Assessing taste and smell alterations in cancer patients undergoing chemotherapy according to treatment

Abstract

Purpose

Taste and smell changes are common side effects in cancer patients undergoing chemotherapy treatments (CT). This can lead to a reduced food enjoyment and an inadequate nutrient intake with a high impact on nutritional status and quality of life. The aim of this study was to evaluate the self-reported chemosensory alterations of patients undergoing chemotherapy according to CT type.

Methods

An observational study was conducted with 151 patients undergoing CT at Oncology Outpatient Unit from Onkologikoa Foundation. An interviewer-assisted questionnaire was designed to investigate chemosensory changes in patients undergoing CT.

Results

Seventy-six percent patients reported taste disorders and 45% smell changes. Xerostomia is the most frequent symptom reported by patients receiving chemotherapy in our study (63.6%), and it is strongly associated to bad taste in mouth (OR = 5.96; CI = 2.37–14.94; p value = 0.000) and taste loss (OR = 5.96; CI = 2.37–14.94; p value = 0.000). Anthracyclines, paclitaxel, carboplatin, and docetaxel were the CT agents producing the highest taste disturbance rates. Cisplatin and 5-Fluorouracil are the CT resulting in the lowest complaints. Logistic regression revealed statistically significant associations between taste loss and carboplatin and docetaxel (OR = 3.50; CI = 1.12–10.90; p value = 0.031) and cold hypersensitivity and oxaliplatin (OR = 12.14; CI = 4.18–35.25; p value = 0.000). Not only platin-based CT such as carboplatin produced dysgeusia, but also anthracyclines and paclitaxel treatments.

Conclusions

The better knowledge of taste and smell alterations according to CT type may provide valuable information for the design of new strategies to tackle CT side effects. It is important to take into account taste and smell dysfunctions and other alterations such as xerostomia together.

Introduction

Chemosensory dysfunctions are common and distressing among cancer patients undergoing radiotherapy (RT) and chemotherapy (CT). Radiotherapy is a very well-recognized cause of chemosensory dysfunction, as can lead to direct damage of taste receptors, synaptic uncoupling and other neurological damage [1]. Taste and smell alterations in cancer patients undergoing RT is quite well described in several studies [2,3,4,5,6]. However, for many cancer patients, CT is the primary form of treatment and its short- and long-term effect on chemosensory alterations is less well understood. The exact mechanism underlying these alterations is not yet known due to the heterogeneity of cancer population studies and the multifactorial etiology of taste and odor abnormalities. It has been suggested that CT targets rapidly dividing cancer cells, but unfortunately, this systemic treatment is not selective, and other rapidly growing non-cancer cells such as mucosal cells, olfactory and gustatory receptors are also sensitive [7,8,9].

Chemosensory alterations include a reduction in smell sensitivity and taste sensitivity (hypogeusia), an absence of taste sensation (ageusia) and distortion of normal taste (dysgeusia) or a taste perception without an external stimulus (phantogeusia). Moreover, other clinical conditions such as dysphagia, xerostomia, mucositis, and nausea are frequent [10, 11]. Xerostomia refers to a subjective experience of mouth dryness reported by patient [12]. It is not a taste or odor disorder per se but is highly related to taste alteration. How xerostomia causes taste alteration is not known, but it is assumed that the decreased secretion and a higher viscosity of saliva interfere with transportation of flavor molecules to olfactory and taste receptors [13, 14]. Chemotherapy information sheets give details about side effects, changes in taste and smell. However, they do not specify the exact alterations and there is little information concerning the impact of different CT on the severity of different taste and smell alterations [15].

Although taste and smell function tends to return to normal after chemotherapy completion [8, 16, 17], it is important to highlight the great impact of chemosensory alterations on the patients’ nutritional status and quality of life during the disease. Decreased sensitivity to taste/smell along with its changes are positively correlated with a decrease in appetite leading to an inadequate energy and nutrient intake, weight loss and therefore affecting their nutritional status [18, 19]. Malnutrition occurs in the majority of patients with cancer and is a major cause of morbidity and mortality in advanced disease [20].

The objective of this study was as follows:

  1. 1.

    To evaluate self-reported taste and smell alteration of patients undergoing chemotherapy according to chemotherapy treatment.

  2. 2.

    To evaluate the impact of different chemotherapy treatments on the severity of different taste and smell alterations.

Materials and methods

Study design and patients

A prospective, observational study was conducted. Patients undergoing CT were recruited from January 2015 to May 2015 at Oncology Outpatient Unit from Onkologikoa Foundation (San Sebastian, Spain). Potentially eligible patients were identified during their outpatient consultation. The study protocol was approved by the Gipuzkoa Clinical Research Ethics Committee and performed in accordance with the Declaration of Helsinki of Good Clinical Practice guidelines. Informed consent was obtained from all individual participants included in the study.

Patients aged 18 years or over scheduled to receive a chemotherapy regimen for the neoadjuvant, adjuvant or metastatic treatment were eligible to participate. Exclusion criteria included head and neck cancer patients due to possible direct damage of taste bud cells by RT or the tumor itself and those medical conditions that may affect sensorial perception such as oral cavity infection or sinusitis. The sample size for this study was estimated to be representative of the population undergoing CT at Onkologikoa Outpatient Unit. Considering 8% of margin of error, 95% confidence level, and 50% heterogeneity, a total sample of 150 patients was required.

Questionnaire design

An interviewer-assisted questionnaire was designed based on existing literature and clinical experience to investigate the subjective multisensory perception changes in patients undergoing CT [21,22,23]. The questionnaire was tested (for duration, easy of understanding…) in a subset of nine patients prior to starting the study. Changes in the procedure and within the questionnaire were considered after the pilot test. The optimized questionnaire we used in our study is included in Supplementary Material (Fig. S1). For the completion of the questionnaire, a 20-min interview was conducted by two trained researchers with each participant during their visits to the Outpatient Unit for CT treatment. All questions refer to their experiences from the beginning of the current CT regimen independently of the CT cycle number.

The 34-item questionnaire was structured into three sections, including eating habits (14 items); sensory alterations, such as taste and smell changes and thermal sensitivity (15 items) and other clinical disorders, such as, nausea, vomiting, dry mouth, mucositis, and dysphagia (5 items). Following the aims of the research as described above, participants rated the importance of their taste and smell changes on a 5-point intensity scale with points as follows: 1 = “no change,” 2 = “low,” 3 = “moderate,” 4 = “intense,” 5 = “very intense.” The last section of questionnaire includes the socio-demographic profile of the respondents. Data regarding cancer diagnosis, current and previous chemotherapy regimen, number of cycles, was obtained from medical records by two nurses from hospital.

Statistical analysis

Descriptive statistics were used to determine the prevalence of chemosensory alterations. Associations among categorical variables (chemosensory complaints, CT, and other clinical complaints) were performed using chi-square analysis for the univariate analysis and binary logistic regression for the multivariate analysis. In the selection method, only variables with p values < 0.05 in the chi-square univariate analysis were evaluated in the initial multivariable model. For the regression analysis, model selection was based on backward conditional elimination. Model’s adequacy was evaluated by multiple indicators, including odds ratios (ORs) with 95% confidence intervals (CIs); an overall test of all parameters using inferencial statistic tests (likelihood ratio and Score tests) and goodness of fit statistics (Hosmer & Lemeshow, Cox & Snell and Negelkerke tests). Simple correspondence analysis (CA) was applied to the chemosensory alterations frequency table, allowing for relationships between chemosensory alterations and CT to be displayed. Symmetrical normalization method with chi-square measure of distance was selected. All statistical analyses were performed using SPSS (V 24.0) software.

Results

Patient characteristics

One hundred fifty-two patients were contacted and 151 accepted to participate in the study. Socio-demographic profile of the studied population (N = 151) is shown in Table 1. The patients’ ages ranged from 28 to 87 years. Most patients were female (64%) with secondary and university education (66%). About 63% of the patients were ex-smoker or current smoker. Patients followed a broad range of CT regimes, that included chemotherapy agents alone or in combination in a total of 46 different protocols. Table 1 contains the main chemotherapy drugs in our study population.

Table 1 Characteristics of the study population

Prevalence of self-reported smell and taste alterations according to chemotherapy treatment

Frequency of responses addressing subjective chemosensory complaints (taste, smell, texture, and temperature), satiety and appetite and other clinical disorders relative to the CT are shown in Table 2 for all subjects (N = 151) and according to chemotherapy treatment.

Table 2 Frequency of responses addressing subjective chemosensory complaints (taste, smell, texture and temperature) relative to the chemotherapy treatment

Chemosensory alterations regarding taste (76%) and smell (45%) were found. Taste loss (43%), metallic taste (40%), bad taste in mouth (45%), dry mouth (64%), and cold hypersensitivity (36%) were the most frequent complaints considering any CT.

Carboplatin and anthracyclines (including doxorubicin and its combinations with other drugs such as cyclophosphamides in AC, docetaxel in TAC and vincristine in CHOP) were the CT presenting highest rates of chemosensory complaints. Cisplatin and 5-fluorouracil were the CT producing lowest frequencies of alterations.

Self-perceived taste and smell changes assessment

The self-perceived taste and smell changes assessment in a five point scale (1–5) according to chemotherapy treatment are shown in Fig. 1a. The taste alteration score was higher in those patients receiving docetaxel (3.8 ± 1.4), followed by carboplatin (3.3 ± 1.4), anthracycline (3.2 ± 1.4), and paclitaxel (3.0 ± 1.4). For smell, patients receiving vinorelbine (3.3 ± 1.9) and anthracyclines (2.7 ± 1.4) reported the highest scores. No patients receiving 5-Fu experienced changes in smell.

Fig. 1
figure1

Self-perceived taste and smell changes assessment according to chemotherapy treatment (a) and cancer type (b) in a 5-point intensity scale (1-“no change” to 5-“very intense”). 5-Fu = 5 fluorouracil. Anthracyclines include doxorubicin and its combinations with other drugs such as cyclophosphamides in AC, TAC, and CHOP

Regarding the cancer type, the self-perceived taste and smell changes assessment in a five-point scale are shown in Fig. 1b. Breast cancer patients consider their taste and smell changes more severe (3.1 ± 1.4 and 2.5 ± 1.6, respectively) than colon (2.5 ± 1.5 and 2.1 ± 1.4, respectively) and lung cancer (2.7 ± 1.5 and 1.8 ± 1.2, respectively) patients do.

Association between chemosensory changes and chemotherapy treatment

For the study of the relationship among CT and chemosensory complaints, those alterations with more than 40% frequency in the contingency table (Table 2), i.e., metallic taste, taste loss, xerostomia, bad taste in mouth, smell change, and cold hypersensitivity were considered for the binary logistic regression. Chi-square test revealed that there was a statistically significant association between CT and some chemosensory alterations such as taste loss (p value = 0.013) and cold hypersensitivity (p value = 0.000). In the multivariate analysis, these chemosensory alterations together with age, gender, and smoking habits were also considered. According to the logistic regression model (shown in Table 3), oxaliplatin (OR = 12.14; 95% CI = 4.18–35.25; p value = 0.000) was independent predictor of cold hypersensitivity. With regard to taste loss, docetaxel (OR = 3.50; 95% CI = 1.12–10.90; p value = 0.031) and carboplatin (OR = 4.81; 95% CI = 1.45–16.02; p value = 0.01) were significant predictors. Actually, the odds for a patient undergoing oxaliplatin for experiencing cold hypersensitivity was 3.50 times greater than the odds for a patient without that CT. The odds for a patient undergoing carboplatin or docetaxel for experiencing taste loss was 3.50 and 4.81 times, respectively, greater than the odds for a patient without those CT. The proposed model was more effective than the null model according to likelihood ratio and Score test. The inferential goodness-of-fit, Hosmer-Lemeshow test, suggested that the model was fit to the data well (see details in Table 3). The association of taste and smell alterations with CT were independent from smoking habits, age and gender in the logistic regression analysis.

Table 3 Association between cold hypersensitivity and taste loss with chemotherapy treatments (CT). Logistic regression results are expressed according to their regression coefficients (β), odds ratios (OR) and their 95% confidence intervals (CI) [SE = standard error]

The correspondence analysis map of chemosensory complaints and chemotherapy treatment is shown in Fig. 2. According to the proportion of explained inertia, dimension one represents 55.3% of the inertia, dimension two 26.8% and dimension three 13.9%. We chose to include the third dimension in our interpretations as it explained 96% of the variance. Anthracyclines are in the middle of the correspondence map, thus the deviation from the expected proportions are relatively small. It means that anthracyclines have no specific taste or smell alterations that differentiates it from other CT agents, as it is averaged on most of the alterations studied. Metallic taste and bad taste in mouth are close to the origin as well, thus they are poor differentiators among different CT. As we can see in Table 2, several patients undergoing CT such as paclitaxel, anthracyclines, and carboplatin reported metallic taste.

Fig. 2
figure2

Correspondence analysis map of chemotherapy treatment (CT) (triangles) and chemosensory alterations (circles). 5-Fu = 5-fluorouracil. Irinotecan and oxaliplatin are combined with 5-Fu in folfiri and folfox respectively treatments. Vinorelbine, paclitaxel, and 5-Fu are administered alone. Gemcitabin and pemetrexed are combined with carboplatin or cisplatin. Anthracycline, doxurrubicin is combined mainly with cyclophosphamide (AC), also with docetaxel (TAC) and vincristine (CHOP). Three dimensions capture 96% of the variance

On the other hand, cold hypersensitivity is further from the origin in the correspondence map (Fig. 2) as it is strongly associated to oxaliplatin- and irinotecan-based regimens, as it was previously confirmed in the logistic regression analysis for cold hypersensitivity, being oxaliplatin statistically significant and irinotecan close to significance (see Table 3).

Moreover, in Fig. 2, we can see that taste loss clusters with docetaxel and carboplatin, oxaliplatin and irinotecan with cold hypersensitivity, anthracyclines and paclitaxel with xerostomia, anthracyclines and vinorelbine with smell changes, and anthracyclines, paclitaxel, and carboplatin with bad taste in mouth and metallic taste. Cisplatin and 5-fluorouracil are the CT agents resulting in the lowest complaints and so, they are located in the extremes of the map. These clusters provide additional information beyond the logistic regression analysis for graphical display.

Association between chemosensory changes and other clinical complaints

As previously mentioned, xerostomia is the most frequent complaint in our study. We found that only 5.4% of patients reported xerostomia alone, whereas 56.4% of patients reported either smell, taste alterations, and xerostomia. Regarding the association between xerostomia and other taste alterations, first, a test of independence using chi-square was applied. The univariate analysis revealed that there was a statistically significant association between xerostomia and other chemosensory complaints such as bad taste in mouth (p = 0.000), general taste changes (p = 0.007), taste acuity loss (p = 0.003), food tastes different (p = 0.009), strange taste (p = 0.001), salt taste change (p = 0.01), and sour taste change (0.04). For the multivariate analysis, these chemosensory alterations together with smoking habits, age, and gender were also considered. Controlling the variables in the final multivariable model, significant independent factors for xerostomia were taste loss (OR = 2.30) and bad taste in mouth (OR = 5.96). Although the final model estimates showed minimal changes with or without the inclusion of other factors such as age, gender, and strange taste, they were retained in the final model (Table 4). Different model combinations reduced considerably the adequacy of the model, making necessary to maintain these factors. The proposed model was more effective than the null model according to likelihood ratio and Score test. The inferential goodness-of-fit, Hosmer-Lemeshow test, suggested that the model was fit to the data well (see details in Table 4). According to the model, the odds of a patient reporting xerostomia of having bad taste in mouth and taste loss were respectively 5.96 and 2.30 times greater than the odds for a patient with no xerostomia.

Table 4 Association between chemosensory complaints and xerostomia of chemosensory complaints, age and gender for xerostomia. Logistic regression results are expressed according to their regression coefficients (β), odds ratios (OR), and their 95% confidence intervals (CI) [SE = standard error]

Discussion

Regarding the prevalence of taste and smell alterations in cancer patients undergoing chemotherapy, the existing literature is really abundant. Prevalence estimates vary considerably among patients considering different measurements approaches of taste and smell alterations, as well as different types of cancer and chemotherapy regimens. The self-reported alterations in cancer patients undergoing chemotherapy, is high, ranging between 45 and 84% for taste and between 5 and 60% for smell alterations [24]. These wide ranges are connected to the heterogeneity of the studies and the lack of validated questionnaires or methodologies for assessing the self-reported chemosensory alterations [10, 25]. In general, our prevalence results are in concordance with other studies, since we found that 76% patients reported taste disorders and 45% smell changes [17]. Other clinical problems such as difficulties swallowing solid and liquid foods (16.6 and 6%, respectively) were not so frequent in our cohort of patients, especially considering that neck and head cancer were excluded.

Although taste and smell are anatomically distinct systems, in the sensory perception of food, they are intimately connected. It is known that the best olfactory function is present between the ages of 20 and 60 years, and then begins to decline [26]. Some studies suggest that the primary reasons in causing olfactory impairment are connected to age-associated factors such as chronic diseases, medications or cumulative damage the olfactory epithelium from repeated infections, instead of being a necessary outcome of aging [27]. Actually, in our study, older patients are not affected more than the younger, suggesting that chemotherapy treatment is the main reason for olfaction loss. Regarding taste, there were also no age-related differences and it is described that loss of taste with age is much less pronounced than the olfaction [28]. Many drugs, such as antihypertensives, diuretics, or antidepressants, might cause taste and smell distortion and xerostomia as side effect. However, we did not consider the patients’ concomitant medications in our study as it is known that the effect of CT on chemosensory alterations is among most severe having an order of magnitude qualitatively different from the rest of drugs; moreover, we ask patients to report their changes from the beginning of the CT independently of their previous medications.

Regarding chemotherapy treatments, patients treated with docetaxel, mainly used for prostate cancer in our study population was the CT with higher self-assessment taste alteration score. Steinbach et al. [16] found that taxane-based chemotherapy such as docetaxel caused more severe taste disorders, especially for the salt taste, which is usually affected the most in case of gustatory function alteration. This is consistent with our results, as we were able to specify that this CT was associated to taste loss. Other taxane-based CT, such as paclitaxel, was associated to different taste alterations such as metallic taste, bad taste in mouth and xerostomia.

Patients undergoing treatment with anthracyclines, paclitaxel, carboplatin, and vinorelbine suffered the highest frequencies for metallic taste, bad taste in mouth, xerostomia, and smell changes. These CTs are characteristic for breast cancer treatment, and so, breast cancer patients reported the highest taste and smell alteration scores. The results in the literature for breast cancer patients’ chemosensory alterations frequencies are contradictory [14, 25, 29], and most of them do not specify the exact taste alteration. In these studies, breast cancer patients received different CT regimes, resulting in very heterogenous groups. Thus, comparisons should be done according to chemotherapy regimen instead of cancer type, especially when head and neck cancer types are not being considered due to the direct damage of taste bud cells by RT or the tumor itself. It is described that a broad range of chemotherapy drugs can be associated to taste and smell alterations [30]. However, studies providing comparisons between agents, the association with specific taste alterations and their impacts on overall taste perception are scarce.

Likewise, patients treated with oxaliplatin- or irinotecan-based regimens, mainly colon cancer patients, suffered from cold hypersensitivity. Cold hypersensitivity is the hallmark of oxaliplatin-induced neurotoxicity. It may appear as soon as after the first injection and although it can disappear after the drug is withdrawn, long-term neuropathy can be found in a significant number of patients [31]. On the contrary, for irinotecan, there is no literature describing its neurotoxicity. But considering that all colon cancer patients with irinotecan treatment at the moment of completing the sensorial questionnaire, had previously oxaliplatin treatment, and the effect of thermal sensitivity with oxaliplatin might go on for several weeks or months, we might attribute to oxaliplatin based regimens the main responsibility for cold hypersensitivity in colon cancer patients.

Xerostomia is the most frequent symptom reported by patients receiving chemotherapy in our study, and it is associated to taste and smell alterations. Decreased saliva secretion alters the amount of chemicals released by the foods, thereby changing the taste. The presence of saliva in the oral cavity is essential for taste perception, as food particles need to be in solution in order to stimulate taste receptor cells in the taste buds within the lingual papillae [12]. The highest saliva stimulation is obtained with sour taste, followed by salt, sweet, and bitter [12]. In our study, we observe a high prevalence of dry mouth complaint, associated to most of CT regimens and a statistically significant association of xerostomia with taste loss. Besides, the strongest association with dry mouth was found for dysgeusia (bad taste in mouth, food tastes different and strange tastes). Dysgeusia can also be described as a bitter, metallic, salty, or unpleasant taste, and it is closely linked to changes in olfaction, as both taste and smell are involved in producing the sense of flavor [9]. Metallic taste is a relevant chemosensory alteration in our study population, however most studies regarding taste changes in patients treated with chemotherapy do not take metallic taste as a specific taste alteration into account. Data regarding the prevalence of metallic taste per cancer type, chemotherapy treatment, and treatment phase are scarce [32]. The exact mechanism underlying the observed metallic taste in patients undergoing chemotherapy is not yet known. The metallic taste may also be generated from the taste of the CT systemic treatments, as they are secreted in saliva and gain direct contact with taste receptors. Several guides and studies [32] point platinum-based drugs as one of the main responsible for producing metallic taste as side effect. However, in our study, patients receiving other non-containing platinum chemotherapy drugs, such as anthracyclines, yielded similar levels of self-reported metallic taste complaint compared carboplatin and higher than cisplatin. Thus, not only metallic components of the drugs, but other biochemical processes must be also implicated in the perception of metallic taste, in a multifactorial way.

Chemosensory interventions to tackle chemosensory dysfunctions have been largely ineffective in spite of the importance of these alterations on patients’ nutritional status and quality of live [17, 33, 34]. These approaches usually consider taste and smell in isolation whereas other key factors connected to sensory perception such as the presence of saliva in the oral cavity should be addressed jointly. A better understanding of how taste receptors work is needed for the design of new strategies to address disgeusia (metallic taste and bad taste in mouth) and dry mouth in cancer patients undergoing chemotherapy. To date, the exact mechanism underlying chemosensory alterations in cancer patients is not yet known because the heterogeneity of the investigated populations and because the research in the biochemical field is scarce, and there are no specific biological biomarkers for chemosensory alterations.

This is the first study that addresses specific chemosensory alterations (metallic taste, taste loss, xerostomia, bad taste in mouth, smell change, and cold hypersensitivity) and their impact according to several chemotherapy regimens. However, there are some limitations that must be acknowledged. We have used a non-validated questionnaire to measure these alterations. Harmonizing procedures should be introduced to standardize self-reported chemosensory alterations questionnaires that are needed for the comparison among different studies. Regarding the reliance of self-reported data, future research might be addressed towards longitudinal studies that incorporate objective measures of chemosensory alterations together with specific molecular biomarkers.

Conclusions

Although taste and smell alteration in patients undergoing chemotherapy have been associated with a decreased appetite and a decreased quality of life, the impact of different chemotherapy treatments on the severity of specific taste and smell alterations is not yet known. There are large research gaps regarding taste and smell alterations in different patient populations and the impact of different chemotherapy regimens.

Xerostomia is the most frequent chemosensory complaint found in our population study, and our findings suggest that xerostomia it is correlated with other taste dysfunctions such as bad taste in mouth and taste loss. Therefore, when designing new strategies in order to cope with these CT side effects is important to consider together taste and smell dysfunctions and other alterations such as xerostomia.

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Acknowledgements

Many thanks to the patients and their families for participating in this study. The expert assistance in statistics provided by Cristina Sarasqueta, biostatistician from Biodonostia, is gratefully acknowledged. All authors drafted, read, and approved the final version of the manuscript. This is contribution number 865 from AZTI.

Funding

This work was partially funded by the Basque Country Government (Department of the Environment, Regional Planning, Agriculture and Fisheries).

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Correspondence to Itziar Tueros.

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Amézaga, J., Alfaro, B., Ríos, Y. et al. Assessing taste and smell alterations in cancer patients undergoing chemotherapy according to treatment. Support Care Cancer 26, 4077–4086 (2018). https://doi.org/10.1007/s00520-018-4277-z

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Keywords

  • Cancer
  • Chemotherapy
  • Xerostomia
  • Metallic taste
  • Dysgeusia