Oral Dysfunction in Patients With Head and Neck Cancer: A Systematic Review.

BACKGROUND
Head and neck cancers (HNCs) and their treatment may cause oral function impairment.


PURPOSE
This study was designed to identify oral dysfunction in patients receiving treatment for HNCs using a systematic review.


METHODS
The PubMed, Embase, and CINAHL databases were searched for studies on oral function impairment in patients receiving treatment for HNCs published between January 2014 and May 2019. Only descriptive, correlational, and interventional quantitative studies that included patients receiving treatment for HNCs who presented with oral dysfunction, were published in English during the aforementioned time frame, and were accessible in full-text versions were selected.


RESULTS
Twenty-eight studies (13 cross-sectional, two longitudinal, 12 randomized controlled trial, and one retrospective chart review) fulfilled the inclusion criteria. Oral mucositis, dysphagia, xerostomia, trismus, and chewing and speech problems were the most common oral dysfunctions. Age, cancer stage, tumor location, treatment modalities, treatment status, treatment dose, and pretreatment oral function were factors associated with oral dysfunction. Although individual interventions were shown to improve oral dysfunction, the related evidence was inconclusive.


CONCLUSIONS/IMPLICATIONS FOR PRACTICE
Primary HNCs and their treatment significantly deteriorate oral function. A holistic and interdisciplinary approach may maximize oral function.


Introduction
Head and neck cancers (HNCs) are one of the most common cancers globally, accounting for 500,000 new cases diagnosed and more than 380,000 deaths annually (Bray et al., 2018). In Taiwan, approximately 6,000 new cases of HNC are diagnosed each year (Taiwan Cancer Registry, 2019). More than 50% of all HNCs present at an advanced stage at initial diagnosis (Bray et al., 2018). Radical resection plus reconstruction combined radiotherapy (RT) or concurrent chemoradiation therapy (CCRT) are the major treatment modes used to treat advanced-stage HNCs (National Comprehensive Cancer Network, 2018). However, surgical resection may change the anatomy of the oral cavity, and postoperative RT or CCRT induces oral mucous membrane lesions in the oral cavity and oropharyngeal region, leading to varying levels of oral dysfunction such as oral mucositis (OM), dysphagia (difficulty swallowing), xerostomia, trismus, and communication dysfunction during and after treatment (Lalla et al., 2017;Tolentino Ede et al., 2011). These dysfunctions may threaten oral intake and eventually lead to malnutrition, frailty, dependence, and cachexia, which increase recurrence rates and reduce survival rates (Büntzel, Micke, Kisters, Büntzel, & Mücke, 2019;Crowder, Douglas, Yanina Pepino, Sarma, & Arthur, 2018).

Inclusion and Exclusion Criteria
Studies were included if they (a) were published in an English peer-reviewed journal between January 2014 and May 2019; (b) included adult patients with HNCs; (c) specifically identified concepts of health-related quality of life (HRQoL) related to oral dysfunction such as dysphagia, difficulty swallowing, difficulty chewing, OM, trismus, speech, and communication dysfunctions; and (d) used a quantitative design. Studies were excluded if they (a) were summary reports, literature reviews, systematic reviews, letters, or case reports; (b) included patients who were diagnosed with HNCs combined with other cancer types; (c) included adolescent or younger patients; (d) focused on pain not specific to oral dysfunction or investigated generic and disease-specific HRQoL (i.e., physical, emotional, social, cognitive, or social); and (e) included interventions that were not led by nurses or other healthcare professionals (e.g., physician, speech-language pathologist, and physical therapist), used an invasive medical intervention (e.g., acupuncture) or medicines, or were designed as RT dose and modality trials.

Data Extraction
The methodological and outcome variables collected from each of the included studies were as follows: author, publication year, sample, main results, and oral function impact symptoms.

Study Selection
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart in Figure 1 presents the stages of the review process, including study identification, inclusion, and exclusion. A search of PubMed, Embase, and CINAHL yielded 487 studies. After duplicates were removed and titles and abstracts were screened, 58 full-text studies were assessed. Of these, 28 fulfilled the inclusion criteria. Of the 30 excluded studies, one investigated HNCs combined with breast cancer, 16 included interventions provided by healthcare professionals other than the aforementioned ones, five applied invasive medical interventions (acupuncture), one was a trial for RT dose and modalities, and seven did not fulfill the oral dysfunction criterion of HRQoL.

Oral Mucositis
OM was assessed in six of the studies.  revealed that patients reported the highest prevalence of OM at 5 weeks after beginning RT and 6 weeks after beginning CCRT; patients who received CCRT reported a higher prevalence than those receiving RT alone. The peak of OM-related symptoms was at 8 weeks after beginning RT and CCRT. High cumulative radiation dose, smoking, and low body mass index were associated with an increased OM risk. CCRT, high cumulative radiation dose, and smoking were also associated with greater numbers of OM-related symptoms. Gussgard, (2015) observed that patients with HNC who received RT or CCRT experienced OM and its impacts when eating hard foods. Hawley et al. (2014) investigated patients with HNCs undergoing RT or CCT who received honey oral rinses and reported no improvement in OM. Charalambous et al. (2018) investigated patients with HNCs and demonstrated that thyme honey mouth rinsing alleviated radiation-induced OM. Funk et al. (2014) observed that patients with HNCs who underwent a dental care program showed candidiasis and OM alleviation. Huang et al. (2018) showed that patients with oral cavity cancer (OCC) who received saline oral rinses had better physical and socioemotional quality of life (QoL) compared with the standard care group at 8 weeks. Taken together, radiation therapy may cause OM, which may impact on eating and nutritional intake and may be improved through appropriate oral care regimens.

Dysphagia (Difficulty Swallowing)
Dysphagia was assessed in 13 of the studies. Chen, Huang, Hung, et al. (2018) surveyed 151 patients with OCC and classified 7.3% (n = 11) with dysphagia. The most common swallowing impairments were as follows: difficulty swallowing dry or hard food and swallowing problems interfering with QoL. Patients with tumors of the tongue had worse functional dysphagia QoL than those with cancers in other locations.  observed that following the swallowing exercise education program effectively improved dysphagia-related emotional QoL during the initial 6 months of treatment in patients with OCC. Dixon et al. (2018) observed that poorer performance status, abnormal pretreatment diet, and enteral feeding during RT were all significantly associated with lower composite and dysphagia in oropharyngeal cancer after CCRT within 2 years. Iriya et al. (2017) surveyed 57 patients with HNCs and observed that oral function did not differ significantly by tumor location. Kamal et al. (2019) surveyed 152 patients with HNCs and observed that 67% of the survivors reported a restricted oral diet (without tube use), 3% had partial tube dependence for some oral intake, and 2% could consume nothing through their mouths (or nothing per oral).
Symptom severity for difficulty swallowing and tooth and gum problems remained significantly associated with functional oral intake. Kamiyanagi et al. (2018) observed that patients with HNCs who had undergone maxillectomy and were wearing the prosthesis had better swallowing ability during the oral stage than their healthy peers. Lazarus et al. (2014) studied patients with oral and oropharyngeal cancer undergoing RT or CCRT and showed that patients who participated in their swallowing exercise program reported no improvements in tongue strength and swallowing efficiency after the program. Messing et al. (2017) included patients with advanced HNCs who participated in prophylactic swallowing therapy with active exercises and reported oromotor functions, pharyngeal impairments, oral pharyngeal swallow efficiencies, and incisal opening at early time points (i.e., 3--6 months). Ohkoshi et al. (2018) surveyed 52 patients with oral cancer and observed that patients treated with anterior or extensive mandibular bone resection reported swallowing

Summary of Studies on Oral Dysfunction in Patients With HNCs
Author ( included 20 ml of thyme honey diluted in 100 ml of purified water just before the RT session, immediately after the RT session, and 6 hours after the session, starting from the fourth week of RT treatment. Patients were required to perform thyme honey rinses of the oral mucosa and then slowly smear the honey on the oral and pharyngeal mucosa (posterior wall of the oropharynx). After completion of RT, the participants continued the treatment protocol (three times a day) at home for 4 more weeks.
Significant effect of the intervention on unbearable pain, dysphagia, xerostomia, and overall QoL. to dilute 20 ml of thyme honey in 100 ml of purified water making gargles in the oral cavity (15 minutes before and after the RT session and 6 hours later), three times a day for 7 weeks (starting from the first day of the fourth week of RT).
Patients in the intervention group were graded lower in the objective assessment of OM (p < .001), maintained their body weight (p < .001), and improved their global health (p = .001) compared with the control group. Patients who received intensitymodulated RT had less trismus and xerostomia than patients who received two-dimensional RT. Patients who were female, at an advanced stage, had completed treatments within 1 year, had higher levels of depression, had more severe trismus, and had higher symptom severity tended to have malnutrition or were at risk of malnutrition.
Trismus (continues) The Journal of Nursing Research

Summary of Studies on Oral Dysfunction in Patients With HNCs, Continued
Author (  RCT -N = 100 -Honey arm (n = 40) -Placebo arm (n = 41) -Patients with HNCs undergoing RT -Intervention protocol: Honey and placebo gels were provided in single-use 5-ml sachets and were to be taken after every oral rinse, i.e., four times a day. Subjects were instructed to pour the product into their mouths directly from the sachets, to circulate the gel in their mouth for at least 30 seconds, and then to swallow. Treatment started on the first day of radiation and was to continue to include the 7 days after the last radiation treatment.
No statistically significant difference was observed between the honey and placebo arms in any of the outcome indicators. Those who completed the study in both treatment arms had low rates of RTOG greater than or equal to Grade 3 mucositis: 35% in the honey group and 43% in the placebo group.

Summary of Studies on Oral Dysfunction in Patients With HNCs, Continued
Author ( No statistically significant differences were observed in the mean GTQ score between the groups before or after the exercise program (data not shown). However, both groups statistically improved in jaw-related problems, eating limitations, and muscular tension at the 3-month follow-up compared with before exercise.

Summary of Studies on Oral Dysfunction in Patients With HNCs, Continued
Author ( RCT -N = 40 -Dynasplint arm (n = 20, stretching plus use of the Jaw Dynasplint, 57.7 years) -Control arm (n = 20, conventional stretching, 57.0 years) -Patients with HNCs undergoing RT until 6 months posttreatment -Intervention protocol: Jaw stretching regimen was composed of stretching the mouth open and laterally for a 30-second hold, moving the jaw in a circle with five repetitions in each direction, passive stretching by applying downward pressure on the mandible with the index finger held for 30 seconds, and circular jaw massage for 30 seconds plus adjunctive use of the Jaw Dynasplint. The Jaw Dynasplint instructions were to wear the device for 30 minutes, three times a day, during cancer treatment and in the early recovery period (3 months posttreatment).
At 6 months after initiation of the preventative regimen, 50% of patients in the Dynasplint arm and 75% in the conventional stretching arm groups continued their assigned therapy. Trismus was diagnosed in two patients in the control arm and in four patients in the Dynasplint arm. Only 25% of patients in the Dynasplint arm used the device as prescribed.
Trismus (continues) Oral Dysfunction in Patients With HNC VOL. 27, NO. 6, DECEMBER 2019 problems and had poor intake at 3 months after surgery. Kamiyanagi et al. (2018) observed that patients with HNCs who received maxillectomy and who wore the prosthesis had better swallowing ability during the oral stage than their healthy peers. Rogus-Pulia et al. (2016) observed that patients with HNCs undergoing CCRT reported significantly lower tongue endurance than reported by healthy people. Romer et al. (2019) identified an impact on postsurgery swallowing function in patients with early-stage OCC who underwent resection. van der Meulen et al. (2014) showed that patients with HNCs who participated in a nurse-led psychosocial program had better swallowing ability 12 months after the intervention. Patients with HNC may experience dysphagia because of tumor location, treatment modalities, or intervention participation.

Trismus
Trismus was assessed in six studies. In their cross-sectional study of 110 nasopharyngeal carcinoma survivors, Chen et al. (2016) showed that the severity of trismus may be greater after receiving two-dimensional RT than after receiving tomotherapy or intensity-modulated radiation therapy (IMRT). van der Geer et al. (2019) reported that 23.6% of their patients with HNCs experienced trismus after treatment. Zatarain et al. (2018) also reported that using a Jaw Dynasplint for 30 minutes, three times a day, during primary or adjuvant RT in patients with HNC is unfeasible as a preventative intervention for trismus. Loorents et al. (2014) observed that patients with HNCs receiving prophylactic training showed no improvement in maximum interincisal openings either during treatment or in the posttreatment period. Similar findings were noted by Pauli et al. (2015). van der Meulen et al. (2014) showed that patients with HNCs who participated in a nurse-led psychosocial program had a lower level of trismus 12 months after their intervention. In summary, radiation therapy causes inflammation and fibrosis of muscles, which may lead to trismus during treatment as well as for an indefinite period afterward.

Xerostomia
Xerostomia was assessed in five studies. Chen et al. (2016) observed that, in 3 months to 5 years of treatment, patients with nasopharyngeal carcinoma who received two-dimensional RT had significantly more severe trismus and xerostomia than did those who received tomotherapy and IMRT. Lazarus et al. (2014) investigated oral and oropharyngeal cancer treated with RT or CCRT and showed that patients who participated in a swallowing exercise program reported no improvement in tongue strength, swallow efficiency, or salivary flow after the training. Rogus-Pulia et al. (2016) showed that patients with HNCs who received CCRT experienced lower tongue endurance and decreased salivary flow rate during the posttreatment period. Charalambous et al. (2017) included patients with HNCs and showed that thyme honey mouth rinsing during RT improved RT-related xerostomia through 6 months posttreatment. In summary, modern RT techniques, including tomotherapy and IMRT and greater protection of salivary glands from RT, offer complementary and alternative palliative treatments for dry mouth.

Difficulty Chewing
Chewing was assessed in four of the studies. Gussgard et al. (2015) observed that patients with HNCs who received RT or CCRT had oral mucosal ulceration and thus had impaired abilities to consume hard foods. Iriya et al. (2017) showed that chewing was not correlated with tumor location. Kamal et al. (2019) observed that HNC survivors had gum problems and that 67% of the survivors reported a restricted oral diet (without tube), 3% had partial tube dependence for some oral intake, and 2% were nothing per oral. Ohkoshi et al. (2018)

Summary of Studies on Oral Dysfunction in Patients With HNCs, Continued
Author (

The Journal of Nursing Research
Shu-Ching CHEN included patients with oral cancer who received anterior or extensive mandibular bone resection and reported poor oral intake at 3 months after surgery. Thus, patients with HNC experience difficulty chewing and distress caused by radiation therapy, oral mucosal lesions, and gum or mandible resection.

Speech Problems
Speech problems were assessed in six of the studies. Balaguer et al. (2019) observed that surgery causes the significant morphological modification of the oral cavity or oropharyngeal structures and thus affects speech. Chen, Yu, et al. (2015) reported that 70.8% of their patients reported a decrease in the amount of time they spoke after surgery compared with before surgery. Patients with higher body-image-related stress, greater symptom severity, and hypopharyngeal or laryngeal cancer reported speaking less after their surgery. Iriya et al. (2017) observed that, in patients with HNCs who had undergone a maxillectomy, oral function did not significantly differ based on tumor location. Romer et al. (2019) showed that patients who had received neck dissections and who were older in age experienced significantly greater impairments in speech. Rosa et al. (2018) revealed that chemoradiotherapy treatment had a greater effect on the voice than on swallowing. Zhang et al. (2018) observed that voice rehabilitation training may not improve post-RT vocal quality in patients with laryngeal cancer and that oral function and psychosocial factors may contribute to speech problems.

Discussion
The Impact on Oral Function of Head and Neck Cancer and Related Treatments Patients with HNCs experience oral dysfunction during active treatment and follow-up, with major oral cavity function impairments including OM, dysphagia, trismus, xerostomia, chewing, and speech problems. These findings are similar to those of Kırca and Kutlutürkan (2017), who indicated that mouth sores, changes in the taste of food, difficulties in swallowing, and a loss of appetite are highly distressing problems during active treatment and peak at the end of treatment. Psychological problems (e.g., feeling vulnerable, feeling sad, and worrying) may co-occur with oral dysfunction. These findings may be attributable to differences in treatment status. Because the time since treatment completion varied across studies, some patients may have developed late or long-term side effects of surgery, RT, or CCRT. Additional studies exploring concurrent oral dysfunction and psychological concerns and comparing oral dysfunction among different stages of cancer treatment trajectories are warranted.

Factors Associated With Oral Dysfunction
Impairment in the oral function of patients with HNCs is often complicated by multiple oral dysfunctions. The results of this study are similar to those of Chiang, Ho, Wang, and Lin (2018), which reported that patients with HNCs who received postoperative RT reported symptom clusters including pain, dry mouth, lack of appetite, sleep disturbance, fatigue, drowsiness, distress, and sadness in Cluster 1 and nausea, vomiting, numbness, shortness of breath, and difficulty remembering in Cluster 2. As this review study was limited to individual problems, additional research will be necessary to understand multiple oral dysfunctions under a diverse set of influencing factors. Some studies have related oral dysfunction to multiple treatment modalities, cancer stages (Kao, Peters, Krishnan, & Ooi, 2016), and tumor locations (Schache et al., 2009). The advanced tumor-node-metastasis stage and the use of adjuvant RT have also been identified as having negative effects on swallowing function (Kao et al., 2016). However, in this review study, evidence supporting that oral function did not differ by tumor location was limited. This inconsistency in the findings may be explained by differences in surgery types and in the use of flap reconstruction. Moreover, patient participation in and compliance with swallowing rehabilitation affects oral function. Although the relationship between disease treatment characteristics and personnel behavior influences the factors of oral function, this topic should be further explored in patients with HNC because of the controversial effect that was observed in the reviewed studies.

Interventions for Oral Dysfunction in Patients With Head and Neck Cancers
Three studies examined the effects of thyme honey mouth rinsing on oral dysfunction, including OM and xerostomia, in patients with HNCs, with the related evidence proving to be inconclusive (Charalambous et al., 2017(Charalambous et al., , 2018Hawley et al., 2014). Nonsignificant improvement was shown in one study (i.e., low, severe OM rate), probably because of participant selection bias. In addition, patients with severe OM had a high dropout rate. Therefore, samples should be identified before initiating an intervention.
Evidence regarding the effects of mouth-opening exercises on trismus was inconsistent (Scherpenhuizen, van Waes, Janssen, Van Cann, & Stegeman, 2015). The effects were not significant in comparison with usual care (Loorents et al., 2014;Pauli et al., 2015;Zatarain et al., 2018). This finding may be explained by the wide variety of intervention components, formats, time frames, and durations in the studies measuring this outcome. Therefore, the effects of mouthopening exercises on trismus are uncertain and lack clinical validation across the studies. Patient motivations for complying with interventions should be considered when designing interventions.

Strengths and Limitations
This review is affected by several limitations. First, this review focused on the oral dysfunction of patients with HNCs without reviewing other literature on dysfunction Oral Dysfunction in Patients With HNC VOL. 27, NO. 6, DECEMBER 2019 as additional studies (e.g., neck or shoulder dysfunction). Further research should integrate the full range of functional impairments attributable to HNCs and their treatments. Second, most of the outcome measures were quantitative. Clinically meaningful, qualitative interviews were not considered. Patients perceive meaning, feeling, and thinking. Thus, qualitative studies are necessary to more completely identify the oral dysfunction concerns of these patients. Finally, the variations in the disease phase (e.g., undergoing treatment, short-term posttreatment, long-term posttreatment/ survival phase) were attributable to differences in the oral dysfunction identification in individual studies. Additional reviews comparing the differences in oral dysfunction between patients undergoing treatment and completing treatment are warranted.

Implications for Practice
This review showed that oral dysfunction is a critical part of the oral-related QoL of patients with HNC. There are differences in oral dysfunction between tumor location and treatment modalities. Healthcare providers should actively assess oral function based on individual factors. Moreover, the review identified the commonly reported oral-dysfunctionrelated symptoms and related concern experiences of patients with HNCs during treatment and survivorship trajectories. Although the current evidence suggests that interventions play a key role in the way patients adjust to oral dysfunction, methodological issues limit the generalization of the results. Healthcare providers should encourage patients to express their oral dysfunction experiences and characteristics and guide patients to use the most effective strategies to minimize functional impairments.

Implications for Research
Findings from this review inform that oral dysfunction involves multiple aspects. There are currently no instruments that address multiple oral functions. Development and validation of an effective and brief screening tool is needed to quickly assess multiple oral dysfunctions in patients with HNC. Although previous studies have reported that the thyme honey mouth-rinsing intervention improves OM and xerostomia and that mouth-opening exercises improve trismus, further high-quality studies with considerations of confounding factors such as pretreatment oral function and compliance should be performed to identify the effects of interventions and of individual factors.

Conclusions
This systematic review provided an overview of the current knowledge concerning the associated factors and changes over time of oral dysfunction in patients with HNCs during the treatment and posttreatment phases. Overall, patients with HNCs reported oral dysfunction 3-4 weeks after the initiation of treatment and reported the highest level of oral dysfunction at the end of treatment.
Oral dysfunction included a range of symptoms, including OM, mouth dryness, eating difficulties, swallowing difficulties, taste changes, and speech dysfunction. Patients with HNC may continue to struggle with these problems into survivorship, which diminishes long-term QoL. We also identified the associated factors of oral dysfunction, including age, cancer stage, tumor location, treatment modalities, treatment status, treatment dose, and pretreatment oral function. Individual interventions reduced the levels of single oral dysfunction in patients with HNCs during treatment and posttreatment. This complex and necessary oral dysfunction is common in patients with HNCs because of the primary disease and its treatment. Healthcare professionals and providers may use holistic and interdisciplinary approaches to maximize oral function.