Managing Hyposalivation in Patients With Cancer Treated With Radiation Therapy 

Hyposalivation and xerostomia are among the most frequent — and most frequently overlooked — toxicities faced by patients undergoing radiotherapy for head and neck cancer (HNC), affecting approximately 78% of patients, according to a study published in 2021.¹ 

These conditions can profoundly degrade patients’ quality of life, altering taste sensations and causing difficulty swallowing (dysphagia).^1-3 They can also lead to damaged oropharyngeal mucosa and mucositis, dental caries (tooth cavities), mouth infections and periodontitis (inflammatory gum disease), pain, difficulty wearing dentures, nutritional deficiencies, dehydration, digestive disorders, and problems speaking, frequently leading to social isolation and contributing to clinical depression.^1-4 Patients with radiotherapy-induced hyposalivation should be referred to nutritionists and dentists, and monitored for mouth infections.

The terms hyposalivation and xerostomia are sometimes treated as synonyms. In reality, they are distinct, if overlapping, phenomena: hyposalivation describes reduced saliva production, whereas xerostomia is the subjectively perceived experience of dry mouth. 

Hyposalivation is frequently detected as a late-onset radiotoxicity affecting survivors after treatment has been completed, the 2021 study’s authors found. But other research suggests that saliva production declines as early as the first week of treatment and becomes more noticeable over time.^1,5 Multivariate analyses in the 2021 study indicated that the most important risk factors for hyposalivation are higher radiation dose and time since the conclusion of radiotherapy.¹ 

Concomitant radiochemotherapy was discounted as a risk factor because it did not reach statistical significance in the study’s multivariate model, but an earlier, 2017 study at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City did identify chemoradiotherapy as a risk factor.⁶ Authors of the 2017 study found that severe hyposalivation peaks within 6 months of the end of intensity-modulated radiotherapy (IMRT) and typically “fades with time.”⁵ 

Other medications, including anticholinergic drugs, antihistamines, antihypertensive drugs, opioids, antidepressants and antipsychotics, and systemic chemotherapy can cause xerostomia.⁵ But how different hyposalivation and xerostomia risk factors interact is unclear.

Detecting and managing radiotherapy-associated hyposalivation, patient education, and supportive care fall largely to oncology nurses. In this column, its pathobiology, prevention, and management are reviewed.

Salivary Gland Biology and Radiation-Associated Pathobiology

Saliva is a complex mixture of water, mucin glycoproteins, electrolytes, enzymes, immune cells and antimicrobial compounds (including mucins, among others) that help maintain a healthy oral microbiome. This mixture maintains oral health and aids in chewing, swallowing, and the earliest enzymatic steps of digestion.⁴ MUC5B, one form of mucin, contributes to saliva’s lubrication function and water retention, and also plays important microbial-ecological roles, killing harmful bacteria while providing glycan nutrients to beneficial bacteria.⁷

Saliva is involved in our ability to taste foods and detect noxious substances, to form food boluses for swallowing, and lubricating the oral surfaces — important not only for swallowing, but also for speaking.^1-4 It protects the gums and oral mucosa, oral pH balance, and tooth enamel.⁴ Saliva production normally follows a circadian rhythm, with less saliva produced at night.⁴ Production is increased by chewing.⁴ 

The salivary glands release saliva produced and stored in tiny collections of grape-bunch-like acini and secreted through tiny ducts into the mouth. There are 3 major bilaterally symmetrical pairs of salivary glands:

• The sublingual glands are found under the floor of the mouth, below either side of the tongue.
• The submandibular glands are below the jaw and secrete saliva from the underside of the tongue.
• The parotid salivary glands are just in front of the ears, with ducts adjacent to the upper molars.

Irradiation damages the epithelial lining of acini and salivary gland ducts through DNA and cell membrane damage, apoptotic cell death, and fibrotic scarring, compromising the ability of acini to produce and store saliva, and of ducts to secrete it. 

Radiation “bystander” effects appear to cause radiotoxicity of salivary gland tissues adjacent to but not within radiotherapy treatment fields.² Radiation hyposalivation involves not only reduced volume of saliva production, but altered saliva pH, consistency, and microbial ecology.² Lab animal studies also implicate impaired DNA repair, inflammation, nerve and vascular damage, and impaired calcium signaling between salivary gland cells in hyposalivation.² 

Because these pathologic processes are progressive, radiation dose-dependent, and cumulative, hyposalivation is often initially subtle, becoming more pronounced and debilitating over time. Acute-onset hyposalivation can occur within the first week of radiotherapy, affecting up to 60% of patients, whereas chronic or late-onset hyposalivation occurs 6 months or longer after radiotherapy.² The severity of acute hyposalivation predicts long-term risk of chronic hyposalivation.²

Diagnosis

Hyposalivation can be quantified and diagnosed using objective measures of saliva volume or scintigraphic imaging, and xerostomia can be diagnosed based on patient reports.² Patients with hyposalivation commonly voice concern about changes in how foods taste, xerostomia, dysphagia, or difficulty speaking.¹ Questionnaires such as the Xerostomia Inventory can help quantify the impacts on patients.¹ 

Typically, unstimulated salivary flow rates are measured after overnight fasting, with the patient seated upright, with their head tilted slightly forward and down, while spitting saliva into a graduated container for 15 minutes.¹ A normal range of unstimulated salivary flow is 0.3-0.4 mL/minute; 0.1 mL/min or less is considered low.⁸ Stimulated salivary flow rate is measured after chewing sugar-free gum: 1-2 mL/min is normal and 0.7 mL/min or less is low.⁸ 

Prevention and Management

Prevention and mitigation are the primary goals of hyposalivation management. Salivary gland sparing in external-beam radiotherapy beam placement planning, conformal and IMRT treatment modalities, radiation dosimetry and dose fractionation, and maxillofacial radiation shields can help reduce irradiation of healthy, nontarget salivary glands.^2,9 Some drugs, such as the free radical scavenger amifostine, may be radioprotective for salivary gland tissue.¹⁰ 

“Limiting the mean dose to both parotid glands (ipsilateral <25 Gy, contralateral <25 Gy) and reducing the use of chemotherapy will likely decrease the rate of [hyposalivation],” concluded the authors of the 2017 MSKCC study.⁶ 

Oral hygiene, alcohol-free rinsing, and tobacco cessation interventions might also reduce the risk of severe radiation-associated hyposalivation sequelae but the evidence base for these interventions remains nascent at best. Sugar-free gum or lozenges and sialogogues (eg, pilocarpine and cevimeline) can stimulate saliva production; artificial saliva sprays or gels are also sometimes prescribed for patients with hyposalivation and xerostomia, but here, too, the evidence base is not mature.¹¹ 

Several recent meta-analyses offer some insight into the existing evidence base for treating hyposalivation. Authors of a 2017 meta-analysis of data from 6 randomized controlled trials concluded that pilocarpine and cevimeline are first-line therapies for patients with radiotherapy-associated xerostomia and hyposalivation, whereas other treatments, (including saliva substitutes, acupuncture-like electrical nerve stimulation, and herbal supplements) are unsupported by the available evidence base.¹² 

Photobiomodulation (PBM, also known as low-level laser therapy [LLLT]) is a therapeutic technique that uses light-emitting diodes to induce cellular healing. A 2020 meta-analysis of 5 clinical trials concluded that stimulated and unstimulated salivary flow rates are improved with PBM and that PBM might reduce the risk of radiation-associated hyposalivation.¹³ 

A 2023 meta-analysis of 170 patients from 3 studies showed that the cholinergic agent bethanechol chloride increased stimulated and unstimulated saliva flow after radiotherapy, and may be an effective treatment in the management of hyposalivation and xerostomia.¹⁴ 

Patient education, supportive care, and referrals for psychosocial support or counseling, nutritional assessment and planning, and dental care, are also important for patients with hyposalivation. 

Currently, the empirical evidence base for preventing and managing radiation hyposalivation is scant but supports the use of salivary gland-sparing radiotherapy techniques, sialogogues, PBM, and bethanechol chloride. In the future, gene therapies or stem cell transplant treatments for hyposalivation might also help patients avoid or contend with this debilitating condition.¹⁰