RADIATION THERAPY - Side Effects and Complication in Head and Neck Treatment. Abeloff: Clinical Oncology, 2nd ed Xerostomia (Dry Mouth) The major salivary glands (parotid, submandibular, and sublingual) produce most of the salivary secretion (up to 80 percent). The rest of the saliva is produced by minor glands scattered throughout the oral cavity. It is estimated that the sublingual glands contribute only 2 to 5 percent of the salivary flow rate. Submandibular glands seem to be as important or more important than parotids in the resting state, although parotid glands become the main contributors under stimulation. When radiation therapy treatment fields include the major salivary glands, many patients will experience dryness of the oral mucosa during the first 1 or 2 weeks of treatment. Not only is the quantity of saliva reduced, but its composition and physical properties are changed as well. Drastic reductions of baseline and reflex production of alkaline and watery secretions of serous acini often persist after the completion of radiation therapy. Without appropriate management, this problem can lead to progressive deterioration of the teeth, mucosa, gingiva, and mandible. PREVENTION AND THERAPY OF RADIATION-INDUCED XEROSTOMIA There are no clinically proven effective agents currently available for the prevention of radiation-induced xerostomia. A placebo-controlled clinical trial is currently accruing patients to investigate the utility of pilocarpine for this. Amifostine is also being evaluated currently. For the treatment of established radiation-induced xerostomia, the following are recommended: Pilocarpine: 5.0 mg PO tid-qid, up to 10 mg PO tid maximum Artificial saliva (Mouthkote, Xerolube, Moistir, Salivert, Sage) Biotene products (gum, toothpaste, mouthwash) The acute radiation response of serous salivary glands has been shown to be due to interphase killing of serous cells. Chronic atrophy of these glands is attributed to the death of the reproductive stem cells and damage to the fibrovascular stroma.Marks   have documented a progressive reduction in salivary flow rates, pH, and secretory immunoglobulin A (IgA) with increasing doses of radiation therapy. These investigators clearly demonstrated a dose response regarding the late effect of radiation on parotid salivary flow. Nine of 10 parotid glands that received less than 1,000 cGy continued to secrete measurable quantities of saliva after stimulation by sour grape drops. This was reduced to 4 of 8 after 3,000 cGy, 3 of 16 after 5,000 cGy, and 0 of 24 after 7,000 cGy. Franzen  found that 15 of 16 patients receiving doses of less than 5,200 cGy showed recovery of secretion beginning 2 months after treatment with continual improvement of the salivary flow up to 18 months. Doses exceeding 6,400 cGy caused irreversibly depressed parotid function in the vast majority of glands. Patients receiving doses of more than 6,400 cGy to one gland only had slight dryness; however, patients with both glands irradiated showed severe problems with salivary flow and discomfort of dryness.  Mira  showed that exclusion of more than 50 percent of both parotids from the direct radiation beam can prevent severe dryness when the rest of the major salivary glands are included in the field. Mira  also reported that patients with high pretreatment salivary flow rates develop less dryness following a particular dose of radiation therapy or treatment volume than patients with low pretreatment flow rates. These workers found that the decrease in flow rate after radiation follows an exponential decay curve. A given dose of radiation therapy reduces flow by approximately the same percentage.  For example, a patient whose initial salivary flow rate is 0.2 ml/min would require reduction by only 50 percent to reach a minimal flow rate of 0.1 ml/min, while patients whose flow rate is 1.0 ml/min would require a 90 percent reduction to reach the same minimal flow rate. The latter patient would require approximately three times as much radiation as the former patient to obtain a minimal flow rate. These same investigators showed that when almost all salivary tissue is irradiated, a dose of 3,500 to 4,000 cGy was capable of inducing minimal flow in patients with high initial flow rates; and that 500 to 1,500 cGy resulted in minimal flow rates in patients with low initial flow rates. Patients in whom minimal flow rates were induced during radiation therapy showed no recovery of flow for up to 17 months after treatment. Age also appears to be an important factor related to the degree of xerostomia after radiation therapy, as young patients are more likely than older patients to recover salivary flow. Prevention and Treatment of Xerostomia Treatment of radiation-induced xerostomia includes the avoidance of any drugs that may also decrease the flow of saliva and contribute to the discomfort of xerostomia. These drugs may include anorectic agents, anticholinergics, antidepressants, antihistamines, antihypertensives, antipsychotics, antiparkinsonian agents, diuretics, caffeine, nicotine, hypnotics, and sedatives. Patients should be advised to take frequent sips of water and suck on ice chips. Since chewing stimulates the flow of saliva, patients with a residual salivary function may be helped by eating foods such as carrots or celery or by chewing sugarless or xylitol-containing gum. Patients with xerostomia are highly susceptible to dental caries and should not use sugar-containing foods or acidic foods or beverages to stimulate salivary flow. Commercial nonprescription solutions used to lubricate the oral tissues may be the only effective treatment for patients without functioning salivary gland parenchyma or whose salivary glands do not respond to stimulation. Virtually all lubricants can provide some short-term relief for patients with xerostomia. Some studies have found that salivary substitutes containing carboxymethylcellulose or hydroxymethylcellulose are more effective in relieving dryness than water- or glycerin-based solutions. Some patients prefer mucopolysaccharide solutions. Xerostomia primarily affects mastication and oral manipulation of dry, absorbent food material. Initiation and duration of the pharyngeal swallow do not appear to be affected.   Patients with severe xerostomia may be helped by eating soft, bland foods, especially cool or cold foods with a high liquid content such as ice cream, popsicles, puddings, watermelon, and grapes. Solid foods can be made easier to swallow by adding gravies, sauces, melted butter, broths, mayonnaise, yogurt, or salad dressing. Dunking bread and other baked foods in milk, tea, or coffee will make them easier to swallow. Some patients may find a pureed diet or a full-liquid diet easier to swallow than solid foods. Adding a liquid high-protein supplement will help ensure that patients are getting enough protein and calories. Hot, spicy, or acidic foods may be irritating and should be eaten with caution. Some patients find that a vaporizer or humidifier in the room, or at the bedside, helps with the discomfort of xerostomia. Frequent oral rinses with an alkaline saline solution may help refresh the taste, moisten the mouth, and promote better hygiene. Two large randomized, double-blind, placebo-controlled, multicenter clinical trials have documented the efficacy of oral pilocarpine (5.0 mg PO tid) in improving salivary flow, oral dryness, mouth comfort, ability to speak, and reduction in the use of oral comfort agents in the post-head- and neck-irradiation setting. Adverse reactions are minimal, the most common being mild to moderate sweating which is dose related. Best results may require continuous treatment for more than 8 weeks.  Most patients report a significant relief of symptoms of xerostomia and improvement in quality of life that does not appear to be dependent upon previous radiotherapy dose/volume parameters, suggesting that oral pilocarpine acts primarily by stimulating ectopic salivary glands and can be of benefit to a whole range of patients suffering from varying severities of xerostomia.  Topical pilocarpine administration has shown results similar to those of systemic treatment but with improved patient tolerance.  One small retrospective trial and one small double-blind, placebo-controlled, randomized trial suggest that pilocarpine (5.0 mg PO qid) started the day before or the same day as radiation therapy, given concurrently with radiation therapy and for 3 months following radiation therapy, results in a lower frequency of oral symptoms and xerostomia during treatment and afterwards. It may not be necessary to continue the use after 3 months to maintain the benefit. Amifostine, as discussed above, appears to protect the salivary glands from the effects of radiation therapy and may prove helpful in preventing or minimizing the effects of xerostomia and loss of taste. In the future, altered radiation therapy fractionation schemes may lead to better preservation of salivary gland function. Leslie  evaluated the function of parotid glands in patients treated by three different radiation therapy schedules 9 or more months after completion of treatment. All patients received radiation therapy confined to one side of the head and neck region, so that the contralateral salivary gland could act as an internal control. Saliva was selectively collected from the parotid glands, and the stimulated flow rate and pH of the saliva were determined bilaterally. Twelve glands that had received conventionally fractionated radiotherapy to a dose of 60 to 66 Gy showed a mean percentage flow of 20 percent and a significant fall in saliva pH. Six glands that had received continuous hyperfractionated accelerated radiation therapy showed mean percentage flows of 65 percent with only slight and nonsignificant falls in saliva pH. These results suggest that treatment of squamous cell carcinoma of the head and neck using a continuous hyperfractionated and accelerated radiation therapy fractionation scheme can lead to improved function of the irradiated parotid gland. These results were attributed to the lower dose per fraction used with subsequent greater repair of sublethal damage between treatment fractions.