Randomized Controlled Trials Comparing the Standard of Care to Alternative Treatments in Patients with Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma: A Systematic Literature Review

Standard of care (SoC) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is surgery with adjuvant radiotherapy (RT) or chemoradiotherapy (for tumors at high risk of recurrence). As long-term prognosis is suboptimal with SoC, this study aimed to summarize findings from recent studies comparing alternative treatments to SoC. A broad systematic literature review (search date: December 1, 2025) searched Embase, MEDLINE, and CENTRAL to identify randomized controlled trials evaluating surgery with RT and/or systemic treatments in the neoadjuvant and/or adjuvant setting in LA-HNSCC. Trials published since 2004 were included in this report if they compared interventions to SoC in terms of event-free survival (EFS) and overall survival (OS) or reported pathological response following neoadjuvant therapy. Fifty-six trials were included in the broader review, of which 25 were included in this report. Trials reporting EFS counted at least recurrence/progression and death as events, except one that did not provide a definition. Improvement in EFS (regardless of definition) was reported with the addition of perioperative pembrolizumab or addition of perioperative camrelizumab with neoadjuvant nab-paclitaxel + carboplatin to surgery + RT ± cisplatin, addition of adjuvant cetuximab or adjuvant cisplatin to surgery + RT, and addition of adjuvant nivolumab to surgery + RT + cisplatin. EFS with other interventions was comparable to SoC. OS was generally comparable between interventions and SoC. Across treatment arms with at least one neoadjuvant chemotherapy agent, pathological complete response rates ranged from 10.5% to 42.6% while it ranged from 0 to 12.9% in treatment arms without any neoadjuvant chemotherapy agent. Some trials reported an association between achieving pathological response and improved survival outcomes in exploratory analyses. Immunotherapy shows promise as an addition to the SoC in LA-HNSCC. OS results are generally comparable and may still be immature in some trials. Evidence on pathological response suggests potential prognostic value for long-term survival outcomes. People with head and neck squamous cell carcinoma that is locally advanced but still able to be removed with surgery are usually treated with surgery followed by radiotherapy. If the tumor has a high risk of coming back, doctors also add chemotherapy to the radiotherapy. Because long-term outcomes remain disappointing with this usual treatment (the standard of care), we reviewed recent randomized controlled trials that tested other options. We searched major databases up to December 1, 2025 to identify trials published since 2004 that compared new approaches with the standard of care and reported event-free survival (time until the cancer returns, worsens, or the patient dies) and overall survival (time alive), or reported tumor response following treatments given before surgery. Our review identified 25 trials that were suitable for inclusion in this report. Some treatments improved event-free survival, including pembrolizumab and camrelizumab (both help the immune system attack cancer) given before and after surgery with radiotherapy and chemotherapy, cetuximab or cisplatin given after surgery with radiotherapy, and nivolumab given after surgery with radiotherapy and chemotherapy. Overall survival was similar between the tested treatments and the standard of care. When chemotherapy was given before surgery, complete disappearance of tumor cells in the removed tissue occurred more often (10.5–42.6%) than when it was not (0–12.9%). Some studies also suggested that better pathological response may result in better long-term outcomes. Overall, immunotherapy appears to be a promising addition to the standard of care, and pathological response may help predict long-term survival.