Evaluation of Chemotherapy-induced Dysgeusia in Patients With Gastrointestinal Cancer: A Pilot Study

Abstract

Background/Aim: Dysgeusia, one of the adverse effects of cancer chemotherapy, and anorexia due to taste disorder can significantly impair the quality of life of patients. However, an evaluation method for dysgeusia has not yet been established. The present prospective study aimed to utilize a combination of subjective and objective assessment methods to evaluate dysgeusia in patients with gastrointestinal cancer initiating chemotherapy, to determine chemotherapeutic drugs and regimens causing dysgeusia, and to assess whether dysgeusia was associated with zinc deficiency.

Patients and Methods: A total of 21 patients with newly diagnosed gastrointestinal cancer were registered between August 2020 to March 2021. The following regimens were also included in the evaluation if the patients did not develop dysgeusia. A total 30 regimens were administered to the patients during the study period. A salt-impregnated test paper (Salsave^®) was used as a subjective assessment, and the chemotherapy-induced taste alteration scale was used as an objective assessment.

Results: Based on physician interviews, dysgeusia was diagnosed in 8 of 21 patients (38%) treated with 8 of 30 regimens (27%). All regimens that resulted in dysgeusia contained platinum-based drugs. The patients who developed dysgeusia had higher controlling nutritional status scores at the start of chemotherapy compared to those who did not develop dysgeusia. In both subjective and objective assessments, the patients with dysgeusia performed significantly worse than those without dysgeusia. Six of the eight patients who developed dysgeusia were administered Novelzine, which did not improve the taste disorder despite the improvement of serum zinc levels.

Conclusion: The combined approach using subjective and objective taste assessment methods was useful in assessing chemotherapy-induced dysgeusia. Mechanisms other than hypozincemia should be considered as contributors to taste disorders caused by platinum-based drugs.

Dysgeusia is a frequent adverse event that occurs during chemotherapy for cancer, reported in approximately 67% of all cases and in 38% of moderate to severe cases (1,2). According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. (3), dysgeusia is not a life-threatening adverse event and therefore is often overlooked in clinical practice. However, altered taste deprives patients of the enjoyment of food and causes nutritional imbalance, leading to impaired quality of life (4-6). Moreover, anorexia associated with dysgeusia may lead to the interruption or discontinuation of chemotherapy; therefore chemotherapy-induced dysgeusia should be carefully managed. However, few studies have elucidated the evaluation and treatment of dysgeusia (6). Although the precise mechanisms underlying chemotherapy-induced dysgeusia remain to be clarified, inhibition of the differentiation and proliferation of cells in taste buds by the direct toxic action of chemotherapeutic drugs and zinc deficiency due to chelation by certain chemotherapeutic agents are implicated in the etiology of dysgeusia (7). In general, cells with a rapid turnover, including those in taste buds, are more susceptible to anticancer drugs compared to other cells (8). Moreover, high levels of zinc are necessary for the regeneration of cells in taste buds, providing support that zinc deficiency might underlie the impairment of gustatory sense (9). However, a recent systematic review article has suggested that zinc supplementation is not effective in chemotherapy-induced dysgeusia (10), and no conclusions have been reached.

The present prospective study aimed to determine the rate of patients with gastrointestinal cancer who developed dysgeusia following treatment with specific chemo-therapeutic drugs or regimens, to determine whether a combination of subjective and objective evaluation methods would be useful in its diagnosis, and to determine the efficacy of zinc supplementation in treating chemotherapy-induced dysgeusia.

Patients and Methods

Patients. This is a prospective cohort study of a total of 21 patients with newly diagnosed gastrointestinal cancer who were initiated on chemotherapy, including a total of 30 regimens, in Nakatsu Municipal Hospital between August 2020 and March 2021. Informed consent was obtained from all patients before the study initiation. Patients who could not provide consent and those with taste abnormalities prior to study initiation were excluded. Patients were divided into two groups: those with dysgeusia (n=8) and those without dysgeusia (n=13).

The present study was performed in accordance with the guidelines for human studies adopted by the ethical guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Nakatsu Municipal Hospital (approval no: NMH2020003). Informed consent was obtained from all patients before the study initiation.

Study design. All patients were scheduled to undergo blood tests, including the measurement of serum zinc levels, and taste tests prior to the start of chemotherapy. Taste tests were performed every two courses after the start of chemotherapy. In patients who developed dysgeusia, blood tests, including the measurement of serum zinc levels, and taste tests were immediately performed and repeated every two courses thereafter. In patients in whom serum zinc levels declined, oral administration of Novelzine was prescribed for at least one month. In patients who were administered Novelzine, serum copper levels were measured along with the serum levels of zinc. In patients who did not develop dysgeusia, the next chemotherapeutic regimen followed and the patient evaluation was conducted in the same manner. The diagnosis of dysgeusia was based on the interview by a physician performed before the start of each chemotherapy course. Taste tests were conducted by a dietitian.

Assessment of dysgeusia. Dysgeusia was diagnosed and graded by a physician according to the CTCAE version 5.0 as follows: grade 1, altered taste but no change in diet; grade 2, altered taste with change in diet (e.g., oral supplements), noxious or unpleasant taste, or loss of taste.

Assessment of taste. Taste tests were conducted using subjective and objective evaluation methods. Subjective evaluation was performed using the chemotherapy-induced taste alterations scale (CiTAS) (11-13). The CiTAS is a self-administered questionnaire composed of 18 items in three dimensions (quantitative changes in the perception of flavors, unpleasant taste changes, and unpleasant symptoms or annoyances). Using a Likert scale ranging from 1 to 5, with a score of 1 indicating no difficulty or absence of the disturbance and a score of 5 indicating maximum difficulty or disturbance, the CiTAS evaluates the four subscales with combinations of items: decline in basic taste, discomfort symptoms, spontaneous abnormal taste, and general taste alterations. Salsave^® (Advantec, Japan), a salt-impregnated test paper, was used for objective evaluation. Salsave^® is composed of a set of seven filter papers with different salt concentrations (0%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, and 1.6%). Each filter paper was placed on the tongue, starting from the filter paper with the lowest salt concentration, to determine the first paper that invoked the salty taste. In the present study, a taste abnormality was defined as a change of two or more levels.

Statistical analyses. The chi-square and Mann-Whitney U-tests were performed to compare the patients with and without dysgeusia. A p-value of <0.05 represented statistically significant differences. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics.

Results

The incidence of dysgeusia was 38.1% (8/21) based on the physician interviews. As shown in Table I, there was no difference in the rate of dysgeusia among the patients with different cancer types and cancer statuses. The incidence rates of dysgeusia according to specific chemotherapeutic agents and regimen were shown in Table II. The incidence of dysgeusia was significantly higher in patients treated with platinum-based regimens than in those treated with regimens not containing platinum [8/16 (50.0%) vs. 0/14 (0%), p=0.002]. The incidence of dysgeusia was also higher in patients treated with platinum-based drugs than in those treated with non-platinum-based drugs [8/16 (50.0%) vs. 9/40 (22.5%), p=0.043].

Table I. Rate of dysgeusia onset according to the cancer type and cancer status.

Table II. Rate of dysgeusia onset based on the chemotherapy regimens and drugs.

S-1: Tegafur/gimeracil/oteracil potassium; CPT-11(IRI): irinotecan hydrochloride hydrate; 5-FU: 5-fluorouracil; LV: levofolinate calcium; GEM: gemcitabine hydrochloride; CDDP: cisplatin; PTX: paclitaxel; LOHP: oxaliplatin.

As shown in Table III, there were no differences in patient background characteristics other than the controlling nutritional status (CONUT) score, a nutritional tool, between the groups with and without dysgeusia. Specifically, the CONUT scores were higher in the group with dysgeusia than in the group without dysgeusia.

Table III. Comparison of demographic and clinicopathologic characteristics between the patients with and without dysgeusia.

CONUT: Controlling nutritional status. *Median (range).

Five of the eight patients who developed dysgeusia had CTCAE grade 2 dysgeusia. Seven patients developed dysgeusia until the start of the four courses of chemotherapy. There were no differences in laboratory values or the nutritional tool scores (Table III) between the start of chemotherapy and the onset of dysgeusia among the eight patients with dysgeusia (data not shown).

In the subjective taste evaluation using the CiTAS, the median total score was not different between the groups with and without dysgeusia at the start of chemotherapy (19.5 vs. 18.0, p=0.095). However, the median score was significantly higher at the time of dysgeusia in patients with dysgeusia than in those without dysgeusia (27.0 vs. 18.0, p<0.001).

Four items that could be analyzed using the CiTAS were compared before and after the development of taste abnormality in the group with dysgeusia: decline in basic taste (decrease in five tastes) and discomfort symptoms (nausea, smell of food, inability to eat hot or oily foods, decreased appetite), spontaneous abnormal taste (bitterness, bad taste), and general taste alterations (loss of taste or aroma). As shown in Table IV, the patients in the dysgeusia group had discomfort symptoms prior to the start of chemotherapy. The discomfort symptoms were worse in the group with dysgeusia at the time of dysgeusia onset, and spontaneous abnormal taste and general taste alterations were also significantly different between the groups with and without dysgeusia.

Table IV. Taste assessment between the patients with dysgeusia and without dysgeusia.

The data are presented as median (range).

In the objective taste evaluation using Salsave^®, there was no significant difference between the groups with dysgeusia and without dysgeusia at the start of chemotherapy (median, 0.7 vs. 0.8; p=0.715). Compared with the patients who did not develop dysgeusia, those who developed dysgeusia tended to be less sensitive to saltiness at the time of dysgeusia onset (median, 1.5 vs. 0.8; p=0.089), as shown in Table IV. The percentage of patients who experienced two or more levels of change in the concentration of saltiness was significantly higher in the group with dysgeusia than in the group without dysgeusia (37.5% vs. 0%, p=0.017). These patients also tended to show a higher score in the self-assessment (data not shown).

The results of the taste test showed that, among the eight patients in the dysgeusia group, only the total score and the discomfort symptoms of the subjective taste test showed differences over time between the start of chemotherapy and the onset of dysgeusia (Table V).

Table V. Taste assessment in patients with dysgeusia.

The data are presented as median (range).

Finally, six of the eight patients who developed dysgeusia had hypozincemia at the time of dysgeusia onset and were therefore treated with Novelzine. Patient evaluation approximately two months after the oral administration of Novelzine showed that the serum zinc levels had improved, however, there were no improvements in the subjective or objective taste tests (Table VI).

Table VI. Effects of Novelzine administration.

The data are presented as median (range).

Discussion

In the present prospective study, we examined the utility of subjective and objective evaluation for chemotherapy-induced dysgeusia based on the self-reports from patients using the CiTAS questionnaire in combination with the objective evaluation using the Salsave^® filter paper test. In the present study, the incidence rate of dysgeusia was 38.1% for patients with all-grade of CTCAE and 23.8% for patients with CTCAE grade 2. These rates are consistent with some previous reports (14,15), but vary from the rates reported in other studies (1-2,4,10,13-17). Importantly, the incidence of chemotherapy-induced dysgeusia is considered to vary among different chemotherapy regimens. In the present study, all chemotherapy regimens in patients who developed dysgeusia included platinum-based drugs (oxaliplatin and cisplatin). In a drug-specific study, half of the patients (8/16) who used platinum-based drugs had dysgeusia. A previous study demonstrated that the chemotherapeutic regimens containing 5-fluorouracil led to dysgeusia more frequently than those without 5-fluorouracil (14,15); however, the rate was 26% (6/23) in the present study.

One of the challenges in the present study was the evaluation of taste. Assessment of dysgeusia is challenging in patients with cancer, and quantitative, validated methodologies for taste evaluation have not yet been established (6,12). Many of the previous studies suggested the presence of a relationship between zinc and chemotherapy-induced taste alterations (8,9,14,16), which was also measured in the present study. Few studies used validated tools for subjective evaluation. The CiTAS, a subjective taste evaluation method developed by a Japanese nurse (11-13), is a questionnaire-based test in which patients are asked to answer 18 items on a 5-point scale. As a short, repeatable test that could be administered quickly, the CiTAS was adopted in the present study. In clinical settings, objective evaluation of dysgeusia includes several methods, including electrogustometry, whole-mouth gustatory testing, and magnetoencephalography (17-19). Several studies have also described objective evaluation methods using paper strips (15,20). In the present study, we used the Salsave^® paper testing as an objective method because of its simplicity and the low cost. The results of both subjective and objective taste evaluation were inconsistent in previous reports (11-13,15,20). Additionally, some studies used either subjective or objective methods but no study to date has used both approaches to evaluate taste alterations. Therefore, we used a combination of subjective and objective evaluations to improve the accuracy of our taste evaluation. In the present study, these tests were performed by a dietitian as part of nutritional guidance.

The CiTAS is a convenient tool to collect information on dysgeusia using a fast and low-cost method and to recognize the symptoms and causes of dysgeusia that could be addressed in patients with cancer. In the current study, at the time of dysgeusia onset, many patients expressed symptoms of discomfort, spontaneous abnormal tastes, and general taste alterations, with particularly strong symptoms of discomfort. Based on these results, we believe that each alteration can be handled accordingly. Specifically, spontaneous abnormal taste sensation such as bitterness can be addressed by instructing the patient to gargle with water or salt water, to eat candy or gum, to drink acidic drinks such as lemon or rose hip tea, to eat soupy foods such as rice porridge or noodles, and foods such as sushi or vinegared dishes. If nausea, a symptom of discomfort, is enhanced by the smell, it may be necessary to let the food cool down before eating, or it can be treated with medication.

Objective evaluation using Salsave^® may be another useful method to objectively determine dysgeusia. In the present study, the threshold for saltiness tended to be higher in the group with dysgeusia, although the difference was not significant. This result was in agreement with the CiTAS taste evaluation, which revealed no obvious decline in the basic taste. However, since only saltiness among the five major tastes (sweet, salty, sour, bitter, and umami) was examined, the details are not clear. We believe that the Salsave^® filter paper test can be easily incorporated as a routine evaluation of patients with cancer undergoing chemotherapy by nutritional support teams.

Zinc is absorbed from the upper digestive tract after binding to metallothionein, a zinc-binding protein that is abundant in the pancreatic juice (21,22). Fluoropyrimidines cause injury of the oral mucosa as well as the gustatory nerve. Moreover, these compounds inhibit the absorption of zinc ions by inducing their chelation (15). The mechanisms underlying of taste disturbances can be classified as peripheral or central neuropathy, external distortion of the taste buds, or internal damage to the taste cells (8). The taste cells in taste buds are replaced approximately every 10 days. In addition, much zinc is localized in the tongue epithelium, which contains the taste buds, and morphological changes in taste receptors from the lack of zinc cause a delay in taste bud turnover, which is also considered to lead to taste disorders. However, in the present study, there was no difference in serum zinc levels between the start of chemotherapy and the onset of dysgeusia in patients in the dysgeusia group (median 64 vs. 58, p=0.563). Furthermore, no improvement in taste was observed after the administration of Novelzine. Some studies reported that zinc did not improve chemotherapy-induced dysgeusia (10,23). However, these studies reported that oxaliplatin administration did not affect the serum zinc levels, the morphology of taste buds, or the numbers of taste cells, indicating that the oxaliplatin-induced taste disorder was not due to zinc deficiency. It is therefore possible that mechanisms other than zinc deficiency play a role in dysgeusia induced by platinum-based chemotherapeutic drugs.

The present study has several limitations. First, the patient population was small and further prospective studies with larger cohort sizes are needed to confirm our findings. Second, all study patients underwent chemotherapy, regardless of the type of cancer and the cancer status (Table I). Further studies should examine the relationship between chemotherapy and dysgeusia based on the affected organ and the cancer status. The present study included a heterogeneous cancer population with different treatment regimens, disease stages, and treatment side effects, which is another limitation.

In conclusion, we demonstrated that dysgeusia should be recognized as an adverse event associated with chemotherapy for gastrointestinal cancer, especially platinum-based chemotherapy, and subjective assessment using the CiTAS and objective assessment using Salsave^® were useful tools to assess taste disturbances in these patients. The lack of improvement in dysgeusia despite zinc supplementation suggests that mechanisms other than zinc deficiency play a role in chemotherapy-induced dysgeusia.

Conflicts of Interest

The Authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

All Authors were involved in this study design. Shigeyuki Nagata and Tomoko Suenaga completed the data analysis and composed the original draft. Shigeyuki Nagata, Seigo Korematsu, and Hiroyuki Orita were involved in the interpretation of the results. All Authors have read and approved the submission.

Acknowledgements

The Authors would like to thank ENAGO for English language editing.