Managing Radiation-induced Xerostomia in Head and Neck Cancer: A 2020–2025 Systematic Review

1. INTRODUCTION

Radiation-induced xerostomia (RIX) is a common and debilitating complication in patients undergoing radiotherapy (RT) for head and neck cancer (HNC) [1, 2]. Approximately 60–90% of patients with HNC experience some degree of xerostomia, which can interfere with speaking, mastication, tasting, and swallowing. These disruptions commonly lead to nutritional deficiencies, an increased risk of dental decay and oral infections, and a notable reduction in overall quality of life [2, 3]. Salivary glands, particularly the parotid glands, are highly sensitive to radiation. Conventional RT commonly causes permanent damage to salivary glands due to insufficient protection of essential structures [4]. While glandular recovery may occur after treatment, persistent xerostomia remains a common concern in many patients treated for HNC. Multiple approaches have been studied to support the prevention and management of xerostomia [3-7]. Advances in RT, including intensity-modulated RT (IMRT) and proton beam therapy (PBT), have enhanced treatment precision by targeting tumors and reducing exposure to nearby salivary glands [5, 6]. These improvements have reduced the frequency and severity of xerostomia. However, xerostomia continues to affect some patients, particularly those receiving high-dose RT or with tumors close to the salivary structures [8, 9]. Various preventive and therapeutic strategies have been developed to address this issue. Pharmacological agents, such as pilocarpine and amifostine, aim to support remaining salivary function or protect glands from radiation-induced injury [10-17]. Artificial saliva substitutes and moisturizers provide palliative relief for patients with xerostomia [18]. More recently, non-pharmacological approaches, including photobiomodulation therapy (PBMT), acupuncture, hyperbaric oxygen therapy (HBOT), electrical nerve stimulation (ENS), and intraoral stents, have shown potential in preserving salivary gland function and enhancing comfort [19]. Moreover, surgical techniques such as pre-RT salivary gland transfer have been explored as preventive options in selected cases [6, 7]. A 2023 review by Nathan et al. highlighted the complex causes of xerostomia in patients treated for HNC and emphasized the importance of a multidisciplinary approach. This includes novel RT planning, systemic therapies, and supportive interventions to improve long-term salivary function and overall well-being [3]. Despite advances in RT techniques, xerostomia remains a major concern for patient survival. In this systematic review, this study aimed to summarize the available literature on the prevention and management of RIX, with a focus on recent publications from 2020 to 2025. By integrating findings from multiple disciplines, this review offers clinicians an updated, evidence-based guide to current strategies and emerging research.

Previous reviews of radiation-induced xerostomia have generally focused on individual management approaches, such as salivary gland-sparing radiotherapy, pharmacologic interventions, or selected supportive therapies. Although these studies have provided important evidence regarding the effectiveness of specific modalities, the literature remains fragmented across preventive, pharmacological, non-pharmacological, surgical, and regenerative strategies. In addition, emerging interventions have not consistently been considered alongside established approaches, limiting direct appraisal of the overall therapeutic landscape and the development of integrated management recommendations. To our knowledge, the present systematic review provides one of the most comprehensive syntheses of evidence published between 2020 and 2025 on the prevention and management of radiation-induced xerostomia. It evaluates five major therapeutic domains within a single PRISMA 2020 framework: advanced radiotherapy techniques, including IMRT and IMPT; pharmacologic therapies, including pilocarpine, cevimeline, and amifostine; non-pharmacological and supportive interventions, including photobiomodulation, electrical nerve stimulation, acupuncture, hyperbaric oxygen therapy, and intraoral stents; and surgical and regenerative approaches, including submandibular gland transfer and mesenchymal stem cell-based therapies. By comparatively synthesizing evidence across these modalities, this review aims to support clinical decision-making, identify current evidence gaps, and highlight priorities for future clinical trials and guideline development. The remainder of the manuscript is organized as follows. Section 2 describes the Materials and Methods, including the search strategy, eligibility criteria, study selection process, and risk-of-bias assessment. Section 3 presents the Results, including findings related to radiotherapy modalities, supportive products, pharmacologic agents, non-pharmacological interventions, and surgical and regenerative approaches. The findings are subsequently interpreted in their clinical context in the Discussion, followed by the Conclusion, which summarizes the principal findings and outlines priorities for future research.

2. MATERIALS AND METHODS

2.2. Critical Evaluation and Data Collection

The database search yielded 670 records: 220 from PubMed, 170 from Web of Science, and 280 from Scopus. After removing 220 duplicates, 450 unique records were retained for title and abstract screening. Of these, 350 were excluded because of irrelevance or failure to meet the inclusion criteria. A total of 100 full-text articles were evaluated for eligibility. Of these, 65 were excluded because of insufficient data (n = 17), unrelated outcomes (n = 20), or irrelevant interventions (n = 28). Ultimately, 35 studies met all the inclusion criteria and were included in the final review. The PRISMA flow diagram (Fig. 1) outlines the full selection process. The extracted data included authorship, publication year, study design, primary findings, and journal sources. Each article was reviewed in full and classified into one of five thematic categories: preventive strategies, artificial saliva substitutes, pharmacological interventions, non-pharmacological approaches, and surgical interventions. Summary tables (Tables 1–9) for each category present the study characteristics and key findings from articles published between 2020 and 2025.

Table 2.

S. No.	First Author	Full Title	Year, Citation	Findings
1.	Cao	Intensity-Modulated Proton Therapy for Oropharyngeal Cancer Reduces Rates of Late Xerostomia	2021, 20	Intensity-modulated proton therapy (IMPT) is associated with less late xerostomia compared with IMRT in patients receiving treatment for oropharyngeal cancer (OPC). Oral cavity dosimetric variables are associated with the occurrence of late xerostomia.
2.	De Felice	Xerostomia and Clinical Outcomes in Definitive Intensity Modulated Radiotherapy (IMRT) Versus Three-dimensional Conformal Radiotherapy (3D-CRT) for Head and Neck Squamous Cell Carcinoma: A Meta-Analysis	2020, 21	IMRT reduces grade ≥ 2 acute and late xerostomia compared with three-dimensional conformal radiotherapy (3D-CRT) and shows no notable improvement in overall survival or loco-regional control.
3.	Gerlach	Radiation-induced oral side effects in head and neck cancer: a scoping review and interdisciplinary recommendations	2026, 22	A mean parotid dose threshold below 25 Gy is required for meaningful functional recovery. Exceeding this threshold results in markedly reduced salivary flow with little or no long-term recovery. IMRT offers substantial salivary gland-sparing potential.
4 .	Yahya	Quality of Life and Patient-Reported Outcomes Following Proton Therapy for Oropharyngeal Carcinoma: A Systematic Review	2023, 23	IMPT shows improved patient-reported outcomes for xerostomia compared with IMRT, particularly in the physical and personal domains.
5.	Youssef	Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Oropharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy	2022, 24	IMPT is associated with lower rates of xerostomia and improved patient-reported outcomes compared with IMRT, and survival outcomes remain comparable.

Table 3.

S. No.	First Author	Full Title	Year, Citation	Findings
6.	Marimuthu	Saliva Substitute Mouthwash in Nasopharyngeal Cancer Survivors With Xerostomia: A Randomized Controlled Trial	2021, 26	Immunologically active saliva substitutes notably improve patient-reported xerostomia scores and unstimulated salivary flow compared with placebo.
7.	Nuchit	Alleviation of Dry Mouth by Saliva Substitutes Improved Swallowing Ability and Clinical Nutritional Status of Post-Radiotherapy Head And Neck Cancer Patients: A Randomized Controlled Trial	2020, 27	Continuous use of saliva substitutes improves symptomatic xerostomia, swallowing ability, and nutritional status in patients who have completed radiotherapy (RT) for head and neck cancer (HNC).
8.	Piboonratanakit	Trehalose Versus Carboxymethylcellulose Oral Spray for Relieving Radiation-Induced Xerostomia in Head And Neck Cancer Patients: A Randomized Controlled Trial	2023, 28	Trehalose spray improves salivary pH and unstimulated salivary flow rate and shows efficacy comparable to that of carboxymethylcellulose (CMC) spray in enhancing xerostomia-related quality of life.
9.	Lanzetti	Management of Oral Hygiene in Head-Neck Cancer Patients Undergoing Oncological Surgery and Radiotherapy: A Systematic Review	2023, 29	Edible saliva gels and oral moisturizing jellies reduce Candida colonization and enhance saliva properties in patients who have completed RT. Integrated supportive programs improve symptomatic xerostomia and increase unstimulated saliva flow in patients who have completed RT for HNC.
10.	Rupe	Sodium-Hyaluronate Mouthwash on Radiotherapy-Induced Xerostomia: A Randomised Clinical Trial	2023, 30	Sodium hyaluronate mouthwash significantly improves xerostomia symptoms and quality of life without adverse effects.
11.	Porangaba	Randomized Double-Blind Placebo-Controlled Study of Salivary Substitute With Enzymatic System for Xerostomia in Patients Irradiated in Head and Neck Region	2024, 31	Salivary substitutes with enzymatic systems show some improvements in symptomatic xerostomia, but differences compared with placebo do not reach statistical significance.

Table 4.

S. No.	First Author	Full Title	Year, Citation	Findings
12.	Watanapokasin	As-Needed Pilocarpine for Radiation-Induced Xerostomia in Head and Neck Cancer Patients	2024, 17	As-needed pilocarpine effectively relieves symptomatic xerostomia with fewer adverse effects and reduces treatment costs compared with fixed-dose regimens.
13.	Gül	Does Lower Dose Pilocarpine Have a Role in Radiation-Induced Xerostomia?	2024, 32	Lower-dose pilocarpine (5–15 mg/day) improves late-stage symptomatic xerostomia, with fewer adverse effects, providing a viable alternative to standard dosing.
14.	Kapourani	A Review on the Role of Pilocarpine on the Management of Xerostomia and the Importance of the Topical Administration Systems Development	2022, 33	Topical pilocarpine formulations, such as mouthwashes and lozenges, provide efficacy comparable to systemic administration while reducing systemic adverse effects, thereby enhancing patient adherence.
15.	Hosseini	Cancer Treatment-Related Xerostomia: Basics, Therapeutics, and Future Perspectives	2024, 34	This comprehensive review examines interventions for cancer treatment-related xerostomia, including cevimeline, and emphasizes the need for more robust clinical trials to confirm their efficacy and safety.
16.	Alsahafi	Clinical evidence for managing radiotherapy-induced oral mucositis and xerostomia in head and neck cancer patients: a review of Phase III–IV trials	2026 ,35	Review of meta-analysis confirming pilocarpine and cevimeline as principal pharmacological interventions for radiation-induced xerostomia, with significantly better efficacy than placebo.

Table 5.

S. No.	First Author	Full Title	Year, Citation	Findings
17.	Cohen	Acupuncture for Chronic Radiation-Induced Xerostomia in Head and Neck Cancer: A Multicenter Randomized Clinical Trial	2024, 39	True acupuncture improves symptomatic xerostomia and quality of life compared with standard oral hygiene, and these improvements last for 12 weeks.
18.	Ni	Acupuncture for Radiation-Induced Xerostomia in Cancer Patients: A Systematic Review and Meta-Analysis	2020, 40	Acupuncture improves symptomatic xerostomia, yet changes in salivary flow rates remain uncertain, and overall study quality is low.
19.	Solarska	Recent Advances in the Prevention and Treatment of Post-Radiotherapy Xerostomia in Patients With Head and Neck Cancer	2022, 41	Acupuncture may improve symptomatic xerostomia; however, effects on salivary flow rates remain unclear, and researchers need stronger evidence.
20.	Dörfler	Umbrella Review: Summary of Findings for Acupuncture as Treatment for Radiation-Induced Xerostomia	2023, 42	Acupuncture may alleviate symptomatic xerostomia, yet current evidence remains low in quality, and researchers need more rigorous studies.

Table 6.

S. No.	First Author	Full Title	Year, Citation	Findings
21.	Salimi	Transcutaneous Electrical Nerve Stimulation to Treat Dry Mouth (Xerostomia) Following Radiotherapy for Head and Neck Cancer. A Systematic Review	2021, 46	Transcutaneous ENS (TENS) is safe and feasible; initiating daily TENS concurrently with radiotherapy yields better outcomes.
22.	Mercadante	Salivary Electrostimulation in the Treatment of Radiation Therapy–Induced Xerostomia (LEONIDAS-2): A Multicenter, Randomized, Double-Masked, Sham-Controlled, Phase 3 Trial	2023 , 47	No differences are observed in primary or secondary outcomes; however, exploratory analyses indicate improvements in xerostomia subscale scores.

Table 7.

S. No.	First Author	Full Title	Year, Citation	Findings
23.	Mosannen	Evaluation of the Effect of Photobiomodulation on Radiation-Induced Xerostomia in Head and Neck Cancer Patients: A Randomized Clinical Trial	2024, 48	PBMT markedly increases stimulated saliva production and reduces patient-reported xerostomia compared with sham treatment.
24.	Heiskanen	Photobiomodulation Therapy for Cancer Treatment-Related Salivary Gland Dysfunction: A Systematic Review	2020, 49	Preliminary outcomes for patients receiving PBMT are positive; however, current evidence remains insufficient to determine its efficacy in managing cancer therapy-related xerostomia.
25.	de Carvalho E Silva	Photobiomodulation for the Management of Xerostomia and Oral Mucositis in Patients With Cancer: A Randomized Clinical Trial	2023, 50	PBMT improves quality of life and decreases patient-reported xerostomia severity compared with the control group.
26.	Schepanski	Long-Term Evaluation of Salivary Glands After Photobiomodulation During Radiotherapy for Head and Neck Cancer	2023 ,51	PBMT preserves salivary gland function during radiotherapy (RT), preventing reductions in salivary flow; however, some patients have experienced a decline 6 months post-RT.
27.	Schepanski	Evaluation of Photobiomodulation Therapy (PBMT) on Salivary Flow and Composition in Head and Neck Cancer Patients Undergoing Radiation Therapy	2024, 52	PBMT improves both salivary flow and composition, enhancing patient comfort during and post-RT. .
28.	Lopez- Garzon Shrateh	Photobiomodulation for restoring salivary flow after radiotherapy in head and neck cancer: a randomised placebo-controlled trial	2025, 53	PBM therapy produced a clinically significant increase in unstimulated salivary flow. No adverse events recorded, suggesting potential regenerative effects
29.	Shrateh	Treatment options for radiation-induced xerostomia in patients with head and neck cancer: a systematic review and meta-analysis	2026, 54	PBMT statistically significantly reduced oral pain severity, consistent tissue-regenerative properties

Table 8.

S. No.	First Author	Full Title	Year, Citation	Findings
29.	Philipsen	The Effect of Hyperbaric Oxygen Therapy in Head and Neck Cancer Patients With Radiation-Induced Dysphagia—A Systematic Review	2024, 58	Evidence for the benefits of HBOT in patients with dysphagia after radiotherapy (RT) for head and neck cancer (HNC) is inconsistent.
30.	Kumar	Radiation Effects in Head and Neck and Role of Hyperbaric Oxygen Therapy: An Adjunct To Management	2024, 59	HBOT is effective in managing post-radiation changes in patients with HNC, including xerostomia.

Table 9.

S. No.	First Author	Full Title	Year, Citation	Findings
31.	Chen	The Efficacy of Positioning Stents in Preventing Oral Complications After Head and Neck Radiotherapy: A Systematic Literature Review	2020, 60	Evidence for preventing xerostomia in patients is weak, and more high- quality studies are needed.
32.	Brandão	Are Intraoral Stents Effective In Reducing Oral Toxicities Caused By Radiotherapy? A Systematic Review And Meta-Analysis	2021, 62	Use of intraoral stents notably reduces oral mucositis, salivary changes, and trismus in patients.
33.	Kawakami	Effectiveness of Intraoral Stents in Reducing Oral Adverse Events During Radiotherapy for Maxillary or Nasal Cavity Malignant Tumors	2024, 63	Intraoral stent use reduces the severity of oral mucositis, potentially benefiting xerostomia management in patients.
34.	Alves	Benefits of Intraoral Stents in Patients With Head and Neck Cancer Undergoing Radiotherapy: Systematic Review	2021, 64	Use of intraoral stents may help reduce oral mucositis, trismus, xerostomia, and radiation exposure to healthy tissues in patients.

3. RESULTS

3.1. Risk of Bias and Methodological Quality

The methodological quality of the included studies varied across study designs. Randomized controlled trials were evaluated using RoB 2, with judgments based on the five predefined bias domains. Systematic reviews and meta-analyses were assessed using AMSTAR 2. The principal methodological concerns across the evidence base included heterogeneity in outcome assessment, relatively small sample sizes in several intervention studies, variation in follow-up duration, and limitations in the reporting of study methods. Detailed RoB 2 domain-level assessments are summarized in Fig. (2).

4. DISCUSSION

This systematic review evaluated the impact of various preventive and therapeutic strategies on radiation-induced xerostomia (RIX) in patients with head and neck cancer (HNC). Substantial evidence demonstrates that advanced radiotherapy techniques, including intensity-modulated radiation therapy (IMRT) and proton beam therapy (PBT), markedly decrease the rate of radiation-induced xerostomia (RIX) in patients with head and neck cancer on comparison with conventional approaches such as three-dimensional conformal radiation therapy (3D-CRT) [21]. This study shows that IMRT was associated with a lower grade of acute xerostomia, and there was a significant difference in late xerostomia between 3D-CRT and IMRT at 1 year and 2 years after treatment [21]. Compared with photon therapy, proton beam therapy (PBT), particularly Intensity-Modulated Proton Therapy (IMPT), provides superior dosimetric advantages over IMRT by delivering lower oral cavity, mean larynx, and mean parotid gland doses than in patients treated with IMRT [24]. The same study shows that IMPT treatment was associated with a significantly lower likelihood of developing grade 2 or higher acute AEs than IMRT [24]. One report shows that IMPT has lower rates of late xerostomia than IMRT [20]. When death was included as a competing risk, the locoregional failure-free survival between the IMPT and IMRT groups was estimated to be similar and not statistically different [24]. The main drawback of proton therapy is the high cost of constructing a cyclotron and maintaining the facility [23].

In the 35 studies included, the hierarchy of evidence indicates that IMRT/IMPT is the cornerstone of RIX prevention, while pharmacologic is used as second-line symptomatic therapy and non-pharmacologic/regenerative for refractory or recovery-targeted situations. Whilst a small increase in salivary flow has been reported with pilocarpine and cevimeline, their efficacy was modest, and compliance was hindered by cholinergic side-effects, consistent with the findings of the Cheng meta-analysis [10] and those of Alsahafi et al. [35]. The evidence regarding the efficacy of the non-pharmacologic modalities is less consistent: photobiomodulation seems to be most effective with concurrent radiotherapy, TENS is showing benefits only in extra-oral application, and acupuncture trials are still heterogeneous and have significant placebo effects. While promising, surgical gland transfer and MSC therapy are both investigational and need long-term safety data before they can be recommended as guidelines. Importantly, there is no single modality that can provide complete radiation sparing, and symptom-targeted interventions are additive, providing durable benefit from the radiation-sparing component. Such a synthesis should be used to inform shared decision-making with patients and to support the development of institution-specific RIX management pathways. Authors' cautious recommendations were supported by moderate confidence in the evidence for radiotherapy planning, modest confidence in the evidence for pharmacological agents, and low to very low confidence in the evidence for regenerative therapies, as assessed using RoB 2 and AMSTAR-2.

Artificial saliva and oral moisturizer products are widely used as standard supportive management for radiation-induced xerostomia (RIX). Across the reviewed studies, all substitutes consistently reduced symptomatic xerostomia, increased salivary pH and flow, and improved quality of life without causing side effects. One study comparing herbal formulations with Hypozalix reported that the group receiving herbal compounds experienced improvement in more xerostomia-related symptoms and quality-of-life domains than the Hypozalix group; however, the lack of objective outcome measures may introduce bias [18]. The same study showed that bioXtra gel increased salivary pH and Candida counts [18]. Another study of patient preference data indicated that gel, mucin, and carmellose were each favored by approximately 27% of patients, while oil was preferred by 17.5%; about 55% wished to continue using carmellose spray compared with 42% for oil [25]. The main results of the randomized controlled trial demonstrated that sodium–hyaluronate mouthwash is effective in reducing the burden of radiation-induced xerostomia symptoms [30].

Current evidence shows that both pilocarpine and cevimeline are effective for managing radiation-induced xerostomia (RIX); both drugs have similar effects on salivary flow and patient-reported symptoms, with no significant difference in overall efficacy [14]. Cevimeline's greater M3 receptor selectivity is thought to give it a better side-effect profile; however, studies have not demonstrated a marked difference in adverse events between these agents [6, 12, 13, 14]. Pilocarpine provides clinical benefit through adjustable dosing and topical formulations that reduce systemic side effects while preserving effectiveness [17, 32, 33]. Methods for delivering cevimeline have not advanced as much as might be expected, given individual perceptions of xerostomia assessment and the potential for placebo effects, as seen especially in cevimeline studies, which complicate direct comparisons [12]. Treatment choice should be individualized by tolerability, dosing flexibility, and patient preference. Larger, well-controlled studies are needed. These will help optimize long-term outcomes and clarify comparative benefits of these agents [6, 34].

Amifostine is a radioprotector initially developed as part of the nuclear warfare programs. One study demonstrated that the drug was delivered by intravenous injection and only one by subcutaneous injection, suggesting that hypodermic administration of the drug may substantially reduce these side effects [16]. The incidence of Grade 2 chronic xerostomia was significantly lower in the amifostine group at each visit compared to the control group [15]. Longitudinal analysis of overall quality-of-life scores indicated a net benefit with amifostine, with this difference approaching statistical significance over two years of follow-up [15]. Progression-free survival rates did not differ significantly between the amifostine and control groups at any time point. Similarly, overall survival did not differ significantly between groups at any measurement interval [15]. Longitudinal analysis demonstrated that patients treated with amifostine were significantly more likely to exhibit meaningful unstimulated saliva production during the one- to two-year post-treatment period [15]. The potential reduction of radiation-induced toxicities by amifostine must be balanced against the risk of amifostine-related toxicities within the context of each patient's treatment strategy [16].

Although the mechanisms underlying acupuncture are not fully understood, evidence from multiple studies suggests potential central nervous system effects mediated by fascial manipulation [39]. Additionally, studies have demonstrated a significant increase in blood flow in the cheek skin of patients with xerostomia [39]. At the end of the treatment period, a meta-analysis of three clinical trials investigating acupuncture found increased stimulated whole saliva production in the acupuncture groups [37]. The stimulated salivary flow rate did not differ significantly between the real acupuncture and sham acupuncture groups. The unstimulated salivary flow rate was not improved in the real acupuncture group compared with the sham acupuncture group [40]. Findings regarding the effect on objective salivary flow rates remain inconsistent. The overall evidence is constrained by study heterogeneity, potential placebo effects, and methodological limitations. High-quality, large-scale randomized controlled trials are necessary to confirm these results.

Extraoral TENS use is consistently effective for radiation-induced xerostomia, while the benefits of intraoral TENS use are more uncertain. A randomized trial by Dalbem Paim et al. demonstrates a beneficial effect of a brief, tailored TENS protocol, with long-term improvements in stimulated salivary flow and xerostomia-related quality of life, suggesting a rehabilitative rather than merely palliative effect of TENS [45]. Given these and other trials, Salimi et al. found that neither conventional TENS nor ALTENS showed any significant adverse effects, and they were both safe and feasible, often comparable with pharmacologic sialogogues, but noted a significant heterogeneity in electrode placement, parameters, and timing, which prevented them from defining an optimal protocol [46]. The LEONIDAS 2 phase 3 trial, on the other hand, did not show any clinically relevant difference between a long-term intraoral neuro electrostimulation device and sham for most salivary and quality-of-life outcomes, and only for limited gains in symptom level [47]. All of these results suggest that the efficacy of ENS is very sensitive to modulation type, type of stimulation site, timing of stimulation, and the importance of establishing standard ENS/ALTENS protocols and conducting more high-quality trials before ENS becomes a routine standard of care for any guidelines.

In the short term, photobiomodulation therapy (PBMT) has demonstrated positive results in decreasing the severity of xerostomia, enhancing saliva flow and quality of life, and has been well tolerated overall [52]. Evidence is, however, limited and inconsistent, and much of it is related to the weak long-term efficacy seen, which is partly due to differences in treatment protocols and study design. Thus, more high-quality RCTs are needed. Other studies have shown that stimulated saliva flow rate was higher in the case group and that subjective xerostomia was lower after the sixth follow-up session following photobiomodulation (PBM) treatment. This decrease was observed in the 4th, 5th, and 6th weeks [48]. The unstimulated salivary levels were higher in the case group than in the control group at follow-up, but this difference was not statistically significant. In particular, week six showed a statistically significant improvement in stimulated saliva [48]. The best laser settings to preserve salivary gland function are not yet known.

HBOT is known to increase vascularity, which helps prevent ischemic tissue damage [59]. Overall, patients undergoing HBOT have a significantly improved quality of life in the short term (0–6 weeks after treatment) compared to patients not undergoing HBOT. But at 1 year, patients in the HBOT group had slightly worse QoL scores than those in the placebo group [55]. In contrast, non-HBOT patients had somewhat variable but generally constant viscosity scores, whereas HBOT patients showed a negative correlation between treatment time and saliva viscosity, indicating progressive improvement [55]. Patients under HBOT also report a heightened sensation of dry mouth, whereas controls experience a slight worsening of dry mouth over time [55]. No increase in salivary flow rate has been shown with HBOT in a mouse model in vivo [56]. In another clinical study, patients with late soft-tissue radiation injury of the salivary glands experienced considerable subjective and objective improvement in xerostomia after undergoing HBOT [57]. Other studies demonstrated improved mouth opening, decreased discharge, and improved sinus drainage, but fistula closure and osteomyelitic changes were not statistically significant and may have required further procedures [59].

The purpose of intraoral stents is to reshape and secure oral tissues during radiotherapy, thereby minimizing acute and late effects in these areas including the oral mucosa, salivary glands and mandible [60-64]. Systematic reviews and clinical studies provide a consistent body of evidence that these devices can significantly reduce the incidence and severity of oral mucositis, trismus, and salivary changes in head and neck radiotherapy, demonstrating their clinical utility within toxicity-reduction strategies [62-64]. However, whether intraoral stents prevent xerostomia is unclear. In the absence of high-quality evidence, Chen et al. concluded that it had no preventive role for xerostomia and highlighted the need for more comprehensive, longer-term randomized and prospective trials [60]. However, positioning stents have been shown to increase unstimulated and stimulated salivary flow and improve xerostomia-related symptoms in an RCT by Mall et al., suggesting that the benefits may be context- and site-specific rather than universal [61]. Within the last decade, some systematic reviews and clinical studies have confirmed the benefit of intraoral stents to reduce the radiation dose to healthy oral tissues and to decrease the incidence or severity of oral mucositis, as well as other advantages such as trismus and salivary function, including in the maxillary and nasal cavity tumors [62-64]. However, differences in study data due to variable stent designs, tumor locations, radiotherapy techniques, and outcome measures make it difficult to draw general conclusions or establish consistent protocols [60-64]. Overall, intraoral stents appear to be low-risk adjuncts, with potential clinical benefits, when applied selectively [60-64]. Additional high-quality evidence is needed to better define their long-term outcomes and to substantiate guideline-level recommendations.

The available and reviewed evidence has some limitations and should be considered. The studies included are very heterogeneous in design, radiotherapy techniques, dosimetry, sample size, and follow-up period, complicating direct comparison and the carrying out of a meta-analysis. Another point of concern is that numerous trials of newer or supportive therapies such as ENS, PBMT, intraoral stents, and cellular therapies are small, sometimes single-center, and lack sufficient power to assess long-term outcomes or less common adverse effects. This English-language time limit from 2020 to 2025 also introduces language and publication bias and may not capture pre-existing foundational research.

Well-designed multicenter, randomized controlled trials with uniform outcome assessments (both subjective scales and objective salivary tests), and sufficient long-term follow-up are needed. Mesenchymal stem cells (MSCs) appear to be a more uniform stem cell therapeutic option [70]. However, data suggest that MSCs may reduce apoptosis, increase salivary protein expression, and promote markers of tissue repair, thereby restoring salivary flow and tissue healing [69]. Future studies need to work towards unifying sources of MSCs and treatment guidelines to improve the management of radiation-induced xerostomia and oral mucositis [69]. However, the clinical efficacy of adipose-derived mesenchymal stem/stromal cells (ASCs) is still uncertain [67, 68]. Improvements in certain measures, such as saliva flow rate and decreased saliva viscosity, have been reported, but these were only short-term and failed to achieve meaningful long-term improvements in function or quality of life. This implies that additional optimization of treatment protocols, such as dosage and frequency, is needed [67, 68]. New gene therapy strategies, such as viral vector-mediated aquaporin-1 gene delivery and CRISPR-Cas9 gene editing, have shown promising preclinical results in restoring salivary gland function following radiotherapy. Nevertheless, their clinical use is still restricted and further studies are required before their use can be recommended in practice [71]. The literature reviewed here has several important gaps. There is a lack of standardized outcome measures, which limits comparability across studies. Non-pharmacological intervention studies are further constrained by small sample sizes. Regenerative therapies, including MSC- and ASC-based approaches, lack long-term follow-up, so the durability of any functional or quality-of-life benefit remains unestablished. Finally, head-to-head comparisons between IMPT and IMRT are needed to define their relative advantages.

CONCLUSION

This study reviewed 35 studies published between 2020 and 2025 that evaluated preventive and therapeutic strategies for radiation-induced xerostomia in patients with head and neck cancer. Advanced radiotherapy techniques, particularly intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT), were associated with sustained reductions in xerostomia. Pilocarpine, cevimeline, and amifostine remained the principal pharmacologic interventions, while photobiomodulation, electrical nerve stimulation, acupuncture, and intraoral stents showed potential as adjunctive therapies in selected patients. Overall, the evidence supported a shift toward individualized, multimodal management strategies aimed at preserving salivary function and improving long-term quality of life. Future studies should prioritize well-designed, adequately powered clinical trials that compare multimodal treatment strategies and establish standardized outcome measures for salivary function and patient-reported xerostomia. Mesenchymal stem cell therapy and submandibular gland transfer have shown promising mechanistic rationale and preliminary safety; however, further clinical evidence is required before they can be recommended for routine practice. Future research should also identify patient-specific factors that can guide treatment selection and support the development of personalized prevention and management pathways.

Future recommendations. Future research should focus on: (i) multicenter, appropriately sized and powered randomized controlled trials with patient-centred outcome measures (e.g., XQ and unstimulated salivary flow) and follow-up longer than 24 months; (ii) head-to-head comparisons between IMPT and IMRT in anatomically suitable populations with HNC; (iii) optimization of dosing, timing and route of administration for pharmacologic and non-pharmacologic interventions; (iv) standardization of photobiomodulation and electrical-stimulation protocols to facilitate pooling across studies; and (v) translational programs for MSC and gene-therapy approaches with a long-term safety framework that is compliant with regulatory guidelines. Incorporating these priorities into international HNC survivorship guidelines will hasten patient-centred care and decrease the worldwide burden of xerostomia caused by radiation therapy.

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