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Managing excessive saliva with salivary gland irradiation in patients with amyotrophic lateral sclerosis

  • Alexander Slade
    Affiliations
    Department of Radiation Oncology at Carle Cancer Center, University of Illinois College of Medicine at Urbana-Champaign, Urbana, IL, USA
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  • Sinisa Stanic
    Correspondence
    Corresponding author at: Carle Cancer Center, Department of Radiation Oncology, 509 West University Avenue, Urbana, Illinois 61801, USA. Tel.: +1 217 383 5092; fax: +1 217 383 3076.
    Affiliations
    Department of Radiation Oncology at Carle Cancer Center, University of Illinois College of Medicine at Urbana-Champaign, Urbana, IL, USA
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Published:February 10, 2015DOI:https://doi.org/10.1016/j.jns.2015.02.008

      Highlights

      • A significant fraction of patients with amyotrophic lateral sclerosis (ALS) are unable to swallow saliva.
      • Anticholinergic agents and botulin toxin injections are not effective for all patients.
      • The majority of ALS patients with excessive salivation respond well to salivary gland irradiation.
      • The response to radiation therapy lasts for several months.
      • Neurologists should consider this treatment option for select patients with ALS and excessive salivation.

      Abstract

      Objective

      A significant fraction of patients with amyotrophic lateral sclerosis (ALS) are unable to swallow saliva, which may result in the spillage of saliva outside of the oral cavity. Although anticholinergic agents and botulin toxin injections are considered the first line of treatment, they have not been effective for all patients. We performed a literature search on therapeutic salivary gland irradiation in patients with ALS.

      Methods

      We searched the PubMed for English language publications up to December 2014 on therapeutic salivary gland irradiation in patients with ALS. The search was performed using the following key words: amyotrophic lateral sclerosis, excessive salivation, sialorrhea, and radiation therapy.

      Results

      The majority of ALS patients with excessive salivation respond well to salivary gland irradiation. The whole bilateral submandibular, and whole or partial bilateral parotid glands have been the target tissue for radiation therapy in most of the published studies. Various radiation therapy regimens have been utilized. The response to radiation therapy lasts for several months.

      Conclusions

      The majority of ALS patients with excessive salivation respond well to salivary gland irradiation. Neurologists should consider this treatment option for select patients with ALS and excessive salivation.

      Keywords

      1. Introduction

      The parotid glands are typically targets of avoidance in patients receiving radiation therapy (RT), for head and neck cancers. However, a small but growing number of studies suggest that targeting the major salivary glands directly may have a therapeutic benefit to some patients with as amyotrophic lateral sclerosis (ALS). ALS is a progressive, paralyzing condition that affects primarily lower motor neurons. It has an incidence of approximately 2–3 per 100,000 people [
      • Hardiman O.
      • van den Berg L.H.
      • Kiernan M.C.
      Clinical diagnosis and management of amyotrophic lateral sclerosis.
      ]. The etiology of ALS remains unknown, but an N-methyl-d-Aspartate receptor antagonist, riluzole, has been shown to slow the progression of the disease [
      • Bensimon G.
      • Lacomblez L.
      • Meininger V.
      A controlled trial of riluzole in amyotrophic lateral sclerosis.
      ]. Despite this, treatment remains generally symptomatic, and the disease typically follows a progressive, ultimately, fatal course. Up to half of patients with ALS will experience some problems with excessive salivary secretions, and refractory drooling (sialorrhea) is a major clinical problem faced by approximately 20% of these patients [
      • Stone C.A.
      • O'Leary N.
      Systematic review of the effectiveness of botulinum toxin or radiotherapy for sialorrhea in patients with amyotrophic lateral sclerosis.
      ]. While the salivary glands, primarily the parotid and submandibular glands, continue to produce nearly 1.5 L of saliva per day, impaired swallowing ability leads to the accumulation and ultimate spillage of saliva outside of the oral cavity, resulting in social embarrassment, skin irritation and infection, and possible aspiration pneumonia.
      While radiation therapy (RT) has been proposed as a treatment for sialorrhea, there are several other treatments that are typically tried before attempting RT. One of the first is prescribing anticholinergic agents [
      • Hardiman O.
      • van den Berg L.H.
      • Kiernan M.C.
      Clinical diagnosis and management of amyotrophic lateral sclerosis.
      ], which can decrease salivary production, but symptom control can often require higher doses over time, leading to undesirable side effects such as urinary retention and constipation. Alternatively, more invasive techniques may be attempted such as botulinum toxin injections directly into the salivary glands [
      • Stone C.A.
      • O'Leary N.
      Systematic review of the effectiveness of botulinum toxin or radiotherapy for sialorrhea in patients with amyotrophic lateral sclerosis.
      ,
      • Verma A.
      • Steele J.
      Botulinum toxin improves sialorrhea and quality of living in bulbar amyotrophic lateral sclerosis.
      ,
      • Costa J.
      • Rocha M.L.
      • Ferreira J.
      • Evangelista T.
      • Coelho M.
      • de Carvalho M.
      Botulinum toxin type-B improves sialorrhea and quality of life in bulbar onset amyotrophic lateral sclerosis.
      ], which is effective, though it has been associated with several severe adverse effects, including worsening dysphagia. Finally, surgical approaches exist, such as salivary duct ligation [
      • Meningaud J.P.
      • Pitak-Arnnop P.
      • Chikhani L.
      • Bertrand J.C.
      Drooling of saliva: a review of the etiology and management options.
      ] and transtympanic neurectomy [
      • Sellars S.L.
      Surgery of sialorrhoea.
      ]. RT could possibly address some of the disadvantages of medical and surgical therapies in managing excessive saliva in this context. It is non-invasive, and it can be effective for several months after a finite number of treatments. In some cases, a single fraction of radiation treatment was enough to document an improvement in sialorrhea [
      • Andersen P.M.
      • Gronberg H.
      • Franzen L.
      • Funegard U.
      External radiation of the parotid glands significantly reduces drooling in patients with motor neurone disease with bulbar paresis.
      ,
      • Neppelberg E.
      • Haugen D.F.
      • Thorsen L.
      • Tysnes O.B.
      Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.
      ]. We performed a literature search on therapeutic salivary gland irradiation in patients with ALS.

      2. Methods

      The PubMed national library database was searched for English language publications up to December 2014 on therapeutic salivary gland irradiation in patients ALS and excessive salivation. The search was performed using the following keywords: amyotrophic lateral sclerosis, excessive salivation, sialorrhea, and radiation therapy. The predetermined criteria for deciding which studies to include were as follows: 1. Specified outcome, 2. Radiotherapy modality described, and 3. Radiation prescription dose specified. A total of 7 reports were identified. Full articles were obtained and were reviewed. The information presented here is extracted from publications. As different investigators often present information differently, pooling data from multiple studies may be inaccurate, and a summary table is included to help the reader better understand the primary data. In addition to PubMed, we also reviewed Database of Abstracts of Reviews of Effects (DARE) and we found no Cochrane Reviews, Protocols for Cochrane Reviews, and other publications based on Cochrane Reviews. Our search of the Embase for Excerpta Medica Database did not reveal any additional published data.

      3. Results

      Table 1 gives a summary of studies on therapeutic salivary gland irradiation in patients with ALS. It can be seen that the majority of ALS patients with excessive saliva respond well to therapeutic salivary gland irradiation. The whole bilateral submandibular, and whole or partial bilateral parotid glands have been the target tissue for radiation therapy in most of the published studies. Various radiation therapy regimens have been utilized with dose ranges from 7 Gy in single radiation therapy fraction to 20 Gy in 5 radiation therapy fractions. The low number of radiation therapy fractions makes this therapy relatively convenient for patients with ALS. The response to irradiation lasts for several months.
      Table 1Summary of studies on therapeutic salivary gland irradiation in patients with amyotrophic lateral sclerosis (ALS).
      First authorInstitutionTreatment volumeDose and fractionationInitial sampleResponse rateDuration of response
      Andersen et al.
      • Andersen P.M.
      • Gronberg H.
      • Franzen L.
      • Funegard U.
      External radiation of the parotid glands significantly reduces drooling in patients with motor neurone disease with bulbar paresis.
      Umeå University, SwedenBilateral parotid gland, and posterior submandibular gland7.0–7.5 Gy in 1 fraction18Patients had a 57% lower salivary secretion rate two weeks after RT compared to before RT. A subjective improvement in drooling was noted in 89% of patients at 4–6 months. Visual analog scale questionnaire was utilized.More than 6 months for 12/18 patients and 4–6 months for 6/18 patients
      Assouline et al.
      • Assouline A.
      • Levy A.
      • Abdelnour-Mallet M.
      • Gonzalez-Bermejo J.
      • Lenglet T.
      • Le Forestier N.
      • et al.
      Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.
      Multi-institutional, FranceBilateral submandibular glands and two thirds of the parotid glands20 Gy in 4 fractions, or 10 Gy in 2 fractions50A complete response was reported in 71% of patients; 26% reported a partial response on the subjective Sialorrhea Scoring Scale (SSS) at 6 months.At 6 months, 2/3 of patients had complete response
      Bourry et al.
      • Bourry N.
      • Guy N.
      • Achard J.L.
      • Verrelle P.
      • Clavelou P.
      • Lapeyre M.
      Salivary glands radiotherapy to reduce sialorrhea in amyotrophic lateral sclerosis: dose and energy.
      Universite d'Auvergne, FranceBilateral submandibular and parotid glands for most patientsVaried, average of 19.1 Gy in 5 fractions21A subjective improvement in sialorrhea was noted in 65% of patients at an average of 7 months follow-up. At doses of 16 Gy or more, 78% of patients reported a subjective improvement. ALS functional rating scale was used.7 months for 65% of patients
      Guy et al.
      • Guy N.
      • Bourry N.
      • Dallel R.
      • Dualé C.
      • Verrelle P.
      • Lapeyre M.
      • et al.
      Comparison of radiotherapy types in the treatment of sialorrhea in amyotrophic lateral sclerosis.
      Universite d'Auvergne, FranceBilateral submandibular and partial parotid glands20 Gy in 5 fractions, or 18 Gy in 4 fractions16A subjective improvement was seen in 80% of patients in 1 month, and 43% of patients reported improvements in 6 months utilizing a Likert and ALS functional rating scales.6 months for 43% of patients
      Harriman et al.
      • Harriman M.
      • Morrison M.
      • Hay J.
      • Revonta M.
      • Eisen A.
      • Lentle B.
      Use of radiotherapy for control of sialorrhea in patients with amyotrophic lateral sclerosis.
      University of British Columbia, CanadaBilateral submandibular sublingual, and tail of parotid glands8 Gy in 1 fraction, or 12.5 Gy in 2 fractions9An average of 1.0 g/5 min reduction of saliva production in three patients in 8 Gy group, and 0.6 g/5 min in two patients in 12.5 Gy group at 2 months follow-up. A subjective improvement in drooling seen in 67% of patients in 8 Gy group and 100% of patients in 12.5 Gy group at 2 months. Subjective degree of drooling scale was utilized.Not reported
      Kasarskis et al.
      • Kasarskis E.J.
      • Hodskins J.
      • St Clair W.H.
      Unilateral parotid electron beam radiotherapy as palliative treatment for sialorrhea in amyotrophic lateral sclerosis.
      University of Kentucky, USAUnilateral parotid gland15 Gy in 3 fractions10All patients reported a subjective improvement in sialorrhea, with improvements for most starting at 2–4 weeks post-treatment, and maximal improvement 6–8 weeks post-treatment. Specific subjective assessment scale was not reported.Not reported
      Neppelberg et al.
      • Neppelberg E.
      • Haugen D.F.
      • Thorsen L.
      • Tysnes O.B.
      Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.
      Haukeland University Hospital, NorwayBilateral to submandibular glands and the majority of the parotid glands7.5 Gy in one fraction14Patients had an average salivary secretion rate 21% lower at 3 months post-treatment compared to pre-treatment rates. Verbal rating scale was used for subjective assessment.Not reported

      4. Discussion

      Though there have been relatively few studies examining the role of RT in the treatment of sialorrhea in ALS patients, there is a near universal subjective improvement in symptoms across these studies, despite the diverse treatment volumes, doses, and patient populations. In most studies, failed treatment with either anticholinergic agents, or botulinum toxin ultimately led to a referral for treatment with RT. Toxicity of treatment was generally reported to be minimal. At the time of irradiation, commonly reported adverse effects included mild pain [
      • Andersen P.M.
      • Gronberg H.
      • Franzen L.
      • Funegard U.
      External radiation of the parotid glands significantly reduces drooling in patients with motor neurone disease with bulbar paresis.
      ,
      • Assouline A.
      • Levy A.
      • Abdelnour-Mallet M.
      • Gonzalez-Bermejo J.
      • Lenglet T.
      • Le Forestier N.
      • et al.
      Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.
      ,
      • Bourry N.
      • Guy N.
      • Achard J.L.
      • Verrelle P.
      • Clavelou P.
      • Lapeyre M.
      Salivary glands radiotherapy to reduce sialorrhea in amyotrophic lateral sclerosis: dose and energy.
      ,
      • Harriman M.
      • Morrison M.
      • Hay J.
      • Revonta M.
      • Eisen A.
      • Lentle B.
      Use of radiotherapy for control of sialorrhea in patients with amyotrophic lateral sclerosis.
      ], erythema [
      • Harriman M.
      • Morrison M.
      • Hay J.
      • Revonta M.
      • Eisen A.
      • Lentle B.
      Use of radiotherapy for control of sialorrhea in patients with amyotrophic lateral sclerosis.
      ], and mucositis [
      • Bourry N.
      • Guy N.
      • Achard J.L.
      • Verrelle P.
      • Clavelou P.
      • Lapeyre M.
      Salivary glands radiotherapy to reduce sialorrhea in amyotrophic lateral sclerosis: dose and energy.
      ]. Long term side effects, including xerostomia [
      • Andersen P.M.
      • Gronberg H.
      • Franzen L.
      • Funegard U.
      External radiation of the parotid glands significantly reduces drooling in patients with motor neurone disease with bulbar paresis.
      ,
      • Neppelberg E.
      • Haugen D.F.
      • Thorsen L.
      • Tysnes O.B.
      Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.
      ,
      • Bourry N.
      • Guy N.
      • Achard J.L.
      • Verrelle P.
      • Clavelou P.
      • Lapeyre M.
      Salivary glands radiotherapy to reduce sialorrhea in amyotrophic lateral sclerosis: dose and energy.
      ,
      • Guy N.
      • Bourry N.
      • Dallel R.
      • Dualé C.
      • Verrelle P.
      • Lapeyre M.
      • et al.
      Comparison of radiotherapy types in the treatment of sialorrhea in amyotrophic lateral sclerosis.
      ] and thickened salivary secretions [
      • Neppelberg E.
      • Haugen D.F.
      • Thorsen L.
      • Tysnes O.B.
      Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.
      ,
      • Assouline A.
      • Levy A.
      • Abdelnour-Mallet M.
      • Gonzalez-Bermejo J.
      • Lenglet T.
      • Le Forestier N.
      • et al.
      Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.
      ], were more commonly reported.
      There are several points common to these studies that condition these results. First, as previously discussed, ALS has a poor prognosis; the median survival after symptom onset is three years [
      • Hardiman O.
      • van den Berg L.H.
      • Kiernan M.C.
      Clinical diagnosis and management of amyotrophic lateral sclerosis.
      ], and even shorter when bulbar symptoms predominate [
      • Stone C.A.
      • O'Leary N.
      Systematic review of the effectiveness of botulinum toxin or radiotherapy for sialorrhea in patients with amyotrophic lateral sclerosis.
      ]. This renders the probability of radiation-induced neoplasia relatively low, as this typically takes a decade or longer to develop. Second, the final sample sizes were often smaller than the initial sample sizes because of patient attrition, due to death and lack of follow-up. With relatively small sample sizes to begin with, many of these studies may have low power. Third, in some studies, a small number of patients needed to receive a second course of RT, to adequately control sialorrhea. Fourth, some studies looked at changes in quantitative measures of sialorrhea, while the others utilized subjective batteries. Finally, the retrospective nature of the studies could make it more difficult to ascertain the degree of improvement from RT. These are all significant limitations of this review article.
      Table 1 shows that various radiation therapy regimens have been employed in the management of sialorrhea in patients with ALS. The irradiation treatment was performed with linear accelerator 4–6 MV photons with opposed lateral fields [
      • Andersen P.M.
      • Gronberg H.
      • Franzen L.
      • Funegard U.
      External radiation of the parotid glands significantly reduces drooling in patients with motor neurone disease with bulbar paresis.
      ,
      • Neppelberg E.
      • Haugen D.F.
      • Thorsen L.
      • Tysnes O.B.
      Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.
      ,
      • Assouline A.
      • Levy A.
      • Abdelnour-Mallet M.
      • Gonzalez-Bermejo J.
      • Lenglet T.
      • Le Forestier N.
      • et al.
      Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.
      ,
      • Bourry N.
      • Guy N.
      • Achard J.L.
      • Verrelle P.
      • Clavelou P.
      • Lapeyre M.
      Salivary glands radiotherapy to reduce sialorrhea in amyotrophic lateral sclerosis: dose and energy.
      ,
      • Guy N.
      • Bourry N.
      • Dallel R.
      • Dualé C.
      • Verrelle P.
      • Lapeyre M.
      • et al.
      Comparison of radiotherapy types in the treatment of sialorrhea in amyotrophic lateral sclerosis.
      ]. In some studies, 6–15 MeV electrons were utilized [
      • Bourry N.
      • Guy N.
      • Achard J.L.
      • Verrelle P.
      • Clavelou P.
      • Lapeyre M.
      Salivary glands radiotherapy to reduce sialorrhea in amyotrophic lateral sclerosis: dose and energy.
      ,
      • Guy N.
      • Bourry N.
      • Dallel R.
      • Dualé C.
      • Verrelle P.
      • Lapeyre M.
      • et al.
      Comparison of radiotherapy types in the treatment of sialorrhea in amyotrophic lateral sclerosis.
      ,
      • Kasarskis E.J.
      • Hodskins J.
      • St Clair W.H.
      Unilateral parotid electron beam radiotherapy as palliative treatment for sialorrhea in amyotrophic lateral sclerosis.
      ]. Whether electron irradiation is associated with less toxicity than photon irradiation, and vice versa, is not possible to conclude from the published data. 3D-CT based planning and combined approach with mixed electrons and photons could be appropriate for many patients. Plotting the response rate as a function of biologically effective dose (BED) was not possible to perform. Unfortunately, the response rate to salivary gland irradiation was not uniformly assessed, and various radiation doses were utilized.
      It seems that RT provides a response that lasts for about 6 months. A half of the analyzed studies did not specify duration of response and it is difficult to draw a firm conclusion. Whether these patients required other treatment modality following RT is largely unknown. The limited published data did not fully address possible additional treatment modalities following RT. A very limited follow-up for the treated patients is another contributing factor.
      Ideally, a comparison of both effectiveness and durability of response to RT to other treatment modalities would be helpful; unfortunately, this is not possible, as the published data for RT did not include such a comparison. In addition, a very limited number of the published studies, small number of treated patients, and various RT regimens preclude such an analysis at this time. The rarity of the disease is another limitation for conducting a prospective study to compare pharmacological interventions with RT in ALS patients.
      As patients with ALS have limited life expectancy, the probability to see radiation induced malignancy is relatively low since it takes a decade or longer to develop following RT. Still, some patients with ALS may have extended survival and a risk for radiation induced malignancy needs to be fully addressed at the time of radiation oncologist's consolation, particularly in patients with an indolent course of ALS. Years ago, Brenner and colleagues [
      • Brenner D.J.
      • Curtis R.E.
      • Hall E.J.
      • Ron E.
      Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.
      ] showed that the estimated risk of developing a radiation-associated second malignancy was 1 in 290 for all prostate cancer patients treated with RT, and this risk was increasing to 1 in 70 for long term survivors. Dörr and Herrmann [
      • Dörr W.
      • Herrmann T.
      Cancer induction by radiotherapy: dose dependence and spatial relationship to irradiated volume.
      ] found that the majority of second cancers are observed in the volume receiving <6 Gy. Sparing normal tissue with 3D planning is important to reduce this second cancer risk.
      While the management of sialorrhea in patients with ALS remains a challenge, the growing literature gives good credence to the role of RT. In all of the studies shown in Table 1, RT was given to patients whose excessive saliva and drooling was refractory to medical management with anticholinergic agents and/or botulinum toxin. Given the potential for side effects of medical treatments and the relatively well-tolerated nature of low-dose RT, it is reasonable to consider RT soon after sialorrhea becomes problematic in these patients. Dental evaluation prior to RT is encouraged, as some patients may experience severe mouth dryness following RT. With increasing prospective studies incorporating larger sample sizes such as a prospective study by Assouline and colleagues from France [
      • Assouline A.
      • Levy A.
      • Abdelnour-Mallet M.
      • Gonzalez-Bermejo J.
      • Lenglet T.
      • Le Forestier N.
      • et al.
      Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.
      ], greater credence can be gained for this effective application of RT. A dose of 20 Gy in 4 fractions on days 1, 3, 8 and 10, targeting bilateral whole submandibular and 2/3 parotid glands seems to be a reasonable approach for RT [
      • Assouline A.
      • Levy A.
      • Abdelnour-Mallet M.
      • Gonzalez-Bermejo J.
      • Lenglet T.
      • Le Forestier N.
      • et al.
      Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.
      ].
      In conclusion, the majority of ALS patients with excessive saliva respond well to therapeutic salivary gland irradiation. The response to irradiation lasts for several months. Neurologists should consider this treatment option for select patients with ALS and excessive salivation.

      Disclosure of interests

      A. Slade: none; S. Stanic: none.

      Acknowledgments

      None.

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