Postoperative adjuvant immunotherapy versus standard of care in resectable locally advanced head and neck squamous cell carcinoma with intermediate- and high-risk factors: a real-world retrospective study

Postoperative adjuvant immunotherapy versus standard of care in resectable locally advanced head and neck squamous cell carcinoma with intermediate- and high-risk factors: a real-world retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Postoperative adjuvant immunotherapy versus standard of care in resectable locally advanced head and neck squamous cell carcinoma with intermediate- and high-risk factors: a real-world retrospective study Xiaoqiong Shi, Minhui Zhu, Jianqiao He, Yingna Gao, Yi Ma, Haopu Li, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5377938/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Improving the prognosis of patients with LA-HNSCC who have intermediate- and high-risk factors has long been a priority for head and neck surgeons. Immunotherapy, particularly programmed cell death protein 1 (PD-1) inhibitor, has shown promise. However, there are currently no reports on the use of PD-1 inhibitors for postoperative adjuvant treatment of these patients. This retrospective study included 59 postoperative intermediate- and high-risk patients with LA-HNSCC. These patients were divided into two groups: a standard therapy group, consisting of patients who received only postoperative risk-adapted adjuvant (chemo)radiation (n = 34), and an adjuvant immunotherapy group, consisting of patients who received adjuvant immunotherapy as a follow-up maintenance regimen after the standard of care (n = 25). Progression-free survival (PFS) and overall survival (OS) by the Response Evaluation Criteria for Solid Tumors was the main outcome. The 2-year PFS and OS rates in the adjuvant immunotherapy group were 80.0% and 95.0%, respectively, compared to 62.1% (χ 2 = 2.465, P = 0.116) and 79.3% (χ 2 = 2.434, P = 0.119) in the standard therapy group. Stratified analysis showed that the 2-year PFS rate for patients in the adjuvant immunotherapy group with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20 significantly improved compared to the standard therapy group (92.9% vs. 62.1%, χ 2 = 4.644, P = 0.031). No serious immune-related adverse events were detected in the adjuvant immunotherapy group. Our study suggests administering PD-1 inhibitor as adjuvant therapy after standard of care shows a trend towards improving 2-year PFS in postoperative intermediate- and high-risk patients with LA-HNSCC. This trend is more pronounced in patients with a CPS of 20 or higher. Future clinical trials are needed to verify these results. head neck cancer immunotherapy PD-1 inhibitor adjuvant therapy retrospective study Figures Figure 1 Figure 2 Introduction According to GLOBOCAN data from 2020, head and neck cancer is the sixth most common cancer, with an estimated 1,000,000 new cases per year projected by 2030 [ 1 ]. Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 90% of these cancers, with potential causes including smoking, drinking, and human papillomavirus (HPV) infection [ 2 ]. Approximately 60% of patients with HNSCC have locally advanced (LA) disease. For these patients, surgery is the primary treatment, but it is often insufficient on its own. The majority of patients require postoperative adjuvant therapy, such as adjuvant radiotherapy or radiochemotherapy (RCT), to improve survival rates. Several factors can affect local regional control and survival after surgery for LA-HNSCC. Microscopically involved resection margins (R1) and extracapsular spread (ECS) of lymph node metastases are the most significant prognostic factors (“high risk”) for poor outcomes. Close margins (R0 < 5 mm), vascular invasion, perineural invasion, and the presence of ≥ 2 lymph node metastases are “intermediate-risk” features predictive of worse disease control [ 3 – 4 ]. Even completely resected intermediate- and high-risk HNSCC are prone to loco-regional recurrence and distant metastasis, with about 45–50% of patients experiencing such events or death within 24 months [ 3 – 5 ]. Improving the prognosis of postoperative intermediate- and high-risk LA-HNSCC remains a significant challenge for head and neck surgeons. Anti-programmed death receptor-1 (Anti-PD-1)/programmed death ligand 1 (PD-L1) antibodies can block the PD-1/PD-L1 signaling pathway and enhance T cell killing activity. They have shown outstanding clinical efficacy and are considered one of the most promising tumor treatment strategies [ 6 ]. Based on the excellent clinical trial results of PD-1 inhibitors in treating patients with recurrent and/or metastatic HNSCC in CheckMate-141 and KEYNOTE-048 [ 7 – 8 ], the US Food and Drug Administration has approved PD-1 inhibitors nivolumab and pembrolizumab for this purpose. Immunotherapy can induce changes in the tumor microenvironment and enhance the sensitivity of subsequent treatments [ 9 ]. Recent clinical studies have combined PD-1 inhibitors with other drugs for neoadjuvant treatment of patients with LA-HNSCC, achieving encouraging results. These studies suggest that PD-1 inhibitors can improve pathologic tumor response and local control in patients with LA-HNSCC. PD-1 inhibitors have been administered to reduce recurrence and eliminate micrometastatic disease after surgery in some studies across solid tumors [ 10 – 11 ]. For postoperative intermediate- and high-risk patients with LA-HNSCC, the risk of loco-regional recurrence and distant metastasis resulting from the expansion of micrometastatic disease is substantial. Can PD-1 inhibitors be used as adjuvant therapy in those patients to reduce recurrence and metastasis? Recent data [ 12 – 13 ] further support that targeting the PD-1/PD-L1 axis in the definitive setting has the potential to improve local control rates and decrease the occurrence of distant metastases by promoting immune surveillance of micrometastatic disease. More importantly, PD-1 inhibitors could significantly improve the patients’ disease-free survival (DFS) when used as adjuvant therapy after standard of care, including non-small cell lung cancer (NSCLC) and nasopharyngeal carcinoma [ 14 – 15 ]. Hitherto, there have been no reports on the use of PD-1 inhibitors for postoperative adjuvant treatment of patients with LA-HNSCC, especially those with intermediate- and high-risk factors. This study was conducted to investigate the role of PD-1 inhibitors as adjuvant therapy in intermediate- and high-risk patients with resectable LA-HNSCC. The primary end points are the 2-year progression-free survival (PFS) rate and overall survival (OS) rate. Material and methods Patient selection This retrospective study was conducted on patients with LA-HNSCC who were treated between September 2015 and September 2023. Data from the electronic case management system of the Department of Otolaryngology—Head and Neck Surgery at Changhai Hospital in Shanghai were analyzed. We found 453 patients who had advanced stage III or IVA/B squamous-cell carcinoma originating in the oropharynx (HPV negative), larynx, or hypopharynx. The patients included in the study should undergo macroscopically complete resection with postoperative intermediate- and high-risk factors and receive risk-adapted adjuvant (chemo)radiation. First, we excluded the 182 patients who were diagnosed with recurrent head and neck squamous cell carcinoma or diagnosed with an additional malignancy, received neoadjuvant immunotherapy before surgery, were not eligible for further surgery, or were treated with definitive RT or CRT. Second, we excluded the 207 patients who had no intermediate- or high-risk characteristics, received adjuvant therapy in other hospitals or rejected adjuvant therapy after surgery. Last, we excluded the five patients who did not complete total adjuvant radiotherapy or with cumulative dose of cisplatin < 200 mg/m2. Eventually, 59 patients were selected for the study. The inclusion criteria were as follows: 1. Patients were over 18 years of old. 2. Patients had advanced stage III or IVA/B HNSCC according to the American Joint Committee on Cancer (AJCC) TNM classification (Seventh edition for the patients treated before January 1, 2017, and Eighth edition for those treated since January 1, 2017). 3. Patients had undergone macroscopically complete resection of diagnosed advanced squamous-cell carcinoma originating in the oropharynx (HPV negative), larynx, or hypopharynx. 4. Patients must have intermediate- or high-risk characteristics, defined by any or all of the following: histologic evidence of invasion in two or more regional lymph nodes; extracapsular extension of nodal disease; microscopically involved mucosal margins of resection (R1) or margins of resection; vascular invasion; or perineural invasion. 5. Induction chemotherapy was allowed preoperatively. 6. Patients must have undergone surgical resection followed by risk-adapted adjuvant (chemo)radiation. 7. Adjuvant radiotherapy or concurrent RCT (cisplatin-based chemotherapy) must have begun within 6 weeks post-surgery. 8. The surgery and postoperative treatment must have been completed in our hospital, and the follow-up data must be complete. Patients who met all of the above inclusion criteria were included in the study. 9.Patients must have provided written informed consent. The exclusion criteria were as follows: 1. Patients diagnosed with recurrent head and neck squamous cell carcinoma. 2. Patients diagnosed with an additional malignancy. 3. Patients diagnosed with immunodeficiency or those receiving systemic steroid therapy or any other form of immunosuppressive therapy. 4. Patients with a known history of active tuberculosis (Bacillus tuberculosis). 5. Patients who received neoadjuvant immunotherapy before surgery. 6. Patients with HIV, HBV, or HCV infection. Surgical procedures and postoperative inventions Selection of surgical procedure: According to the National Comprehensive Cancer Network (NCCN) guideline, for patients with T1, T2, and selected T3 laryngeal and hypopharyngeal cancers, endoscopic resection or open partial laryngectomy is feasible to achieve the objective of preserving laryngeal function. Meanwhile, patients with stage T3–T4 HNSCC are amenable to total laryngectomy. Induction chemotherapy was chosen as preoperative treatment to reduce the tumor size, and larynx-preserving surgery was performed. Specific surgical techniques included transoral resection, hemilaryngectomy, supraglottic laryngectomy, partial laryngectomy, and pharyngectomy, with partial laryngectomy. Changes have been highlighted in red in the revised manuscript. PD-L1 expression: PD-L1 testing of the tumor specimens by IHC was performed by Daen Medical with monoclonal antibodies 22c3. PD-L1 expression on both tumor and tumor-infiltrating immune cells was evaluated. For tumor cells, membranous staining of any intensity was considered positive. Only inflammatory cells infiltrating invasive tumor and in adjacent intra- and peri-tumoral stroma were scored. Combined positivity score (CPS) was calculated by summing the numbers of PD-L1–positive tumor cells and immune cells and dividing by the total number of viable tumor cells. PD-L1 positivity was defined as a CPS 1. Risk-adapted adjuvant (chemo)radiation: Postoperative intermediate-risk patients with LA-HNSCC were treated with adjuvant radiotherapy (60 Gy radiation). Patients with high-risk features were defined as resection margins (R1) or extracapsular spread (ECS) of lymph node metastases. Those patients were treated with adjuvant chemoradiotherapy (66 Gy radiation and concurrent cisplatin). Standard adjuvant radiotherapy dose ranged from 60 to 66 Gy, which was administered in 30–33 fractions over 6 to 7 weeks. When concurrent chemotherapy with cisplatin was used, patients received cisplatin with 100 mg/m2 every 3 weeks (Q3W) or cisplatin with 40 mg/m2 every week (Q1W). The cumulative dose did not exceed 300 mg/m2 of body surface area. A minimum of 200 mg/m2 cisplatin was given to all patients. Adjuvant immunotherapy: There were a total of 25 patients in the adjuvant immunotherapy therapy group. After completing risk-adapted adjuvant (chemo)radiation, the patients received a PD-1 inhibitor intravenously with a total of 12 cycles. Among them, 18 patients were treated with pembrolizumab, 5 were treated with camrelizumab, and 2 were treated with tislelizumab. All these drugs were given at a dose of 200 mg every 3 weeks. All of the patients were informed about the surgical procedure, therapeutic regime, and potential complications. This retrospective chart review study involving human participants was conducted in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of Changhai Hospital (Approval No. CHEC-Y2020-065). Follow-up Follow-up information was obtained through outpatient visits and telephone calls. The follow-up period began on the date of surgical treatment, with the most recent follow-up occurring in April 2024. Patients' survival times, from the date of surgical treatment to the most recent follow-up or the date of death, were recorded. Patients were monitored to assess their disease status every 3 months during the first 3 years post-surgery, every 6 months during years 4 to 5, and annually thereafter. Follow-up evaluations included physical examinations, electronic fiberoptic examinations, chest X-rays, abdominal ultrasonography, CT and/or MRI scans of the head and neck, and bone scans. If conventional examinations suggested the possibility of recurrence or metastasis, patients received PET-CT scans and biopsies to confirm recurrence or metastasis. Statistical analysis All of the survival outcomes were calculated starting from the date of surgery. We considered the following survival endpoints. –OS includes death from all causes. PFS includes local recurrence or distant metastases of HNSCC and death from all causes. Continuous variables with a normal distribution were compared between groups using the t-test, while categorical variables were compared using the chi-square test and Fisher test. Survival was estimated using the Kaplan–Meier method. A p-value of < 0.05 was considered to be the threshold for statistical significance. All of the statistical analyses were performed using SPSS 22 or GraphPad Prism 9. Results Clinic and pathological characteristics After applying the inclusion and exclusion criteria, the study population consisted of 59 patients (57 males and 2 females) with an average age of 59.8 ± 8.7 years. All of the patients had either intermediate- or high-risk characteristics. The standard of care involved surgical resection followed by risk-adapted adjuvant (chemo)radiation. The patients were divided into two groups: a standard therapy group, consisting of patients who received only the standard of care (n = 34), and an adjuvant immunotherapy group, consisting of patients who received adjuvant immunotherapy as a follow-up maintenance regimen after the standard of care (n = 25) (Fig. 1 ). The initial characteristics of all of the patients are shown in Table 1 and Table 2 . There were no significant differences in sex, age, smoking status, binge drinking, clinical staging, primary tumor staging, reginal lymph node staging, and postoperative pathologic adverse features between the two groups (all P > 0.05). Table 1 Patient demographic and clinical characteristics Characteristic Standard therapy group (n = 34) Adjuvant immunotherapy group (n = 25) t , χ 2 , or F* P Age, years Median 58.8 61.2 1.073 0.305 Range 35–73 39–73 Male, n (%) 33 (97.1%) 24 (96.0%) 0.049 0.825 Smoking, n (%) 5.539 0.063 Current 29 (85.3%) 16 (64.0%) Former 0 (0.0%) 2 (8.0%) Never 5 (14.7%) 7 (28.0%) Drinking, n (%) 1.770 0.413 Current 22 (64.7%) 15 (60.0%) Former 0 (0.0%) 1 (4.0%) Never 12 (35.3%) 9 (36.0%) Clinical stage 2.746 0.098 Ⅲ 2 (5.9%) 5 (20.0%) Ⅳ 32 (94.1%) 20 (80.0%) Primary site of disease 21.918 0.000 Oropharynx 0 (0.0%) 2 (8.0%) Larynx 30 (88.2%) 9 (36.0%) Hypopharynx 4 (11.8%) 14 (56.0%) Induction chemotherapy 5.281 0.022 Yes 9 (26.5%) 14 (56.0%) No 25 (73.5%) 11 (44.0%) Type of surgery, n (%) 4.157 0.041 Partial laryngectomy 14 (41.2%) 17 (68.0%) Total laryngectomy 20 (58.8%) 8 (32.0%) Data are n (%). * t for age; F for male sex; χ 2 for smoking status, binge drinking, clinical staging, primary site of disease, preoperative induction chemotherapy, type of surgery. Table 2 Patient pathological characteristics after surgery Characteristic Standard therapy group (n = 34) Adjuvant immunotherapy group (n = 25) pT classification 6.974 0.073 pT1 2 (5.9%) 2 (8.0%) pT2 8 (23.5%) 11 (44.0%) pT3 18 (52.9%) 5 (20.0%) pT4 6 (17.7%) 7 (28.0%) pN classification 3.265 0.353 pN0 1 (2.9%) 1 (4.0%) pN1 3 (8.8%) 3 (12.0%) pN2 28 (83.4%) 16 (64.0%) pN3 2 (5.9%) 5 (20%) PD-L1 CPS 38.114 0.000 ≥ 20 0 (0.0%) 17 (68.0%) < 20 0 (0.0%) 2 (8.0%) Unknown 34 (100%) 6 (24.0%) Adverse features 0.820 0.365 Intermediate-risk 29 (85.3%) 19 (76.0%) High risk 5 ( 14.7%) 6 (24.0%) Data are n (%). PD-L1, programmed death ligand 1; CPS, combined positive score The primary sites of HNSCC in this study were the oropharynx, larynx, and hypopharynx. The standard therapy group was primarily dominated by laryngeal carcinoma, whereas the adjuvant immunotherapy group was primarily dominated by hypopharyngeal carcinoma (χ2 = 21.918, P = 0.000). Additionally, the proportion of preoperative induction chemotherapy in the standard therapy group was significantly lower than in the adjuvant immunotherapy group (26.5% vs. 56.0%, χ2 = 5.281, P = 0.022). The larynx preservation rate in the standard therapy group was also significantly lower than in the adjuvant immunotherapy group (41.2% vs. 68.0%, χ2 = 4.157, P = 0.041). Survival outcome As of the last follow-up date, April 1, 2024, the median follow-up was 32.6 months (range, 6–81 months). In the standard therapy group, 2 patients were lost to follow-up at 6 and 8 months, 9 patients experienced disease progression (relapse or metastasis), and 9 patients died from all causes. In the adjuvant immunotherapy group, 4 patients experienced disease progression (relapse or metastasis), one of them died one month after abandoning treatment following disease progression, and all the other patients did not undergo disease progression at the most recent follow-up (Supplementary Fig. 1–3). Survival analyses were performed for both groups. There was no statistically significant difference between the standard therapy group and the adjuvant immunotherapy group in the 2-year PFS rate (62.1% vs. 80.0%, χ2 = 2.465, P = 0.116) and 2-year OS rate (79.3% vs. 95.0%, χ2 = 2.434, P = 0.119) (Fig. 2 A, 2 B). Considering that PD-L1 expression could affect the efficacy of PD-1 inhibitors, patients in the adjuvant immunotherapy group were stratified by PD-L1 combined positive score (CPS) ≥ 20 as the standard. The 2-year PFS rates for the standard therapy group, adjuvant immunotherapy group, and adjuvant immunotherapy group with PD-L1 CPS ≥ 20 were 62.1%, 80.0%, and 92.9%, respectively. The adjuvant immunotherapy group with PD-L1 CPS ≥ 20 had a significantly better 2-year PFS rate compared to the standard therapy group (χ2 = 4.644, P = 0.031) (Fig. 2 C), but there was no statistically significant difference between the adjuvant immunotherapy group and the adjuvant immunotherapy group with PD-L1 CPS ≥ 20 in the 2-year PFS rate (χ2 = 1.053, P = 0.305). The 2-year OS rates in the standard therapy group, adjuvant immunotherapy group, and adjuvant immunotherapy group with PD-L1 CPS ≥ 20 were 79.3%, 95.0%, and 100.0%, respectively. There were no significant differences in the 2-year OS rates between any of the groups (all P > 0.05) (Fig. 2 D). Treatment-related adverse events The laryngeal preservation rate in the adjuvant immunotherapy group was significantly higher than that in the standard therapy group, which was attributable to preoperative induction therapy (68.0% vs. 41.2%, χ 2 = 4.159, P = 0.041). The most common-grade 1–2 treatment-related adverse events in the adjuvant immunotherapy were leukopenia (3/25, 12.0%), skin-related toxicity (1/25, 4.0%), immune pneumonia (1/25, 4.0%), and immune hepatitis (1/25, 4.0%). No severe adverse events were reported during the treatment (Table 3 ). Table 3 Treatment-related adverse events in the adjuvant immunotherapy Adjuvant immunotherapy group (n = 25) Any grade Grade 3–5 Blood and lymphatic system disorders, n (%) Anaemia 0 (0%) 0 (0%) Neutropenia 3 (7.5%) 0 (0%) Thrombocytopenia 0 (0%) 0 (0%) Skin and subcutaneous tissue disorders, n (%) Dermatitis acneiform 0 (0.0%) 0 (0%) Rash 1 (4.0%) 0 (0%) Reactive telangiosis 0 (0%) 0 (0%) Immune related diseases, n (%) 0 (0%) immune pneumonia 1 (2.5%) 0 (0%) immune hepatitis 1 (2.5%) 0 (0%) Data are n (%). Adverse events are presented according to the Medical Dictionary for Regulatory Affairs system organ class. Discussion In this retrospective case review of 59 patients with LA-HNSCC who have pathological intermediate or high-risk factors, we found that risk-adapted adjuvant (chemo)radiation followed by immune checkpoint inhibitor (ICI) therapy tended to improve patient survival compared with risk-adapted adjuvant (chemo)radiation alone, particularly in the CPS ≥ 20 population. Our findings suggest that ICIs as an adjuvant treatment in patients who have intermediate- and high-risk factors play an important role in improving prognosis and prolonging survival, while also being safe and well tolerated. In the future, large-scale phase III clinical studies are needed to verify our results. Immunotherapy is currently the first-line treatment for patients with recurrent and/or metastatic HNSCC, significantly improving patient survival. Nivolumab, a PD-1 inhibitor, improved OS in patients with platinum-resistant R/M SCCHN in the Phase III CheckMate-141 trial [ 7 ]. In the phase III KEYNOTE-048 trial [ 8 ], pembrolizumab, either alone or combined with chemotherapy, improved OS in patients with untreated R/M HNSCC compared to the EXTREME regimen (cetuximab combined with chemotherapy of platinum and 5-fluorouracil). These trial results have greatly changed the treatment landscape for R/M HNSCC. However, for patients with LA-HNSCC, the role of PD-1 inhibitors in the primary curative setting remains unclear, especially for those with intermediate- and high-risk factors following upfront surgery. For patients with LA-HNSCC, combining immunotherapy with conventional treatment modalities presents new opportunities to reduce recurrence and metastasis. Early studies have indicated potential benefit of ICIs combined with CRT in treating LA-HNSCC. However, the three major phase III studies—JAVELIN H&N-100, REACH, and KEYNOTE-412 —have not met their primary endpoints [ 16 – 18 ]. The antitumor immune response stimulated by PD-1/PD-L1 inhibitors may be mediated by the expansion of antitumor CD8 + T cells within tumor-draining lymph nodes [ 19 ]. The addition of immune checkpoint inhibitors during CRT treatment did not provide survival benefits to patients with locally advanced HNSCC. This may be attributed to tumor-draining lymph nodes, which are standardly included within the radiation fields, resulting in the depletion of antitumor CD8 + T cells and abrogation of systemic antitumor immunity. Recent clinical studies have explored the use of ICIs alone or in combination with other drugs as neoadjuvant treatments for LA-HNSCC to enhance treatment efficacy and improve surgical outcomes. According to published clinical trial data [ 20 – 21 ], neoadjuvant immunotherapy offers clinical benefits, such as improved pathologic tumor response and disease control, reduced rate of high-risk pathology, and cancer downstaging, although long-term follow-up data are still needed. As immunotherapy advances into the perioperative setting, an increasing number of clinical trials are investigating the benefits of PD-1 inhibitor as an adjuvant therapy for resectable cancer. The IMpower010 trial (NCT02486718) [ 22 ] demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab after chemotherapy in both the PD-L1-positive and all of the resected stage II-IIIA non-small-cell lung cancer (NSCLC) populations. Similarly, the KEYNOTE-091 trial [ 14 ] showed that pembrolizumab significantly improved DFS compared to placebo without new safety concerns in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Based on these results, pembrolizumab emerges as a potential new treatment option for stage IB-IIIA NSCLC post-complete resection and adjuvant chemotherapy, regardless of PD-L1 expression. A phase 3 trial (NCT03700476) demonstrated induction-concurrent RCT with sintilimab, a PD-1 inhibitor, improved event-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma compared to standard RCT [ 15 ]. The DIPPER study highlighted the benefits of camrelizumab following gemcitabine and cisplatin induction chemotherapy and subsequent concurrent cisplatin radiotherapy in patients with locally advanced nasopharyngeal carcinoma, significantly reducing the risk of recurrent and metastasis with mild toxicity. Although the DIPPER study results are not yet officially published, they were reported at the 2024 American Society of Clinical Oncology Annual Meeting. Postoperative intermediate- and high-risk patients with LA-HNSCC face the risk of recurrence and metastasis after standard of care. How to improve survival outcomes and reduce the risk of recurrence and metastasis poses a significant challenge for clinicians. The aforementioned clinical studies have demonstrated that immunotherapy following concurrent RCT for locally advanced nasopharyngeal carcinoma and after surgery and chemotherapy for resectable lung cancer can yield significant survival benefits. These treatments enhance local disease control, reduce tumor recurrence and metastasis, and improve patients' PFS. Furthermore, PD-1 inhibitors have a favorable toxicity profile even in the heavily pretreated recurrent HNSCC population [ 7 ](Ferris et al., 2016). Therefore, it is reasonable to believe that immunotherapy as adjuvant treatment after standard of care can offer remarkable clinical benefits to patients with LA-HNSCC who have intermediate- and high-risk factors. Haque et al. have previously reported that risk factors for HNSCC recurrence after salvage surgery are similar to established pathological risk factors at initial diagnosis [ 23 ]. A subsequent prospective study [ 24 ] has indicated that adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well-tolerated and that 2-year disease-free survival following adjuvant nivolumab is 71.4% (95% CI 57.8–88.1), which is much longer than a historical control sample of salvage surgery alone with similar baseline characteristics. To date, no studies have reported the results of ICIs as adjuvant therapy following postoperative standard treatment in patients with LA-HNSCC who have intermediate- and high-risk factors. To the best of our knowledge, this is the first report on the use of ICIs as an adjuvant therapy for resectable patients with LA-HNSCC who have intermediate- and high-risk factors. Our study showed that patients in the adjuvant immunotherapy group exhibited a trend towards a higher 2-year PFS rate compared to the standard therapy group, particularly among patients with a PD-L1 CPS of 20 or more. This suggests that immunotherapy as an adjuvant treatment for resectable LA-HNSCC with intermediate- and high-risk factors plays an important role in improving prognosis and prolonging patient survival. Additionally, it highlights CPS as an important biomarker for identifying the potential beneficiary population. Prospective clinical trials are needed to further validate our results. Improving the prognosis of patients with LA-HNSCC who have intermediate- and high-risk factors has long been a priority for head and neck surgeons, as many of these patients face recurrent or metastatic disease. Various adjuvant treatments have been attempted to improve outcomes, including oral tyrosine-kinase inhibitors (TKIs) and mTOR inhibitors, but these have proven ineffective. For example, afatinib administrated as a maintenance therapy did not significantly improve 2-year DFS compared to placebo following post-operative RCT in patients with HNSCC [ 25 ]. Additionally, adding afatinib to postoperative radiation therapy (PORT) for patients with intermediate- and high-risk HNSCC resulted in unacceptable toxicity, particularly in those requiring high-dose PORT to the oral cavity [ 26 ]. Adjuvant therapy with everolimus, an mTOR inhibitor, significantly improved two-year PFS and OS only in p16-negative and TP53mut patients at high risk of cancer recurrence who were disease-free after definitive local therapy for advanced-stage HNSCC [ 27 ]. Currently, an ongoing trial [ 28 ] is exploring the potential benefits of combining chemoradiation with a WEE1 inhibitor in patients with high-risk histopathological features after surgical resection, but no positive findings have been reported yet. In this study, the adjuvant immunotherapy showed a trend towards improving the survival of patients with LA-HNSCC who have intermediate- and high-risk factors; however, the statistical difference was not significant. Several factors might account for this. First, as a retrospective study, it had a short observation period of 2 years with PFS and OS rates as the primary end points. This limited timeframe might have affected the ability to demonstrate a significant benefit of adding a PD-1 inhibitor, and the benefits of immunotherapy may become more apparent with longer follow-up. Second, PD-L1 expression likely plays a crucial role in the efficacy of adjuvant immunotherapy. Nearly one-third of patients in the adjuvant immunotherapy group had low or unknown CPS. Nevertheless, we observed a significant benefit in 2-year PFS for patients with a CPS 20 or more, thus indicating that PD-L1 is an important biomarker for predicting the benefits of adjuvant immunotherapy. Third, the composition of the standard therapy and adjuvant immunotherapy groups differed in terms of cancer types. The standard therapy group primarily consisted of patients with laryngeal cancer, whereas the adjuvant immunotherapy group was mainly included patients with hypopharyngeal cancer. Although the primary sites of laryngeal and hypopharyngeal cancer are adjacent, the oncological characteristics are different. Hypopharyngeal cancer has a poorer prognosis and a lower DFS and laryngeal function preservation rates compared to laryngeal cancer [ 29 – 30 ]. This disparity in cancer types between the two groups might have contributed to the lack of significant benefit in the adjuvant immunotherapy group. Interestingly, despite the higher proportion of hypopharyngeal cancer patients with hypopharyngeal cancer in the adjuvant immunotherapy group with a PD-L1 CPS of ≥ 20 (64.7% vs. 11.8% in the standard treatment group), the 2-year PFS rate in this group significantly improved compared to the standard treatment group. This suggests that administering a PD-1 inhibitor as maintenance monotherapy after the standard of care for resectable HNSCC with intermediate- and high-risk factors can significantly enhance local regional control, reduce distant metastasis, and prolong patient survival, especially for patients with a PD-L1 CPS of 20 or more. Our study has several limitations. First, all of the patients in this study were from a single center, which may not fully represent the results of other medical institutions. Second, the sample size of the study limited our ability to detect differences between the two groups. Third, the types of PD-1 inhibitors used in the study were consistent, including camrelizumab, pembrolizumab, and tislelizumab. Finally, retrospective studies inherently have bias and confounding factors, although statistical analyses showed that the baseline clinical characteristics of the patients in both groups were generally consistent. Conclusions In conclusion, PD-1 inhibitors administered as maintenance monotherapy after standard care improved PFS in patients with postoperative intermediate- and high-risk LA-HNSCC, especially for those with a PD-L1 CPS of 20 or more. The adverse events caused by adjuvant immunotherapy were acceptable and did not lead to treatment interruption. To date, the use of adjuvant immunotherapy as a first-line treatment for patients with HNSCC has been very limited, and no established guidelines exist for its use in postoperative patient with LA_HNSCC who have intermediate and high-risk factors. Therefore, this study represents an important step towards incorporating adjuvant immunotherapy into the treatment of resectable LA-HNSCC with intermediate- and high-risk factors. Future studies are needed to validate our results. Abbreviations PD 1 Programmed cell death protein 1 PFS Progression free survival OS Overall survival PD-L1 Programmed death ligand 1 CPS Combined positive score HNSCC Head and neck squamous cell carcinoma HPV Human papillomavirus LA Locally advanced RCT Radiochemotherapy ECS Extracapsular spread Anti-PD-1 Anti-programmed death receptor-1 DFS Disease-free survival NSCLC Non-small cell lung cancer AJCC American Joint Committee on Cancer ICI Immune checkpoint inhibitor TKIs Tyrosine-kinase inhibitors Declarations Acknowledgments We thank LetPub (www.letpub.com.cn) for its linguistic assistance during the preparation of this manuscript. Funding This work was supported by the National Natural Science Foundation of China under Grant No. 81972537. Competing Interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contributions XQS and JQH provided clinical specimens and information. XQS and MHZ performed the data analysis and drafted the manuscript. HLZ and CYZ designed the study. YNQ, HPZ, MY and LZ participated in the study design and coordinated the drafting of the manuscript. XQS, MHZ and JQH contributed equally to this work. All the authors read and approved the final manuscript. Data Availability Statement The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author. Ethics approval The study was approved by the ethics committee of Changhai Hospital (Approval No. CHEC-Y2020-065). 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Oncotarget 12:2223–2226. https://doi.org/10.18632/oncotarget.27987 Tao Y, Aupérin A, Sun X et al (2020) Avelumab–cetuximab–radiotherapy versus standards of care in locally advanced squamous-cell carcinoma of the head and neck: The safety phase of a randomised phase III trial GORTEC 2017-01 (REACH). Eur J Cancer 141:21–29. https://doi.org/10.1016/j.ejca.2020.09.008 Machiels J-P, Tao Y, Licitra L et al (2024) Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial. Lancet Oncol 25:572–587. https://doi.org/10.1016/S1470-2045(24)00100-1 Buchwald ZS, Nasti TH, Lee J et al (2020) Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy. J Immunother Cancer 8:e000867. https://doi.org/10.1136/jitc-2020-000867 Wise-Draper TM, Takiar V, Mierzwa ML et al (2021) Association of pathological response to neoadjuvant pembrolizumab with tumor PD-L1 expression and high disease-free survival (DFS) in patients with resectable, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC). JCO 39:6006–6006. https://doi.org/10.1200/JCO.2021.39.15_suppl.6006 Uppaluri R, Chernock R, Mansour M et al (2021) Enhanced pathologic tumor response with two cycles of neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC). JCO 39:6008–6008. https://doi.org/10.1200/JCO.2021.39.15_suppl.6008 Felip E, Altorki N, Zhou C et al (2023) Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 34:907–919. https://doi.org/10.1016/j.annonc.2023.07.001 Haque S, Karivedu V, Riaz MK et al (2019) High-risk pathological features at the time of salvage surgery predict poor survival after definitive therapy in patients with head and neck squamous cell carcinoma. Oral Oncol 88:9–15. https://doi.org/10.1016/j.oraloncology.2018.11.010 Leddon JL, Gulati S, Haque S et al (2022) Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck. Clin Cancer Res 28:3464–3472. https://doi.org/10.1158/1078-0432.CCR-21-4554 Racadot S, Thennevet I, Ouldbey Y et al (2023) Afatinib maintenance therapy following post-operative radiochemotherapy in head and neck squamous cell carcinoma: Results from the phase III randomised double-blind placebo-controlled study BIB2992ORL (GORTEC 2010–02). Eur J Cancer 178:114–127. https://doi.org/10.1016/j.ejca.2022.10.023 Margalit DN, Haddad RI, Tishler RB et al (2019) A Phase 1 Study of Afatinib in Combination with Postoperative Radiation Therapy with and Without Weekly Docetaxel in Intermediate- and High-Risk Patients with Resected Squamous Cell Carcinoma of the Head and Neck. Int J Radiat Oncol Biol Phys 105:132–139. https://doi.org/10.1016/j.ijrobp.2019.04.034 Nathan C-AO, Hayes DN, Karrison T et al (2022) A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck. Clin Cancer Res 28:5040–5048. https://doi.org/10.1158/1078-0432.CCR-21-4290 Kong A, Good J, Kirkham A et al (2020) Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the WISTERIA trial protocol. BMJ Open 10:e033009. https://doi.org/10.1136/bmjopen-2019-033009 Torre LA, Bray F, Siegel RL et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108. https://doi.org/10.3322/caac.21262 Bradley PJ (2019) Epidemiology of Hypopharyngeal Cancer. In: Bradley PJ, Eckel HE (eds) Advances in Oto-Rhino-Laryngology. S. Karger, AG, pp 1–14 Statements & Declarations Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5377938","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":376321911,"identity":"e16b4f15-8ca8-445d-9c93-9a0542cbb8e4","order_by":0,"name":"Xiaoqiong Shi","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoqiong","middleName":"","lastName":"Shi","suffix":""},{"id":376321913,"identity":"c10d44be-c09c-4963-84d2-0d2da968fbae","order_by":1,"name":"Minhui Zhu","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Minhui","middleName":"","lastName":"Zhu","suffix":""},{"id":376321917,"identity":"e26fbfc9-3564-4699-9118-c08866ce79b0","order_by":2,"name":"Jianqiao He","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jianqiao","middleName":"","lastName":"He","suffix":""},{"id":376321919,"identity":"2088b170-d639-40be-840a-e6228a75241e","order_by":3,"name":"Yingna Gao","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yingna","middleName":"","lastName":"Gao","suffix":""},{"id":376321921,"identity":"741fd9f8-ef01-46fc-b7ab-9b8d2495b100","order_by":4,"name":"Yi Ma","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Ma","suffix":""},{"id":376321923,"identity":"04a47412-58ae-45a7-afa5-d74a4a71f725","order_by":5,"name":"Haopu Li","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haopu","middleName":"","lastName":"Li","suffix":""},{"id":376321925,"identity":"30043c63-89c1-4504-b016-b4f95e00bdab","order_by":6,"name":"Guoning Yu","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guoning","middleName":"","lastName":"Yu","suffix":""},{"id":376321927,"identity":"9f180a8a-5bdc-46e2-b3ed-b1229490923a","order_by":7,"name":"Lin Zhao","email":"","orcid":"","institution":"Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Zhao","suffix":""},{"id":376321928,"identity":"03b8d8ee-732e-4a2e-acc2-dc307c125ca7","order_by":8,"name":"Hongliang Zheng","email":"","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hongliang","middleName":"","lastName":"Zheng","suffix":""},{"id":376321929,"identity":"9e318810-d8a4-43c2-b1bf-d6f7ba738dd1","order_by":9,"name":"Caiyun Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIie3PsQrCMBCA4YRAu5x2jfgSJwVxKO2rtAQyBfEBHCIFXcS5j+EjiIeddHdwcHIWBHEQUUHXtqNg/umG++COMZfrB/MtMPEeAsEnxzNGcS2B1Yd0Zjn1ipFWzQluS92F85rbWhLs6DIaH2K7N9iNcCWYT5tlJZHDNCzKk5oUBkODhzYDrfdVJJGACjxSQhpUBk+CSehXEgi2SPAg5b0IDZC4rSXM9PLWlGKAMstZIyJNKFoLSqWfE5+jVl7dL6/DwgtcKUmIz263exQHPpWV5Ftmv5PXZP1d0nTR5XK5/rAnEuVKHxOjW0QAAAAASUVORK5CYII=","orcid":"","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":true,"prefix":"","firstName":"Caiyun","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2024-11-02 11:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5377938/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5377938/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70044298,"identity":"766dc442-b110-4183-8a88-c6778001b349","added_by":"auto","created_at":"2024-11-27 18:51:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":206043,"visible":true,"origin":"","legend":"\u003cp\u003eStudy schema and patient flow\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5377938/v1/b2ce6662ff4c1cfc9f66de94.png"},{"id":70043897,"identity":"2ebcc28a-525c-47a7-9cfc-226e30ca8eac","added_by":"auto","created_at":"2024-11-27 18:43:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":165132,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival outcomes. ST, standard therapy; AI, adjuvant immunotherapy; Obs, observed number of events. (A) Comparison of the 2-year PFS rate between the standard therapy group and the adjuvant immunotherapy group (P = 0.116). (B) Comparison of the 2-year OS rate between the standard therapy group and the adjuvant immunotherapy group (\u003cem\u003eP \u003c/em\u003e= 0.119). (C) Comparison of the 2-year PFS rate between the standard therapy group and the adjuvant immunotherapy group for patients with PD-L1 CPS ≥ 20 (\u003cem\u003eP \u003c/em\u003e= 0.031).\u003cstrong\u003e \u003c/strong\u003e(D) Comparison of the 2-year OS rate between the standard therapy group and the adjuvant immunotherapy group for patients with PD-L1 CPS ≥ 20 (\u003cem\u003eP \u003c/em\u003e= 0.071).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5377938/v1/3f0fc21792a0efa8c3fc5736.png"},{"id":70147804,"identity":"bbed2f5c-dc72-426e-819c-a5c54f5cacc6","added_by":"auto","created_at":"2024-11-29 01:01:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":950144,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5377938/v1/81da88d0-00db-4b79-a792-951c915f760f.pdf"},{"id":70043898,"identity":"8b607ac1-39e4-461b-8d65-5c720dc57c78","added_by":"auto","created_at":"2024-11-27 18:43:49","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1019698,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-5377938/v1/c08690163f871cdf6923f61b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Postoperative adjuvant immunotherapy versus standard of care in resectable locally advanced head and neck squamous cell carcinoma with intermediate- and high-risk factors: a real-world retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAccording to GLOBOCAN data from 2020, head and neck cancer is the sixth most common cancer, with an estimated 1,000,000 new cases per year projected by 2030 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 90% of these cancers, with potential causes including smoking, drinking, and human papillomavirus (HPV) infection [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Approximately 60% of patients with HNSCC have locally advanced (LA) disease. For these patients, surgery is the primary treatment, but it is often insufficient on its own. The majority of patients require postoperative adjuvant therapy, such as adjuvant radiotherapy or radiochemotherapy (RCT), to improve survival rates. Several factors can affect local regional control and survival after surgery for LA-HNSCC. Microscopically involved resection margins (R1) and extracapsular spread (ECS) of lymph node metastases are the most significant prognostic factors (\u0026ldquo;high risk\u0026rdquo;) for poor outcomes. Close margins (R0\u0026thinsp;\u0026lt;\u0026thinsp;5 mm), vascular invasion, perineural invasion, and the presence of \u0026ge;\u0026thinsp;2 lymph node metastases are \u0026ldquo;intermediate-risk\u0026rdquo; features predictive of worse disease control [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Even completely resected intermediate- and high-risk HNSCC are prone to loco-regional recurrence and distant metastasis, with about 45\u0026ndash;50% of patients experiencing such events or death within 24 months [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Improving the prognosis of postoperative intermediate- and high-risk LA-HNSCC remains a significant challenge for head and neck surgeons.\u003c/p\u003e \u003cp\u003eAnti-programmed death receptor-1 (Anti-PD-1)/programmed death ligand 1 (PD-L1) antibodies can block the PD-1/PD-L1 signaling pathway and enhance T cell killing activity. They have shown outstanding clinical efficacy and are considered one of the most promising tumor treatment strategies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Based on the excellent clinical trial results of PD-1 inhibitors in treating patients with recurrent and/or metastatic HNSCC in CheckMate-141 and KEYNOTE-048 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], the US Food and Drug Administration has approved PD-1 inhibitors nivolumab and pembrolizumab for this purpose. Immunotherapy can induce changes in the tumor microenvironment and enhance the sensitivity of subsequent treatments [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recent clinical studies have combined PD-1 inhibitors with other drugs for neoadjuvant treatment of patients with LA-HNSCC, achieving encouraging results. These studies suggest that PD-1 inhibitors can improve pathologic tumor response and local control in patients with LA-HNSCC.\u003c/p\u003e \u003cp\u003ePD-1 inhibitors have been administered to reduce recurrence and eliminate micrometastatic disease after surgery in some studies across solid tumors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. For postoperative intermediate- and high-risk patients with LA-HNSCC, the risk of loco-regional recurrence and distant metastasis resulting from the expansion of micrometastatic disease is substantial. Can PD-1 inhibitors be used as adjuvant therapy in those patients to reduce recurrence and metastasis? Recent data [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] further support that targeting the PD-1/PD-L1 axis in the definitive setting has the potential to improve local control rates and decrease the occurrence of distant metastases by promoting immune surveillance of micrometastatic disease. More importantly, PD-1 inhibitors could significantly improve the patients\u0026rsquo; disease-free survival (DFS) when used as adjuvant therapy after standard of care, including non-small cell lung cancer (NSCLC) and nasopharyngeal carcinoma [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Hitherto, there have been no reports on the use of PD-1 inhibitors for postoperative adjuvant treatment of patients with LA-HNSCC, especially those with intermediate- and high-risk factors.\u003c/p\u003e \u003cp\u003eThis study was conducted to investigate the role of PD-1 inhibitors as adjuvant therapy in intermediate- and high-risk patients with resectable LA-HNSCC. The primary end points are the 2-year progression-free survival (PFS) rate and overall survival (OS) rate.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted on patients with LA-HNSCC who were treated between September 2015 and September 2023. Data from the electronic case management system of the Department of Otolaryngology\u0026mdash;Head and Neck Surgery at Changhai Hospital in Shanghai were analyzed. We found 453 patients who had advanced stage III or IVA/B squamous-cell carcinoma originating in the oropharynx (HPV negative), larynx, or hypopharynx. The patients included in the study should undergo macroscopically complete resection with postoperative intermediate- and high-risk factors and receive risk-adapted adjuvant (chemo)radiation. First, we excluded the 182 patients who were diagnosed with recurrent head and neck squamous cell carcinoma or diagnosed with an additional malignancy, received neoadjuvant immunotherapy before surgery, were not eligible for further surgery, or were treated with definitive RT or CRT. Second, we excluded the 207 patients who had no intermediate- or high-risk characteristics, received adjuvant therapy in other hospitals or rejected adjuvant therapy after surgery. Last, we excluded the five patients who did not complete total adjuvant radiotherapy or with cumulative dose of cisplatin\u0026thinsp;\u0026lt;\u0026thinsp;200 mg/m2. Eventually, 59 patients were selected for the study.\u003c/p\u003e \u003cp\u003eThe inclusion criteria were as follows: 1. Patients were over 18 years of old. 2. Patients had advanced stage III or IVA/B HNSCC according to the American Joint Committee on Cancer (AJCC) TNM classification (Seventh edition for the patients treated before January 1, 2017, and Eighth edition for those treated since January 1, 2017). 3. Patients had undergone macroscopically complete resection of diagnosed advanced squamous-cell carcinoma originating in the oropharynx (HPV negative), larynx, or hypopharynx. 4. Patients must have intermediate- or high-risk characteristics, defined by any or all of the following: histologic evidence of invasion in two or more regional lymph nodes; extracapsular extension of nodal disease; microscopically involved mucosal margins of resection (R1) or margins of resection; vascular invasion; or perineural invasion. 5. Induction chemotherapy was allowed preoperatively. 6. Patients must have undergone surgical resection followed by risk-adapted adjuvant (chemo)radiation. 7. Adjuvant radiotherapy or concurrent RCT (cisplatin-based chemotherapy) must have begun within 6 weeks post-surgery. 8. The surgery and postoperative treatment must have been completed in our hospital, and the follow-up data must be complete. Patients who met all of the above inclusion criteria were included in the study. 9.Patients must have provided written informed consent.\u003c/p\u003e \u003cp\u003eThe exclusion criteria were as follows: 1. Patients diagnosed with recurrent head and neck squamous cell carcinoma. 2. Patients diagnosed with an additional malignancy. 3. Patients diagnosed with immunodeficiency or those receiving systemic steroid therapy or any other form of immunosuppressive therapy. 4. Patients with a known history of active tuberculosis (Bacillus tuberculosis). 5. Patients who received neoadjuvant immunotherapy before surgery. 6. Patients with HIV, HBV, or HCV infection.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurgical procedures and postoperative inventions\u003c/h3\u003e\n\u003cp\u003e Selection of surgical procedure: According to the National Comprehensive Cancer Network (NCCN) guideline, for patients with T1, T2, and selected T3 laryngeal and hypopharyngeal cancers, endoscopic resection or open partial laryngectomy is feasible to achieve the objective of preserving laryngeal function. Meanwhile, patients with stage T3\u0026ndash;T4 HNSCC are amenable to total laryngectomy. Induction chemotherapy was chosen as preoperative treatment to reduce the tumor size, and larynx-preserving surgery was performed. Specific surgical techniques included transoral resection, hemilaryngectomy, supraglottic laryngectomy, partial laryngectomy, and pharyngectomy, with partial laryngectomy. Changes have been highlighted in red in the revised manuscript.\u003c/p\u003e \u003cp\u003ePD-L1 expression: PD-L1 testing of the tumor specimens by IHC was performed by Daen Medical with monoclonal antibodies 22c3. PD-L1 expression on both tumor and tumor-infiltrating immune cells was evaluated. For tumor cells, membranous staining of any intensity was considered positive. Only inflammatory cells infiltrating invasive tumor and in adjacent intra- and peri-tumoral stroma were scored. Combined positivity score (CPS) was calculated by summing the numbers of PD-L1\u0026ndash;positive tumor cells and immune cells and dividing by the total number of viable tumor cells. PD-L1 positivity was defined as a CPS 1.\u003c/p\u003e \u003cp\u003eRisk-adapted adjuvant (chemo)radiation: Postoperative intermediate-risk patients with LA-HNSCC were treated with adjuvant radiotherapy (60 Gy radiation). Patients with high-risk features were defined as resection margins (R1) or extracapsular spread (ECS) of lymph node metastases. Those patients were treated with adjuvant chemoradiotherapy (66 Gy radiation and concurrent cisplatin). Standard adjuvant radiotherapy dose ranged from 60 to 66 Gy, which was administered in 30\u0026ndash;33 fractions over 6 to 7 weeks. When concurrent chemotherapy with cisplatin was used, patients received cisplatin with 100 mg/m2 every 3 weeks (Q3W) or cisplatin with 40 mg/m2 every week (Q1W). The cumulative dose did not exceed 300 mg/m2 of body surface area. A minimum of 200 mg/m2 cisplatin was given to all patients.\u003c/p\u003e \u003cp\u003eAdjuvant immunotherapy: There were a total of 25 patients in the adjuvant immunotherapy therapy group. After completing risk-adapted adjuvant (chemo)radiation, the patients received a PD-1 inhibitor intravenously with a total of 12 cycles. Among them, 18 patients were treated with pembrolizumab, 5 were treated with camrelizumab, and 2 were treated with tislelizumab. All these drugs were given at a dose of 200 mg every 3 weeks.\u003c/p\u003e \u003cp\u003eAll of the patients were informed about the surgical procedure, therapeutic regime, and potential complications. This retrospective chart review study involving human participants was conducted in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of Changhai Hospital (Approval No. CHEC-Y2020-065).\u003c/p\u003e\n\u003ch3\u003eFollow-up\u003c/h3\u003e\n\u003cp\u003eFollow-up information was obtained through outpatient visits and telephone calls. The follow-up period began on the date of surgical treatment, with the most recent follow-up occurring in April 2024. Patients' survival times, from the date of surgical treatment to the most recent follow-up or the date of death, were recorded.\u003c/p\u003e \u003cp\u003ePatients were monitored to assess their disease status every 3 months during the first 3 years post-surgery, every 6 months during years 4 to 5, and annually thereafter. Follow-up evaluations included physical examinations, electronic fiberoptic examinations, chest X-rays, abdominal ultrasonography, CT and/or MRI scans of the head and neck, and bone scans. If conventional examinations suggested the possibility of recurrence or metastasis, patients received PET-CT scans and biopsies to confirm recurrence or metastasis.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll of the survival outcomes were calculated starting from the date of surgery. We considered the following survival endpoints. \u0026ndash;OS includes death from all causes. PFS includes local recurrence or distant metastases of HNSCC and death from all causes. Continuous variables with a normal distribution were compared between groups using the t-test, while categorical variables were compared using the chi-square test and Fisher test. Survival was estimated using the Kaplan\u0026ndash;Meier method. A p-value of \u0026lt;\u0026thinsp;0.05 was considered to be the threshold for statistical significance. All of the statistical analyses were performed using SPSS 22 or GraphPad Prism 9.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eClinic and pathological characteristics\u003c/h2\u003e \u003cp\u003eAfter applying the inclusion and exclusion criteria, the study population consisted of 59 patients (57 males and 2 females) with an average age of 59.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7 years. All of the patients had either intermediate- or high-risk characteristics. The standard of care involved surgical resection followed by risk-adapted adjuvant (chemo)radiation. The patients were divided into two groups: a standard therapy group, consisting of patients who received only the standard of care (n = 34), and an adjuvant immunotherapy group, consisting of patients who received adjuvant immunotherapy as a follow-up maintenance regimen after the standard of care (n\u0026thinsp;=\u0026thinsp;25) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The initial characteristics of all of the patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. There were no significant differences in sex, age, smoking status, binge drinking, clinical staging, primary tumor staging, reginal lymph node staging, and postoperative pathologic adverse features between the two groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient demographic and clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStandard therapy group (n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdjuvant immunotherapy group (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e, χ\u003csup\u003e2\u003c/sup\u003e, or F*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.305\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u0026ndash;73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39\u0026ndash;73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (97.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (96.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.825\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.539\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (85.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (64.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (28.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrinking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.770\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.413\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (64.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (35.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (36.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅢ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅣ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (94.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (80.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary site of disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21.918\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOropharynx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLarynx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (88.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (36.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypopharynx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (56.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.281\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (26.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (56.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (73.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (44.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of surgery, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial laryngectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (68.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal laryngectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (58.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (32.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are n (%). *\u003cem\u003et\u003c/em\u003e for age; F for male sex; χ\u003csup\u003e2\u003c/sup\u003e for smoking status, binge drinking, clinical staging, primary site of disease, preoperative induction chemotherapy, type of surgery.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient pathological characteristics after surgery\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStandard therapy group (n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdjuvant immunotherapy group (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.974\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (23.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (44.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (52.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (17.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (28.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epN classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.353\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (12.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (83.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (64.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD-L1 CPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (68.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (24.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse features\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.820\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.365\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate-risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (85.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (76.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 ( 14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (24.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are n (%). PD-L1, programmed death ligand 1; CPS, combined positive score\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe primary sites of HNSCC in this study were the oropharynx, larynx, and hypopharynx. The standard therapy group was primarily dominated by laryngeal carcinoma, whereas the adjuvant immunotherapy group was primarily dominated by hypopharyngeal carcinoma (χ2\u0026thinsp;=\u0026thinsp;21.918, P\u0026thinsp;=\u0026thinsp;0.000). Additionally, the proportion of preoperative induction chemotherapy in the standard therapy group was significantly lower than in the adjuvant immunotherapy group (26.5% vs. 56.0%, χ2\u0026thinsp;=\u0026thinsp;5.281, P\u0026thinsp;=\u0026thinsp;0.022). The larynx preservation rate in the standard therapy group was also significantly lower than in the adjuvant immunotherapy group (41.2% vs. 68.0%, χ2\u0026thinsp;=\u0026thinsp;4.157, P\u0026thinsp;=\u0026thinsp;0.041).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival outcome\u003c/h3\u003e\n\u003cp\u003eAs of the last follow-up date, April 1, 2024, the median follow-up was 32.6 months (range, 6\u0026ndash;81 months). In the standard therapy group, 2 patients were lost to follow-up at 6 and 8 months, 9 patients experienced disease progression (relapse or metastasis), and 9 patients died from all causes. In the adjuvant immunotherapy group, 4 patients experienced disease progression (relapse or metastasis), one of them died one month after abandoning treatment following disease progression, and all the other patients did not undergo disease progression at the most recent follow-up (Supplementary Fig.\u0026nbsp;1\u0026ndash;3). Survival analyses were performed for both groups.\u003c/p\u003e \u003cp\u003eThere was no statistically significant difference between the standard therapy group and the adjuvant immunotherapy group in the 2-year PFS rate (62.1% vs. 80.0%, χ2\u0026thinsp;=\u0026thinsp;2.465, P\u0026thinsp;=\u0026thinsp;0.116) and 2-year OS rate (79.3% vs. 95.0%, χ2\u0026thinsp;=\u0026thinsp;2.434, P\u0026thinsp;=\u0026thinsp;0.119) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA,\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Considering that PD-L1 expression could affect the efficacy of PD-1 inhibitors, patients in the adjuvant immunotherapy group were stratified by PD-L1 combined positive score (CPS)\u0026thinsp;\u0026ge;\u0026thinsp;20 as the standard. The 2-year PFS rates for the standard therapy group, adjuvant immunotherapy group, and adjuvant immunotherapy group with PD-L1 CPS\u0026thinsp;\u0026ge;\u0026thinsp;20 were 62.1%, 80.0%, and 92.9%, respectively. The adjuvant immunotherapy group with PD-L1 CPS\u0026thinsp;\u0026ge;\u0026thinsp;20 had a significantly better 2-year PFS rate compared to the standard therapy group (χ2\u0026thinsp;=\u0026thinsp;4.644, P\u0026thinsp;=\u0026thinsp;0.031) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), but there was no statistically significant difference between the adjuvant immunotherapy group and the adjuvant immunotherapy group with PD-L1 CPS\u0026thinsp;\u0026ge;\u0026thinsp;20 in the 2-year PFS rate (χ2\u0026thinsp;=\u0026thinsp;1.053, P\u0026thinsp;=\u0026thinsp;0.305). The 2-year OS rates in the standard therapy group, adjuvant immunotherapy group, and adjuvant immunotherapy group with PD-L1 CPS\u0026thinsp;\u0026ge;\u0026thinsp;20 were 79.3%, 95.0%, and 100.0%, respectively. There were no significant differences in the 2-year OS rates between any of the groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eTreatment-related adverse events\u003c/h3\u003e\n\u003cp\u003eThe laryngeal preservation rate in the adjuvant immunotherapy group was significantly higher than that in the standard therapy group, which was attributable to preoperative induction therapy (68.0% vs. 41.2%, χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;4.159, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.041). The most common-grade 1\u0026ndash;2 treatment-related adverse events in the adjuvant immunotherapy were leukopenia (3/25, 12.0%), skin-related toxicity (1/25, 4.0%), immune pneumonia (1/25, 4.0%), and immune hepatitis (1/25, 4.0%). No severe adverse events were reported during the treatment (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment-related adverse events in the adjuvant immunotherapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAdjuvant immunotherapy group (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 3\u0026ndash;5\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood and lymphatic system disorders, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin and subcutaneous tissue disorders, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDermatitis acneiform\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReactive telangiosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune related diseases, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eimmune pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eimmune hepatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are n (%). Adverse events are presented according to the Medical Dictionary for Regulatory Affairs system organ class.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective case review of 59 patients with LA-HNSCC who have pathological intermediate or high-risk factors, we found that risk-adapted adjuvant (chemo)radiation followed by immune checkpoint inhibitor (ICI) therapy tended to improve patient survival compared with risk-adapted adjuvant (chemo)radiation alone, particularly in the CPS\u0026thinsp;\u0026ge;\u0026thinsp;20 population. Our findings suggest that ICIs as an adjuvant treatment in patients who have intermediate- and high-risk factors play an important role in improving prognosis and prolonging survival, while also being safe and well tolerated. In the future, large-scale phase III clinical studies are needed to verify our results.\u003c/p\u003e \u003cp\u003eImmunotherapy is currently the first-line treatment for patients with recurrent and/or metastatic HNSCC, significantly improving patient survival. Nivolumab, a PD-1 inhibitor, improved OS in patients with platinum-resistant R/M SCCHN in the Phase III CheckMate-141 trial [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In the phase III KEYNOTE-048 trial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], pembrolizumab, either alone or combined with chemotherapy, improved OS in patients with untreated R/M HNSCC compared to the EXTREME regimen (cetuximab combined with chemotherapy of platinum and 5-fluorouracil). These trial results have greatly changed the treatment landscape for R/M HNSCC. However, for patients with LA-HNSCC, the role of PD-1 inhibitors in the primary curative setting remains unclear, especially for those with intermediate- and high-risk factors following upfront surgery.\u003c/p\u003e \u003cp\u003eFor patients with LA-HNSCC, combining immunotherapy with conventional treatment modalities presents new opportunities to reduce recurrence and metastasis. Early studies have indicated potential benefit of ICIs combined with CRT in treating LA-HNSCC. However, the three major phase III studies\u0026mdash;JAVELIN H\u0026amp;N-100, REACH, and KEYNOTE-412 \u0026mdash;have not met their primary endpoints [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The antitumor immune response stimulated by PD-1/PD-L1 inhibitors may be mediated by the expansion of antitumor CD8\u0026thinsp;+\u0026thinsp;T cells within tumor-draining lymph nodes [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The addition of immune checkpoint inhibitors during CRT treatment did not provide survival benefits to patients with locally advanced HNSCC. This may be attributed to tumor-draining lymph nodes, which are standardly included within the radiation fields, resulting in the depletion of antitumor CD8\u0026thinsp;+\u0026thinsp;T cells and abrogation of systemic antitumor immunity. Recent clinical studies have explored the use of ICIs alone or in combination with other drugs as neoadjuvant treatments for LA-HNSCC to enhance treatment efficacy and improve surgical outcomes. According to published clinical trial data [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], neoadjuvant immunotherapy offers clinical benefits, such as improved pathologic tumor response and disease control, reduced rate of high-risk pathology, and cancer downstaging, although long-term follow-up data are still needed.\u003c/p\u003e \u003cp\u003eAs immunotherapy advances into the perioperative setting, an increasing number of clinical trials are investigating the benefits of PD-1 inhibitor as an adjuvant therapy for resectable cancer. The IMpower010 trial (NCT02486718) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab after chemotherapy in both the PD-L1-positive and all of the resected stage II-IIIA non-small-cell lung cancer (NSCLC) populations. Similarly, the KEYNOTE-091 trial [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] showed that pembrolizumab significantly improved DFS compared to placebo without new safety concerns in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Based on these results, pembrolizumab emerges as a potential new treatment option for stage IB-IIIA NSCLC post-complete resection and adjuvant chemotherapy, regardless of PD-L1 expression. A phase 3 trial (NCT03700476) demonstrated induction-concurrent RCT with sintilimab, a PD-1 inhibitor, improved event-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma compared to standard RCT [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The DIPPER study highlighted the benefits of camrelizumab following gemcitabine and cisplatin induction chemotherapy and subsequent concurrent cisplatin radiotherapy in patients with locally advanced nasopharyngeal carcinoma, significantly reducing the risk of recurrent and metastasis with mild toxicity. Although the DIPPER study results are not yet officially published, they were reported at the 2024 American Society of Clinical Oncology Annual Meeting.\u003c/p\u003e \u003cp\u003ePostoperative intermediate- and high-risk patients with LA-HNSCC face the risk of recurrence and metastasis after standard of care. How to improve survival outcomes and reduce the risk of recurrence and metastasis poses a significant challenge for clinicians. The aforementioned clinical studies have demonstrated that immunotherapy following concurrent RCT for locally advanced nasopharyngeal carcinoma and after surgery and chemotherapy for resectable lung cancer can yield significant survival benefits. These treatments enhance local disease control, reduce tumor recurrence and metastasis, and improve patients' PFS. Furthermore, PD-1 inhibitors have a favorable toxicity profile even in the heavily pretreated recurrent HNSCC population [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e](Ferris et al., 2016). Therefore, it is reasonable to believe that immunotherapy as adjuvant treatment after standard of care can offer remarkable clinical benefits to patients with LA-HNSCC who have intermediate- and high-risk factors.\u003c/p\u003e \u003cp\u003eHaque et al. have previously reported that risk factors for HNSCC recurrence after salvage surgery are similar to established pathological risk factors at initial diagnosis [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A subsequent prospective study [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] has indicated that adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well-tolerated and that 2-year disease-free survival following adjuvant nivolumab is 71.4% (95% CI 57.8\u0026ndash;88.1), which is much longer than a historical control sample of salvage surgery alone with similar baseline characteristics. To date, no studies have reported the results of ICIs as adjuvant therapy following postoperative standard treatment in patients with LA-HNSCC who have intermediate- and high-risk factors.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first report on the use of ICIs as an adjuvant therapy for resectable patients with LA-HNSCC who have intermediate- and high-risk factors. Our study showed that patients in the adjuvant immunotherapy group exhibited a trend towards a higher 2-year PFS rate compared to the standard therapy group, particularly among patients with a PD-L1 CPS of 20 or more. This suggests that immunotherapy as an adjuvant treatment for resectable LA-HNSCC with intermediate- and high-risk factors plays an important role in improving prognosis and prolonging patient survival. Additionally, it highlights CPS as an important biomarker for identifying the potential beneficiary population. Prospective clinical trials are needed to further validate our results.\u003c/p\u003e \u003cp\u003eImproving the prognosis of patients with LA-HNSCC who have intermediate- and high-risk factors has long been a priority for head and neck surgeons, as many of these patients face recurrent or metastatic disease. Various adjuvant treatments have been attempted to improve outcomes, including oral tyrosine-kinase inhibitors (TKIs) and mTOR inhibitors, but these have proven ineffective. For example, afatinib administrated as a maintenance therapy did not significantly improve 2-year DFS compared to placebo following post-operative RCT in patients with HNSCC [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Additionally, adding afatinib to postoperative radiation therapy (PORT) for patients with intermediate- and high-risk HNSCC resulted in unacceptable toxicity, particularly in those requiring high-dose PORT to the oral cavity [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Adjuvant therapy with everolimus, an mTOR inhibitor, significantly improved two-year PFS and OS only in p16-negative and TP53mut patients at high risk of cancer recurrence who were disease-free after definitive local therapy for advanced-stage HNSCC [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Currently, an ongoing trial [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] is exploring the potential benefits of combining chemoradiation with a WEE1 inhibitor in patients with high-risk histopathological features after surgical resection, but no positive findings have been reported yet.\u003c/p\u003e \u003cp\u003eIn this study, the adjuvant immunotherapy showed a trend towards improving the survival of patients with LA-HNSCC who have intermediate- and high-risk factors; however, the statistical difference was not significant. Several factors might account for this. First, as a retrospective study, it had a short observation period of 2 years with PFS and OS rates as the primary end points. This limited timeframe might have affected the ability to demonstrate a significant benefit of adding a PD-1 inhibitor, and the benefits of immunotherapy may become more apparent with longer follow-up. Second, PD-L1 expression likely plays a crucial role in the efficacy of adjuvant immunotherapy. Nearly one-third of patients in the adjuvant immunotherapy group had low or unknown CPS. Nevertheless, we observed a significant benefit in 2-year PFS for patients with a CPS 20 or more, thus indicating that PD-L1 is an important biomarker for predicting the benefits of adjuvant immunotherapy. Third, the composition of the standard therapy and adjuvant immunotherapy groups differed in terms of cancer types. The standard therapy group primarily consisted of patients with laryngeal cancer, whereas the adjuvant immunotherapy group was mainly included patients with hypopharyngeal cancer. Although the primary sites of laryngeal and hypopharyngeal cancer are adjacent, the oncological characteristics are different. Hypopharyngeal cancer has a poorer prognosis and a lower DFS and laryngeal function preservation rates compared to laryngeal cancer [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This disparity in cancer types between the two groups might have contributed to the lack of significant benefit in the adjuvant immunotherapy group. Interestingly, despite the higher proportion of hypopharyngeal cancer patients with hypopharyngeal cancer in the adjuvant immunotherapy group with a PD-L1 CPS of \u0026ge;\u0026thinsp;20 (64.7% vs. 11.8% in the standard treatment group), the 2-year PFS rate in this group significantly improved compared to the standard treatment group. This suggests that administering a PD-1 inhibitor as maintenance monotherapy after the standard of care for resectable HNSCC with intermediate- and high-risk factors can significantly enhance local regional control, reduce distant metastasis, and prolong patient survival, especially for patients with a PD-L1 CPS of 20 or more.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, all of the patients in this study were from a single center, which may not fully represent the results of other medical institutions. Second, the sample size of the study limited our ability to detect differences between the two groups. Third, the types of PD-1 inhibitors used in the study were consistent, including camrelizumab, pembrolizumab, and tislelizumab. Finally, retrospective studies inherently have bias and confounding factors, although statistical analyses showed that the baseline clinical characteristics of the patients in both groups were generally consistent.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, PD-1 inhibitors administered as maintenance monotherapy after standard care improved PFS in patients with postoperative intermediate- and high-risk LA-HNSCC, especially for those with a PD-L1 CPS of 20 or more. The adverse events caused by adjuvant immunotherapy were acceptable and did not lead to treatment interruption. To date, the use of adjuvant immunotherapy as a first-line treatment for patients with HNSCC has been very limited, and no established guidelines exist for its use in postoperative patient with LA_HNSCC who have intermediate and high-risk factors. Therefore, this study represents an important step towards incorporating adjuvant immunotherapy into the treatment of resectable LA-HNSCC with intermediate- and high-risk factors. Future studies are needed to validate our results.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e1 Programmed cell death protein 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS Progression\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efree survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e\n\u003cp\u003eOS Overall survival\u003c/p\u003e\u003cp\u003ePD-L1 Programmed death ligand 1\u003c/p\u003e\u003cp\u003eCPS Combined positive score\u003c/p\u003e\u003cp\u003eHNSCC Head and neck squamous cell carcinoma\u003c/p\u003e\u003cp\u003eHPV Human papillomavirus\u003c/p\u003e\u003cp\u003eLA Locally advanced\u003c/p\u003e\u003cp\u003eRCT Radiochemotherapy\u003c/p\u003e\u003cp\u003eECS Extracapsular spread\u003c/p\u003e\u003cp\u003eAnti-PD-1 Anti-programmed death receptor-1\u003c/p\u003e\u003cp\u003eDFS Disease-free survival\u003c/p\u003e\u003cp\u003eNSCLC Non-small cell lung cancer\u003c/p\u003e\u003cp\u003eAJCC American Joint Committee on Cancer\u003c/p\u003e\u003cp\u003eICI Immune checkpoint inhibitor\u003c/p\u003e\u003cp\u003eTKIs Tyrosine-kinase inhibitors\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank LetPub (www.letpub.com.cn) for its linguistic assistance during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China under Grant No. 81972537.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXQS and JQH provided clinical specimens and information. XQS and MHZ performed the data analysis and drafted the manuscript. HLZ and CYZ designed the study. YNQ, HPZ, MY and LZ participated in the study design and coordinated the drafting of the manuscript. XQS, MHZ and JQH contributed equally to this work. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics committee of Changhai Hospital (Approval No. CHEC-Y2020-065).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209\u0026ndash;249. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3322/caac.21660\u003c/span\u003e\u003cspan address=\"10.3322/caac.21660\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVigneswaran N, Williams MD (2014) Epidemiologic Trends in Head and Neck Cancer and Aids in Diagnosis. 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Karger, AG, pp 1\u0026ndash;14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStatements \u0026amp; Declarations\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"head neck cancer, immunotherapy, PD-1 inhibitor, adjuvant therapy, retrospective study","lastPublishedDoi":"10.21203/rs.3.rs-5377938/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5377938/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eImproving the prognosis of patients with LA-HNSCC who have intermediate- and high-risk factors has long been a priority for head and neck surgeons. Immunotherapy, particularly programmed cell death protein 1 (PD-1) inhibitor, has shown promise. However, there are currently no reports on the use of PD-1 inhibitors for postoperative adjuvant treatment of these patients. This retrospective study included 59 postoperative intermediate- and high-risk patients with LA-HNSCC. These patients were divided into two groups: a standard therapy group, consisting of patients who received only postoperative risk-adapted adjuvant (chemo)radiation (n = 34), and an adjuvant immunotherapy group, consisting of patients who received adjuvant immunotherapy as a follow-up maintenance regimen after the standard of care (n\u0026thinsp;=\u0026thinsp;25). Progression-free survival (PFS) and overall survival (OS) by the Response Evaluation Criteria for Solid Tumors was the main outcome. The 2-year PFS and OS rates in the adjuvant immunotherapy group were 80.0% and 95.0%, respectively, compared to 62.1% (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;2.465, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.116) and 79.3% (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;2.434, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.119) in the standard therapy group. Stratified analysis showed that the 2-year PFS rate for patients in the adjuvant immunotherapy group with programmed death ligand 1 (PD-L1) combined positive score (CPS)\u0026thinsp;\u0026ge;\u0026thinsp;20 significantly improved compared to the standard therapy group (92.9% \u003cem\u003evs.\u003c/em\u003e 62.1%, χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;4.644, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031). No serious immune-related adverse events were detected in the adjuvant immunotherapy group. Our study suggests administering PD-1 inhibitor as adjuvant therapy after standard of care shows a trend towards improving 2-year PFS in postoperative intermediate- and high-risk patients with LA-HNSCC. This trend is more pronounced in patients with a CPS of 20 or higher. Future clinical trials are needed to verify these results.\u003c/p\u003e","manuscriptTitle":"Postoperative adjuvant immunotherapy versus standard of care in resectable locally advanced head and neck squamous cell carcinoma with intermediate- and high-risk factors: a real-world retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-27 18:43:44","doi":"10.21203/rs.3.rs-5377938/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b6ad0b8f-39ba-41e3-af2f-0a5f601cfdf5","owner":[],"postedDate":"November 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-29T00:53:18+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-27 18:43:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5377938","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5377938","identity":"rs-5377938","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}