Xerostomia
        Topical oral antimicrobials
Dysgeusia
Fatigue
Nutritional Compromise

Xerostomia

Xerostomia is caused by a marked reduction in salivary gland secretion [1,2] and has a significant impact on quality of life.[3] Symptoms and signs of xerostomia include dryness, burning sensation of the tongue, fissures at lip commissures, atrophy of dorsal tongue surface, difficulty in wearing dentures (edentulous patients), and increased thirst.

Radiation therapy can damage salivary glands, causing xerostomia (symptoms of dry mouth) and salivary hypofunction. In addition, selected chemotherapeutic agents (singly or in combination) have been implicated in causing salivary dysfunction; however, this effect has not been well documented.

Ionizing radiation to salivary glands results in inflammatory and degenerative effects on salivary gland parenchyma, especially serous acinar cells. Salivary flow decreases within 1 week after starting radiation treatment and xerostomia becomes apparent when doses exceed 10 Gy. Doses larger than 54 Gy are generally considered to induce irreversible dysfunction. The degree of dysfunction is related to the radiation dose and volume of glandular tissue in the radiation field. Parotid glands may be more susceptible to radiation effects than submandibular, sublingual, and other minor salivary glandular tissues. Salivary gland tissues that have been excluded from the radiation portal may become hyperplastic, partially compensating for the nonfunctional glands at other oral sites. Generally stated, some degree of salivary gland recovery is seen over the first 6 months after radiation therapy. Maximum recovery is generally reported by 12 months posttherapy, but it is usually incomplete and the overall degree of dryness can range from mild to severe. One study demonstrated successful surgical submandibular gland transfer to the submental space resulting in a functioning gland even after radiation with appropriate shielding.[4]

Xerostomia alters the mouth’s buffering capacity and mechanical cleansing ability, thereby contributing to dental caries and progressive periodontal disease. Development of dental caries also is accelerated in the presence of xerostomia due to reduction in delivery to the dentition of antimicrobial proteins normally contained in saliva.

Saliva is necessary for the normal execution of oral functions such as taste, swallowing, and speech. Unstimulated whole salivary flow rates less than 0.1 mL per minute are considered indicative of xerostomia (normal salivary flow rate = 0.3–0.5 mL/minute). Xerostomia produces the following changes in the mouth that collectively cause patient discomfort and increased risk for oral lesions:

• Salivary viscosity increases, with resultant impaired lubrication of oral tissues.



• Buffering capacity is compromised, with increased risk for dental caries.



• Oral flora becomes more pathogenic.



• Plaque levels accumulate due to the patient’s difficulty in maintaining oral hygiene.



• Acid production after sugar exposure results in further demineralization of the teeth and leads to dental decay.

Patients who experience xerostomia must maintain excellent oral hygiene to minimize risk for oral lesions. Periodontal disease can be accelerated and caries can become rampant unless preventive measures are instituted. Multiple preventive strategies should be considered (refer to the list on the Oral and Dental Management of the Xerostomic Patient below). The following is an example of a patient protocol:

Perform systematic oral hygiene at least 4 times a day (after meals and at bedtime):

• Use a fluoridated toothpaste when brushing.



• Apply a prescription-strength fluoride gel at bedtime to clean teeth.



• Rinse with a solution of salt and baking soda 4 to 6 times a day (½ tsp salt and ½ tsp baking soda in 1 cup warm water) to clean and lubricate the oral tissues and to buffer the oral environment.



• Avoid foods and liquids with a high sugar content.



• Sip water to alleviate mouth dryness.

Oral and Dental Management of the Xerostomic Patient [2]

• Plaque removal:
  • Tooth brushing.
  
  
  
  • Flossing.
  
  
  
  • Other oral hygiene aids.
  
  
  



• Remineralizing solutions:
  • Fluoride and calcium/phosphates.
  
  
  
  • Topical high concentration fluorides.
  
  
  
  • Children: topical and systemic.
  
  
  
  • Adults: topical.
  
  
  



• Topical antimicrobial rinses:
  • Chlorhexidine solutions/rinses (Peridex).
  
  
  
  • Povidone iodine oral rinses.
  
  
  
  • Tetracycline oral rinses.
  
  
  



• Sialogogues:
  • pilocarpine (Salagen)
  
  
  
  • cevimeline (Evoxac)
  
  
  
  • bethanechol
  
  
  
  • antholetrithione (Sialor)
  
  
  

 [Note: Prescription-strength fluorides should be used because nonprescription fluoride preparations are inadequate in the face of moderate-to-high dental caries risk. If drinking water does not have adequate fluoride content to prevent dental decay, then oral fluoride (i.e., drops, vitamins, etc.) should be provided.]

Use of topical fluoride has demonstrable benefit in minimizing caries formation. During radiation treatment, it has been recommended that topical 1% sodium fluoride gel be applied daily into mouth guards that are placed over the upper and lower teeth. The appliances should remain in place for 5 minutes, after which the patient should not eat or drink for 30 minutes.

Management of xerostomia also includes use of saliva substitutes or sialagogues. Saliva substitutes or artificial saliva preparations (oral rinses containing hydroxyethylcellulose, hydroxypropylcellulose, or carboxymethylcellulose) are palliative agents that relieve the discomfort of xerostomia by temporarily wetting the oral mucosa. Sialagogues pharmacologically stimulate saliva production from intact salivary glandular tissues.[1,5] Submandibular gland transfer has been used for xerostomia.[6]

Pilocarpine is the only drug approved by the U.S. Food and Drug Administration for use as a sialogogue (5-mg tablets of pilocarpine hydrochloride) for radiation xerostomia. Treatment is initiated at 5 mg by mouth 3 times a day; dose is then titrated to achieve optimal clinical response and minimize adverse effects. Some patients may experience increased benefit at higher daily doses; however, incidence of adverse effects increases proportionally with dose. The patient’s evening dose may be increased to 10 mg within 1 week after starting pilocarpine. Subsequently, morning and afternoon doses may also be increased to a maximum 10 mg per dose (30 mg/day). Patient tolerance is confirmed by allowing 7 days between increments. The most common adverse effect at clinically useful doses of pilocarpine is hyperhidrosis (excessive sweating); its incidence and severity are proportional to dosage. Nausea, chills, rhinorrhea, vasodilation, increased lacrimation, bladder pressure (urinary urgency and frequency), dizziness, asthenia, headache, diarrhea, and dyspepsia are also reported, typically at doses higher than 5 mg 3 times a day. Pilocarpine usually increases salivary flow within 30 minutes after ingestion. Maximal response may occur only after continual use. In a randomized study of 249 patients with head and neck cancer, however, the concomitant use of pilocarpine during radiation did not have a positive impact on quality of life or patient assessment of salivary function despite the maintenance of salivary flow.[7]

Cevimeline (30 mg 3 times a day) also appears anecdotally to have efficacy in managing radiation-induced xerostomia. Although to date cevimeline is only approved for use in the management of Sjögren syndrome, appropriate clinical trials are under way and its efficacy should soon be established. While cevimeline has greater selective affinity for M3 muscarinic receptors than pilocarpine, whether this can prove advantageous for treating radiation xerostomia remains unclear.

Amifostine is an organic thiophosphate approved for the protection of normal tissues against the harmful effects of radiation or chemotherapy, including reduction of acute or late xerostomia in patients with head and neck cancer. Studies have reported varying degrees of effectiveness.[8,9] One randomized prospective study reported that intravenous amifostine administered during head and neck radiation therapy reduces the severity and duration of xerostomia 2 years after amifostine treatment, without apparent compromise of locoregional tumor control rates, progression-free survival, or overall patient survival.[10]

Oral antimicrobials may also be of value. For example, chlorhexidine gluconate is a broad spectrum antimicrobial with in vitro activity against gram-positive and gram-negative organisms, yeast, and other fungal organisms. It also has the desirable properties of sustained binding to oral surfaces and minimal gastrointestinal absorption, thereby limiting adverse systemic effects.

Use of chlorhexidine gluconate in the prophylaxis of oral infections shows promise in reducing inflammation and ulceration, as well as in reducing oral microorganisms in high-risk patient groups. Chlorhexidine gluconate 0.12% oral rinse may be used in conjunction with prophylactic topical and systemic antimicrobials in the high-risk patient populations. Chlorhexidine oral rinse has been used in combination with fluoride gel to control cariogenic flora. Chlorhexidine oral rinse may be used as a mouthwash and gargle, but should not be ingested. Commercially marketed formulations may also contain appreciable quantities of alcohol, which may exacerbate xerostomia. This may be particularly important since xerostomia may cause a shift toward a more cariogenic flora.

Dysgeusia can be a prominent symptom in patients who are receiving chemotherapy or head/neck radiation.[11-16] Etiology is likely associated with several factors including direct neurotoxicity to taste buds, xerostomia, infection, and psychologic conditioning.

Patients receiving cancer chemotherapy may experience unpleasant taste secondary to diffusion of drug into the oral cavity. In addition, chemotherapy patients often describe dysgeusia in the early weeks after cessation of the cytotoxic therapy. The symptom in general is reversible, however, and taste sensation returns to normal in the ensuing months.

By comparison, however, a total fractionated radiation dose higher than 3,000 Gy reduces acuity of sweet, sour, bitter, and salt tastes. Damage to the microvilli and outer surface of the taste cells has been proposed as the principal mechanism for loss of the sense of taste. In many cases, taste acuity returns in 2 to 3 months after cessation of radiation. However, many other patients develop permanent hypogeusia. Zinc supplementation (zinc sulfate 220 mg 2 times a day) has been reported to be useful in some patients; the overall benefit of this treatment remains unclear.[17-19]

Cancer patients undergoing high-dose chemotherapy and/or radiation can experience fatigue related to either disease or its treatment.[20] These processes can produce sleep deprivation or metabolic disorders which collectively contribute to compromised oral status. For example, the fatigued patient will likely have impaired compliance with mouthcare protocols designed to otherwise minimize risk of mucosal ulceration, infection, and pain. In addition, biochemical abnormalities are likely involved in many patients. The psychosocial component can also play a major role, with depression contributing to the overall status. (Refer to the PDQ summary on Fatigue for more information.)

Patients with head and neck cancer are at high risk for nutritional problems. The malignancy itself, poor nutrition before diagnosis, and the complications of surgery, radiation, and chemotherapy all contribute to malnutrition.[21] In cancer patients, loss of appetite can also occur secondary to mucositis, xerostomia, taste loss, dysphagia, nausea, and vomiting. Quality of life is compromised as eating becomes more problematic. Oral pain with eating may lead to selection of foods that do not aggravate the oral tissues, often at the expense of adequate nutrition. Nutritional deficiencies can be minimized by modifying the texture and consistency of the diet and by adding more frequent meals and snacks to increase calories and protein. Ongoing nutrition assessment and counseling with a registered dietitian should be part of the patient’s treatment plan.[22]

Many patients who receive radiation therapy alone are able to tolerate soft foods; however, as treatment progresses, most patients must transition to liquid diets using high-calorie, high-protein liquid nutritional supplements, and some may require enteral feeding tubes to meet their nutritional needs. Almost all patients receiving concurrent chemotherapy and radiation therapy will become fully dependent on enteral nutritional support within 3 to 4 weeks of therapy. Numerous studies have demonstrated the benefit of enteral feedings initiated at the onset of treatment, before significant weight loss has occurred.[23,24]

Oral nutrition is reinstituted after treatment has concluded and the radiated site has adequately healed. Oral nutrition often requires a team approach. The assistance of a speech and swallowing therapist to assess for any swallowing dysfunction resulting from surgery or treatment is often necessary and beneficial in easing the transition back to solid foods. The number of tube feedings can be decreased as a patient's oral intake increases, with tube feeding being discontinued when 75% of a patient's nutrition needs are being met orally. Although most patients will resume adequate oral intake, many will continue to experience chronic complications such as taste changes, xerostomia, and varying degrees of dysphagia that can affect their nutritional status and quality of life.[21,22]

References

1. LeVeque FG, Montgomery M, Potter D, et al.: A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients. J Clin Oncol 11 (6): 1124-31, 1993.  [PUBMED Abstract]
   
   
2. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
3. Jellema AP, Slotman BJ, Doornaert P, et al.: Impact of radiation-induced xerostomia on quality of life after primary radiotherapy among patients with head and neck cancer. Int J Radiat Oncol Biol Phys 69 (3): 751-60, 2007.  [PUBMED Abstract]
   
   
4. Seikaly H, Jha N, McGaw T, et al.: Submandibular gland transfer: a new method of preventing radiation-induced xerostomia. Laryngoscope 111 (2): 347-52, 2001.  [PUBMED Abstract]
   
   
5. Epstein JB, Burchell JL, Emerton S, et al.: A clinical trial of bethanechol in patients with xerostomia after radiation therapy. A pilot study. Oral Surg Oral Med Oral Pathol 77 (6): 610-4, 1994.  [PUBMED Abstract]
   
   
6. Rieger J, Seikaly H, Jha N, et al.: Submandibular gland transfer for prevention of xerostomia after radiation therapy: swallowing outcomes. Arch Otolaryngol Head Neck Surg 131 (2): 140-5, 2005.  [PUBMED Abstract]
   
   
7. Scarantino C, LeVeque F, Swann RS, et al.: Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients. J Support Oncol 4 (5): 252-8, 2006.  [PUBMED Abstract]
   
   
8. Buentzel J, Micke O, Adamietz IA, et al.: Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled phase III study. Int J Radiat Oncol Biol Phys 64 (3): 684-91, 2006.  [PUBMED Abstract]
   
   
9. Sasse AD, Clark LG, Sasse EC, et al.: Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys 64 (3): 784-91, 2006.  [PUBMED Abstract]
   
   
10. Wasserman TH, Brizel DM, Henke M, et al.: Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial. Int J Radiat Oncol Biol Phys 63 (4): 985-90, 2005.  [PUBMED Abstract]
    
    
11. Bartoshuk LM: Chemosensory alterations and cancer therapies. NCI Monogr (9): 179-84, 1990.  [PUBMED Abstract]
    
    
12. State FA, Hamed MS, Bondok AA: Effect of vincristine on the histological structure of taste buds. Acta Anat (Basel) 99 (4): 445-9, 1977.  [PUBMED Abstract]
    
    
13. Garrick R: Neurologic complications. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 958-79. 
    
    
14. Fetting JH, Wilcox PM, Sheidler VR, et al.: Tastes associated with parenteral chemotherapy for breast cancer. Cancer Treat Rep 69 (11): 1249-51, 1985.  [PUBMED Abstract]
    
    
15. Marinone MG, Rizzoni D, Ferremi P, et al.: Late taste disorders in bone marrow transplantation: clinical evaluation with taste solutions in autologous and allogeneic bone marrow recipients. Haematologica 76 (6): 519-22, 1991 Nov-Dec.  [PUBMED Abstract]
    
    
16. Mattsson T, Arvidson K, Heimdahl A, et al.: Alterations in taste acuity associated with allogeneic bone marrow transplantation. J Oral Pathol Med 21 (1): 33-7, 1992.  [PUBMED Abstract]
    
    
17. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. Hamilton, Canada: BC Decker Inc, 2003, pp 113-28. 
    
    
18. Ripamonti C, Zecca E, Brunelli C, et al.: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 82 (10): 1938-45, 1998.  [PUBMED Abstract]
    
    
19. Silverman JE, Weber CW, Silverman S Jr, et al.: Zinc supplementation and taste in head and neck cancer patients undergoing radiation therapy. J Oral Med 38 (1): 14-6, 1983 Jan-Mar.  [PUBMED Abstract]
    
    
20. Visser MR, Smets EM: Fatigue, depression and quality of life in cancer patients: how are they related? Support Care Cancer 6 (2): 101-8, 1998.  [PUBMED Abstract]
    
    
21. Robinson CA: Enteral nutrition in adult oncology. In: Elliott L, Molseed LL, McCallum PD, eds.: The Clinical Guide to Oncology Nutrition. 2nd ed. Chicago, Ill: American Dietetic Association, 2006, pp 138-55. 
    
    
22. Kagan SH, Sweeney-Cordes E: Head and neck cancers. In: Kogut VJ, Luthringer SL, eds.: Nutritional Issues in Cancer Care. Pittsburgh, Pa: Oncology Nursing Society, 2005, pp 103-16. 
    
    
23. Beer KT, Krause KB, Zuercher T, et al.: Early percutaneous endoscopic gastrostomy insertion maintains nutritional state in patients with aerodigestive tract cancer. Nutr Cancer 52 (1): 29-34, 2005.  [PUBMED Abstract]
    
    
24. Tyldesley S, Sheehan F, Munk P, et al.: The use of radiologically placed gastrostomy tubes in head and neck cancer patients receiving radiotherapy. Int J Radiat Oncol Biol Phys 36 (5): 1205-9, 1996.  [PUBMED Abstract]
    
    

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