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The role of radiation therapy in the management of sialorrhea
Int. J. Radiation Oncology Biol. Phys., Vol. 41, No. 5, pp. 1113–1119, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/98 $19.00 1 .00
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Clinical Investigation THE ROLE OF RADIATION THERAPY IN THE MANAGEMENT OF SIALORRHEA MARTIN BORG, M.D., F.R.A.C.R.*
AND
FRED HIRST, M.B.B.S., M.R.C.P. (U.K.)†
*Department of Radiation Oncology, Adelaide, South Australia,; and †Director, Services for the Elderly, Palmerston North Hospital, New Zealand Purpose: Sialorrhea is the unintentional loss of saliva and other contents from the mouth. Most patients with this condition are elderly, requiring palliative treatment. These patients have neuropathology with associated poor performance status. Treatment prescribed for this disabling and distressing condition has often been of a surgical nature and described in young patients. It would be inapplicable to the elderly. The aim of this study was to review the role of radiation therapy in the management of sialorrhea. Previous reports are few in number and are cautionary because of adverse effects which have been described, including dryness of the mouth. Methods and Materials: A total of 34 patients were referred to the Department of Radiation Oncology, Palmerston North Hospital, between 1966 and August 1994, of whom only 1 patient received treatment prior to 1985. Three patients declined treatment and were, therefore, excluded from this review. Thirty-one patients, including 14 males and 17 females, of median age 72 years received 1 or more radiation treatments for sialorrhea. The patients were followed up for a median of 12 months, ranging from 6 months to 27 years. Results: Initially, 82% (28/34) of treatments were associated with a satisfactory response. Six patients relapsed, of whom five experienced relapse within 6 months of initial treatment. Two patients were re-treated, one of whom achieved a complete response. Up to the time of review 64% (23/36) of treatments maintained a satisfactory response. The varied fractionation regimens used were not shown to affect the response rate; low doses were shown to be as effective as higher doses, and were not associated with any significant acute or late side effects. Only 4 patients developed long-term side effects. However, response rates were superior for patients treated with electrons, as opposed to orthovoltage therapy, and in particular when electron energies greater than 7 megavolts were used (76% vs. 38% maintained response, p < 0.05). Responses were also superior for patients treated with radiation fields which encompassed both parotid and submandibular glands (74% vs. 33% maintained response, p < 0.01). Conclusions: Radiation therapy has proven to be a safe and effective treatment in this group of patients, thereby avoiding the adverse effects of anticholinergic medication and invasive surgical procedures. © 1998 Elsevier Science Inc. Sialorrhea, Radiotherapy, Major salivary glands.
the secretion of the parotid and submandibular glands (7, 8). There are very few reports in the literature describing the use of radiation therapy in the treatment of sialorrhea secondary to nonmalignant causes (9). This study aimed to evaluate the role and effectiveness of radiation therapy in the management of sialorrhea in nonmalignant disease.
INTRODUCTION Sialorrhea (excessive salivation or chronic drooling) is defined as the unintentional loss of saliva and other contents from the mouth. The term implies excessive secretion of saliva, which may be considered an antisocial behavior, the expression of which can impede successful integration into the community (1–3). The treatment of sialorrhea varies, depending on its etiology, and involves a number of professionals including speech therapists, plastic surgeons, geriatricians, and neurologists (3, 4). More than 75% of the 1.5 liters per day of salivary secretion is produced by the major paired salivary glands (5, 6). Radiotherapy to the posterior oral cavity encompassing the major salivary glands generally induces dryness of the mouth as a result of its effect on
MATERIALS AND METHODS The records of all patients referred to the Radiotherapy Department at Palmerston North Hospital, New Zealand, between 1966 and August 1994, with a diagnosis of sialorrhea, were reviewed retrospectively. Only 1 of these patients received treatment prior to 1985. Thirty-four patients were referred, of whom 3 declined treatment and were,
Reprint requests to: Dr. Martin Borg, Department of Radiation Oncology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia Acknowledgments—We are indebted to colleagues (past and
present) at Palmerston North Hospital for allowing us to include their patients in this review. Accepted for publication 20 April 1998. 1113
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Fig. 1. Age of 31 patients treated with radiotherapy.
therefore, excluded from this review. The 31 patients in the study comprised 14 males and 17 females, of median age 72 years (range 24 – 88 years, Fig. 1), whose performance status, where known, was generally poor. Fourteen patients were of ECOG (Eastern Cooperative Oncology Group) performance status 3 or more, and 10 of EGOC status 2 or less. The performance status of 8 patients was not recorded. Table 1 lists the various medical conditions associated with sialorrhea in this group of patients. The patients were all referred following failure of alternative medical treatment modalities, although none of the patients had undergone surgical treatment prior to referral to the Radiotherapy Department (Table 2). Patients were followed for a median of 12 months (mean 39 months), ranging from 6 months to 27 years. Twenty-seven treatments were delivered to bilateral parotid and submandibular glands through separate, ipsilateral fields, the field size varying from 7 cm 3 7 cm to 10 cm 3 8 cm. Nine treatments were delivered to smaller fields encompassing a portion of both parotid glands, the field size ranging from 5 cm 3 5 cm to 7 cm 3 6 cm. Two patients received treatment on more than one occasion. There was a
wide variation in the radiation technique used. Twentyseven treatments were delivered with electrons (the energy ranging from 6 –18 megavoltage electrons, MeV, the dose prescribed to the 90% isodose) and eight treatments were delivered with orthovoltage therapy (200 –250 kilovoltage, the dose prescibed to the surface) (Tables 3 and 4). The dose, dose per fraction, and overall treatment time varied considerably between the various regimens (Table 5). Complete responses (C) were noted in patients achieving complete salivary control; that is, with complete resolution of dribbling and absence of soiling of clothes. Partial responses (P) were recorded in those patients with improved but not complete salivary control, where dribbling did not interfere with the patient’s quality of life and where garments did not have to be changed because of soiling. Patients who continued to complain of excessive drooling, such that this interfered with their quality of life and where upper garments had to be frequently changed, were recorded as nonresponders (N). Results between treatment modalities were compared using the chi-square test and log-rank significance levels (10,11).
Table 2. Preradiotherapy treatment Table 1. Medical condition of 31 patients treated with radiotherapy Medical condition
Number
Noninfective parotitis Congenital/birth trauma Motor neuron disease Parkinson’s disease Alzheimer’s disease Postcerebrovascular accident (post-CVA) Quadriplegia/paraplegia (other than CVA) Friedreich’s ataxia
2 2 2 7 2 13 2 1
Treatment modality
Number
Surgery Medical Suction drainage Physiotherapy Anticholinergics Failed Side effects Declined Unknown Antibiotics (for parotitis)
None 2 28 22 17 4 (stopped) 1 7 2
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Table 4. Depth dose characteristics for orthovoltage beams
Table 3. Depth dose characteristics for electron beams 2
Phillips, KV (5 cm2 field) Depth (mm)
Phillips SL 75, MeV (6 cm field) Depth (mm) % Depth dose
6 MeV
7 MeV
9 MeV
12 MeV
13 MeV
15 MeV
18 MeV
90 80 50
18 20 25
22 25 29
29 33 40
35 41 44
37 43 50
39 45 56
45 52 66
RESULTS Initially, 34 treatments were delivered resulting in 18 complete responses and 10 partial responses. Four patients did not respond to treatment. The responses in the remaining 2 cases were recorded as unknown as these 2 patients were lost to follow-up. For the purposes of statistical analysis these were recorded as nonresponders. Therefore, initially 28 treatments achieved a satisfactory response (82%, 28/ 34). Six patients relapsed of whom two were re-treated, one achieving a complete response and the second no response at all, so that at the time of this review 23 treatments (64%, 23/36) resulted in a satisfactory (maintained) response to radiotherapy (Table 5). Although the majority of the patients were followed for a relatively short period of time, 5 of the relapses occurred within 6 months. One other patient relapsed at 5 years, at the time of progression of the underlying disorder (motor neuron disease). The duration of response varied according to the patients’ underlying medical illness and advanced age (Fig. 2). Responses were tabulated against the different fractionation regimens used. No correlation was found between these regimens and the response rates (Table 5). However, when responses were compared against the radiation technique used, response rates were found to be superior for patients treated with electrons, in particular when an electron energy greater than 7 MeV was used (76 vs. 38%; Tables 6 and 7). The difference was statistically significant (p , 0.05, x2 5 4.04, confidence limits of 59 –93%). Responses were also superior for patients treated with field sizes of 7 cm 3 7 cm, or greater, where both parotid and submandibular glands were encompassed by bilateral radiation portals (74 vs. 33%, p , 0.01, x2 5 5.56, confidence limits of 58 –99%; Table 8). Treatment was, in general, well tolerated. Eight patients reported acute side effects, including 1 oral candidiasis, 8 mild skin reactions and 1 mild mucositis. Four patients developed persistent late effects, including 3 with troublesome thick secretions and 1 with temporomandibular joint fusion. At the time of review, 15 patients had died of their underlying illness. None of the deaths were treatment-related. DISCUSSION Several nonmalignant conditions lead to the development of sialorrhea, some of which are listed in Table 1. These
% Depth dose
200 KV
220 KV
250 KV
90 80 50
16 27 57
17 28 58
17 28 60
conditions are usually associated with poor oral motor control which causes an open-mouth posture, impaired eating ability, problems with communication, and constant drooling of saliva (2, 3). Some authors suggest that sialorrhea develops as a result of impaired swallowing and lip closure (2). However, it is also believed that a component of sialorrhea is due to excessive salivation, as in children with cerebral palsy and in adults with hemiplegia (2, 12). Sialorrhea leads to problems with articulation, feeding, swallowing, aspiration, reading, computers, loss of self-esteem and, eventually, social isolation. Such patients must put up with constant soiling of clothes and linen, the presence of an offensive odor, and excoriation of skin (2, 12). Specific treatment for sialorrhea is thus essential, both for the patient and the caregiver to improve the quality of life and social interaction. Several methods of treatment have been recommended in the literature. The ability to measure the response to treatment is limited because of the difficulty in quantifying the amount of drooling and the many factors that affect salivary secretion such as the size of the salivary gland, sex, age, diurnal rhythms, mechanical and gustatory stimulation, emotional state, and posture (3, 5, 13, 14). Several authors have attempted to quantify the extent of excessive salivation by using scales of severity, volume of drooling, or frequency of drooling (3, 4, 15, 16). One such classification subdivides patients into mild (saliva dripping on to lip but not beyond vermilion), moderate (where saliva reached the skin), and severe (where saliva drips on to clothing, books, papers, and so on). This group of patients, often children, also usually suffers from severe speech impairment (15). In this review, patients were subdivided into 3 groups according to their response to treatment (complete, partial, and nonresponders). The management of this condition varies with the underlying cause, and involves several professionals from various disciplines. Treatment is reportedly most successful in young children, where maturation of oral function may occur, and in older children and adults with relatively mild salivary control problems (12). It is thus not surprising to note quite a variation in the treatment modalities recommended and/or used in the management of this condition, either alone or in combination. Patients reviewed in this study also received a variety of treatments prior to referral for consideration of radiation therapy (Table 2). The data available from the literature generally reflects the bias of the authors and there is little randomized data to support or
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Table 5. Responses to fractionated regimens used in the treatment of sialorrhea Response (36 treatments)# Fractionation regimen 15 20 24 18 30 30 39 42 40 44 10 6 12
Gy/5 fractions 3 3 Gy (daily) Gy/5 fractions 3 4 Gy (daily) Gy/6 fractions 3 4 Gy (daily) Gy/3 fractions 3 6 Gy (1 fraction weekly) Gy/6 fractions 3 5 Gy (3 fractions weekly) Gy/10 fractions 3 3 Gy (daily) Gy/13 fractions 3 3 Gy (daily) Gy/14 fractions 3 3 Gy (daily) Gy/11 fractions 3 3.63 Gy (daily) Gy/22 fractions 3 2 Gy (daily) Gy/12 fractions 3 0.83 Gy (daily) Gy/1 fraction (1 fraction weekly) Gy/2 fractions 3 6 Gy (1 fraction weekly)
C (19)
P (10)
N (5)
R (6)
UNK (2)
Percentage response C 1 P maintained# (23/36 treatments)
1 5 1* 2 2# 3 1 — — 1 2 — 1
2 1 1 — 1* 2* — 1* — — — 1 1*
1 1 1# — 1 — — — 1 — — — —
— — 1* — 1* 2* — 1* — — — — 1*
— — — 1 — — 1 — — — — — —
75 86 33 100 50 60 100 0 0 100 100 100 50
Abbreviations: C 5 complete; P 5 partial; N 5 none; R 5 relapse; UNK 5 unknown (lost to follow-up). * Denotes relapse. # Two patients re-treated.
refute the authors’ conclusions (9, 14, 17). Some of the commonly recommended therapies include: 1. Anticholinergic medication—Twenty-two patients included in this review received this treatment. However, these drugs need to be taken over a prolonged period of time, and may contribute to polypharmacy problems which are common with elderly patients. Anticholinergics are poorly tolerated and are commonly associated with adverse reactions and symptomatic relief which is often only temporary (18, 19). 2. Various surgical procedures including parotidectomy (superficial or total), denervation procedures, and salivary duct transposition. Complications secondary to these procedures may arise as a result of the underlying
etiology, patient’s age and general medical condition. Parotidectomy may also lead to facial nerve palsy. Other surgical procedures include neuroablative procedures such as parasympathetic denervation via tympanic nerve resection, in association with division of the chorda tympani nerve, with inevitable loss of taste in the anterior two-thirds of the tongue, and transposition of the salivary ducts and orifice to the pharynx. Various reports suggest that over 80% of patients undergoing a surgical procedure would benefit, but most of these would have been referred after failed conservative treatment. They would also generally be young, otherwise fit patients in whom one would wish to avoid the use of radiation therapy (14, 20, 21). In the more common conditions as
Fig. 2. Duration of response to radiation therapy up to time of review.
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Table 6. Responses by radiation technique— electron therapy Electrons (MeV) (28 treatments) 6, 7 9 12, 13 15 18 C 1 P (initial) C 1 P (maintained)* C 1 P (maintained)* excluding 6, 7 MeV electrons
C
P
— 4* 8 2 3
2 1 1 1 2
N
R
— 1 1 — 1 2 — 1 — — 82% (23/27) 71% (20/28)
UNK 1 1 — — —
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Table 7. Responses by radiation technique— orthovoltage therapy Orthovoltage (KV) (8 treatments) 200 220 250 C 1 P (initial) C 1 P (maintained)*
C
P
2 — —
1 — 2
N
R
— 1 1 — 2* 1 71% (5/7) 38% (3/8)
UNK — — —
For definition of abbreviations, see Table 5. * One patient re-treated. 76% (19/25)
For definition of abbreviations, see Table 5. * One patient re-treated.
listed in Table 1, these procedures would be inappropriate, likely to be declined by the patient, or these patients would be considered too unfit to undergo a surgical procedure (2, 3, 18, 20). None of the patients in this study were referred following a surgical procedure, reflecting the elderly group of patients reviewed, a large proportion of whom were of poor performance status. This may also be due to physician bias. 3. Compression bandages, which are generally recommended in patients where the underlying cause is a fistula (3, 22). None of the patients in this study suffered from this condition. 4. Behavioral modification, physiotherapy, oral appliances, and occupational, physical, and speech therapy. This therapy would aim to enhance head control, improve muscle tone, and stabilize the relation of body position. It is probably the least traumatic of recommended therapies and usually is a component of the patient’s overall general management in combination with other treatments (2). 5. Radiotherapy—Very few reports in the literature refer to the use of this modality in the treatment of sialorrhea, and usually unfavorably (2, 14, 23). Certainly, it should be avoided in children, because of the risk of inducing malignancy and arresting normal growth, thereby leading to facial asymmetry, dental caries, and osteonecrosis. The latter risks may be avoided with the use of lower doses of radiation therapy. The largest review of the use of radiation therapy in this setting (that of 9 patients) reported no long-term side effects after a median follow-up of 33 months, although other authors felt this to be a relatively short period of follow-up (2, 9). However, most patients referred for radiation treatment are elderly, with limited life expectancy and are, therefore, not expected to develop long-term side effects. Twenty-two out of 31 patients in this study were above the age of 60 years, of whom just under half succumbed of their underlying condition in spite of the short median follow-up of only 12 months. Radiation-induced xerostomia is a well-known distressing
side effect of radiotherapy delivered to the head and neck region. Animal studies have shown that the target of radiation injury is the serous acinic cell of salivary tissue (8). Pathological changes seen in rhesus monkeys’ salivary glands were shown to resemble parotid glands removed from human patients following radical neck dissection after radiation therapy. Radiation therapy affects both the stimulated secretion and the basal resting flow of major salivary glands. The submandibular glands are believed to be responsible for unstimulated basal resting secretion (8, 23). Lower doses of radiation therapy are able to effectively reduce the basal secretion rates as reported by a number of authors (9, 16, 22). However, none were able to recommend a minimal dose as standard therapy in the management of sialorrhea because of the small number of patients reviewed. Lower doses would reduce the inconvenience of multiple attendances, of often ill patients, the side effects of this treatment, and the associated cost. This review confirms that the response rates were not dependant on the dose, dose per fraction, or overall treatment time (Table 5). This may be due to the rapidity with which patients develop a dry mouth during a course of radiation therapy to the oral cavity, probably reflecting the high degree of radiosensitivity of the serous acinic cells which form the major part of the parotid gland, and which undergo interphase cell death after radiation therapy (7). Unpublished data also suggests that the alpha/beta ratio of the linear quadratic equation for serous cells may be as high as 77 Gy. The sensitivity of the serous glands to low biologically effective doses was reflected by the 50% effect level being at around the equivalent of 5 3 2 Gy. (Dr. David R. Wigg, Director, Department of Radiobiology, Royal Adelaide Hospital, South Australia, oral communication, April 1996). Most treatments (82%) were initially associated with a satisfactory response to radiation therapy. This response was maintained following 64% of treatments up to the time of review. Some authors have reported higher response rates, while others have suggested that a proportion of patients would not respond to radiation therapy irrespective of the dose delivered (9, 14). One author also reported that “megavoltage radiation to the salivary gland was not as destructive histologically as orthovoltage”, although this conclusion may relate to the equipment available at the time of the publication (24). Results from this study suggest that
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Table 8. Responses by field size area C1P
Response (36 treatments)* Area (cm2)
C
P
N
R
UNK
$49
16*
8
2
4
1
,49
3
2
3*
2
1
Initial (34 treatments)
Maintained* (36 treatments)
23/26 (82%) 5/8 (63%)
20/27 (74%) 3/9 (33%)
* Two patients re-treated.
patients treated with appropriate radiation energies so as to deliver a dose that would adequately encompass the deep lobe of the parotid gland, achieve superior response rates (76% vs. 38%, p , 0.05; Tables 6 and 7). The differences between the two groups were statistically significant in spite of the small number of patients reviewed. Patients treated with less than 9 MeV electrons, which delivers 80% of the dose at a depth of less than 2 cm, and all those who were treated with orthovoltage therapy (which delivers a suboptimal dose to the required target volume), obtained inferior results (Tables 3 and 4). Major textbooks recommend electron energies of 12–16 megavolts, or the use of photons with the dose prescribed to a depth of 4 –5 cm (25). Furthermore, results also suggest that treatment is significantly more effective if the radiation portals encompass both the parotid and submandibular glands (74% vs. 33%, p , 0.01). Inclusion of the submandibular glands will ensure effective control of the basal resting flow. Careful planning technique, therefore, should not only minimize the side effects associated with radiation treatment, but also ensure adequate dose delivery to the target volume, thereby resulting in an adequately maintained response rate in the majority of patients treated with radiation therapy. Few patients in this study developed side effects following radiation therapy. Only 13% (4/31) of patients developed significant late effects. The development of thick secretions in these patients may well be avoided by sparing the upper portion of the parotid gland in the radiation field. Temporomandibular joint fibrosis should be avoided by reducing the total dose and dose per fraction. It was not possible in this review to correlate side effects with the field sizes and treatment setup used in these patients. It was also difficult to study side effects in patients with severe intellectual disabilities. However, radiotherapy would seem to be a less traumatic approach than operative intervention in this group of patients.
Too few patients were re-treated to allow for any meaningful conclusion to be made on the most appropriate method of managing relapses following radiation therapy.
CONCLUSION This review confirms that radiation therapy has a role in the management of patients suffering from sialorrhea, particularly in patients who are elderly and of poor performance status. Radiation therapy has been shown to be both safe and effective. It avoids the potential adverse effects associated with anticholinergic medication and/or surgery, which are not well tolerated in the elderly, or those with intellectual disability or neuropathology. A treatment schedule such as 5 fractions of 4 Gy each to a total of 20 Gy using 9 –18 MeV electrons prescribed to the 100% isodose, encompassing both parotid and submandibular glands with ipsilateral fields, would be expected to achieve the desired response without causing significant morbidity and with minimal discomfort to the patient. The effectiveness of radiation therapy is reflected in the following letter written by the medical director of a local hospital for the mentally ill and intellectually disabled, where one of the inpatients received a short course of radiation therapy to both parotid glands to a dose of 20 Gy in 5 fractions: “The staff have been most impressed by the result. There have been no skin problems, and the patient appears very much happier than before the treatment. There is no spontaneous coughing and spluttering at the sight of food, and only occasionally when being fed. The patient is now happy to sit up, rather than, as previously, lying on one side all the time. While I expected a positive outcome, I was surprised by an improvement in the patient’s mood, as previously I had always noted the patient to be somewhat irritable and unhappy.”
REFERENCES 1. Barbera, G. Roentgen. Treatment of Salivary Fistula. Policlinico (Sezione Pratica) 43:1773–1776, 1936. 2. Bartolocci, A. A. Estimation and Comparison of Proportions. In: Buyse, M. E., Staquet, M. J., and Silverster, R. J., Cancer Clinical Trials, Oxford, Oxford Unity Press 337–360, 1990.
3. Bax, M. Editorial. Drooling. Developmental Medicine and Child Neurology 34:847– 848, 1992. 4. Blasco, A. P., Allare, J. H. Drooling in the developmentally disabled: Management practices and recommendations. Dev. Med. Child Neurol. 34:849 – 862; 1992.
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5. Cheng, V.S.T., Downs, J., Herbert, D. et al. The Function of the Parotid Gland Following Radiation Therapy for Head and Neck Cancer. International Journal of Radiation Oncology, Biology and Physics 7:253–258, 1981. 6. Creech, R. D. ‘Saliva’. In: Blasco, P. A. Allare, J. H., Hollahan, J., et al. Concensus Statement of the Consortium on Drooling. Washington, D.C.: UCPA, Inc, 1991. 7. Crysdale, W. S. Management Options for the Drooling Patient. Ear, Nose and Throat, Journal 68:820 – 830, 1989. 8. Crysdale, W. S., White, A. Submandibular Duct Relocation for Drooling: A 10-year Experience with 194 Patients. Otolaryngology, Head and Neck Surgery 101:87–92, 1989. 9. Dawes, C. The Chemistry and Physiolgoy of Saliva. In: Shaw, J. H., Sweeney, E. A., Cappuccino, C. C., Meller, S. M. (Editors), Textbook of Oral Biology, Publishers Philadelphia: W. B. Saunders, 1978. 10. Dawes, C. and Ong, B. Y. Circadian Rhythms in Flow Rate and Proportional Contribution of Parotid to Whole Saliva Volume in Man. Archives of Oral Biology 18:1145–1153, 1973. 11. Elzay, R.P., Levitt, S.H., Sweeney, W.T. Histologic Effect of Fractionated Doses of Selectively Applied Megavoltage Irradiation on the Major Salivary Glands of the Albino Rat. Radiology 93:146 –152, 1969. 12. Fear, D. W., Hitchcock, R. P., Fonseca, R. J. Treatment of Chronic Drooling: A Preliminary Report. Oral Surgery, Oral Medicine, Oral Pathology 66:163–166, 1988. 13. Frank, R. M., Herdly, J., Philippe, E. Acquired Dental Defects and Salivary Gland Lesions After Irradiation for Carcinoma. Journal of American Dental Associaton 70:868 – 883, 1965. 14. Good, R. L., Smith, R. A. Surgical Management of Sialorrhoea. The Laryngoscope 1078 –1089, 1970. 15. Lashley, K. L. Changes in the Amount of Salivary Secretion Associated with Cerebral Lesions. American Journal of Physiology 43:62–72, 1917.
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16. Makhani, J. S. Dribbling of Saliva in Children with Cerebral Palsy and its Management. Indian Journal of Paediatrics 41: 272–277, 1974. 17. Mandour, M. A., El-Sheik, M. M. & El-Garem, F. Tympanic Neurectomy for Parotid Fistula. Archives of Otolaryngology 102:327–329, 1976. 18. Peto, R., Pike, M. C., Armitage, P., et al. Design and Analysis of Randomised Clinical Trials Requiring Prolonged Observation of Each Patient. British Journal of Cancer 35:1, 9 –12, 1977. 19. Reddihough, D., Johnson, H. Ferguson, E. The Role of a Saliva Control Clinic in the Management of Drooling. Journal of Paediatric Child Health 28:394 –397, 1992. 20. Robinson, A.C.R., Khoury, G. G., Robinson, P. M. Role of Irradiation in the Suppression of Parotid Secretions. The Journal of Layrngology and Otlogy 103:594 –595, 1989. 21. Schneyer, L. H. and Levin, L. K. Rate of Secretion of Individual Salivary Gland Pairs in Men under Two Conditions of Stimulation. Journal of Dental Research 33:716 –717, 1954. 22. Shannon, I. L., Trodohl, J. N., Starcke, E. N. Radiosensitivity of the Human Parotid Gland. Proceedings of the Society for Experimental Biology and Medicine 157:50 –3, 1978. 23. Simpson, J. R. Salivary Glands. In: Principles and Practice of Radiation Oncology, Perez, C. A., Brady, L. W. Second edition. J. B. Lippincott, Co. 657– 671, 1992. 24. Sochaniwskyj, A. E. Drool Quantification: Neuroninvasive technique. Archives of Physical Medicine Rehabilitation 63: 605– 607, 1982. 25. Stephens, L. C., Ang, K. K., Schultheiss, T. E. et al. Target Cell and Mode of Radiation Injry in Rhesus Salivary Glands. Radiotherapy and Oncology 7:165–174, 1986. 26. Wilkie, T. F., Brody, G. S. The Surgical Treatment of Drooling: A Ten-Year Review. Plastic and Reconstructive Surgery 59:791–798, 1977.
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Clinical Investigation THE ROLE OF RADIATION THERAPY IN THE MANAGEMENT OF SIALORRHEA MARTIN BORG, M.D., F.R.A.C.R.*
AND
FRED HIRST, M.B.B.S., M.R.C.P. (U.K.)†
*Department of Radiation Oncology, Adelaide, South Australia,; and †Director, Services for the Elderly, Palmerston North Hospital, New Zealand Purpose: Sialorrhea is the unintentional loss of saliva and other contents from the mouth. Most patients with this condition are elderly, requiring palliative treatment. These patients have neuropathology with associated poor performance status. Treatment prescribed for this disabling and distressing condition has often been of a surgical nature and described in young patients. It would be inapplicable to the elderly. The aim of this study was to review the role of radiation therapy in the management of sialorrhea. Previous reports are few in number and are cautionary because of adverse effects which have been described, including dryness of the mouth. Methods and Materials: A total of 34 patients were referred to the Department of Radiation Oncology, Palmerston North Hospital, between 1966 and August 1994, of whom only 1 patient received treatment prior to 1985. Three patients declined treatment and were, therefore, excluded from this review. Thirty-one patients, including 14 males and 17 females, of median age 72 years received 1 or more radiation treatments for sialorrhea. The patients were followed up for a median of 12 months, ranging from 6 months to 27 years. Results: Initially, 82% (28/34) of treatments were associated with a satisfactory response. Six patients relapsed, of whom five experienced relapse within 6 months of initial treatment. Two patients were re-treated, one of whom achieved a complete response. Up to the time of review 64% (23/36) of treatments maintained a satisfactory response. The varied fractionation regimens used were not shown to affect the response rate; low doses were shown to be as effective as higher doses, and were not associated with any significant acute or late side effects. Only 4 patients developed long-term side effects. However, response rates were superior for patients treated with electrons, as opposed to orthovoltage therapy, and in particular when electron energies greater than 7 megavolts were used (76% vs. 38% maintained response, p < 0.05). Responses were also superior for patients treated with radiation fields which encompassed both parotid and submandibular glands (74% vs. 33% maintained response, p < 0.01). Conclusions: Radiation therapy has proven to be a safe and effective treatment in this group of patients, thereby avoiding the adverse effects of anticholinergic medication and invasive surgical procedures. © 1998 Elsevier Science Inc. Sialorrhea, Radiotherapy, Major salivary glands.
the secretion of the parotid and submandibular glands (7, 8). There are very few reports in the literature describing the use of radiation therapy in the treatment of sialorrhea secondary to nonmalignant causes (9). This study aimed to evaluate the role and effectiveness of radiation therapy in the management of sialorrhea in nonmalignant disease.
INTRODUCTION Sialorrhea (excessive salivation or chronic drooling) is defined as the unintentional loss of saliva and other contents from the mouth. The term implies excessive secretion of saliva, which may be considered an antisocial behavior, the expression of which can impede successful integration into the community (1–3). The treatment of sialorrhea varies, depending on its etiology, and involves a number of professionals including speech therapists, plastic surgeons, geriatricians, and neurologists (3, 4). More than 75% of the 1.5 liters per day of salivary secretion is produced by the major paired salivary glands (5, 6). Radiotherapy to the posterior oral cavity encompassing the major salivary glands generally induces dryness of the mouth as a result of its effect on
MATERIALS AND METHODS The records of all patients referred to the Radiotherapy Department at Palmerston North Hospital, New Zealand, between 1966 and August 1994, with a diagnosis of sialorrhea, were reviewed retrospectively. Only 1 of these patients received treatment prior to 1985. Thirty-four patients were referred, of whom 3 declined treatment and were,
Reprint requests to: Dr. Martin Borg, Department of Radiation Oncology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia Acknowledgments—We are indebted to colleagues (past and
present) at Palmerston North Hospital for allowing us to include their patients in this review. Accepted for publication 20 April 1998. 1113
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Fig. 1. Age of 31 patients treated with radiotherapy.
therefore, excluded from this review. The 31 patients in the study comprised 14 males and 17 females, of median age 72 years (range 24 – 88 years, Fig. 1), whose performance status, where known, was generally poor. Fourteen patients were of ECOG (Eastern Cooperative Oncology Group) performance status 3 or more, and 10 of EGOC status 2 or less. The performance status of 8 patients was not recorded. Table 1 lists the various medical conditions associated with sialorrhea in this group of patients. The patients were all referred following failure of alternative medical treatment modalities, although none of the patients had undergone surgical treatment prior to referral to the Radiotherapy Department (Table 2). Patients were followed for a median of 12 months (mean 39 months), ranging from 6 months to 27 years. Twenty-seven treatments were delivered to bilateral parotid and submandibular glands through separate, ipsilateral fields, the field size varying from 7 cm 3 7 cm to 10 cm 3 8 cm. Nine treatments were delivered to smaller fields encompassing a portion of both parotid glands, the field size ranging from 5 cm 3 5 cm to 7 cm 3 6 cm. Two patients received treatment on more than one occasion. There was a
wide variation in the radiation technique used. Twentyseven treatments were delivered with electrons (the energy ranging from 6 –18 megavoltage electrons, MeV, the dose prescribed to the 90% isodose) and eight treatments were delivered with orthovoltage therapy (200 –250 kilovoltage, the dose prescibed to the surface) (Tables 3 and 4). The dose, dose per fraction, and overall treatment time varied considerably between the various regimens (Table 5). Complete responses (C) were noted in patients achieving complete salivary control; that is, with complete resolution of dribbling and absence of soiling of clothes. Partial responses (P) were recorded in those patients with improved but not complete salivary control, where dribbling did not interfere with the patient’s quality of life and where garments did not have to be changed because of soiling. Patients who continued to complain of excessive drooling, such that this interfered with their quality of life and where upper garments had to be frequently changed, were recorded as nonresponders (N). Results between treatment modalities were compared using the chi-square test and log-rank significance levels (10,11).
Table 2. Preradiotherapy treatment Table 1. Medical condition of 31 patients treated with radiotherapy Medical condition
Number
Noninfective parotitis Congenital/birth trauma Motor neuron disease Parkinson’s disease Alzheimer’s disease Postcerebrovascular accident (post-CVA) Quadriplegia/paraplegia (other than CVA) Friedreich’s ataxia
2 2 2 7 2 13 2 1
Treatment modality
Number
Surgery Medical Suction drainage Physiotherapy Anticholinergics Failed Side effects Declined Unknown Antibiotics (for parotitis)
None 2 28 22 17 4 (stopped) 1 7 2
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Table 4. Depth dose characteristics for orthovoltage beams
Table 3. Depth dose characteristics for electron beams 2
Phillips, KV (5 cm2 field) Depth (mm)
Phillips SL 75, MeV (6 cm field) Depth (mm) % Depth dose
6 MeV
7 MeV
9 MeV
12 MeV
13 MeV
15 MeV
18 MeV
90 80 50
18 20 25
22 25 29
29 33 40
35 41 44
37 43 50
39 45 56
45 52 66
RESULTS Initially, 34 treatments were delivered resulting in 18 complete responses and 10 partial responses. Four patients did not respond to treatment. The responses in the remaining 2 cases were recorded as unknown as these 2 patients were lost to follow-up. For the purposes of statistical analysis these were recorded as nonresponders. Therefore, initially 28 treatments achieved a satisfactory response (82%, 28/ 34). Six patients relapsed of whom two were re-treated, one achieving a complete response and the second no response at all, so that at the time of this review 23 treatments (64%, 23/36) resulted in a satisfactory (maintained) response to radiotherapy (Table 5). Although the majority of the patients were followed for a relatively short period of time, 5 of the relapses occurred within 6 months. One other patient relapsed at 5 years, at the time of progression of the underlying disorder (motor neuron disease). The duration of response varied according to the patients’ underlying medical illness and advanced age (Fig. 2). Responses were tabulated against the different fractionation regimens used. No correlation was found between these regimens and the response rates (Table 5). However, when responses were compared against the radiation technique used, response rates were found to be superior for patients treated with electrons, in particular when an electron energy greater than 7 MeV was used (76 vs. 38%; Tables 6 and 7). The difference was statistically significant (p , 0.05, x2 5 4.04, confidence limits of 59 –93%). Responses were also superior for patients treated with field sizes of 7 cm 3 7 cm, or greater, where both parotid and submandibular glands were encompassed by bilateral radiation portals (74 vs. 33%, p , 0.01, x2 5 5.56, confidence limits of 58 –99%; Table 8). Treatment was, in general, well tolerated. Eight patients reported acute side effects, including 1 oral candidiasis, 8 mild skin reactions and 1 mild mucositis. Four patients developed persistent late effects, including 3 with troublesome thick secretions and 1 with temporomandibular joint fusion. At the time of review, 15 patients had died of their underlying illness. None of the deaths were treatment-related. DISCUSSION Several nonmalignant conditions lead to the development of sialorrhea, some of which are listed in Table 1. These
% Depth dose
200 KV
220 KV
250 KV
90 80 50
16 27 57
17 28 58
17 28 60
conditions are usually associated with poor oral motor control which causes an open-mouth posture, impaired eating ability, problems with communication, and constant drooling of saliva (2, 3). Some authors suggest that sialorrhea develops as a result of impaired swallowing and lip closure (2). However, it is also believed that a component of sialorrhea is due to excessive salivation, as in children with cerebral palsy and in adults with hemiplegia (2, 12). Sialorrhea leads to problems with articulation, feeding, swallowing, aspiration, reading, computers, loss of self-esteem and, eventually, social isolation. Such patients must put up with constant soiling of clothes and linen, the presence of an offensive odor, and excoriation of skin (2, 12). Specific treatment for sialorrhea is thus essential, both for the patient and the caregiver to improve the quality of life and social interaction. Several methods of treatment have been recommended in the literature. The ability to measure the response to treatment is limited because of the difficulty in quantifying the amount of drooling and the many factors that affect salivary secretion such as the size of the salivary gland, sex, age, diurnal rhythms, mechanical and gustatory stimulation, emotional state, and posture (3, 5, 13, 14). Several authors have attempted to quantify the extent of excessive salivation by using scales of severity, volume of drooling, or frequency of drooling (3, 4, 15, 16). One such classification subdivides patients into mild (saliva dripping on to lip but not beyond vermilion), moderate (where saliva reached the skin), and severe (where saliva drips on to clothing, books, papers, and so on). This group of patients, often children, also usually suffers from severe speech impairment (15). In this review, patients were subdivided into 3 groups according to their response to treatment (complete, partial, and nonresponders). The management of this condition varies with the underlying cause, and involves several professionals from various disciplines. Treatment is reportedly most successful in young children, where maturation of oral function may occur, and in older children and adults with relatively mild salivary control problems (12). It is thus not surprising to note quite a variation in the treatment modalities recommended and/or used in the management of this condition, either alone or in combination. Patients reviewed in this study also received a variety of treatments prior to referral for consideration of radiation therapy (Table 2). The data available from the literature generally reflects the bias of the authors and there is little randomized data to support or
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Table 5. Responses to fractionated regimens used in the treatment of sialorrhea Response (36 treatments)# Fractionation regimen 15 20 24 18 30 30 39 42 40 44 10 6 12
Gy/5 fractions 3 3 Gy (daily) Gy/5 fractions 3 4 Gy (daily) Gy/6 fractions 3 4 Gy (daily) Gy/3 fractions 3 6 Gy (1 fraction weekly) Gy/6 fractions 3 5 Gy (3 fractions weekly) Gy/10 fractions 3 3 Gy (daily) Gy/13 fractions 3 3 Gy (daily) Gy/14 fractions 3 3 Gy (daily) Gy/11 fractions 3 3.63 Gy (daily) Gy/22 fractions 3 2 Gy (daily) Gy/12 fractions 3 0.83 Gy (daily) Gy/1 fraction (1 fraction weekly) Gy/2 fractions 3 6 Gy (1 fraction weekly)
C (19)
P (10)
N (5)
R (6)
UNK (2)
Percentage response C 1 P maintained# (23/36 treatments)
1 5 1* 2 2# 3 1 — — 1 2 — 1
2 1 1 — 1* 2* — 1* — — — 1 1*
1 1 1# — 1 — — — 1 — — — —
— — 1* — 1* 2* — 1* — — — — 1*
— — — 1 — — 1 — — — — — —
75 86 33 100 50 60 100 0 0 100 100 100 50
Abbreviations: C 5 complete; P 5 partial; N 5 none; R 5 relapse; UNK 5 unknown (lost to follow-up). * Denotes relapse. # Two patients re-treated.
refute the authors’ conclusions (9, 14, 17). Some of the commonly recommended therapies include: 1. Anticholinergic medication—Twenty-two patients included in this review received this treatment. However, these drugs need to be taken over a prolonged period of time, and may contribute to polypharmacy problems which are common with elderly patients. Anticholinergics are poorly tolerated and are commonly associated with adverse reactions and symptomatic relief which is often only temporary (18, 19). 2. Various surgical procedures including parotidectomy (superficial or total), denervation procedures, and salivary duct transposition. Complications secondary to these procedures may arise as a result of the underlying
etiology, patient’s age and general medical condition. Parotidectomy may also lead to facial nerve palsy. Other surgical procedures include neuroablative procedures such as parasympathetic denervation via tympanic nerve resection, in association with division of the chorda tympani nerve, with inevitable loss of taste in the anterior two-thirds of the tongue, and transposition of the salivary ducts and orifice to the pharynx. Various reports suggest that over 80% of patients undergoing a surgical procedure would benefit, but most of these would have been referred after failed conservative treatment. They would also generally be young, otherwise fit patients in whom one would wish to avoid the use of radiation therapy (14, 20, 21). In the more common conditions as
Fig. 2. Duration of response to radiation therapy up to time of review.
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Table 6. Responses by radiation technique— electron therapy Electrons (MeV) (28 treatments) 6, 7 9 12, 13 15 18 C 1 P (initial) C 1 P (maintained)* C 1 P (maintained)* excluding 6, 7 MeV electrons
C
P
— 4* 8 2 3
2 1 1 1 2
N
R
— 1 1 — 1 2 — 1 — — 82% (23/27) 71% (20/28)
UNK 1 1 — — —
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Table 7. Responses by radiation technique— orthovoltage therapy Orthovoltage (KV) (8 treatments) 200 220 250 C 1 P (initial) C 1 P (maintained)*
C
P
2 — —
1 — 2
N
R
— 1 1 — 2* 1 71% (5/7) 38% (3/8)
UNK — — —
For definition of abbreviations, see Table 5. * One patient re-treated. 76% (19/25)
For definition of abbreviations, see Table 5. * One patient re-treated.
listed in Table 1, these procedures would be inappropriate, likely to be declined by the patient, or these patients would be considered too unfit to undergo a surgical procedure (2, 3, 18, 20). None of the patients in this study were referred following a surgical procedure, reflecting the elderly group of patients reviewed, a large proportion of whom were of poor performance status. This may also be due to physician bias. 3. Compression bandages, which are generally recommended in patients where the underlying cause is a fistula (3, 22). None of the patients in this study suffered from this condition. 4. Behavioral modification, physiotherapy, oral appliances, and occupational, physical, and speech therapy. This therapy would aim to enhance head control, improve muscle tone, and stabilize the relation of body position. It is probably the least traumatic of recommended therapies and usually is a component of the patient’s overall general management in combination with other treatments (2). 5. Radiotherapy—Very few reports in the literature refer to the use of this modality in the treatment of sialorrhea, and usually unfavorably (2, 14, 23). Certainly, it should be avoided in children, because of the risk of inducing malignancy and arresting normal growth, thereby leading to facial asymmetry, dental caries, and osteonecrosis. The latter risks may be avoided with the use of lower doses of radiation therapy. The largest review of the use of radiation therapy in this setting (that of 9 patients) reported no long-term side effects after a median follow-up of 33 months, although other authors felt this to be a relatively short period of follow-up (2, 9). However, most patients referred for radiation treatment are elderly, with limited life expectancy and are, therefore, not expected to develop long-term side effects. Twenty-two out of 31 patients in this study were above the age of 60 years, of whom just under half succumbed of their underlying condition in spite of the short median follow-up of only 12 months. Radiation-induced xerostomia is a well-known distressing
side effect of radiotherapy delivered to the head and neck region. Animal studies have shown that the target of radiation injury is the serous acinic cell of salivary tissue (8). Pathological changes seen in rhesus monkeys’ salivary glands were shown to resemble parotid glands removed from human patients following radical neck dissection after radiation therapy. Radiation therapy affects both the stimulated secretion and the basal resting flow of major salivary glands. The submandibular glands are believed to be responsible for unstimulated basal resting secretion (8, 23). Lower doses of radiation therapy are able to effectively reduce the basal secretion rates as reported by a number of authors (9, 16, 22). However, none were able to recommend a minimal dose as standard therapy in the management of sialorrhea because of the small number of patients reviewed. Lower doses would reduce the inconvenience of multiple attendances, of often ill patients, the side effects of this treatment, and the associated cost. This review confirms that the response rates were not dependant on the dose, dose per fraction, or overall treatment time (Table 5). This may be due to the rapidity with which patients develop a dry mouth during a course of radiation therapy to the oral cavity, probably reflecting the high degree of radiosensitivity of the serous acinic cells which form the major part of the parotid gland, and which undergo interphase cell death after radiation therapy (7). Unpublished data also suggests that the alpha/beta ratio of the linear quadratic equation for serous cells may be as high as 77 Gy. The sensitivity of the serous glands to low biologically effective doses was reflected by the 50% effect level being at around the equivalent of 5 3 2 Gy. (Dr. David R. Wigg, Director, Department of Radiobiology, Royal Adelaide Hospital, South Australia, oral communication, April 1996). Most treatments (82%) were initially associated with a satisfactory response to radiation therapy. This response was maintained following 64% of treatments up to the time of review. Some authors have reported higher response rates, while others have suggested that a proportion of patients would not respond to radiation therapy irrespective of the dose delivered (9, 14). One author also reported that “megavoltage radiation to the salivary gland was not as destructive histologically as orthovoltage”, although this conclusion may relate to the equipment available at the time of the publication (24). Results from this study suggest that
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Table 8. Responses by field size area C1P
Response (36 treatments)* Area (cm2)
C
P
N
R
UNK
$49
16*
8
2
4
1
,49
3
2
3*
2
1
Initial (34 treatments)
Maintained* (36 treatments)
23/26 (82%) 5/8 (63%)
20/27 (74%) 3/9 (33%)
* Two patients re-treated.
patients treated with appropriate radiation energies so as to deliver a dose that would adequately encompass the deep lobe of the parotid gland, achieve superior response rates (76% vs. 38%, p , 0.05; Tables 6 and 7). The differences between the two groups were statistically significant in spite of the small number of patients reviewed. Patients treated with less than 9 MeV electrons, which delivers 80% of the dose at a depth of less than 2 cm, and all those who were treated with orthovoltage therapy (which delivers a suboptimal dose to the required target volume), obtained inferior results (Tables 3 and 4). Major textbooks recommend electron energies of 12–16 megavolts, or the use of photons with the dose prescribed to a depth of 4 –5 cm (25). Furthermore, results also suggest that treatment is significantly more effective if the radiation portals encompass both the parotid and submandibular glands (74% vs. 33%, p , 0.01). Inclusion of the submandibular glands will ensure effective control of the basal resting flow. Careful planning technique, therefore, should not only minimize the side effects associated with radiation treatment, but also ensure adequate dose delivery to the target volume, thereby resulting in an adequately maintained response rate in the majority of patients treated with radiation therapy. Few patients in this study developed side effects following radiation therapy. Only 13% (4/31) of patients developed significant late effects. The development of thick secretions in these patients may well be avoided by sparing the upper portion of the parotid gland in the radiation field. Temporomandibular joint fibrosis should be avoided by reducing the total dose and dose per fraction. It was not possible in this review to correlate side effects with the field sizes and treatment setup used in these patients. It was also difficult to study side effects in patients with severe intellectual disabilities. However, radiotherapy would seem to be a less traumatic approach than operative intervention in this group of patients.
Too few patients were re-treated to allow for any meaningful conclusion to be made on the most appropriate method of managing relapses following radiation therapy.
CONCLUSION This review confirms that radiation therapy has a role in the management of patients suffering from sialorrhea, particularly in patients who are elderly and of poor performance status. Radiation therapy has been shown to be both safe and effective. It avoids the potential adverse effects associated with anticholinergic medication and/or surgery, which are not well tolerated in the elderly, or those with intellectual disability or neuropathology. A treatment schedule such as 5 fractions of 4 Gy each to a total of 20 Gy using 9 –18 MeV electrons prescribed to the 100% isodose, encompassing both parotid and submandibular glands with ipsilateral fields, would be expected to achieve the desired response without causing significant morbidity and with minimal discomfort to the patient. The effectiveness of radiation therapy is reflected in the following letter written by the medical director of a local hospital for the mentally ill and intellectually disabled, where one of the inpatients received a short course of radiation therapy to both parotid glands to a dose of 20 Gy in 5 fractions: “The staff have been most impressed by the result. There have been no skin problems, and the patient appears very much happier than before the treatment. There is no spontaneous coughing and spluttering at the sight of food, and only occasionally when being fed. The patient is now happy to sit up, rather than, as previously, lying on one side all the time. While I expected a positive outcome, I was surprised by an improvement in the patient’s mood, as previously I had always noted the patient to be somewhat irritable and unhappy.”
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5. Cheng, V.S.T., Downs, J., Herbert, D. et al. The Function of the Parotid Gland Following Radiation Therapy for Head and Neck Cancer. International Journal of Radiation Oncology, Biology and Physics 7:253–258, 1981. 6. Creech, R. D. ‘Saliva’. In: Blasco, P. A. Allare, J. H., Hollahan, J., et al. Concensus Statement of the Consortium on Drooling. Washington, D.C.: UCPA, Inc, 1991. 7. Crysdale, W. S. Management Options for the Drooling Patient. Ear, Nose and Throat, Journal 68:820 – 830, 1989. 8. Crysdale, W. S., White, A. Submandibular Duct Relocation for Drooling: A 10-year Experience with 194 Patients. Otolaryngology, Head and Neck Surgery 101:87–92, 1989. 9. Dawes, C. The Chemistry and Physiolgoy of Saliva. In: Shaw, J. H., Sweeney, E. A., Cappuccino, C. C., Meller, S. M. (Editors), Textbook of Oral Biology, Publishers Philadelphia: W. B. Saunders, 1978. 10. Dawes, C. and Ong, B. Y. Circadian Rhythms in Flow Rate and Proportional Contribution of Parotid to Whole Saliva Volume in Man. Archives of Oral Biology 18:1145–1153, 1973. 11. Elzay, R.P., Levitt, S.H., Sweeney, W.T. Histologic Effect of Fractionated Doses of Selectively Applied Megavoltage Irradiation on the Major Salivary Glands of the Albino Rat. Radiology 93:146 –152, 1969. 12. Fear, D. W., Hitchcock, R. P., Fonseca, R. J. Treatment of Chronic Drooling: A Preliminary Report. Oral Surgery, Oral Medicine, Oral Pathology 66:163–166, 1988. 13. Frank, R. M., Herdly, J., Philippe, E. Acquired Dental Defects and Salivary Gland Lesions After Irradiation for Carcinoma. Journal of American Dental Associaton 70:868 – 883, 1965. 14. Good, R. L., Smith, R. A. Surgical Management of Sialorrhoea. The Laryngoscope 1078 –1089, 1970. 15. Lashley, K. L. Changes in the Amount of Salivary Secretion Associated with Cerebral Lesions. American Journal of Physiology 43:62–72, 1917.
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16. Makhani, J. S. Dribbling of Saliva in Children with Cerebral Palsy and its Management. Indian Journal of Paediatrics 41: 272–277, 1974. 17. Mandour, M. A., El-Sheik, M. M. & El-Garem, F. Tympanic Neurectomy for Parotid Fistula. Archives of Otolaryngology 102:327–329, 1976. 18. Peto, R., Pike, M. C., Armitage, P., et al. Design and Analysis of Randomised Clinical Trials Requiring Prolonged Observation of Each Patient. British Journal of Cancer 35:1, 9 –12, 1977. 19. Reddihough, D., Johnson, H. Ferguson, E. The Role of a Saliva Control Clinic in the Management of Drooling. Journal of Paediatric Child Health 28:394 –397, 1992. 20. Robinson, A.C.R., Khoury, G. G., Robinson, P. M. Role of Irradiation in the Suppression of Parotid Secretions. The Journal of Layrngology and Otlogy 103:594 –595, 1989. 21. Schneyer, L. H. and Levin, L. K. Rate of Secretion of Individual Salivary Gland Pairs in Men under Two Conditions of Stimulation. Journal of Dental Research 33:716 –717, 1954. 22. Shannon, I. L., Trodohl, J. N., Starcke, E. N. Radiosensitivity of the Human Parotid Gland. Proceedings of the Society for Experimental Biology and Medicine 157:50 –3, 1978. 23. Simpson, J. R. Salivary Glands. In: Principles and Practice of Radiation Oncology, Perez, C. A., Brady, L. W. Second edition. J. B. Lippincott, Co. 657– 671, 1992. 24. Sochaniwskyj, A. E. Drool Quantification: Neuroninvasive technique. Archives of Physical Medicine Rehabilitation 63: 605– 607, 1982. 25. Stephens, L. C., Ang, K. K., Schultheiss, T. E. et al. Target Cell and Mode of Radiation Injry in Rhesus Salivary Glands. Radiotherapy and Oncology 7:165–174, 1986. 26. Wilkie, T. F., Brody, G. S. The Surgical Treatment of Drooling: A Ten-Year Review. Plastic and Reconstructive Surgery 59:791–798, 1977.