Hearing Loss and Middle Ear Effusion in Nasopharyngeal Carcinoma Following Radiotherapy: Dose–Response Relationship and Normal Tissue Complication Probability Modeling

Wungcharoen, Prem; Prayongrat, Anussara; Tangjaturonrasme, Napadon

doi:10.1055/s-0045-1805045

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Original Research • Int Arch Otorhinolaryngol. 29 (2) • 2025 • https://doi.org/10.1055/s-0045-1805045 linkcopy

Hearing Loss and Middle Ear Effusion in Nasopharyngeal Carcinoma Following Radiotherapy: Dose–Response Relationship and Normal Tissue Complication Probability Modeling^*

Authorship SCIMAGO INSTITUTIONS RANKINGS

Introduction Radiotherapy is the primary treatment for nasopharyngeal carcinoma. Radiation exposure to the cochlea and middle ear can cause hearing loss.

Objective To develop a multivariable normal tissue complication probability (NTCP) model to predict the risk of hearing impairment in nasopharyngeal cancer patients based on clinical and radiation dosimetry features and to identify the key factors associated with hearing loss.

Methods A retrospective review of 229 patients was conducted. We recorded the audiometry and presence of middle ear effusion (MEE) and compared findings before and after therapy. The factors included age, gender, signs and symptoms at presentation, tumor staging, prescribed dose at the tumor and high-risk nodal region, cochlea, and concurrent chemotherapy treatment. The model was formulated using multivariate logistic regression.

Results Age of more than 50 years, high primary staging, and dose at the cochlea > 43 Gy were major risk factors for sensorineural hearing loss. The final NTCP model for hearing loss comprised age and cochlea dose with an area under the curve (AUC) of 0.644; the predicted risk ranged from 15.84 to 44.52%. Locally advanced disease and cochlea dose greater than 44 Gy were risk factors for MEE; the predicted risk ranged from 20.42 to 51.99%.

Conclusion Age over 50, T stages 3 and 4, and > 43 Gy dose to the cochlea were significantly associated with an increased risk of sensorineural hearing loss and MEE. The developed NTCP model provides information to predict these risks, aiding in treatment planning and decision-making to avoid complications.

Keywords
nasopharyngeal neoplasms; hearing loss; radiotherapy; proton; otitis media with effusion

Baseline characteristics at presentation		Patients (n = 229)	Percentage (%)	Treatment characteristics		Patients (n = 229)	Percentage (%)
Gender	Female	81	35.37	Radiation technique	IMRT	24	10.49
Gender	Male	148	64.63	Radiation technique	VMAT	205	89.51
Age	< 50 years	102	44.54	Concurrent chemotherapy	No	16	6.99
Age	≥ 50 years	127	55.46	Concurrent chemotherapy	Yes	213	93.01
Signs and symptoms	Nasal	122	53.27	Follow-up audiogram (days)	< 31	3	1.31
	Aural	102	44.54		31–90	74	32.31
	Neck mass	103	44.97		91–180	55	24.02
	Neural	26	11.35		181–365	48	20.97
TNM stage	T (%)	N (%)	M (%)		> 365	49	21.39
0		50 (21.9)	222 (96.9)	Average follow-up (days)		254.86
1	66 (28.8)	61 (26.6)	7 (3.1)	Median follow-up (days)		130
2	58 (25.3)	92 (40.2)
3	55 (24.0)	26 (11.4)
4	50 (21.8)

Analyzed factors	Group I: normal hearing (N = 133)	Group II: hearing loss (N = 96)	p-value
Gender: male – n (%)	85 (63.9)	63 (65.6)	0.79
Age in years (IQR)	49 (39–56)	55.5 (43.5–61)	0.002*
Age groups: n (%)
• < 50 years • ≥ 50 years	68 (51.1) 65 (48.9)	34 (35.4) 62 (64.6)	0.04*
Symptoms at presentation: n (%)
Aural	55 (41.4)	47 (49)	0.25
Nasal	66 (49.6)	56 (58.3)	0.19
Mass	59 (44.4)	44 (45.8)	0.83
Neural	11 (8.3)	15 (15.6)	0.11
Staging: n (%)
T3–4	53 (39.6)	52 (54.2)	0.03*
N2–3	64 (47.8)	54 (56.3)	0.20
M1	2 (1.5)	5 (5.2)	0.11
Treatment protocol
D_max: GTV-NP (IQR) in cGy	7,428 (7,301–7,529)	7,458 (7,306–7,578)	0.42
D_max: CTV-NP (IQR) in cGy	7,274 (7,156–7,431)	7,302 (7,107.5–7,455.5)	0.53
D_max: PTV-70 (IQR) in cGy	7,192 (6,997–7,325)	7,252 (6,990–7,376.5)	0.32
Using chemotherapy: n (%)	119 (89.5)	94 (97.9)	0.28
Analyzed factors	Group I: post-RT normal hearing, ears (N = 321)	Group II: post-RT hearing loss, ears (N = 137)	p-value
D_mean: cochlear dose (IQR) in cGy	4,157 (3,588–5,017)	4,817 (3,893–5,810)	< 0.001*

Analyzed factors		Univariate analysis		Multivariate analysis
Factors	Reference	OR (95%CI)	p-value	aOR (95%CI)	p-value
Male	Female	1.12 (0.73–1.71)	0.06
Age group ≥ 50 years	< 50	1.68 (1.11–2.53)	0.01*	1.67 (1.09–2.55)	0.02*
T 3–4	0–2	1.60 (1.07–2.39)	0.02*
N 2–3	0–1	1.42 (0.95–2.13)	0.29
M1	0	1.79 (0.61–5.27)	0.29
Cochlear dose≥ 4,300 cGy	< 4,300	2.58 (2.69–3.92)	< 0.001*	2.57 (1.68–3.92)	< 0.001*

Age at RT ≥ 50 years	Cochlear dose > 43 Gy	Modifying factor S (x)	Risk factor for hearing loss (%)
Yes	Yes	−0.22	44.52
Yes	No	−1.16	23.86
No	Yes	−0.73	32.51
No	No	−1.67	15.84

Analyzed factors	Group I: no MEE post-RT (N = 123)	Group II: new MEE post-RT (N = 92)	p-value
Gender: male – n (%)	77 (62.6)	61 (66.3)	0.58
Age in years (IQR)	50 (40–59)	52.5 (41.5–58)	0.55
Age groups: n (%)
• < 50 years • ≥ 50 years	49 (39.8) 74 (60.2)	50 (54.3) 42 (45.7)	0.72
Symptoms at presentation: n (%)
Aural	46 (37.4)	47 (51.1)	0.04*
Nasal	67 (54.5)	48 (52.2)	0.74
Mass	51 (41.5)	48 (52.2)	0.12
Neural	8 (6.5)	16 (17.4)	0.01*
Staging: n (%)
T3–4	45 (36.6)	53 (57.6)	0.002*
N2–3	62 (50.4)	49 (53.3)	0.68
M1	6 (4.9)	1 (1.1)	0.12
Treatment protocol
D_max: GTV-NP (IQR) in cGy	7,458 (7,294–7,540)	7,411.5 (7,302.5–7,577.5)	0.92
D_max: CTV-NP (IQR) in cGy	7,272 (7,143–7,438)	7,293.5 (7,165.5–7,453.5)	0.45
D_max: PTV-70 (IQR) in cGy	7,190 (6,982–7,357)	7,234 (7,007.5–7,341)	0.42
Using chemotherapy, n (%)	113 (91.9)	89 (96.7)	0.55
Analyzed factors	Group I: no MEE post RT, ears (N = 123)	Group II: new MEE post RT, ear (N = 92)	p-value
D_mean: cochlear dose (IQR) in cGy	4,255 (3,591–5,314)	4,601 (3,765–5,687)	< 0.001*

Analyzed factors		Univariate		Multivariate
Factors	Reference	OR (95%CI)	p-value	aOR (95%CI)	p-value
Male	Female	1.05 (0.67–1.67)	0.80
Age group ≥ 50 years	< 50	1.09 (0.71–1.69)	0.69
T3–4	0–2	2.95 (1.88–4.63)	< 0.001*	2.76 (1.75–4.35)	< 0.001*
N2–3	0–1	1.04 (0.67–1.61)	0.86
M1	0	0.21 (0.03–1.66)	0.14
Cochlear dose (cGy)	< 4,400	1.80 (1.16–2.81)	0.01*	1.54 (0.98–2.43)	0.06

T-stages 3 and 4	Cochlear dose > 44 Gy	Modifying factor S (x)	Risk factor for MEE (%)
Yes	Yes	0.08	51.99
Yes	No	−0.35	41.33
No	Yes	−0.93	28.29
No	No	−1.36	20.42

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[TFN1] Abbreviations: IMRT, intensity-modulated radiotherapy; M, metastasis; N, node; T, tumor; TNM, tumor, node, and metastasis staging; VMAT, volumetric modulated arc therapy.

Hearing Loss and Middle Ear Effusion in Nasopharyngeal Carcinoma Following Radiotherapy: Dose–Response Relationship and Normal Tissue Complication Probability Modeling*

Hearing Loss and Middle Ear Effusion in Nasopharyngeal Carcinoma Following Radiotherapy: Dose–Response Relationship and Normal Tissue Complication Probability Modeling^*