Head and neck squamous cell carcinoma (HNSCC) arises in the mucosal epithelium of the oral cavity, pharynx, and larynx, representing the most prevalent form of cancer within the head and neck. This region is anatomically intricate, serving crucial roles in essential functions such as eating, speaking, and breathing (1). The majority of HNSCC patients receive a diagnosis of localized or locally advanced disease, with standard treatment typically involving a combination of radiotherapy, surgery, and possibly chemotherapy tailored to individual risk levels (2). However, individuals diagnosed with locally advanced HNSCC face a significant risk of both local recurrence (approximately 15-40%) and distant metastasis, with a 5-year overall survival rate of only 50% (3). While platinum-based chemotherapy, like the Docetaxel + cisplatin + 5-fluorouracil (5-FU) regimen, is the standard neoadjuvant treatment for HNSCC patients, research indicates that these strategies may not always effectively extend patient survival or prevent progression due to insensitivity or resistance to these chemotherapeutic agents (4–6). Novel treatment approaches are essential to enhance survival rates or lessen the burden of conventional therapies.

Recently, the academic community has increasingly acknowledged the efficacy of immune checkpoint inhibitors, specifically monoclonal antibodies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), in managing relapsed or metastatic HNSCCs. Preclinical studies indicate that neoadjuvant PD-1/PD-L1 pathway blockade may be more effective than adjuvant blockade, leveraging tumor antigens within the preoperative immune environment for enhanced efficacy (7, 8). In a phase Ib study, the effectiveness and safety of neoadjuvant immunoradiotherapy in patients with locally advanced HNSCC were highlighted, demonstrating an MPR of 86%, a complete pathologic response of 67%, and a clinical-to-pathologic downstaging rate of 90% (9). Several current trials investigating neoadjuvant immunotherapy for HNSCC, focusing on single or dual immunotherapy, as well as combinations with chemotherapy or radiotherapy, have displayed encouraging outcomes (10–12).

This meta-analysis endeavors to gather findings from current clinical studies to evaluate the effectiveness and safety of various neoadjuvant immunotherapy combination treatments for managing locally advanced HNSCC, offering additional clinical treatment alternatives.

This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (13). The comprehensive protocol has been registered online with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42024553753). As this review and meta-analysis did not involve the use of individual patient data, it was not subject to institutional review board approval.

Neoadjuvant therapy using immune checkpoint inhibitors has shown promise across a range of cancer types, including melanoma (41), non-small cell lung cancer (42), and bladder cancer (43). PD-1 inhibitors, specifically nivolumab and pembrolizumab, have been sanctioned for treating recurrent/metastatic HNSCC, showcasing extended OS in contrast to chemotherapy (44–46). Ongoing clinical trials have investigated neoadjuvant immunotherapies, either as standalone treatments or in combination with other medications. This meta-analysis represents the pioneering effort to assess the effectiveness and safety of various neoadjuvant immunotherapy combinations in treating patients with locally advanced HNSCC. Drawing from 32 concise studies involving 1,943 patients, our analysis quantitatively amalgamates the efficacy and safety data concerning neoadjuvant immunotherapy. Through direct subgroup analyses and sensitivity assessments, we observed that both the NICT group (OR=0.62, 95% CI: 0.41-0.84) and the NIRT group (OR=0.76, 95% CI: 0.60-0.91) surpassed the NI group (OR=0.11, 95% CI: 0.05-0.17) in achieving a higher MPR rate. However, there was no statistically significant variance between the NICT and NIRT groups. No statistically significant difference was observed in the pCR rates among the NI, NICT, and NIRT groups upon calculation. When evaluating the clinical imaging outcome metrics, we observed that the NICRT group (OR=0.65, 95% CI: 0.31-0.99) outperformed the NICT group (OR=0.11, 95% CI: 0.02-0.19) and the NIRT group (OR=0.10, 95% CI: -0.01-0.21) in terms of achieving a CR rate. However, there was no statistically significant difference in the PR rate and SD rate among the NI, NICT, and NIRT groups, although they remained higher than the NICRT group. When examining the ORR, while there were numerical discrepancies among the four groups, no statistical differences were detected. ORR serves as a valuable clinical parameter for assessing tumor treatment response through imaging; however, it has limitations, especially in the context of immunotherapy. Inflammatory pseudotumor presents histologically as a benign process characterized by acute and chronic inflammatory cells, exhibiting similar imaging features (47). This occurrence is frequently observed in patients undergoing immunotherapy, attributed to the immune impact of PD-1 inhibitors. The solid mass comprises both tumor and immune cells, resulting in a skewed assessment of ORR. Once more, there was no statistically significant variance in surgical resection rates between the NI and NICT groups.

Furthermore, this meta-analysis evaluating the safety of various neoadjuvant immunotherapies revealed that the NI group exhibited significantly lower rates of grade ≥3 TRAEs compared to the other three groups, while showing notably higher rates of grade ≥3 irAEs than the other three groups. However, no statistical differences were found between the NICT, NIRT, and NICRT groups concerning both grade ≥3 TRAEs and grade ≥3 irAEs. Treatment-related deaths, attributed to general disease, site conditions, and vascular rupture, were identified in a single study. In this study, two patients in the avelumab group experienced such events, while one patient in the placebo group passed away due to acute respiratory failure (12). Other largely controllable adverse events, including hypothyroidism, fatigue, nausea, diarrhea, oral and non-oral pain, rash/psoriasis, myalgia, constipation, cough, elevated creatinine, dyspnea, back spasms, and hypertension, as well as immune-related colitis, hyperbilirubinemia, thrombocytopenia, and proteinuria, did not lead to severe adverse consequences or increased postoperative mortality rates.The main clinical outcomes for patients with tumors are overall survival (OS) and progression-free survival (PFS), both crucial measures assessing the clinical benefits achieved by the patient. In a study by Xia Li et al., the 2-year PFS was 27% (95% CI: 18-36%) in the NI group and 44% (95% CI: 32-56%) in the NICT group, showing a statistically significant difference (P = 0.041). The 2-year OS rates in the NI and NICT groups were 61% (95% CI: 52-70%) and 70% (95% CI: 60-80%), with no statistically significant difference (P = 0.681) (27). The studies included in our meta-analysis had relatively brief follow-up durations. Consequently, the identification of superior treatment options would be facilitated by the availability of randomized controlled trials (RCTs) reporting clinical outcomes over three to five years.

Surgical resection typically stands as the primary option for locally advanced HNSCC (3). A notable ORR post-neoadjuvant therapy indicates a reduced tumor burden, making it conducive for surgical intervention. The scope of surgical resection is guided by pre-neoadjuvant imaging assessments. Further exploration is warranted to ascertain if post-treatment imaging can inform adjustments to the surgical approach and if patients achieving CR can be managed with radiotherapy alone, bypassing surgery. HPV infection serves as a significant oncogenic factor in HNSCC and is recognized as a positive prognostic indicator for the survival of HNSCC patients undergoing conventional chemotherapy and radiotherapy. Through transcriptomic analysis of 280 HNSCC cases from the TCGA database, it was observed that HPV-positive tumors demonstrated heightened immunogenicity compared to HPV-negative tumors, characterized by increased infiltration of activated CD8+ T cells (1). This underscores the role of HPV infection in stimulating the immune response. Nevertheless, the extent to which HPV-infected patients may derive greater benefits from immunotherapy remains largely unexplored.

This systematic review and meta-analysis indicate that patients with locally advanced HNSCC might benefit from neoadjuvant immunotherapy, particularly when used in conjunction with chemotherapy or radiotherapy. Nonetheless, additional data is required to definitively confirm its efficacy.