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Taste and smell changes in cancer patientsIJpma, Irene

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Taste and smell changes in cancer patients

Irene IJpma

Paranymphs:

Jolien M. Admiraal

Olaf P. Geerse

The studies presented in this thesis were performed within the framework of Top

Institute Food and Nutrition at the Neuroimaging Center Groningen and the Department

of Medical Oncology, University of Groningen, University Medical Center Groningen.

The publication of this thesis was financially supported by TI Food and Nutrition, Stichting

Werkgroep Interne Oncologie, the University of Groningen and University Medical Center

Groningen, and is gratefully acknowledged.

Cover design and lay-out: Erik Huisman, Irene IJpma

Icons cover designed by: Freepik from Flaticon

Printed by: Ipskamp Printing

ISBN (printed version): 978-90-367-9691-0

ISBN (digital version): 978-90-367-9690-3

© 2017 Irene IJpma

Taste and smell changes in cancer patients

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de rector magnificus prof. dr. E. Sterken

en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op

woensdag 3 mei 2017 om 14.30 uur

door

Irene IJpma

geboren op 2 juli 1985 te Veendam

Promotores Prof. dr. G.J. ter Horst Prof. dr. A.K.L. Reyners Prof. dr. M.M. Lorist Copromotor Dr. R.J. Renken Beoordelingscommissie Prof. dr. G.J. Navis Prof. dr. I.J. de Jong Prof. dr. ir. E. Kampman

Contents

Chapter 1 General introduction

Chapter 2 Changes in taste and smell function, dietary intake, food

preference, and body composition in testicular cancer patients

treated with cisplatin-based chemotherapy

Clinical Nutrition, 2016, in press

Chapter 3 Taste and smell function in testicular cancer survivors treated

with cisplatin-based chemotherapy in relation to dietary intake,

food preference, and body composition

Appetite 2016;105:392-399

Chapter 4 Metallic taste in cancer patients treated with chemotherapy

Cancer Treatment Reviews 2015;41:179-186

Chapter 5 Metallic taste in cancer patients treated with systemic therapy: a

questionnaire-based study

Nutrition and Cancer 2017;69:140-145

Chapter 6 The palatability of oral nutritional supplements: before, during,

and after chemotherapy

Supportive Care in Cancer 2016;24:4301-4308

Chapter 7 General discussion

Chapter 8 Summary

Nederlandse samenvatting (summary in Dutch)

Dankwoord

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General introduction

1

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1

Taste and smellTaste 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 functionTaste 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,

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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 functionSmell 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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Taste and smell changes in patients with cancerPatients 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.

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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,

14

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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 patientsIn 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).

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Aim and thesis outlineThe 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.

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[31] Cohen J, Laing DG, Wilkes FJ, Chan A, Gabriel M, Cohn RJ. Taste and smell dysfunction in childhood cancer survivors. Appetite 2014;75:135-40.

[32] Yeomans MR. Taste, palatability and the control of appetite. Proc Nutr Soc 1998;57:609-15.

[33] Ravasco P. Aspects of taste and compliance in patients with cancer. Eur J Oncol Nurs 2005;9 Suppl 2:S84-91.

[34] Gosney M. Are we wasting our money on food supplements in elder care wards? J Adv Nurs 2003;43:275-80.

[35] Ozçagli TG, Stelling J, Stanford J. A study in four European countries to examine the importance of sensory attributes of oral nutritional supplements on preference and likelihood of compliance. Turk J Gastroenterol 2013;24:266-72.

[36] Rajpert-De Meyts E, Skakkebaek NE, Toppari J. Testicular Cancer Pathogenesis, Diagnosis and Endocrine Aspects. In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc; 2000.

[37] Schiffman SS, Graham BG. Taste and smell perception affect appetite and immunity in the elderly. Eur J Clin Nutr 2000;54 Suppl 3:S54-63.

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[39] Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. Medical treatment of advanced testicular cancer. JAMA 2008;299:672-84.

[40] Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L, et al. Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol 2007;8:784-96.

[41] van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MWJ, Ribot JG, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2007;25:4370-8.

[42] Willemse PM, Burggraaf J, Hamdy NAT, Weijl NI, Vossen CY, van Wulften L, et al. Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors. Br J Cancer 2013;109:60-7.

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Irene IJpmaRemco J. Renken Jourik A. Gietema Riemer H.J.A. SlartManon G.J. MensinkJoop D. LefrandtGert J. Ter HorstAnna K.L. Reyners

Published in Clinical Nutrition, article in press

Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy

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AbstractBackground & aims: Taste and smell changes due to chemotherapy may contribute

to the high prevalence of overweight in testicular cancer patients (TCPs). This study

investigates the taste and smell function, dietary intake, food preference, and body

composition in TCPs before, during, and up to 1 year after cisplatin-based chemotherapy.

Methods: Twenty-one consecutive TCPs participated. At baseline TCPs were compared

to healthy controls (N = 48). Taste strips and ‘Sniffin’ Sticks’ were used to determine

psychophysical taste and smell function. Subjective taste, smell, appetite, and hunger

were assessed using a questionnaire. Dietary intake was analyzed using a food frequency

questionnaire. Food preference was assessed using food pictures varying in taste

(sweet/savoury) and fat or protein content. A Dual-Energy X-ray Absorptiometry (DEXA)

scan was performed to measure whole body composition.

Results: Compared to controls, TCPs had a lower smell threshold (p = 0.045) and

lower preference for high fat sweet foods at baseline (p = 0.024). Over time,

intra-individual psychophysical taste and smell function was highly variable. The

salty taste threshold increased at completion of chemotherapy compared to baseline

(p = 0.006). A transient decrease of subjective taste, appetite, and hunger feelings

was observed per chemotherapy cycle. The percentage of fat mass increased during

chemotherapy compared to baseline, while the lean mass and bone density decreased

(p < 0.05).

Conclusions: Coping strategies regarding subjective taste impairment should especially

be provided during the first week of each chemotherapy cycle. Since the body

composition of TCPs already had changed at completion of chemotherapy, intervention

strategies to limit the impact of cardiovascular risk factors should probably start during

treatment.

Keywords: Taste, smell, food, body composition, testicular cancer, cisplatin

chemotherapy

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Introduction Taste and smell perception play a significant role in appetite, dietary intake, and food

choice [1]. Cancer patients often experience changes in taste and smell perception

during chemotherapy. These chemosensory changes can result in change of dietary

intake, malnutrition, weight loss, and a decreased quality of life [2-4].

The nature of taste and smell changes is variable among cancer patients during

chemotherapy [5]. Data regarding the affected taste quality (sweet, sour, salty or

bitter) are inconsistent and both increased and decreased sensations have been found.

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 different disease phases. A recent longitudinal study investigated the taste function,

food liking, and appetite in 52 breast cancer patients treated with anthracycline

and/or taxane-based chemotherapy [2]. In that study, a decreased taste function

was found, particularly during the first days (day 4-6) of a chemotherapy cycle. The

changes in taste, appetite, and food liking were temporary per chemotherapy cycle.

Another longitudinal study investigated the taste and smell function in 87 patients with

breast cancer or a gynaecologic malignancy, heterogeneous regarding chemotherapy

regimen and disease stage [6]. A decreased taste and smell function was found during

chemotherapy, which recovered almost completely within 3 months after chemotherapy.

In addition, a decrease in taste and smell function was found in a subset of that study,

consisting of 12 ovarian cancer patients treated with carboplatin-based therapy [7].

Testicular cancer patients (TCPs) are an interesting study population to investigate

the effect of taste and smell changes due to chemotherapy, given the homogeneity

regarding treatment with cisplatin-based chemotherapy and the curative intent. 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) [8-10]. Moreover, hypogonadism is a common side effect

of an orchidectomy, influencing body composition. Given these possible complications

of a curative treatment in this young population, attention to dietary intake, food

preference, and body composition is warranted, both during and after chemotherapy.

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The aim of this study was to investigate whether a systematic pattern of changes

in taste and smell function, food preference, dietary intake, and body composition can

be found and persists over time in TCPs treated with cisplatin-based chemotherapy.

Materials and methods Study population TCPs scheduled to receive first line chemotherapy consisting of bleomycin, etoposide

and cisplatin (BEP) or etoposide and cisplatin (EP) were eligible to participate. Patients

received three or four 3-weekly cycles of chemotherapy. Patients received a standard

regime with intravenous antiemetics during each cycle of chemotherapy on day 1

before start (150 mg fosaprepitant, 1 mg granisetron, and 10 mg dexamethasone), 8 mg

dexamethasone at day 1, 2 and 3 after chemotherapy, and metoclopramide if necessary

(3 x 10 mg). Patients eligible to participate were 18-50 years of age at start of treatment

and were able to comprehend Dutch. Patients were excluded when they had a mental

disability and/or comorbidities affecting taste and/or smell function. Forty patients

were planned to recruit. Patients were compared to a healthy control group just before

start of chemotherapy to explore possible differences in taste and smell function, food

preference, dietary intake, and body composition due to the presence of disseminated

disease. The controls were recruited as part of a cross-sectional study. In that study,

controls were matched to a group of testicular cancer survivors regarding age, gender,

and nationality. Inclusion criteria of the controls were: 18-50 years old and ability to

comprehend Dutch (both reading and writing). Exclusion criteria were: medication

use, mental disability, a history of cancer, and taste and/or smell abnormalities.

All participants gave written informed consent. The longitudinal as well as the

cross-sectional study were approved by the ethical committee at the University Medical

Center Groningen (NCT01641172).

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Methods Figure 1 displays the collected data at each time point. For the healthy controls, all

measurements were performed only once. The questionnaire regarding subjective taste,

smell, appetite, and hunger was only completed by the patients. Data on height, smoking

status, level of education, and sports level were collected during a structured interview

at baseline. Data concerning disease and treatment were derived from medical records.

Collected data Pre-CT

Baseline

During first cycle

Day 7 first cycle

Before second cycle

Day 1 second cycle

During second cycle

Day 7 second cycle

End second cycle

Day 21 second cycle

At completion

1 month after start last cycle

7 months after start

CT

1 year after start

CT

T0 T1 T2 T3A T3B T4 T5 T6

Age x

Smoking status x

Sports level x

Educational level x

Height x

Weight x x x x x x x

Taste function x x x x x x x

Smell function x x x x x x x

Subjective taste, smell, hunger, appetite

x x x x x x x

Dietary intake x x x x x x

Food preference x x x x x x x

Body composition x x x

Hormone levels x x x

Figure 1 Collected data at each time point. CT = chemotherapy.

26

Psychophysical taste function Filter-paper taste strips (Burghart, Wedel, Germany) were used to determine sweet,

sour, salty, and bitter taste thresholds [11]. The following standard concentrations of

each taste were used: sweet: 0.05, 0.1, 0.2, and 0.4 g/ml sucrose; sour: 0.05, 0.09,

0.165, and 0.3 g/ml citric acid; salty: 0.016, 0.04, 0.1, and 0.25 g/ml sodium chloride;

bitter: 0.0004, 0.0009, 0.0024, and 0.006 g/ml quinine hydrochloride. Participants had

to choose one of five possible answers: sweet, sour, salty, bitter or no taste. Scores for

each taste range from 0 to 4. A total taste score was derived by summing the scores of

each taste and ranged from 0 to 16.

Psychophysical smell function To assess the psychophysical smell function, ‘Sniffin’ Sticks’ (Burghart, Wedel, Germany)

were used [12,13]. This test consists of pen-like odour dispensing devices. The

measurement includes three parts: a threshold (THR) test, a discrimination (DIS) test,

and an identification (ID) test. A standard series of pens with 16 dilutions of n-butanol

was used to measure the THR. Three pens were presented in a randomized order, of

which one contained the odorant and two solvent. Participants had to identify the pen

containing the odorant. To measure the DIS, 16 triplets (two equal odorants and one

different odorant) were presented. Participants had to discriminate which of the three

pens smelled differently. To measure the ID, 16 common odours were presented and the

participants had to identify the odour using a multiple choice task. The THR score ranges

from 1 to 16. The DIS and ID scores range from 0 to 16. A total smell score was derived

by summing the THR, DIS and ID, resulting in a threshold, discrimination, identification

(TDI) score (range 1-48). The extended version of the ‘Sniffin’ sticks’ was used, which

contains 32 odour combinations for the DIS test and 32 odours for the ID test [14]. The

combinations of pens were randomized across participants and test sessions.

Dietary intake Dietary intake was assessed using a food frequency questionnaire (FFQ), which has been

validated to estimate the intake of energy, macronutrients, fatty acids, cholesterol,

fiber, folate, vitamin B6, and B12 for the Dutch population [15-17]. It is an 183-item

questionnaire, in which participants report the consumption frequency of a defined list

of foods over the past month. The FFQs were checked for missing or unusual reports,

2

27


and if necessary, additional information was obtained from participants by telephone.

Unusual reports were defined as a difference between the amount of bread and sandwich

fillings of more than two and/or reports with less than 16 or more than 40 dinners per

month. The Dutch food composition database 2011 was used to convert the data into

nutrients [18].

Food preference Food preference was assessed using a computer task consisting of food pictures varying

in taste (sweet/savoury) and in fat or protein content [19,20]. Relative food preference

was investigated by showing paired food pictures on a tablet device (Apple, iPad2).

The relative food preference was measured as the frequency of choice for each food

category. Two sets of 16 pictures of snack products were used. One picture set contained

four foods of each of the following categories: high fat savoury (HFSA), high fat sweet

(HFSW), low fat savoury (LFSA), and low fat sweet (LFSW). The other set contained

similar categories based on protein content: high protein savoury (HPSA), high protein

sweet (HPSW), low protein savoury (LPSA), and low protein sweet (LPSW). The order of

the picture sets was randomized among the participants. More details of the specific

food stimuli and corresponding energy and macronutrient composition have been

described elsewhere [19,20]. A paired presentation of 16 foods of each set was shown

and participants had to select the food they would like to eat most at that point in time.

One food from one of the four categories was paired with one food from the remaining

categories, forming a series of 96 trials of each picture set.

Subjective taste, smell, appetite, and hunger The Appetite, Hunger and Sensory Perception (AHSP) questionnaire was used to determine

taste, smell, appetite, and hunger feelings subjectively [21]. This questionnaire includes

29 questions (5-point Likert scale) on taste perception (8 items, range 8-40), smell

perception (6 items, range 6-30), appetite (6 items, range 6-30), and feelings of hunger

(9 items, range 9-45). A higher score corresponds to a more positive feeling regarding

perceived taste and smell, a better appetite, and more hunger feelings.

28

Body composition A digital scale was used to measure body weight in light clothing, without shoes. Body mass

index (BMI) was calculated (kg/m2). A Dual-Energy X-ray Absorptiometry (DEXA) scan was

performed to measure body composition using a Hologic Discovery A densitometer (Hologic

Inc., Bedford, MA, USA). The total fat (total; trunk and abdominal fat mass separately),

lean, and bone mass (kg and %), and android-to-gynoid ratio were determined. Bone mineral

density of the lumbar spine (LS; anterior-posterior projection at L1–L4) was measured

(g/cm2) and expressed as a T-score [22].

Hormone levels In all participants blood samples were collected in the morning to measure testosterone

and luteinizing hormone (LH) levels.

Statistical analysis Descriptive statistics are presented as median with interquartile range (IQR) or

percentage. A linear mixed model was used to investigate taste, smell, dietary intake,

and food preference over time (T0-T4). An unstructured covariance type was used to

model the covariance structure among repeated measures. Test session was entered

as fixed effect in the model (T0 as baseline). Contrast comparisons were carried out to

explore possible differences during the second cycle (T2 versus T3A). All models were

estimated using maximum likelihood. The related-samples Wilcoxon signed-rank test

was used to compare all outcome variables at T5 and T6 to baseline (given the smaller

sample size at these time points). The Mann-Whitney U-test was used to compare

outcome variables between patients and controls at baseline. No adjustments were

made for multiple comparisons, given the exploratory nature of the present study.

A two-tailed p-value < 0.05 was considered statistically significant. Statistical analyses

were performed using SPSS, version 22 (IBM SPSS Inc. Chicago, IL).

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29


Results Characteristics of the study population Twenty-one consecutive patients with disseminated testicular cancer were enrolled

in the study. Data of 48 controls were derived from a parallel cross-sectional study.

Table 1 shows the baseline characteristics of the patients and controls. Measurements

were performed from July 2012 to April 2015. Four patients dropped out because they

did not want to continue the study (after T0: N = 2, after T1: N = 1, after T3A: N = 1).

One patient completed all measurements, but completed only the smell tests at T3

due to a treatment related adverse event. Another patient completed T0-T5, except

for the measurement at T1 due to a treatment related adverse event. Ten patients

completed all measurements up to T5 and seven patients up to T6 before the end of

the study period. One patient developed an oral candidiasis during the first and second

chemotherapy cycle.

Psychophysical taste and smell function Compared to controls, patients had a lower smell threshold at baseline

(p = 0.045; Table 2). Within patients, a wide variation of taste and smell changes was

found (see supplementary data for temporal dynamics of taste and smell function;

Table I). The threshold for salty taste was increased at completion of chemotherapy

(T4) compared to baseline (T0). No differences in smell function were found during

the course of treatment and follow-up period (T1 trough T6) in patients compared to

baseline (Table 2). The patients scored lower for odour discrimination and total smell

function during the second chemotherapy cycle (T3A) than before the start of the

second cycle (T2) (p = 0.008 and p = 0.018 respectively).

30

Table 1 Baseline characteristics of testicular cancer patients and healthy controls.

P-valueControls(N = 48)

Patients(N = 21)

32 (29-36)32 (27-36)Age (years), median (IQR)

80.7 (75.1-87.6)82.9 (74.4-91.6)Body weight (kg)

1.85 (1.79-1.90)1.82 (1.78-1.90)Height (m)

23.5 (21.7-25.8)24.3 (22.2-26.4)BMI (kg/m2)

Smoking, N (%)

29 (60)12 (57) No

10 (20)4 (19) Yes

9 (20)5 (24) Ex

Sports, N (%)

8 (17)7 (33) Never

17 (35)3 (14) 1-2 times/week

23 (48)11 (52) 3 or more times/week

0.0056 (5-7)4 (4-6)Educational level (range 1-7), median (IQR)a

Chemotherapy regime, N (%)

20 (95) BEP

1 (5) EP

Number of chemotherapy courses, N (%)

15 (71) 3

6 (29) 4

Type of cancer, N (%)

9 (43) Seminoma

12 (57) Non-seminoma

Prognosis, N (%)b

16 (76) Good

5 (24) Intermediate

0 Poor

IQR = Interquartile range, BEP = bleomycin, etoposide and cisplatin; EP = etoposide and cisplatin.

Only p-values < 0.05 are shown. aHighest completed educational level: range 1 (primary school) - 7 (university). bPrognosis classification according to the International Germ Cell Consensus Classification Group (IGCCCG).

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31


Table 2 Median (IQR) scores of taste and smell function of cancer patients at each time point and healthy controls

at baseline. P-values display differences in taste or smell function at each time point compared to baseline across

patients. The last column represents the main effect of time (p-value of fixed effect).

P-valuePatientsT6

(N = 7)

PatientsT5

(N = 10)

PatientsT4

(N = 17)

PatientsT3A

(N = 18)

PatientsT2

(N = 18)

PatientsT1

(N = 18)

PatientsBaseline(N = 21)

Controls

(N = 48)

Taste

4(3-4)

3(2-4)

3 (2-4)

3(2-4)a

3(2-4)

3(2-4)

3 (2-4)

3(3-4)

Sweet[0-4]

2(1-3)

2(2-2)

2 (2-3)

1(1-3)a

2(1-3)

2(2-2)

2(1-3)

2 2-3)

Sour [0-4]

0.0252(1-3)

3(1-3)

2(2-3)

P = 0.006

3(2-3)

3(2-3)

2 2-3)

3(3-3)

3(2-4)

Salty [0-4]

3(2-3)

2(1-4)

3(2-4)

2(1-3)a

3(1-3)

3(2-4)

3(3-4)

3(2-4)

Bitter[0-4]

11 (7-11)

9 (7-12)

10 (8-12)

10 (5-12)a

10 (6-13)

10 (7-11)

10 (9-12)

12 (9-13)

Total taste[0-16]

Smell

9.8(6.0-10.0)

8.8(7.4-10.3)

9.0(6.8-11.1)

9.8(8.4-10.8)

9.4(8.8-11.2)

10.0(7.5-10.8)

8.8(7.5-10.8)

7.6b

(6.5-9.0)THR[1-16]

14 (11-14)

14 (12-14)

13 (11-15)

13 (10-13)

14 (12-15)

13 (11-15)

13 (12-14)

13(11-14)

DIS[0-16]

13 (12-14)

13 (10-14)

13 (11-15)

13 (12-14)

13 (12-14)

13 (12-14)

13 (12-15)

13(11-14)

ID[0-16]

36.8(29.0-38.8)

34.5(30.6-37.0)

35.8(31.1-38.5)

34.6(32.4-38.3)

36.5(32.9-40.0)

35.0(31.5-39.9)

34.5(32.6-38.3)

33.5(30.5-35.3)

TDI[1-48]

IQR = Interquartile range, THR = threshold, DIS = discrimination, ID = Identification, aN = 17. Only p-values < 0.05

are shown. bSignificant difference between patients and controls at baseline (p = 0.045).

32

Subjective taste and smell function, appetite, and hunger Subjective taste function, appetite, and hunger feelings decreased during

the first (T1) and second chemotherapy cycle (T3A) compared to baseline

(Table 3). These parameters and smell function were also lower during the

second cycle (T3A) compared to before the start of the second cycle (T2)

(taste: p = 0.001, smell: p = 0.024, appetite: p = 0.001, hunger: p < 0.001). Appetite was

increased 1 year after the start of chemotherapy (T6) compared to baseline (Table 3).

Table 3 Median (IQR) scores of subjective taste, smell, appetite, and hunger feelings among testicular cancer

patients at each time point. P-values display differences of subjective taste, smell, appetite or hunger at each

time point compared to baseline across patients. The last column represents the main effect of time (p-value of

fixed effect).

P-valuePatientsT6

(N = 7)

PatientsT5

(N = 10)

PatientsT4

(N = 17)

PatientsT3A

(N = 18)

PatientsT2

(N = 18)

PatientsT1

(N = 18)


0.00230(29-32)

32(28-32)

28(23-32)

25 (19-29)

P = 0.001

29 (26-32)

25 (19-28)

P < 0.001

31 (27-32)

Taste[8-40]

0.04822(20-25)

22(20-25)

22(20-26)

21(17-23)

23(20-25)

22(21-24)

22(21-24)

Smell[6-30]

0.00226(25-26)

P = 0.042

25(23-26)

24(21-26)

22(17-23)

P = 0.009

24(22-26)

18(13-22)

P = 0.002

23 (21-26)

Appetite[6-30]

0.00338(37-43)

40(37-44)

38(34-41)

34(27-37)

P = 0.027

40(37-42)

31(27-39)

P = 0.004

37 (33-39)

Hunger[9-45]

IQR = Interquartile range. Only p-values < 0.05 are shown.

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33


Dietary intake The dietary intake of patients before start of chemotherapy was comparable with the

intake of controls (supplementary material; Table II). Within patients, no significant

differences in dietary intake were found over time (supplementary material; Table II).

Food preference Compared to controls, choice for HFSW was lower in patients at baseline

(p = 0.024; Table 4). Within patients, several differences in food choice were found

during and after chemotherapy compared to baseline, but no systematic pattern was

found regarding taste (sweet/savoury) or fat or protein content (Table 4). The choice

of LPSW was higher during the second cycle (T3A) than before the start of the second

cycle (T2) (p = 0.025).

Body composition and hormone levels The total body composition of the patients was comparable to controls at baseline

(Table 5). Within patients, the percentage of fat mass increased after chemotherapy

compared to baseline, while the lean mass decreased (Table 5). The bone density

(lumbar spine) decreased (Table 5). Body weight and BMI increased 6 months after the

start of chemotherapy compared to baseline (evaluable in 10 patients, median (IQR);

Body weight: T0 79 (65-88) kg vs. T5 83 (69-89) kg, p = 0.028; BMI: T0 23.3 (21.0-27.0)

kg/m2 vs. T5 24.7 (21.6-27.6) kg/m2, p = 0.036). See supplementary material for the

body composition of patients available at both T0 and T4 (Table III).

Compared to controls, the testosterone level of patients was lower at baseline

(p = 0.007; Table 5). Within patients, no significant changes in hormone levels were

found (Table 5).

34

Table 4 Food preference (median (IQR)) for high fat savoury (HFSA), high fat sweet (HFSW), low fat savoury

(LFSA), low fat sweet (LFSW) and high protein savoury (HPSA), high protein sweet (HPSW), low protein savoury

(LPSA), low protein sweet (LPSW) of testicular cancer patients at each time point and healthy controls at baseline.

P-values display differences in food preference at each time point compared to baseline across patients. The last

column represents the main effect of time (p-value of fixed effect).

P-valuePatientsT6

(N = 7)

PatientsT5

(N = 10)

PatientsT4

(N = 17)

PatientsT3A

(N = 17)

PatientsT2

(N = 18)

PatientsT1

(N = 17)


Controls

(N = 48)

Fat

0.03228 (15-33)

27 (17-36)

21 (16-33)

P = 0.014

34 (23-40)

26 (23-35)

32 (22-41)

31 (25-40)

27 (19-33)

HFSA

33 (30-40)

28 (22-35)

28 (22-36)

24 (10-32)

30 (26-39)

24 (17-30)

26 (20-34)

34 (27-41)a

HFSW

17 (12-28)

23 (20-31)

23 (20-29)

29 (17-36)

22 (15-30)

23 (19-33)

21 (17-27)

18 (14-25)

LFSA

20 (8-26)

21 (13-26)

21 (13-28)

17 (8-20)

13 (10-21)

13 (9-24)

18 (9-22)

14 (11-22)

LFSW

Protein

0.00721 (16-32)

P = 0.018

24 (14-34)

P = 0.041

21 (10-29)

P = 0.001

29 (16-36)

26 (13-34)

P = 0.002

30 (16-35)

28 (19-36)

24 (19-30)

HPSA

28(18-30)

28(16-34)

28(23-33)

P = 0.011

24(15-31)

27(18-29)

25(17-30)

23(16-34)

27(23-31)

HPSW

0.01420(18-22)

P = 0.034

24(14-27)

24(20-31)

28(25-39)

P = 0.001

24 20-34)

24(17-34)

19(13-26)

18(11-24)

LPSA

29(25-31)

26(22-29)

24(16-29)

13(11-23)

P = 0.010

24(15-32)

20(15-30)

27(16-30)

27(18-33)

LPSW

IQR = Interquartile range. Only p-values < 0.05 are shown. aSignificant difference between patients and controls

at baseline (p = 0.024).

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35


Table 5 Body composition and hormone levels (median IQR) of testicular cancer patients at baseline, one month

after the last chemotherapy cycle and one year after the start of chemotherapy and healthy controls at baseline.

P-values display significant differences in body composition at each time point compared to baseline across

patients.

PatientsT6

(N = 7)

PatientsT4

(N = 11)


Controls

(N = 48)

Body composition

83.7(76.8-95.6)

78.8(71.0-90.9)b

82.9 74.4-91.6)

80.7(75.1-87.6)

Body weight, kg

25.3(22.4-28.6)

24.4(21.9-26.3)b

24.3(22.2-26.4)

23.5 (21.7-25.8)

BMI (kg/m²)

21.5 (15.5-31.5)

23.5 (17.6-27.7)P = 0.050

22.8 (15.2-26.1)a

19.2(16.5-23.7)

Fat mass, kg

26.1 (24.2-32.1)P = 0.028

27.1 (24.0-29.6)P = 0.016

24.3 (20.4-29.4)a

23.4 (21.9-27.8)

Fat mass, %

58.0 (55.0-63.6)

56.8 (55.5-64.5)P = 0.007

63.2 (56.5-68.1)a

59.2(53.7-62.8)

Lean mass, kg

70.0(64.8-72.7)P = 0.028

69.6(66.9-72.5)P = 0.016

72.5 (67.4-75.8)a

72.6(69.2-74.0)

Lean mass, %

3.0(2.7-3.2)

3.0 (2.8-3.3)

3.1(2.7-3.4)a

2.9(2.6-3.1)

Bone mass, kg

3.1 (3.1-3.9)P = 0.028

3.3 (3.2-3.7)3.6 (3.1-4.0)a3.6 (3.1-3.9)Bone mass, %

1.01(0.86-1.13)

0.91(0.85-1.08)

0.94 (0.83-1.12)a

0.94 (0.84-1.06)

Android/gynoid ratio

-0.5(-0.9- -0.4)P = 0.034

-0.5(-1.3-0.4)P = 0.010

-0.2(-0.8-1.6)a

-0.4(-1.2-0.6)

T-score lumbar spine

Hormone levels

16.3(12.0-22.4)

21.5(15.9-26.56)b

19.0(14.2-21.0)d

24(19-28)c

Testosterone (nmol/l)

5.5(4.5-9.7)h

8.8(7.1-11.1)g

3.9(0.3-5.7)f

3.5(2.8-4.9)e

Luteinizing hormone (LH) (U/l)

IQR = Interquartile range. aN = 18, bN =17, cN = 46, dN = 15, eN =38 , fN = 14, g=12, hN = 6.

36

Discussion A transient decrease in subjective taste function, appetite, and hunger feelings was

found in TCPs during the consecutive chemotherapy cycles. A study in breast cancer

patients treated with anthracycline and/or taxane containing chemotherapy showed

a similar transient effect of taste function per chemotherapy cycle [2]. Based on our

results and those reported in that study, would advocate to provide coping strategies

during the first week of each chemotherapy cycle, since taste function is most severely

affected at these time points.

The subjective taste dysfunction was not corroborated by psychophysical taste

dysfunction. The recognition thresholds for sweet, sour, salty, and bitter taste may not

reflect changes in subjective taste dysfunction. Likewise, previous studies have shown

inconsistency between self-reported taste and measured taste function [23,24]. Patients

have a tendency to report taste dysfunction, while it is actually a smell dysfunction

[23]. However, subjective taste function was neither corroborated by psychophysical

smell function in the current study. Psychophysical taste and smell function were highly

variable within and between TCPs, even though we focused on a homogeneous cancer

population. Furthermore, the quality of the reported subjective taste dysfunction may

be different between patients. The heterogeneity of the nature of taste and smell

changes in TCPs suggests that an individual approach is needed regarding strategies to

cope with taste and smell dysfunction.

The percentage of fat mass in TCPs increased after chemotherapy compared to

baseline, while the lean mass decreased. Moreover, the bone density of these patients

decreased. The change in body composition and bone density was already present at

completion of the last chemotherapy cycle. Similarly, previous studies in TCPs found

an increase in abdominal subcutaneous and visceral fat volume respectively 3 and

9 months after the start of chemotherapy [10] and a decreased bone density 1 year

after chemotherapy [25]. Dexamethasone, given as antiemetic during chemotherapy

treatment, may have influenced the body composition of these patients. Furthermore,

testosterone level may have played a role in the increased percentage of fat mass

in TCPs as well. In a parallel cross-sectional study, performed in 50 testicular cancer

survivors 1-7 years post-chemotherapy and 50 age-matched healthy men, we found

a higher BMI, more fat mass (which was more distributed in the abdominal area),

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37


and less lean mass in testicular cancer survivors compared to the healthy controls

[26]. Moreover, we found that a higher fat mass, BMI and android/gynoid ratio were

related to a lower testosterone level in testicular cancer survivors [26]. Possibly,

testosterone level may have played a role in the increased appetite in TCPs 1 year after

chemotherapy as well. However, we have to note that the results at 1 year after

chemotherapy (T6) are based on a small number of patients (N = 7).

Given the early change in body composition in TCPs, intervention strategies to

limit the impact of cardiovascular risk factors should probably start immediately at the

beginning of chemotherapy. It seems advisable to perform interventions not only during

chemotherapy, but also during long-term follow-up, since changes in body compensation

were found in TCPs at completion of chemotherapy and 1 year after chemotherapy.

Additionally, the results of our parallel cross-sectional study indicate differences in body

composition between testicular cancer survivors and healthy controls over the long term

[26]. Future studies are needed to explore whether these long-term effects can be

prevented by interventions during or early after the completion of chemotherapy.

Strengths of the present study are the longitudinal design, use of a control group,

and the homogeneous study population regarding cancer type, treatment, and treatment

phase. A limitation is the small sample size at follow-up.

In conclusion, there is a transient subjective taste impairment during consecutive

cycles of cisplatin combination chemotherapy for disseminated testicular cancer.

When intervention strategies are designed, coping strategies should especially be

provided during the first week of each chemotherapy cycle. Since the body composition

already changed within the 12 weeks of chemotherapy treatment, cardiovascular risk

management should probably also be started at the initiation of chemotherapy.

38

Role of funding source The project is funded by TI Food and Nutrition, a public-private partnership on

precompetitive research in food and nutrition. The funders had no role in the study

design, data collection and analysis, decision to publish, or in the preparation of the

manuscript.

AcknowledgementsThe research is funded by TI Food and Nutrition. All authors drafted, read and approved

the final version of the manuscript.

Conflict of interestThe authors declare no conflict of interest.

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[11] Mueller C, Kallert S, Renner B, Stiassny K, Temmel AFP, Hummel T, et al. Quantitative assessment of gustatory function in a clinical context using impregnated “taste strips”. Rhinology 2003;41:2-6.

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[13] Wolfensberger M, Schnieper I, Welge-Lüssen A. Sniffin’Sticks: a new olfactory test battery. Acta Otolaryngol 2000;120:303-6.

[14] Haehner A, Mayer A, Landis BN, Pournaras I, Lill K, Gudziol V, et al. High test-retest reliability of the extended version of the “Sniffin’ Sticks” test. Chem Senses 2009;34:705-11.

[15] Feunekes GI, Van Staveren WA, De Vries JH, Burema J, Hautvast JG. Relative and biomarker-based validity of a food-frequency questionnaire estimating intake of fats and cholesterol. Am J Clin Nutr 1993;58:489-96.

[16] Verkleij-Hagoort A, de Vries JHM, Stegers MPG, Lindemans J, Ursem NTC, Steegers-Theunissen R. Validation of the assessment of folate and vitamin B12 intake in women of reproductive age: the method of triads. Eur J Clin Nutr 2007;61:610-5.

[17] Siebelink E, Geelen A, de Vries JHM. Self-reported energy intake by FFQ compared with actual energy intake to maintain body weight in 516 adults. Br J Nutr 2011;106:274-81.

[18] Nevo (2011). Dutch Food Composition Database 2011. The Hague: Stichting Nevo. 2011.

[19] Griffioen-Roose S, Finlayson G, Mars M, Blundell JE, de Graaf C. Measuring food reward and the transfer effect of sensory specific satiety. Appetite 2010;55:648-55.

[20] Griffioen-Roose S, Mars M, Finlayson G, Blundell JE, de Graaf C. The effect of within-meal protein content and taste on subsequent food choice and satiety. Br J Nutr 2011;106:779-88.

[21] Mathey MF. Assessing appetite in Dutch elderly with the Appetite, Hunger and Sensory Perception (AHSP) questionnaire. J Nutr Health Aging 2001;5:22-8.

[22] Kelly TL, Wilson KE, Heymsfield SB. Dual energy X-Ray absorptiometry body composition reference values from NHANES. PLoS One 2009;4:e7038.

[23] Soter A, Kim J, Jackman A, Tourbier I, Kaul A, Doty RL. Accuracy of self-report in detecting taste dysfunction. Laryngoscope 2008;118:611-7.

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[24] Landis BN, Welge-Luessen A, Brämerson A, Bende M, Mueller CA, Nordin S, et al. “Taste Strips” - a rapid, lateralized, gustatory bedside identification test based on impregnated filter papers. J Neurol 2009;256:242-8.

[25] Willemse PM, Hamdy NAT, de Kam ML, Burggraaf J, Osanto S. Changes in bone mineral density in newly diagnosed testicular cancer patients after anticancer treatment. J Clin Endocrinol Metab 2014;99:4101-8.

[26] IJpma I, Renken RJ, Gietema JA, Slart RHJA, Mensink MGJ, Lefrandt JD, et al. Taste and smell function in testicular cancer survivors treated with cisplatin-based chemotherapy in relation to dietary intake, food preference, and body composition. Appetite 2016;105:392-9.

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Supplementary materialTable I Median (IQR) difference in taste and smell function compared to baseline among testicular cancer patients.

T6-T0(N = 7)

T5-T0(N = 10)

T4 – T0(N = 17)

T3 – T0(N = 18)

T2 – T0(N = 18)

T1 – T0(N = 18)

Taste1.00

(0.00/2.00)0.00

(-1.00/1.00)0.00

(0.00/1.00)0.00a

(-0.50/1.00)0.00

(-0.25/0.00)0.00

(-1.00/1.00)Sweet[0-4]

1.00(0.00/1.00)

0.00(0.00/1.00)

0.00(0.00/1.00)

0.00a

(-1.00/0.00)0.00

(-1.00/0.25)0.00

(-1.00/1.00)Sour [0-4]

-1.00(-1.00/0.00)

-1.00(-1.00/0.25)

-1.00(-1.00/0.00)

0.00a

(-1.00/0.00)0.00

(-1.00/0.00)0.00

(-1.00/0.00)Salty [0-4]

0.00(-1.50/2.00)

0.00(-2.00/1.00)

0.00(-1.00/1.00)

-1.00a

(-2.00/0.00)-0.50

(-1.00/0.25)0.00

(-1.00/0.00)Bitter[0-4]

1.00(-1.00/2.00)

-1.00(-3.00/1.00)

0.00(-2.00/0.50)

-1.00a

(-3.50/1.00)-0.50

(-3.00/1.00)-1.00

(-2.25/1.00)Total taste[0-16]

Smell-0.50

(-1.00/1.50)0.50

(-0.44/1.13)-1.25

(-2.00/3.75)0.88

(-0.81/2.31)1.00

(-1.63/3.31)0.13

(-2.00/3.50)THR[1-16]

0.00(0.00/1.00)

0.00(-1.00/2.00)

0.00(-1.00/1.00)

0.00(-3.00/2.00)

2.00(-1.00/2.00)

0.00(-2.00/1.25)

DIS[0-16]

-1.00(-3.00/1.00)

-1.00(-2.25/-0.50)

0.00(-2.00/2.00)

-1.00(-2.25/0.25)

0.00(-2.00/1.00)

-0.50(-1.00/1.25)

ID[0-16]

-1.50(-3.75/0.50)

-2.00(-4.31/3.56)

1.50(-3.63/4.50)

0.25(-3.81/1.44)

1.00(-1.38/5.50)

0.38(-3.19/5.25)

TDI[1-48]

IQR = Interquartile range. aN = 17.

42

Table II Dietary intake (median (IQR)) of testicular cancer patients at each time point and healthy controls at

baseline.

PatientsT6

(N = 7)

PatientsT5

(N = 9)

PatientsT4

(N = 15)

PatientsT3B

(N = 18)

PatientsT2

(N = 18)


Controls

(N = 46)

12.1(7.1-17.0)

11.4(8.7-12.6)

9.7(8.1-12.4)

11.0(9.4-14.7)

11.0(9.1-15.4)

11.2(9.8-12.8)

11.2(9.4-13.0)

Total energy (MJ/day)

108.8(72.0-134.4)

97.6(83.6-113.0)

76.7(60.6-105.4)

88.3(77.3-113.9)

86.1(72.5-117.0)

93.7(79.7-115.9)

91.3(75.7-98.6)

Protein (g/day)

294.3(203.2-503.8)

294.7(215.8-366.2)

242.7(212.6-348.4)

293.4(242.1-374.5)

302.6(269.8-374.8)

303.7(246.1-343.9)

316.3(270.8-358.1)

Carbohydrates (g/day)

121.9(60.9-159.9)

107.1(79.6-125.0)

91.0(79.0-127.6)

113.2(78.8-165.0)

104.4(82.6-159.4)

106.4(86.1-127.2))

92.3(82.6-130.8)

Total fat (g/day)

51.6(23.0-60.5)

35.0(26.6-48.9)

32.0(24.7-39.7)

40.4(30.0-53.9)

36.0(28.7-54.2)

36.1(27.3-46.6)

30.6(27.7-42.6)

Saturated fat (g/day)

IQR = Interquartile range.

Table III Body composition and hormone levels (median IQR) of testicular cancer patients at baseline (T0) and one

month after the last chemotherapy cycle (T4).

P-valuePatientsT4

PatientsT0

N

78.8 (71.0-90.9)77.1 (70.1-89.0)17Body weight, kg

24.4 (21.9-26.3)23.5 (21.9-26.1)17BMI (kg/m²)

0.05023.5 (17.6-27.7)22.4 (15.2-25.7)11Fat mass, kg

0.01627.1 (24.0-29.6)23.3 (20.6-29.3)11Fat mass, %

0.00756.8 (55.5-64.5)60.3 (57.0-67.4)11Lean mass, kg

0.01669.6 (66.9-72.5)73.5 (67.7-75.8)11Lean mass, %

3.0 (2.8-3.3)3.0 (2.8-3.3)11Bone mass, kg

3.3 (3.2-3.7)3.6 (3.1-4.0)11Bone mass, %

0.91 (0.85-1.08)0.92 (0.84-1.11)10Android/gynoid ratio

0.010-0.5 (-1.3-0.4)-0.1 (-1.3-0.7)11T-score lumbar spine

IQR = Interquartile range.

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Irene IJpmaRemco J. RenkenJourik A. Gietema Riemer H.J.A. Slart Manon G.J. Mensink Joop D. LefrandtGert J. Ter HorstAnna K.L. Reyners

Published in Appetite 2016;105:392-399

Taste and smell function in testicular cancer survivors treated with cisplatin-based chemotherapy in relation to dietary intake, food preference, and body composition

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AbstractBackground: Chemotherapy can affect taste and smell function. This may contribute

to the high prevalence of overweight and metabolic syndrome in testicular cancer

survivors (TCS). Aims of the study were to evaluate taste and smell function and possible

consequences for dietary intake, food preference, and body composition in TCS treated

with cisplatin-based chemotherapy.

Methods: Fifty TCS, 1-7 years post-chemotherapy, and 50 age-matched healthy

men participated. Taste and smell function were measured using taste strips and

‘Sniffin’ Sticks’, respectively. Dietary intake was investigated using a food frequency

questionnaire. Food preference was assessed using food pictures varying in taste

(sweet/savoury) and fat or protein content. Dual-Energy X-ray Absorptiometry was

performed to measure body composition. Presence of metabolic syndrome and

hypogonadism were assessed.

Results: TCS had a lower total taste function, a higher bitter taste threshold, higher

Body Mass Index (BMI), and more (abdominal) fat than controls (p < 0.05). No differences

in smell function and dietary intake were found. Testosterone level was an important

determinant of body composition in TCS (p = 0.016).

Conclusion: Although taste function was impaired in TCS, this was not related to a

different dietary intake compared to controls. Lower testosterone levels were associated

with a higher BMI, fat mass, and abdominal fat distribution in TCS.

Keywords: Taste, smell, food, body composition, cancer, chemotherapy

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Introduction Cancer patients treated with chemotherapy often experience changes in taste and

smell, with a prevalence ranging from 45 to 84% and 5-60% for taste and smell changes,

respectively [1]. These changes can be transient and recover within several months

after chemotherapy [2,3], although some reports state that taste and smell changes

occur years after treatment [4-6]. Literature regarding these long-term taste and

smell changes and their possible effect on dietary intake, food preference, and body

composition is scarce.

Taste and smell changes in cancer patients have been associated with a decreased

energy intake, body weight, and quality of life [2,7]. Conversely, patients may develop

unhealthy eating patterns due to taste and smell changes, resulting in overweight [8,9].

A cross-sectional study in 118 patients with chemosensory changes of various etiologies

showed that patients with a decreased taste and/or smell function reported weight gain

more often, whereas patients with a distorted or phantom taste and/or smell reported

weight loss more frequently [9]. In a cross-sectional study, cancer patients with only

smell changes reported weight gain more often than patients with both taste and smell

changes during chemotherapy [8]. Several studies indicate a high prevalence of obesity

among cancer survivors years after cancer treatment [10,11]. Whether changes in taste

and smell perception play a role in cancer survivors remains to be elucidated.

Since the introduction of cisplatin, metastatic testicular cancer has become a

highly curable disease [12]. 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 [11,13,14]. Moreover,

hypogonadism is a common side effect of orchidectomy, influencing body composition

[15]. Metabolic syndrome is a clustering of at least three of five of the following medical

conditions: elevated waist circumference, elevated triglycerides, reduced high-density

lipoprotein (HDL), elevated blood pressure, and elevated fasting glucose [16]. Dietary

intake has been linked to individual components of the metabolic syndrome [16]. Given

the increase in BMI and increased risk of cardiovascular disease and metabolic syndrome,

attention to dietary intake of these patients seems warranted.

The present cross-sectional study investigated the taste and smell function

in testicular cancer survivors (TCS) treated with cisplatin-based chemotherapy. The

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consequences of possible taste and smell dysfunction were explored regarding dietary

intake, food preference, and body composition.

Materials and methods Study population Patients cured from disseminated testicular cancer (seminoma or non-seminoma),

treated with first line chemotherapy consisting of etoposide and cisplatin with or without

bleomycin were eligible. Patients received three or four cycles of chemotherapy with a

cycle interval of 21 days. Inclusion criteria were: complete remission after chemotherapy

with no evidence of disease at follow-up, age 18-50 years, and ability to comprehend

Dutch. Exclusion criteria were: other chemotherapeutic regimes, active testicular

cancer, mental disability, and co-morbidities affecting taste and/or smell function,

such as neurologic disorders, rhinosinusitis, liver or renal problems, hyperactivity or

hypoactivity of the thyroid gland or diabetes. The age group of 18-50 years was chosen

to reduce confounds due to age, since taste and smell function are known to decrease

with advancing age [17]. Furthermore, testicular cancer patients are relatively young,

with a peak prevalence between 25 and 40 years of age [18]. Patients were matched

with healthy males regarding age and nationality. Exclusion criteria were: medication

use, mental disability, cancer history, and known morbidities affecting taste and/or

smell function. Family and friends of the TCS were asked to participate in this study as

healthy controls. Moreover, other healthy males without connection with the TCS were

asked to participate as healthy controls using posters and flyers. The age of the controls

was matched with the age of TCS. Therefore, the inclusion criterion with regard to

age was narrowed at times for the control group throughout the study. TCS visiting

the outpatient clinic for follow-up were informed both orally and in writing about the

study. The treating physicians performed the recruitment of those participants. The

researchers and a physician recruited the healthy controls. For TCS, data regarding

eligibility were derived from medical records. For controls, eligibility was checked by

telephone by a physician. All participants gave written informed consent. The study was

approved by the ethical committee at the University Medical Center Groningen (UMCG)

(NCT01641172).

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Methods For TCS, all tests were performed during routine follow-up visits 1, 3, 5 or 7 years after

start of chemotherapy at the UMCG. All measurements were performed once in TCS

and controls. Data on height, smoking, education, and sports level (sport frequency per

week: never, 1-2 times/week, 3 or more times/week) were collected during a structured

interview. Data concerning disease and treatment were derived from medical records.

Taste Filter-paper taste strips (Burghart, Wedel, Germany) were used to measure sweet, sour,

salty, and bitter taste thresholds [19]. This is a validated tool to assess the taste function

and an appropriate test in clinical context, given the short time needed for testing. The

following, standard, concentrations of each taste were used: sweet: 0.05, 0.1, 0.2,

and 0.4 g/ml sucrose; sour: 0.05, 0.09, 0.165, and 0.3 g/ml citric acid; salty: 0.016,

0.04, 0.1, and 0.25 g/ml sodium chloride; bitter: 0.0004, 0.0009, 0.0024, and 0.006

g/ml quinine hydrochloride. The taste strips were placed in the middle of the tongue

for whole mouth testing. The taste strips were presented in increasing concentrations

in a randomized order. The participants were not allowed to smoke, brush teeth, use

chewing gum or to eat or drink anything else than water 1 h prior to the measurement.

Participants chose one of five possible answers (sweet, sour, salty, bitter or no taste).

The mouth was rinsed with water before the assessment of each taste strip. Scores for

each taste range from 0 to 4. A total taste score (range 0-16) was derived by summing

all scores.

Smell ‘Sniffin’ Sticks’ (Burghart, Wedel, Germany) were used to measure smell function

[20]. This test consists of pen-like odour-dispensing devices and includes tests for

odour threshold (THR), discrimination (DIS), and identification (ID). For the THR-test,

a standard series of pens with 16 dilutions of n-butanol was used. Three pens were

presented in randomized order, one contained the odorant and two solvent. Participants

had to identify the odorant-containing pen. For the DIS-test, 16 triplets (two equal, one

different odour) were presented. Participants had to discriminate which pen smelled

differently. For the ID-test, 16 common odours were presented. Participants had to

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identify the odour using a 4-option multiple-choice task. The THR-score ranges from

1 to 16. The DIS- and ID-scores range from 0 to 16. A total smell score was derived by

summing the THR, DIS and ID, resulting in a threshold, discrimination, identification

(TDI) score (range 1-48) [21]. The extended version of the ‘Sniffin’ sticks’ was used,

containing 32 odour combinations for the DIS-test and 32 odours for the ID-test [22].

Each participant received a unique combination of 16 out of 32 triplets for the DIS-test,

and a unique combination of 16 out of 32 pens for the ID-test.

Dietary intakeDietary intake was assessed using a food frequency questionnaire (FFQ), which has been

validated to estimate the intake of energy, macronutrients, fatty acids, cholesterol, fiber,

folate, and vitamin B12 for the Dutch population [23-25]. It is a 183-item questionnaire,

in which participants report the consumption frequency of a defined list of foods over

the past month. The FFQs were checked for missing/unusual reports, and if necessary,

additional information was obtained by telephone. Data were converted into energy and

nutrient intake using the Dutch food composition database 2011 [26]. Underreporting

was addressed by computing a ratio of energy intake to energy requirement. Energy

requirement was calculated by the Harris-Benedict equation, with an activity factor

of 1.4 (defined as a moderate activity level) [27]. Participants with a ratio of energy

intake:energy requirement <0.7 were considered as underreporters, whereas those

with a ratio of energy intake:energy requirement ≥0.7 were considered as adequate

reporters.

Food preference Food preference was assessed using a computer task with food pictures varying in

taste (sweet/savoury) and in fat or protein content [28,29]. Preceding the food picture

task, subjective appetite ratings on hunger, fullness, prospective consumption, and

appetite for something sweet and savoury were measured using a 100-mm visual

analogue scale, anchored with ‘not at all’ to ‘extremely’. The order of the picture sets

(‘fat-pictureset’ and ‘protein-pictureset’) was randomized among participants. Two sets

of 16 pictures of snack products were used. One picture set contained four foods of

each of the following categories: high fat savoury (HFSA), high fat sweet (HFSW), low

fat savoury (LFSA), and low fat sweet (LFSW). The other set contained similar categories

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based on protein content: high protein savoury (HPSA), high protein sweet (HPSW),

low protein savoury (LPSA), and low protein sweet (LPSW). For details of the specific

food stimuli and corresponding energy and macronutrient composition, see [28,29].

A paired presentation of 16 foods of each set was shown where participants selected the

food they wanted to eat most right now. One food from one of the four categories was

paired with one food from the remaining categories to form a series of 96 trials of each

picture set. The relative food preference was measured as the frequency of choice for

each food category, while the median reaction time was used as indication for implicit

wanting. Participants were unaware of measuring their reaction time.

Body composition A digital scale was used to measure bodyweight in light clothing, without shoes. Body

Mass Index (BMI) was calculated (kg/m2). Pre-chemotherapy body weight was derived

from medical records. Dual-Energy X-ray Absorptiometry was used to measure body

composition using a Hologic Discovery A densitometer (Hologic Inc., Bedford, MA, USA).

Total fat (total; trunk and abdominal fat mass separately), lean, and bone mass (kg and

%), and android-to-gynoid ratio were determined. Bone mass density of the lumbar spine

was measured (gram/cm2) and expressed as T-score [30].

Metabolic syndrome and hormone levels Prevalence of metabolic syndrome was determined using the guideline from the

American Heart Association/National Heart, Lung, and Blood Institute [16]. Blood

samples were collected to measure glucose, triglyceride, HDL-cholesterol, testosterone,

and luteinizing hormone (LH) levels after an overnight fast. Blood pressure and waist

circumference were derived from medical records.

Subjective taste and smell The Appetite, Hunger and Sensory Perception questionnaire was used to assess taste and

smell subjectively [31]. This questionnaire includes 29 questions (5-point Likert scale) on

taste (8 items, range 8-40), smell (6 items, range 6-30), appetite (6 items, range 6-30),

and hunger (9 items, range 9-45). A higher score corresponds to a more positive feeling

regarding perceived taste and smell, a better appetite, and more hunger feelings.

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Statistical analysis Descriptive statistics are presented as mean ± standard deviation, median with

interquartile range (IQR), or percentage. The 10th percentile of controls on total taste

has been defined to separate hypogeusia from normogeusia [19,20,32]. TCS with a

score below this 10th percentile were defined as hypogeusic. Regression analyses were

performed adjusted for age, smoking, and education. Regression analyses containing a

dependent variable regarding body composition were additionally adjusted for sports

level. For ordinal regression, the probit model was used unless the link function is

mentioned in results. Participants with missing data on a variable relevant for a specific

analysis were excluded (indicated in tables). Underreporters were excluded when

dietary intake was part of the analysis. Spearman’s rho Correlation (rs) was performed

to investigate the relation between energy intake and food preference to check for

misreporting.

All outcome variables were compared between TCS and controls. The Chi-square

test was used to compare smoking status and sports level. The Mann-Whitney U test was

used to compare age, education, dietary intake, and food preference. Ordinal regression

was used to compare taste and smell function. Linear regression was used to compare

body composition.

Analyses to explore the relation between taste function and dietary intake, food

preference, and body composition were performed within TCS. Factor analysis (principal

component with Varimax rotation) was applied to dietary intake and body composition

to derive a set of uncorrelated variables for further analysis. Ordinal regression was

used to investigate the relation between taste function and dietary intake factors,

implicit wanting, and body composition factors. Linear regression was used to examine

the relation between body composition and dietary intake, implicit wanting, and

hormone levels. Correlations (Spearman’s rho (rs)) were used to examine associations

between taste and smell function and subjective taste, smell, appetite, and hunger, to

investigate a relation in taste function and time after chemotherapy (1, 3, 5 or 7 years),

all outcome variables and time after chemotherapy, to examine the relation between

taste function and bodyweight/BMI change, and to explore the relation between taste

and smell function and testosterone level. The paired t-test was used to compare

actual with pre-chemotherapy body weight/BMI. The Mann-Whitney U test was used to

53


compare taste function with respect to presence of the metabolic syndrome. Statistical

analyses were performed using SPSS, version 22 (SPSS Inc. Chicago, IL). A two-tailed

p-value < 0.05 was considered statistically significant.

Results Participant characteristics Sixty-seven TCS were asked to participate. Fifty TCS participated in the study. Reasons

for not participating were: study too time consuming (N = 13), lack of interest in the

study (N = 1) or unknown reasons (N = 3). Fifty controls participated in the study. Two

controls were excluded from analysis, because of health issues (diabetes mellitus 2,

N = 1; autoimmune disease, N = 1). Table 1 shows the basic characteristics of the TCS

and controls.

Taste and smell function Table 2 shows the taste and smell function of the TCS and controls. TCS had a lower

total taste function (p = 0.033) and a higher bitter taste threshold (p = 0.018) than

controls (Table 2). The 10th percentile of the controls was 7 for total taste. Ten TCS

(20%) were defined as hypogeusic. No differences in smell function were found between

TCS and controls. No relation was found between taste or smell function and years

after chemotherapy or change in body weight/BMI. No difference in taste function

was found between TCS with and without the metabolic syndrome. Subjective scores

(median (IQR), N = 48) of taste, smell, appetite and hunger feelings of TCS were: taste

function: 29 (26-31); smell function: 22 (20-25); appetite: 24 (22-26); hunger feelings:

37 (34-39). The taste and smell function of TCS were not significantly correlated with

subjective taste, smell, appetite or hunger feelings.

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Table 1 Basic characteristics of testicular cancer survivors (TCS) and their controls.

TCS (N = 50)

Controls (N = 48)

P-value

Age (years), mean ± SD 33 ± 6 33 ± 7

Smoking, N (%) 0.055

No 19 (38) 29 (60)

Yes 12 (24) 10 (20)

Ex 19 (38) 9 (20)

Sports, N (%) 0.026

Never 20 (40) 8 (17)

1-2 times/week 16 (32) 17 (35)

3 or more times/week 14 (28) 23 (48)

Educational level (range 1-7)a, median (IQR) 4 (4-6) 6 (5-7) < 0.001

Metabolic syndrome, N (%) 10 (20)

Years after chemotherapy, N (%)

1 7 (14)

3 23 (46)

5 12 (24)

7 8 (16)


BEP 47 (94)

EP 3 (6)


3 29 (58)

4 21 (42)


Seminoma 6 (12)

Non-seminoma 44 (88)

aHighest completed educational level: range 1 (primary school) – 7 (university).

BEP = bleomycin, etoposide and cisplatin; EP = etoposide and cisplatin.

55


Table 2 Median (IQR) scores [range] of taste and smell function in testicular cancer survivors (TCS) compared to

controls, adjusted for age, smoking status, and educational level.

TCS(N = 50)

Controls(N = 48)

P-value

Taste

Sweet [0-4] 3 (2-4) 3 (3-4)

Sour [0-4] 2 (1-3) 2 (2-3)

Salty [0-4] 3 (2-4) 3 (2-4)

Bitter [0-4] 2 (1-3) 3 (2-4) 0.018

Total taste [0-16] 9 (7-11) 12 (9-13) 0.033

Smell

Threshold [1-16] 8.5 (6.5-10.1) 7.6 (6.5-9.0)

Discrimination [0-16] 13 (12-14) 13 (11-14)

Identification [0-16] 13 (12-14) 13 (11-14)

TDI [1-48] 33.6 (31.5-37.8) 33.5 (30.5-35.3)

IQR = Interquartile range, TDI = Threshold Discrimination Identification score.

Only p-values < 0.05 are shown.

Dietary intake No clinically relevant differences in dietary intake were found between TCS and controls

(Table 3). Both TCS and controls had a higher intake of protein, carbohydrates, saturated

fat, folate, and vitamin B12 compared to the Dutch Guidelines, whereas the fiber intake

was lower compared to guidelines for both TCS and controls. Two factors were identified

using factor analysis within the dietary intake of TCS (supplementary material;

Table I). The first factor was characterized by intake of macronutrients, cholesterol,

vitamin B12, and fiber (highly correlated with energy intake; rs = 0.849, p < 0.001).

Folate, vitamin B6, and alcohol intake loaded high on the second factor. No relation was

found between dietary intake and years after chemotherapy.

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Table 3 Median (IQR) dietary intake of testicular cancer survivors (TCS) and controls.

TCS(N = 38)a

Controls(N = 42)a

P-value DutchGuidelines

Total energy (MJ/day) 11.8 (9.7-14.3) 11.4 (9.9-13.4)

Protein (g/day) 94.7 (82.1-125.0) 92.7 (76.8-99.6)

Protein/ body weight (g/kg) 1.1 (0.9-1.4) 1.1 (0.9-1.2) 0.8b

Carbohydrates (g/day) 341.0 (269.8-407.3) 322.9 (281.9-367.0)

Carbohydrates (en%) 46.8 (43.3-50.3) 47.8 (43.8-50.5) 40b

Total fat (g/day) 106.6 (89.5-133.2) 95.3 (85.6-132.9)

Total fat (en%) 33.9 (31.1-37.9) 33.9 (32.0-37.8) 20-40b

Saturated fat (g/day) 38.0 (29.2-49.0) 31.1 (28.1-44.4)

Saturated fat (en%) 11.8 (10.2-13.1) 11.2 (9.8-13.3) < 10b

Mono-unsaturated fat (g/day) 38.2 (31.3-49.1) 34.7 (28.5-46.7)

Poly-unsaturated fat (g/day) 22.5 (17.3-29.3) 22.6 (18.6-27.1)

Linoleic acid (g/day) 19.3 (14.4-26.2) 19.0 (15.8-23.1)

ALA (g/day) 2.5 (1.8-3.1) 2.2 (2.0-3.0)

EPA (g/day) 0.04 (0.02-0.09) 0.04 (0.03-0.09)

DHA (g/day) 0.05 (0.02-0.10) 0.05 (0.03-0.09)

Fiber (g/day) 27.6 (21.2-34.8) 29.9 (23.9-36.0) 30-40c

Total cholesterol (mg/day) 222.8 (182.2-290.1) 201.9 (140.3-266.7)

Vitamin B6 (mg/day) 2.1 (1.6-2.6) 1.9 (1.6-2.3) 1.5d

Folate (mcg/day) 317.8 (268.4-428.7) 351.6 (286.4-426.3) 300d

Vitamin B12 (mcg/day) 4.5 (3.5-6.1) 3.5 (2.8-4.4) 0.001 2.8d

Alcohol (g/day) 10.5 (4.7-25.6) 10.8 (3.7-19.3)

aUnderreporters excluded from analysis TCS: N = 3, controls: N = 4. bHealth Council of the Netherlands. Dietary

Reference Intakes: energy, proteins, fats and digestible carbohydrates. The Hague, 2001. cHealth Council of the

Netherlands. Guideline for dietary fiber intake. The Hague, 2006. dHealth Council of the Netherlands. Dietary

Reference Intakes: vitamin B6, folic acid, and vitamin B12. The Hague, 2003.

57


Food preference No significant differences between TCS and controls regarding frequency of choice for

taste (sweet/savoury) or fat or protein content were found (Table 4). The TCS were

faster in choosing the categories HFSA (p = 0.022), HFSW (p = 0.028), and LFSW foods

(p = 0.027) than controls.

A better total taste function corresponded with a shorter reaction time for HFSW

(p = 0.009). A lower bitter taste threshold was associated with a shorter reaction time for

HFSW (negative log-log; p = 0.003). A higher bitter threshold corresponded with a shorter

reaction time for HPSA (p = 0.022). No relation was found between food preference and

years after chemotherapy. No evidence was found for discrepancies between dietary

intake and food preference.

Body composition and hormone levels The TCS had a higher body weight (p = 0.024), BMI (p = 0.021), more body fat (kg)

(p = 0.036), and less lean mass (kg) (p = 0.040) than controls (Table 5). Body fat of

the TCS was more distributed in the abdominal area (p = 0.001). Two factors were

identified for the body composition within TCS (supplementary material; Table II).

A positive score on the first factor was characterized by relatively more fat mass, a

higher BMI and android-to-gynoid ratio. A higher score on the second factor represented

a higher bone density. No relation was found between body composition or BMI change

in relation to taste, dietary intake or food preference. A higher score on the first factor

(fat mass, BMI, android/gynoid ratio) was associated with a lower testosterone level

within TCS (Fig. 1; p = 0.016). For a relation per body composition parameter, see

supplementary material; Fig. I. No relation was found between taste and smell function

and testosterone level in TCS. No relation was found between testosterone level or body

composition and years after chemotherapy. A higher LH level was correlated with longer

time after chemotherapy: rs = 0.376, p = 0.020, evaluable in 38 TCS.

58

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Table 4 Median (IQR) of relative food preference (frequency of choice) and implicit wanting (reaction time) for

high fat savoury (HFSA), high fat sweet (HFSW), low fat savoury (LFSA), low fat sweet (LFSW) and high protein

savoury (HPSA), high protein sweet (HPSW), low protein savoury (LPSA), low protein sweet (LPSW) of testicular

cancer survivors (TCS) and controls.

Frequency of choice Reaction time (ms) P-value

TCS

(N = 50)

Controls

(N = 48)

TCS

(N = 50)

Controls

(N = 48)

Fat

HFSA 28 (22-32) 27 (19-33) 1435 (1317-1629)* 1636 (1354-1909) 0.022

HFSW 31 (19-41) 34 (27-41) 1371 (1196-1692)* 1673 (1320-2065) 0.028

LFSA 20 (14-27) 18 (14-25) 1754 (1296-2160) 1826 (1520-2328)

LFSW 19 (13-26) 14 (11-22) 1612 (1367-2036)* 1864 (1462-2535) 0.027

Protein

HPSA 26 (21-32) 24 (19-30) 1552 (1350-2032) 1770 (1449-2241)

HPSW 26 (20-30) 27 (23-31) 1629 (1361-2086) 1721 (1536-2104)

LPSA 19 (12-27) 18 (11-24) 1815 (1468-2174) 1964 (1629-2561)

LPSW 25 (17-34) 27 (18-33) 1616 (1346-1951) 1867 (1449-2172)

IQR = Interquartile range. Only p-values < 0.05 are shown.

59


Table 5 Body composition and hormone levels, median (IQR) of testicular cancer survivors (TCS) compared to

controls. Body composition: adjusted for age, smoking status, educational and sports level.

TCS (N = 50)

Controls (N = 48)

P- value

Body composition

Body weight, kg 85.5 (77.6-98.2) 80.7 (75.1-87.6) 0.024

Height, m 1.85 (1.78-1.90) 1.85 (1.79-1.90)

BMI (kg/m²) 25.5 (22.6-27.8) 23.5 (21.7-25.8) 0.021

Fat mass, kg 23.2 (18.6-28.7)a 19.2 (16.5-23.7) 0.036

Fat mass, % 27.7 (22.5-31.5)a 23.4 (21.9-27.8)

Lean mass, kg 59,4 (55.3-65.4)a 59.2 (53.7-62.8) 0.040

Lean mass, % 69.1 (65.1-73.7)a 72.6 (69.2-74.0)

Bone mass, kg 2.9 (2.7-3.2)a 2.9 (2.6-3.1)

Bone mass, % 3.4 (3.1-3.5)a 3.6 (3.1-3.9)

Android/gynoid ratio 1.05 (0.98-1.20)a 0.94 (0.84-1.06) 0.001

T-score lumbar spine -0.2 (-0.8-1.0)b -0.4 (-1.2-0.6)

Weight pre-chemotherapy 80.0 (70.0-94.1)c

BMI pre-chemotherapy 24.7 (21.8-26.8)c

Weight change 2.7 (-0.6-8.9)c <0.001

BMI change 0.8 (-0.2-2.7)c 0.004

Hormone levels

Testosterone (nmol/l) 17 (14-22)d 24 (19-28)a <0.001

Luteinizing hormone (LH) (U/l) 5.9 (3.9-9.4)e 3.5 (2.8-4.9)f 0.001

IQR = Interquartile range. aN = 46, bN = 48, cN = 49, dN = 43, eN = 42, fN =38. Only p-values < 0.05 are shown.

60

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3530252015105

Fact

or 1

Bod

y co

mpo

siti

on

3

2

1

0

-1

-2

-3

Fig. 1 Body composition and testosterone levels in testicular cancer survivors (N = 40, p = 0.016). A higher score

on the first factor is characterized by relatively more fat mass, a higher BMI and android/gynoid ratio, adjusted

for age, smoking status, educational and sports level.

Discussion A high prevalence of taste dysfunction was found in TCS. Similarly, taste dysfunction

has been found in survivors of various childhood cancer types at least five years

post-treatment [5]. In that study [5], no relation was found between taste function and

food preference, which is in line with our present findings. Moreover, taste dysfunction

has been shown in head and neck cancer survivors 1-19 years post-treatment [6,15,33,34].

None of these studies investigated dietary intake or food preference.

No differences in smell function were found between TCS and controls. In line

with our study, a cross-sectional study in 51 survivors of various childhood cancers found

a high prevalence of taste dysfunction (28%) and a low prevalence of smell dysfunction

(4%) [5]. Also other studies found no significant impact of cisplatin-based therapy on

odour identification [35,36] and odour threshold [35,37]. One of those studies showed

a decreased pleasantness for food odours in 15 lung cancer patients [35]. These results

suggest that cisplatin rather influences food pleasantness than psychophysical smell

function.

61


Despite differences in taste function and BMI between TCS and controls, no

differences were found in dietary intake. Literature regarding the dietary intake of

TCS is scarce. One study performed a dietary history at least one year after the end of

cisplatin-based chemotherapy in 57 testicular cancer patients [38]. Most TCS reported a

good appetite, no unusual eating habits, and trying to eat healthier than before therapy,

such as eating less fat and more vegetables. In the present study, both TCS and controls

had a higher intake of protein, carbohydrates, saturated fat, folate, and vitamin B12

compared to the Dutch Guidelines, whereas the fiber intake was lower for both TCS and

controls. Although no difference in dietary intake was found between TCS and controls,

TCS may have a greater need to consume their intake closer to the guidelines, given the

increased risk of cardiovascular disease and metabolic syndrome in TCS.

The level of underreporting of dietary intake may be higher in TCS than in

controls, since overweight and obese individuals are more likely to underreport their

dietary intake [39,40]. To control to some degree of underreporting in the present study,

underreporters were excluded from analysis and possible discrepancies between dietary

intake and food preference were checked. The measurement of implicit wanting was

probably less influenced by underreporting, since participants were unaware of the

measured reaction time during the food preference task. The faster reaction times for

HFSA, HFSW and LFSW foods of TCS implicate a higher implicit wanting for these foods

in TCS compared to controls. However, whether the faster reaction times reflect ‘true’

implicit wanting is a matter of debate, since no relations were found between implicit

wanting and body composition.

The mechanism resulting in taste dysfunction in TCS is unknown. Possible

explanations include a reduction in the number of taste receptors, changes in structure

or functioning of taste receptor cells, and abnormal neuronal activity as a result of

cytotoxic effects of chemotherapy [41].

To check the ‘normalness’ of our controls, the normative values of taste strips

were used (N = 69, 36 women) [19]. The median scores of our controls were lower for

sweet, sour, and total taste. This is not surprising, given that women have a better

taste function than men [42] and the normative values are based on both men and

women. Therefore, we can assume that our controls had a normal taste function. For

the general population, prevalence rates of approximately 1% for taste dysfunction [43]

and 1%-3% for smell function [43,44] have been reported. It is difficult to define the

62

3

true prevalence of taste and smell dysfunction among the general population, given

differences in assessment methods between studies and the variety within populations

regarding age, gender, and health status (such as medication use).

The higher BMI of our TCS is consistent with previous findings in TCS [11,38,45].

The prevalence of metabolic syndrome (20%) was slightly lower than previously reported

(26%) [46]. A longitudinal study in 19 TCS found an increase in abdominal subcutaneous

and visceral fat volume nine months after chemotherapy [45]. Overweight has been

found in breast cancer survivors as well. A study in 53 premenopausal women showed

that chemotherapy-treated breast cancer patients had more fat mass and less lean mass

compared to patients only treated with local therapy, whereas no changes in energy

intake were found between the two treatment groups over time [47]. In line with our

study, these findings suggest that changes in body composition in cancer survivors were

not associated with a different dietary intake. However, it should be noted that the

study population of premenopausal women is vastly different than the TCS. Present

findings suggest that rather a low testosterone level explained the higher BMI, fat mass,

and abdominal fat distribution in TCS. A longitudinal study is needed to confirm this

relationship.

Strengths of our study are the homogeneous study population regarding

cancer type and treatment and the use of a healthy control group. A limitation is the

cross-sectional design. Longitudinal studies are needed to investigate whether taste

changes are persistent or whether patients have already a decreased taste function

pre-chemotherapy. Furthermore, the analysis of dietary intake was based on nutrient

intake. Using food based data better reflects food intake and enables comparison

between taste and smell changes and the intake of foods groups. Moreover, a crude

measure to assess the sports level was used (reported sport frequency per week). Future

studies regarding body composition in cancer patients have to take detailed information

regarding sports- and/or activity level into account.

Although TCS had a lower taste function, especially for bitter taste, these

differences were not related to a different dietary intake compared to controls and no

relation was found between taste and body composition in TCS. A lower testosterone

level may play an important role in the higher BMI, fat mass, and abdominal fat

distribution in TCS.

63


Conflict of interestThe authors declare no conflict of interest.

Role of funding sourceThe project is funded by TI Food and Nutrition, a public-private partnership on

precompetitive research in food and nutrition. The funders had no role in the study

design, data collection and analysis, decision to publish, or in the preparation of the

manuscript.

AcknowledgementsThe research is funded by TI Food and Nutrition. All authors drafted, read, and approved

the final version of the manuscript. We would like to thank Antina de Boer, Petra Diemer

and Anne Verhallen for their practical assistance.

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[43] Hoffman HJ, Ishii EK, MacTurk RH. Age-related changes in the prevalence of smell/taste problems among the United States adult population. Results of the 1994 disability supplement to the National Health Interview Survey (NHIS). Ann N Y Acad Sci 1998;855:716-22.

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[45] Willemse PM, van der Meer RW, Burggraaf J, van Elderen SGC, de Kam ML, de Roos A, et al. Abdominal visceral and subcutaneous fat increase, insulin resistance and hyperlipidemia in testicular cancer patients treated with cisplatin-based chemotherapy. Acta Oncol 2014;53:351-60.

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[47] Demark-Wahnefried W, Peterson BL, Winer EP, Marks L, Aziz N, Marcom PK, et al. Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2001;19:2381-9.

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Supplementary materialTable I Component-loading matrix with Varimax-rotation of nutrients assessed by FFQ within testicular cancer

survivors (TCS) (N = 38). Factors with eigenvalues greater than 1 were retained. Total energy, total fat,

mono-unsaturated fat, and fatty acids were not included in the factor analysis to avoid high multicollinearity

(r > 0.9) between variables.

Component loadings

Factor 1

‘Macronutrients, cholesterol,

vitamin B12, and fiber intake’

Factor 2

‘Folate, vitamin B6, and alcohol

intake’

Saturated fat 0.894 0.047

Protein 0.848 0.374

Cholesterol 0.842 -0.089

Carbohydrates 0.823 0.355

Vitamin B12 0.732 0.195

Fiber 0.610 0.590

Poly-unsaturated fat 0.605 0.383

Folate 0.298 0.841

Vitamin B6 0.410 0.834

Alcohol -0.135 0.683

Variance explained, % 55.8 15.5

Table II Component-loading matrix with Varimax-rotation of body composition parameters within testicular

cancer survivors (TCS) (N = 46). Factors with eigenvalues greater than 1 were retained.

Component loadings

Factor 1

‘Fat mass’

Factor 2

‘Bone density’

Fat mass, % 0.962 0.055

Lean mass, % -0.949 -0.092

BMI (kg/m2) 0.855 0.273

Bone mass, % -0.839 0.417

Android/gynoid ratio 0.763 0.189

T-score lumbar spine 0.130 0.969

Variance explained, % 64.4 20.6

68

3

Fig. I Testosterone level and body composition parameters in testicular cancer survivors adjusted for age, smoking

status, education and sports level.


3530252015105

Fat

mas

s (%

)

45

40

35

30

25

20

15

Fig. Ia Testosterone level and fat mass % in testicular cancer survivors, adjusted for age, smoking status, education

and sports level. N = 40, p = 0.058. Regression coefficients: Offset = 30.6%, slope = -0.29 %/nmol/l.


3530252015105

Lean

mas

s (%

)

80

75

70

65

60

55

Fig. Ib Testosterone level and lean mass % in testicular cancer survivors, adjusted for age, smoking status,

education and sports level. N = 40, p = 0.060. Regression coefficients: Offset = 66.7%, slope = -0.27 %/nmol/l.

69



3530252015105

Bon

e m

ass

(%)

6

5

4

3

2

Fig. Ic Testosterone level and bone mass % in testicular cancer survivors, adjusted for age, smoking status,

education and sports level. N = 40, p = 0.105. Regression coefficients: Offset = 2.8%, slope = -0.02 %/nmol/l.


3530252015105

BM

I (k

g/m

2)

45

40

35

30

25

20

15

Fig. Id Testosterone level and BMI in testicular cancer survivors, adjusted for age, smoking status, education and

sports level. N = 43, p = 0.012. Regression coefficients: Offset = 32.3 kg/m2, slope = -0.30 kg/m2/nmol/l.

70

3


3530252015105

And

roid

/gyn

oid

rati

o

1,4

1,2

1,0

,8

Fig. Ie Testosterone level and android/gynoid ratio in testicular cancer survivors, adjusted for age, smoking

status, education and sports level. N = 40, p = 0.001. Regression coefficients: Offset = 1.1, slope = -0.01 /nmol/l.

71


Irene IJpmaRemco J. RenkenGert J. Ter HorstAnna K.L. Reyners

Published in Cancer Treatment Reviews 2015;41:179-186

Metallic taste in cancer patients treated with chemotherapy

4

74

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Abstract Background: Metallic taste is a taste alteration frequently reported by cancer patients

treated with chemotherapy. Attention to this side effect of chemotherapy is limited. This

review addresses the definition, assessment methods, prevalence, duration, etiology,

and management strategies of metallic taste in chemotherapy treated cancer patients.

Methods: Literature search for metallic taste and chemotherapy was performed in

PubMed up to September 2014, resulting in 184 articles of which 13 articles fulfilled

the inclusion criteria: English publications addressing metallic taste in cancer patients

treated with FDA-approved chemotherapy. An additional search in Google Scholar, in

related articles of both search engines, and subsequent in the reference lists, resulted

in 13 additional articles included in this review. Cancer patient forums were visited to

explore management strategies.

Findings: Prevalence of metallic taste ranged from 9.7% to 78% among patients with

various cancers, chemotherapy treatments, and treatment phases. No studies have

been performed to investigate the influence of metallic taste on dietary intake, body

weight, and quality of life. Several management strategies can be recommended for

cancer patients: using plastic utensils, eating cold or frozen foods, adding strong herbs,

spices, sweetener or acid to foods, eating sweet and sour foods, using ‘miracle fruit’

supplements, and rinsing with chelating agents.

Interpretation: Although metallic taste is a frequent side effect of chemotherapy and

a much discussed topic on cancer patient forums, literature regarding metallic taste

among chemotherapy treated cancer patients is scarce. More awareness for this side

effect can improve the support for these patients.

Keywords: Metallic taste, cancer patients, chemotherapy

75


Introduction The majority of patients with cancer will be treated with chemotherapy during the course

of their disease. Remarkably, several side effects of chemotherapy seem to be accepted,

whereas suitable management strategies are often not provided. Taste changes,

particularly the occurrence of metallic taste, is one of these neglected side effects.

Taste changes are common in 45–84% of the cancer patients treated with chemotherapy

[1]. These taste changes refer to an absence of taste perception (ageusia), a decreased

or increased taste sensitivity (hypogeusia or hypergeusia), a distorted taste perception

(dysgeusia), or a taste perception without an external stimulus (phantogeusia) [2]. Taste

alterations have been associated with a poor appetite, a decreased energy and nutrient

intake, changes in food preference, and a decreased quality of life [3–9]. Cancer patients

can experience taste changes during chemotherapy treatment, which can last for a few

hours, weeks, or several months after chemotherapy discontinuation [3,10,11].

A metallic taste is a typical taste alteration reported by cancer patients. In a

study among patients with various cancer types, 29 of 37 (78%) patients described their

perceived taste change as metallic after at least two cycles of various chemotherapy

treatments [12]. Another study reported physical and psychosocial complaints in 204

cancer patients [13]. The medical oncologists of these patients were also asked to

specify which complaints they knew their patients encountered. A metallic taste was

reported by approximately one-third of the patients, whereas the medical oncologists

perceived this symptom only in one-tenth of these patients.

Although, a metallic taste seems to be a frequent side effect of chemotherapy,

literature on this subject is scarce. For this review all available studies regarding

metallic taste in cancer patients treated with Food and Drug Administration (FDA)

approved chemotherapy were analyzed. This review addresses the definition of metallic

taste, assessment methods, prevalence, duration, possible causes due to chemotherapy,

and management strategies.

76

4

Search strategy The electronic database PubMed was used to conduct a comprehensive search on

metallic taste and chemotherapy up to September 2014. The following strategy was

adapted across the database: (‘‘Antineoplastic Agents’’ [Mesh] OR ‘‘Antineoplastic

Agents’’ [Pharmacological Action] OR cancer OR chemotherapy*) AND (‘‘Olfaction

Disorders/chemically induced’’ [Mesh] OR ‘‘Taste Disorders/chemically induced’’ [Mesh]

OR ((metal OR metals OR metallic) AND taste*)). This search resulted in 184 articles, of

which 13 articles were included [2,12,14–24]. Articles not related to metallic taste in

cancer patients treated with FDA-approved chemotherapy, without English translation

or abstract, and animal studies were excluded. Many studies do not have metallic taste

as their primary focus. As a consequence, relevant articles can be missed in a PubMed

search based on titles and abstracts. Therefore, the search was expanded with a Google

Scholar search on ‘metallic taste AND chemotherapy’ in full texts instead of titles and

abstracts only. Furthermore, related articles of both search engines were examined

and subsequent reference list searches were carried out. This search resulted in 13

additional articles, which addressed aspects of metallic taste in cancer patients treated

with chemotherapy and articles that investigated characteristics of metal salts eliciting

a metallic sensation in healthy participants [10,13,25–35]. Figure 1 shows the flow

diagram of the selection procedure of the articles. Cancer patient forums were visited

to explore management strategies.

77


Fig. 1 Flow diagram of the selection procedure of the articles.

184 articles identified by PubMed database search 133 ‘clearly not relevant’ articles excluded

based on title and abstract (N) -‐ Based on subject (73) -‐ No English translation (21) -‐ Animal or cell line studies (23) -‐ No abstract available (16)

51 articles

13 articles

38 articles excluded after reading full-‐text (N) based on: -‐ Metallic taste not mentioned (21) -‐ Metallic taste mentioned, only reference to other article (5)

-‐ Review (4) -‐ No chemotherapy (3) -‐ Phase I trial (2) -‐ Only radiotherapy (1) -‐ Unclear description of smell (1) -‐ No recent type of chemotherapy (1)

13 additional articles identified by Google Scholar search, related articles, reference list searches

Total 26 articles

26 references contributing to: -‐ Definition [2,14,15,18] -‐ Prevalence [10,12,13,15,16,19-‐21,27,32,33] -‐ Duration [15,17,22] -‐ Assessment metal salts [25,26,28-‐31] -‐ Management strategies [2,12,17,21,24,33,34] -‐ Causes [23,35]

78

4

Definition of metallic taste Cancer patients treated with chemotherapy report sensations, such as a ‘metallic

taste’, ‘chemical taste’, ‘drug taste’, ‘blood taste’ and ‘bitter taste’ [14,15]. Of

these sensations, a metallic taste is most commonly reported by patients treated with

chemotherapy [10,12,16,17]. It is unclear whether all these tastes refer to the same

sensation. Probably, these sensations are hard to explain for patients, since it is often

the first experience with this kind of taste. Therefore, a metallic taste is difficult to

recognize as compared to the primary tastes sweet, sour, salty, and bitter. Metallic

taste has been described as a phantogeusia [2,18]. However, it is unclear whether this

metallic taste is a true taste phantom or whether external cues are involved. In food

science, metallic taste has been characterized as ‘a peculiar mouthfeel, which is similar

to that observed when an iron nail or metal foil is placed in the mouth’ [36]. Metallic

sensations are also reported as a side effect of drugs [37], specific foods [38], artificial

sweeteners [39], electrical stimulation of the tongue or chorda tympani nerve [40,41],

burning mouth syndrome [42], during pregnancy [43], and as a result of damage by

stapedectomy or anesthesia of the chorda tympani nerve [44,45]. Furthermore, the

evoked sensations of metal salts, such as iron, copper and zinc, have been described as

metallic [25,26]. Especially ferrous sulfate (FeSO4) has been proposed as a distinctive

metallic compound and is used as a reference standard in food sensory evaluation [46].

Assessment of metallic taste Questionnaires, interviews, and stimulation with metal salts eliciting a metallic sensation

have been used to assess metallic taste. These methods will be described hereafter.

Questionnaires Several questionnaires regarding taste changes have been used to assess metallic taste

in cancer patients. A study used a self-developed 33-item questionnaire, which included

an alternative ‘other’ response option next to the options of change in sweet, salty,

sour, and bitter taste, where patients could report metallic taste [32]. Another study

used a questionnaire on 12 physical symptoms associated with chemotherapy [13].

Patients had to report if and on how many days they experienced the symptoms during

the preceding week. One item in this questionnaire was ‘metallic taste in mouth’. No

79


other questions regarding taste changes were included. The questionnaires used in two

studies could not be retrieved [12,16]. To our knowledge, no questionnaire has been

developed specifically focusing on metallic taste.

Interviews In three studies, metallic taste in chemotherapy treated cancer patients was studied by

an interview [10,15,27]. Two of these studies performed a 30-min telephone interview

using a self-developed Sensory Information Questionnaire (SIQ) [10,27]. The SIQ contains

open-ended as well as focused questions related to taste, smell, touch, hearing, and

vision. In a third study, interviews on general health, medication use, oral symptoms,

taste changes, smoking, and oral hygiene habits were held [15]. Taste changes

were determined by asking the patients whether they experienced taste changes

(yes/no). Next, patients with taste changes were asked regarding the type of taste

change (hypogeusia, hypergeusia, dysgeusia or ageusia) and to give a specific subjective

description of the experienced taste changes.

Stimulation with metal salts eliciting a metallic taste No studies have compared the metallic taste reported by cancer patients treated with

chemotherapy with the metallic sensation evoked by metal salts. The following studies

give insight into the characteristics of metal salts and factors associated with the

reported metallic taste evoked by these metal salts in healthy participants.

A study performed in 18 healthy participants (eight men; age 19–33 years)

investigated the detection thresholds of three iron salts: ferrous sulfate (FeSO4),

ferrous chloride (FeCl2), and ferrous gluconate (FeGlu) [28]. For each stimulus, serial

dilutions were made by a factor of 2.5, with 0.0125 mol/L as the highest concentration.

A triangle test including the stimulus and two blanks (water) was carried out at each

selected concentration, starting at the lowest concentration. The test was finished when

participants made three correct discriminations in a series or when all concentrations

were evaluated. The best estimated threshold for each participant was considered

as the geometric mean of the concentration including the last error and the next

higher concentration. Wide ranges of detection thresholds were found with median

detection thresholds of 202, 81, and 13 μmol/L for FeSO4, FeCl2, and FeGlu respectively.

Furthermore, ten of these 18 participants and three other participants (six men; age

80

4

20–42 years) were asked to describe the taste of each stimulus as sweet, sour, salty, bitter,

metallic, astringent or they could describe another taste. The proportion of participants who

described the iron compounds as a metallic taste decreased as the concentration increased

(F(2, 24) = 8.23, p = 0.0019). Higher concentrations of FeSO4 and FeCl2 were more

frequently described as bitter and a higher concentration of FeGlu as sour. Metallic taste

was more frequently reported for the three concentrations of FeSO4 and FeCl2 compared

to the concentrations of FeGlu.

The contribution of retronasal smell to the evoked metallic sensation of metal

salts has been investigated by stimulation of metal salts with and without nasal occlusion

in healthy participants. A reduction of perceived intensity to baseline was found for

FeSO4, whereas no reduction was seen for copper sulfate (CuSO4), zinc sulfate (ZnSO4),

solid metals, and electric stimuli [25,29,30]. These results suggest that the metallic

sensation evoked by FeSO4 is likely in part due to retronasal smell.

Qualitative differences have been found between metal salts. In a study,

19 healthy participants (five men; age 20–34 years) had to sort iron (FeSO4, FeCl2, and

FeGlu), calcium (calcium chloride; CaCl2 and calcium lactate), magnesium (magnesium

sulfate; MgSO4 and magnesium chloride; MgCl2), and zinc (ZnSO4 and zinc chloride; ZnCl2)

on the basis of the similarity of the evoked sensation [31]. The concentrations of the

divalent salts were adjusted to equalize intensity ratings. Compounds representing sweet

(sucrose), sour (citric acid), salty (sodium chloride), bitter (quinine hydrochloride), and

astringency (aluminum ammonium sulfate; (NH4)Al(SO4)) were also sorted. The sorting

task was performed with and without nasal occlusion to eliminate retronasal cues.

Next, multidimensional scaling and cluster analysis of the sorting data were performed

to provide a visual representation of the pattern of similarities among the stimuli.

Without nasal occlusion, four clusters among the divalent salts were found: a metallic

group (FeSO4 and FeGlu), a bitter group (quinine, CaCl2, MgSO4, and FeCl2), an astringent

group ((NH4)Al(SO4), ZnCl2, and ZnSO4), and calcium lactate. With nasal occlusion, three

clusters were found: the metallic group merged with the astringent group, whereas

the bitter group and calcium lactate remained the same [31]. Another study used a

trained descriptive panel (two men, five women; age 21–58 years) to determine the

sensory characteristics of ten divalent salts and showed comparable results [26]. The

trained panelists examined a variety of reference standards including both commercial

food products and chemical references to obtain consensus for the concept of metallic

81


sensations. At the end of training, the experience with the entire reference was set as a

definition of metallic taste. Metallic taste and metallic aftertaste were most pronounced

for the iron compounds (FeSO4, FeCl2, and FeGlu). The zinc compounds (ZnSO4 and ZnCl2)

were most pronounced in astringency and a glutamate-like sensation. With magnesium

(MgSO4 and MgCl2) and calcium (CaCl2, calcium lactate, and glycerophosphate) the

highest sensation of bitterness was reported [26]. Another study performed in healthy

participants showed also that FeSO4 was described as metallic and ZnSO4 as astringent,

whereas CuSO4 was more described as bitter [25].

Solid metals and electric stimuli have also been used to investigate the metallic

sensation in healthy participants [29]. Stimulation with solid stimuli (2 cm copper disk,

2 cm half zinc half copper, copper foil, and zinc foil) and electrical stimuli (1.5 and 3.0V

battery) were performed using a self-fabricated device consisting of a plastic handle

attached to the stimuli for placement on the tongue or oral tissues. Stimulation of the

anterior tongue evoked the highest rated intensity, followed by the medial tongue,

whereas responses to stimulation of the inside upper lip were very low. Furthermore,

reports concerning metallic taste following electrical and chemical stimulation were

more frequent when the word ‘metallic’ was predetermined on a list compared to a

free-choice option.

In summary, metallic taste was most reported after stimulation with iron

compounds. The type and concentration of metal salt, the presence of retronasal cues,

the stimulated area of the tongue, and the way of questioning the evoked sensation

influenced reporting metallic taste. No studies have been performed to investigate

detection and recognition thresholds of metal salts in cancer patients.

Prevalence of metallic taste caused by chemotherapy Most studies regarding taste changes in patients treated with chemotherapy do not take

metallic taste as a specific taste alteration into account. The prevalence of metallic taste

in patients treated with chemotherapy has been reported in seven studies (Table 1). The

prevalence ranges from 9.7% to 78% in those studies. Four studies used a questionnaire

[12,13,16,32] and in the other studies an interview was carried out [10,15,27].

82

4

Two studies specifically focused on breast cancer patients, whereas the other

studies investigated heterogeneous cancer populations. All studies investigated taste

changes during chemotherapy in various treatment phases. One study reported taste

changes in a heterogeneous cancer population consisting of patients during treatment

as well as patients during follow-up [13]. Different chemotherapeutic agents evoked

different sensations in patients. One study investigated sensory changes in 40 breast

cancer patients receiving one to six cycles of either cyclophosphamide, doxorubicin,

and 5-fluorouracil (CAF, N = 25) or cyclophosphamide, methotrexate, and 5-fluorouracil

(CMF, N = 15) [27]. Ten of the 25 (40%) patients receiving CAF reported a metallic

taste, which occurred during and after chemotherapy administration (time points

not specified). In contrast, four of the 15 (27%) breast cancer patients receiving CMF

reported a bitter taste, whereas the frequency of metallic taste in these patients was

not mentioned. Another study found that 34 of 44 (77%) cancer patients reported taste

changes directly after one to six cycles of CAF or cisplatin, of which metallic, bitter,

distorted, and sweet taste were mentioned the most (prevalence per descriptor not

specified) [10]. The patients treated with CAF were more likely to describe the taste

change as metallic, whereas the patients treated with cisplatin described the taste

change more frequently as bitter (frequencies not specified). The remaining studies

did not report metallic taste for chemotherapeutic agents specifically [12,13,15,16,32].

Nevertheless, the American Cancer Society reports in a ‘guide to cancer drugs’ that

cisplatin can cause a metallic taste [47].

A study in 248 patients with various cancer types who received at least two cycles

of chemotherapy found that patients who reported metallic taste tended to be younger

than patients without a metallic taste (age 54 ± 14 years versus 60 ± 15 years; p = 0.001)

[16]. Furthermore, patients who reported nausea, reported more frequently metallic

taste compared to patients without nausea (frequencies not specified).

In a study regarding food avoidance in a heterogeneous cancer population, at

least 26 of 72 (36%) of the patients reported metallic taste [33]. These 26 patients

received cyclophosphamide as part of their treatment and reported a slight, but

lingering, metallic taste. All patients reported that this metallic taste did not affect

their food intake.

Furthermore, metallic taste has been described in a case report of a 64-year

old woman with a squamous cell carcinoma on the right external naris treated with 5%

83


topical fluorouracil [19]. The patient reported a constantly present metallic taste after

three days of treatment. The metallic taste did not interfere with the ability to consume

food. The metallic taste lasted for four days and disappeared by itself without further

sequelae. The patient continued the treatment as initially directed.

Another case report describes a 67-year old man with a 12-year history of

cutaneous T-cell lymphoma treated with romidepsin and metallic taste [20]. The

treatment consisted of 14 mg/m2 romidepsin given as a 4-h infusion on day 1, 8, and 15

of each 28-day cycle. The patient reported a metallic taste during the first treatment

cycle. Furthermore, ageusia was reported during the last infusion of the third treatment

cycle. After a revised treatment schedule (romidepsin infusions only on day 1 and 9 of

each cycle), the taste recovered gradually and returned to normal within two to three

months after discontinuation of treatment.

Finally, metallic taste has been described in a case-report of a 90-year old women

treated with gemcitabine for pancreatic cancer [21]. The patient reported a metallic

taste starting approximately 1 h after treatment from the first to the fifth day of each

chemotherapy cycle.

Duration of metallic taste alteration Studies investigating the duration of the metallic taste in this population are scarce.

Both onset and duration of the metallic taste are unclear. Besides, it is unclear whether

the metallic taste is a continuous sensation or an evoked sensation by food products.

One longitudinal study found that 15 of 45 (33%) breast cancer patients reported a

metallic or drug taste in the second or third week after the sixth cycle of adjuvant

chemotherapy with cyclophosphamide, epirubicin or methotrexate, and 5-fluorouracil

(CEF or CMF) [15]. Six months after chemotherapy no patients reported a metallic or

drug taste anymore. No other studies have investigated the prevalence longitudinally.

In a study regarding the experience and coping strategies of taste changes in breast

cancer patients receiving docetaxel or paclitaxel, one patient receiving docetaxel

described a metallic taste approximately four or five days after the treatment during a

semi-structured interview [22]. Semi-structured interviews in ten colorectal cancer

patients treated with oxaliplatin-containing chemotherapy reported a metallic taste

that was constantly present in the mouth (number of patients not specified) [17].

84

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86

4

Possible causes of metallic taste due to chemotherapy Several mechanisms may be involved in causing a metallic taste. Metallic taste has

been described as a phantogeusia [2,18]. It has been hypothesized that localized taste

damage can result in taste phantoms as a result of inhibitory interactions among areas of

the central nervous system which receive input from the cranial nerves mediating taste

[45]. Taste phantoms can be produced when the input of one taste nerve is interrupted

and releases its inhibition and, as a consequence, neural signals from other taste nerves

are intensified. Nevertheless, it is unclear whether metallic taste is a true taste phantom

or whether external cues are involved. Reported external cues are described hereafter.

The metallic taste may originate from the taste of chemotherapeutic agents,

implying a direct influence on taste in the mouth. Many drugs are secreted in saliva

and gain direct contact with taste-receptors [48]. Several chemotherapeutic agents,

such as cisplatin and carboplatin, contain the metal compound platinum. Patients may

taste this platinum compound during chemotherapy treatment. It is unclear whether the

quantity of chemotherapeutic agents detected in saliva reflects the metallic taste and

its intensity experienced by cancer patients.

A metallic taste could also be due to a decreased detection threshold for metals

in cancer patients treated with chemotherapy. This could explain the commonly used

management strategy of using plastic utensils instead of metallic silverware during

eating by patients [2,34]. Patients can experience a bitter or metallic taste during the

consumption of red meat [21]. This might be due to the iron containing compounds in

red meat. The metallic taste may cause an aversion for red meat, which is often seen

in cancer patients [49]. Based on clinical experience, some patients describe a ‘blood

taste’ during chemotherapy. Possibly, the iron-containing compounds in blood could

explain this effect. The taste of metallic silverware and iron-containing compounds may

be experienced more intense by cancer patients because of a lower threshold for metals.

Possibly, retronasal smell plays a role as well. As previously mentioned, the

perceived intensity of the metallic sensation following FeSO4 stimulation decreased

when the nose of healthy participants was occluded, implying the development of

retronasal smell [25,29]. This retronasal perception in the mouth may develop due

to a biochemical reaction, lipid oxidation. Lipid oxidation is catalyzed by metals and

87


contributes to the production of odorous compounds, including carbonyls that cause

a metallic taste sensation. A recent study investigated the effect of stimulation with

ferrous (Fe2+), cupric (Cu2+), cuprous (Cu+), and ferric (Fe3+) ion solutions on salivary

lipid oxidation in healthy participants (22 participants, age 19–53 years participated in

various parts of the study) [35]. Salivary lipid oxidation (measured as malondialdehyde

(MDA) concentration) was significantly higher after rinsing the mouth with the Fe2+

solution compared to the control solution (reagent water) (0.33 ± 0.12 μmol/L versus

0.12 ± 0.03 μmol/L (p < 0.001) in 19 participants (11 men, age 24–53 years). Furthermore,

stimulation with Fe2+ resulted in the highest lipid oxidation, followed by Cu2+, Cu+, and

Fe3+ in 13 participants (seven men, 24– 53 years). Differences in qualitative perception

between the stimuli were not reported.

A recent longitudinal study investigated the relation between taste and smell

changes, salivary parameters, and salivary lipid oxidation in 22 patients with primary

malignant brain tumors and 22 healthy controls [23]. Treatment consisted of six

weeks radiation in combination with temozolomide followed by six monthly cycles of

temozolomide. The salivary levels of metals, electrolytes, total protein, and salivary

lipid oxidation did not provide a reliable measure for taste and smell changes in the

cancer patients. However, since patients were not asked to report metallic taste, a

possible relation between metallic taste and saliva electrolyte, metal parameters and

saliva lipid oxidation remains unclear. This comparison may be relevant since differences

in salivary parameters between cancer patients and healthy controls were found: cancer

patients had significantly lower salivary Zn, Fe (both before and after Fe2+ rinse), and

oral pH levels (p < 0.05) compared to healthy controls, whereas salivary lipid oxidation,

total protein, sodium (Na), potassium (K), Cu, phosphorus (P), sulfur (S), and Mg levels

were significantly higher (p < 0.05) as averaged across all times.

Management strategies Several strategies have been suggested to manage metallic taste. The most commonly

mentioned strategy is to use plastic utensils instead of metallic silverware [2,34]. One

study showed that 26 patients with cyclophosphamide as part of their treatment reported

a slight, but lingering, metallic taste. Three of these patients reported that using plastic

utensils made food more palatable [33]. Not using metal utensils and consuming ice

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water was helpful for a pancreatic cancer patient treated with gemcitabine [21].

A study performed in patients with lymphoma, breast, lung or ovarian cancer after

at least two chemotherapy cycles investigated self-care strategies to manage taste

changes [12]. First, patients had to fill out a taste change questionnaire. Next, a

20-item taste change suggestion sheet of management strategies was provided to the

patients. Suggestions included adding more or less seasonings, eating foods at room

temperature, and using plastic utensils. Approximately two weeks later, patients had

to fill out the same taste change questionnaire and a questionnaire to identify the used

self-management strategies. Patients had to tick one of the following boxes: ‘did not

try’, ‘tried but did not help’, ‘helped a little’ or ‘helped a lot’. Eating cold foods was

more helpful for patients who reported a metallic taste compared to patients without a

metallic taste. The effectiveness of using plastic utensils was not specified. In another

study, one colorectal cancer patient treated with oxaliplatin-containing chemotherapy

used very strong flavors in foods, such as lots of salt, to reduce the metallic taste [17].

Furthermore, a pilot study has been carried out using the fruit Synsepalum

dulcificum, also known as ‘miracle fruit’, to improve the food palatability for patients

treated with chemotherapy [24]. ‘Miracle fruit’ has been developed as a sweetness

enhancer [50]. It contains the protein miraculin, which binds to sweet receptors on

the tongue, turning sour foods into sweet. Therefore, certain unpleasant tastes, like

metallic, can be masked for a short duration [50]. Eight patients with various cancer

types, chemotherapy regimens, and treatment phases (4–12 cycles) with taste changes

received a miracle fruit supplement for two weeks following a crossover placebo

design. Dietary intake was recorded using a 28-day food diary. Patients had to chew the

supplement completely, swallow the substance, and had to wait for 5 min before eating.

Next, patients had to report the consumed food, the portion size, and the taste of the

food compared to the previous experience without using the supplement (better, same

or worse). The duration of the effect of the supplement was reported as well. Five out

of eight patients experienced a metallic taste and reported that this taste disappeared

with the use of the supplement. The taste changes of the foods after ingesting the

supplement lasted for 20–30 min. All patients reported that the taste of food improved

during supplement use and an increased food intake was found in some of the patients

[24].

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As previously mentioned, lipid oxidation seems to play a role in the development

of metallic taste. Lipid oxidation may be reduced or prevented by using antioxidants and

chelating agents. One study investigated the effect of antioxidants (vitamin C and E),

chelating agents (Ethylenediaminetetraacetic acid (EDTA) and lactoferrin), and water

(control) on the perceived intensity of metallic taste and lipid oxidation in healthy

participants (22 participants, age 19–53 years participated in various parts of the study)

[35]. Participants had to sip and rinse 3 ml of an antioxidant or chelating agent solution

and subsequently an 18 μmol/L ferrous iron solution. This procedure was also performed

in reversed order. Next, the participants had to rate the intensity of the metallic taste

on a scale from 0 to 12. A moderate to high intensity of metallic taste was reported

when participants rinsed their mount with the antioxidant or chelating agent solution

before ingestion of the ferrous iron solution. However, a decreased perceived intensity

for metallic taste was found when lactoferrin, EDTA, rinse water, vitamin E and vitamin

C (from highest to lowest difference in intensity) were ingested after the ferrous iron

solution. The antioxidants vitamin C and E seemed not very effective in removing the

metallic taste, since the intensity ratings for metallic taste were even lower after the

reagent water rinse. The chelating agents EDTA and lactoferrin were most effective, in

which lactoferrin completely eliminated the metallic taste in all participants.

Cancer patients have reported their useful management strategies on cancer

patient forums. Using plastic utensils for eating and cooking, as well as eating cold or

frozen foods, and chewing on (lemonade) ice blocks were frequently recommended.

To overpower the metallic taste, using strong herbs and spices and strong flavored

gum, mints and hard candies have been advised. Furthermore, both using sweet and

sour foods, and adding sweetener or acid (like lemons, limes or oranges) to foods were

helpful for patients [51–56].

Conclusion Given the limited literature and attention to metallic taste in cancer patients treated

with chemotherapy, this side effect of chemotherapy seems not to be a problem.

Nevertheless, metallic taste is a frequent side effect of chemotherapy and a much

discussed topic on cancer patient forums. More awareness for this side effect can result

in better support for these patients.

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Although taste changes have been associated with a poor appetite, a decreased

energy and nutrient intake, changes in food preference, and a decreased quality of life

[3–9], the impact of metallic taste on these parameters is not known. Studies specifically

focused on metallic taste can yield information concerning the characteristics of this

sensation and the effects on food preference, dietary intake, body weight, and quality

of life.

A combination of cyclophosphamide, doxorubicin, and fluorouracil (CAF), as

well as platinum based chemotherapy regimens have been reported to induce metallic

taste [27,47]. However, data regarding the prevalence of metallic taste per cancer

type, chemotherapy treatment, and treatment phase are scarce. These data may help

to identify patients at risk for developing metallic taste. For these cancer patients,

management strategies can be helpful.

The management strategies reported on cancer patients forums, can be used as

guideline by health care professionals to support patients reporting a metallic taste.

Furthermore, using miracle fruit and rinsing with chelating agents, such as lactoferrin

and EDTA, are worthwhile to try for these cancer patients [24,35]. Nevertheless, given

the limited data regarding these management strategies, their effectiveness has to be

explored.

To date, no metal salt solution, solid metal or electric stimulus has been identified

that reflects the metallic taste reported by cancer patients treated with chemotherapy.

Such a stimulus is essential to imitate this metallic taste in healthy participants and

can be used to develop suitable management strategies. Besides, such a stimulus can

be useful for the food industry to develop or adapt food products to make foods more

palatable for patients reporting a metallic taste.

Conflict of interest There are no known conflicts of interest associated with this publication and there has

been no financial support for this work that could have influenced its outcome.

Acknowledgments The research was funded by TI Food and Nutrition. All authors drafted, read and

approved the final version of the manuscript.

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Irene IJpmaErik R. TimmermansRemco J. RenkenGert J. Ter HorstAnna K.L. Reyners

Published in Nutrition and Cancer 2017;69:140-145

Metallic taste in cancer patients treated with systemic therapy: a questionnaire-based study

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AbstractA metallic taste is reported by cancer patients as a side effect of systemic therapy.

Despite the high prevalence, this taste alteration has received limited attention.

The present study investigated: 1) the prevalence of metallic taste in cancer

patients treated with systemic therapy; 2) possible predictors of metallic taste;

3) characteristics of metallic taste. A heterogeneous population of 127 cancer patients,

who had received systemic treatment in the past year or were still on treatment,

completed a questionnaire developed for this study. Fifty-eight of 127 (46%) patients

reported taste changes in the preceding week. Of these patients, 20 (34%) reported a

metallic taste. Patients treated with chemotherapy, concomitant radiotherapy, as well

as targeted therapy reported metallic taste. Women experienced metallic taste more

often than men. Patients experiencing a metallic taste also reported more frequently

that they were bothered by sour food and that everything tasted bitter. The experience

of metallic taste was highly variable among patients. In conclusion, metallic taste is

a frequently experienced taste alteration by cancer patients. Patients treated with

chemotherapy, concomitant radiotherapy, and targeted therapy are all at risk for this

taste alteration. However, not all patients reported this alteration as bothersome.

Keywords: metallic taste, taste changes, cancer patients, systemic therapy

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Introduction Taste changes are common in cancer patients as a result of systemic therapy. Taste

changes have been associated with a decreased appetite, dietary intake, and quality of

life [1-7]. The taste perception of cancer patients can be absent (ageusia), decreased

(hypogeusia), increased (hypergeusia), distorted (dysgeusia), or taste can be perceived

without an external stimulus (phantogeusia) [8].

Most studies regarding taste changes in cancer patients have focused on the

presence of taste changes in general (yes/no) or investigated changes in the perception

of the primary tastes sweet, sour, salty, and bitter. A metallic taste is a typical taste

alteration frequently reported by cancer patients [9]. A recent review showed a

prevalence of metallic taste ranging from 10% to 78% in cancer patients treated with

chemotherapy [10]. Despite the high prevalence of metallic taste, this taste alteration

has received limited attention. A cross-sectional study among patients with various

cancer types showed that patients, who reported weight loss since the start of treatment,

were more likely to report an increased sensitivity to metallic and salty taste, compared

to patients who reported weight gain or no weight change [11]. The consequences of

metallic taste regarding food intake, food preference, and quality of life are unknown.

To the best of our knowledge, no study has focused on metallic taste specifically, so far.

The present study aimed to investigate the prevalence of metallic taste in

cancer patients treated with systemic therapy and to explore possible predictors of

metallic taste regarding age, gender, treatment type, time since most recent treatment,

and factors related to taste changes. Furthermore, characteristics of metallic taste,

including the perceived intensity, the duration, and consequences regarding food intake

were explored.

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Methods Study population Cancer patients who had received systemic treatment in the past year or were still

on treatment, with the ability to comprehend Dutch (both reading and writing),

were eligible for inclusion. Patients were heterogeneous regarding cancer type and

treatment. During a time period of 3 wk, all eligible patients were invited to participate

during their regular follow-up visit at the Medical Oncology outpatient clinic of the

University Medical Center Groningen. Moreover, eligible hospitalized patients were

asked to participate during a period of 1 wk. During the 3-wk time period that patients

visited the outpatient clinic, all patients were asked to participate at the discretion

of their treating physician. Eligible patients admitted to the ward were identified at

the discretion of the attending physician. Patients received the questionnaire from the

treating physician or nurse during the outpatient visits or from a researcher during

hospitalization. The patients completed the questionnaire during the visit of the

outpatient clinic or during hospitalization. The study was conducted in accordance with

the Dutch regulations for research.

Questionnaire A questionnaire was constructed for the present study, since no Dutch questionnaire

was available that addressed our specific research questions. Most questions were

based on the English version of a validated chemotherapy-induced taste alteration scale

(CiTas) [12]. The scale of the Japanese CiTas appeared not to be appropriate for the

Dutch population, since no appropriate translation of the English grading (no, slightly,

somewhat, quite, and very much) could be established. Therefore, the scale was altered

in a 4-point scale as used in the questionnaire of the European Organisation for Research

and Treatment of Cancer (EORTC), the EORTC QLQ- C30 (1 = not at all, 2 = a little,

3 = quite a bit, and 4 = very much) [13]. English questions of the CiTas were translated

into Dutch and back to English by the researchers and a bilingual physician. Furthermore,

questions concerning the ability to detect taste, food aversions, factors that might affect

taste (e.g., dry mouth), and metallic taste were added [8,14,15]. Adaptations regarding

responding scales were made to make the questionnaire uniform. An initial draft of

the questionnaire was reviewed by an experienced panel consisting of five researchers

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in the field of tasting, a medical oncologist, and a data analyst. Next, the draft of

the questionnaire was pilot-tested among 30 cancer patients, heterogeneous in age,

cancer type, and treatment, to ensure all questions were clear and were interpreted as

intended. Based on this pilot, several questions were added or adapted. For example,

the questions regarding trouble keeping food down and dry mouth were added, since

several patients came up with these symptoms related to their taste changes. Moreover,

examples of certain foods that raise an aversion (such as the question “Sweet food

bothers me”) were removed from the questionnaire, as several patients based their

answers on the examples of foods instead of the taste.

The finalized 47-item questionnaire consisted of three parts (see supplementary

material). The first part contained eight questions regarding disease and treatment. The

last question of the first part was: “Have you experienced a change in taste since your

diagnosis?” When patients ticked the box “yes,” they experienced a change in taste

somewhere during their course of the disease. All patients filled out this part. The second

part consisted of 30 closed questions regarding taste, smell, appetite, food aversions,

and factors associated with taste. This part was only filled out by patients who reported

to have taste changes in the preceding week. This time window was used to minimize

the relay on memory to assess a recent and precise experienced taste sensation. The last

two questions of the second part were: “Have you experienced certain foods to taste

differently than before your diagnosis?” and “Have you experienced a continuous taste

in your mouth that you did not experience before your diagnosis?” The response options

included: blood, bitter, something chemical, something musty, drugs, metallic, sweet,

salty, sour, and “other, namely.” Multiple answers were possible. Patients who ticked

the box “metallic” for one of these questions or for both questions were defined as

experiencing a metallic taste. Only this last category of patients filled out the last part

of the questionnaire. This third part contained five statements regarding the intensity,

the consequences regarding the ability to eat in general and certain foods, and the

evoked sensation (by food products or a continuous sensation) of metallic taste using the

same 4-point scale as previously mentioned.

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Statistical analysis Descriptive statistics are presented as mean ± standard deviation or percentages.

Multiple logistic regression (forward stepwise likelihood ratio method) was used to

investigate the relation between metallic taste and several parameters listed in the

following sections. Two models were used. The first model explored the relation

between metallic taste and characteristics of patients and treatment. The model

included the following parameters: age, gender, treatment type, and time since most

recent treatment (N = 58). The second model additionally included the responses

regarding taste changes and factors associated with taste changes. Patients who filled

out “I do not know” at one or more questions were excluded from analysis, resulting

in 38 patients included in model 2. As this number of patients is low compared to the

number of tested parameters, overfitting may occur. Therefore, a third analysis was

used with only significant parameters from model 2 to maximize the sample size. The

model included only age, gender, treatment type, time since most recent treatment,

and the response on “sour food bothers me,” “fatty food bothers me,” and “everything

tastes bitter” (N = 54).

To explore the relation between metallic taste and treatment type, treatments

were divided into the following treatment groups: platinum-based chemotherapy,

taxane-based chemotherapy, other chemotherapy, hormonal therapy, tyrosine kinase

inhibitor therapy, other targeted therapy, and concomitant systemic treatment with

radiotherapy. The time since most recent treatment was divided into less than 1 mo

ago, between 1 and 3 mo ago, and more than 3 mo ago. Patients who received daily

treatment were grouped into the category of most recent treatment less than 1 mo

ago. Statistical analyses were performed using SPSS, version 22 (SPSS Inc. Chicago, IL).

A two-tailed p-value <0.05 was considered statistically significant.

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Results Characteristics of study population A total of 255 patients were asked to participate in the study. Of these patients, 127

(50%) filled out the questionnaire. The characteristics of the patients are shown in

Table 1.

Table 1 Characteristics of the patients.

Cancer patients (N = 127)

Age (years), mean ± SD 56.8 ± 13.7

Gender, male N (%) 54 (43)

Treatment group, N (%)

Platinum-based CT 27 (21)

Taxane-based CT 9 (7)

Other CT 33 (26)

Hormonal therapy 13 (10)

TKI treatment 13 (10)

Other targeted treatment 23 (18)

Concomitant radiotherapy 9 (7)

Most recent treatment, N (%)

< 1 month ago 109 (86)

Between 1 – 3 months ago 8 (6)

> 3 months ago 10 (8)

Number of received CT courses, N (%)

1 9 (13)

2 14 (20)

3 16 (23)

4 16 (23)

5 3 (4)

6 8 (12)

> 6 3 (4)

Duration of treatment (HT and TT), N (%)

< 1 month 4 (8)

Between 1 – 3 months 17 (35)

> 3 months 28 (57)

CT = chemotherapy, TKI = tyrosine kinase inhibitors, HT = hormonal therapy,

TT = targeted therapy.

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Prevalence of taste changes Of the 127 cancer patients, 79 (62%) reported taste changes since diagnosis. Of these 79

patients, 58 (46% of total) had taste changes in the preceding week.

Of the 127 patients, 20 (16%) patients (5 male, 15 female) reported a metallic

taste in their mouth and/or that food had a metallic taste. Thus, 34% of the 58 patients

who had taste changes in the preceding week experienced a metallic taste (since

only patients who reported to have taste changes in the preceding week filled out the

questions regarding metallic taste). Patients treated with chemotherapy, concomitant

radiotherapy, as well as targeted therapy reported metallic taste with a prevalence of

at least 10% (Table 2). Of all treatments, taxane-based chemotherapy had the highest

prevalence of metallic taste (4 out of 9; 44%).

Table 2 Prevalence of taste changes and metallic taste across treatment groups.

Treatment group (TG) N Taste changes since diagnosis

N (% of TG)

Taste changes preceding week

N (% of TG)

Metallic taste N (% of TG)

Platinum-based CT 27 20 (74) 12 (44) 4 (15)

Taxane-based CT 9 7 (78) 6 (67) 4 (44)

Other CT 33 21 (64) 17 (52) 6 (18)

Hormonal therapy 13 9 (69) 5 (39) 2 (15)

TKI treatment 13 7 (54) 7 (54) 1 (8)

Other targeted treatment 23 11 (48) 8 (35) 2 (9)

Concomitant radiotherapy 9 4 (44) 3 (33) 1 (11)

CT = chemotherapy, TKI = tyrosine kinase inhibitors.

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Characteristics of metallic taste Table 3 displays the responses of 19 patients (one patient reporting metallic taste

did not fill out the last part of the questionnaire) to the statements concerning the

characteristics of metallic taste. A high diversity was found across patients regarding

the perceived intensity, the consequences regarding the ability to eat in general or

certain foods, the evoked sensation, and the duration. Eight of 19 patients reported that

metallic taste was one of the most negative aspects of their taste changes.

Table 3 Responses to the statements (frequency, N) concerning the characteristics of metallic taste: perceived

intensity, sensation evoked by food products, continuous sensation, consequences regarding the ability to eat in

general, consequences regarding the ability to eat certain foods, and duration (N = 19).

Statement Not at all A little Quite a bit Very much I do not know

The metallic taste:

is intense 1 13 5 - -

becomes stronger when I eata 10 4 3 1 -

is present throughout the day 4 14 1 - -

bothers me with food in general 7 5 5 1 1

bothers me only with certain foods 6 6 4 1 2

Duration metallic taste < 1 week 1 week-1 month

1-3 months > 3 months I do not know

1 7 4 4 3

aN = 18.

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Predictors of metallic taste Logistic regression with age, gender, treatment group, and time since most recent

treatment as independent variables (N = 58) showed that gender was significantly

associated with metallic taste (Table 4). Women reported metallic taste more often

than men. The second model (N = 37) showed that patients experiencing a metallic taste

reported that they were bothered by sour and fatty foods and that everything tasted

bitter, more often (Table 5). In the third model (N = 54), only the aversion to sour foods

and the bitter taste remained significant related to metallic taste (Table 6).

Table 4 Predictors of metallic taste including age, gender, treatment group, and time since most recent treatment

in the logistic model (N = 58).

95% CI for Odds Ratio

Included B (SE) Lower Odds Ratio Upper

Constant -1.53 (0.49)

Gender 1.53 (0.61) 1.38 4.60 15.32

Table 5 Predictors of metallic taste including age, gender, treatment group, time since most recent treatment,

and factors associated with taste changes in the logistic model (N = 38).



Constant -19.89 (8.43)

Gender 4.88 (2.43) 1.13 130.95 15235.98

Sour food bothers me 2.78 (1.37) 1.11 16.17 234.70

Fatty food bothers me 1.99 (1.09) 0.86 7.32 62.30

Everything tastes bitter 5.28 (2.39) 1.81 195.80 21141.98

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Table 6 Predictors of metallic taste including age, gender, treatment group, time since most recent treatment,

and the three questions related to metallic taste derived from the second model in the logistic model (N = 54).



Constant -5.49 (1.59)

Gender 2.03 (0.80) 1.59 7.59 36.36

Sour food bothers me 0.88 (0.41) 1.07 2.41 5.42

Everything tastes bitter 1.81 (0.87) 1.13 6.14 33.44

Discussion One-third of all patients with taste changes and 16% of all patients reported metallic

taste in this heterogeneous group of cancer patients. Previous studies have shown a

prevalence of metallic taste in cancer patients treated with chemotherapy ranging from

10% to 78% [16-22]. Also, metallic taste in patients treated with radiotherapy has been

reported previously [23]. To our knowledge, this is the first study that reports metallic

taste in patients receiving targeted therapy.

Metallic taste is a much-discussed topic on cancer patient forums. Some

patients who experience metallic taste ask desperately for help on these forums to

obtain information regarding suitable management strategies. In the present study,

the experience of metallic taste was highly variable across the patients. Metallic taste

seems not to be bothersome for all patients.

Cancer patients who experienced metallic taste reported more often that

everything tasted bitter. In other studies, “metallic or bitter taste” has been reported

as a taste alteration instead of “metallic taste” only. Our data confirm that metallic

taste and bitter taste are closely related.

Women reported metallic taste more often than men. Also, previous studies

performed in cancer patients found that taste changes were more prevalent in women

compared to men [7,11,16], whereas other studies found no gender differences [3,22].

A study in 89 lung cancer patients showed that women reported more often stronger

sensations, while men reported weaker sensations more frequently [24]. Reasons for

gender differences regarding taste changes are currently unknown. In general, there

is evidence that women have a greater taste and smell sensitivity than men [25,26].

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Therefore, female cancer patients may be more prone to changes in taste function than

men.

The participation rate of fifty percent was quite low in the present study. Patients

were asked to participate during regular outpatient visits or hospitalization. Since no

extra time was scheduled for the present study, the recruitment of patients was added

to the regular work of the treating physicians and nurses. Moreover, not all outpatient

visits were suitable to recruit patients (e.g., after discussing progressive disease).

Patients reporting metallic taste reported that they were bothered by sour and

fatty foods, more frequently. However, the association between metallic taste and the

aversion to fatty foods needs to be interpreted carefully, since the sample size was

small in the logistic model including factors associated with taste changes. Health care

professionals can draw attention to the risk of an aversion to these foods to support

patients experiencing a metallic taste. The following management strategies can be

advised when patients suffer from a metallic taste: the use of plastic utensils; to eat

cold or frozen foods; adding strong herbs, spices, sweetener, or acid to foods; eating

sweet and sour foods; to use “miracle fruit” supplements; and to rinse with chelating

agents [10]. The use of sour foods and adding sour taste to foods is in contradiction to

the present finding that patients who experienced metallic taste more often reported

that they were bothered by sour foods. Future studies are needed to clarify this possible

relationship.

Metallic sensations have also been reported as a side effect of drugs [27] and

throughout pregnancy [28]. Moreover, metallic taste might be elicited by oral yeast

infections [29], burning mouth syndrome [30], damage by stapedectomy or anesthesia

of the chorda tympani [31,32], artificial sweeteners [33], and dental amalgam fillings

[34]. These factors may have influenced the prevalence of metallic taste in the current

study. However, only patients who experienced taste changes in the preceding week

completed the questionnaire with regard to metallic taste and were asked to reflect on

new symptoms previously unknown to them. Therefore, the reported metallic taste may

be due to drug effects or infection, but not due to the other above-mentioned causes.

In conclusion, metallic taste is a side effect of systemic therapy that is not

commonly addressed by health care professionals. However, one-third of all patients

with taste changes and 16% of all patients reported metallic taste during their treatment.

Patients treated with chemotherapy, concomitant radiotherapy, hormonal therapy, and

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other targeted therapy are all at risk of experiencing a metallic taste. However, not all

patients find this type of taste alteration bothersome.

AcknowledgmentsThe research was funded by TI Food and Nutrition. All authors drafted, read and


Conflict of interestThe authors declare that they have no conflict of interest.

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[2] Bossola M, Cadoni G, Bellantone R, Carriero C, Carriero E, Ottaviani F, et al. Taste intensity and hedonic responses to simple beverages in gastrointestinal cancer patients. J Pain Symptom Manage 2007;34:505-12.

[3] Brisbois TD, de Kock IH, Watanabe SM, Baracos VE, Wismer WV. Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life. J Pain Symptom Manage 2011;41:673-83.

[4] Hutton JL, Baracos VE, Wismer WV. Chemosensory dysfunction is a primary factor in the evolution of declining nutritional status and quality of life in patients with advanced cancer. J Pain Symptom Manage 2007;33:156-65.


[6] Schiffman SS. Intensification of sensory properties of foods for the elderly. J Nutr 2000;130:927S-30S.


[8] Hong JH, Omur-Ozbek P, Stanek BT, Dietrich AM, Duncan SE, Lee YW, et al. Taste and odor abnormalities in cancer patients. J Support Oncol 2009;7:58-65.

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[9] American Cancer Society. Nutrition for the person with cancer. Available at: http://m.cancer.org/treatment/survivorshipduringandaftertreatment/nutritionforpeo-plewithcancer/nutritionforthepersonwithcancer/nutrition-during-treatment-taste-smell-changes [assessed 17.04.16].

[10] IJpma I, Renken RJ, Ter Horst GJ, Reyners AKL. Metallic taste in cancer patients treated with chemotherapy. Cancer Treat Rev 2015;41:179-86.

[11] Coa KI, Epstein JB, Ettinger D, Jatoi A, McManus K, Platek ME, et al. The Impact of Cancer Treatment on the Diets and Food Preferences of Patients Receiving Outpatient Treatment. Nutr Cancer 2015:1-15.

[12] Kano T, Kanda K. Development and validation of a chemotherapy-induced taste alteration scale. Oncol Nurs Forum 2013;40:E79-85.

[13] Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76.

[14] Mattes RD, Arnold C, Boraas M. Learned food aversions among cancer chemotherapy patients. Incidence, nature, and clinical implications. Cancer 1987;60:2576-80.

[15] Thomson WM, Chalmers JM, Spencer AJ, Williams SM. The Xerostomia Inventory: a multi-item approach to measuring dry mouth. Community Dent Health 1999;16:12-7.

[16] Bernhardson B, Tishelman C, Rutqvist LE. Self-reported taste and smell changes during cancer chemotherapy. Support Care Cancer 2008;16:275-83.

[17] Jensen SB, Mouridsen HT, Bergmann OJ, Reibel J, Brünner N, Nauntofte B. Oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy in breast cancer patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:217-26.

[18] McDaniel RW, Rhodes VA. Development of a preparatory sensory information videotape for women receiving chemotherapy for breast cancer. Cancer Nurs 1998;21:143-8.

[19] Newell S, Sanson-Fisher R, Girgis A, Bonaventura A. How well do medical oncologists’ perceptions reflect their patients’ reported physical and psychosocial problems? Data from a survey of five oncologists. Cancer 1998;83:1640-51.

[20] Rehwaldt M, Wickham R, Purl S, Tariman J, Blendowski C, Shott S, et al. Self-care strategies to cope with taste changes after chemotherapy. Oncol Nurs Forum 2009;36:E47-56.

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[22] Wickham RS, Rehwaldt M, Kefer C, Shott S, Abbas K, Glynn Tucker E, et al. Taste changes experienced by patients receiving chemotherapy. Oncol Nurs Forum 1999;26:697-706.

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[23] Halyard MY, Jatoi A, Sloan JA, Bearden JD3rd, Vora SA, Atherton PJ, et al. Does zinc sulfate prevent therapy-induced taste alterations in head and neck cancer patients? Results of phase III double-blind, placebo-controlled trial from the North Central Cancer Treatment Group (N01C4). Int J Radiat Oncol Biol Phys 2007;67:1318-22.

[24] McGreevy J, Orrevall Y, Belqaid K, Wismer W, Tishelman C, Bernhardson B. Character-istics of taste and smell alterations reported by patients after starting treatment for lung cancer. Support Care Cancer 2014;22:2635-44.

[25] Soter A, Kim J, Jackman A, Tourbier I, Kaul A, Doty RL. Accuracy of self-report in detecting taste dysfunction. Laryngoscope 2008;118:611-7.

[26] Doty RL, Cameron EL. Sex differences and reproductive hormone influences on human odor perception. Physiol Behav 2009;97:213-28.

[27] Doty RL, Shah M, Bromley SM. Drug-induced taste disorders. Drug Saf 2008;31:199-215.

[28] Nordin S, Broman DA, Olofsson JK, Wulff M. A longitudinal descriptive study of self-reported abnormal smell and taste perception in pregnant women. Chem Senses 2004;29:391-402.

[29] Greenspan D, Shirlaw PJ. Management of the oral mucosal lesions seen in association with HIV infection. Oral Dis 1997;3 Suppl 1:S229-34.

[30] López-Jornet P, Camacho-Alonso F, Andujar-Mateos P, Sánchez-Siles M, Gómez-Garcia F. Burning mouth syndrome: an update. Med Oral Patol Oral Cir Bucal 2010;15:e562-8.

[31] Bull T. Taste and the chorda tympani. J Laryngol Otol 1965;79:479-93.

[32] Yanagisawa K, Bartoshuk LM, Catalanotto FA, Karrer TA, Kveton JF. Anesthesia of the chorda tympani nerve and taste phantoms. Physiol Behav 1998;63:329-35.

[33] Zygler A, Wasik A, Namieśnik J. Analytical methodologies for determination of artificial sweeteners in foodstuffs. TrAC Trends in Analytical Chemistry 2009;28:1082-102.

[34] Ziff MF. Documented clinical side-effects to dental amalgam. Adv Dent Res 1992;6:131-4.

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5

5. Have you been treated with chemotherapy in the past?

a) No

b) Yes, namely:

6. Are you receiving radiotherapy at the moment?

a) No

b) Yes

The following questions concern taste changes that you may have

experienced during the course of your disease.

7. Have you experienced a change in taste since your diagnosis?

a) No (if this is the case, you have now completed the questionnaire)

b) Yes

8. What do you believe is the cause of these taste changes?

a) The taste changes are caused by the disease

b) The taste changes are caused by the treatment

c) The taste changes are caused by the disease, as well as the

treatment

d) The taste changes are caused by something else

e) I am not able to answer that

Type(s) of chemotherapy: Number of courses: Period of time:

Supplementary materialQuestionnaire

Gender: Male / Female

Age: ____ years

1. Diagnosis (type of cancer):

If you are not receiving any treatment at the moment, please continue with

question 4.

2. What type of cancer treatment are you receiving at the moment?

Please indicate the name of the medication.

In case of a combination of treatments, please specify all treatments.

3. How many courses have you received so far (in case of chemotherapy)

or how long have you been on treatment (in case of other therapy)?

4. When did you receive your most recent treatment?

a) Less than a week ago

b) Between a week and a month ago

c) Between a month and three months ago

d) More than three months ago

113


5. Have you been treated with chemotherapy in the past?

a) No

b) Yes, namely:

6. Are you receiving radiotherapy at the moment?

a) No

b) Yes

The following questions concern taste changes that you may have

experienced during the course of your disease.

7. Have you experienced a change in taste since your diagnosis?

a) No (if this is the case, you have now completed the questionnaire)

b) Yes

8. What do you believe is the cause of these taste changes?

a) The taste changes are caused by the disease

b) The taste changes are caused by the treatment

c) The taste changes are caused by the disease, as well as the

treatment

d) The taste changes are caused by something else


Type(s) of chemotherapy: Number of courses: Period of time:

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5

The remaining questions concern the experience of your taste during this week. If you consider your taste to be normal this week (like before the diagnosis), you do not need to fill out the rest of the questionnaire. Could you specify to which extent each statement is applicable to you?

Please circle the number that most closely fits your condition.

Not at all A little Quite a bit Very much I do not know

9. I feel nauseous

1

2

3

4

5

10. The smell of food bothers me

1 2 3 4 5

11. I have difficulty keeping food down

1 2 3 4 5

12. My appetite is reduced

1

2

3

4

5

13. I have a dry mouth

1 2 3 4 5

14. I have difficulty with swallowing certain foods.

1 2 3 4 5

15. Sweet food bothers me

1 2 3 4 5

16. Salty food bothers me

1 2

3 4 5

17. Sour food bothers me

1 2 3 4 5

115



18. Bitter food bothers me

1

2

3

4

5

19. My appetite is increased

1 2 3 4 5

20. I like to eat sweets

1 2 3 4 5

21. Chocolate bothers me

1 2 3 4 5

22. I have difficulty eating red meat (beef, horse, pork or lamp)

1 2 3 4 5

23. Fatty food bothers me

1 2 3 4 5

24. Hot food bothers me

1 2 3 4 5

You can proceed to the next page.

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5

Could you indicate per taste how you perceive this taste compared to before

the start of your treatment?


I do not taste it anymore

I have a lot of trouble tasting it

I have some trouble tasting it

It tastes normal

It tastes stronger

I do not know

25. Food in general

1

2

3

4

5

6

26. Sweet taste 1 2 3 4 5 6

27. Salty taste 1 2 3 4 5 6

28. Sour taste

1 2 3 4 5 6

29. Bitter taste

1 2 3 4 5 6

117


Could you specify to which extent each statement is applicable to you?


Not at all A little Quite a bit Very much

I do not know

30. I am unable to perceive the smell of food

1

2

3

4

5

31. Everything tastes bad

1 2 3 4 5

32. Food does not taste as it should

1 2 3 4 5

33. I have a bitter taste in my mouth

1 2 3 4 5

34. I have a bad taste in my mouth

1 2 3 4 5

35. Everything tastes bitter

1

2 3 4 5

36. I would rather eat cold food than hot food

1

2 3 4 5

37. Everything tastes good

1 2 3 4 5

38. The taste changes have a negative effect on my quality of life

1 2 3 4 5

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5

39. Patients may experience a different taste regarding certain foods.

In such a case, the taste of certain food is different than it used to be.

Have you experienced certain foods to taste differently than before your

diagnosis?

a) I have not experienced a different taste to certain foods

b) I have experienced a different taste to certain foods,

this taste resembles the taste of (multiple answers possible):

o Blood

o Bitter

o Something chemical

o Something musty

o Drugs

o Metallic

o Sweet

o Salty

o Sour

o Other, namely:

119


40. Patients may experience a continuous taste in their mouth.

Have you experienced a continuous taste in your mouth that you did not

experience before your diagnosis?

a) I have not experienced a continuous taste in my mouth

b) I have experienced a continuous taste in my mouth,

this taste resembles the taste of (multiple answers possible):

o Blood

o Bitter

o Something chemical

o Something musty

o Drugs

o Metallic

o Sweet

o Salty

o Sour

o Other, namely: Please answer the following questions only if you ever experienced a metallic taste. If you never experienced a metallic taste, you have completed the questionnaire.

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Could you specify for each statement to which extent it is applicable to you?

Please circle the answer that is most applicable to you.


41. The metallic taste is intense

1

2

3

4

5

42. The metallic taste bothers me with food in general

1 2 3 4 5

43. The metallic taste bothers me only with certain foods

1 2 3 4 5

44. The metallic taste becomes stronger when I eat

1 2 3 4 5

45. The metallic taste is present throughout the day

1 2 3 4 5

46. Have you experienced this metallic taste as one of the most negative

aspects of your taste changes?

a) No

b) Yes

c) I do not know

47. How long have you been experiencing this metallic taste?

a) Less than a week

b) Between a week and a month

c) Between a month and three months

d) More than three months


You have completed the questionnaire. Thank you for your cooperation.

121


Irene IJpmaRemco J. RenkenGert J. Ter HorstAnna K.L. Reyners

Published in Supportive Care in Cancer 2016;24:4301-4308

The palatability of oral nutritional supplements: before, during, and after chemotherapy

6

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6

Abstract Purpose: Oral nutritional supplements (ONS) are commonly prescribed to malnourished

patients to improve their nutritional status. Taste and smell changes in patients with

cancer can affect the palatability of ONS. The present study investigated: (1) the

palatability of six ONS in testicular cancer patients before, during the first two cycles,

and after chemotherapy; (2) the relation between the palatability and taste and smell

function; (3) the metallic taste of these ONS.

Methods: Twenty-one testicular cancer patients undergoing first-line cisplatin-based

chemotherapy participated. Two milk-based (vanilla; strawberry), two juice-based

(apple; orange), and two yoghurt-based (vanilla-lemon; peach-orange) ONS were

tested. A questionnaire was used to assess the palatability of ONS and to which extent

the attribute ‘metallic’ was applicable. Taste and smell function were measured using

taste strips and ‘Sniffin’ Sticks’, respectively.

Results: The palatability of ONS was highly variable among patients. The milk-based

strawberry ONS was preferred most before, during, and after chemotherapy. The liking

of the milk-based vanilla ONS tended to decrease over time (p = 0.053), whereas the

liking of the other ONS remained stable. A higher smell threshold and a lower sour taste

threshold were correlated to a decreased liking of the milk-based vanilla ONS. The two

juice-based ONS tended to taste more metallic during than before chemotherapy.

Conclusion: Health care professionals and patients should be aware that the palatability

of ONS can change over time. Regular structured contact between health care

professionals and patients regarding the choice of ONS seems warranted.

Keywords: Oral nutritional supplements, taste, smell, metallic, cancer, chemotherapy

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Introduction Malnutrition is a common problem in cancer patients with a prevalence ranging

from 30 to 85% [1-3]. Oral nutritional supplements (ONS) are commonly prescribed

to malnourished patients to improve their nutritional status [4]. ONS can be used in

addition to normal food consumption to increase the nutrient intake. A variety of ONS

is available, including milk-, juice-, and yoghurt-based ONS in several flavours. The

hedonic evaluation of orosensory food cues under standardized conditions, also referred

to as palatability [5], plays an important role in the acceptance of ONS [6-8].

Cancer patients undergoing chemotherapy often experience taste and smell

changes [9-12]. These chemosensory changes can affect the perceived flavour of ONS.

Although frequently prescribed, research regarding the palatability of ONS in patients

with cancer is limited. A study in 60 patients with gastrointestinal cancer, of which

47 patients were evaluable at follow-up, found no changes in preference for a fresh

milk-based, an ultra-high-temperature (UHT) milk-based, and a fruit-based ONS after

5 weeks of chemotherapy compared to pre-chemotherapy [13]. Another study in 50

patients treated with pelvic radiotherapy (N = 38 at follow-up) found no changes in

preference for ONS varying in protein source (elemental, peptide, and polymeric) after

6 weeks of radiotherapy compared to pre-treatment [14]. The relation between taste

and smell function and ONS preference was not explored in those studies. Furthermore,

the time between the delivery of chemotherapy and study measurements was not

specified. This may be important, since differences in taste function, appetite, and food

liking can be apparent even within a chemotherapy cycle. A recent study in 52 breast

cancer patients treated with anthracycline and/or taxane based chemotherapy showed

a decrease in taste function, especially during the first days of a chemotherapy cycle

[10]. Changes in taste, appetite, and food liking were cyclic and transient. Therefore,

measurements at one time point are unlikely to reflect perception throughout the entire

chemotherapy period. This may also be the case for radiotherapy. However, to the best

of our knowledge, this has not been investigated systematically in a longitudinal study.

The relation between taste and smell changes in patients with cancer and the

palatability of ONS is currently unknown. The relationship between taste function and

the palatability of ONS has been addressed by Kennedy et al. (2010) in 48 healthy older

adults (63–85 years) compared to younger adults (18–33 years) [15]. In that study [15]

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6

the detection and recognition threshold for sweet taste, the perceived intensity of

sweetness, overall liking, and ranked preference of three types of ONS were explored.

Although older adults had higher sweet thresholds compared to young adults, no

difference was found in the perceived intensity of sweetness of the ONS [15]. However,

a higher perceived sweetness was associated with overall product dislike for all three

ONS across both age groups [15]. Whether a relationship exists between the taste and

smell function and the palatability of ONS in cancer patients needs to be explored.

A metallic taste is frequently reported by cancer patients treated with

chemotherapy with a prevalence ranging from 10 to 78% [16]. The mechanism causing

metallic taste is still unknown. Metallic taste may be a specific taste alteration

like a change in threshold for sweet, sour, salty or bitter taste. Moreover, metallic

taste may be a combination of a gustatory and olfactory sensation, implicating

‘metallic flavour’ would be a better term for the experienced sensation. Metallic taste

may also be a particular bad taste in the mouth due to the taste of chemotherapeutic

agents. Whether certain types of ONS elicit a metallic sensation and may thereby

influence the acceptance of ONS in patients with cancer remains to be elucidated.

The present study has the following objectives: (1) to investigate the palatability

of six ONS (two milk-based, two juice-based, and two yoghurt-based) in testicular cancer

patients treated with cisplatin-based chemotherapy, (2) to explore the relation between

ONS palatability and the taste and smell function of these patients, (3) to examine

the metallic taste of the ONS. Measurements were performed at five time points:

prior to chemotherapy, during the first cycle, before and during the second cycle, and

1 month after start of the last cycle. Since taste and smell function and food liking can

vary throughout the chemotherapy treatment, we hypothesised that by measuring the

palatability of ONS at multiple time points throughout the chemotherapy treatment,

changes in the palatability of ONS can be detected and that changes in taste and smell

function can influence the palatability of ONS. Furthermore, we hypothesised that the

attribute of metallic taste varies between the ONS types (milk- juice- or yoghurt-based)

and can change within a treatment period.

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Materials and methods Study population Patients with disseminated testicular cancer scheduled to receive first line

cisplatin-based chemotherapy consisting of bleomycin, etoposide and cisplatin (BEP)

or etoposide and cisplatin (EP) aged 18–50 years were eligible to participate in this

study. Patients received three or four cycles of chemotherapy with a cycle interval of

21 days. Inclusion criteria were: age 18–50 years at start of treatment and ability to

comprehend Dutch (both reading and writing). Exclusion criteria were: mental disability

and co-morbidities affecting taste and/or smell function, such as neurologic disorders,

rhinosinusitis, liver or renal problems, hyperactivity or hypoactivity of the thyroid

gland or diabetes. Patients had not received other chemotherapy types or concurrent

radiotherapy prior to the present study. All patients gave written informed consent.

The study was approved by the ethical committee of the University Medical Center

Groningen (NCT01641172).

Methods The present study is part of a larger study regarding taste and smell changes in testicular

cancer patients. The taste and smell function and the palatability of ONS were assessed

at the following time points: pre-chemotherapy (T0; baseline), during the first cycle

(T1; day seven of the first cycle), before the second cycle (T2; day one of the second

cycle prior to drug administration), during the second cycle (T3; day seven of the second

cycle), and after chemotherapy (T4; 1 month after start of the last cycle). Measurements

were performed at the same time of the day for all patients: late morning to early

afternoon. The measurements were conducted in the same order for all patients:

(1) smell test, (2) taste test, (3) palatability ONS. At baseline, data on height, smoking

status, educational level, and sports level were collected during a structured interview.

A digital scale was used to measure bodyweight in light clothing, without shoes. Body

mass index (BMI) was calculated as weight (kg) divided by the square of height (m2).

Data concerning disease and treatment were derived from medical records.

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Oral nutritional supplements To study the effect of chemotherapy on the pleasantness of ONS regarding type and flavour,

a variety of ONS was selected. Six ONS (Nutricia Advanced Medical Nutrition-Danone)

were tested: two high protein milk-based (vanilla and strawberry), two juice-based

(apple and orange), and two yoghurt-based (vanilla-lemon and peach-orange) ONS. All

ONS had a energy density of 150 kcal/100 ml. The nutrient content varied between the

three ONS categories (supplementary material; Table I).

Procedure The ONS were served in 30 ml clear plastic tubs at cold temperature. The patients were

asked to take at least one sip of each sample. Next, patients had to fill out a questionnaire

regarding the palatability and sensory attributes of the ONS on a seven-point scale

(supplementary material). The questionnaire comprised nine closed questions regarding

the palatability, 16 attributes, and two open questions. The following two questions

were used from this questionnaire regarding the palatability and metallic taste of ONS:

“How much do you like the taste of this product?” (1 = dislike very much, 7 = like very

much) and “Please, specify to which extent ‘metallic’ is applicable to the product”

(1 = strongly disagree, 7 = strongly agree). The patients received a warming-up sample

(semi-skimmed milk) and completed the questionnaire to get used to the procedure. The

ONS were presented in randomized order among patients and test sessions. All samples

were labelled with a three-digit-code, varying over test sessions to avoid recognition

bias by numbers. Patients were blinded to which ONS was being served. Patients rinsed

their mouth with water after each sample.

Taste and smell function Filter-paper taste strips (Burghart, Wedel, Germany) were used to measure recognition

thresholds for sweet, sour, salty, and bitter taste [17]. The patients were requested not

to smoke, brush teeth, use chewing gum or to eat or drink with the exception of water

1 h prior to the measurement. The following standard concentrations of each taste

were used: sweet: 0.05, 0.1, 0.2, and 0.4 g/ml sucrose; sour: 0.05, 0.09, 0.165, and

0.3 g/ml citric acid; salty: 0.016, 0.04, 0.1, and 0.25 g/ml sodium chloride; bitter:

0.0004, 0.0009, 0.0024, and 0.006 g/ml quinine hydrochloride. The taste strips were

placed in the middle of the tongue for whole mouth testing. The taste strips were

127


presented in increasing concentrations in a randomized order. Patients had to choose

one of five possible answers (sweet, sour, salty, bitter or no taste). Patients rinsed

their mouth with water after each taste strip. Scores for each taste range from 0 (no

concentrations correctly identified) to 4 (all concentrations correctly identified). A total

taste score (range 0-16) was derived by summing the scores for all tastes.

‘Sniffin’ Sticks’ (Burghart, Wedel, Germany) were used to measure the smell

function [18,19]. In brief, this test consists of pen-like odour dispensing devices

and includes three parts: a threshold (THR) test, a discrimination (DIS) test, and an

identification (ID) test. The pens were presented approximately 2 cm under the middle

of the nose. To measure the THR, a standard series of pens with 16 dilutions of n-butanol

was used. Three pens were presented in a randomized order, one contained the odorant

and two solvent. The patients had to identify the pen containing the odorant in two

successive trials, which triggered a reversal of the staircase. The THR was defined as

the mean of the last four reversals. For the DIS test, 16 triplets (two equal and one

different odorant) were presented. The patients had to discriminate which of the three

pens smelled differently. For the ID test, 16 common odours were presented and the

patients had to identify the odour using a multiple choice task presented on a list of

four different odorants. For the THR and DIS test, there was a 30-s interval between

the presentation of the first pen of a triplet and the presentation of the first pen of the

following triplet. The pens for the ID test and the taste strips were presented at a 30-s

interval. The patients were requested not to smoke, brush teeth, use chewing gum or

to eat or drink with the exception of water 15 min prior to the measurement. The THR

score ranges from 1 to 16. The DIS and ID scores range from 0 to 16. A total smell score

was derived by summing the THR, DIS and ID, resulting in a threshold, discrimination,

identification (TDI) score (range 1-48). The extended version of the ‘Sniffin’ Sticks’ was

used, containing 32 odour combinations for the DIS test and 32 odours for the ID test

[20]. Each patient received a unique combination of 16 out of 32 triplets for the DIS test,

and a unique combination of 16 out of 32 pens for the ID test.

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Metallic taste Two aspects of metallic taste were addressed. Patients had to report to which extent

metallic was applicable to the ONS. Furthermore, patients had to report whether they

experienced a metallic taste as a side effect of chemotherapy. To examine this second

aspect, patients were asked to respond to the following open-ended questions regarding

their subjective taste perception since the start of treatment: “Have you experienced

a change in taste?” and “Have you experienced certain foods to taste differently?”. In

addition, patients had to report how often they experienced a continuous bad taste in

their mouth (never, rarely, sometimes, often or always) and patients had to describe the

experienced taste with the following response options “sweet, sour, salty, bitter or other

namely”. Patients were classified as experiencing a metallic taste, when they reported

a metallic taste as a change in taste or as a bad taste in the mouth. By exploring both

aspects of metallic taste, investigation whether especially the patients who experienced

a metallic taste as a side effect of chemotherapy reported that metallic taste was

applicable to ONS could be performed. Moreover, this enables investigation whether a

metallic taste is applicable for specific types of ONS in cancer patients.

Statistical analysis Descriptive statistics are presented as median with interquartile range (IQR) or

percentage. Possible differences in palatability and metallic taste between the ONS

per test session were investigated using the Friedman test, followed by the post-hoc

related-samples Wilcoxon signed-rank test. A linear mixed model was used to investigate

taste and smell function and the liking and metallic taste of each ONS separately, over

time. An unstructured covariance type was used to model the covariance structure

among repeated measures. For ONS showing a significant change or a trend towards

significance in liking or metallic taste over time, possible differences in liking and

metallic taste were compared to baseline and possible differences during the second

cycle were explored. Test session was entered as fixed effect in the model (T0 as

baseline). Contrast comparisons were carried out to explore possible differences during

the second cycle (T2 versus T3). All models were estimated using maximum likelihood.

Spearman’s rho correlation (rs) was used to investigate the relation between taste and

smell function and the liking of each ONS over all test sessions. For ONS showing a

significant change in liking compared to baseline, spearman’s rho correlation was used

129


to explore the relation between changes in taste and smell function and the change in

liking compared to baseline. For taste and smell parameters without a change over time

(i.e. all parameters, except salty taste), the mean of the taste and smell parameters

over all test sessions was used for correlations (instead of the change over time of

these parameters). Spearman’s rho correlation was used to explore the correlation

between overall liking and metallic taste of ONS over all test sessions, across all ONS

and per ONS separately. The Mann-Whitney U test was used to compare the scores

to which extent ‘metallic’ was applicable for each ONS with respect to presence of

metallic taste in patients. For this end, the highest rating reported by each patient

during test sessions in which patients reported a metallic taste (T3 and T4) was used.

Patients with missing data on a variable relevant for a specific analysis were excluded

(indicated in tables). Given the exploratory nature of the study, no adjustments were

made for multiple comparisons. A two-tailed p-value of less than 0.05 was considered

statistically significant. Statistical analyses were performed using SPSS, version 22 (SPSS

Inc. Chicago, IL).

Results Characteristics of the study population Twenty-eight patients were asked to participate. Twenty-one patients were enrolled

in the study. Reasons for not participating were: study too time consuming (N = 2) or

unknown reasons (N = 5). The baseline characteristics of the patients are shown in Table

1. Four patients stopped their participation prematurely (after T0: N = 2, after T1:

N = 1, after T3: N = 1). Three patients completed four out of five measurements due to

illness during chemotherapy (T1: N = 1, T3: N = 2).

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6

Table 1 Baseline characteristics of patients.

Patients (N = 21)

Age (years), median (IQR) 32 (27-36)

Body weight (kg) median (IQR) 82.9 (74.4-91.6)

Height (m) median (IQR) 1.82 (1.78-1.90)

BMI (kg/m2) median (IQR) 24.3 (22.2-26.4)

Smoking, N (%)

No 12 (57)

Yes 4 (19)

Ex 5 (24)

Sports level, N (%)

Never 7 (33)

1-2 times/week 3 (14)

3 or more times/week 11 (52)

Educational level (range 1-7)a, median (IQR) 4 (4-6)


BEP 17 (81)

EP 1 (5)

BEP/VIP 3 (14)


3 15 (71)

4 6 (29)


Seminoma 9 (43)

Non-seminoma 12 (57)

IQR = Interquartile range, BEP = bleomycin, etoposide and cisplatin; EP = etoposide and cisplatin, VIP = etopside,

ifosfamide and cisplatin. aHighest completed educational level: range 1 (primary school) - 7 (university).

131


Palatability of ONS Table 2 shows the liking scores of each ONS per test session. The liking of the milk-based

vanilla ONS tended to decrease over time (p = 0.053), whereas the liking of the other

ONS remained stable. The liking of the milk-based vanilla ONS decreased before and

during the second cycle and after chemotherapy compared to baseline (T2: p = 0.025;

T3: p = 0.008; T4: p = 0.030). See supplementary material (Table IIa) for estimates

of fixed effects. No difference in liking of the milk-based strawberry ONS was found

compared to baseline. Figure 1 shows the liking scores of the milk-based vanilla and

strawberry over time. A wide variation in ONS liking was found among patients (see

supplementary material (Table III) for difference in liking compared to baseline).

A difference in liking between the ONS was found prior to chemotherapy (T0, p = 0.019),

during the first cycle (T1, p = 0.001), and after chemotherapy (T4, p < 0.001). Patients

preferred the milk-based strawberry ONS during all test sessions. The liking of this ONS

was significantly higher than the juice-based orange (p = 0.010) and the yoghurt-based

vanilla-lemon (p = 0.021) ONS prior to chemotherapy (T0) and higher than all other ONS

during the first cycle (T1) and after chemotherapy (T4) (p < 0.05). See supplementary

material (Table IV) for the ranked preference based on liking scores of the ONS per test

session.

Table 2 Median (IQR) liking score of each ONS per test session (1 = dislike very much, 7 = like very much).

Pre-CT(baseline)

T0(N = 21)

During first cycle

T1(N = 18)

Before second cycle

T2(N = 18)

During second cycle

T3(N = 16)


T4(N = 17)

P-value

Milk-basedVanilla

5 (3-6) 4 (2-5) 4 (2-5)* 3 (1-5)** 3 (3-5)* 0.053

Milk-basedStrawberry

5 (3-6) 6 (5-6) 5 (3-6) 5 (3-6) 5 (4-6) 0.008a

Juice-basedApple

5 (3-5) 4 (3-5) 4 (3-5) 4 (3-6) 5 (3-6) 0.151

Juice-basedOrange

4 (3-5) 3 (2-4) 3 (3-5) 5 (2-5) 4 (3-6) 0.587

Yoghurt-basedVanilla-Lemon

3 (2-5) 3 (2-5) 4 (2-5) 3 (2-6) 3 (2-5) 0.379

Yoghurt-basedPeach-Orange

4 (3-6) 3 (2-5) 4 (3-5) 4 (3-6) 3 (2-5) 0.262

P-values display differences in liking at each time point compared to baseline. The last column represents

the main effect of time (p-value of fixed effect). IQR = Interquartile range. *p < 0.05, **p < 0.01. a indicating

difference between T1 and T2 (no difference in liking compared to baseline).

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6

A

Milk-based vanilla

After chemoDuring second cycle

Before second cycle

During first cycle

Before chemo

Liki

ng s

core

7

6

5

4

3

2

1

* ** *

B

Milk-based strawberry


Before second cycle

During first cycle

Before chemo

Liki

ng s

core

7

6

5

4

3

2

1

Fig. 1 Liking score over time of 1A milk-based vanilla and 1B milk-based strawberry ONS. *p < 0.05, **p < 0.01.

133


Taste and smell function and the palatability of ONS The threshold for salty taste increased after chemotherapy (T4) compared to baseline

(median (IQR); T0: 3 (3–3) and T4: 2 (2–3); p = 0.006). No changes in the other primary

tastes or in smell function were found in patients compared to baseline (data not shown).

A higher threshold for sweet and sour taste was correlated with a higher liking of

the milk-based strawberry ONS (sweet: rs = -0.23, p = 0.026; sour: rs = -0.32, p = 0.002).

A higher threshold for sour taste was correlated with a higher liking of the juice-based

orange ONS (rs = -0.21, p = 0.044). A lower threshold for sweet and bitter taste was

correlated with a higher liking of the yoghurt-based peach-orange ONS (sweet: rs = 0.22,

p = 0.040; bitter: rs = 0.29, p = 0.006). No significant correlations were found between

the salty taste threshold and the liking of ONS.

A lower threshold for sour taste was correlated with a decreased liking of

milk-based vanilla ONS before the second cycle (T2) and after chemotherapy (T4)

compared to baseline (T2-T0: rs = -0.57, p = 0.026; T4-T0: rs = -0.53, p = 0.043).

A higher smell threshold was correlated to a lower liking of the milk-based vanilla

ONS over all time points (rs = 0.23, p = 0.030), the juice-based orange ONS (rs = 0.21,

p = 0.043), and the yoghurt-based vanilla-lemon and peach-orange ONS (rs = 0.24,

p = 0.021 and rs = 0.25, p = 0.017, respectively). No significant correlations were found

between the liking of ONS and the smell DIS and ID.

A higher smell threshold was correlated with a decrease in liking of the milk-based

vanilla during the first cycle (T1) compared to baseline (rs = 0.65, p = 0.006).

Metallic taste and the palatability of ONSTable 3 shows the scores to which extent ‘metallic’ was applicable for each ONS per

test session. No difference was found regarding this attribute between the ONS per

test session. Overall, metallic taste of ONS was associated with a lower liking of ONS

(rs = -0.34, p < 0.001). Metallic taste was also associated with a lower liking per ONS

separately: milk-based vanilla: rs = -0.29, p = 0.005); milk-based strawberry: rs = -0.26,

p = 0.013; juice-based apple: rs = -0.36, p < 0.001; juice-based orange: rs = -0.53,

p < 0.001; yoghurt-based vanilla-lemon: rs = -0.26, p = 0.013; yoghurt-based peach-orange:

rs = -0.020, p = 0.064).

The metallic taste of the juice-based apple ONS increased over time (p = 0.037)

(Table 3). The metallic taste of this ONS increased during the first cycle (T1) and after

A

Milk-based vanilla


Before second cycle

During first cycle

Before chemo

Liki

ng s

core

7

6

5

4

3

2

1

* ** *

B

Milk-based strawberry


Before second cycle

During first cycle

Before chemo

Liki

ng s

core

7

6

5

4

3

2

1

Fig. 1 Liking score over time of 1A milk-based vanilla and 1B milk-based strawberry ONS. *p < 0.05, **p < 0.01.

134

6

chemotherapy (T4) compared to baseline (p = 0.019 and p = 0.006, respectively).

An increased trend for metallic taste of the juice-based orange ONS was found

(p = 0.056). The metallic taste of this ONS increased before the second cycle (T2) and

after chemotherapy (T4) compared to baseline (p = 0.005 and p = 0.045, respectively).

See supplementary material (Table IIb) for estimates of fixed effects.

Five of 21 patients (24%) reported a metallic taste. Three of these patients

experienced a metallic taste during the second cycle (T3) and two patients reported

metallic taste after chemotherapy (T4). The score to which extent ‘metallic’ was

applicable for each ONS was higher for patients experiencing a metallic taste compared

to patients who did not experience a metallic taste (median score of 6 versus 5,

p = 0.035).

Table 3 Median (IQR) score to which extent ‘metallic’ was applicable for each ONS per test session (1 = strongly

disagree, 7 = strongly agree).

Pre-CT(baseline)

T0(N = 21)

During first cycle

T1(N = 18)

Before second cycle

T2(N = 18)

During second cycle

T3(N = 16)


T4(N = 17)

P-value

Milk-basedVanilla

2 (1-4) 1 (1-3) 3 (1-5) 2 (1-4) 2 (1-5) 0.043a

Milk-basedStrawberry

1 (1-3) 1 (1-3) 2 (1-3) 1 (1-2) 2 (1-2) 0.209

Juice-basedApple

2 (1-2) 3 (1-5)* 2 (1-4) 2 (1-5) 2 (2-5)** 0.037

Juice-basedOrange

1 (1-3) 2 (1-5) 4 (2-6)** 3 (1-5) 3 (2-5)* 0.056

Yoghurt-basedVanilla-Lemon

2 (1-4) 2 (1-4) 3 (1-5) 3 (1-5) 3 (2-5) 0.078

Yoghurt-basedPeach-Orange

2 (1-4) 2 (1-4) 2 (1-3) 2 (1-5) 3 (2-5) 0.210

P-values display differences in applicability of ‘metallic’ at each time point compared to baseline. The last

column represents the main effect of time (p-value of fixed effect)

IQR = Interquartile range. *p < .05, **p < .01. aindicating difference between T1 and T2 (no difference in metallic

taste compared to baseline).

135


Discussion The present study examined for the first time the palatability of several ONS types

and flavours at multiple time points during treatment. In line with previous studies

which measured the palatability only at one time point during treatment [13,14], no

effect of treatment was found for the palatability of five out of six ONS, suggesting that

preference for most types and flavours of ONS remain stable over time.

The palatability of the milk-based vanilla ONS tended to decrease over time,

whereas the high liking of the milk-based strawberry ONS remained stable. The flavour,

rather than the nutrient content, played a role in the decreased preference of the

milk-based vanilla ONS, since the macro- and micronutrient content of these two ONS

were identical. Moreover, the taste and smell function of patients with cancer may

have played a role, since a higher smell threshold and a lower sour taste threshold were

associated with a decreased liking of the milk-based vanilla ONS.

Patients preferred the milk-based strawberry ONS before, during, and after

chemotherapy over the other five ONS. Other studies have also shown a preference for

milk-based over juice-based ONS in patients with cancer [13] and in a heterogeneous

group of malnourished patients [21]. Nevertheless, a wide variation in pleasantness was

found among patients. Therefore, a variety of ONS types and flavours should be offered

to patients, so they can choose the product they like most. The pleasantness of the

milk-based vanilla ONS tended to decrease over time. As a consequence, health care

professionals should inform patients that the palatability of ONS can change over time

and regular structured contact between health care professionals and patients regarding

the choice of ONS is warranted.

The metallic taste of both juice-based ONS tended to increase during

chemotherapy. These results suggest that juice-based ONS are the least suitable ONS for

patients experiencing a metallic taste, which has a high prevalence in cancer patients

treated with chemotherapy [16]. Patients were not specifically asked whether they

experienced a metallic taste during the present study. Nevertheless, approximately

25% of the patients reported metallic taste using a questionnaire including a question

regarding the description of the experienced taste alteration (sweet, sour, salty, bitter

or “other namely”). The patients reported ‘metallic’ using this alternative response

option. Future studies with larger sample size including the investigation of the

136

6

mechanism of metallic taste are needed to explore the relation between metallic taste

experienced by patients with cancer and the metallic taste of ONS in more detail. More

detailed information may improve the palatability of ONS for patients who experience

a metallic taste.

Strengths of the present study are the longitudinal design including multiple time

points during chemotherapy and the homogeneous study population regarding type of

cancer and treatment, and treatment phase. A limitation is that no conclusion can be

drawn regarding the compliance to ONS, since only the palatability of the ONS was

assessed. Furthermore, the threshold of umami taste was not investigated. The umami

taste may be relevant, since this is linked to the enjoyment of protein rich food. However,

the umami taste may not always be recognized by the western population and including

the measurement of the umami threshold together with the other primary tastes may

be confusing for participants [22]. Finally, although sweet milk-based ONS and more

sour-like juice- and yoghurt-based ONS were used in the present study, the patients

were not asked regarding the perceived intensity of sweetness, sourness, saltiness, and

bitterness of the ONS. Information concerning the basic orientation of the ONS may

relate to the taste function of the patients and the palatability of ONS.

To conclude, a variety of types of ONS and flavours should be offered to

malnourished patients with cancer throughout the whole treatment period, since

preference is variable among patients and the palatability of certain ONS can change

over time. Furthermore, the taste and smell function can influence the palatability of

ONS. Health care professionals should inform patients that the palatability of ONS can

change over time and regular structured contact between health care professionals and

patients regarding the choice of ONS is warranted.

Acknowledgments The research was funded by TI Food and Nutrition. All authors drafted, read, and


Conflict of interest The ONS used in the present study were supplied by Danone.

137


Funding sourceThe project is funded by TI Food and Nutrition, a public-private partnership on

precompetitive research in food and nutrition. The public partner (University Medical

Center Groningen) is responsible for the study design, data collection and analysis,

decision to publish, and preparation of the manuscript. The private partners (Danone

and FrieslandCampina) have contributed to the project through regular discussion.

References[1] Pressoir M, Desné S, Berchery D, Rossignol G, Poiree B, Meslier M, et al. Prevalence, risk

factors and clinical implications of malnutrition in French Comprehensive Cancer Centres. Br J Cancer 2010;102:966-71.

[2] Segura A, Pardo J, Jara C, Zugazabeitia L, Carulla J, de Las Peñas R, et al. An epide-miological evaluation of the prevalence of malnutrition in Spanish patients with locally advanced or metastatic cancer. Clin Nutr 2005;24:801-14.

[3] Wie G, Cho Y, Kim S, Kim S, Bae J, Joung H. Prevalence and risk factors of malnutrition among cancer patients according to tumor location and stage in the National Cancer Center in Korea. Nutrition 2010;26:263-8.

[4] Stratton RJ, Elia M. A review of reviews: A new look at the evidence for oral nutritional supplements in clinical practice. Clinical Nutrition Supplements 2007;2:5-23.

[5] Yeomans MR. Taste, palatability and the control of appetite. Proc Nutr Soc 1998;57:609-15.

[6] Ravasco P. Aspects of taste and compliance in patients with cancer. Eur J Oncol Nurs 2005;9 Suppl 2:S84-91.

[7] Gosney M. Are we wasting our money on food supplements in elder care wards? J Adv Nurs 2003;43:275-80.

[8] Ozçagli TG, Stelling J, Stanford J. A study in four European countries to examine the importance of sensory attributes of oral nutritional supplements on preference and likelihood of compliance. Turk J Gastroenterol 2013;24:266-72.

[9] Coa KI, Epstein JB, Ettinger D, Jatoi A, McManus K, Platek ME, et al. The Impact of Cancer Treatment on the Diets and Food Preferences of Patients Receiving Outpatient Treatment. Nutr Cancer 2015;67:339-53.


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[12] Gamper E, Giesinger JM, Oberguggenberger A, Kemmler G, Wintner LM, Gattringer K, et al. Taste alterations in breast and gynaecological cancer patients receiving chemotherapy: prevalence, course of severity, and quality of life correlates. Acta Oncol 2012;51:490-6.

[13] Rahemtulla Z, Baldwin C, Spiro A, McGough C, Norman AR, Frost G, et al. The palatability of milk-based and non-milk-based nutritional supplements in gastrointestinal cancer and the effect of chemotherapy. Clin Nutr 2005;24:1029-37.

[14] McGough C, Peacock N, Hackett C, Baldwin C, Norman A, Frost G, et al. Taste preferences for oral nutrition supplements in patients before and after pelvic radiotherapy: a double-blind controlled study. Clin Nutr 2006;25:906-12.

[15] Kennedy O, Law C, Methven L, Mottram D, Gosney M. Investigating age-related changes in taste and affects on sensory perceptions of oral nutritional supplements. Age Ageing 2010;39:733-8.

[16] IJpma I, Renken RJ, Ter Horst GJ, Reyners AKL. Metallic taste in cancer patients treated with chemotherapy. Cancer Treat Rev 2015;41:179-86.


[18] Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. ‘Sniffin’ sticks’: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses 1997;22:39-52.



[21] Darmon P, Karsegard VL, Nardo P, Dupertuis YM, Pichard C. Oral nutritional supplements and taste preferences: 545 days of clinical testing in malnourished in-patients. Clin Nutr 2008;27:660-5.

[22] Bellisle F. Experimental studies of food choices and palatability responses in European subjects exposed to the Umami taste. Asia Pac J Clin Nutr 2008;17 Suppl 1:376-9.

139


Supplementary material

Table I Nutritional value of the ONS.

ONS Nutritional value per 100 ml

Kcal Protein (g) Carbohydrate (g) Fat (g)

Nutricia Nutridrink Protein Vanilla

150 10.0 15.6 5.3

Nutricia Nutridrink Protein Strawberry

150 10.0 15.6 5.3

Nutricia NutridrinkJuice style Apple

150 4.0 33.5 -

Nutricia NutridrinkJuice style Orange

150 4.0 33.5 -

Nutricia NutridrinkYoghurt style Vanilla-Lemon

150 6.0 18.7 5.8

Nutricia NutridrinkYoghurt style Peach-Orange

150 6.0 18.7 5.8

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Questionnaire: Oral Nutritional Supplements

Look at the product. Note: Do not taste yet! Please, answer the following question: Based on the sample appearance how much do you expect to like the taste of this product? I dislike it very much

I dislike it moderately

I dislike it slightly

I neither like nor dislike it

I like it I like it

moderately I like it very much

Smell the product. Note: Do not taste yet! Please, answer the following question: Based on the sample smell, how much do you expect to like the taste of this product? I dislike it very much




I like it I like it


Please, take a sip and answer the following question: How much do you like the taste of this product? I dislike it very much




I like it I like it


Please take another sip and answer the following questions: How much do you like the sweetness of this product? I dislike it very much




I like it I like it


141


How much do you like the texture/mouth feel of this product? I dislike it very much




I like it I like it


How much do you like the thickness of this product? I dislike it very much




I like it I like it


Please answer the following questions after swallowing the product. After swallowing, how much do you like the aftertaste of this product? I dislike it very much




I like it I like it


After swallowing, how much do you like the feeling in your mouth associated with the product? I dislike it very much




I like it I like it


Indicate to what extent you agree with this statement: “If I need oral nutritional supplements, with extra energy and nutrients when having eating difficulties in future, I would be happy to choose this product” I strongly disagree

I largely disagree

I disagree somewhat

I neither agree nor disagree

I agree somewhat

I largely agree

I strongly agree

142

6

Please find the list below with possible attributes regarding this product. Please, specify to which extent each attribute is applicable to this product”

I strongly disagree

I neither agree nor disagree

I strongly agree

Natural Artificial Fresh Bland/tasteless Creamy Sticky Easy to swallow Metallic Watery Sickly (“Weeïg”) Refreshing Slimy/viscous Smooth Granular Light Heavy Would any other description be applicable? Yes No

Yes, please indicate: Do you have comments regarding this product?

143


Table IIa Palatability of milk-based vanilla ONS: Estimates of fixed effects.

Parameter Estimate SE df t P-value 95% CI

Lower bound Upper bound

Intercept 4.33 0.35 21.00 12.54 < 0.001 3.61 5.05

Session 1 0 0

Session 2 -0.66 0.34 20.03 -1.93 0.067 -1.38 0.05

Session 3 -0.90 0.37 20.16 -2.42 0.025 -1.68 -0.12

Session 4 -1.15 0.39 19.77 -2.93 0.008 -1.96 -0.33

Session 5 -0.69 0.29 20.18 -2.34 0.030 -1.30 -0.08

Table IIb Metallic taste of juice-based apple ONS: Estimates of fixed effects.

Parameter Estimate SE df t P-value 95% CI

Lower bound Upper bound

Intercept 2.14 0.35 21.00 6.09 <0.001 1.41 2.87

Session 1 0 0

Session 2 0.90 0.35 19.22 2.57 0.019 0.17 1.64

Session 3 0.44 0.39 19.93 1.14 0.267 -0.37 1.25

Session 4 0.53 0.39 18.42 1.36 0.190 -0.29 1.35

Session 5 1.11 0.36 18.52 3.12 0.006 0.36 1.86

144

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1.

General discussion

7

150

7

Interpretation of the main findings and clinical implicationsHeterogeneity of taste and smell changesPrevious studies regarding taste and smell changes in cancer patients mostly focused

on heterogeneous cancer populations with various malignancies, treatments, and

treatment phases. These studies have shown a highly variable pattern of taste and smell

changes in cancer patients treated with chemotherapy [1]. In contrast, we focused

on a homogenous population of testicular cancer patients treated in first line with

cisplatin-based chemotherapy and measured taste and smell function at specific time

points prior to, during, and after chemotherapy (Chapter 2). Despite the homogeneity

regarding type of cancer and treatment as well as treatment phase, psychophysical taste

and smell changes proved to be highly diverse in our study population. The reported

palatability of oral nutritional supplements (ONS) was also notably variable among

these patients (Chapter 6). For metallic taste, heterogeneity was found as well, since

metallic taste was reported by cancer patients treated with chemotherapy, concomitant

radiotherapy, as well as by patients treated with targeted therapy (Chapter 5). Moreover,

the reported experience of metallic taste was highly variable in those patients.

The heterogeneity of taste and smell changes implicates that dietary advice

should be provided on an individual base for cancer patients suffering from taste and

smell changes. Offering a variety of foods with different flavours can help. Currently,

the Ikazia hospital in Rotterdam is running a project using an individual approach for

patients suffering from taste dysfunction [2]. First, patients perform a taste test to

explore which flavours they prefer. Next, the chefs of the hospital adapt foods by means

of these personal taste tests to improve food acceptance. Moreover, the hospital offers

three types of bread: a fresh, a savoury, and a sweet type [3]. Patients can choose the

type of bread they like the most, depending on their taste and/or smell changes. Such

an individual approach can also be used for the development of ONS. A solution may be

to offer ONS where patients can add sweetness, sourness, saltiness or bitterness to the

product themselves depending on their taste perception to increase the pleasantness of

these products.

A drawback of an individual dietary approach advice includes that patients

have to try which foods they like during chemotherapy based on trial and error. In our

151

General discussion

longitudinal study performed in testicular cancer patients undergoing cisplatin-based

chemotherapy, no systematic pattern in psychophysical taste and smell changes was

found (Chapter 2). Previous studies in patients with breast cancer and/or a gynaecologic

malignancy showed a decrease in psychophysical taste [4,5] and smell function [5] during

chemotherapy. It is currently unknown which factors are responsible for a systematic

pattern of taste and smell changes. Cancer type, gender, chemotherapy regimen

and/or metabolic factors may play a role. Therefore, future studies with a large cohort

of cancer patients with different malignancies and treatments measuring taste and smell

function at specific time points before, during, and after treatment are warranted.

Data of large cohorts will allow cluster analysis to explore whether systematic patterns

of taste and smell changes exist within certain groups regarding cancer type, gender

and/or chemotherapy regimen. Those results can be used to give dietary advice prior to

chemotherapy, based on expected taste and smell changes.

Taste dysfunction: comparison between testicular cancer patients and survivorsIn the cross-sectional study, ten of fifty (20%) testicular cancer survivors had taste

dysfunction (Chapter 3). Especially, the bitter taste threshold was higher in survivors

compared to healthy controls. Based on these results, the question remains whether

this taste dysfunction was due to chemotherapy or whether the survivors already had

a decreased taste function prior to chemotherapy. The longitudinal study (Chapter 2)

showed that the taste function of testicular cancer patients prior to chemotherapy was

comparable to the taste function of healthy controls. In addition, no change in bitter

threshold was found in testicular cancer patients during chemotherapy. These results

suggest that the taste dysfunction in testicular cancer survivors was not an acute effect

of chemotherapy.

Weight gain in cancer survivorsThe longitudinal study showed that the percentage of fat mass in testicular cancer

patients, which was comparable with healthy controls at baseline, increased during

chemotherapy (Chapter 2). Results of the cross-sectional study suggest a persistent

change in body composition, since testicular cancer survivors had a higher BMI, more

fat mass, and more abdominal fat compared to healthy controls (Chapter 3). Given that

152

7

the body composition already changed at the start of chemotherapy and the persistent

nature of this alteration, monitoring body composition should already start at the start

of treatment. In addition, attention to lifestyle, dietary intake, and activity level is

needed for these patients to limit the impact of cardiovascular risk factors.

It can be questioned whether cancer survivors need the same strategy to lose

weight as overweight or obese people without a history of cancer. Results of the

cross-sectional study showed that a lower testosterone level was associated with the

higher BMI, fat mass, and abdominal fat distribution in testicular cancer survivors

(Chapter 3). Nutritional support in hospitals is mainly focused on the management

of malnutrition and weight loss. Patients experiencing weight gain are often referred

to dieticians in primary care. Since other mechanisms probably underlie the weight

gain in cancer survivors, treatment should not be focused on reducing energy intake

only. Other factors, like testosterone level, may need to be monitored as well. Since

activity level affects body composition, changes in activity level may be involved in the

change of body composition after chemotherapy as well. We assessed the sports level

among testicular cancer patients only at baseline using a crude measure (reported sport

frequency per week). Future studies regarding body composition in cancer patients have

to take detailed information regarding possible changes in sports- and/or activity level

into account.

Metallic tasteMetallic taste is a taste alteration frequently reported by cancer patients treated with

chemotherapy, with a prevalence ranging from 10% to 78% (Chapter 4). Despite the

high prevalence, the cause of metallic taste in cancer patients is still unknown. Data

regarding the mechanism of metallic taste will help to decrease or even prevent the

occurrence of metallic taste in cancer patients. Besides, a better understanding of this

sensation will help to find suitable management strategies to support cancer patients

experiencing a metallic taste.

So far, metallic taste in cancer patients has been assessed using questionnaires

and interviews. Nevertheless, other methods are needed to explore the mechanism of

this sensation. A stimulus that reflects the metallic taste experienced by cancer patients

can be of help. Ferrous sulfate (FeSO4) is a good candidate, since the evoked sensation

of this compound has been described as metallic by healthy participants (Chapter 4).

153

General discussion

Besides, such a stimulus can be used to imitate metallic taste in healthy participants to

explore suitable strategies to mitigate effects of metallic taste. The metallic sensation

of FeSO4 is likely in part due to retronasal smell, since the perceived intensity of the

perceived sensation decreases with nasal occlusion in healthy participants. The role

of retronasal smell in the metallic taste sensation can be investigated by examining

the perceived sensation in cancer patients experiencing metallic taste with and

without a nose clip. Moreover, saliva measurements can be performed to detect

chemotherapeutic agents in cancer patients with and without the experience of metallic

taste to investigate a possible direct influence on taste in the mouth. These measures

will add information to the possible mechanism of a metallic sensation as experienced

by cancer patients. First, metallic taste may be a specific taste alteration like a change

in threshold for sweet, sour, salty or bitter taste. Exploring a detection threshold for

metallic taste in cancer patients can test the hypothesis whether cancer patients have

a decreased threshold for metallic. Second, metallic taste may be a combination of a

gustatory and olfactory sensation. When both taste and smell are involved, ‘metallic

flavour’ would be a better term for the experienced sensation than a ‘metallic taste’.

Third, metallic taste may be a particular bad taste in the mouth due to the taste of

chemotherapeutic agents.

For cancer patients experiencing a metallic taste, specific types of ONS can

be developed, taking into account management strategies to cope with metallic taste.

Specific types of ONS for patients bothered by a metallic taste could be effective to

improve their nutritional status. Several management strategies for cancer patients

experiencing metallic taste can be recommended, including the use of plastic utensils,

eating cold or frozen foods, adding strong herbs, spices, sweetener or acid to foods, and

eating sweet and sour foods (Chapter 4). Sweet and sour flavoured ONS may be preferred

by patients experiencing metallic taste. Moreover, frozen ONS can be helpful. Possibly,

these ice-cream style ONS evoke more positive emotions and associations compared to

the available clinical drinks, resulting in increased food enjoyment. Furthermore, ONS

with added spices or herbs to overpower the metallic taste can be useful to develop.

Adding spices or herbs are better options than adding salt to products, given the adverse

effects of salt on blood pressure and cardiovascular health [6]. Finally, juice-based ONS

seem to be the least suitable ONS for cancer patients experiencing a metallic taste,

since the metallic taste of this ONS type increased during chemotherapy (Chapter 6).

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7

Methodological considerations for future researchAs a result of our research experience, several methodological considerations for

future research need to be addressed. We measured taste function using taste strips

(Chapter 2 and 3). This method consists of four concentrations of sweet, sour, salty,

and bitter taste, resulting in a score ranging from zero (no concentrations correctly

identified) to four (all concentrations correctly identified) per taste. A total taste score

is derived by summing the scores of each taste. This is an appropriate method to find a

rough answer to the question whether patients have a normal or impaired taste function.

However, when the aim is to investigate relationships between taste thresholds of each

taste quality and other factors, such as dietary intake or food preference, an ordinal

variable (range 0-4) limits statistical analyses. Therefore, a ‘more continuous’ variable

by using more concentration steps of each taste quality is required. This will allow

researchers to investigate taste changes more specifically and to explore the specific

relationship between taste thresholds and possible associations, such as dietary intake,

food preference, and body composition.

We used pictures of sweet and savoury foods varying in fat and protein content

to assess food preference (Chapter 2 and 3). It can be questioned whether using food

pictures reflects true food preference in cancer patients. Cancer patients may rely

on their memory whether they like a product or not during a test using food pictures

and may therefore override their changes in taste and smell perception. This may be

especially the case for foods that have not been consumed during their treatment. Using

real foods instead of food pictures may better predict changes in food preference in

cancer patients.

The study regarding the palatability of ONS, included questions regarding liking,

wanting, and attributes of ONS using a seven-point scale (Chapter 6). To measure ONS

preference, the two milk-based (vanilla and strawberry), two juice-based (apple and

orange) and two yoghurt-based (vanilla-lemon and peach-orange) ONS were ranked based

on their liking score. With this method the most preferred ONS or ranked preference

cannot be retrieved when multiple ONS have the same liking score. Asking participants

to rank the products from the most to the least liked product or using a 100-mm visual

analogue scale (VAS) will add more detailed information regarding food preference.

These measures may better predict food choice.

155

General discussion

To estimate the magnitude of the change in taste and smell function in cancer

patients due to chemotherapy, a baseline measurement prior to chemotherapy is

crucial. Nevertheless, the recruitment of cancer patients for research before the start

of their treatment is difficult. Often, the time span between diagnosis and start of

treatment is short. Moreover, this is a difficult and stressful period for most patients

since the diagnosis of cancer has a major impact. In addition, studies concerning taste

and smell changes require significant effort and concentration of participants. This may

be difficult for some patients who are about to start with treatment. Measurements

during treatment are easier to realize as long as patients are not too nauseated or

tired to perform the tests. These difficulties concerning recruitment are less relevant

for cancer survivors, which makes recruitment of this study group easier compared to

cancer patients. Future researchers should consider whether their research question

regarding taste and smell changes can be answered without a measurement prior to

chemotherapy or whether the study can be performed in cancer survivors instead of

cancer patients undergoing treatment.

In brief, future studies regarding taste and smell changes in cancer patients

have to include: 1) measurement of taste and smell function with continuous outcome

variables, 2) offering a variety of foods with a diversity of flavours and flavour intensity,

3) product ranking regarding preference. The combination of these aspects will provide

useful information regarding food preference and management strategies for patients

with taste and/or smell changes. These data can be used as guideline by health care

professionals to support patients reporting taste and smell changes.

ConclusionTaste and smell changes appear to be heterogeneous, even when focusing on a

homogeneous cancer population. This implicates that dietary advice should be given on

an individual base for cancer patients suffering from taste and smell changes. This seems

also to be the case for cancer patients experiencing a metallic taste. Furthermore, the

body composition of testicular cancer patients changes already during chemotherapy.

This implicates that intervention strategies aimed to limit the impact of cardiovascular

risk factors should probably start during treatment.

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7

References[1] Boltong A, Keast R. The influence of chemotherapy on taste perception and food hedonics:

a systematic review. Cancer Treat Rev 2012;38:152-63.

[2] Unieke smaakmakers. Available at: http://www.ikazia.nl/over-ikazia/nieuws/unieke-smaakmakers. [accessed 9.7.2015].

[3] Ook op RTV. Speciaal brood geeft patiënten smaak weer terug. Available at: http://www.ikazia.nl/over-ikazia/nieuws/ook-op-rtv-speciaal-brood-geeft-pati%C3%ABnten-smaak-weer-terug. [accessed 9.7.2015].



[6] He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens 2009;23:363-84.

157

General discussion

Summary

8

160

8

SummaryTaste and smell perception play a significant role in appetite, dietary intake, and food

choice. Cancer patients often experience changes in taste and smell perception during

chemotherapy. These chemosensory changes can result in malnutrition, weight loss,

and a decreased quality of life. Furthermore, patients may develop unhealthy eating

patterns due to taste and smell changes, resulting in overweight. Previous studies

regarding taste and smell changes are mostly performed in heterogeneous cancer

populations with various malignancies, treatments, and treatment phases and found no

consistency in the nature of taste and smell changes.

This thesis aimed to investigate taste and smell changes and their short- and

long-term consequences in a homogeneous population of testicular cancer patients

treated with cisplatin-based chemotherapy. Moreover, metallic taste experienced by

cancer patients was explored.

In Chapter 2, short-term changes in psychophysical and subjective taste and

smell function, food preference, dietary intake, and body composition in testicular

cancer patients undergoing cisplatin-based chemotherapy were investigated.

Twenty-one consecutive testicular cancer patients participated. Measurements were

carried out prior to chemotherapy, during the first cycle, before and during the second

cycle, at completion of chemotherapy, and seven months and one year after the start of

chemotherapy. Patients were compared to a healthy control group at baseline to explore

possible differences in taste and smell function, food preference, dietary intake, and

body composition due to the disease. Compared to controls, testicular cancer patients

had a lower smell threshold and a lower preference for high fat sweet foods at baseline.

Over time, intra-individual psychophysical taste and smell function was highly variable.

The salty taste threshold increased at completion of chemotherapy compared to baseline.

A transient decrease of subjective taste, appetite, and hunger feelings was observed

per chemotherapy cycle. The percentage of fat mass increased during chemotherapy

compared to baseline, while the lean mass decreased. Moreover, the bone density

of these patients decreased. These results indicate that coping strategies regarding

subjective taste impairment should especially be provided during the first week of

each chemotherapy cycle. In addition, since the body composition of testicular cancer

patients already had changed at completion of chemotherapy, intervention strategies to

limit the impact of cardiovascular risk factors should probably start during treatment.

161

Summary

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. These

outcome variables were assessed in 50 testicular cancer survivors and 50 age-matched

healthy men. The cancer survivors had a lower total taste function and a higher bitter

taste threshold than controls. No differences in smell function and dietary intake were

found. Furthermore, the cancer survivors had a higher BMI, and more (abdominal) fat

compared to controls. Within survivors, body composition was not associated with taste

function, dietary intake or food preference, whereas testosterone level was an important

determinant of body composition. These results indicate that a low testosterone level

rather than taste dysfunction, dietary intake or food preference explain the higher BMI,

fat mass, and abdominal fat distribution in testicular cancer survivors.

In Chapter 4, a literature review was performed to assess all available studies

regarding metallic taste in cancer patients treated with chemotherapy. The definition

of metallic taste, assessment methods, prevalence, duration, possible causes due to

chemotherapy, and management strategies were addressed. Prevalence of metallic

taste ranged from 9.7% to 78% among patients with various cancers, chemotherapy

treatments, and treatment phases. No studies were performed to investigate the

influence of metallic taste on dietary intake, body weight, and quality of life. Based on

literature and information on cancer patient forums, several management strategies can

be recommended for cancer patients: using plastic utensils, eating cold or frozen foods,

adding strong herbs, spices, sweetener or acid to foods, eating sweet and sour foods,

using ‘miracle fruit’ supplements, and rinsing with chelating agents. Furthermore,

studies have been carried out regarding the characteristics of metal salts eliciting

a metallic taste in healthy participants. To date, no metal salt solution, solid metal

or electric stimulus has been identified that reflects the metallic taste reported by

cancer patients treated with chemotherapy. Such a stimulus is essential to imitate this

metallic taste in healthy participants and can be used to develop suitable management

strategies. Results of the review indicated that metallic taste is a frequent side effect

of chemotherapy and a much discussed topic on cancer patient forums, but literature

regarding metallic taste among chemotherapy treated cancer patients is scarce. More

awareness for this side effect can improve the support for these patients.

162

8

In Chapter 5, a study was performed to investigate the prevalence of metallic

taste in 127 cancer patients treated with systemic therapy and to explore possible

predictors of metallic taste regarding age, gender, treatment type, treatment phase,

and factors related to taste changes. Furthermore, characteristics of metallic taste,

including the perceived intensity, the duration, and consequences regarding food intake

were explored. A questionnaire was constructed for the present study to answer these

research questions. Fifty-eight of 127 (46%) cancer patients reported taste changes in

the preceding week. Of these patients, 20 (34%) reported a metallic taste. Patients

treated with chemotherapy, concomitant radiotherapy, as well as targeted therapy

reported metallic taste with a prevalence of at least 10%. Women experienced metallic

taste more often than men. Patients experiencing a metallic taste, also reported more

frequently that they were bothered by sour food and that everything tasted bitter.

A tendency was found between metallic taste and aversion to fatty foods. The experience

of metallic taste was highly variable among patients. Results of this study indicate that

patients treated with chemotherapy, concomitant radiotherapy, and targeted therapy

are all at risk for this taste alteration. However, not all patients reported this alteration

as bothersome.

Oral nutritional supplements (ONS) are commonly prescribed to malnourished

patients to improve their nutritional status. Taste and smell changes in patients with

cancer can affect the palatability of ONS. In Chapter 6, the palatability of six ONS

(two milk-based, two juice-based, and two yoghurt-based) was investigated in testicular

cancer patients treated with cisplatin-based chemotherapy at five time points: prior

to chemotherapy, during the first cycle, before and during the second cycle, and at

completion of chemotherapy. Furthermore, the relation between ONS palatability and

the taste and smell function of these patients was explored. Moreover, the metallic

taste of the different ONS types was examined. Twenty-one testicular cancer patients

undergoing first-line cisplatin-based chemotherapy participated. A questionnaire was

used to assess the palatability of ONS and to which extent the attribute ‘metallic’ was

applicable. Overall, the palatability of ONS was highly variable among patients. The

milk-based strawberry ONS was preferred most before, during, and after chemotherapy.

The liking of the milk-based vanilla ONS tended to decrease over time, whereas the

liking of the other ONS remained stable. A higher smell threshold and a lower sour taste

threshold were correlated to a decreased liking of the milk-based vanilla ONS. The

two juice-based ONS tended to taste more metallic during than before chemotherapy.

163

Summary

Results of this study indicate that health care professionals and patients should be aware

that the palatability of ONS can change over time. Regular structured contact between

health care professionals and patients regarding the choice of ONS seems warranted.

In Chapter 7, the main findings of this thesis and their clinical implications

are discussed. Given the heterogeneity of taste and smell changes, dietary advice

on an individual base is needed for patients suffering from taste and smell changes.

Additionally, given that the body composition of testicular cancer patients changes

already during chemotherapy, implicates that intervention strategies aimed to limit the

impact of cardiovascular risk factors should start early.

Studies investigating the relation between taste and smell function and suitable

strategies to manage these chemosensory changes are warranted. Moreover, intervention

studies examining the impact of combined programs involving both dietary and physical

activity modification on body composition, metabolic syndrome, and cardiovascular

disease in testicular cancer survivors are warranted. Obtained data from these studies

will help to inform patients regarding diet, physical activity, and lifestyle to prevent

long-term complications of treatment.

Nederlandse samenvatting (summary in Dutch)

166

Nederlandse samenvatting (summary in Dutch)De perceptie van smaak en geur speelt een significante rol bij eetlust, voedselinname

en voedselvoorkeur. Patiënten met kanker ervaren vaak veranderingen in smaak- en

geurperceptie tijdens chemotherapie. Deze chemosensorische veranderingen kunnen

resulteren in ondervoeding, gewichtsverlies en een verlaging van de kwaliteit van

leven. Verder kunnen patiënten door smaak- en reukveranderingen ongezonde

eetgewoonten ontwikkelen, resulterend in overgewicht. Eerdere studies naar smaak- en

reukveranderingen bij patiënten met kanker zijn voornamelijk uitgevoerd in heterogene

patiëntenpopulaties variërend in soort kanker, soort behandeling en behandelingsfase.

De resultaten van deze studies betreffende de aard van de smaak- en reukveranderingen

zijn inconsistent.

Het doel van dit proefschrift was om de smaak- en reukveranderingen en

de korte- en langetermijneffecten te onderzoeken in een homogene populatie van

zaadbalkankerpatiënten behandeld met cisplatin-bevattende chemotherapie. Verder

werd metaalsmaak bij patiënten met kanker onderzocht.

In Hoofdstuk 2 is een studie beschreven waarin de korte termijn

veranderingen in psychofysiologische en subjectieve smaak- en reukfunctie, voedsel-

voorkeur, voedselinname en lichaamssamenstelling van patiënten met zaadbalkanker

werden onderzocht. Eénentwintig patiënten met zaadbalkanker participeerden in dit

onderzoek. Metingen werden uitgevoerd voor de start van chemotherapie, tijdens de

eerste kuur, voor en tijdens de tweede kuur, één maand na start van de laatste kuur,

zeven maanden en één jaar na start van de chemotherapie. Resultaten van patiënten

voor de start van chemotherapie werden vergeleken met een gezonde controlegroep

om mogelijke verschillen in smaak- en reukfunctie, voedselvoorkeur, voedselinname en

lichaamssamentelling ten gevolge van de ziekte te onderzoeken. Vergeleken gezonde

controles hadden de patiënten met zaadbalkanker een lagere geurdrempel en minder

voorkeur voor zoete voedingsmiddelen hoog in vet voorafgaande aan de chemotherapie.

Gedurende de chemotherapie was de psychofysiologische smaak- en reukfunctie erg

variabel binnen en tussen patiënten. De drempel van de smaak zout was verhoogd vlak

na de afronding van chemotherapie vergeleken voor de start van chemotherapie. Een

tijdelijke verlaging van subjectieve smaak, eetlust en hongergevoel was gevonden per

chemokuur. Het vetpercentage van patiënten steeg tijdens de chemotherapie, terwijl

167

Nederlandse samenvatting

het percentage van de vetvrije massa daalde. Bovendien daalde de botdichtheid van

deze patiënten. Deze resultaten tonen aan dat copingstrategieën voor subjectieve

smaakverandering vooral aan het begin van elke chemokuur moeten worden aangeboden.

Verder zouden interventie strategieën gericht op het beperken van cardiovasculaire

risicofactoren waarschijnlijk al tijdens de chemotherapie moeten starten, gezien dat

de lichaamssamenstelling van patiënten met zaadbalkanker al veranderd tijdens de

chemotherapie.

In Hoofdstuk 3 is een studie beschreven waarin de smaak- en reukfunctie

en de invloed op de voedselinname, voedselvoorkeur en lichaamssamenstelling

werden onderzocht bij overlevenden van zaadbalkanker één tot zeven jaar na

cisplatin-bevattende chemotherapie. Dit werd onderzocht bij 50 overlevenden van

zaadbalkanker en 50 voor leeftijd gematchte gezonde mannen. De overlevenden van

kanker hadden een lagere totale smaakfunctie en een hogere drempel voor de smaak

bitter vergeleken de controles. Er waren geen verschillen gevonden in de reukfunctie

en voedselinname. Verder hadden de overlevenden een hogere ‘Body Mass Index’ (BMI)

en meer (abdominaal) lichaamsvet vergeleken de controles. De lichaamssamenstelling

was niet gerelateerd aan de smaakfunctie, voedselvoorkeur of voedselinname bij de

overlevenden van kanker. Het testosteronlevel speelde wel een belangrijke rol bij de

lichaamssamenstelling. Deze resultaten tonen aan dat eerder een laag testosteronlevel

de hogere BMI, totale vetmassa en abdominale vetverdeling verklaard bij overlevenden

van zaadbalkanker, dan de smaakfunctie, voedselinname of voedselvoorkeur.

In Hoofdstuk 4 is een literatuuronderzoek beschreven waarin alle beschikbare

studies over metaalsmaak bij patiënten met kanker behandeld met chemotherapie

werden onderzocht. De definitie van metaalsmaak, meetmethoden, prevalentie, duur,

mogelijke oorzaken bij chemotherapie en copingstrategieën zijn behandeld. The prevalentie

van metaalsmaak varieerde tussen de 9.7% en 78% bij patiënten met verschillende soorten

kanker, soorten chemotherapie en fases van behandeling. Er waren geen studies gevonden

waarin de invloed van metaalsmaak op voedselinname, lichaamsgewicht en kwaliteit van

leven werd onderzocht. Gebaseerd op literatuur en informatie op fora voor patiënten

met kanker, zijn er verschillende copingstrategieën aan te bevelen voor patiënten:

gebruik van plastic bestek, het eten van koud of bevroren voedsel, toevoegen van sterke

kruiden, specerijen, zoete of zure smaken aan voedsel, het eten van zoete en zure

voedingsmiddelen, gebruik van ‘miracle fruit’ supplementen en spoelen met

168

chelaatvormer. Verder zijn er studies bij gezonde proefpersonen uitgevoerd waarin de

karakteristieken van metaalzouten die een metaalsmaak opwekken werden onderzocht.

Op dit moment is er nog geen metaalzoutoplossing, vast metaal of elektrische stimulus

geïdentificeerd die de metaalsmaak bij patiënten met kanker nabootst. Een dergelijke

stimulus is noodzakelijk om deze metaalsmaak na te bootsen bij gezonde proefpersonen

en kan gebruikt worden om copingstrategieën te ontwikkelen. De resultaten van het

literatuuronderzoek tonen aan dat metaalsmaak een veel voorkomende bijwerking van

chemotherapie is en dat het een veel besproken onderwerp of fora voor patiënten met

kanker is. Literatuur over metaalsmaak is echter schaars. Meer bewustzijn en inzicht

zouden de support voor deze patiënten kunnen verbeteren.

In Hoofdstuk 5 is een studie beschreven waarin de prevalentie van metaalsmaak

bij 127 kankerpatiënten behandeld met systeemtherapie werd onderzocht. Ook

werden mogelijke voorspellers van metaalsmaak betreffende leeftijd, geslacht, soort

behandeling, fase van behandeling en factoren geassocieerd met smaakveranderingen

onderzocht. Eveneens werden karakteristieken van metaalsmaak, zoals de ervaren

intensiteit, duur en consequenties met betrekking tot voedselinname onderzocht. Om

deze onderzoeksvragen te beantwoorden, is er een vragenlijst ontwikkeld voor deze

studie. Van de 127 patiënten met kanker, rapporteerden 58 (46%) smaakveranderingen

in de afgelopen week. Van deze patiënten, rapporteerden 20 (34%) metaalsmaak. Zowel

patiënten behandeld met chemotherapie, concomitant radiotherapie als doelgerichte

therapie rapporteerden metaalsmaak, met een prevalentie van minstens 10%. Vrouwen

rapporteerden vaker een metaalsmaak dan mannen. Patiënten die metaalsmaak

ervoeren, rapporteerden ook vaker dat zuur voedsel tegen stond en dat alles bitter

smaakte. Een tendens was gevonden voor een relatie tussen metaalsmaak en een

aversie voor vette voedingsmiddelen. De ervaring van metaalsmaak was erg variabel

tussen de patiënten. Resultaten van deze studie tonen aan dat patiënten behandeld met

chemotherapie, concomitant radiotherapie en doelgerichte therapie allemaal het risico

lopen om metaalsmaak te ervaren. Echter, niet alle patiënten ervoeren metaalsmaak als

storend.

Drinkvoeding wordt vaak voorgeschreven bij ondervoede patiënten om de

voedingstoestand te verbeteren. Smaakveranderingen bij patiënten met kanker kunnen

de smakelijkheid van drinkvoeding beïnvloeden. In Hoofdstuk 6 is een studie beschreven

waarin de smakelijkheid van zes verschillende drinkvoedingen (twee op melkbasis, twee

op sapbasis en twee op yoghurtbasis) werden onderzocht bij zaadbalkankerpatiënten

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Nederlandse samenvatting

behandeld met cisplatin-bevattende chemotherapie. Dit werd op vijf momenten gemeten:

vóór de start van chemotherapie, tijdens de eerste kuur, voor en tijdens de tweede

kuur en één maand na start van de laatste chemokuur. Ook werd de relatie tussen de

smakelijkheid van de drinkvoeding en de smaak- en reukfunctie onderzocht. Verder werd

de metaalsmaak van de verschillende soorten drinkvoedingen onderzocht. Eénentwintig

patiënten met zaadbalkanker participeerden in de studie. De smakelijkheid en de

mate waarin metaalsmaak van toepassing was werden onderzocht met behulp van een

vragenlijst. Over het algemeen was de smakelijkheid van de drinkvoedingen erg variabel

tussen de patiënten. De drinkvoeding op melkbasis met aardbeiensmaak had de grootste

voorkeur voor, tijdens en na chemotherapie. De smakelijkheid van de drinkvoeding op

melkbasis met vanillesmaak neigde te dalen gedurende de chemotherapie, terwijl de

smakelijkheid van de andere drinkvoedingen stabiel bleef. Een hogere geurdrempel en

een lagere drempel voor de smaak zuur was gecorreleerd aan een lagere smakelijkheid

van de drinkvoeding op melkbasis met vanillesmaak. De twee drinkvoedingen op sapbasis

neigden meer naar metaal te smaken tijdens de chemotherapie vergeleken met voor

de start van chemotherapie. Resultaten van deze studie indiceren dat professionals in

de gezondheidzorg zich bewust moeten zijn dat de smakelijkheid van drinkvoedingen

kan veranderen gedurende de chemotherapie. Regelmatig en gestructureerd contact

tussen professionals in de gezondheidzorg en patiënten met betrekking tot de keuze van

drinkvoeding lijkt noodzakelijk.

In Hoofdstuk 7 worden de belangrijkste bevindingen die uit dit proefschrift

naar voren zijn gekomen en hun klinische implicaties besproken. Door de heterogeniteit

van smaak- en reukveranderingen is voedingsadvies op een individuele niveau nodig

voor patiënten met kanker die last hebben van smaak- en reukveranderingen. Verder

zouden interventie strategieën om de invloed van cardiovasculaire risicofactoren te

beperken waarschijnlijk al tijdens de chemotherapie moeten starten, gezien dat de

lichaamssamenstelling van patiënten met zaadbalkanker al veranderd tijdens de

chemotherapie.

Studies gericht op de relatie tussen smaak- en reukveranderingen en

copingstrategieën zijn nodig. Verder zijn gecombineerde interventiestudies gericht

op zowel voeding als lichamelijke activiteit en de invloed op lichaamssamenstelling,

metabool syndroom en hart- en vaatziekten bij patiënten zaadbalkanker noodzakelijk.

Verkregen data van deze studies helpen om patiënten te informeren over de voeding,

lichamelijke activiteit en leefstijl om complicaties van behandeling te voorkomen.

Dankwoord

172

DankwoordHet is af! Dan is nu het moment om iedereen te mogen bedanken die heeft bijgedragen

aan het tot stand komen van dit proefschrift.

Allereerst wil ik alle proefpersonen bedanken voor hun deelname. Hun bereidheid om

deel te nemen aan onderzoek, soms in moeilijke periodes in het leven, heeft ervoor

gezorgd dat ik dit proefschrift heb kunnen schrijven.

Veel dank gaat uit naar mijn promotoren en copromotor: prof. dr. G.J. ter Horst,

prof. dr. A.K.L. Reyners, prof. dr. M.M. Lorist en dr. R.J. Renken.

Beste Gert, veel dank voor je prettige en laagdrempelige begeleiding. Fijn dat

je altijd uitgebreid de tijd nam voor overleg. Ook een fijne gedachte dat ik altijd even

binnen kon lopen als de deur van jouw kantoor open stond.

Beste An, je hebt me geleerd om met een klinische blik naar mijn data te kijken.

Ik bewonder de snelheid en precisie waarin jij stukken kan doorlezen. Dankzij jouw

snelle feedback en oog voor detail, werden de manuscripten een stuk sterker en kon ik

meestal gelijk weer verder.

Beste Monicque, jouw kritische feedback tijdens de besprekingen met het

TIFN-team gaf me vaak stof tot nadenken. Interessant om de onderzoeken vanuit een

andere invalshoek te bekijken. Hier heb ik veel van geleerd.

Beste Remco, bedankt voor de fijne samenwerking. Wat heb ik veel van je geleerd

op het gebied van statistiek, maar ook met het oog op planning. Jouw enthousiasme

werkte vaak aanstekelijk. Fijn dat je altijd uitgebreid de tijd nam om mijn vragen, en

soms ook de ‘beren op de weg’, te bespreken.

De leden van de leescommissie, prof. dr. ir. E. Kampman, prof. dr. G.J. Navis en

prof. dr. I.J. de Jong, wil ik hartelijk danken voor hun tijd en bereidheid om mijn

proefschrift te beoordelen.

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Dankwoord

Dit onderzoek was een onderdeel van het TIFN project ‘Sensory & Liking’. Graag wil

ik alle collega’s binnen dit project hartelijk danken voor de leerzame en vruchtbare

samenwerking: Erik van der Linden, Sanne Boesveldt, René de Wijk, Renate Winkels,

Gerry Jager, Ben Lawlor, Annelies van der Stelt, Hugo Weenen, Martijn Veltkamp, Sanne

Griffioen-Roose, Sarah Simpson, Marion Coeleman en Corine Beemster.

Mede-promovendi Swetlana, Yfke, Jelle, Heleen en Iris: bedankt voor de

gezelligheid en jullie betrokkenheid gedurende dit gezamenlijke project. Luca: bedankt

voor de fijne samenwerking en uiteraard ook voor het lekkere Italiaanse eten voor het

team.

Prof. dr. ir. C. de Graaf, beste Kees, ik vond het leuk om onze samenwerking

tijdens mijn scriptie van de master Voeding en Gezondheid te kunnen voortzetten bij dit

project. Ik bewonder je expertise op het gebied van sensorisch onderzoek.

Beste Manon, wat heb ik ontzettend veel van jou geleerd met betrekking tot de

praktische uitvoering van onderzoek. Bedankt voor de fijne samenwerking en uiteraard

ook voor de randomisatieschema’s.

Alle co-auteurs wil ik hartelijk bedanken voor hun bijdrage aan de artikelen. Door

jullie feedback vanuit verschillende expertises werden de manuscripten naar een hoger

niveau gebracht.

Prof. dr. J.A. Gietema, beste Jourik, bedankt voor de hulp en het meedenken bij

het TASTY-onderzoek. Ik bewonder je expertise op het gebied van klinisch onderzoek.

Dr. J.D. Lefrandt, beste Joop, bedankt voor je enthousiaste hulp. Door jouw

kritische blik konden resultaten scherper worden opgeschreven.

Prof. dr. R.H.J.A. Slart, beste Riemer, bedankt voor je hulp en inbreng bij de

uitkomstmaten van de DEXA-scans.

Ook wil ik alle artsen en verpleegkundigen die hebben bijgedragen aan de werving

van deelnemers voor het onderzoek hartelijk danken. Prof. dr. E.G.E. de Vries, beste

Liesbeth, bedankt voor het meedenken over het project en de support. Hink en Niek,

bedankt voor de vriendelijke samenwerking met het oog op onze gemeenschappelijke

onderzoekspopulatie.

174

Graag wil ik mijn paranimfen bedanken.

Lieve Jolien, wat hebben we veel beleefd in de afgelopen jaren. Wij als ‘andere

onderzoekers’ naast de arts-onderzoekers bij de Medische Oncologie. Ik heb ook veel van

je geleerd op het gebied van statistiek. Ontzettend bedankt voor de fijne samenwerking

en dat je altijd voor me klaar stond (en staat).

Beste Olaf, ik was erg benieuwd wie mijn nieuwe kamergenoot zou worden. Toen

kwam jij binnen met al je vrolijkheid. Wat hebben we gelachen (en natuurlijk ook heel

hard gewerkt).

In de afgelopen periode heb ik ervaren hoe leuk het is om studenten te begeleiden.

Graag wil ik de studenten bedanken die mij geholpen hebben. Petra en Anne, bedankt

voor de hulp met de metingen en jullie bijdrage aan het TASTY-onderzoek. Erik, bedankt

voor je inzet bij het metaalsmaak-onderzoek. We hebben een mooie bijdrage geleverd

aan wetenschappelijk onderzoek.

Lieve Antina, bedankt voor je hulp als onderzoeksassistent bij de uitvoering van de

metingen. Ik ben dankbaar dat deze periode ook een waardevolle vriendschap

heeft opgeleverd. Leuk dat we elkaar nog steeds zien, ondanks de grote afstand

Groningen-Leuven.

De diëtisten van de Wageningen Universiteit: Jeanne, Saskia, Els, Karin en Corine:

bedankt voor de hulp met betrekking tot het meten en coderen van de voedselinname

bij het TASTY-onderzoek.

Medewerkers van de Medische Oncologie. Het secretariaat: Bianca, Gretha en Hilda,

bedankt voor de prettige samenwerking en praktische hulp rondom de onderzoeken.

Gerry Sieling, bedankt voor je hulp bij allerlei zaken rondom het onderzoek. Menno

en Stanley, bedankt voor jullie vriendelijke facilitaire hulp. Nynke Zwart en Gerrie

Steursma, bedankt voor de hulp bij het verwerken van de bloedbuizen.

Andere collega’s op de gang van de oncologie. Marijke en Bea, bedankt voor de gezellige

lunches en de verfrissende blokjes om in de pauze.

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Dankwoord

Jan-Bernard, bedankt voor de hulp op het gebied van statistiek en uiteraard ook voor

het bouwen van de mooie app voor het TASTY-onderzoek.

Hedwig, bedankt voor de secretariële ondersteuning vanuit het NIC. Altijd leuk om even

kort bij te praten als ik de overtocht van het UMCG naar het NIC had gemaakt.

Medewerkers van de Nucleaire Geneeskunde en het Vaatlab: bedankt voor de vriendelijke

samenwerking bij het inplannen en uitvoeren van de metingen voor het onderzoek.

Lieve vrienden en familie, bedankt voor alle steun en gezelligheid. Wat ontzettend fijn

dat jullie altijd voor mij klaar staan.

Lieve Erik, bedankt dat je er altijd voor mij bent. En ook zeer belangrijk: bedankt voor

de enorme hulp bij de lay-out en de über-mooie voorkant van dit proefschrift!

Lieve mama, bedankt voor je onvoorwaardelijke steun en dat je altijd trots op mij bent.

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