Radiotherapy‐Induced Otitis Media With Effusion in Nasopharyngeal Carcinoma: A Meta‐Analysis

Nevin Yi Meng Chua; Yong Hoe Chan; Woei Shyang Loh; De Yun Wang

doi:10.1002/lary.70535

. 2026 Apr 1;136(9):3718–3731. doi: 10.1002/lary.70535

Radiotherapy‐Induced Otitis Media With Effusion in Nasopharyngeal Carcinoma: A Meta‐Analysis

Nevin Yi Meng Chua ^1,^✉, Yong Hoe Chan ¹, Woei Shyang Loh ², De Yun Wang ³

PMCID: PMC13460465 PMID: 41923272

ABSTRACT

Objective

Nasopharyngeal carcinoma carries a significant health burden in Asia, with incidence reaching up to 25 per 100,000. Post‐radiotherapy otitis media with effusion develops in 32.4% of NPC patients, representing the most frequent otologic toxicity. This meta‐analysis provides the first quantitative synthesis of post‐radiotherapy OME risk in NPC patients with technique‐specific estimates for clinical decision‐making.

Data Sources

PubMed, Embase, and Cochrane Library were searched from inception through April 23, 2025, using controlled vocabulary terms related to nasopharyngeal carcinoma, radiotherapy modalities, and otitis media with effusion. Additional articles were identified through reference screening.

Review Methods

Observational studies published as full‐length English articles reporting OME development in NPC patients following radiotherapy were included. The Newcastle‐Ottawa Scale assessed bias. Random‐effects modeling with risk difference (RD) as the effect measure was used, with Hartung‐Knapp adjustment applied to mitigate small‐study effects. Findings were reported per PRISMA guidelines.

Results

Eight studies comprising 10 cohorts (582 patients, mean age 50.4 years) were included. Among all NPC patients undergoing radiotherapy (n = 962), the overall RD was 0.08 (95% CI: 0.01–0.15, p = 0.0078). For OME‐naïve patients, the relative risk of acquiring OME post‐RT was 0.18 (95% CI: −0.06 to 0.42, p < 0.0001). Technique‐specific analysis revealed conventional two‐dimensional radiotherapy (2D‐RT) risk of 0.18 (95% CI: −0.24 to 0.60), three‐dimensional conformal radiotherapy (3D‐CRT) risk of 0.18 (95% CI: −0.13 to 0.49), and intensity‐modulated radiotherapy (IMRT) risk of 0.19 (95% CI: 0.01–0.27). Chemotherapy exposure and NPC stage showed no significant association.

Conclusion

Radiotherapy significantly increases OME risk in NPC patients with marked technique‐specific variation, enabling personalized counseling and evidence‐based surveillance protocol development.

Trial Registration:

CRD420251012963

Keywords: Eustachian tube dysfunction, nasopharyngeal carcinoma, otitis media with effusion, radiation dose–response relationship, radiotherapy

This meta‐analysis of eight studies comprising 582 NPC patients provides the first quantitative synthesis of radiotherapy‐induced otitis media with effusion (OME), demonstrating a significant overall risk difference of 0.18 (95% CI: −0.06 to 0.42, p < 0.0001) in OME naive ears. Technique‐specific analysis revealed comparable OME acquisition risks across 2D‐RT (RD 0.18), 3D‐CRT (RD 0.18), and IMRT (RD 0.19), with neither chemotherapy exposure nor tumour stage showing significant association to OME development. These findings establish post‐radiotherapy OME as a consistent and technique‐independent otologic toxicity in NPC, underscoring the need for routine audiologic surveillance and evidence‐based patient counselling across all radiotherapy modalities.

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1. Introduction

Nasopharyngeal carcinoma (NPC) represents a major global health burden. It is among the most common head and neck malignancies in Southern China and Southeast Asia [1], with incidence reaching up to 25 per 100,000 in some endemic regions [2]. Its incidence has also been increasing in populations across Polynesia and the Africas, placing significant medical burdens on these regions [3]. Driven by Epstein–Barr virus (EBV) associated carcinogenesis, NPC often presents at a locally advanced stage but remains highly radiosensitive [4]. With contemporary radiotherapy (RT) techniques and combined‐modality treatment, 5‐year overall survival now exceeds 80% in many series [5], creating a large and growing cohort of long‐term survivors [6]. As survival improves, clinical focus shifts from tumor control alone to the prevention and management of treatment‐related morbidity that can substantially impair quality of life.

Otitis media with effusion (OME) is one of the most frequent and clinically impactful otologic sequelae after RT for NPC [7]. A significant proportion of NPC survivors develop OME following RT, making it the single most common middle‐ear complication [8]. Persistent middle‐ear effusions lead to conductive and mixed hearing loss, recurrent otorrhoea, and chronic otitis media, with significant downstream effects on speech discrimination, social interaction, and overall quality of life [9]. In many patients, OME necessitates repeated procedures such as myringotomy or tympanostomy tube insertion, each carrying additional risks in irradiated ears. Despite this, OME is often under‐recognized compared with other late toxicities such as temporal lobe necrosis [10] or osteoradionecrosis [11], despite its cumulative morbidity being substantial at the population level.

Importantly, the pathophysiologic mechanisms underlying RT‐induced OME in NPC dose deposition to the eustachian tube, middle ear mucosa, and nasopharyngeal mucociliary apparatus are not unique to NPC [12]. Similar radiation fields and dose distributions are employed in other skull base malignancies, including skull base chordomas and pituitary/clival lesions [13]. As a result, insights into the dose–response relationship, temporal course, and management of RT‐induced OME in NPC survivors have broader relevance for patients receiving high‐dose RT to the skull base and adjacent structures. Understanding OME in NPC therefore informs not only NPC survivorship care but also has broader applicability in the design of safer RT plans and follow‐up protocols for a wide range of skull base diseases.

Prior reviews [14] on OME post head and neck RT treatments remain largely narrative and do not provide NPC‐specific, quantitative estimates that clinicians can use in decision making [7]. In particular, existing literature does not: (1) distinguish between overall changes in OME prevalence and the incidence of new‐onset OME in patients without pre‐treatment effusion; (2) compare absolute OME risk across RT techniques (two‐dimensional radiotherapy (2D‐RT), three‐dimensional conformal radiotherapy (3D‐CRT), intensity‐modulated radiotherapy (IMRT)); or (3) integrate dose–response data and management strategies into a coherent, evidence‐based framework. Consequently, physicians counseling NPC patients before RT can only state in broad terms that “RT increases the risk of OME,” without being able to quantify that risk, stratify it by technique, patient factors, or translate it into concrete surveillance and treatment algorithms. Moreover, current OME guidelines are derived largely from pediatric, non‐irradiated populations and provide limited guidance for adult NPC survivors with irreversible eustachian tube damage. Thus, our review aims to address these gaps in knowledge and add on to the existing repository of OME studies, possibly influencing future treatment guidelines and discussions with patients about the risks of NPC therapy.

1.1. PICO Question

The PICO question utilized in our study can be seen in Table 1.

TABLE 1.

PICO question utilized.

Population	Adult (≥ 18Y/O) patients diagnosed with nasopharyngeal carcinoma (NPC) through a biopsy who have undergone curative‐intent radiotherapy
Intervention	Treatment with different radiotherapy modalities including intensity‐modulated radiotherapy (IMRT), 3D conformal radiotherapy, or conventional external beam radiotherapy.
Context	NPC patients not receiving radiotherapy (if available) OR Subgroup analyses of radiation techniques/doses (e.g., IMRT vs. 2D‐RT)
Outcome	Primary: (1) Pooled absolute incidence: of OME at 1, 3, and 5 years post‐radiotherapy (2) Risk difference calculation for OME development compared to non‐irradiated controls Secondary: (1) Mean time to OME onset (2) Complication rates of OME interventions (chronic otitis media, tympanic membrane perforation) (3) Relationship between chemotherapy and OME development
Study types	Observational cohort studies, RCTs, Cross‐sectional studies, case–control studies

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2. Methodology

We searched three electronic databases—PubMed, Embase and Cochrane Library from inception through 23 April 2025 using both free texts and controlled vocabulary terms on keywords related to “nasopharyngeal carcinoma,” “radiotherapy,” “otitis media with effusion” and “serous otitis media”. We also looked for additional articles via the “snowball” search technique by screening the list of references of included articles. We have included the full search strategy in Supporting Information (Data S1,S2,S3).

2.1. Study Selection, Data Extraction, Risk of Bias Assessment and Quality of Evidence

Two authors (N.Y.C.M and Y.H.C) retrieved records and screened all abstracts to determine eligibility. Subsequently, each author independently retrieved the full texts to confirm eligibility for inclusion prior to data extraction. In case of any disagreement, consensus on the eligibility for inclusion was reached by discussion. Two authors (D.Y.W and W.S.L) reviewed and verified the extracted data. The study selection process is illustrated in Figure 1.

PRISMA diagram (Page 5). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

In this systematic review and meta‐analysis, we included any observational studies published as full‐length articles in peer‐reviewed journals that reported on the association between the development of OME in adult NPC patients post‐RT. The exposure group included adults with NPC who had undergone RT. Our study lacked a comparator group as RT is the standard first‐line treatment for NPC, and no studies have withheld this treatment from patients due to ethical concerns. Outcomes of interest included any markers of OME.

We excluded studies without adequate data on outcome measure, non‐English studies, and non‐full‐length articles.

Where available, we extracted both unadjusted and maximally adjusted measures of associations of OME with RT for NPC reported in each study. We collected key data items relating to study design, participant characteristics, exposure (RT for treatment of NPC) and outcome measure (presence of OME). The full list of data items is included in the Supporting Information (Data S4).

Two authors (N.Y.C.M and Y.H.C) independently applied the Newcastle‐Ottawa scale (NOS) tool to evaluate for risk of bias.

2.2. Data Analysis

We performed separate meta‐analyses for individual outcomes using the inverse variance‐weighted mixed‐effects model, pooling unadjusted and maximally adjusted effect measures separately. Between‐study heterogeneity was considered significant if the Q‐test p‐value was < 0.10 or if the I [2] statistic was ≥ 50%. We performed subgroup analyses to evaluate if the presence of OME prior to RT distorted the relative risk of developing OME post‐RT and to assess the effects of various RT modalities on the risk of developing post‐RT OME.

This review is registered on PROSPERO (CRD420251012963) and reported following the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) guidelines. Institutional review board approval was not required for this study because it involved data extracted from literature available in the public domain. Attempts were made to contact the corresponding authors of the respective papers if there was any missing data noted.

2.3. Outcomes Measured

The primary outcome of interest was the risk of developing OME post RT. Secondary outcomes included the effect chemotherapy might have had on OME development. OME was defined as the presence of middle ear effusion without acute infection, diagnosed using guideline‐endorsed methods [15], including otoscopy, pneumatic otoscopy, adjunctive tympanometry and/or audiometry. All included studies used at least one of these objective modalities to document effusion, as detailed in Table S1.

2.4. Unit of Data Analysis

The unit of analysis consisted of individual ears or individual patients. Two included studies reported separate cohorts within the same study. Vainer et al. reported two cohorts of patients with one cohort (termed “Vainer 2024(a)”) comprising patients treated with 3D‐CRT and the other (termed “Vainer 2024(b)”) comprising patients treated with IMRT. Likewise, Tsang et al. reported two cohorts of patients as well, with one (termed “Tsang 2012(a)”) undergoing 2D‐RT and the other (termed “Tsang 2012(b)”) undergoing IMRT. Given the substantial differences in radiation dose distribution and resultant ototoxicity profiles between RT techniques, pooling these heterogeneous treatment cohorts would introduce significant confounding effects on OME development. Following the Cochrane Handbook [16] guidance for studies with multiple, non‐overlapping treatment groups, each radiotherapy modality cohort was treated as an independent comparison. It should also be noted that several studies reported the number of patients with OME instead of ears. As our study intends to use risk difference (RD) as the effect size, the unit of analysis can either be the number of patients or ears regardless due to the nature of RD calculations.

2.5. Statistical and Meta‐Synthesis

The statistical analysis was conducted using Revman and R (version 4.4.1) with the meta and metafor packages. RD was selected as the effect measure due to its clinical interpretability in quantifying and comparing absolute risk of OME pre‐ and post‐RT. Given the ethical imperative of radiotherapy as standard‐of‐care treatment for NPC patients, withholding established curative treatment would not follow ethical guidelines, thus necessitating a within‐subject pre‐post intervention design utilizing pre‐radiotherapy otologic status as the control baseline. Due to some NPC patients having OME prior to radiotherapy, RD was used to quantify the absolute change in OME prevalence from pre‐ to post‐RT in the entire cohort (Figure 2), reflecting the populationattributable burden of R‐Tinduced OME. For consistency and interpretability, the same effect measure was applied in the analysis restr‐icted to OME‐naïve ears/patients (Figure 3), where a RD from a baseline of zero corresponds directly to the incidence proportion of new‐onset post‐RT OME among previously unaffected ears/patients. The values used in Figure 3 either came directly from the article stating the number of OME‐naïve ears/patients that developed OME post RT or was derived by subtracting the number of ears/patients with OME pre RT from the number of ears/patients with OME‐post RT with appropriate subtractions made from the total number of ears/patients in the cohort itself.

Forest plot illustrating risk of OME development post‐RT (page 8). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

Forest plot illustrating risk of OME development post‐RT only in OME‐naive ears (page 8). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

This methodological approach [17] eliminates between‐subject variability by using each patient as their own control while maintaining ethical treatment standards. A random‐effects model using the restricted maximum likelihood (REML) estimator was employed to account for between‐study heterogeneity, with confidence intervals calculated via the Hartung‐Knapp adjustment to mitigate small‐study effects. Subgroup analyses were conducted to assess for causes of between‐study heterogeneity. Leave‐one‐out analysis was conducted to assess individual study influence. Publication bias was evaluated through funnel plot asymmetry testing (Egger's regression) and trim‐and‐fill analysis.

2.5.1. Declaration Statement

Findings in this study were reported per the PRISMA 2020 reporting guideline [18] and the PRISMA 2020 reporting checklist.

3. Results

The PRISMA flowchart in Figure 1 illustrates the process by which our articles were selected. From our initial database search, 1544 abstracts were retrieved, of which 979 were screened after the removal of duplicates. Ultimately, eight studies [8, 19, 20, 21, 22, 23, 24, 25] were included for both qualitative and quantitative analyses (Table 2).

TABLE 2.

Characteristics of studies included in review.

	First author, year	Study design	Article title	Region	Overall participants	Participants with OME prior to RT	Mean/median age/years (control population)	Mean/median age/years (study population)
1	Wang, 2004 [19]	Prospective study	A Long‐Term Study on Hearing Status in Patients with Nasopharyngeal Carcinoma after Radiotherapy	Taiwan	220	69 ears	NR	NR
2	Vainer, 2024 [20]	Retrospective study	Post‐radiation middle ear effusion in NPC patients: Analysis of patient, tumor, and radiation factors	Israel	17	0 patients	55.4 years	59.2 years
2	Vainer, 2024 [20]	Retrospective study		Israel	56	14 patients	55.4 years	59.2 years
3	Hsin, 2013 [8]	Retrospective study	Postirradiation otitis media with effusion in nasopharyngeal carcinoma patients treated by intensity‐modulated radiotherapy	Taiwan	105	43 ears	43.6 years
4	Kew, 2000 [21]	Retrospective study	Middle Ear Effusions After Radiotherapy: Correlation With Pre‐Radiotherapy Nasopharyngeal Tumor Patterns	Hong Kong	32	19 ears	47.6 years (range 21–75 years)
5	Young, 2001 [22]	Longitudinal study	Mechanism of hearing loss in irradiated ears: a long‐term longitudinal study	Taiwan	10	5 ears	42.0 years (range 22–62 years)
6	Tsang, 2012 [23]	Restropective study	Long‐Term Hearing Results and Otological Complications of Nasopharyngeal Carcinoma Patients: Comparison between Treatment with Conventional Two‐Dimensional Radiotherapy and Intensity‐Modulated Radiotherapy	Hong Kong	40	1 ear	47.9 years
6	Tsang, 2012 [23]	Restropective study		Hong Kong	42	1 ear	46.2 years
7	Chi, 2015 [24]	Retrospective study	Inner Ear Deficits in Irradiated Nasopharyngeal Carcinoma Survivors	Taiwan	36	0 ears	56.0 years (range 29–71 years)
8	Wakisaka, 2010 [25]	Retrospective study	Incidence of long‐term ipsilateral and contralateral ototoxicity following radiotherapy for nasopharyngeal carcinoma	Japan	24	17 ears	55.9 years (range 25–83 years)

	NPC staging (TMN)				WHO classification			Type of RT used	Concurrent chemotherapy
	I	II	III	IV	I	II	III	Type of RT used	Chemotherapy agent	% of patients undergoing chemotherapy
1	NR	NR	NR	NR	NR	NR	NR	2DRT	Cisplatin	112 (51.0%)
2	2	14	23	34	2	32	39	3D‐CRT	Cisplatin	70 (95.9%)
2	2	14	23	34	2	32	39	IMRT	Cisplatin	70 (95.9%)
3	10	40	31	24	NR	NR	NR	IMRT	Cisplatin	95 (90.5%)
4	NR	NR	NR	NR	NR	NR	NR	Whole head RT	NR	NR
5	NR	NR	NR	NR	NR	NR	NR	Whole head RT	NR	NR
6	0	82	0	0	NR	NR	NR	2DRT	Cisplatin	1 (0.02%)
6	0	82	0	0	NR	NR	NR	IMRT	Cisplatin	1 (0.02%)
7	4	8	11	13	NR	NR	NR	3D‐CRT	Cisplatin	24 (66.7%)
8	5	9	4	6	NR	NR	NR	3D‐CRT	Cisplatin	9 (37.5%)

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3.1. Study Characteristics

Six retrospective, one prospective, and one longitudinal cohort study were included in our final analysis. Two included studies, —Vainer et al. and Tsang et al.—reported two separate cohorts within the same study. In total, we evaluated 10 cohorts consisting of 582 patients with an estimated mean age of 50.4 years. The studies included used a mix of photon‐based RT modalities such as 2D‐RT, 3D‐CRT, and IMRT.

3.2. Risk of Bias

The Newcastle–Ottawa Scale (NOS) was utilized to assess the risk of bias in these cohort studies (Table 3).

TABLE 3.

NOS tool for assessing the risk of bias in observational cohort studies included in our review.

Study	Selection 1	Selection 2	Selection 3	Selection 4	Comparability	Outcome 1	Outcome 2	Outcome 3	Total/study quality
Wang, 2004	★	★	★	★	★★	★	★	★	9/High
Hsin, 2013	★		★	★	★★	★	★	★	8/High
Vainer, 2024	★		★	★	★	★	★	★	7/Moderate
Wakisaka, 2011			★	★	★	★	★	★	6/Moderate
Chi, 2015			★	★	★	★	★		5/Low‐Moderate
Tsang, 2012	★	★	★	★	★★	★	★	★	9/High
Young, 2021	★		★		★	★	★	★	6/Moderate
Yu, 2023	★		★	★	★	★	★	★	7/Moderate

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Note: The presence of “★” indicates that the study fulfills that aspect of the NOS criteria.

Selection 1: Representativeness of the cases.

Selection 2: Selection of the non‐exposed cohort.

Selection 3: Ascertainment of exposure.

Selection 4: Demonstration that outcome of interest was not present at start of study.

Comparability: Comparability of cohorts on the basis of the design or analysis (worth 2 “★”).

Outcome 1: Assessment of outcome.

Outcome 2: Was follow‐up long enough for outcomes to occur.

Outcome 3: Adequacy of follow up of cohort.

3.2.1. Risks of Developing OME After Undergoing RT

The incidence of OME pre‐ and post‐RT was pooled and used to assess for RD. The incidence of OME in each study is presented in Table S1. The values in Table S1 were subsequently used to plot the forest plot illustrating the risk of NPC patients developing RT‐induced OME (Figure 2).

When analyzing all NPC patients who underwent RT, regardless of their OME status prior, pooled analysis of 10 cohorts (n = 962 post‐RT ears) demonstrated a significant overall RD of 0.08 (95% CI: 0.01–0.15, p = 0.0078). This suggests that at least 8% of OME cases can be attributable to radiotherapy as some patients with OME pre‐RT (i.e., OME secondary to NPC itself) may have experienced resolution of OME from tumor shrinkage (Figure 2). Substantial heterogeneity was observed (I² = 59.7%), with RD ranging from −0.02 to 0.26. Variability was also reflected in the follow‐up durations of each study (3–120 months) and the time frame in which each study assessed for the development of OME.

To address the confounding effect of pre‐existing OME on our analysis, a forest plot (Figure 3) was constructed excluding all patients with OME prior to RT using values from Table S2, representing the prevalence of OME in OME‐naïve patients only. A study (Young 2001) [22] was excluded as its methodology made it impossible to differentiate the risk of OME in OME‐naïve patients. For OME‐naïve patients, the relative risk of acquiring OME post RT was 0.18 (95% CI: 0.09–0.27, p < 0.0001). Substantial heterogeneity was observed (I² = 81.0%), with relative risk estimates ranging from 0.04 to 0.38. This substantiates that RT can result in the resolution of OME in patients with OME secondary to NPC. Conversely, for OME‐naïve patients, around 18% are at risk of developing post‐RT OME.

3.2.2. Subgroup Analysis on OME Risk by Type of RT

IMRT was found to increase the risk of OME development the most at 0.19 (95% CI: 0.01–0.27) followed by both 2DRT and 3D‐CRT at 0.18 (95% CI: −0.24 to 0.60) and 0.18 (95% CI: −0.13 to 0.49) respectively (Figure 4).

Forest plot illustrating risk of OME development post‐RT only in OME‐naïve ears subtyped by RT modality (page 9). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

3.3. Publication Bias

Publication bias assessed using a funnel plot (Figure 5) illustrated potential publication bias in our study. Visual inspection reveals an asymmetrical distribution of studies, with notable clustering toward the left side of the graph and several outliers showing larger RD. The Egger's regression test (Table S3) was used to provide a statistical assessment of potential publication bias. With an intercept of 1.771 (SE = 0.066, t = 1.008, p = 0.3431), it indicates no statistically significant evidence of small‐study effects or publication bias.

Funnel plot to assess for publication bias (page 9).

3.4. Leave One Out Analysis

Leave‐one‐out (LOO) sensitivity analysis (Table S4) of the data points used in Figure 3 reveals that the meta‐synthesis effect estimate remains largely robust across most study exclusions, with one notable exception. When omitting Tsang 2012(b), we observed the most substantial impact on the pooled RD values, with an absolute change of 0.035 to the current RD. The consistent RD estimates suggest that our findings are not unduly influenced by any single study except Tsang 2012(b). This pattern indicates that while overall conclusions remain valid, the Tsang 2012(b) study contributes disproportionately to both the magnitude of the effect estimate and the observed heterogeneity, warranting careful consideration when interpreting the clinical significance of our original results.

3.5. Chemotherapy's Effect on OME

Secondary analysis was further conducted to assess the potential role of concurrent chemotherapy as a risk factor for OME development post‐RT. Studies were stratified based on the proportion of patients in the study itself receiving chemotherapy: high exposure studies (≥ 80%, n = 3 cohorts), moderate exposure (50%–79%, n = 2 cohorts), and low exposure (< 50%, n = 3 cohorts).

The pooled OME risk estimates (Table S5) were 0.0220 (95% CI: −0.292 to 0.336) for high chemotherapy exposure cohorts, 0.0015 (95% CI: −0.129 to 0.132) for moderate exposure cohorts, and 0.0371 (95% CI: −0.039 to 0.114) for low exposure cohorts. No statistically significant differences were observed between strata (p = 0.891, p = 0.982, and p = 0.345, respectively), and there was minimal heterogeneity within each stratum (Q‐scores: 0.082, p = 0.959). The test for subgroup differences showed no significant association between chemotherapy exposure levels and OME risk (overall p > 0.05). These findings suggest that chemotherapy exposure, as stratified in the included cohorts, does not appear to be a significant independent risk factor for OME development.

3.6. Relationship Between NPC Staging and OME

The relationship between NPC staging and post‐RT OME development appears to be limited. Hsin et al. [8] demonstrated that tumor staging was not associated with the development of postirradiation OME. Existing factors such as pretreatment OME and radiation‐induced eustachian tube damage were found to be more significant predictive factors. Similarly, the analysis of individual ears revealed that OME could develop contralateral to the primary tumor side, suggesting that radiation toxicity rather than direct tumor effects predominantly influences OME development. These findings are consistent with what Tsang et al. [23] and Young et al. [22] reported. Taken together, it seems that while tumor staging remains crucial for NPC treatment planning and prognosis, it may not serve as a reliable predictor for post‐radiotherapy OME development.

4. Discussion

This meta‐analysis provides the first quantitative synthesis of post‐radiation OME risk in NPC patients undergoing radiotherapy. We demonstrate that radiotherapy significantly increases OME risk, with a pooled RD of 0.08 (95% CI: 0.01–0.15) in the overall cohort, rising to 0.18 (95% CI: 0.09–0.27) when analysis is restricted to OME‐naïve ears. In practical terms, this indicates that approximately one in five previously unaffected ears will develop OME after NPC radiotherapy. By separating overall change in prevalence from incident OME in OME‐naïve patients, these data provide clinicians with concrete, ear‐level estimates for counseling patients about their individual risk.

Subgroup analysis showed that OME risk was strikingly similar across radiotherapy techniques, with pooled RD of 0.18–0.19 for 2D‐RT, 3D‐CRT and IMRT with overlapping confidence intervals. Rather than implying a clear hierarchy of modality‐specific risk, this pattern underscores that clinically important OME is a shared toxicity of head and neck irradiation, independent of whether older two‐dimensional fields or state‐of‐the‐art IMRT are used. Existing studies [8, 20] have suggested that IMRT may paradoxically increase local otologic toxicity in some settings by inevitably including the eustachian tube and middle ear within clinical target volumes and by delivering higher integral dose to surrounding tissues [26, 27, 28]. Nevertheless, our findings indicate that transitioning from conventional to conformal techniques has not eliminated the problem of RT‐induced OME. This has important implications for centres worldwide, including those that still rely on 2D‐RT or 3D‐CRT as well as those using IMRT and supports a shift from assuming that newer techniques will solve OME to actively recognizing and managing it as a persistent, global survivorship issue.

4.1. Pathophysiology of RT‐Induced OME

Radiation induces both ultrastructural and histologic injury to the eustachian tube and middle ear mucosa [29]. Even at doses as low as 40 Gy, ciliated epithelial cells exhibit fusion, misalignment and collapse with secretion stasis and disrupted cellular architecture [30]. The submucosal stroma subsequently develops pronounced fibrosis, collagen deposition and widened intercellular spaces, changes that irreversibly compromise mucosal integrity and predispose to effusion [31]. Functionally, mucociliary clearance is profoundly impaired; irradiated patients show no saccharin transit at 20 min versus 5 min in controls and this deficit persists beyond 6 months [32, 33, 34]. Nasal mucosa is similarly vulnerable, with mucociliary failure appearing at threshold doses of 37–39 Gy within 3 months of IMRT [35]. Concurrently, RT activates a cytokine‐driven inflammatory cascade with transtympanic TNF‐α inducing effusion in 70% of cases [36]; IL‐1β, IL‐6, IL‐8, and TNF‐α rise over the first 72 h, correlating with neutrophil‐rich fluids [37, 38] and VEGF upregulated by HIF‐1α enhances vascular permeability and effusion formation via VEGFR2 activation [39, 40, 41]. Finally, dose–response analyses confirm that Eustachian Tube dosages > 52.75 Gy and mastoid dosages (M.D0.5CC) > 41 Gy significantly elevate OME risk (OR = 3.77, p = 0.012; OR = 1.27, p = 0.033) [12, 20].

4.2. Consequences of RT‐Induced OME

RT‐induced OME can result in hearing loss and chronic otitis media (COM). Middle‐ear effusions cause conductive shifts of 15–20 dB at speech frequencies when cochlear doses exceed 43 Gy, with deficits persisting long‐term [12, 42]. RT‐induced OME increases the risk of bone‐conduction deterioration by three‐ to five‐fold, demonstrating how mucosal inflammation [43] potentiates sensorineural damage within the same auditory pathway [7]. An existing study [8] found that the progression of COM post‐IMRT was common as well, with the number of NPC patients diagnosed with COM tripling after IMRT therapy compared to pre‐IMRT. Chi et al. [24] found two‐thirds of vestibulocochlear deficits a decade post‐treatment were secondary to persistent middle‐ear disease rather than primary cochlear injury. Despite IMRT reducing catastrophic complications like external auditory canal necrosis, median pure‐tone averages still decline 7 dB over five years [42, 44], demonstrating that improved dose sculpting alone cannot eliminate effusion‐mediated ototoxicity. Histopathological studies [45] and subsequent ultrastructural investigations have identified round‐window inflammatory mediator diffusion and scala‐tympani cytokine influx [46, 47] as mechanisms by which sustained OME converts to irreversible hair‐cell loss, mirroring the clinical co‐occurrence of conductive and sensorineural components.

4.3. Temporal Considerations and Clinical Course

RT‐induced OME in NPC patients evolves through a predictable sequence driven by eustachian tube dysfunction [48]. In the acute phase (0–6 months), inflammation predominates: new B‐type tympanograms appear in 25%–33% of ears within 3 months and 88% of previously normal tubes become dysfunctional, accounting for all early OME cases [43, 48]. Although many effusions resolve, 20%–30% persist beyond 1 year in modern IMRT cohorts, reflecting submucosal fibrosis and cartilaginous scarring [8, 20]. From 1 to 5 years, some patients experience partial remission, but complete resolution is rare. Late mucociliary failure and isthmus stenosis are other factors that often cause OME rates to rise after 5 years [49]. Comparable time courses occur in other notable radiation sequelae, rhinosinusitis peaks at 3–6 months (47%–68%) [35, 50, 51], skull‐base osteoradionecrosis arises at a mean of 45.6 months [11] and temporal‐lobe necrosis emerges at a median of 33–38 months (4.6%–8.5%) [10], supporting a unified, stepwise model of tissue injury. At the molecular level, ionizing radiation generates reactive oxygen species that fragment DNA and release DAMPs, activating inflammasomes within 24 h [52, 53]. A caspase‐1–driven cytokine surge, dominated by TNF‐α and IL‐1, peaks early with sustained ROS activating c‐Jun, NF‐κB, and TGF‐β1 signaling, driving myofibroblast conversion, and collagen deposition over months [54, 55]. Chronic oxidative stress and endothelial damage subsequently lead to hypoxia, cellular senescence, and progressive fibrosis [56]. In the eustachian tube and middle ear mucosa, this cascade silences ciliary activity within days [57], thickens the isthmus and stiffens support structures—transforming normal tubes into persistently dysfunctional conduits predisposed to effusion even years after state‐of‐the‐art radiotherapy [20].

4.4. Clinical Implications

No dedicated clinical practice guidelines exist for the management of RT‐induced OME [58]; current practice is largely extrapolated from pediatric, non‐irradiated OME guidelines [59, 60] that recommend a 3‐month period of watchful waiting before intervention. These recommendations do not reflect the chronic, often irreversible eustachian tube dysfunction seen after skull‐base irradiation, where cohort studies have documented effusions and tube impairment persisting well beyond 12 months and in some cases for up to a decade after treatment. Our findings therefore support NPC‐specific follow‐up protocols that include routine otologic and audiologic assessment at approximately 3, 6, and 12 months post‐RT, using the 12‐month visit as a key decision point to escalate evaluation or intervention in patients with persistent, symptomatic effusions.

The 18% absolute risk of new‐onset OME in OME‐naïve ears provides a concrete figure for pre‐treatment counseling, moving OME from a vague “ear complication” to a quantifiable toxicity that can be discussed alongside xerostomia, temporal lobe necrosis, and osteoradionecrosis when patients weigh long‐term risks. For individuals whose employment or daily function depends heavily on hearing [15], this quantified risk should prompt closer baseline audiometry, more intensive surveillance, and early referrals to otology.

The broadly similar OME risk observed across 2D‐RT, 3D‐CRT, and IMRT indicates that RT‐induced OME is not confined to outdated technology but is a shared toxicity of head and neck irradiation worldwide. Centres in low‐ and middle‐income countries that still rely on 2D‐RT or 3D‐CRT and high‐income centres using IMRT should therefore all anticipate OME, screen for it, and incorporate its management into standard NPC survivorship pathways.

Finally, the lack of strong associations between chemotherapy exposure or tumor stage and OME, together with dose–volume data implicating eustachian tube and mastoid doses, suggests that the most promising levers for risk reduction lie in radiotherapy planning and otology‐led interventions. Incorporating eustachian tube and mastoid dose‐volume constraints where feasible, identifying high‐risk patients (baseline OME, prior ear disease, borderline audiometry) for early otology input and rigorously evaluating emerging interventions such as balloon eustachian tuboplasty or novel local therapies in irradiated ears should be priorities for international research collaborations.

4.5. Current Management Strategies for RT‐Induced OME

RT‐induced OME in NPC patients presents distinct management challenges due to radiation causing irreversible eustachian tube damage and persistent mucosal inflammation [61, 62, 63, 64, 65, 66, 67, 68, 69, 70]. Current management strategies for RT‐induced OME are summarized in this table (Table S6). Spontaneous resolution after RT is rare (4%–17.6%), compared to roughly 75% in pediatric OME [69, 70]. Simple myringotomy is now favored as the current first‐line therapy; a 2024 meta‐analysis found otorrhea rates of 6.7%–20% versus 32%–60% for tympanostomy tubes, although myringotomy often requires repeat procedures [71]. Tympanostomy tubes in irradiated ears carry high complication rates, with one series reporting discharge in 47.8% of tube cases versus 10.9% after myringotomy [70]. Emerging options also include laser myringotomy with intratympanic steroids, which achieved 78.3% symptom relief but left 21.7% with persistent otorrhea [64] and balloon eustachian tuboplasty, which alone produced only 1.7% complete recovery over 24 months [61]. Despite these advances, all modalities have significant drawbacks underscoring the need for individualized risk stratification. We propose a stepwise framework beginning with 3–6 months of observation, followed by myringotomy for persistent effusions, with tympanostomy tubes reserved for severe or refractory cases. This approach balances efficacy and morbidity and can be tailored to each patient's risk profile.

4.6. Study Strengths

Our investigation demonstrates several methodological strengths enhancing the reliability and clinical applicability of our findings. Statistical rigor was achieved through random‐effects modeling with restricted maximum likelihood estimation, Hartung‐Knapp confidence interval adjustments, comprehensive heterogeneity assessment using I [2] statistics and leave‐one‐out sensitivity analyses. This represents the first meta‐analysis providing technique‐specific quantitative risk estimates for RT‐induced OME, filling a critical evidence gap identified in previous narrative reviews. Our comprehensive search strategy across three major databases with snowball methodology ensured exhaustive literature capture, while employing RD as the primary outcome measure provides clinically interpretable absolute risk estimates essential for patient counseling and healthcare planning.

4.7. Study Limitations

Several limitations warrant acknowledgment. High heterogeneity reflects substantial variability across studies, potentially limiting the precision of our pooled estimates although this was expected given our focus on NPC patients. The predominance of observational cohort studies without randomized controlled trials inherently increases susceptibility to selection bias, confounding, and methodological variability. Geographic concentration in Asian populations limits generalizability to other ethnicities, while temporal variability in radiation techniques introduces potential era‐of‐treatment confounding.

4.8. Further Research Directions

Our findings demonstrate that radiotherapy for NPC significantly increases OME risk, manifesting as early or late complications. Future research should focus on minimizing OME risk through several approaches. Studies should investigate patient optimization strategies, including prophylactic eustachian tube balloon dilation for high‐risk patients, analogous to pre‐radiotherapy dental evaluation in oral cancers to prevent osteoradionecrosis. Evaluating various radiotherapy techniques and their associated OME risk should also be prioritized. Prospective longitudinal studies with standardized outcome measures, uniform radiation techniques, and consistent follow‐up protocols are needed to validate our risk estimates while minimizing methodological heterogeneity [72]. Individual patient data meta‐analyses would enable sophisticated adjustment for confounding variables, exploration of dose–response relationships, and investigation of patient‐specific risk factors contributing to OME development [73]. Finally, biomarker discovery research should identify predictive markers for OME susceptibility, potentially incorporating genetic polymorphisms affecting radiation sensitivity, inflammatory responses, and tissue repair mechanisms [74, 75].

5. Conclusion

This meta‐analysis represents the first comprehensive quantitative synthesis of RT‐induced OME risk in NPC patients. In OME‐naive NPC patients, the risk of developing OME post RT extends to 18%. Additionally, we demonstrate technique‐specific variation in RT‐induced OME risk, with IMRT conferring the highest risk, followed by 2D‐RT and 3D‐CRT. These findings necessitate a revision of existing OME management paradigms and provide quantitative evidence for developing specialized post‐RT OME surveillance protocols and treatment algorithms for NPC survivors.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1: PubMed search strategy from inception until 23rd April 2025.

Data S2: Embase search strategy from inception until 23rd April 2025.

Data S3: Cochrane search strategy from inception until 23rd April 2025.

Data S4: Data extracted from each article included in the review.

Table S1: Table of OME prevalence and diagnosis in studies included (values used to plot Figure 2) (page 8).

Table S2: Table of OME prevalence in OME‐naïve ears/patients only (values used to plot Figure 3) (page 8).

Table S3: Egger's regression test for publication bias (page 9).

Table S4: Leave‐One‐Out analysis for sensitivity analysis (page 9).

Table S5: Chemotherapy stratification of studies and effect on OME risk (page 9).

Table S6: Summary of studies assessing management strategies for post‐RT OME (page 14).

LARY-136-3718-s001.docx^{(49.5KB, docx)}

Chua N. Y. M., Chan Y. H., Loh W. S., and Wang D. Y., “Radiotherapy‐Induced Otitis Media With Effusion in Nasopharyngeal Carcinoma: A Meta‐Analysis,” The Laryngoscope 136, no. 9 (2026): 3718–3731, 10.1002/lary.70535.

[Correction added on 14 April 2026, after first online publication: The copyright line was changed.]

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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