Increased Incidence of Mastoiditis in Nasopharyngeal Carcinoma following Anti-PD-1 Therapy: A Propensity-Matched Analysis

doi:10.21203/rs.3.rs-2251490/v1

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Increased Incidence of Mastoiditis in Nasopharyngeal Carcinoma following Anti-PD-1 Therapy: A Propensity-Matched Analysis

https://doi.org/10.21203/rs.3.rs-2251490/v1

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Background

Mastoiditis can be triggered by radiotherapy and is closely associated with hearing loss. We aimed to explore the incidence rate of mastoiditis in locally advanced nasopharyngeal carcinoma (LANPC) patients following anti-programmed death 1 (PD-1) therapy.

Methods

Patients with primary locoregionally advanced nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin-based chemotherapy with or without anti-PD-1 therapy between from January 2020 to January 2022 in one medical facility were retrospectively reviewed. Group A received neoadjuvant chemotherapy (NACT) + concurrent chemoradiotherapy (CCRT) + anti-PD-1 therapy, while Group B did not receive anti-PD-1 therapy. A propensity score matching (PSM) method was used to match patients from each group in a 1:1 ratio. Severity of mastoiditis was evaluated by magnetic resonance imaging (MRI), specifically, mastoid opacification was graded from mild to severe on a scale of 0–3.

Results

In total, 146 out of 259 eligible patients were propensity matched, with 73 patients in Group A and 73 patients in Group B. No significant differences were observed in the patient and tumor characteristics between Group A and Group B. There were no significant differences between the two groups for the incidence rates of severe mastoiditis before NACT, before CCRT and 0 month following CCRT; while the incidence rates of severe mastoiditis 3, 6 months following CCRT in the Group A versus Group B were 34.2% versus 20.5% (p = 0.044), 37.7% versus 21.9% (p ＜ 0.001), were significance different respectively. The analysis of variance (ANOVA) with repeated measures showed that anti-PD-1 therapy (p = 0.031) significantly increased the incidence rate of severe mastoiditis in LANPC patients compared to that of immunotherapy-free patients following CCRT (p < 0.001).

Conclusions

LANPC patients following anti-PD-1 therapy experienced severe mastoiditis with an increased probability.

nasopharyngeal carcinoma

mastoiditis

anti-PD-1 therapy

propensity-score matching

Nasopharyngeal carcinoma (NPC) caused the endemic in Southeast Asia and Southern China, and an age-standardized incidence rate of 3.0 to 10.2 per 100 000 population has been reported in China [1–3]. Mastoiditis is manifested as mastoid effusion and occurred frequently in patients with NPC before and after radical radiotherapy. A rise in the incidence of mastoiditis following nasopharyngeal radiation has been reported to range from 15–50%, and with the addition of intensity-modulated radiotherapy (IMRT), the incidence of mastoiditis becomes stable because of its high target area adaptability[4–7]. Mastoiditis in NPC patients reduces life quality and its manifested symptoms include ear fullness or pressure, tinnitus, pain, otorrhea and even hearing loss[8]. Immune checkpoint inhibitors (ICIs) have shown to improve clinical outcomes in treating patients with diverse types of cancer and have been frequently used in treating patients with early cancer states[9, 10]. Several results showed that programmed death 1 (PD-1) inhibitor was well tolerated in patients with relapsed or metastatic NPC (RM-NPC) and medicated tumoricidal activity during the course of treatment, or in combination with platinum-based chemotherapy[11–15]. Recently, the associated risk factors of mastoiditis have been assessed during the course of two-dimensional conventional radiotherapy (2D-CRT) and IMRT[7, 16–18], but the incidence rate of mastoiditis following immunotherapy remains unknown. Given that immunotherapy can cause numerous immune-related adverse events (irAEs)[19, 20], the present study intended to investigate whether mastoiditis, an inflammatory disease, can occur as a type of irAEs following immunotherapy among NPC patients, and to explore its related incidence rate.

Study population

In our retrospective study, all recruited patients were newly diagnosed NPC and admitted to Sun Yat-sen University Cancer Center between January 2020 and January 2022. The present study was approved by the Institutional Ethical Review Board of the Sun Yat-sen University Cancer Center (Guangzhou, China, B2022-174-01), and informed consent was obtained from all patients. The principles of the Helsinki Declaration guided the treatment protocols. The inclusion criteria for this study were: (1) newly diagnosed, pathologically confirmed, and previously untreated NPC; (2) M0 stage NPC; (3) treated with platinum-based neoadjuvant chemotherapy, or with radical radiotherapy with IMRT, or with anti-PD-1 therapy; (4) complete and regular imaging examination; and (5) age between 18 and 70 years old. Exclusion criteria were as follows: (1) previous diagnosis of malignant tumors or other concomitant malignant diseases; (2) distant metastasis at the time of diagnosis; (3) behavioral status score, Karnofsky Performance Status score (KPS score) ≤ 70 points; (4) severe medical complications, important organ (heart, lung, liver, kidney) dysfunction or neuropsychiatric disorders at the time of diagnosis; (5) aged > 70 years; (6) unable to withstand chemotherapy; (7) interruption of radiotherapy or anti-PD-1 therapy. In this retrospective study, a total of 259 patients met inclusion criteria and were recruited. Based on whether or not received anti-PD-1 therapy, patients were divided into the immunotherapy (Group A, n = 73) and immunotherapy-free (Group B, n = 73) subgroups by propensity match, respectively.

Clinical staging

Demographic information (age, sex, KPS and body-mass-index (BMI)) and current medical history (disease course, AJCC TNM 8 staging, World Health Organization (WHO) pathological type, treatment regimen) were collected[21]. Clinical tumor staging of T and N stage was determined by magnetic resonance imaging (MRI) and M stage by PET/CT according to the criteria from American Joint Committee on Cancer TNM Staging Manual, 8th edition[22]. At each follow-up time point, 2 blinded expert reviewers individually assessed the degree of mastoiditis through MRI in each patient using diagnostic criteria as well as their own individual clinical experience.

Treatment

Radiation therapy

All patients (n = 146) were treated with a full course of IMRT. The primary nasopharyngeal gross tumor volume (GTVnx) and metastatic retropharyngeal nodes were determined based on MRI and/or PET-CT imaging, endoscopic and clinical findings. Enlarged retropharyngeal lymph nodes are also delineated in GTVnx. GTVnd was defined as gross tumor volume of neck metastasis lymph node. The clinical target high-risk volume (CTV1) was defined as a subclinical disease consisting of a 0.5–1.0 cm margin (0.2 to 0.3 margin posteriorly) surrounding the GTVnx, and it must include the whole nasopharynx wall, as well as the high-risk sites of microscopic extension. The clinical target low-risk volume (CTV2) consisted of CTV1 and a 0.5–1.0 cm margin (0.2 to 0.3 margin posteriorly) to encompass the low-risk sites of microscopic extension, the level of the lymph node and the elective neck area (all N0 patients routinely delineated bilateral IIa, IIb, III, and Va regions, while N1–3 patients additionally delineated ipsilateral IV, Vb, or supraclavicular fossa regions). The prescribed doses of PTVs of GTVnx, CTV1, CTV2 and CTVnd were mainly 69.96Gy, 59.4Gy, 54Gy and 69.96Gy in 33 fractions, respectively. Patients were treated with one fraction daily, 5 days/week. The dose received by each organs at risk (OAR) was limited to tolerance according to the RTOG 0225 protocol[23].

Chemotherapy

All patients (n = 146) received platin-based chemotherapy, which was given as neoadjuvant and concurrent therapy. For patients with locally advanced nasopharyngeal carcinoma (LANPC), guidelines recommend concurrent chemoradiotherapy (CCRT) following neoadjuvant chemotherapy (NACT) as the preferred standard of care of choice[24, 25]. The NACT regimens included GP (n = 111), TP (n = 8), PF (n = 8), TPF (n = 13) or TPC (n = 6). GP: 1.0 g/m2 gemcitabine on day 1, 8 and 80 mg/m2 cisplatin on day 1. TP: 260 mg/m2 paclitaxel and 80 mg/m2 cisplatin on day 1; 260 mg/m2 paclitaxel and 30 mg/m2 lobaplatin on day 1; 70 mg/m2 docetaxel and 70 mg/m2 nedaplatin on day 1; 70 mg/m2 docetaxel and 30 mg/m2 lobaplatin on day 1. PF: 80 mg/m2 cisplatin on day 1 and 800 mg/ m2 fluorouracil civ on days 1–5. TPF: 260 mg/m2 paclitaxel or 60 mg/m2 docetaxel on day 1, 60 mg/m2 cisplatin on day 1 and 500 mg/ m2 fluorouracil civ on days 1–5. TPC: 200 mg/m2 paclitaxel on day 1, 60 mg/m2 cisplatin on day 1 and 1000 mg/m2 capecitabine twice daily for 14 days every 3 weeks. Cycles were repeated every 3 weeks for a total of 3 cycles, followed by radiotherapy (RT) performed concurrently with platin-based chemotherapy. In Group A, more patients received neoadjuvant GP (n = 46, 63.0%) than TPC (n = 13, 17.8%) whereas patients in Group B more often had neoadjuvant GP (n = 65, 89.0%) than PF (n = 8, 11.0%) therapy. The reasons for deviating from the institutional guidelines included organ dysfunction suggesting intolerance to chemotherapy, patient refusal, and the discretion of the doctors in individual cases. No patient discontinued chemoradiotherapy during our study.

Anti-PD-1 therapy

At the time of the study, immune checkpoint inhibitors were gradually popularized and applied in LANPC. Camrelizumab, toripalimab and tislelizumab were administered intravenously every 3 weeks at initial doses of 200 mg, 240 mg and 200 mg, respectively, until progress disease or death. A total of 73 patients received full doses of Anti-PD-1. 66 (45.2%) patients received camrelizumab, 6 (4.1%) received toripalimab, 1 (0.7%) received tislelizumab, 73 (50.0%) had not received anti-PD-1 therapy. The proportions of patients received the first dose of anti-PD-1 therapy starting in the neoadjuvant, concurrent, and adjuvant phases were 26.0 (17.8%), 43 (29.5%), and 4 (2.7%), respectively.

MRI

All patients underwent standard MRI and were follow-up in our institution: 0 (before NACT), 2 (before CCRT), 4 (0 months after CCRT), 7 (3 months after CCRT), 10 (6 months after CCRT) months after diagnosed. All MRI examinations were performed on a 3.0T or 1.5T scanner. The following sequences were obtained for each patient: unenhanced T1-weighted imaging (T1WI) in the axial, coronal and sagittal planes; unenhanced T2-weighted imaging (T2WI) in the axial planes; enhanced T1WI in the axial, coronal and sagittal planes; diffusion-weighted magnetic resonance imaging (DWI). The parameters of these sequences are listed in supplemental Table 1. Digital Imaging and Communications in Medicine (DICOM) images of spin echo pre-enhanced axial T2WI were selected for further analysis.

Image assessment and volume measurement

The collected MR images at all levels of the target patients were summarized, and the image evaluation was independently performed by two radiologists and one clinician, respectively. The radiologists and clinicians possess more than 10 years of experience in imaging diagnosis of head and neck cancer, and were trained in the delineating of the mastoid opacity areas, and independently outlining the corresponding mastoid contours. If there would be a disagreement on the conclusions, consensus would be reached by discussion. The diagnostic criteria for mastoiditis were based on reports by Platzek et al.[26] as follows: a) fluid accumulation, increased contrast enhancement of the mastoid and restricted diffusion in the mastoid, which were defined as signs of mastoiditis; b) subperiosteal fluid collection, extracranial contrast enhancement adjacent to the mastoid and restricted extracranial diffusion adjacent to the mastoid, which were interpreted as signs of a subperiosteal abscess; and c) all subperiosteal abscesses were defined as severe mastoiditis, regardless of the volume of the opacified structure.

Due to the inconsistent mastoid turbidity ratio of the left and right mastoids in NPC patients, the present study independently examined both mastoids. The MRI scanning images were conveyed to 3D Slicer 4.10[27], a free and open source and multi-platform software package widely used for medical, biomedical, and related imaging research. Mastoid contours were manually delineated on each image based on T2-weighted axial images, then mastoid volume was calculated by volume rendering method. After delineating the mastoid profile, two investigators calculated the mean value of the mastoid turbidity ratio, which is the basis for grading mastoiditis on each side. Mastoid turbidity ratio was used as a radiologic surrogate for mastoid effusion and was scored as Grade 0 (< 5% of the volume of the opacified structure), 1 (6–33%), 2 (34–67%) or 3 (68–100%), as illustrated by Sun Y et al [7].

Patient follow-up and statistical analysis

All patients underwent MRI at time points of diagnosed and during relevant treatment phases. Here, the main time frame of mastoiditis data was within 6 months after radiotherapy. Propensity-score matching (PSM) logistic regression modeling was performed using the known covariates (gender, age, KPS, BMI, pathology, T stage and N stage) with consideration of confounding effects. Patients with missing data for the propensity matched variables were excluded from the analysis. Nearest-neighbor 1:1 matching was used, with the caliper set at 0.2. A new set of matched immunotherapy and immunotherapy-free pairs was generated, from which covariates were assessed using the independent sample t test or Fisher's exact test to assess the success of the matching algorithm.

The primary outcome was incidence rates of mastoiditis. Incidence rates of mastoiditis over time were calculated, and subgroups were compared using the Pearson Chi square test. Effect of anti-PD-1 treatment on the incidence of mastoiditis was compared using repeated measures analysis of variance (ANOVA).

R version 4.1.2 was used for all statistical analyses. Gender, KPS, WHO histological grade, T classification, N classification, and chemotherapy used were categorical variables and were described by percentage (%) indicators. Continuous variables were expressed as mean and standard deviation (SD). All tests were 2-sided for statistical significance testing, and p value < 0.05 was considered statistically significant.

Enrollment and Demographics

Between January 2020 and January 2022, 259 patients with histologically proven nasopharyngeal carcinoma met the inclusion/exclusion criteria and were recruited for the study. 146 out of 259 eligible patients were propensity matched. In the overall PSM group(n = 146), median age at diagnosis was 42.0 years (95%CI = 40.8 to 44.3); median BMI was 22.5 kg/m² (95%CI = 22.6 to 23.8); 108 men (74.0%); 140 (95.9%) patients with KPS score of 90. The majority of patients had tumors T3/4 size (89.7%) and nonkeratinising type (WHO II type) (97.9%). An approximately equal number of patients with 32.2%(n = 47) had cN1, 37.0%(n = 54) cN2 and 28.0%(n = 42) cN3 tumors. 73 patients (Group A) received chemoradiotherapy and 73 patients (Group B) received additional anti-PD-1 therapy. Figure 1 presents a flow diagram of the patients. Table 2 summarizes the baseline demographic and clinical characteristics after PSM. Tumor characteristics were comparable between the two subgroups.

Table 1

Parameters for the magnetic resonance sequences
Sequence obtained	Scanner	Scanning method	TE (ms)	pixel size (mm)	FOV (mm)	ST/spacing (mm) ) (mm)
AX T2WI	Achieva	TSE	89.0	3.20ⅹ2.96	240ⅹ240	5.0/6.0
AX T2WI	TrioTim	TSE	89.0	3.84ⅹ3.07	240ⅹ240	5.0/6.0
AX T2WI	uMR 560	FSE	111.0	3.84ⅹ2.68	240ⅹ240	5.0/6.0
AX T2WI	uMR 780	FSE	113.0	3.84ⅹ2.68	240ⅹ240	5.0/6.0
AX T2WI	uMR 790	FSE	120.0	3.84ⅹ2.68	240ⅹ240	5.0/6.0
AX T2WI	Discovery MR750	FSE	93.0	3.84ⅹ3.20	240ⅹ240	5.0/6.0
AX T2WI	Discovery MR750W	FSE	120.0	3.84ⅹ3.20	240ⅹ240	5.0/6.0
AX T2WI	SIGNA Premier	FSE	75.0	3.84ⅹ3.20	240ⅹ240	5.0/6.0
AX T2WI	SIGNA Pioneer	FSE	86.0	3.84ⅹ2.88	240ⅹ240	5.0/6.0
AX T2WI	Ingenia CX	TSE	100.0	3.52ⅹ3.09	240ⅹ240	5.0/6.0
AX T2WI	Aera	TSE	77.0	3.84ⅹ2.60	240ⅹ225	5.0/6.0
TE, echo time; FOV, field of view; ST, slice thickness; AX T2WI, axial T2-weighted image; TSE, turbo spin-echo; FSE, fast spin-echo.

Table 2

Baseline characteristics (n = 146 patients)
	Immunotherapy (Group A, n = 73)	Immunotherapy-free (Group B, n = 73)	P-value
Sex			0.85
female	18 (24.7%)	20 (27.4%)
male	55 (75.3%)	53 (72.6%)
Age			0.73
Mean (SD)	42.9	42.3
Median [95CI%]	43.0 (40.5 to 45.3)	41.0 (39.6 to 44.9)
KPS			1.00
80	3 (4.1%)	3 (4.1%)
90	70 (95.9%)	70 (95.9%)
BMI			0.64
Mean (SD)	23.0	23.3
Median [95CI%]	22.6 (22.2 to 23.9)	22.5 (22.4 to 24.2)
Pathology^a			1.00
1	2 (2.7%)	1 (1.4%)
2	71 (97.3%)	72 (98.6%)
T			1.00
1	2 (2.7%)	2 (2.7%)
2	5 (6.8%)	6 (8.2%)
3	36 (49.3%)	36 (49.3%)
4	30 (41.1%)	29 (39.7%)
N			0.85
0	2 (2.7%)	1 (1.4%)
1	25 (34.2%)	22 (30.1%)
2	25 (34.2%)	29 (39.7%)
3	21 (28.8%)	21 (28.8%)
Overall^b			0.90
II	1(1.4%)	2(2.7%)
III	26(35.6%)	24(32.9%)
IVA	46(63.0%)	47(64.4%)
a WHO: World Health Organization.
b AJCC: American Joint Committee on Cancer, 8th edition.

Incidence of mastoiditis after PSM

Patients were divided into three groups according to the severity of mastoiditis prior to radiotherapy: G0M cohort, G1-2M cohort, and G3M cohort with grade 0, 1 or 2, and 3 mastoidites prior to treatment[7]. Between January 2020 and January 2022, 146 patients were screened for eligibility, 292 mastoids were analyzed for comparison. Based on the diagnostic criteria previously reported by Platzek et al, mastoiditis was confirmed in 104 (35.6%) of 292 mastoids. Figure 2 shows grade 3 mastoiditis over time of an adult patient with biopsy-proven nasopharyngeal carcinoma on MRI.

By propensity-score matching, for Group A versus Group B, the incidence of grade 3 mastoiditis was 21.9% versus 20.5% prior to NACT and 10.3% versus 8.2%, 15.1% versus 11.0%, 34.2% versus 20.5%, 37.7% versus 21.9% prior to CCRT and 0, 3, 6 months following CCRT, respectively (Fig. 3). The percentage of patients was numerically higher in Group A (37.7%) than in Group B (21.9%) 6 months following CCRT, which is statically significant (p ＜ 0.001). Table 3 showed that the distribution of mastoiditis severity was similar in both subgroups prior to treatment, but the mastoiditis in Group A became more severe following chemoradiotherapy.

Table 3

Mastoiditis grade in different treatment phase of patients’ mastoids (n = 292 mastoids)
	Immunotherapy (Group A, n = 146)	Immunotherapy-free (Group B, n = 146)	P-value
Prior to NACT			0.98
0	94(64.4%)	94(64.4%)
1	11(7.5%)	12(8.2%)
2	9(6.2%)	10(6.8%)
3	32(21.9%)	30(20.5%)
Prior to CCRT			0.87
0	95(65.1%)	98(67.1%)
1	27(18.5%)	29(19.9%)
2	9(6.2%)	7(4.8%)
3	15(10.3%)	12(8.2%)
0 month after CCRT			0.51
0	78(53.4%)	84(57.5%)
1	26(17.8%)	31(21.2%)
2	20(13.7%)	15(10.3%)
3	22(15.1%)	16(11.0%)
3 months after CCRT			0.044
0	54(37.0%)	68(46.6%)
1	29(19.9%)	28(19.2%)
2	13(8.9%)	20(13.7%)
3	50(34.2%)	30(20.5%)
6 months after CCRT			< 0.001
0	46(31.5%)	80(54.8%)
1	26(17.8%)	20(13.7%)
2	19(13.0%)	14(9.6%)
3	55(37.7%)	32(21.9%)

Incidence of mastoiditis in G0M cohort

Mastoids with Grade 0 were selected prior to treatment, resulted in a total of 188 mastoids of 292 mastoids. Among them, 94 mastoids in Group A and 94 mastoids in Group A were included. Grade distribution of mastoiditis 6 months following radiotherapy was calculated, as shown in Fig. 4. For the G0M cohort, in Group A and B, the incidence rates of severe mastoiditis were 0.0% and 0.0% prior to NACT, and were 1.1% and 2.1%, 6.4% and 5.3%, 28.7% and 17.0%, 31.9% and 17.0% prior to CCRT and 0, 3, and 6 months following CCRT, respectively. The percentage of patients was significantly higher in Group A (31.9%) than in Group B (17.0%). Therefore, for newly diagnosed NPC patients without mastoiditis, anti-PD-1 therapy might be a potential risk factor for mastoiditis.

Repeated-measures ANOVA

Trends of mean changes in grade of mastoiditis are shown in Fig. 5, the repeated-measures ANOVA analysis revealed that the immunotherapy (F = 4.70, p = 0.031), time (F = 40.08, p < 0.001) and both together (F = 5.77, p < 0.001) have a significant impact on the incidence of severe mastoiditis during the course of treatment in the G0-3M cohort. As shown in Table 3, there was a statistically significant difference in the proportion of patients with the grade 3 mastoiditis in month 3 post-CCRT between both Group A and B (50/146 (34.2%) vs. 30/146 (20.5%), χ2 = 8.11, P = 0.044). Further, a statistically significant difference in the proportion of patients with grade 3 mastoiditis in month 6 post-CCRT was also observed between both subgroups (55/146 (37.7%) vs. 32/146 (21.9%), χ2 = 16.80, P < 0.001). In sum, the ANOVA repeated measures analysis showed that significantly higher incidences of severe mastoiditis in Group A in months 3 and 6 post-CCRT were observed, compared to Group B.

NPC caused an endemic in southern China and East-southern Asia, with an incidence rate as high as 20–30 per 100 000[28, 29]. NPC patients with a higher T stage often have mastoiditis at the initial phase of diagnosis, mainly manifested through tinnitus and hearing loss. Although radiotherapy can induce radiation-related mastoiditis to some extent, the incidence rate of mastoiditis gradually decreases in post-treatment[7, 18]. Overall, cancer survival of NPC has been increasing in the past decades by improved tumour control through the introduction of IMRT, but the quality of life needs to be further improved in the era of post-treatment[24]. Since the era of immunotherapy started, the anti-PD-1 agents such as camrelizumab and toripalimab have shown clinical efficacy in the treatment of RM-NPC accompanied with a sufficient safety profile in China[12, 13]. Recently, immunotherapy has been widely recognized as a superior treatment option for LANPC[30]. Considering the evidence that inflammatory response is associated with ICIs treatment[31], it is hypothesized that NPC patients received ICIs treatment might experience an increasing incidence of severe mastoiditis.

Over the last several decades, the incidence rate of mastoiditis, which closely related to hearing problems, as a complication of NPC has not significantly decreased, and our study showed that this incidence rate was still 35.6%[4, 7]. NPC patients with mastoiditis often have tinnitus, hearing loss, swelling, pain, and other symptoms, which greatly impacts the quality of life in those patients[26, 32, 33]. Therefore, a therapeutic approach to prevent/treat NPC-caused mastoiditis is urgently needed. MR is ideal for detecting mastoiditis and possesses a superior ability to distinguish opacities than CT[34, 35]. MR findings in NPC patients with mastoiditis can show several parameters such as the tympanic cavity, the mastoid antrum and air cells opacified[26, 34], and therefore volume rendering performed on this basis can effectively detect mastoiditis and grade well.

Immune checkpoint inhibitors against PD-1 which shows a promising therapeutic effect and plays an important role for cancer treatment in the present era, exemplified by the humanized monoclonal antibodies pembrolizumab and nivolumab, have been approved for the treatment of patients with relapsed squamous cell carcinoma of the head and neck after previous platinum-based therapy. Recently, the promising antitumor activity and good tolerance of PD-1 therapies including nivolumab, pembrolizumab, toripalimab and camrelizumab were reported in several phase 1/2 trials for recurrent or metastatic NPC[36]. Treatment of cancers with PD-1 pathway inhibitors can lead to irAEs, which could be serious and even fetal. Therefore, clinicians should be aware of the characteristics of irAEs associated with the use of such drugs[37]. Camrelizumab and toripalimab, as a humanized anti-PD-1 antagonist IgG4 mAb (IgG4 monoclonal antibody), can cause different irAEs that are unpredictable and can affect different target organs, however irAEs related mastoiditis is rarely reported[19]. IgG4-related disease[38], such as IgG4-related pleural disease, hypophysitis, pancreatitis and cholangiopathy, can occur frequently[39–41]. Adam I. et all. reported that mastoiditis originated from IgG4-related disease (IgG4-RD), associated with elevated serum IgG4 concentrations[42–44]. Our results suggest the irAE related mastoiditis may require treatment such as hormones or rituximab[20, 45].

Previously reported incidence rate of mastoiditis in NPC patients prior to treatment is consistent with results observed in our study (Grade 3, 20.0% vs. 21.2%), and those studies founded a temporary increase in morbidity 3 months in post-radiotherapy (31.0% vs. 27.4%)[7]. These results generally suggest that IMRT can potentially induce mastoiditis. For the G0M cohort, the incidence rate of grade 3 mastoiditis in NPC patients without immunotherapy (17.0%) decreased in month 6 post-CCRT compared to that reported in previous studies (23.0%). With the advancement of radiotherapy for NPC and the accumulation of clinical evidence and experience, and anti-PD-1 will continue to be widely used for treating LANPC[10]. In our study, 89.7% of NPC patients with stage T3/4, and half of them had anti-PD-1 therapy, which may explain why the incidence rate of grade 3 mastoiditis in post-radiotherapy has not decreased in the past decade.

To our knowledge, our study is the first to reveal the potential clinical impact of ICIs on the incidence of mastoiditis in NPC patients. We found that after PSM, the incidence rate of grade 3 mastoiditis in the immunotherapy subgroup decreased significantly through the neoadjuvant chemotherapy from 21.9–10.3%, and showed a gradually increasing trend in post-radiotherapy from 10.3–37.7%, whereas the incidence rate of grade 3 mastoiditis in the immunotherapy-free subgroup decreased through the neoadjuvant chemotherapy from 20.5–8.2%, then increased from 8.2% back to 21.9%. Furthermore, among NPC patients with grade 0 mastoiditis prior to treatment, we observed a clear and drastic trend of an increasing incidence rates of mastoiditis in immunotherapy subgroups compared to that in immunotherapy-free subgroup, indicating that immunotherapy may significantly increase the incidence rate of mastoiditis in NPC patients. Moreover, the results of repeated-measures ANOVA revealed that a significantly higher incidence rate of mastoiditis in the immunotherapy subgroup was observed, and the effect of duration on incidence could be estimated as a stepwise change in treatment modalities. Therefore, we suggest that for LANPC patients received anti-PD-1 therapy, relevant preventive follow-up and treatment strategies should be adopted to deal with this increasing incidence rate of mastoiditis[24]. In sum, anti-PD-1 therapy combined with radiotherapy has potential to cause mastoiditis in NPC patients, which should be paid more attention to.

There are several strengths of the present study. Firstly, the quantitative assessment of mastoiditis was performed by an artificial intelligent platform. Second, all recruited NPC patients were treated with standard treatment under the Chinese Society of Clinical Oncology (CSCO) guide for NPC[46], such uniform treatment was ensured. Third, balanced matching between both subgroups makes our results more robust and convincing, demonstrating that anti-PD-1 therapy increases the incidence rate of mastoiditis in NPC patients in post-radiotherapy. Finally, irAEs are of special concern to clinical oncologists, and mastoiditis become a common pathological phenomenon given the special anatomy of NPC arising from the nasopharyngeal cavity.

Our study has several limitations. Firstly, it exists putative limitations inherent to the nature of a retrospective study. Second, the longest duration of follow up was 6 months post-radiotherapy, and a longer duration than 6 months may be required to explore/investigate further potential changes in the incidence rate of mastoiditis. Third, although we assessed the impact of anti-PD-1 therapy on incidence rate of mastoiditis, potential physiological mechanisms and preventive measures have not yet been explored or investigated in the present study. Further, it might exist selection bias in the present study due to relatively larger number of patients in the immunotherapy-free subgroup. Finally, mastoiditis-related quality of life survey was not detailly documented, so the subjective symptoms of individual patients cannot be completely determined yet.

To our knowledge, this study is the first to report the incidence rate of mastoiditis in LANPC patients treated with ICIs. Mastoiditis is a radiation-induced disease, usually diagnosed by MRI, and its incidence rate was observed to increase in NPC patients received anti-PD-1 therapy in our study. This result highlights the importance of surveillance and close follow-up of mastoiditis in NPC patients received ICIs in the post era of radical radiotherapy. These measurements may provide potential opportunities for NPC patients to improve their quality of life. Finally, well-designed and large-scale studies are warranted to confirm these findings.

LANPC locally advanced nasopharyngeal carcinoma

PD-1 programmed death 1

NACT neoadjuvant chemotherapy

CCRT concurrent chemoradiotherapy

PSM propensity-score matching

ANOVA analysis of variance

NPC nasopharyngeal carcinoma

IMRT intensity-modulated radiotherapy

ICIs immune checkpoint inhibitors

RM-NPC relapsed or metastatic NPC

2D-CRT two-dimensional conventional radiotherapy

IrAEs immune-related adverse events

KPS score Karnofsky Performance Status score

BMI body-mass-index

WHO World Health Organization

MRI magnetic resonance imaging

GTVnx gross tumor volume of nasopharynx

GTVnd gross tumor volume of neck metastasis lymph node

CTV1 clinical target high-risk volume

CTV2 clinical target low-risk volume

OAR organs at risk

CRT chemoradiotherapy

T1WI T1-weighted imaging

T2WI T2-weighted imaging

DWI diffusion-weighted magnetic resonance imaging

DICOM Digital Imaging and Communications in Medicine

IgG4 mAb IgG4 monoclonal antibody

IgG4-RD IgG4-related disease

CSCO guide Chinese Society of Clinical Oncology guide

Ethics approval and consent to participate

This study was approved by the Institutional Ethical Review Board of the Sun Yat-sen University Cancer Center (Guangzhou, China, B2022-174-01), and complied with the 2016/679 General Regulation on Personal Data Protection regarding the use of anonymised population data. All methods were performed in accordance with the relevant national guidelines and regulations (the 1964 Helsinki Declaration and its later amendments or comparable ethical standards). As the current study was a retrospective assessment of routine data, the Institutional Ethical Review Board of the Sun Yat-sen University Cancer Center waived the need for individual informed consent.

Consent for publication

Not applicable.

Availability of data and materials

The datasets analyzed during the current study have been deposited in the Research Data Deposit public platform (www.researchdata.org.cn) (accession code RDDA2022934283) to validate the authenticity of this study. The raw dataset is available from the corresponding author upon reasonable request.

Competing interests

All authors declare no competing interests.

Funding

This work was supported by Enterprise joint fund of Guangdong Provincial Foundation for basic and applied basic research (2021A1515220021), The National Natural Science Foundation of China (Grant/Award Number: 81902638), Program of Sun Yat-Sen University for Clinical Research 5010 Program (No.2015011), Wu Jieping Medical Foundation (Grant/Award Number: 320.6750.2021‐01‐38).

Authors’ contributions

HYJ, CMY designed and implemented the study. LYL, ZWJ completed the data collection and management. LYL, WK and ZWJ performed the statistical analyses. HYJ, CMY have accessed and verified the underlying data. LYL, WK, ZWJ, CSY and LHF wrote the manuscript. HYJ, LJ and CMY contributed to the review & editing of the current manuscript. All authors contributed to the interpretation of the data and critical revision of the manuscript. All authors approved the final version of the manuscript.

Acknowledgements

We acknowledge the significant contribution of the patients, families, researchers, and clinical staff.

Author details

¹Department of Nasopharyngeal Carcinoma, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China. ²Department of Medical Imaging, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China. ³State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China. ⁴Institute of Molecular Medicine and Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

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No competing interests reported.

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Increased Incidence of Mastoiditis in Nasopharyngeal Carcinoma following Anti-PD-1 Therapy: A Propensity-Matched Analysis

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study population

Clinical staging

Treatment

Radiation therapy

Chemotherapy

Anti-PD-1 therapy

MRI

Image assessment and volume measurement

Patient follow-up and statistical analysis

Results

Enrollment and Demographics

Incidence of mastoiditis after PSM

Incidence of mastoiditis in G0M cohort

Repeated-measures ANOVA

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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