Introduction
Childhood cancer survival rates have markedly improved in recent decades [
1]. Increased survival can be attributed to providing more intensive therapies. However, as a result, almost all such children suffer from bothersome or severe treatment-related side effects [
2]. Nausea, vomiting, and loss of appetite are well-known side effects among childhood cancer patients, interfering with food intake [
3]. Taste changes have been found to be the third most common bothersome symptom (prevalence 60.3%) [
2]. These changes are an often overlooked side effect contributing to inadequate food intake, which in turn affects nutritional status [
4]. Poor nutritional status in children with cancer is associated with increased infections, poor survival, and impaired health-related quality of life [
5,
6].
Studies investigating changes in smell and taste among childhood cancer patients are rare. Skolin and colleagues found that children with cancer undergoing chemotherapy had significant lower scores for bitter taste and made more taste recognition errors compared with controls [
7]. However, this cross-sectional study was heterogeneous regarding chemotherapy (i.e., patients receiving doxorubicin, methotrexate, ifosfamide, cytarabine, procarbazine, dacarbazine, cisplatin, or cyclophosphamide per protocol depending on diagnosis and treatment phase), and only ten patients (median age 14.5 years) underwent a taste test. Qualitative studies indicated that changes in taste were the predominant cause of eating problems and altered food preferences in children with cancer, although specific food choices were highly variable [
7,
8]. Changes in taste are often accompanied by changes in smell function. This has been found in adult patients undergoing various chemotherapy regimens (e.g., anthracycline, taxane, platinum containing) but has not been studied in childhood cancer patients during chemotherapy [
9]. Only one study evaluated both smell and taste function in pediatric patients (
n = 10) after bone marrow transplantation, but not during chemotherapy [
10]. As current evidence comes from small studies and lack the assessment of smell function in childhood cancer patients during chemotherapy, prospective studies are needed to measure smell and taste function in children with cancer during chemotherapy.
Before investigating smell and taste changes in childhood cancer patients extensively, it must be considered whether psychophysical smell and taste assessments can be obtained without unpleasant side effects. For example, if children with cancer are rather sensitive to odors, which are regularly seen in adult patients, they might experience nausea when certain odors are presented [
11]. Therefore, this study aimed to examine whether measurements of smell, taste, and fungiform papillae density are feasible (i.e., completed by more than 60% of the patients) in children with cancer and if those tests require adjustments. Furthermore, smell and taste function, fungiform papillae density, and eating behavior were evaluated during chemotherapy (i.e., before and after a cycle) and compared with healthy controls, results of which contribute to a burgeoning understanding of smell and taste changes and their consequences in children with cancer.
Discussion
The present study has shown that assessing smell, taste, and fungiform papillae density is feasible in children with cancer, as more than 60% of the patients were able to complete the tests. Although feasible, some adaptions are deemed necessary regarding time duration and difficulty level of the tests. Furthermore, we showed that taste function increased in childhood cancer patients during chemotherapy, especially for sweet and bitter taste. Lower smell thresholds were found in patients compared with healthy controls, which suggest that both smell and taste sensitivity increased in children with cancer.
Regarding smell function, a wide step method was used for the threshold test to enhance concentration and reduce time of investigation. This method has never been used in children but has been shown reliable in adults [
13]. Due to the size of our control group, and its distribution across different age categories, it was not possible to compare the threshold scores with those derived from a regularly used narrow step method [
22]. Still, the wide step method provides an advantage for threshold testing in participants where time of investigation should be kept as short as possible [
13]. Although only one discrimination test was prematurely terminated due to nausea, several patients noted that they did not like the intensity and large number of odorants either. Concerning odor identification, children were often not familiar with some of the odorants (e.g., turpentine, apple) from the odor identification test. This finding is consistent with a study among German children [
23]. The Universal Sniff Test, a recently developed international odor identification test for children, will be more suitable as odorants are selected on familiarity [
24]. This test is now commercially available, including normative values for children aged 6–17 years [
22].
As smell thresholds are less influenced by age, contribute to a large extent to the diagnosis of smell loss, and seem affected the most in our study population, the assessment of smell function in children with cancer should include at least an odor threshold test [
25,
26]. However, the assessment of several components of smell function, instead of a single component, is preferred. Therefore, a suitable odor identification task for children, such as the Universal Sniff Test, should be added. Odor discrimination does not seem to have much added value in children with cancer, and child-friendly tasks are lacking. Removing this task will save at least 10 min.
Investigating taste function and papillae density can be considered feasible, although the assessment of papillae density was more problematic in children with cancer. The main obstacle was not the measurement, which relatively few children disliked
, but rather obtaining a proper photograph of the tongue. Photographs regularly failed due to movement of the tongue or being taken in poorly lit rooms. Sometimes, fungiform papillae were invisible because of a white layer on the surface of the tongue. The so-called oral thrush, or oral candidiasis, is common among people with a weakened immune system [
27]. In addition, papillae density was not significantly different between the groups nor correlated with taste function in patients. Although feasible, the limitations and current results do not warrant further investigation of fungiform papillae density in children with cancer. Practical issues need to be overcome first to reduce the burden on children with cancer.
Results of our study seem to indicate that smell function sensitizes in children with cancer, showing lower smell thresholds compared with controls. Smell function did not change significantly after a cycle of chemotherapy in patients. Our findings are in contrast with those of previous studies who examined adults receiving chemotherapy. For example, women undergoing chemotherapy for breast cancer or gynecological malignancies showed increased smell thresholds during chemotherapy [
9]. In addition, men undergoing chemotherapy for testicular cancer showed no changes in smell function [
28]. Although there was no measurement before diagnosis, and it cannot be ruled out that lower smell thresholds were already present before diagnosis, several children with cancer (
n = 8) reported a better or much better smell perception since the start of chemotherapy. This may well be an underestimation. Increased smell sensitivity was typically judged as negative. Possibly, some children conflated their evaluation of their altered sense of smell with their altered smell sensitivity leading them to rate their sense of smell as “worse” after chemotherapy. Future research on subjective smell and taste sensitivity in children with cancer requires more careful instruction and phrasing of questions.
The current study showed increased sweet, bitter, and total taste function after a cycle of chemotherapy. So far, evidence regarding smell and taste function in childhood cancer patients during chemotherapy is limited to cross-sectional studies with small sizes. Those studies generally show reduced taste perception for all taste qualities, or bitter taste only, in children with cancer compared with healthy controls [
7,
29]. When reviewing prospective studies among adults receiving chemotherapy, changes in sweet taste and, to a lesser extent, bitter taste seem more common than changes in salt or sour perception [
30]. However, taste changes in the current subset of childhood cancer patients were characterized by increased perception of sweet and bitter taste, while adults generally experience a decreased perception of these taste qualities during chemotherapy. Maybe other pathways are involved in children compared with adults.
The etiology of smell and taste changes during chemotherapy is not fully understood. In general, damage to sensory receptor cells and abnormal neuronal activity are thought to be the major cause of these distortions [
31]. Smell and taste receptor cells have high turnover rates, as do cancer cells, and particularly rapidly dividing cells are affected by chemotherapy. With respect to specific chemotherapeutic substances, drugs such as methotrexate, vincristine, cisplatin, carboplatin, doxorubicin, cyclophosphamide, 6-mercaptopurine, and 5- fluorouracil all seem to be associated with taste changes in adults but not necessarily with smell changes [
32]. Taste changes may be also related to oral mucositis, poor oral hygiene, infections, or a dry mouth. In addition, it is presumed that cancer-related inflammation can trigger apoptosis of the taste bud cells through cytokine signaling pathways, thereby contributing to the development of taste disorders [
33]. An enhanced ability to smell during chemotherapy, potentially resulting in food aversions and nausea, might be a strengthened defense mechanism of the sensory organ to avoid ingestion of potentially harmful substances into the body [
34]. However, many questions remain regarding smell and taste changes during chemotherapy.
Taste function was correlated with eating behavior and feeding strategies in children with cancer. This is in line with qualitative studies that already highlighted the influence of taste changes on food preferences and eating behavior [
7,
8,
35]. Since eating behavior and food preferences are still developing in children, and are strongly influenced by the chemical senses, it is suggested that the impact of smell and taste changes in the long term could be large as well [
36,
37]. To prevent children with cancer from inadequate food intake and bad dietary habits due to this phenomenon, longitudinal studies are needed to identify the course of smell and taste changes and its consequences regarding food intake and eating behavior during and after chemotherapy.
This study aimed to investigate feasibility of smell, taste, and papillae density assessment in children with cancer. Therefore, the current results regarding smell and taste function do not allow for strong conclusions and should be considered tentative. Even if it is the largest study to date, the size of the current study is small, lacks a measurement at diagnosis, and varies in time intervals between measurements. Nevertheless, the prospective study design and control group make the results of this feasibility study already useful for a burgeoning understanding of smell and taste changes in children with cancer during chemotherapy.
In conclusion, the assessment of smell and taste function and fungiform papillae density is feasible in children with cancer. Future longitudinal studies should focus on smell (threshold and identification) and taste function in children with cancer, whereas the assessment of fungiform papillae density should be omitted. In addition, results of the current study suggest a remarkable increased smell and taste sensitivity in children with cancer, which was an unexpected finding and requires further investigation.
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