ has been defined as the combination of taste and smell, together with texture
and trigeminal (chemical irritation) sensations [6].
Odours are detected by olfactory sensory neurons, which are located at the top
of the nasal cavity (olfactory epithelium). After detection, olfactory signals are sent
to the olfactory bulb via the olfactory nerve (CN I). Smell is the only human sense
that bypasses the thalamus and connects directly to the forebrain. The neurons of the
olfactory epithelium synapse with the neurons in the olfactory bulb of the cerebral
cortex. The synapses occur in rounded structures called ‘glomeruli’. Every neuron
responds to different odours, although with varying intensity. Neurons expressing the
same odorant receptor send their axon to the same glomerulus. From the olfactory
bulb olfactory signals are mostly sent to the piriform cortex and subsequently to the
orbitofrontal cortex [5,6]. Like taste receptor cells, olfactory receptor neurons have
the ability to regenerate. Olfactory receptor neurons have an average lifespan of 1-2
months [1,5].
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1
Taste and smell changes in patients with cancer
Patients with cancer undergoing chemotherapy often experience treatment-related side
effects. Common side effects are: fatigue, hair loss, nausea, vomiting, loss of appetite,
and changes in taste and smell perception [7-9]. Research has most often focused on
nausea and vomiting, whereas taste and smell changes have received less attention.
Nevertheless, taste and smell changes are common in cancer patients treated with
chemotherapy with a prevalence ranging from 45% to 84% for taste changes and 5%
to 60% for smell changes [10]. Taste and smell changes can be categorized into the
following categories: absence of perception, decreased sensitivity, increased sensitivity,
distorted perception or hallucination (Table 1) [11,12].
Changes in taste and smell perception can have detrimental effects in cancer
patient’s daily life. These chemosensory changes in patients with cancer have been
associated with appetite loss [13-16], a decreased energy intake [17-21], weight
loss [19,22], reduced food enjoyment [18,23], nausea [14-16], high levels of distress
[24], depressed mood [15], early satiation [16], and a lower general quality of life
[19,21]. Furthermore, patients may develop unhealthy eating patterns due to taste
and smell changes, resulting in overweight. A cross-sectional study in 118 patients
with chemosensory changes of various etiologies and 40 healthy controls showed that
patients with a decreased taste and/or smell function reported weight gain more
often. In contrast, patients with a distorted or phantom taste and/or smell reported
weight loss more frequently [25]. A study in a heterogeneous cancer population of 539
patients showed that patients with only smell changes reported more often weight gain
than patients with both taste and smell changes [26]. Several studies indicate a high
prevalence of obesity among cancer survivors [27,28]. Whether changes in taste and
smell perception play a role remains to be elucidated.
The nature of taste and smell changes varies among patients with cancer during
chemotherapy. So far, data regarding the affected taste quality (sweet, sour, salty or
bitter) are inconsistent. Furthermore, both increased and decreased sensations have
been found [29]. This can be due to the fact that most studies regarding taste and smell
changes are performed in heterogeneous cancer populations with various malignancies,
treatments, and treatment phases.
12
General introduction
Table 1 Categorization of taste and smell changes [11,12].
Taste dysfunction
Ageusia
Complete loss of ability to taste
Hypogeusia
Decreased sensitivity to taste perception
Hypergeusia
Increased sensitivity to taste perception
Dysgeusia
Distortion of taste perception
Phantogeusia
Perception of taste without an external stimulus
Smell dysfunction
Anosmia
Complete loss of ability to smell
Hyposmia
Decreased sensitivity to odour perception
Hyperosmia
Increased sensitivity to odour perception
Dysosmia
Distortion of odour perception
Phantosmia
Perception of odour without an external stimulus
The exact mechanism underlying taste en smell changes in cancer patients treated
with chemotherapy is unknown. An important factor seems to be damage of taste and
smell receptor cells. Chemotherapy agents act on rapidly dividing cells. Consequently,
not only cancer cells are affected, but taste en smell receptor cells as well, given their
high turnover rate. This can explain the fact that taste and smell function can be transient
and recover within several months after chemotherapy [16,17,30]. However, taste and
smell changes have been reported in patients with cancer years after treatment [31].
Probably, additional factors are involved in the etiology of taste and smell changes in
those patients. Literature regarding these long-term taste and smell changes is scarce.
Most studies regarding taste changes in patients with cancer have focused on the
presence of taste changes in general (yes/no) or investigated changes in the perception
of the taste qualities sweet, sour, salty, and bitter. A metallic taste is a typical taste
alteration frequently reported by patients with cancer. This taste alteration has received
limited attention. Therefore, we will focus on metallic taste in this thesis (Chapter 4
and 5).
Oral Nutritional Supplements (ONS)
ONS are commonly prescribed to malnourished patients to improve their nutritional
status. ONS can be used in addition to normal food consumption to increase nutrient
intake. The hedonic evaluation of orosensory food cues under standardized conditions,
13
1
also referred to as palatability [32], plays an important role in the acceptance of ONS
[33-35]. Besides, the perceived flavour of the ONS may be affected by changes in taste
and smell perception in patients with cancer. Previous research has not focused on the
relation between taste and smell changes in patients with cancer and the palatability of
ONS. This thesis will provide further insights on this subject (Chapter 6).
Testicular cancer patients
In this thesis we will specifically focus on the study population of testicular cancer patients
(Chapter 2). Since most studies regarding taste and smell changes are performed in
heterogeneous cancer populations with various malignancies and treatments, testicular
cancer patients are an interesting study population, given their homogeneity regarding
gender, cancer type, and standardized chemotherapy regimen. Besides, these cancer
patients are relatively young, with a peak prevalence between 25 and 40 years of age
[36]. This will reduce confounds due to age, since taste and smell function are known to
decrease with advancing age [37].
Approximately 700 patients are diagnosed with testicular cancer each year in
the Netherlands [38]. Initial treatment of testicular cancer consists of orchidectomy.
When metastases are present, systemic treatment with cisplatin-based chemotherapy is
indicated [39]. Currently, most patients receive cisplatin-based chemotherapy consisting
of bleomycin, etoposide and cisplatin (BEP) or etoposide and cisplatin (EP). The patients
receive three or four cycles of chemotherapy with a cycle interval of 21 days.
Since the introduction of cisplatin, metastatic testicular cancer has become a
highly curable disease [40]. Given the long life expectancy of these patients with a
10-year survival rate of more than 95% [40], long-term effects can be investigated. The
downside of this treatment is the possible development of long-term complications, such
as the high prevalence of overweight and metabolic syndrome, and the increased risk
of cardiovascular disease (CVD) [27,41,42]. Given the increase in BMI and increased risk
of CVD, attention to dietary intake and food preference of testicular cancer survivors
seems warranted. In this thesis we will provide insights on the taste and smell function,
food preference, dietary intake, and body composition of these survivors (Chapter 3).
14
General introduction
Aim and thesis outline
The studies described in this thesis aim to investigate taste and smell changes and their
short- and long-term consequences in patients with cancer. With knowledge regarding
the nature, prevalence, and duration of taste and smell changes, a better prediction of
food acceptance can be given at the start, during, and after chemotherapy to maintain
a healthy diet or, if necessary, improve the diet. Besides, this research aims at obtaining
valuable information for industry with regard to the development of (medical) food
products.
In Chapter 2, short-term changes in taste and smell function, food preference,
dietary intake, and body composition are investigated in testicular cancer patients
treated with cisplatin-based chemotherapy.
In Chapter 3, long-term taste and smell dysfunction and the influence on dietary
intake, food preference, and body composition are explored one to seven years after
testicular cancer survivors were treated with cisplatin-based chemotherapy.
Next to changes in the perception of the primary tastes, the experience of metallic
taste reported by patients with cancer is examined. First, a literature review is carried
out to investigate all available studies regarding metallic taste in cancer patients treated
with chemotherapy (Chapter 4). The definition of metallic taste, assessment methods,
prevalence, duration, possible causes due to chemotherapy, and management strategies
are addressed. Next, a study is carried out to explore the prevalence of metallic taste
in cancer patients treated with systemic therapy (Chapter 5). Furthermore, possible
predictors of metallic taste regarding age, gender, treatment type, treatment phase,
and factors related to taste changes are investigated. In addition, characteristics of
metallic taste, including the perceived intensity, the duration, and consequences
regarding food intake are explored.
In Chapter 6, the palatability of ONS is examined in testicular cancer patients
treated with cisplatin-based chemotherapy. Moreover, the relation between the
palatability and taste and smell function of these patients and whether certain types of
ONS elicit a metallic sensation are investigated.
Finally, in Chapter 7 the main results of all studies are discussed. Implications
and suggestions for future research are presented.
15
1
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General introduction
19