Abstract
Introduction
The prognosis of advanced oral squamous cell carcinoma (OSCC) remains poor, with a 5-year survival rate below 50%. While immune checkpoint inhibitors have improved outcomes in recurrent or metastatic head and neck squamous cell carcinoma, the efficacy of preoperative chemoimmunotherapy for locally advanced OSCC remains under investigation. This study aimed to evaluate pathological responses and survival outcomes in OSCC patients receiving neoadjuvant chemoimmunotherapy followed by surgery.
Methods
In this retrospective cohort study, 30 patients with stage III–IV OSCC were treated with one of two induction regimens: toripalimab plus gemcitabine and cisplatin, or tislelizumab with nab-paclitaxel, cisplatin, and low-dose radiotherapy. All patients underwent radical resection after two cycles. Pathological response was assessed based on residual viable tumor (RVT) proportion. Radiologic response was evaluated per RECIST 1.1. Survival analysis was performed using Kaplan-Meier methods.
Results
The pathological complete response (pCR) and major pathological response (MPR) rates at the primary site were both 30.0%. Achieving a radiologic partial response was significantly associated with achieving an MPR (P=0.018). With a median follow-up of 28.5 months, the 3-year overall survival (OS) and disease-free survival (DFS) rates were 80.9% and 65.0%. Patients achieving a pPR or better had significantly improved OS (P=0.007) and DFS (P=0.023). Lymph node metastasis, particularly ≥3 positive nodes, was strongly associated with poor survival (P<0.001). A stromal fibroblast proportion ≥70% correlated with better OS (P=0.023).
Conclusion
Neoadjuvant chemoimmunotherapy followed by surgery yields promising pathological responses and survival outcomes in locally advanced OSCC. The degree of pathological response and lymph node status are critical prognostic factors. Notably, pCR does not universally guarantee favorable outcomes, underscoring the need for vigilant postoperative monitoring.
Introduction
Oral squamous cell carcinoma (OSCC) is a prevalent malignancy of the head and neck, which has a poor prognosis in advanced stages, with a 5-year survival rate below 50%. 1 For advanced OSCC, combination therapy has been demonstrated to yield superior outcomes compared to monotherapy. 2 With the advancement of immunotherapy, immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have demonstrated significant efficacy in treating platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), as evidenced by the CheckMate-141 and KEYNOTE-048 trials.3,4
However, for patients with resectable locally advanced OSCC, the potential benefits of preoperative immunotherapy remain a subject of active investigation. Although neoadjuvant immunotherapy has yielded promising results in HNSCC (KEYNOTE-689), 5 specific data focusing on its application in OSCC are limited. This study aimed to evaluate the pathological responses and survival outcomes of patients with locally advanced OSCC who received neoadjuvant immunochemotherapy followed by radical surgery at our institution.
Materials and Methods
Study Design and Patient Selection
We conducted a retrospective cohort study of patients with OSCC who were treated at the Fifth Affiliated Hospital of Sun Yat-sen University between January 2021 and July 2024. The reporting of this study conforms to the STROBE guidelines. 6 Eligible patients were adults (≥18 years) with histopathologically confirmed, primary oral cavity squamous cell carcinoma at clinical stage III-IV (AJCC 8th edition). All participants had undergone radical surgery following neoadjuvant immunochemotherapy. Key exclusion criteria included a history of other head and neck tumors, prior radiotherapy to the region, previous exposure to PD-1/PD-L1 inhibitors, intolerance to two cycles of neoadjuvant therapy, or patient refusal of surgery. The study protocol was approved by the Ethics Committee of the Fifth Affiliated Hospital of Sun Yat-Sen University (approval No. [2020] Ethics No. (K66-2); approved on September 24, 2020). Written informed consent was obtained from all participants.
Treatment Regimens
Enrolled patients received one of two preoperative induction immunochemotherapy regimens:
Regimen 1: Patients received two 21-day cycles of toripalimab (240 mg intravenously on day 1), combined with gemcitabine (1000 mg/m2 on days 1 and 8) and cisplatin (80 mg/m2 on day 1).
Regimen 2: Patients received two 21-day cycles of tislelizumab (200 mg on day 1), albumin-bound paclitaxel (100 mg/m2 on days 1, 8, and 15), and cisplatin (25 mg/m2 on days 1, 8, and 15). Concurrently, they received low-dose radiotherapy (LDR) using IMRT with a simultaneous integrated boost technique. A total dose of 8 Gy was prescribed to the planning target volume in 8 fractions of 1 Gy each, delivered on days 1, 2, 8, and 15 of each cycle.
Radical surgical resection was performed approximately four weeks after the initiation of the second treatment cycle. The surgical extent was determined based on the pre-treatment anatomical boundaries, with minimal modification despite observed tumor regression. Adjuvant radiotherapy was recommended for eligible patients. All patients underwent pre-treatment and pre-surgery magnetic resonance imaging for assessment.
Radiological and Pathological Response Assessment
Radiologic responses were evaluated by radiologists according to RECIST version 1.1. Pathological response was independently assessed by three experienced pathologists. The proportion of residual viable tumor (RVT) within the total tumor bed area at the primary site was calculated using hematoxylin and eosin (H&E) staining, supplemented by immunohistochemistry as needed. Responses were categorized as follows: pathological complete response (pCR, 0% RVT), major pathological response (MPR, >0% to ≤10% RVT), partial pathological response (pPR, >10% to ≤50% RVT), and no pathological response (pNR, >50% RVT). Additionally, the stromal components of the primary tumor specimens, including the proportions of necrotic tissue, fibroblasts, and inflammatory cells, were quantitatively analyzed.
Statistical Analysis
All statistical analyses were performed using SPSS software (version 22.0; IBM Corporation). Associations between categorical variables, such as radiologic and pathologic responses, were examined using the Chi-squared test. Survival outcomes were estimated with the Kaplan-Meier method. The Fisher’s exact test was used to analyze the relationships between the degree of pathological response and other pathological parameters. Cox regression model with Firth’s penalized likelihood was performed by R (version 4.5.3).
Results
Patient and Treatment Characteristics
Baseline Characteristics of the 30 Enrolled Patients
Abbreviation: LDR, low-dose radiotherapy.
All patients completed two cycles of neoadjuvant therapy and proceeded to surgery. The surgical procedure involved radical tumor resection with ipsilateral or bilateral neck dissection; flap reconstruction was performed when necessary. Of the 30 patients, 24 received adjuvant radiotherapy 4–6 weeks postoperatively, while the remaining 6 declined further treatment. At the time of analysis, the median follow-up was 28.5 months (range, 1–49).
Radiologic and Pathologic Response
Representative imaging from a patient with T4N2bM0 OSCC of the mandible illustrates a striking response in both the primary lesion and a metastatic lymph node (Figure 1). Pathological assessment of the primary site revealed that 9 patients (30.0%) achieved a pathological complete response (pCR), 9 (30.0%) a major pathological response (MPR), 3 (10.0%) a partial pathological response (pPR), and 9 (30.0%) had no pathological response (pNR) (Figure 2). Pathologically positive lymph nodes were identified in 7 patients (23.3%). All patients underwent R0 resection. Pathological and radiographical response to chemoimmunotherapy. Pre-treatment and post-treatment magnetic resonance (MR) images of a 58-year-old patient, demonstrating significant regression of both the primary mandibular lesion and a metastatic lymph node. Corresponding pathological specimens (H&E staining) before and after treatment confirm a pathological complete response (pCR) in the primary tumor The corresponding waterfall plots of radiologic and pathological responses for each patient. Among the 30 patients, 9 (30.0%) patients achieved pCR at the primary site, 9 (30.0%) achieved MPR, 3 (10.0%) achieved pPR, and 9 (30.0%) achieved pNR

Radiologic response was evaluable in 27 patients, as severe artifacts from dental prostheses compromised assessment in 3. Among these, 13 (48.1%) achieved a partial response (PR), 12 (44.4%) had stable disease (SD), and 2 (7.4%) experienced progressive disease (PD) (Figure 2). Achieving a radiologic PR was significantly associated with achieving a pathological MPR (P = 0.018), suggesting that MRI findings may serve as a useful predictor of pathologic response. Overall, the clinical downstaging rate after neoadjuvant therapy was 83.3% (25/30).
PD-L1 expression data were available for 25 patients, of whom 21 (84.0%) were positive (defined as a tumor proportion score ≥1% or a combined positive score ≥20). Although PD-L1 positive patients showed a higher response rate, the difference was not statistically significant, likely due to the high prevalence of positivity in the cohort. Additionally, adjuvant radiotherapy was not associated with OS or DFS in this cohort of patients, which may be attributable to the fact that the vast majority of patients (24/30) in this cohort received adjuvant radiotherapy.
Survival Outcomes
During follow-up, five patients (16.7%) died between 1 and 20 months post-surgery; four deaths were due to oral cancer and one to lung cancer (Figure 3A). The estimated 3-year overall survival (OS) rate was 80.9% (95% CI: 65.8%–96.0%), and the 3-year disease-free survival (DFS) rate was 65.0% (95% CI: 46.2%–83.8%). Survival outcomes of the cohort. (A) Swimmer plot illustrating individual patients’ survival status, recurrence events, and pathological response. Kaplan-Meier curves compare (B) overall survival (OS) between major pathological responders (MPR+pCR) and non-major responders (pPR+pNR); (C) OS between any pathological responders (MPR+pCR+pPR) and non-responders (pNR); (D) disease-free survival (DFS) between any pathological responders and non-responders; (E) OS by final pathologic stage (I-II vs. III-IV); (F) DFS by final pathologic stage (I-II vs. III-IV); (G) OS by lymph node status; (H) DFS by lymph node status; (I) OS by stromal fibroblast proportion. Log-rank test was used to calculate P values
Five patients developed local recurrence. Notably, two of these recurrences occurred in patients who had achieved pCR at the primary site; the other three were in patients with no pathological response. Additionally, two patients developed metachronous second primary tumors. One patient developed a second primary squamous cell carcinoma on the contralateral tongue, and another was diagnosed with primary lung cancer, which was the cause of death. Both of these patients had initially achieved pCR at their primary OSCC site (Figure 3A).
Pathology-Based Survival Analysis
Survival was significantly better among patients who achieved a major pathological response or better (MPR+pCR). Using MPR as the cutoff, OS was significantly improved (P = 0.023) (Figure 3B), though DFS was not. When the cutoff was extended to include pPR (i.e., pCR+MPR+pPR vs. pNR), both OS (P = 0.007) and DFS (P = 0.023) were significantly better (Figure 3C and D), indicating that any pathologic response beyond pNR confers a clinical benefit. In contrast, a radiologic PR was not associated with superior survival.
Patients with a final pathologic stage of I or II had significantly better OS (P = 0.035) and DFS (P = 0.009) (Figure 3E and F) than those with stage III or IV disease. However, primary tumor characteristics alone (T stage, tumor bed size, depth of invasion) were not significantly associated with survival. Conversely, the presence of pathological lymph node metastasis was strongly associated with worse OS (P < 0.001) and DFS (P = 0.009) (Figure 3G and H), with an even poorer prognosis when ≥3 nodes were involved (OS and DFS, both P < 0.001) (Supplementary Figure 1 A, B).
Analysis of cellular components in the primary tumor specimens revealed that patients with a cancer cell proportion below the median of 50% had significantly better OS (P = 0.007) and DFS (P = 0.023) (Supplementary Figure 1 C, D). Furthermore, within the stromal compartment, a high fibroblast proportion (exceeding 70%) was associated with better OS (P = 0.023) (Figure 3I). In contrast, the proportions of inflammatory cells and necrotic tissue, as well as the presence of vascular or perineural invasion, showed no significant correlation with survival.
Survival Analysis Using Stratified Log-Rank Tests
*One of the induction regimen groups exhibited no lymphovascular invasion events, thus precluding statistical computation.
Multivariable Firth Penalized Cox Regression Analysis for Disease-Free Survival
Finally, we investigated the relationship between pathological response and other parameters. As expected, achieving MPR or pCR was closely associated with primary tumor bed size, T stage, depth of invasion, and cancer cell proportion—factors intrinsically linked to the residual viable tumor calculation. Among stromal features, a high fibroblast proportion (≥70%) or a low inflammatory cell proportion (<30%) was associated with a lower likelihood of achieving pCR.
Discussion
This retrospective study evaluated the efficacy of neoadjuvant chemoimmunotherapy followed by surgery in a dedicated cohort of 30 patients with locally advanced oral squamous cell carcinoma (OSCC). The safety profile of the induction regimen used here has been previously reported7,8; none of the present patients experienced treatment-related adverse events that necessitated surgical delay.
The pCR rate of the primary lesion in this group of patients after induction chemoimmunotherapy was 30% (9/30), and also the MPR rate was 30% (9/30). Among these, one patient who achieved pCR in the primary lesion still had a metastatic lymph node detected in the neck. Earlier studies of neoadjuvant chemoimmunotherapy for head and neck squamous cell carcinomas (HNSCC) have reported favorable outcomes: an MPR rate of 74.1 %, pCR rate of 37 %, and 1-year DFS of 95.8 % (95 % CI 73.9 %–99.4 %). 9 Wu et al observed similar results (MPR 63 %, pCR 55.6 %, 1-year progression-free and overall survival 97.9 %), 10 whereas Wang et al reported slightly lower figures (MPR 54.5 %, pCR 36.4 %). 11 These investigations, however, enrolled predominantly oropharyngeal cancers, which are more chemosensitive than oral cavity primaries. Compared with oropharyngeal tumors, OSCC is generally better differentiated, and data on induction immunochemotherapy for oral cavity primaries are scarce. Focusing on OSCC patients, Huang et al reported an MPR rate of 60 % and a pCR rate of 30 % (2-year OS 95 %, DFS 90 %). 12 Liu et al recently documented an exceptionally high MPR rate of 76.4 % with outstanding 2-year outcomes (OS 94.1 % [95 % CI 86.5 %–100.0 %], DFS 93.9 % [95 % CI 86.1 %–100.0 %]) in oral cancer patients. 13 The results observed in this patient group are consistent with those reported by Huang et al. The observed differences may be primarily attributed to variations in chemotherapy regimens and patient sensitivity to anti-PD-L1 therapy. Liu et al employed the TPF (Docetaxel+ Cisplatin+5-Fluorouracil) chemotherapy regimen, whereas Huang et al used a regimen of paclitaxel plus cisplatin.12,13 In the present study, the regimens consisted of gemcitabine plus cisplatin or nab-paclitaxel plus cisplatin. Furthermore, this study featured a longer follow-up period compared to previous research, with a 3-year overall survival rate of 80.9% (95% CI, 65.8%–96.0%) and a disease-free survival rate of 65.0% (95% CI, 46.2%–83.8%).
A major pathological response is widely recognized as a surrogate marker for favorable prognosis in solid tumors, including breast, lung, and gastrointestinal cancers,14-16 and is a key endpoint in HNSCC trials. 17 In our cohort, patients achieving MPR had significantly improved OS, though the DFS benefit was not statistically significant, potentially due to the limited sample size and the unexpected occurrence of recurrences and second primary malignancies in four patients who had achieved pCR. Furthermore, multivariable survival analysis indicated that pCR/MPR is not an independent prognostic factor for DFS. This finding suggests that pCR may not be an absolute prognostic guarantor in OSCC, contrasting with reports of near 100% 2-year survival in patients with MPR. 13 We meticulously reviewed two pCR cases that developed local recurrence. Both had advanced primary tongue cancers (T3N2M0 and T4N2M0) and did not undergo flap reconstruction. We hypothesize that the surgical resection might not have fully adhered to the pre-treatment anatomical boundaries, potentially contributing to recurrence. This observation raises a critical, unresolved question regarding the optimal surgical extent after significant neoadjuvant response. Consistent with Liu et al., 13 we found that any pathological response beyond no response (i.e., pPR or better) was a significant predictor of improved OS and DFS. This suggests that the threshold for a clinically meaningful response might be pPR, not solely MPR, in OSCC patients receiving chemoimmunotherapy.
Additionally, we examined the relationship between other postoperative pathological indicators and prognosis. As noted in the results section, post-chemotherapy clinical stage significantly affected both OS and DFS. However, this correlation was not linked to primary tumor bed shrinkage but rather to residual tumor cells in lymph nodes—with more than 3 positive lymph nodes showing a stronger association with poor prognosis. The number of metastatic lymph nodes has been established as a critical mortality predictor in oral cavity cancer. 18 While previous studies note lower response rates in lymph nodes compared to primary tumors,12,13 our data further underscore that residual nodal disease remains a paramount indicator of adverse prognosis despite modern chemoimmunotherapy.
Cellular composition of the post-treatment specimen also provided prognostic insights. A residual cancer cell fraction below the median (50%) predicted superior survival, complementing the RVT-based response categories. Following chemoimmunotherapy induction, the pathological changes observed in primary lesion tissue specimens with favorable treatment response are generally as follows: plasma cell aggregation is present in and around the tumor bed, accompanied by a localized multinucleated giant cell reaction and stromal fibrosis; inflammatory cells within the tumor bed consist mainly of plasma cells, neutrophils, and histiocytes. We attempted to analyze the stromal components beyond tumor cells, specifically categorizing the stroma into inflammatory cells, fibroblasts, and necrotic components. In the study of neoadjuvant nivolumab therapy, paired single-cell RNA sequencing data obtained before and after treatment revealed a marked increase in fibroblast abundance. 19 Previous research has demonstrated that, in PD-L1–positive head and neck cancers, only an immune checkpoint inhibitor is sufficient to promote normalization of the tumor microenvironment, a process that involves fibroblast remodeling. 20 Whether the fibroblasts that proliferate following immunotherapy are cancer-associated fibroblasts or normal fibroblasts, and what specific roles they play, remain open questions warranting further investigation. Notably, in the present study, a fibroblast proportion exceeding 70% was found to be associated with significantly improved overall survival. This suggests that such fibroblasts may represent a manifestation of microenvironmental normalization.
Unlike lung cancer, MRI offers advantages in the radiological evaluation of head and neck squamous cell carcinoma. In 2024, Lin et al first proposed that a nomogram based on intratumoral and peritumoral MRI radiomics features outperformed the widely used biomarker CPS in predicting pathological complete response to neoadjuvant immunotherapy in head and neck squamous cell carcinoma. 21 Subsequently, Lan et al demonstrated that MRI deep learning features can enhance traditional imaging analysis and robustly predict the response of head and neck squamous cell carcinoma patients to neoadjuvant immunotherapy. 22 In the present study, achieving a radiologic PR was significantly associated with achieving a pathological MPR. This finding is consistent with previous results; however, further investigation into additional MR imaging biomarkers is warranted.
Similar to other studies, resistance to neoadjuvant immunotherapy and chemotherapy may occur.23,24 Patients who do not respond to treatment are at high risk of tumor recurrence or have a very poor prognosis. In this cohort, five patients did not achieve clinical downstaging, and four of them experienced local recurrence and death, further validating the above perspective.
Limitations
This study has several limitations. Its retrospective nature and the use of two different induction regimens may introduce selection bias and limit the strength of conclusions. The small sample size and relatively short follow-up period necessitate validation of our findings in larger, prospective studies with longer follow-up.
Conclusion
In summary, this study demonstrates that neoadjuvant chemoimmunotherapy followed by surgery yields promising survival outcomes in locally advanced OSCC. The degree of pathological response and, most importantly, lymph node status are critical prognostic factors. Finally, achieving pCR does not universally guarantee a favorable outcome, underscoring the necessity of vigilant postoperative monitoring and further research to optimize surgical strategies and adjuvant therapy in this new treatment paradigm.
Supplemental Material
Supplemental Material - Survival and Pathological Outcomes of Neoadjuvant Chemoimmunotherapy Followed by Surgery in Locally Advanced Oral Squamous Cell Carcinoma
Supplemental Material for Survival and Pathological Outcomes of Neoadjuvant Chemoimmunotherapy Followed by Surgery in Locally Advanced Oral Squamous Cell Carcinoma by Zixia Wang, Yongliang Li, Jiaxin Feng, Lifen Wu, Tong Li, Xinbiao Zhu, Lizhong Liang in Cancer Control
Footnotes
Ethical Considerations
The study was approved by the Ethics Committee of the Fifth Affiliated Hospital of Sun Yat-Sen University (approval No. [2020] Ethics No. (K66-2); approved on September 24, 2020).
Consent to Participate
Informed consent was obtained from all individual participants included in this study. All data collected were anonymized to ensure participant confidentiality.
Author Contributions
Lizhong Liang designed this study and revised the article. Zixia Wang performed statistical analysis and wrote the initial draft of the article. Yongliang Li analyzed the pathological specimens for this study. Jiaxin Feng conducted imaging analyses of the patients. Lifen Wu, Tong Li, and Xinbiao Zhu were responsible for patient data collection and follow-up work.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
The data generated in the present study may be requested from the corresponding author.
Supplemental Material
Supplemental material for this article is available online.
Appendix
References
Supplementary Material
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