Two-year follow-up outcomes of neoadjuvant therapy in oral squamous cell carcinoma: an exploratory systematic review and meta-analysis

Abstract

Objectives

Neoadjuvant therapy has been increasingly explored as a treatment strategy for oral squamous cell carcinoma (OSCC) and may be associated with favorable pathological responses. However, its long-term efficacy and safety have not yet been systematically evaluated. Therefore, this study aimed to comprehensively synthesize the available evidence regarding the clinical outcomes of neoadjuvant therapy in patients with OSCC.

Methods

We systematically searched three electronic databases (PubMed, Embase, and the Cochrane Library) for relevant studies evaluating neoadjuvant therapy in OSCC. Eligible studies published up to June 1, 2025 were included. A random-effects meta-analysis was performed to estimate pooled proportions of disease-free survival (DFS) and overall survival (OS). Safety outcomes were assessed based on the incidence of grade 3 or higher treatment-related adverse events (TRAEs). Data extraction and quality assessment were independently performed by two reviewers in accordance with the PRISMA guidelines.

Results

A total of ten studies involving 578 patients met the eligibility criteria and were included in the analysis. The pooled DFS rates at 12 and 24 months were 68% and 41%, respectively. Correspondingly, the pooled OS rates were 83% at 12 months and 52% at 24 months. The pooled incidence of grade 3–4 treatment-related adverse events was 19%.

Conclusions

Neoadjuvant therapy demonstrates encouraging efficacy and an acceptable safety profile in patients with OSCC. Nevertheless, further high-quality studies with longer follow-up periods are required to confirm these findings.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12903-026-08737-1.

Introduction

Head and neck cancer is the seventh most common malignancy worldwide and represents a heterogeneous group of tumors originating from the upper aerodigestive tract [1]. Among the various histological subtypes, squamous cell carcinoma accounts for more than 90% of head and neck malignancies [2, 3]. Oral squamous cell carcinoma (OSCC), originating in the oral mucosa, represents a particularly prevalent subtype within head and neck squamous cell carcinoma (HNSCC) [2]. According to Global Cancer Statistics 2020, approximately 377,000 new cases of oral cavity cancer are diagnosed annually worldwide [4]. Despite its prevalence, OSCC often presents diagnostic challenges, with more than half of patients being diagnosed at a locally advanced stage at initial presentation [2, 5]. The current standard treatment consists of primary surgical resection followed by risk-adapted adjuvant radiotherapy or chemoradiotherapy [6, 7]. However, the 5-year overall survival rate remains at only 50% [5, 8], underscoring the urgent need for the development of novel therapeutic strategies.

Neoadjuvant therapy, aimed at reducing locoregional disease burden prior to surgical intervention, represents an increasingly attractive treatment paradigm. Studies have demonstrated that neoadjuvant chemotherapy can induce pathological responses in patients with locally advanced OSCC. Specifically, major pathological response (MPR) rates of 27.7% and 33% have been reported for neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) and cisplatin and 5-fluorouracil (PF) chemotherapy regimens, respectively. Furthermore, these regimens have yielded impressive clinical regression rates of 80.6% (TPF) and 82% (PF) in patients with locally advanced OSCC [9, 10]. Concurrently, the field of immunotherapy for solid tumors has undergone substantial advancement [11–13]. Anti-programmed cell death-1 (PD-1) inhibitors are now approved for first- and second-line palliative treatment of recurrent or metastatic HNSCC [14–17]. In particular, nivolumab, an anti-PD-1 inhibitor, has been shown to reduce the hazard ratio for mortality by 32% and improve 2-year overall survival nearly threefold (to 16.9%) compared to chemotherapy in patients with recurrent or metastatic HNSCC [17, 18]. The KEYNOTE-048 trial further illustrated the prolonged response duration achieved with immunotherapy, demonstrating a five-fold increase compared to chemotherapy in recurrent or metastatic HNSCC [15]. Uppaluri et al. demonstrated that neoadjuvant pembrolizumab reduced the 1-year relapse rate in patients with locally advanced, human papillomavirus (HPV)-negative HNSCC exhibiting high-risk pathology (positive margins and/or extranodal extension) [19]. Consistent with these findings, Wise-Draper et al. reported significantly improved 1-year DFS rates in patients achieving a pathological response to neoadjuvant pembrolizumab compared to those who did not (93% vs. 72%) [20]. This accumulating evidence of success has further propelled widespread interest in the application of immunotherapies in the neoadjuvant setting [5].

Prior research on neoadjuvant therapy has largely consisted of individual trials or investigations involving limited cohorts of OSCC patients. Consequently, a comprehensive synthesis of the totality of existing evidence has been lacking. To definitively establish the long-term efficacy and safety profile of neoadjuvant therapy, long-term follow-up outcomes are essential. Therefore, we conducted a systematic review and meta-analysis to evaluate the long-term efficacy and safety of neoadjuvant or preoperative therapy in patients with OSCC, focusing on outcomes with follow-up durations of at least two years. Pooled estimates of disease-free survival (DFS), overall survival (OS), and treatment-related adverse events (TRAEs) were calculated.

Materials and methods

Study design

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [21].

Literature search

A comprehensive search of PubMed, Embase, and the Cochrane Library was conducted to identify studies reporting outcomes of neoadjuvant or preoperative therapy in patients with OSCC. The search included all eligible publications up to June 1,2025.Only studies published in peer-reviewed journals were included, while grey literature, such as dissertations, conference abstracts, and unpublished data, was not considered.The search strategy was developed using a combination of controlled vocabulary (Medical Subject Headings [MeSH] in PubMed and Emtree terms in Embase) and free-text terms. The following search terms were used: (((Oral Squamous Cell Carcinoma) OR (OSCC)) OR (Oral Cavity Squamous Cell Carcinoma)) AND (((((Neoadjuvant Therapy) OR (preoperative therapy)) OR (chemotherapy)) OR (immunotherapy)) OR (targeted therapy)). Boolean operators (AND, OR) were applied to combine search terms appropriately. The detailed search strategy for each database is provided in the Supplementary Material. An updated literature search was conducted prior to the final analysis to ensure the inclusion of the most recent studies(July 2025).Only studies published in English were considered. The reference lists of relevant articles were also manually screened to identify additional eligible studies.

Eligibility criteria for study inclusion

Studies were considered eligible if they met the following criteria:

(1) retrospective or prospective studies evaluating neoadjuvant or preoperative systemic or multimodal therapy in patients with OSCC; (2) patients aged 18 years or older; (3) diagnosis of OSCC confirmed by surgical pathology or cytopathology; (4) studies including at least 14 patients; (5) studies reporting follow-up outcomes for at least two years after neoadjuvant therapy; (6) studies providing data on predefined clinical outcomes.

Studies were excluded if they met any of the following criteria:

(1) duplicate publications; (2) studies with insufficient sample size; (3) studies not related to neoadjuvant therapy for OSCC; (4) case reports, conference abstracts, comments, letters, or review articles; (5) studies lacking pathological confirmation based on cytopathological or histopathological examination.

In this study, neoadjuvant therapy was defined in a broad clinical context as treatment administered prior to surgery, including both conventionally resectable cases and initially unresectable cases treated with the aim of enabling subsequent surgical resection.

In addition, patients with recurrent or metastatic disease, as well as those initially considered unsuitable for surgery, were also included. These patients were selected on the basis that, following systemic therapy, they might have the potential to be converted to a resectable status or to be incorporated into a treatment strategy with surgical intent.

The eligibility of studies was independently assessed by two reviewers based on the predefined inclusion and exclusion criteria. Any disagreements were resolved through discussion until a consensus was reached.

Data extraction and outcome measures

Data extraction was also performed independently by two reviewers using standardized data collection forms in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [21]. The following information was extracted from each eligible study: author name, year of publication, patient recruitment period, country of origin, study design (prospective or retrospective), number of patients included, patient demographic characteristics (age and sex distribution), primary tumor site (including tongue, gingiva, buccal mucosa, floor of the mouth, hard palate, and intraosseous lesions), duration of follow-up, and treatment modalities.

The clinical outcomes of interest included disease-free survival (DFS), overall survival (OS), and treatment-related adverse events (TRAEs). DFS and OS outcomes were extracted at predefined follow-up time points of 1 year, 2 years, when available.

Any discrepancies between the two reviewers during the data extraction process were resolved through discussion until consensus was reached.

Risk of bias assessment

The risk of bias in the included studies was independently evaluated by two reviewers using the RoBANS tool [22]. Any disagreements were resolved through discussion with a third reviewer.

Statistical analysis and data synthesis

Statistical analyses were performed using Stata version 17.0 (StataCorp, College Station, TX, USA).A random-effects meta-analysis of proportions was conducted to estimate the pooled rates of disease-free survival (DFS), overall survival (OS), and grade 3–4 treatment-related adverse events (TRAEs) [23, 24]. The Freeman–Tukey double arcsine transformation was applied when appropriate to stabilize variance.Between-study heterogeneity was assessed using Cochran’s Q test and the I² statistic, with I² values greater than 50% indicating substantial heterogeneity. Publication bias was assessed for the primary outcomes, including 2-year disease-free survival (DFS) and 2-year overall survival (OS), using funnel plots and Egger’s regression test. Funnel plot asymmetry was evaluated by visual inspection, and Egger’s test was used to assess small-study effects.All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant.

Results

Study selection

The study selection process is summarized in (Fig. 1). The database search yielded 5,644 records. After removing 1,160 duplicate entries, 4,484 titles and abstracts were screened. Thirty-two studies were considered potentially eligible and underwent full-text evaluation. Of these, 21 articles were excluded due to incomplete data and one study was excluded because of an unmatched study population. Finally, ten studies met the predefined inclusion criteria and were included in the present systematic review and meta-analysis [25–34]. The certainty of evidence for all outcomes was rated as low due to the predominance of retrospective studies, substantial heterogeneity, and imprecision (Supplementary Table S1).

Fig. 1.

Flow diagram of the study selection process

Characteristics of the included studies

Table 1 summarizes the characteristics of the ten included studies. Most studies adopted a retrospective design. The sample sizes ranged from 14 to 143 patients, and the age of participants varied from 26 to 85 years. A male predominance was observed across all studies.

Table 1.

Characteristics of the included studies

Study	Study period	Country	Study design	Patients, No.	Age (y)	Male: female	Primary tumor site						FU time (months), median	Treatments
							Tongue	Gingiva	Buccal	Mouth floor	Hard palate	Intraosseous
Stanford-Moore et al. [28]	2000–2020	America	Retro	38	67 ± 10.75	22:16	0	0	0	0	0	38	44.3	chemoradiation therapy
Kashyap et al. [26]	NA	India	Retro	14	38(29–59)	12:2	2	0	12	0	0	0	14.6	chemotherapy
Yoshida et al. [29]	2004–2012	Japan	Retro	24	62	14.:10	36	0	7	2	0	14	60	chemotherapy
Kina et al. [27]	2009–2017	Japan	Retro	106	61 ± 13	65:41	69	19	13	5	0	0	60	chemotherapy
Yamakawa et al. ([30]	2017–2019	Japan	Retro	143	65 (36–93)	103:40	52	57	10	22	2	0	10.6	Immunotherapy
Naruse et al. [31]	2013–2017	Japan	Retro	31	64 (26–81)	24.:7	10	14	1	4	0	2	NA	chemoimmunotherapy
Li et al. [32]	2020–2022	China	Retro	104	57.5 (26–86)	68:36	49	27	13	11	4	0	31	chemoimmunotherapy
Shen et al. [33]	2018–2021	China	Retro	30	58 (38–79)	25:5	NA						13.5	immunoradiotherapy
Liu et al. [34]	2021–2022	China	Prospective randomized trial	68	50.7 (32–68)	59:9	36	8	16	8	0	0	32	chemoimmunotherapy
Ju et al. [25]	2020–2021	China	Prospective study	20	59.5 (36–73)	11:9	11	3	5	1	0	0	18.5	chemoimmunotherapy

Regarding the primary tumor location, five studies investigated tumors of the tongue [25, 27, 29, 32, 34], two focused on the gingiva [30, 31], one examined buccal mucosa tumors [26], and one reported intraosseous tumors [28]. One study did not specify the primary tumor site [33].

In terms of geographic distribution, most studies were conducted in Asian countries, including four from China [25, 32–34], four from Japan [27, 29–31], and one from India [26], while one study was conducted in the United States [28].

The treatment strategies varied among the included studies. Chemoimmunotherapy was used in four studies [25, 31, 32, 34], and chemotherapy alone in three studies [26, 27, 29]. The remaining studies reported chemoradiotherapy [28], immunoradiotherapy [33], and immunotherapy [30], each in a single study.

Risk of bias assessment

The methodological quality of the included studies, as assessed using the RoBANS tool (Fig. 2), indicated variable risk of bias across domains.

Fig. 2.

Risks of bias in the trials included in the meta-analysis. +, Low risk of bias; –, high risk of bias;? unclear risk of bias

Most studies were rated as having a low or unclear risk of bias in domains such as random sequence generation and allocation concealment, reflecting limited reporting in retrospective designs.

All studies demonstrated a low risk of bias in blinding of outcome assessment, selective reporting, and other potential sources of bias.

However, nine studies were judged to have a high risk of bias related to the blinding of participants and personnel, as they did not implement patient or investigator blinding. The remaining study presented an unclear risk of bias in this domain due to insufficient information [25].

Furthermore, two studies were identified as having a high risk of bias due to incomplete outcome data, while the remaining studies were at low risk in this domain.

Disease-free survival

A total of 578 patients from the ten included studies were eligible for the analysis of disease-free survival (DFS) at both 1-year and 2-year follow-up intervals. The pooled analysis demonstrated that the DFS rate at 1 year was 0.68 (95% CI: 0.41–0.90), indicating that approximately two-thirds of patients remained disease-free within the first year following treatment.

However, considerable heterogeneity was observed among the included studies (I² = 97.39%, p < 0.001), suggesting substantial variability in the DFS outcomes reported across the different studies. Such heterogeneity may be related to differences in treatment strategies, patient populations, tumor locations, and study designs among the included studies.

At the 2-year follow-up, the pooled DFS rate decreased to 0.41 (95% CI: 0.16–0.69), reflecting a decline in disease-free survival over time. Similarly, significant heterogeneity persisted across studies (I² = 97.62%, p < 0.001). The forest plots illustrating the pooled DFS outcomes and the individual study estimates are presented in (Figs. 3, 4 and 5).

Fig. 3.

Serial pooled DFS and OS during the follow-up period

Fig. 4.

One-year DFS of neoadjuvant therapy

Fig. 5.

Two-year DFS of neoadjuvant therapy

Overall survival

All 578 patients from the included studies were also included in the analysis of overall survival (OS) at 1-year and 2-year follow-up intervals. The pooled meta-analysis revealed that the 1-year OS rate was 0.83 (95% CI: 0.65–0.96), suggesting that the majority of patients survived during the first year following treatment.

Nevertheless, a high degree of heterogeneity was observed across the studies (I² = 95.85%, p < 0.001), indicating substantial variation in survival outcomes among the included studies.

At the 2-year follow-up, the pooled OS rate declined to 0.52 (95% CI: 0.24–0.80). Significant heterogeneity remained present among the included studies (I² = 97.80%, p < 0.001), suggesting differences in long-term survival outcomes across study populations and treatment approaches. The forest plots summarizing the pooled OS outcomes are shown in (Figs. 3, 6, and 7).

Fig. 6.

One-year OS of neoadjuvant therapy

Fig. 7.

Two-year OS of neoadjuvant therapy

Grade 3–4 treatment-related adverse events

The safety of neoadjuvant therapy was evaluated by analyzing the incidence of grade 3–4 treatment-related adverse events (TRAEs) reported in the included studies.

The meta-analysis yielded a pooled incidence of 0.19 (95% CI: 0.07–0.35) for grade 3–4 TRAEs. Although the overall incidence of severe treatment-related toxicity was relatively low, substantial heterogeneity was observed among the included studies (I² = 93.42%, p < 0.001). This variability may reflect differences in treatment regimens, patient characteristics, and reporting standards across the included studies.

The forest plot summarizing the pooled incidence of grade 3–4 TRAEs is presented in (Fig. 8).

Fig. 8.

Grade 3 and 4 adverse events of neoadjuvant therapy

Publication bias assessment for 2-year DFS and OS

Publication bias was assessed using funnel plots and Egger’s regression test for the primary outcomes (2-year DFS and 2-year OS), as presented in the Supplementary Materials. Visual inspection of the funnel plots revealed no obvious asymmetry, with a relatively even distribution of studies. Egger’s test did not demonstrate statistically significant publication bias for 2-year DFS (P = 0.316) or 2-year OS (P = 0.369)(Fig S1).

Discussion

Oral squamous cell carcinoma (OSCC) is a common malignancy with an unfavorable prognosis, often impairing speech, swallowing, and facial appearance [35]. Surgical resection remains the primary treatment for resectable disease [36]. However, due to the subtle and non-specific nature of early symptoms, many patients are diagnosed at an advanced stage, limiting the feasibility of surgery [37].

Beyond macroscopic tumor shrinkage, neoadjuvant therapy may also influence tumor histopathological features and the tumor microenvironment. OSCC is characterized by an infiltrative growth pattern, with invasive potential commonly assessed by depth of invasion (DOI), worst pattern of invasion (WPOI), lymph node metastasis, and other features such as perineural invasion (PNI), lymphovascular invasion (LVI), and surgical margin status, all of which are closely associated with recurrence and survival outcomes [35, 38]. Certain molecular subtypes, including those with high PD-L1 or EGFR expression, have been linked to more aggressive tumor behavior [35, 38].

Histopathological heterogeneity in head and neck cancers may further complicate diagnosis and treatment decisions, highlighting the importance of accurate pathological evaluation [39, 40].Following neoadjuvant therapy, increasing attention has been given to pathological response assessment, including partial pathological response (PPR), major pathological response (MPR), and pathological complete response (pCR), which have been associated with improved disease-free survival and may serve as surrogate markers of treatment efficacy [41].

In addition, neoadjuvant therapy may modulate the tumor immune microenvironment (TIME), enhancing antitumor immune responses through mechanisms such as increased CD8⁺ T-cell infiltration and immunogenic cell death. Combined strategies, including PD-1 blockade with EGFR-targeted therapy, have shown tumor shrinkage alongside immune modulation, although these findings also suggest the coexistence of immune activation and immune suppression pathway [42, 43]. In addition, emerging locoregional approaches, such as electrochemotherapy (ECT), have also demonstrated promising response rates in selected patients [44].

To our knowledge, this is among the few studies focusing on patients with oral squamous cell carcinoma (OSCC) receiving neoadjuvant therapy with a minimum follow-up duration of two years. Among the 578 OSCC patients included, the pooled incidence of treatment-related adverse events (TRAEs) was 0.19 (95% CI: 0.07–0.35) over the extended follow-up period. Furthermore, pooled disease-free survival (DFS) and overall survival (OS) rates at one year were 0.68 (95% CI: 0.41–0.90) and 0.83 (95% CI: 0.65–0.96), respectively, suggesting that neoadjuvant therapy may be associated with comparatively favorable 1-year and 2-year DFS and OS estimates; however, these findings should be interpreted as descriptive rather than evidence of superiority over standard treatment. The observed decline in DFS from 1 to 2 years indicates that a substantial proportion of patients experience disease recurrence or progression after the initial treatment period. In contrast, the relatively preserved OS suggests that subsequent treatments, including surgery and adjuvant therapies, may partially mitigate the impact of recurrence on survival. This discrepancy between DFS and OS highlights the complex treatment trajectory of OSCC and suggests that early tumor response does not necessarily translate into sustained long-term disease control.

The management of oral squamous cell carcinoma (OSCC) typically involves a multimodal approach integrating surgery and neoadjuvant therapy. For resectable disease, surgery alone or in combination with neoadjuvant therapy remains the main curative strategy, whereas in unresectable or incompletely resected cases, neoadjuvant therapy may facilitate subsequent surgical intervention depending on individual patient conditions. Neoadjuvant therapy, including chemotherapy, radiotherapy, and immunotherapy, plays an important role in reducing tumor burden and improving resectability, particularly in borderline resectable cases, although its precise indications remain controversial [45–47]. Accumulating evidence also supports the pathological benefits of neoadjuvant therapy. Pathological response, including major pathological response (MPR) and pathological complete response (pCR), has been associated with reduced residual tumor burden and improved surgical outcomes, and may serve as a surrogate marker linking short-term treatment efficacy to long-term survival [48].

However, evidence regarding survival benefit remains inconsistent. While a meta-analysis of randomized controlled trials (RCTs) demonstrated no significant difference in overall survival (OS) or disease-free survival (DFS) between neoadjuvant chemotherapy followed by surgery and upfront surgery [46], other studies have suggested potential advantages, particularly among treatment responders [10]. Pathological response has been identified as an independent predictor of OS and DFS [9, 45, 49, 50]. Zhong et al. reported no instances of positive margins in either the neoadjuvant chemotherapy or upfront surgery groups [9, 49], and has also been used to guide surgical margin planning in borderline resectable cases [45]. In addition, neoadjuvant chemotherapy has been associated with lower rates of positive or close surgical margins and may facilitate organ preservation in selected patients [45].

Taken together, current evidence suggests that neoadjuvant chemotherapy followed by surgery may offer a potential advantage in reducing positive surgical margin rates. However, the non-uniform shrinkage of tumors and the persistence of viable tumor cells at the periphery remain important considerations [51, 52]. In addition, some studies indicate that neoadjuvant therapy may reduce the risk of distant metastasis and enable conversion from unresectable to resectable disease in a subset of patients, thereby improving surgical feasibility [53–55].

In recent years, immunotherapy has also shown promising potential in the treatment of OSCC. Available evidence suggests that neoadjuvant immunotherapy, alone or in combination with radiotherapy or chemotherapy, is generally well tolerated and may provide survival benefits [2, 33, 56]. However, these findings are primarily derived from small-scale studies and require further validation.

Despite the growing application of neoadjuvant treatment strategies, evidence regarding their long-term efficacy remains limited, particularly due to the lack of systematically analyzed extended follow-up data. In this context, the present study integrates the available evidence and suggests that neoadjuvant therapy may be associated with favorable 1-year and 2-year DFS and OS outcomes, which should be interpreted cautiously given the non-comparative nature of the included studies.

The heterogeneity observed in this meta-analysis may be related to differences in study design, patient characteristics, treatment regimens, and follow-up durations, as well as the predominance of single-arm studies.Given the presence of variability across studies, the pooled estimates should be interpreted with appropriate caution. In this context, the quantitative synthesis is better considered as providing an overall indication of trends rather than precise effect estimates.

Furthermore, variations in treatment settings and the inclusion of patients with complex or advanced disease may have further contributed to the observed heterogeneity. Although the reported incidence of treatment-related adverse events (TRAEs) appeared relatively low, this finding should be interpreted cautiously. The included treatment regimens varied substantially, with distinct toxicity profiles across chemotherapy, immunotherapy, and combination strategies. Therefore, the safety outcomes reported in this study are regimen-dependent and non-comparative in nature. Overall, these findings suggest that neoadjuvant therapy may be feasible in selected patients with OSCC; however, its safety profile should be interpreted in the context of specific treatment regimens and the non-comparative nature of the available evidence.

Limitations

This study has several limitations. First, the number of included studies was relatively small, and most were retrospective in design, which may affect the robustness of the findings. Second, variations in neoadjuvant treatment strategies, patient characteristics, and sample sizes across studies may have introduced heterogeneity and influenced the stability of the pooled estimates. In addition, the lack of reported blinding in most studies may increase the risk of bias in outcome assessment.

Due to the absence of time-to-event data, hazard ratio–based meta-analysis could not be performed, and censoring as well as variability in follow-up duration across studies were not accounted for, which may affect the accuracy and comparability of the pooled survival estimates. Finally, all included studies were single-arm and non-comparative, precluding direct comparisons with standard treatment strategies.

Conclusion

In conclusion, this systematic review and meta-analysis suggests that neoadjuvant therapy may be associated with potentially acceptable short-term survival outcomes in patients with oral squamous cell carcinoma (OSCC). Further well-designed prospective studies with standardized treatment strategies and clearly defined clinical settings are warranted.

Abbreviations

DFS

Disease-free survival

OS

Overall survival

TRAEs

Treatment-related adverse events

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

HNSCC

Head and neck squamous cell carcinomaAbbreviations

Author’ contributions

Conception and design: Yue Wang, Shuhan Wang, Yu Zhang (Unit 1);Data acquisition: Shuhan Wang, Yu Zhang (Unit 2), Yamin Dong; Data extraction and quality assessment: Yu Zhang (Unit 1), Yu Zhang (Unit 2), Yamin Dong; Statistical analysis and interpretation: Yue Wang, Yu Zhang (Unit 1), Yamin Dong; Manuscript drafting: Yue Wang, Shuhan Wang, Gang Dong; Critical revision of the manuscript: Yu Zhang (Unit 2), Yu Zhang (Unit 1), Yamin Dong.

Funding

2025 Open Research Project of the School of Stomatology, Qilu Medical University(KQ25ZF02).

Data availability

All data included in this meta-analysis were extracted from previously published studies available in PubMed, Embase, and the Cochrane Library. No new datasets were generated. The extracted data supporting the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study is a meta-analysis based solely on published literature retrieved from public databases (PubMed, Embase, and the Cochrane Library). Since no identifiable individual patient data were involved, ethical approval and informed consent were not required.

Consent for publication

All authors have agreed to publish this manuscript.

Competing interests

The authors declare no competing interests.