Radiation Therapy for Sialorrhea in Patients With Amyotrophic Lateral Sclerosis: A Case Series and Critical Review

Abstract

Purpose

Radiation therapy (RT) for sialorrhea has historically used 3-dimensional techniques that broadly irradiate both major and minor salivary glands. However, some reports indicate that treatment of minor salivary glands may contribute to excessive xerostomia. In this retrospective case series, we assessed the efficacy and tolerability of oral-cavity-sparing volumetric modulated arc therapy (VMAT) and bilateral electron field radiation for sialorrhea in patients with amyotrophic lateral sclerosis (ALS) and reviewed the relevant literature.

Methods and Materials

From 2014 to 2025, 6 patients with bulbar-onset ALS and medically refractory sialorrhea were treated with RT to the parotid and submandibular glands (20 Gy in 5 fractions) at a single institution. Five patients received VMAT with 6 MV photons, and one received bilateral 16 MeV electrons. Clinical response, medication use, toxicity, and dosimetry were assessed. A PubMed search using “sialorrhea,” “RT,” and “amyotrophic lateral sclerosis” was performed for the literature review.

Results

At a median follow-up of 15.05 months (range, 3.0-61.7 months), 5 of 6 patients (83.3%) achieved symptomatic improvement, with an average 60% patient-reported reduction in salivation and ≥2 point improvement in ALS Functional Rating Scale saliva subscore. Two discontinued anticholinergics, and 1 achieved complete resolution for 3 years. Acute toxicities with VMAT were mild and self-limiting, most commonly parotitis and thickened secretions. The patient treated with electrons developed grade 2 mucositis, not observed with VMAT. Late toxicities, including xerostomia, were minimal and transient. Dosimetry showed higher larynx and oral cavity doses with electrons, whereas VMAT delivered slightly higher spinal cord doses. Critical literature review supported RT as an effective and well-tolerated intervention.

Conclusions

RT provides durable relief of refractory sialorrhea in ALS with manageable toxicity. VMAT response is comparable with historical outcomes and may offer dosimetric advantages that correlate with reduced acute toxicities, although its clinical benefit and cost-effectiveness warrant further validation.

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of motor neurons, leading to progressive disability and ultimately death.¹ Current treatment options remain limited, with only 3 U.S. Food and Drug Administration-approved medications that modestly slow disease progression.² As such, multidisciplinary care focusing on symptom management and quality of life is essential.³ However, ALS management poses considerable costs and health care burdens for patients, their families, and health care systems.⁴

Among the most burdensome of ALS symptoms is sialorrhea, affecting over half of patients, particularly with bulbar-onset disease. Sialorrhea arises from impaired clearance of saliva due to orofacial and palatal weakness, leading to malnutrition, impaired speech, and increased aspiration risk.⁵ One such approach to mitigating these risks involves radiation therapy (RT), which, although most commonly applied in treating malignancies, has also demonstrated benefits in select benign conditions for over a century.⁶ In head and neck cancers, RT is well-known to cause xerostomia by reducing salivary gland function—an effect that can be therapeutically leveraged in treating sialorrhea.

Most published RT series have used three-dimensional (3D) techniques, but modern conformal approaches such as intensity modulated RT (IMRT) and volumetric modulated arc therapy (VMAT) may improve dosimetry and reduce toxicity. Here, we present a retrospective case series of patients with ALS treated with VMAT compared with bilateral electron fields, followed by a critical review of the literature.

Methods and Materials

Between November 2014 and June 2025, 6 patients with bulbar-onset ALS and medically refractory sialorrhea (ie, persistent symptoms despite ≥2 trials of anticholinergic agents) received RT at a single institution (Table 1). The cohort included 1 female and 5 male veterans (mean age, 58.8 years; range, 54-66 years). All received prior medical therapy, including anticholinergics (scopolamine patch [n = 6], sublingual atropine [n = 6], glycopyrrolate [n = 3], and hyoscyamine [n = 3]), tricyclic antidepressants (n = 2), and botulinum toxin injections (n = 1), with limited benefit or intolerable side effects. At baseline, most presented with severe drooling, oropharyngeal dysphagia, laryngospasm, and frequent choking; some required percutaneous endoscopic gastrostomy tubes and at-home suctioning. Baseline Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS)⁷ saliva subscores ranged from 0 (drooling requiring constant tissue) to 4+ (saliva excess with some drooling).

Table 1.

Patient characteristics, treatment details, and clinical outcomes following radiation therapy for sialorrhea in ALS

Patient	Sex	Age	Treatments for sialorrhea before RT	RT technique	Average follow-up duration (mo)	Response	Adverse effects: acute and late
1	M	54	Scopolamine, atropine	Bilateral electron fields, 16 MeV	61.7	Reported "significant improvement"	Acute: thickened saliva, significant mucositis (2-4 wk) Late: none
2	M	66	Scopolamine, atropine, hyoscyamine, antidepressants (TCA), glycopyrrolate, Nuedexta	IMRT/VMAT photon fields, 6 MV	6.7	80%-90% reduction in saliva, maintained with PRN glycopyrrolate	Acute: parotitis, thickened saliva (2-4 wk) Late: none
3	M	55	Scopolamine, atropine, hyoscyamine, glycopyrrolate, and home suction	IMRT/VMAT photon fields, 6 MV	21.6	60% reduction in saliva, durable response	None
4	F	59	Scopolamine patches, sublingual atropine, hyoscyamine, and glycopyrrolate	IMRT/VMAT photon fields, 6 MV	8.5	Reduced atropine	Acute: parotitis, thickened saliva Late: none
5	M	65	Scopolamine, atropine drops, TCA, botox	IMRT/VMAT photon fields, 6 MV	39.8	60% reduction in saliva with complete resolution of symptoms for 3 y. Minimal sialorrhea maintained with scopolamine and atropine	Acute: none Late: dry mouth
6	M	54	Scopolamine, atropine, and guaifenesin	IMRT/VMAT photon fields, 6 MV	3.0	50% reduction in saliva, maintained with scopolamine and hyoscyamine	Acute: parotitis, fatigue, mild skin irritation Late: nausea with associated weight loss

Abbreviations: IMRT = intensity modulated radiation therapy; VMAT = volumetric modulated arc therapy; PRN = pro re nata.

Patients were positioned supine with a headrest conformed to the posterior contour of the head and neck, and a thermoplastic mask fixed at 3 points to a carbon fiber base plate to achieve head immobilization. RT was administered to bilateral parotid and submandibular glands to a total dose of 20 Gy in 5 fractions over an average of 5 days (range, 4-9 days). This dosing schedule followed the recommended regimen from Borg and Hirst⁸ and subsequent studies, including Bourry et al,⁹ to elicit a superior response and minimize toxicity. Five patients received VMAT using 6 MV x-rays, and 1 patient received bilateral 16 MeV enface electron fields (Fig. 1). Electron treatment planning was computed tomography-based, with target depth and electron energy selected on a patient-specific basis using 3D planning to ensure adequate target coverage while minimizing dose to adjacent structures. Treatment efficacy was evaluated through patient and/or caretaker interviews and ALSFRS saliva subscores. A satisfactory salivary response was defined as complete or partial symptom improvement.

Figure 1.

Comparison of radiation therapy plans for sialorrhea: 3D electron fields (A, C, E) versus VMAT (B, D, F). Axial (A, B) and coronal (C, D) orientations are shown, with dose-volume histograms (E, F) depicting target (PTV, red) and organs-at-risk (larynx, blue; oral cavity, magenta; spinal cord, orange). Abbreviations: PTV = planning target volume; VMAT = volumetric modulated arc therapy; 3D = three dimensional.

Results

Median follow-up time after RT was 15.05 months (range, 3.0-61.7 months). Four patients (66.7%) died during follow-up, and 2 (33.3%) remained alive at the time of analysis. Median post-RT survival time was 1.5 years (range, 1-6 years). One- and two-year overall survival was 66.7% and 40%, respectively.

Five of the six patients (83.3%) reported a satisfactory response. When asked to estimate their reduction in salivation numerically, patients reported a mean subjective improvement of 60% (range, 50%-90%). Two (2/5) patients discontinued anticholinergics entirely, and the remainder maintained minimal sialorrhea with scopolamine patch, sublingual atropine, or glycopyrrolate as needed. One VMAT patient achieved complete resolution of symptoms for 3 years. The single nonresponder reported no significant change or reduction in salivation, but reduced atropine use; subsequent gastrojejunostomy tube placement precluded further sialorrhea assessment. Posttreatment ALSFRS saliva subscores improved by ≥2 points for all patients with recorded scores (5/6), ranging from 2 (moderate saliva) (n = 2) to 4 (normal) (n = 1).

Acute side effects were mild and self-limiting. Among VMAT-treated patients, 3 (3/5) developed transient parotitis, dry mouth, mild fatigue, and mild skin irritation after the first fraction, which resolved by the end of treatment. Two VMAT patients reported temporarily increased saliva (1/5) and secretion thickness (1/5), controlled with Mucinex. Notably, the patient treated with bilateral electron fields developed significant grade 2 mucositis and thickened secretions 2 to 4 weeks posttreatment—toxicities not observed in the VMAT cohort.

Long-term side effects were minimal and limited to 2 months in the VMAT cohort. One patient experienced dry mouth, and another experienced nausea with associated 6-lb weight loss, both of which self-resolved. The single patient treated with electron therapy did not report any late toxicities.

Dose distributions to extrasalivary organs varied by radiation technique. The enface electron plan delivered higher maximum doses of radiation to the larynx (25 Gy) and oral cavity (26 Gy) compared with VMAT (20 ± 1.3 Gy and 21 ± 1.1 Gy, respectively). Mean electron doses were also higher (9 Gy to both sites) compared with VMAT (larynx: 6.0 ± 2.2 Gy, oral cavity: 7.8 ± 1.9 Gy). However, VMAT delivered a higher maximum dose to the spinal cord (8.6 ± 0.9 Gy vs 5 Gy with electrons).

Conclusion

Because of its incurability, ALS is treated with disease-modifying treatments and palliative care to improve patients’ quality of life. Sialorrhea is a common symptom of ALS and is often refractory to pharmacologic therapy due to lack of response or unbearable side effects. Our case series demonstrates that RT to the parotid and submandibular glands provides safe and effective palliation, with 83.3% of patients achieving durable symptomatic improvement after a regimen of 20 Gy in 5 fractions.

These results align with prior reports showing initial response rates of 75% to 100% after RT and 43% to 75% at 4 to 9 months.^1,8,10, 11, 12, 13, 14, 15, 16 IMRT/VMAT was generally well tolerated, while electron therapy was associated with more significant mucositis. Our observed toxicity rate (∼40%) was higher than previous reports (13%-30%)^1,8,14; however, this may reflect the small sample size of the current study. Future higher-powered studies are needed to elucidate the precise association of radiation technique with toxicity.

Both techniques provided clinical benefits, but our findings suggest that IMRT-based approaches may reduce treatment-related toxicities through improved dosimetry. Here, VMAT seemed to provide quality of life improvements, sustained over several years in some patients, with limited toxicity: most patients treated with VMAT experienced mild and transient side effects, whereas the patient treated with electrons developed more pronounced mucositis and thickened secretions. VMAT planning directives to minimize dose to the oral cavity may contribute to lessened toxicity; however, the differences reported here are purely descriptive in nature, and larger-scale studies are needed to support our hypotheses.

Because of the small sample size with uneven cohorts, statistical analysis was not possible, and comparative conclusions are thereby limited. The lack of objective salivary flow measurements poses another limitation; however, because the primary objective of palliative RT is improved quality of life and symptomatic relief, patient-reported outcomes remain clinically meaningful.

The findings discussed here and in the following Critical Review support the use of radiation for the treatment of sialorrhea in patients with ALS. Further investigations are warranted to elucidate the recommended techniques and dose regimens to maximize therapeutic outcomes, minimize unwanted toxicities, and improve patient quality of life.

Discussion and Critical Review

Overview of Sialorrhea in ALS

Epidemiology and clinical presentation

Global ALS incidence is approximately 1.68 per 100,000 person-years of follow-up, with higher rates among populations of European descent (including North America).¹⁷ The Centers for Disease Control reports that White, non-Hispanic males older than 60 years with a family history of ALS are more likely to develop the condition, and American veterans also have elevated risk, although the cause is unknown.^18,19 ALS pathophysiology remains incompletely understood; however, the “gene-time-environment”²⁰ and multihit hypotheses suggest that ALS arises from cumulative genetic predispositions and environmental triggers.²¹

ALS causes progressive motor neuron death in the motor cortex, brainstem, and spinal cord,¹ and presents heterogeneously with upper and lower motor neuron signs.²² Onset is often insidious, with patients experiencing significant functional deficits at diagnosis.²³ Death typically follows 2 to 5 years after diagnosis due to respiratory failure, although disease onset may present earlier, and slower-progressing forms of ALS exist.²⁴

Major ALS phenotypes include classical, bulbar, flail arm or leg, pyramidal, and respiratory.²⁵ Bulbar-onset disease typically presents with facial, tongue, and pharyngeal muscle weakness, and is commonly associated with sialorrhea and dysphagia.²² Sialorrhea, resulting from impaired clearance of saliva due to orofacial weakness and spasticity,^11,26 affects over half of all patients, with approximately 20% having moderate-to-severe symptoms.^5,27

Saliva is primarily produced by the parotid, submandibular, and sublingual glands. The parotid glands, a purely serous gland, produce up to 66% of total daily saliva flow (1.0-1.5 L) and are activated during chewing, while the submandibular glands produce unstimulated saliva, and the sublingual glands create mucus.^5,28 Abnormalities in salivation, as in ALS, can cause skin maceration, dysphagia, malnutrition, exacerbation of dysarthria, and increased risk of aspiration pneumonia.^5,29

Current treatments

Although there are disease-modifying therapies approved for ALS (ie, Riluzole, Edaravone, and Tofersen), they do not stop its progression.³ Therefore, symptom control remains the primary therapeutic goal.²³ The American Academy of Neurology advises early referral to specialized multidisciplinary clinics to assess rehabilitation needs and improve quality of life.³⁰ Optimal sialorrhea management, in particular, is critical to mitigate pulmonary aspiration risk, which is associated with high mortality.³¹ Measurements of sialorrhea include the ALSFRS for monitoring ALS disease progression and assessing bulbar muscular function, the Oral Secretion Scale for ALS hypersialorrhea, and the Sialorrhea Scoring Scale (SSS), originally developed for Parkinson’s disease but adaptable for ALS.32, 33, 34 Treatment options for sialorrhea include anticholinergic drugs, botulinum toxin, RT, and, rarely, surgery.

Considered first-line for sialorrhea, anticholinergics are often limited by side effects such as sedation, delirium, thickened mucous secretions, skin reactions, pupillary abnormalities, and urinary retention; over 30% of patients have a poor response or contraindications.⁵ Botulinum toxin injections into the parotid and/or submandibular glands provide relief up to 4 months; however, side effects include dysphagia, dysarthria, and bulbar weakness, and dosing regimens lack standardization.^5,12

ALS poses profound physical, psychological, and financial burdens on patients and their caregivers, as common symptoms are compounded by emotional distress and difficult end-of-life decisions.³⁵ Management of the condition often falls on family members, who devote 10 to 14 hours of assistance daily in cases of severe disease.^36,37 Not unexpectedly, caregivers experience high rates of anxiety and depression.³⁸ Furthermore, the cumulative demands of care contribute to substantial health care and societal costs,⁶ estimated to be $1.02 billion annually in the United States.⁶ Considering the significant reduction in patient quality of life, caregiver wellbeing, and socioeconomic costs, improved therapeutic options for management and treatment should be pursued.

RT is an emerging method to treat medically refractory sialorrhea, offering promising efficacy with fewer side effects compared with anticholinergic medications³⁹ and potential for a more durable response.

Overview of RT for Sialorrhea

Radiobiological mechanism

Radiation-induced salivary gland injury is well documented in head and neck cancer treatment, where 63% to 93% of patients experience reduced saliva secretion and xerostomia.^40,41 Although the biochemical basis of RT-induced injury to salivary glands is not fully understood, irradiation is known to injure salivary gland acinar cells and microvascular endothelial cells, which activate significant and rapid increases in acidic and neutral sphingomyelinases, leading to endothelial cell apoptosis.⁴² In mouse models, salivary gland microvascular density was reduced by 45% following radiation.⁴³

In the United States, thousands of patients receive RT for benign conditions each year, including intracranial meningioma, vestibular schwannoma, paraganglioma, hidradenitis suppurativa, orbital pseudotumor, fascial fibromatosis, keloids, and osteoarthritis.⁶ Although there is potential for low-dose ionizing radiation to induce secondary malignancy, the risk is low in patients with ALS because of limited life expectancy.^12,44

History of RT for sialorrhea

Borg and Hirst⁸ published the first reported use of RT for ALS-associated sialorrhea management in 1998. Thirty-one patients were treated to a range of doses (6-44 Gy in 1-22 fractions) with 6- to 18-MeV enface electron fields, with the dose prescribed to the 90% isodose or 200 to 250 kV orthovoltage therapy prescribed to the surface. Complete (CR) or partial response (PR) occurred in 82% of patients, with 64% maintaining control at a median follow-up of 1 year. A positive response was characterized as patient-reported resolution of dribbling, absence of soiled clothes, and improved salivary control. Increased response was associated with bilateral parotid and submandibular gland irradiation and dose of >7 MeV electrons, with no correlations to dose or fractionation. After this seminal publication, subsequent studies confirmed these findings and provided additional data regarding efficacy, toxicity, effective techniques, and treatment planning approaches, summarized in Table 2.

Table 2.

Summary of studies using RT for management of sialorrhea in patients with ALS

Article	Study type	Number of patients	Technique	Target	Average dose and fractionation (range)	Average follow-up duration (range)	Response	Adverse effects: acute and late
Bourry et al1	Retrospective	21	Photon (n = 13) Electron (n = 8)	Bilateral submandibular and parotid glands (n = 18) Bilateral submandibular and 1 parotid (n = 1) Bilateral parotids (n = 2)	19.1 (3-48) Gy/5 (1-16) fractions × 4 (3-8) Gy	10.4 mo (0.4-26)	65% total; 50% photons; 87.5% electrons; 78.6% if total dose ≥16 Gy	Acute: oral pain, mucositis, edema, xerostomia Late: oral pain (n = 4, photon)
Neppelberg et al11	Prospective	17	Photon: 4 or 6 MV	Bilateral submandibular and parotid glands excluding upper parts of parotids	7.5 Gy/1 fraction × 7.5 Gy	1 wk; 2 wk; 3 mo	60% after 1 wk; 51% after 2 wk; 21% after 3 mo	Acute: slight skin redness in irradiated area (n = 1); viscous saliva (n = 9); xerostomia during meals (n = 2); lump in throat (n = 1); swelling in front of ears (n = 1) Late: none
Borg and Hirst10	Retrospective	31	Electron: 6-18 MeV (n = 27) Orthovoltage: 200-250 kV (n = 8)	Bilateral parotid and submandibular glands	32 (6-44) Gy/9 (1-22) fractions × 5 (3-6) Gy	39 mo (6 mo-27 y)	82% initially; 64% at 6 mo; 76% with electrons >7 MeV	Acute: oral candidiasis (n = 1), mild skin reactions (n = 8), mild mucositis (n = 1). Late: thick secretions (n = 3), temporomandibular joint fusion (n = 1)
Kasarskis et al12	Retrospective	10	Electron: >9 MeV, 3D	Single parotid gland	15 Gy/3 fractions × 5 Gy	8 wk	100% reduction in sialorrhea; discontinued anticholinergics (n = 5)	None reported
Guy et al13	Prospective	16	Electron: 6-15 MeV (n = 7) Photon: 5.5 MV, 3D (n = 9)	Bilateral submandibular and parotid glands	Electron: 20 Gy/5 fractions × 4 Gy Photon: 18 (4-48) Gy/4 (1-11) fractions × 5 Gy (4-7 Gy)	1 and 6 mo	80% at 1 mo; 43% at 6 mo	Acute: mouth dryness (n = 2), pain and edema (n = 1) Late: none
Assouline et al14	Prospective	50	Photon: 6 MV, 3D	Bilateral submandibular and 2/3 parotid glands	10 Gy/2 fractions × 5 Gy (n = 30) 20 Gy/4 fractions × 5 Gy (n = 20)	6 mo	End of RT: 92% complete response (CR), 8% partial response (PR); 6 mo: 71% CR 26% PR	Acute: taste modification, mild pain, xerostomia, saliva thickening, and swallowing difficulty Late: saliva thickening (n = 2)
Stalper and Moser15	Retrospective	19	Photon: 250 kV (n = 14) Electron: 8-14 MeV (n = 5)	Bilateral parotids	16 Gy/8 (n = 16) or 1 (n = 3) fractions × 2 Gy	24 mo	Initial response: 74%; CR (n = 11), PR (n = 3)	Acute: pain in parotid area (n = 6); dry mouth (n = 4) Late: none
Andersen et al16	Prospective	18	Photon: 4-6 MV, fixed-SSD	Bilateral parotid glands and posterior submandibular gland	7.0 Gy/1 fraction × 7.0 Gy (n = 13) 7.5 Gy/1 fractions × 7.5 Gy (n = 5)	14 d	89% response; discontinued anticholinergics (n = 12)	Acute: transient aching pain in cheeks Late: xerostomia (n = 1)
Harriman et al17	Prospective	9	Not specified	Submandibular and sublingual glands	8 Gy/1 fraction × 8 Gy (n = 5) 12.5 Gy/2 fractions × 6.25 Gy (n = 4)	6 mo	Decreased salivary secretion rate and drooling (n = 5)	Acute: erythema and burning of skin (n = 4), sore throat (n = 2), nausea (n = 1) Late: none

Abbreviations: ALS = amyotrophic lateral sclerosis; RT = radiation therapy; 3D = three dimensional.

Response and durability

All reported cases involved patients with clinically confirmed ALS and problematic sialorrhea refractory to anticholinergics or botulinum toxin, due to inadequate response or intolerable side effects. Therapeutic efficacy was assessed through salivation scoring, clinical inspection, and patient interviews. Three studies employed standardized scales such as the ALSFRS or the 9-grade SSS,^9,12,13 whereas others relied on patient-reported changes in drooling, clothes soiling, and napkin use for blotting saliva.^8,11,14 Additional quantitative methods included measuring resting salivary secretion with glass tubes¹⁰ or preweighed cotton rolls.^15,16 Other instruments included a 4-point Likert scale,¹² a saliva thickening visual analog scale,¹³ and a drooling severity scale.¹⁶

Patients generally responded positively, with most studies reporting response rates >75%, and some achieving up to 100% reduction in sialorrhea¹¹ and 92% CR¹³ at the end of RT. In studies comparing CR and PR, more patients achieved CR (eg, scores of 1-3 on SSS per Assouline et al)¹³ than PR (scores of 4-6).¹⁴ However, response rates declined over time, with 6-month efficacy ranging from 43% to 71%. Neppelberg et al¹⁰ reported the lowest response rate of 21% at 3 months. The difference between CR and PR also narrowed over time: Assouline et al¹³ described an initial 92% CR and 8% PR, which decreased to 71% CR and 26% PR at 6 months.

Reirradiation, performed in 5 studies between 3 and 6 months (range, 1-15),^9,8,10,13,14 was feasible and generally beneficial for patients who did not initially respond or had recurrence of symptoms after treatment. Responses varied from 25% to 100%,^9,8,10,13,14 with minimal adverse effects, supporting RT as a safe retreatment option.

Technique: field size, RT modality, dose and fractionation, correlation with response

Most studies employed electrons (6-18 MeV)^9,8,11,12,14 or photons (4-6 MeV),^9,10,12, 13, 14, 15 and one used orthovoltage.⁸ Studies comparing modalities consistently found electrons more effective in long-term measurements, typically at 6 months: Bourry et al⁹ reported an 87.5% response rate with electrons versus 50% for photons; Borg and Hirst⁸ observed 76% electrons versus 38% for orthovoltage; Guy et al¹² similarly concluded electrons were superior to photons.

Target volumes typically included the parotid glands bilaterally^9,11,12,12, 13, 14, 15 or unilaterally,^9,11 with several also treating bilateral submandibular glands.^9,11,12,12, 13, 14, 15 Some protocols spared the upper third of the parotids to reduce toxicity.^10,13,16 Harriman et al¹⁵ uniquely included the sublingual glands. Field size was generally not reported except by Borg and Hirst,⁸ who found a higher response rate with field size ≥49 cm² (74% compared with 33%).

Dose and fractionation regimens varied widely from 3 to 48 Gy in 1 to 22 fractions, but were most commonly 20 Gy in 4 to 5 fractions.^9,12,13 Dose-response relationships remain unclear: Bourry et al⁹ reported 78.6% of responders received ≥16 Gy, but Andersen et al¹⁵ found 89% satisfactory responses with only 7.0 to 7.5 Gy. Assouline et al observed superior response with 20 Gy compared with 10 Gy; however, Guy et al^12,13 found no significant correlation with response across a 4 to 48 Gy photon dose range. Similarly, Harriman et al¹⁶ found no difference between 8 Gy or 12.5 Gy in patients with end-stage ALS (but >50% were deceased by 6 months). Although there could be a moderate correlation of dosage with response, more studies with stronger power are needed to draw conclusions.

Toxicities: acute and late

Acute toxicities were generally mild, most commonly oral pain,^9,12, 13, 14^,16 localized skin irritation,^8,10,15,16 and xerostomia.^9,10,13 Less frequent effects included taste modification,¹³ increased salivary viscosity,^10,13 nausea,¹⁶ mucositis,⁹ oral candidiasis,⁸ sore throat,¹⁶ and globus sensation.¹⁰ Chronic toxicities were rare and largely limited to oral pain (n = 4),⁹ saliva thickening (n = 5),^8,13 xerostomia (n = 1),¹⁵ and temporomandibular joint fusion (n = 1).⁸ Five studies reported no late toxicities. Acute and chronic toxicities were not correlated with dosage or fractionation but appeared related to RT technique: photon therapy was associated with higher rates of chronic oral pain,⁹ acute pain,¹² and edema¹² compared with electrons.^9,12

Bilateral irradiation of the submandibular and parotid glands was generally well tolerated, with side effects mostly self-limiting. The only study to include sublingual glands reported the highest acute toxicity rate (78%) but no late effects.¹⁶ Irradiation of the parotids produced minimal toxicity: Kasarskis et al¹¹ observed no adverse effects in patients treated with a unilateral parotid gland, and Stalpers et al¹⁴ reported acute pain and dry mouth with no long-term effects in patients treated with bilateral parotids. It remains unclear whether sparing the upper parotids reduces toxicity, although this has been suggested in the literature.^12,45 Finally, no RT-associated mortalities were reported.

Ati et al⁴⁶ reported a 76-year-old woman with severe ALS-related sialorrhea refractory to anticholinergics and botulinum toxin treated with IMRT to the bilateral submandibular and parotid glands with 20 Gy in 4 fractions. Within 49 days, salivary weight was significantly reduced (3.010-0.541 g) with marked improvement in both the SSS (9 → 1) and Oral Secretion Scale (0 → 3), sustained for >3 months. Only mild fatigue was noted. After 4.5 months, symptom recurrence with thickened secretions prompted reirradiation (10 Gy in 2 fractions), reducing suctioning frequency from 6-8 to 2-3 times per day. Mild worsening occurred 6 months later, controlled with glycopyrrolate; no further treatment was required.

Possible advantages of IMRT/VMAT

IMRT and VMAT may offer advantages over traditional electron or 3D conformal techniques by enabling highly conformal dose distributions that selectively target the parotid and submandibular glands while minimizing radiation exposure to adjacent structures, such as the oral cavity, larynx, and pharyngeal constrictors. This improved precision may reduce the risk of acute mucositis and xerostomia, which can significantly impact comfort and nutrition in patients already compromised by bulbar dysfunction. In our case series, most patients treated with VMAT achieved durable symptomatic improvement with only mild, transient side effects, whereas the patient treated with electrons developed more pronounced mucositis and thickened secretions. These descriptive findings may suggest the role of modern conformal techniques in maintaining efficacy while improving tolerability; however, technique selection should be made on a patient-specific basis. Furthermore, cost-effectiveness must be considered, as VMAT has a higher cost per treatment course (which may or may not be offset by potential benefits, including reduced toxicity and improved organ-at-risk sparing).⁴⁷ As such, further studies are needed to elucidate the clinical advantages of IMRT/VMAT compared with traditional electron techniques.

Refractory sialorrhea in patients with ALS carries a profound impact on quality of life, contributing to social distress, impaired communication, and increased risk of aspiration. Treatment options remain limited, and while existing studies are small, they consistently demonstrate that radiation therapy offers meaningful and durable palliation. Taken together, these findings support the incorporation of RT into the standard treatment paradigm for ALS-associated sialorrhea.

Disclosures

None.