Oral health problems among palliative and terminally ill patients: an integrated systematic review

Background High incidence of treatable oral conditions has been reported among palliative patients. However, a large proportion of palliative patients lose their ability to communicate their sufferings. Therefore, it may lead to under-reporting of oral conditions among these patients. This review systematically synthesized the published evidence on the presence of oral conditions among palliative patients, the impact, management, and challenges in treating these conditions. Methods An integrative review was undertaken with defined search strategy from five databases and manual search through key journals and reference list. Studies which focused on oral conditions of palliative patients and published between years 2000 to 2017 were included. Results Xerostomia, oral candidiasis and dysphagia were the three most common oral conditions among palliative patients, followed by mucositis, orofacial pain, taste change and ulceration. We also found social and functional impact of having certain oral conditions among these patients. In terms of management, complementary therapies such as acupuncture has been used but not well explored. The lack of knowledge among healthcare providers also posed as a challenge in treating oral conditions among palliative patients. Conclusions This review is first in its kind to systematically synthesize the published evidence regarding the impact, management and challenges in managing oral conditions among palliative patients. Although there is still lack of study investigating palliative oral care among specific group of patients such as patients with dementia, geriatric or pediatric advanced cancer patients, this review has however provided baseline knowledge that may guide health care professionals in palliative settings.


Introduction
High incidence of oral conditions were often reported among palliative patients either direct or indirect primary cause such as salivary gland dysfunction in non-Hodgkin's lymphoma or fatigue which may affect patient's ability to undertake oral care hygiene [1,2]. Medical management of palliative conditions such as chemotherapy were often reported which can produce oral complications among these patients [2]. For example, the National Cancer Institute at the National Institutes of Health, United States of America reported that 80% of patients receiving myeloablative chemotherapy will develop oral complications, and palliative drugs such as bisphosphonates and analgesics were associated with oral mucositis and taste disturbance [3].
Early diagnosis and treatment of oral conditions among palliative patients could minimize their pain and suffering [2]. However, evidence shows that 40% of palliative patients lose their ability to communicate their oral health needs. Therefore, they may suffer treatable oral conditions for a prolonged period of time [4], or they may not complain of discomfort in their oral cavity which they believe to be an inevitable effect of their treatment [5]. This may contribute to under-reporting as well as underestimation of oral conditions among palliative patients, which may result in failure among health professionals to completely appreciate the problem. A literature review of oral care for cancer patients in 2001 reported that oral care is given by junior staffs with less experience and the practice needs to be transferred to oncology nurses [6]. Furthermore, a survey of international supportive health care providers (n = 212) (with 35% response rate) recommended to develop evidencebased practice protocol for oral care management [7].
This systematic review aimed to synthesize the published evidence on oral conditions among palliative patients, impact, management and challenges in managing oral conditions among palliative patients.

Data sources
Search strategy was devised by the research team with chosen five databases in specific period in English language with comprehensive search terms to not omit any relevant potential primary studies. The detailed data sources are explained in Table 1.

Study selection
Inclusion criteria specified that studies must be: (1) in full-text, (2) published between years 2000 to 2017, and (3) primary articles focusing on palliative patients and their oral conditions. Figure 1 illustrates Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of study selection process [8]. The initial combined search identified 25,311 articles from 5 databases and from other sources (manual searching and through references). Removal of duplicates resulted in 13,263 studies. Screening of relevant abstracts resulted in 1230 studies. Further screening for inclusion criteria resulted in 67 studies which were read to ensure applicability to our study. This resulted in 28 articles being excluded. All reviewers screened and discussed preliminary findings to reach a consensus on studies to be included that resulted in total of 19 articles for further analysis.

Data extraction
In the data extraction process [9], study details were extracted into a table (Table 1). This was done by two reviewers (Z.R., and D.R.). All reviewers discussed each article to reach consensus regarding the study details. For each included study, the following information was extracted: author(s), year published, title, purpose, setting, participants, study design, and oral conditions present. The impact, management and challenges of oral problems among palliative patients were also extracted and summarized according to our research questions.

Assessment of study quality
As our review included both qualitative and quantitative studies, we did not use any scoring for assessing the quality of studies included. Rather, the quality of the identified studies was assessed using Joanna Briggs Institute (JBI) critical appraisal tool [10]. As a result, only studies that were thoroughly appraised (have clearly defined inclusion criteria, study subjects and setting described in detail, exposure measured in a valid and reliable way, standard criteria used for measurement of condition, identification of confounding factors, outcomes measured in a valid and reliable way, and appropriate statistical analysis used) and agreed by all involved reviewers were included in this systematic review to write the findings. Language Primary studies in English language Search terms "oral condition" OR "oral disease" OR "dental disease" OR "mouth disease" OR "mouth condition" OR mucositis OR stomatitis OR candidiasis OR cheilitis OR xerostomia OR "periodontal disease" OR halitosis OR thrush OR "angular cheilitis" OR "denture stomatitis" OR gingivitis OR periodontitis OR "mouth ulcer" OR "aphthous ulcer" AND palliative OR terminally-ill OR "terminally ill" OR "advanced disease" OR "advanced illness" OR dying OR end-of-life OR hospice OR cancer AND treatment OR intervention OR therapy OR management OR "oral care" OR "mouth care" OR "dental management" AND "end-of-life care"

Data analysis
Extracted data from all included studies were analyzed using the Whittemore and Knafl [9] principles of integrative review with four stages: data reduction, data display, data comparison, and conclusion and verification. At data reduction stage, all 19 primary sources included in the integrative review were divided into subgroups; initially based on types of study (qualitative and quantitative), sample (cancer patients, non-malignant palliative conditions and oral conditions among palliative patients) and then by a predetermined conceptual classification aligning with the aims of this review and then analyzed by topic. Each primary source was reduced to a single page (available on request from authors). This helped us to systematically compare primary sources on specific issues, variables and sample characteristics. It also allowed us to organize the data into a manageable framework. At stage 2 (data display), the single page data from the 19 included studies was extracted and displayed in the form of a table (see Table 1). This helped us to visualize the patterns and relationships between and within primary data sources. At stage 3 (data comparison), we used constant comparison as a method of an iterative process of examining data to identify themes that had similar patterns and relations. Finally at stage 4 (conclusion and verification), patterns using primary data were verified and any similarities, differences and any spurious findings were identified, in order to ensure that valuable information was not lost. Five consecutive meetings were held in order to identify and reach a consensus on the final themes.
Other oral conditions reported are stomatitis [11], salivary hypofunction [5], mucosal erythema [5], fungal infection [5], periodontitis [12], cold sores [14], dental caries [16], gingival inflammation [16], tongue coating and inflammation [16], bleeding spots [16], plaque [17], food particles and fungus infection [17], sores and scabs [17], viscous ropy saliva and chapped lips [17], halitosis [17], problems using dentures [17], problems with oral secretions [18], dysarthria [19], oral yeast carriage [24], mucosal friction [25], and bouts of ulceration and infection [27]. Table 3 presents our findings associating the social and functional impact of oral conditions [5,[25][26][27][28]. Our review also revealed social and functional impact of having oral conditions among palliative patients. Social impact include feeling worried, bothered, a feeling of less satisfying life, shame, anxiety, depression, increased feelings of being a patient rather than a person, not wanting people to be around them which affected their social interaction and resulted in loneliness [5,[25][26][27][28]. Functional impact include difficulties in swallowing, speaking and eating, food restriction, sense of oral dryness and pain, which resulted in lack of food enjoyment [5,26,28]. Table 4 presents our findings on the management of some oral conditions among palliative patients and their effectiveness [11,15,17,[19][20][21][22][23] Our study revealed that the common management options for xerostomia are drug and medical treatments [15], lubricating lips and mucosa [17], acupuncture [19], and standard oral care which improved dry mouth (in 80% or more) of the patients [11]. For candidiasis, a single-dose fluconazole 150 mg via mouth was found to be very effective as the symptoms decreased significantly (P < 0.001) in most patients [20], and local antifungal treatments were reported to be efficacious in 78.1% of the patients [23]. A substantial improvement of dysphagia was also observed after fifth treatment of acupuncture [19], however, its management using step-based pharmacological intervention and topically acting drugs caused worsening of swallowing and soreness of mouth [22]. Also, the management of mucositis using step-based pharmacological intervention and topically-acting drugs did not improve the oral condition [22], however, an indomethacin oral spray has been proven to relieve pain after 25 min [21]. Oral discomfort in palliative care: results of an exploratory study of the experiences of terminally ill patients.

Management of oral conditions among palliative patients
To examine oral discomfort from the perspective of terminally ill patients.

Australia
Terminally-ill patients Qualitative interview

Xerostomia 2. Bouts of ulceration and infection
Treatment challenges of oral conditions in palliative patients Table 5 presents our findings on the challenges in treating oral conditions among palliative patients [17,18]. Only 2 of the included papers addressed the challenges in treating oral conditions among palliative patients. Kvalheim et al. (2016) found that some of the challenges were the lack of knowledge/routine, patient cooperation, resources, priority given to oral problems, as well as difficulty in accessing the mouth and retching. Bogaardt et al. (2015) observed underestimation of reported oral problems among palliative patients by rating significantly lower incidence and severity problems by the nursing staff compared to the patients' relatives.

Discussion
To our knowledge, this review is first of its kind to systematically and comprehensively synthesize the published evidence on oral conditions among palliative patients, impact, management and challenges in the management. Our review found that the most common oral conditions among palliative patients are xerostomia, oral candidiasis, dysphagia, mucositis, orofacial pain, taste change and ulceration. A previous study by Saini et al. (2009) has also stated xerostomia, oral candidiasis, mucositis, dysphagia, ulceration, taste disorders and pain as the most common oral problems among palliative patients [2]. Another discussion paper on oral cavity complications of patients with advanced cancer also found that xerostomia, oral candidiasis and taste alterations are very common among these patients which could lead to malnutrition and communication disorder [29]. In addition, Mulk et al. (2014) described the role of dentist in palliative team and categorized xerostomia and trouble in swallowing as the indication of terminal phase of life [30]. Chen (2015) proposed an oral health care model for seriously-ill old people and stated that xerostomia is a major problem in all dying stages (decline, pre-active dying and actively dying) which worsen with each stage due to kidney failure, dehydration, and the use of anticholinergic medications during the actively dying phase [31]. Our review also revealed social and functional impact of having certain oral conditions among palliative patients. In agreement, Saini et al. (2009) stated that oral lesions have an immense impact on the quality of life of patients with complex advanced diseases, causing considerable morbidity to patient's physical condition due to reduced oral intake and weight loss, as well as psychological well-being due to impaired communication and feelings of exclusion and social isolation. Mulk et al. (2014) explained that the most common psychological problem for the elderly requiring a palliative approach is depression, and due to the lack of proper oral hygiene among depressed patients, they often present with halitosis (bad breath) which may cause people around them to stay away from them, causing severe social impact among these patients.
Our review also reported various treatment options for several oral conditions. For example, using salivary substitutes for xerostomia, and using fluconazole for candidiasis, and its effectiveness among palliative patients. Xerostomia, orofacial pain and taste change had functional impact which include swallowing difficulty, speaking difficulty, eating difficulty, food restriction, dryness and pain, with significant correlation between caregivers' and care recipients' ratings (p < 0.001)

Rydholm & Strang
Xerostomia was reported to have psychosocial effects, including shame, increased feelings of being a patient rather than a person and a tendency to avoid social contact, resulting in loneliness.
Xerostomia was reported to be associated with loss of oral function, such as in articulation and swallowing.

Rohr et al.
Orofacial pain prevent patient from sharing and enjoying meals with friends and family, which limit their social outings and participation at special occasions. Participants were more 'tentative' in holding a conversation with others due to speech difficulties, hence avoiding 'close physical contact' with their loved ones.
Xerostomia was described as 'constantly there', causing swallowing difficulties and loss of taste. Difficulty of swallowing was also described as 'unbearable at times'.

Wilberg et al.
Xerostomia and taste alterations were associated with anxiety (p = 0.04) and depression (p = 0.34) n/a *n/a not available

Meidell & Rasmussen
Acupuncture treatment twice a week for 5 weeksa total of ten treatments.
Measurements were using visual analogue scale (VAS), consisted of a horizontal line, 0-10 cm, where 0 represented no problem or discomfort and 10 represented severe problems and discomfort. The feeling of dryness of the mouth declined for all the participants as the series of treatment proceeded. In most cases a substantial improvement could not be noted until after fifth treatments. VAS decreased from 7.5 to 4.8 after fifth treatments (P < 0.001). Between the sixth and tenth treatments, the VAS decreased from 4.8 to 3.3 (P < 0.001). The VAS decreased from 7.5 before the baseline to 3.3 before the tenth treatment (P < 0.001).

Nakajima
Standard oral care by nursing staff of the wards, which include moisturizing, brushing, and oral cleaning (such as tongue coating removal) or oral massage performed by ward staff on a regular basis to resolve dry mouth). Intervention by specialist oral care team (specialist oral care) was performed as needed.
The rate of dry mouth improvement by oral care intervention was investigated by the severity (Grade 1, 2 and 3). All grade 1 cases were improved by standard oral care (100%). Grade 2 dry mouth was improved by standard oral care in 85% in good oral intake group (oral food intake was 30% or more) and 71% in poor oral intake group (oral food intake was less than 30%). Six ineffective cases of poor oral intake group were treated with specialist oral care, resulting in an improvement rate of 83%. Grade 3 dry mouth was improved by standard oral care in 40% in good oral intake group, and 2 ineffective cases were treated with specialist oral care, resulting in an improvement rate of 80%. In poor oral intake group, improvement was achieved by standard oral care in 67%, Acupuncture treatment twice a week for 5 weeksa total of ten treatments.
Measurements were using visual analogue scale (VAS), consisted of a horizontal line, 0-10 cm, where 0 represented no problem or discomfort and 10 represented severe problems and discomfort. A substantial improvement of dysphagia was not obvious until after fifth treatments when the VAS had decreased from 5.6 to 4.1 (P < 0.001). Between the sixth and tenth treatments, the VAS decreased from 4.1 to 3.7 (P = 0.81). The VAS decreased from 5.6 before the baseline to 3.7 before the tenth treatment (P = 0.01).

Ling & Larsson
Step-based pharmacological intervention 1. Acetaminophen 2. NSAID 3. Opioids 4. Adjuvant medication -Amitryptilin, gabapentin, or pregabalin were considered due to neurotic pain, mainly tumor-related. -Betametasone was considered for optimized antiinflammatory effect, impaired general condition, or antiemetic effect. Topically acting drugs -Lidocain and benzydamine were prescribed at RT start by the dental services at the hospital to all patients with an irradiated mouth.

Mucositis Ling & Larsson
Step-based pharmacological intervention 1.Acetaminophen 2.NSAID 3.Opioids 4.Adjuvant medication -Amitryptilin, gabapentin, or pregabalin were considered due to neurotic pain, mainly tumor-related. -Betametasone was considered for optimized antiinflammatory effect, impaired general condition, or antiemetic effect. Topically acting drugs Lidocain and benzydamine were prescribed at RT start by the dental services at the hospital to all patients with an irradiated mouth.

Momo et al. Indomethacin (IM) oral spray (OS)
Pain relief was achieved in 93% patients at 25 (5-60) min after applying the IM-OS preparation (15.6 ± 3.4 μg/kg) and Saini et al. (2009) also reported similar treatment options for some oral conditions as in the present study, they highlighted that one of the management option for dysphagia is to remove coating or plaque from teeth, and removal of dental prosthesis to clean and rectify for any technical error for mucositis, whilst emphasizing that the management of oral problems in palliative patients should be carried out as a team work and treatment protocol should be available to guide non-dentist and dental expert. On the other hand, a clinical paper on the management of oral mucositis in cancer patients found that the current clinical management of mucositis is largely focused on palliative measures such as pain management, nutritional support and maintenance of good oral hygiene, with several promising therapeutic agents in various stages of clinical development [32]. However, none of the studies mentioned complimentary therapies such as acupuncture as a treatment option neither for xerostomia and dysphagia nor any oral conditions among palliative patients. Our review also highlights that the lack of knowledge among healthcare providers posed a challenge in treating oral conditions among palliative patients. A study reported that training and involvement of dental professionals in caring for palliative patients seem to remain limited [33]. On the other hand, evidence also report that patients and their families are less likely to prioritize oral care needs due to increased diseases burden, transportation difficulties and psychological distress at the end of life [4]. This study also found patient cooperation as a challenge in treating oral conditions among palliative patients as it was explained that is due to the process of transferring palliative patients to dental offices for oral examination and treatment that could be physically challenging and stressful for these patients.
Apart from the above, it can be seen that among the scientific articles included in the literature review, two papers are concerning head and neck cancer patients [21], which may be more significant on the patient's oral well-being conditions, both for the localization of the tumor and the regional radiotherapy. Therefore, future reviews can focus on patients with specific types of cancer and their oral conditions. This would greatly contribute to the body of knowledge on palliative care. Regardless, our review has provided baseline knowledge that can guide health care professionals in palliative settings.

Conclusion
This review summarizes the diverse oral conditions that challenge the quality of life of palliative patients. Evidence is emerging on various treatment options for management of oral conditions among diverse palliative conditions. Our review also highlights the lack of evidence investigating palliative oral care among specific group of patients such as patients with dementia, geriatric or pediatric advanced cancer patients. Yet, this review provides baseline comprehensive knowledge and practice of quality oral care for palliative patients that may guide health care professionals in palliative settings.  Management Effectiveness analgesic effects were maintained for 120 (10-360) min. The pain was significantly decreased after using the spray (3.6 ± 0.7 vs. 2.4 ± 0.9, p < 0.01). Moreover, urinary IM excretion rates after applying the IM spray preparation were 1.8 ± 0.8% of the IM oral spray dose (130.5 ± 77.7 μg/kg/day), which was markedly lower than that following oral administration of IM (60%). No adverse events were observed following application of the spray.
*n/a not available

Bogaardt et al
• Nursing staff rated the incidence and severity of swallowing problems lower than the relatives (p < 0.0001) • Nursing staff rated the median severity of frequent coughing (p = 0.012) and loss of appetite (p = 0.001) significantly lower compared to the relatives'

Availability of data and materials
The datasets used for the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.