Type of study
During radiotherapy (%)
1–3 months post radiotherapy (%)
3–6 months post radiotherapy (%)
6–12 months post radiotherapy (%)
1–2 years post radiotherapy (%)
>2 years post radiotherapy (%)
All studies
93.0
73.6
79.0
82.9
77.6
85.3
Conventional radiotherapy
81.4
70.9
83.2
71.5
83.8
90.9
3-D conformal radiotherapy
None reported
46.7
74.5
90.3
75.4
69.4
Intensity-modulated radiation therapy
100
89.4
72.7
90.1
66.0
68.1
Radioactive Iodine
The prevalence of xerostomia 1–2 years post radioactive iodine has been estimated to be 33.6 % [15].
Chemotherapy
The prevalence of xerostomia during chemotherapy has been estimated to be 49.9 % [15]. It appears (from the limited literature) that xerostomia is usually an acute complication of chemotherapy, i.e. the xerostomia improves following cessation of the chemotherapy.
Aetiology
There are numerous causes of SGD in the general population [16], with the most common cause being drug treatment [17]. SGD is a side effect of many drugs [18], including many of the drugs used in day-to-day clinical practice [19]. Similarly, there are numerous causes of SGD in the oncology population (Box 4.1) [9, 20–28], with the most common cause again being drug treatment [9]. SGD is a side effect of many of the drugs used in supportive care/palliative care (e.g. analgesics, anti-emetics) [9]. Drug-induced SGD is discussed in detail in Chap. 3.
Box 4.1 Causes of Salivary Gland Dysfunction in Patients with Cancer
Related to Cancer Treatment
Radiotherapy to the Head and Neck Region
The development of salivary gland dysfunction is related to the cumulative dose of radiotherapy and the volume of salivary gland tissue included in the treatment field [15]. Salivary flow rates decrease during the radiotherapy (with a reduction occurring in the first week of treatment) and then further decrease in the 1–3 months post radiotherapy [15]. Over time, there is some limited improvement in salivary flow rates, and SWSFRs are generally higher than UWSFRs.
Parotid-sparing intensity-modulated radiotherapy (IMRT) can reduce the prevalence/severity of salivary gland dysfunction, but does not prevent the development of xerostomia due to damage to the minor salivary glands and the submandibular glands (which are the major sources of salivary mucin, i.e. intraoral lubrication). IMRT is discussed in detail in Chap. 9. Currently, it is unclear whether concomitant chemotherapy has any effect on the development of salivary gland dysfunction [15].
Pathophysiology
Xerostomia is usually the result of a decrease in the volume of saliva secreted (i.e. salivary gland hypofunction). Indeed, normal subjects usually complain of a dry mouth when their UWSFR falls by 50 % [29]. However, xerostomia may also result from a change in the composition of the saliva secreted [30]. Indeed, Davies et al. reported that 15 % of advanced cancer patients with xerostomia had a “normal” UWSFR (i.e. ≥ 0.1 ml/min) and that 53 % of advanced cancer patients with xerostomia had a “normal” SWSFR (i.e. ≥ 0.5 ml/min) [9].
Clinical Features
The clinical features of SGD are very variable (Table 4.2) [31] and reflect the differing functions of saliva [16]. SGD is associated with a number of oral problems but is also associated with more generalised problems. Indeed, SGD is associated with a significant negative impact on quality of life (Box 4.2) [15, 32].
Table 4.2
Complications of salivary gland dysfunction [31]
|
General problems
|
Oral discomfort
|
|
Lip discomfort
|
|
|
Cracking of lips
|
|
|
Eating-related problems
|
Anorexia
|
|
Taste disturbance
|
|
|
Difficulty chewing
|
|
|
Difficulty swallowing
|
|
|
Decreased intake of nutrition
|
|
|
Speech-related problems
|
Difficulty speaking
|
|
Oral hygiene
|
Poor oral hygiene
|
|
Halitosis
|
|
|
Oral infections
|
Oral candidosis
|
|
Dental caries
|
|
|
Periodontal disease
|
|
|
Salivary gland infections
|
|
|
Systemic infections
|
Secondary to oral infection (e.g. pneumonia, septicaemia)
|
|
Dental/denture problems
|
Dental erosion (leading to dental sensitivity/trauma to oral mucosa)
|
|
Poorly fitting dentures (leading to trauma to oral mucosa)
|
|
|
Psychosocial problems
|
Embarrassment
|
|
Anxiety
|
|
|
Depression
|
|
|
Social isolation
|
|
|
Miscellaneous problems
|
Sleep disturbance
|
|
Difficulty using oral transmucosal medication (i.e. sublingual/buccal medication)
|
|
|
Oesophagitis
|
|
|
Urinary frequency (secondary to increased intake of fluid)
|
The clinical features of SGD vary from individual to individual and may vary within an individual over time. Patients with xerostomia may have some or none of the aforementioned clinical features. In addition, the xerostomia may be of varying frequency and varying severity and lead to varying levels of distress (Table 4.3) [9]. Similarly, patients with salivary gland hypofunction may have some or none of the aforementioned clinical features (including xerostomia).
Table 4.3
Clinical features of xerostomia in patients with advanced cancer [9]
|
Characteristic
|
Descriptor
|
Percentage
|
|---|---|---|
|
Frequency
|
“Rarely”
|
4
|
|
“Occasionally”
|
20
|
|
|
“Frequently
|
40
|
|
|
“Almost constantly”
|
36
|
|
|
Severity
|
“Slight”
|
14
|
|
“Moderate”
|
37
|
|
|
“Severe”
|
33
|
|
|
“Very severe”
|
16
|
|
|
Distress
|
“Not at all”
|
16
|
|
“A little bit”
|
21
|
|
|
“Somewhat”
|
23
|
|
|
“Quite a bit”
|
26
|
|
|
“Very much”
|
14
|
It is important to emphasise that there may be a discrepancy between the symptoms experienced by patients and the signs identified by healthcare professionals. The “classic” signs of salivary gland hypofunction include dryness of the oral mucosa, dryness of the lips, absence of a “pool” of saliva in the floor of the mouth, fissuring of the oral mucosa (especially of the tongue) and cracking of the lips [2]. However, patients with xerostomia, and some patients with salivary gland hypofunction, may have no obvious abnormalities on examination. Hence, a normal oral examination does not preclude a diagnosis of SGD (see below).
Box 4.2 Quotations from Cancer Patients with Xerostomia [32]
“It’s so dry and sticky, my mouth glues, sometimes I have difficulties even opening my mouth”.“Eating takes a long time, I stayed there at the table for 30–45 min after everybody else. I had to sip before each swallowing, totally about 1 l of water”.“My voice disappears totally as a consequence of dryness of the mouth, and it is very tiresome to talk”.“We were to celebrate my birthday and I had helped to prepare salmon and looked forward to have dinner with the family. The taste alteration was incredible, the food tasted of absolutely nothing or possibly of wheat flour; I was disappointed and depressed and felt sorry for myself, I couldn’t feel or share happiness with my family during that occasion”.“…the problems are there constantly, my illness is there constantly, I am never free”.
Assessment
A wide range of investigations may be employed in the management of SGD in the general population. Some of these investigations are used to diagnose SGD (e.g. measurement of salivary flow rates), whilst other investigations are used to determine the cause of the SGD (e.g. detection of autoantibodies). However, most of these investigations are not indicated in the assessment of SGD in the cancer population. Indeed, a diagnosis of SGD can invariably be made on the basis of routine clinical skills, i.e. taking a history and performing an examination [2].
Table 4.4 shows the relevant National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) relating to cancer treatment [33]. These criteria are widely used in clinical practice/clinical trials and are recommended by organisations such as the Food and Drug Administration (United States of America). However, research suggests that similar observer-completed assessment tools may have poor interobserver reliability, may not correlate with objective measures of SGD and (particularly) may not correlate with subjective measures of SGD [34].
Table 4.4
National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 3
|
Adverse event (AE)
|
Grade 1 – “mild” AE
|
Grade 2 – “moderate” AE
|
Grade 3 – “severe” AE
|
Grade 4 – life-threatening/life-disabling AE
|
Grade 5 – death due to AE
|
|---|---|---|---|---|---|
|
Dry mouth/salivary gland (xerostomia)
|
Symptomatic (dry or thick saliva) without significant dietary alteration; unstimulated salivary flow >0.2 ml/min
|
Symptomatic and significant oral intake alteration (e.g. copious water, other lubricants, diet limited to purees and/or soft, moist foods); unstimulated saliva 0.1–0.2 ml/min
|
Symptoms leading to inability to adequately aliment orally, IV fluids, tube feedings or TPN indicated; unstimulated saliva <0.1 ml/min
|
–
|
–
|
|
Short name – dry mouth
|
|||||
|
Salivary gland changes/saliva
|
Slightly thickened saliva; slightly altered taste (e.g. metallic)
|
Thick ropy, sticky saliva; markedly altered taste; alteration in diet indicated; secretion-induced symptoms not interfering with ADL
|
Acute salivary gland necrosis; severe secretion-induced symptoms interfering with ADL
|
Disabling
|
–
|
|
Short name – salivary gland changes
|
Management
SGD is a heterogeneous condition and so requires individualised management. The management of SGD depends on a variety of different factors, including the aetiology/pathophysiology of the SGD, the clinical features of the SGD, the general condition of the patient, the dental status of the patient, the treatment preferences of the patient, the availability of specific interventions and the affordability of specific interventions [31]. The management of SGD involves a number of different strategies, including: (a) the prevention of SGD, (b) the treatment of the cause of SGD, (c) the symptomatic treatment of SGD, (d) the prevention of the complications of SGD and (e) the treatment of the complications of SGD [31].
Prevention of SGD
As discussed above, SGD is extremely common in patients that have received conventional radiotherapy to the head and neck region. A number of strategies have been used to try to prevent radiotherapy-related SGD, including surgical transfer of salivary glands (i.e. submandibular glands) [35], use of novel radiotherapy techniques (e.g. IMRT) and use of radioprotectors (e.g. amifostine) [36]. Recently, the Oral Care Study Group of Multinational Association of Supportive Care in Cancer (MASCC) reviewed the data on these strategies and recommended the use of IMRT but was unable to make recommendations about the surgical transfer of salivary glands or the use of amifostine [37].
Treatment of the Cause of SGD
Box 4.1 shows the main causes of cancer-related SGD. Some of these causes may be amenable to a specific intervention, although most are not amenable to any intervention. Drug treatment is the most common cause of cancer-related SGD [9]. In theory, it is possible to discontinue or substitute the relevant drugs. However, it is often difficult to discontinue these drugs, since they are needed to manage the underlying cancer or another serious condition. Similarly, it is usually futile to substitute these drugs, since the SGD is a side effect of the class of drug, rather than a side effect of the individual drug [18].
It should be noted that researchers are starting to investigate novel techniques to repair damaged salivary glands, including the utilisation of gene therapy and tissue engineering [38].
Symptomatic Treatment of SGD
The symptomatic treatment of SGD involves the use of saliva stimulants (agents that promote saliva secretion) and saliva substitutes (agents that replace missing saliva). There are good reasons for prescribing saliva stimulants rather than saliva substitutes [4]. Thus, saliva stimulants increase the secretion of “normal” saliva and so will ameliorate xerostomia and the other clinical features of SGD. In contrast, saliva substitutes, which are very different from normal saliva (i.e. physically, chemically), will usually only ameliorate xerostomia. Moreover, in studies that have compared saliva stimulants with saliva substitutes, patients have generally expressed a preference for the saliva stimulants [39, 40]. Nevertheless, some patients do not respond to treatment with saliva stimulants and so will require treatment with saliva substitutes (e.g. some patients with radiation-induced SGD).
Saliva Stimulants
-
Chewing gumChewing gum increases salivary flow by two mechanisms: ~85 % of the increase is related to stimulation of chemoreceptors within the oral cavity (i.e. taste effect), whilst ~15 % of the increase is related to stimulation of mechanoreceptors in/around the oral cavity (i.e. chewing effect) [41]. Patients with SGD should use “sugar-free” chewing gum, and patients with dental prostheses should use “low-tack” (less sticky) chewing gum.Chewing gum has been reported to be effective in the management of xerostomia in various groups of patients, including patients with radiation-induced SGD [40] and advanced cancer patients with drug-induced SGD [42]. Moreover, chewing gum has been reported to be more effective than organic acids and artificial saliva in studies involving mixed groups of patients with SGD [39, 40]. It should be noted that studies involving patients with radiation-induced SGD have produced variable results, with some reporting good results [40] and others less good results [39].Chewing gum is generally well tolerated. However, side effects can occur and may be related to: (a) chewing, e.g. jaw discomfort and headache; (b) inappropriate ingestion, e.g. respiratory tract obstruction and gastrointestinal obstruction; (c) non-allergic reactions to additives, e.g. oral discomfort and flatulence; and (d) allergic reactions to additives, e.g. stomatitis and perioral dermatitis. Chewing gum is an acceptable form of treatment for most patients, including most elderly patients [42, 43].
-
Organic acids
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