Parotid gland function during and following radiotherapy of malignancies in the head and neck. A consecutive study of salivary flow and patient discomfort.

Radiotherapy of tumours in the head and neck region usually involves the salivary glands in the treatment volume with ensuing dryness and discomfort. In the present study, a prospective evaluation of the same patients were performed before, during radiotherapy and 6, 12 and 18 months after the end of treatment. Three different groups were outlined, one receiving doses not exceeding 45 Gy, another 47-52 Gy and a third group treated with doses over 64 Gy. All but one of the patients receiving doses less than 52 Gy showed a recovery of secretion beginning after 2 months with a continuous improvement of the salivary flow up to 18 months. Doses exceeding 64 Gy caused irreversibly depressed parotid function in the vast majority of glands. The subjective experience of discomfort with dry mouth was not at all correlated to the initial flow rate. Treatment with unilateral technique and doses below 52 Gy caused just no or slight dryness and 3 out of 4 patients with bilateral involvement of the glands displayed problem with subjective dryness even after 18 months. Doses over 64 Gy with one gland involved had only slight dryness, however, patients with both glands affected showed severe problems with dryness. It has to be emphasised that there were relatively large interindividual differences with respect to salivary flow and discomfort of dryness. It is obvious that these patients need a careful dose planning and a close follow up with co-operation between radiotherapeutists and dentists.

Can alpha-tocopherol and beta-carotene supplementation reduce adverse radiation effects on salivary glands?

In this study, we evaluated whether supplementation with antioxidant vitamins can reduce the adverse effects of irradiation on the salivary glands in the rat. Four groups of adult Sprague-Dawley rats were given a basic diet providing 0.6 mg alpha-tocopherol and no beta-carotene per day. In two groups the basic diet was supplemented with 3.4 mg alpha-tocopherol and 6 mg beta-carotene per day from 14 days before irradiation until 12 days after completed irradiation. One group of rats given basic diet and one group given supplemented diet were irradiated with 7 Gy daily for five consecutive days. Isoproterenol and pilocarpine-stimulated whole saliva was collected from all rats 2, 4 and 26 weeks after irradiation. Vitamin-supplemented irradiated rats had higher secretion rates on all three occasions compared with those of irradiated rats given basic diet. The changes in saliva composition seen in irradiated rats were less accentuated in vitamin-supplemented, irradiated rats. The proportions of acinar cells were significantly decreased both in parotid and submandibular glands 26 weeks after irradiation. Supplementation with alpha-tocopherol and beta-carotene did not alter the morphology of the glands.

Bilateral irradiation of head and neck induces an enhanced expression of substance P in the parasympathetic innervation of the submandibular gland.

Substance P and calcitonin gene-related peptide (CGRP) are present in nerve fibers innervating the submandibular gland. Radiotherapy of tumors in the head and neck region usually embraces the salivary glands in the irradiated field and consequently a dramatic decrease in salivary function is seen. In this study, the submandibular glands and ganglia of rats subjected to fractionated irradiation were examined by use of immunohistochemical techniques for demonstration of substance P and CGRP. Irradiation was given on five consecutive days (daily doses of 6-9 Gray) with unilateral or bilateral irradiation techniques. Specimens of control and experimental animals were processed in parallel. A marked increase in the expression of substance P in the ganglionic cells--presumably parasympathetic--and in the number of fibers showing substance P-like immunoreactivity in association with acini and small ducts was seen in response to bilateral irradiation. (Surprisingly, unilateral irradiation of the parotid area had no effect on peptide distribution in the irradiated gland and ganglion). No changes in the pattern of CGRP immunoreactivity occurred. In the trigeminal ganglion, which supplies the submandibular gland with the majority of the sensory substance P- and CGRP-containing nerve fibers, no changes in the expression of substance P or CGRP immunoreactivity were seen. The results suggest that bilateral irradiation leads to an increase in the synthesis of substance P-like substance in the parasympathetic ganglionic cells supplying the submandibular gland with secretory nerves, and can thus be an additional factor in explaining the altered secretory capacity of salivary glands.

External radiation of the parotid glands significantly reduces drooling in patients with motor neurone disease with bulbar paresis.

The parotid glands and part of the submandibular glands were irradiated in 18 amyotrophic lateral sclerosis patients with very advanced disease and severe drooling problems. In a prospective study, a single dosage of 7.0-7.5 Gy was administered bilateral to the larger part of the parotid glands and the posterior parts of the submandibular glands. Salivary secretion rate was assayed before and after radiotherapy. Sixteen out of eighteen patients reported satisfactory to good reduction in drooling lasting up to 4-6 months, 1/18 developed xerostomia and needed saliva substitutes, and 1/18 reported no effect. Caregivers reported positive effect in all patients. The procedure was well tolerated with few side effects. Low dosage external radiotherapy of the salivary glands is effective in reducing drooling satisfactorily in ALS patients, especially in well-hydrated patients.

Parotid saliva composition during and after irradiation of head and neck cancer.

Parotid saliva composition was studied before, during and up to 18 months after the irradiation period in 16 cancer patients treated for malignancies in the head and neck region. Stimulated parotid saliva was collected prior to radiotherapy and, when possible, weekly during treatment. New samples were taken 2, 4, 6, 12 and 18 months after the end of radiotherapy. Nine of the 16 patients were treated with bilateral irradiation fields and 7 patients with unilateral irradiation fields, with a total dose not exceeding 52 Gy. During the entire irradiation period the fraction of glands producing measurable volumes of saliva decreased to 40%. In the postirradiation period the number of active glands gradually increased and saliva secretion rate returned to an average of 72% of the initial value 18 months after the end of irradiation. The concentrations of the measured variables increased already during the first week of radiotherapy and at the end of the treatment period the concentrations for total protein, salivary peroxidase, hexosamine and salivary IgA were significantly increased. The concentrations for total protein, salivary peroxidase and salivary IgA were still increased 6 months after the end of irradiation. At the 18-months observation all concentrations had returned to normal, as evaluated in a paired t-test. The majority of glands irradiated with 40-52 Gy recovered not only in secretion rates but also with respect to the components studied in this investigation.

Acute radiation effects on saliva composition in rats with different vitamin A levels in serum.

Irradiation of the head and neck often causes loss of salivary gland function which may lead to severe oral discomfort. The effects of a single dose of 25 Gy given to rats with different serum levels of vitamin A were studied. The salivary secretion rate as well as concentrations of protein, hexosamine, amylase and electrolytes, and the activities of two antibacterial glycoproteins were measured. At an adequate level of vitamin A in the diet, irradiation significantly reduced whole saliva secretion rate, and decreased the concentration of salivary sodium, calcium and hexosamine as well as the activity of a glycoprotein agglutinating a serotype c strain of S. mutans. Peroxidase, amylase and potassium were not significantly affected. The reductions seen at an adequate level of vitamin A were not reduced by supplementation of excess dietary retinol. The damage caused by irradiation was enhanced by vitamin A deficiency as seen in the reduced protein and hexosamine concentrations.

[Radiation of parotid glands for salivary flow reduction in amyotrophic lateral sclerosis]. / Naruzhnoe obluchenie okoloushnykh zhelez dlia umen'sheniia sliunotecheniia pri bokovom amiotroficheskom skleroze.

Radiation of the parotid and submandibular glands was performed in 18 patients with pronounced hypersalivation at a late stage of amyotrophic lateral sclerosis (ALS). Single bilateral radiation of the parotid and posterior submandibular glands was made in the dosage of 7.0-7.5 Gy. Salivation volume was measured before and after the radiation therapy. Sixteen patients exhibited satisfactory and marked salivary flow reduction during 4-6 months. Xerostomia developed in 1 patient who needed assignment of artificial salivary substitute and 1 patient did not respond to the therapy. The patient's caregivers reported a positive effect in all the cases. Tolerance of the therapy was good except rare side effects. Radiation of the parotid glands significantly reduced salivary flow in ALS, especially in patients receiving an adequate amount of water.

Fractionated irradiation and early changes in salivary glands. Different effects on potassium efflux, exocytotic amylase release and gland morphology.

Irradiation is a potent treatment modality of head and neck cancer. However, the irradiation is usually associated with an influence on salivary glands with ensuing dryness and discomfort for the patients. In the present study we used different in vitro secretory models and morphologic characterization of rat parotid gland. Radiation was given to one gland on a 5-day schedule with 6 MV photons (total dose 20, 30, 35, 40, 45 Gy). The contralateral gland served as control, and the analysis of glands were performed 10 days after the last irradiation treatment. The noradrenaline stimulated electrolyte secretion (86rubidium tracer for potassium) was decreased in relation to the irradiation dose and in comparison to contralateral control glands. Noradrenaline stimulated exocytotic amylase release was not affected by irradiation and, there were no signs of obvious quantitative morphologic alterations after irradiation compared with controls. The results suggest that there are differences in the sensitivity to radiation for the two different secretory processes in salivary glands, and, thus, the structures regulating electrolyte and fluid secretion seem to be more vulnerable to irradiation than the process of exocytosis. The results, however, do not allow discrimination between temporary cellular impairment and irreversible damage leading to cell death.

Dietary intake in head and neck irradiated patients with permanent dry mouth symptoms.

Radiotherapy of the head and neck region, which includes the major and minor salivary glands in the radiation field, usually leads to temporary or permanent xerostomia. This may affect eating and increase the risk of inadequate intake of energy and nutrients. The aim of the present study was to investigate the effects of radiotherapy-induced xerostomia on energy and nutrient intake in individuals treated for malignancies in the head and neck region. The dietary intake of 24 patients with a low chewing stimulated whole saliva flow rate (< 0.5 ml/min) and in age and sex matched controls with normal flow rate (> 1.0 ml/min) was recorded for 7 days. The average daily energy intake was nearly 300 kcal lower in the irradiated patients with dry mouth symptoms than in the control group. The mean intake in the former group was 1925 kcal per day whereas the control group had an intake of 2219 kcal per day. Irradiated patients with dry mouth symptoms had significantly lower mean intakes of vitamin A, beta-carotene, vitamin E, vitamin B6, folacine, iron and zinc than those in the control group. There was also a lower intake of vitamin C, but this was not statistically significant. The intake of vitamins A and C exceeded or reached the levels recommended in the Swedish Nutritional recommendations, but the average intakes of fibre, iron, beta-carotene, vitamin E, zinc, selenium, and iron did not reach recommended levels, in neither the experimental nor the control group. There was a slight positive correlation between energy intake and saliva secretion rate in the control group, but the energy intake was totally independent of variations in secretion rate in the irradiated patients with low secretion rate.

Rat salivary gland function after fractionated irradiation.

The aim of this study was to investigate longitudinal effects of fractionated irradiation, with various total doses, on salivary gland function in the rat. Female Sprague-Dawley rats were irradiated with 4, 5, 6, 7 or 8 Gy per day on five consecutive days. Irradiation was given to the head and neck region. Whole saliva was collected before and 2, 15 and 26 weeks after irradiation. In general the effects of irradiation on salivary gland function were found to be related to dose and time after exposure. Secretion rates were significantly decreased two weeks after irradiation with doses of 30 Gy or higher, after 15 weeks with 25 Gy or higher, and after 26 weeks with 20 Gy or higher. Response patterns to irradiation differed between the salivary constituents. Thus, the conclusions from this study are that early and late effects display different patterns and that the model used to study variations in salivary gland function after fractionated irradiation must be adjusted to the question addressed.

Does bombesin-like peptide mediate radiation-induced anorexia and satiety?

Bombesin (BN) and its mammalian counterpart gastrin-releasing peptide (GRP) act as neuroregulatory hormones and peripheral and central satiety-inducing agents. Previously, we demonstrated that irradiation induces an increase in the expression of BN/GRP in the innervation of the salivary glands in rats. We therefore carried out a study using radioimmunoassay (RIA) analysis and immunohistochemistry to examine whether saliva contains BN and whether irradiation affects the BN release to saliva in rats. Immunoreactivity for BN was detected not only in the innervation of the parenchyma but also in the duct cells and in the lumina of the ducts, suggesting entrance of BN into saliva. The RIA analysis confirmed that rat saliva contains a BN-like peptide. The observation shows that saliva contains this peptide but that there is no significant increase following the radiation schedule used. Nevertheless, the occurrence of an enhanced expression of BN in different peripheral tissues such as the salivary and laryngeal glands should be taken into consideration when discussing the clinically important problem of reduced food intake and anorexia in cancer patients.