Taste disturbance in patients with advanced cancer: a scoping review of clinical features and complications

Purpose The purpose of this scoping review is to appraise the published literature on taste disturbance in patients with advanced cancer, with the specific objectives being to determine its prevalence, clinical features and complications. Methods This scoping review was conducted using the recommended methodological framework. A detailed search of databases (Medline, Embase, CINAHL and PsycInfo) was conducted to identify eligible studies: eligible studies needed to include patients with advanced cancer and needed to include details of clinical features and/or complications of taste disturbance. Standard bibliographic/systematic review software was used to store the records and manage the review process, respectively. Results Twenty-five studies were identified from the database searches. The studies identified included eight physical and/or psychological symptom studies, six symptom cluster studies, five oral symptom studies and six taste and/or smell specific studies. Detailed data is presented on the clinical features and complications of taste disturbance and on the symptom clusters involving taste disturbance in this cohort of patients. Conclusion This scoping review identified a relatively small number of relevant studies involving a relatively small number of participants. Nevertheless, it confirms that taste disturbance is a common problem in patients with advanced cancer and is associated with significant morbidity because of the primary condition and the associated complications.


Introduction
Taste is defined as "the perception derived when chemical molecules stimulate taste receptors in areas of the tongue, soft palate and oropharyngeal region of the oral cavity to perceive the five basic taste qualities: "sweet, sour, salty, bitter and umami" [1].The terms "taste" and "flavour" are often used interchangeably in real life, clinical practice [2,3] and the medical literature [4].However, taste and flavour are distinct entities with flavour encompassing a combination of taste, smell, texture and temperature [5].Food hedonics encompasses the palatability of foods, where 'liking' food is defined as "the immediate experience or anticipation of pleasure from the orosensory stimulation of eating a food" [6].Taste disturbance can present as a distortion of normal taste sensation (dysgeusia), a reduction in taste sensation (hypogeusia), increased taste sensation (hypergeusia) or as an absence of taste sensation (ageusia) [7].
Taste disturbance can be evaluated subjectively through patient-reported assessments or by objective assessments.In the clinical setting, it can be measured objectively by measuring oral taste sensitivity to tastants through thresholds to some or all the five basic tastes [8].No independently diagnostic biochemical measures are available [9].
Taste disturbance is relatively common in the general population; data from the US National Health and Nutrition Examination Survey (2013-2014) suggested that the prevalence of objective taste disturbance defined as failing to identify quinine/bitter taste, was 17.3% amongst the US general population [10].There are a number of different causes for taste disturbance [11], including dental (periodontal) disease, upper respiratory tract infection, medication-related (e.g.antihypertensives, antimicrobials), dental procedure-related trauma, tonsillectomy, middle ear surgery, 1 3 562 Page 2 of 14 Bell's palsy and burning mouth syndrome.Taste and smell disorders often occur simultaneously [9].
Equally, taste disturbance is especially common in patients with cancer [12].Taste disturbance may occur at diagnosis (treatment naive patients) [13], during anticancer treatment [14], following anticancer treatment (chronic side effect) [15], at disease progression and into cancer survivorship [16].There are a number of potential causes of taste disturbance in cancer patients, including direct effects of the cancer, indirect effects of the cancer (i.e.paraneoplastic syndromes), adverse effects of anticancer treatments, adverse effects of supportive care measures and co-morbidities (and their management) [17].It should be noted that the literature already contains a number of reviews relating to taste disturbance in specific subgroups of cancer patients (e.g.lung cancer) [18][19][20] and specific anticancer treatments (e.g. head and neck radiotherapy) [21].
It has been known for some time that patients with advanced cancer often develop taste disturbances [22].However, taste disturbance is considered an "orphan symptom", which is defined as "symptoms not regularly assessed in clinical practice, and consequently little studied and not properly treated" [23].The aim of this scoping review is to appraise the published literature on taste disturbance in patients with advanced cancer, with the specific objectives being to determine its prevalence, clinical features (i.e.subjective and objective) and impact on the patients (i.e.physical and psycho-social).It appears that there is no analogous scoping review within the clinical literature.

Methods
This scoping review was conducted using the methodological framework developed by Arksey and O'Malley [24] and incorporating updated guidance on this methodology [25].The PRISMA Extension for Scoping Reviews (PRISMA-ScR) was used to report the findings [26].

Search strategy
A detailed search of four electronic databases (Medline, Embase, CINAHL and PsycInfo) was conducted in October 2022.The search strategy for Medline is shown in Appendix.The search strategy was adapted as needed for each electronic database.The search was re-run in January 2023 to check for any new references.

Study eligibility criteria
Eligible studies needed to include patients with advanced cancer, as defined by the National Cancer Institute/NCI, USA: "Cancer that is unlikely to be cured or controlled with treatment.The cancer may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body" [27].Studies which included mixed groups of patients with cancer were excluded, unless results for the patients with advanced cancer were separately reported.Studies which focussed on patients with advanced head and neck cancer, and studies that focussed on cancer patients receiving anticancer treatment were excluded.Eligible studies also needed to include details of clinical features and/or complications of taste disturbance.Studies reporting mixed chemosensory changes were excluded, unless results for taste changes were separately reported.Case reports, review articles and other records without original information were not included.Studies involving children (< 19 years) and non-English language studies were excluded.

Data management and synthesis
EndNote 20™ bibliographic software (Clarivate Analytics LLP, USA) was used to store the records retrieved from all the searches.Screening of the records was completed using Covidence systematic review software (Veritas Health Innovation, Australia).
Two reviewers (MH and AD) independently screened the titles and abstracts for full text articles to review.A third reviewer (MC) was available to resolve potential conflicts relating to record inclusion.Two reviewers (MH and AS) independently reviewed the full text articles and extracted the relevant information using a review-specific template.A third reviewer (AD) was available to resolve conflicts relating to data extraction.
The reference lists of all retrieved full text articles, pertinent chapters in major palliative care textbooks and pertinent sections of major palliative care guidelines were hand searched for other relevant records.Other sources of relevant records included the researchers themselves.

Assessment
The six taste and/or smell specific studies were generally small (median: 48 participants, range: 15-192 participants).All studies involved a subjective assessment, whilst three studies included an objective assessment [31,44,45].Currently, there is no validated tool to assess taste disturbances in this group of patients; four studies [30,41,44,45] utilised the Taste and Smell Survey [53]; and the other studies used non-validated, study-specific questionnaires.Similarly, there is no agreed method for assessing objective taste disturbances in this group of patients (or indeed other groups of patients) [58]; two studies used commercial taste strips [44,45] and one study used liquid tastants [31].
Importantly, the terminology used in the studies varied, which may have had an effect on the results obtained, especially prevalence statistics: "abnormal taste", "absence of taste", "altered taste", "any taste disturbances", "bad or altered taste", "changes in my sense of taste", "changes in food tasting", "change in the way food tastes", "a food tastes different than it used to", "food tasted differently", "persistent bad taste in my mouth", "reduction of taste", "taste alteration", "taste change", "taste disturbance(s)" and "taste problems".No studies included questions regarding flavour, as opposed to taste.This issue has been highlighted in previous literature reviews involving other cohorts of oncology patients [59].

Epidemiology
The prevalence of taste disturbance varied widely in the studies included in this scoping review (median: 55%, range: 27-93%) [35,44].Alsirafy et al. reported that no patients reported this symptom on open questioning, although 27% patients gave a positive response on systematic assessment (with 41.5% of these patients reporting "moderate"/"severe" intensity) [35].Importantly, certain studies reported that different assessment tools produced different prevalence figures [38,44,45].

Symptom clusters
Table 2 shows studies reporting physical and/or psychological symptom clusters involving taste disturbance [28,32,37,43,48,50].The symptom clusters identified varied from study to study and varied within study (depending on the outcome measure chosen and the statistical method utilised) [28].It should be noted that there are many other studies reporting physical and/or psychological symptom clusters in patients with advanced cancer, but which did not include the symptom of taste disturbance [62].Davies et al. (2021) investigated symptom clusters involving specifically oral symptoms and found an association between the presence of taste disturbance and the presence of a "dirty mouth", and "coating of tongue" (Spearman's rank correlation coefficient = 0.7) and also an association between the frequency of taste disturbance and the frequency of "dry mouth" (Spearman's rank correlation coefficient = 0.6) [38].No analogous studies were identified in the literature.

Impact of taste disturbances
Taste disturbance may have a major impact on the experience and pleasure associated with eating and drinking, with patients reporting aversions to a variety of foods (e.g.meat) and/or drinks (e.g.alcohol) [31,63].Some adopt compensatory strategies such as seasoning food in an attempt to make it palatable [64] or changing their behaviour by 'taking control' of when and what they ate [65].
Indeed, taste disturbance may have a major impact on nutritional intake [30,41] and is one of the preeminent "nutritional impact symptoms" in patients with advanced cancer [38].Moreover, taste disturbance appears to be a relevant issue in many patients with the cancer-related anorexia/cachexia syndrome [63], with the severity of taste disturbance greater in patients with refractory cachexia, than patients with pre-cachexia, cachexia or without cachexia [66].
Unsurprisingly, taste disturbance may be associated with low mood/depression [64], social isolation (i.e.avoidance of social eating) and an impaired quality of life [30,41].

Discussion
This unique scoping review identified a relatively small number of relevant studies involving a relatively small number of participants.Nevertheless, it confirms that taste disturbance is a common problem in patients with advanced cancer and is associated with significant morbidity (because of the primary condition and the associated complications).The results suggest that this socalled "orphan" symptom warrants greater recognition from patients, family carers and especially healthcare professionals.
Importantly, taste disturbance may be amenable to treatment [67] which may result in increased enjoyment of eating and drinking, decreased morbidity and increased quality of life.In addition, resolution/improvement in taste disturbance may prevent/limit malnutrition, which is a major cause of death in this group of patients [68].Thus, it is important to screen patients for taste disturbance and refer affected patients to an oncology dietician or other appropriate healthcare professional for further assessment/ management.
This scoping review has also identified gaps in the current literature and topics for future research in this cohort of patients: (a) observational studies to determine the "risk factors" for taste disturbance (e.g.cancer diagnosis and performance status) -this data would facilitate targeted screening for the problem; (b) observational studies to determine the aetiologies of taste disturbance overall -this data would also facilitate targeted screening for the problem; (c) observational studies to determine the aetiologies of different subtypes of taste disturbance (e.g.ageusia and dysgeusia) -this data would facilitate targeted treatment for the problem; (d) observational studies of patient/family carers unmet 562 Page 12 of 14 needs and priorities for management; (e) development/ validation studies of a taste-specific assessment tool for this group of patients -there is a need for a tool that not only assesses the problem but can also assess the response to treatment for the problem, utilising patientreported outcome measures.

Fig. 1
Fig. 1 Flow chart of article inclusion

Table 1
Clinical features of taste disturbance in patients with advanced cancer [53]), urological (10%) Median age: 75 yr (range 46-93 yr) Female: 36.5% Non-validated questionnaire (modified version of Taste and Smell Survey)[53]Prevalence of "any changes in your sense of taste?", "persistent bad taste in my mouth" Subjective taste change (bitter, salt, sour and sweet): options -"stronger", "as strong", "weaker", "I cannot taste it at all" Objective taste change (bitter, salt, sour and sweet) using commercial taste strips

Table 2
Symptom clusters including taste disturbance in patients with advanced cancer

Table 2 (
Eight different statistical techniques, including repeating the original HCA of symptom prevalence HCA of symptom prevalence, HCA of symptom prevalence at different thresholds and HCA of symptom prevalence with Kappa statistic produced an identical taste-related symptom cluster (see above); the other statistical techniques produced variations on the taste-related symptom cluster (see below)