{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:23:12Z","timestamp":1790864592303,"version":"4.1.0"},"reference-count":115,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Perioperative immune checkpoint inhibition (ICI) has moved from investigational window studies to phase III supported strategies for resectable, locally advanced head and neck squamous cell carcinoma (HNSCC), with direct consequences for surgical timing, neck management, reconstruction and pathology workflows.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a narrative review of phase III perioperative trials and key neoadjuvant studies in resectable HNSCC, focusing on outcomes and practical questions most relevant to surgeons and multidisciplinary teams (MDTs): pathway timing and attrition, operability, perioperative safety and feasibility of standardized response assessment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Phase III evidence supports two complementary perioperative approaches: (i) neoadjuvant PD-1 priming followed by surgery and risk\u2212adapted postoperative radiotherapy\/chemoradiotherapy with continued PD-1 blockade, improving event\u2212free survival compared with standard care; and (ii) postoperative nivolumab added to adjuvant chemoradiotherapy in patients with pathological high\u2212risk features, improving disease\u2212free survival. Across neoadjuvant programs, short preoperative ICI exposure was generally feasible without compromising resectability but requires protected timelines to avoid delays to curative treatment. Key surgical considerations include management of the tumor\u2212draining lymph nodes, anticipation of immune\u2212related adverse events affecting wound healing and rehabilitation, and coordination of treatment with systemic therapy. Pathologic response, preferably reported as percent residual viable tumor separately in the primary tumor bed and nodal compartments, is currently the most widely used endpoint and a prerequisite for response\u2212adapted de\u2212escalation or escalation studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Perioperative ICI turns curative\u2212intent HNSCC care into a tightly timed program. Successful implementation will depend on standardized pathology and radiology workflows, MDT\u2212owned scheduling and prospective registries to define optimal sequencing and salvage after perioperative PD-1 exposure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1799437","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T09:51:02Z","timestamp":1778838662000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Perioperative immunotherapy in resectable HNSCC: biological rationale to practical multidisciplinary implementation"],"prefix":"10.3389","volume":"16","author":[{"given":"Michel","family":"Bila","sequence":"first","affiliation":[{"name":"Dept. of Oral and Maxillofacial surgery, Head and Neck surgery, University Hospital Antwerp","place":["Antwerp, Belgium"]},{"name":"Dept. of Translational Neurosciences, University of Antwerp","place":["Antwerp, Belgium"]},{"name":"Vlaamse Werkgroep Hoofd-HalsTumoren (VWHHT)","place":["Gent, Belgium"]},{"name":"Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Vander Poorten","sequence":"additional","affiliation":[{"name":"Vlaamse Werkgroep Hoofd-HalsTumoren (VWHHT)","place":["Gent, Belgium"]},{"name":"Otorhinolaryngology - Head and Neck Surgery, Leuven Cancer Institute, University Hospitals Leuven","place":["Leuven, Belgium"]},{"name":"Department of Oncology, section Head and Neck Oncology, KU Leuven (Katholieke Universiteit Leuven)","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Meulemans","sequence":"additional","affiliation":[{"name":"Vlaamse Werkgroep Hoofd-HalsTumoren (VWHHT)","place":["Gent, Belgium"]},{"name":"Otorhinolaryngology - Head and Neck Surgery, Leuven Cancer Institute, University Hospitals Leuven","place":["Leuven, Belgium"]},{"name":"Department of Oncology, section Head and Neck Oncology, KU Leuven (Katholieke Universiteit Leuven)","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"Huvenne","sequence":"additional","affiliation":[{"name":"Vlaamse Werkgroep Hoofd-HalsTumoren (VWHHT)","place":["Gent, Belgium"]},{"name":"Department of Head and Neck Surgery, Ghent University Hospital","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"De Vos","sequence":"additional","affiliation":[{"name":"Dept. of Oral and Maxillofacial surgery, Head and Neck surgery, University Hospital Antwerp","place":["Antwerp, Belgium"]},{"name":"Dept. of Translational Neurosciences, University of Antwerp","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Willaert","sequence":"additional","affiliation":[{"name":"Dept. of Oral and Maxillofacial Surgery, University Hospital Leuven","place":["Leuven, Belgium"]},{"name":"Oral and Maxillofacial Surgery \u2013 Imaging and Pathology (OMFS-IMPATH) Research Group, Department of Imaging and Pathology, Faculty of Medicine KU Leuven (Katholieke Universiteit Leuven)","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joke","family":"De Ceulaer","sequence":"additional","affiliation":[{"name":"Vlaamse Werkgroep Hoofd-HalsTumoren (VWHHT)","place":["Gent, Belgium"]},{"name":"Dept. of Oral and Maxillofacial Surgery, AZ Sint-Jan Brugge-Oostende (General Hospital Sint-Jan Brugge-Oostende)","place":["Bruges, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Clement","sequence":"additional","affiliation":[{"name":"Vlaamse Werkgroep Hoofd-HalsTumoren (VWHHT)","place":["Gent, Belgium"]},{"name":"Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven","place":["Leuven, Belgium"]},{"name":"Department of General Medical Oncology, Universitair Ziekenhuis (UZ) Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1056\/NEJMoa2415434","article-title":"Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer","volume":"393","author":"Uppaluri","year":"2025","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.2955","article-title":"Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial","volume":"6","author":"Schoenfeld","year":"2020","journal-title":"JAMA Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"6081","DOI":"10.1200\/JCO.2023.41.16_suppl.6081","article-title":"Neoadjuvant durvalumab and tremelimumab in resectable locally advanced SCC of the oral cavity: DUTRELASCO study","volume":"41","author":"Bila","year":"2023","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-1695","article-title":"Neoadjuvant and adjuvant pembrolizumab in resectable locally advanced, human papillomavirus\u2013unrelated head and neck cancer: a multicenter, phase II trial","volume":"26","author":"Uppaluri","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3977","article-title":"Impact of neoadjuvant durvalumab with or without tremelimumab on CD8+ tumor lymphocyte density, safety, and efficacy in patients with oropharynx cancer: CIAO trial results","volume":"26","author":"Ferrarotto","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"S1169","DOI":"10.1016\/j.annonc.2020.08.2270","article-title":"LBA40 Neoadjuvant nivolumab and nivolumab plus ipilimumab induce (near-) complete responses in patients with head and neck squamous cell carcinoma: the IMCISION trial","volume":"31","author":"Zuur","year":"2020","journal-title":"Ann Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"6068","DOI":"10.1200\/JCO.2021.39.15_suppl.6068","article-title":"Pathologic and radiographic responses in a window of opportunity for durvalumab plus metformin trial for squamous cell carcinoma of the head and neck (HNSCC)","volume":"39","author":"Curry","year":"2021","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2021.2191","article-title":"Neoadjuvant PD-1\/PD-L1 inhibitors for resectable head and neck cancer","volume":"147","author":"Masarwy","year":"2021","journal-title":"JAMA Otolaryngology\u2013Head Neck Surg"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/jitc-2021-002568","article-title":"Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial","volume":"9","author":"Ferris","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0577","article-title":"Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease","volume":"6","author":"Liu","year":"2016","journal-title":"Cancer Discov"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-2209","article-title":"Neoadjuvant PD-1 immune checkpoint blockade reverses functional immunodominance among tumor antigen\u2013specific T cells","volume":"26","author":"Friedman","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"4298","DOI":"10.1038\/s41467-022-31941-w","article-title":"Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC","volume":"13","author":"Saddawi-Konefka","year":"2022","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.02.007","article-title":"CD4+ T cell activation distinguishes response to anti-PD-L1+anti-CTLA4 therapy from anti-PD-L1 monotherapy","volume":"57","author":"Franken","year":"2024","journal-title":"Immunity"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.02508","article-title":"Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the phase III KEYNOTE-048 study","volume":"41","author":"Harrington","year":"2022","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31999-8","article-title":"Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomized, open-label, phase 3 study","volume":"393","author":"Cohen","year":"2019","journal-title":"Lancet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.17_suppl.LBA2","article-title":"NIVOPOST-OP (GORTEC 2018-01): a phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse","volume":"43","author":"Bourhis","year":"2025","journal-title":"J Clin Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.5815","article-title":"A systematic review of neoadjuvant and definitive immunotherapy in locally advanced head and neck squamous cell carcinoma","volume":"12","author":"Nindra","year":"2023","journal-title":"Cancer Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-3351","article-title":"Phase II clinical trial of neoadjuvant and adjuvant pembrolizumab in resectable local-regionally advanced head and neck squamous cell carcinoma","volume":"28","author":"Wise-Draper","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.ejca.2020.02.016","article-title":"A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation","volume":"131","author":"Lala","year":"2020","journal-title":"Eur J Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.7609","article-title":"Phase I study of single-agent anti\u2013programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates","volume":"28","author":"Brahmer","year":"2010","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30151-2","article-title":"Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomized, controlled trial","volume":"20","author":"Rozeman","year":"2019","journal-title":"Lancet Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2100070","article-title":"Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"1","author":"Abou-Alfa","year":"2022","journal-title":"NEJM Evidence"},{"key":"B23","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.oraloncology.2018.04.008","article-title":"Nivolumab vs investigator\u2019s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression","volume":"81","author":"Ferris","year":"2018","journal-title":"Oral Oncol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"viii729","DOI":"10.1093\/annonc\/mdy424.045","article-title":"KEYNOTE-048: phase III study of first-line pembrolizumab (P) for recurrent\/metastatic head and neck squamous cell carcinoma (R\/M HNSCC)","volume":"29","author":"Burtness","year":"2018","journal-title":"Ann Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00100-1","article-title":"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 randomized, double-blind, phase 3 trial","volume":"25","author":"Machiels","year":"2024","journal-title":"Lancet Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2018-0405","article-title":"JAVELIN Head and Neck 100: a phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer","volume":"15","author":"Yu","year":"2019","journal-title":"Future Oncol"},{"key":"B27","article-title":"JAVELIN head and neck 100 trial discontinued due to efficacy doubts","volume-title":"Targeted oncology - immunotherapy, biomarkers, and cancer pathways","author":"Tucker","year":"2026"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.1483","article-title":"Atezolizumab in high-risk locally advanced squamous cell carcinoma of the head and neck: a randomized clinical trial","volume":"333","author":"Haddad","year":"2025","journal-title":"JAMA"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-01068-0","article-title":"Tumor ecosystem and microbiome features associated with efficacy and resistance to avelumab plus chemoradiotherapy in head and neck cancer","author":"Riaz","year":"2026","journal-title":"Nat Cancer"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-01067-1","article-title":"Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma","volume":"7","author":"Silver","year":"2026","journal-title":"Nat Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2023.02.011","article-title":"Proton pump inhibitors and antibiotics adversely effect the efficacy of nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck","volume":"184","author":"Wada","year":"2023","journal-title":"Eur J Cancer"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2016.08.046","article-title":"The impact of radiation treatment time on survival in patients with head and neck cancer","volume":"96","author":"Shaikh","year":"2016","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B33","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.oraloncology.2015.10.012","article-title":"Improved prognosis for patients with oral cavity squamous cell carcinoma: analysis of the National Cancer Database 1998-2006","volume":"52","author":"Schwam","year":"2016","journal-title":"Oral Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2021.1744","article-title":"The substantial omission of indicated postoperative radiotherapy in patients with advanced-stage oral cancer in the US\u2014a call to action","volume":"147","author":"Awan","year":"2021","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.21873\/INVIVO.12907","article-title":"Five-year follow-up of patients with head and neck cancer treated with nivolumab and long-term responders for over two years","volume":"36","author":"Matsuo","year":"2022","journal-title":"In Vivo"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.anl.2022.02.006","article-title":"Real-world 2-year long-term outcomes and prognostic factors in patients receiving nivolumab therapy for recurrent or metastatic squamous cell carcinoma of the head and neck","volume":"49","author":"Otsuki","year":"2022","journal-title":"Auris Nasus Larynx"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2023.106664","article-title":"Exploring long-term responses to immune checkpoint inhibitors in recurrent and metastatic head and neck squamous cell carcinoma","volume":"149","author":"Bila","year":"2024","journal-title":"Oral Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23535","article-title":"Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer","volume":"36","author":"Campian","year":"2014","journal-title":"Head Neck"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3109\/07357907.2012.762780","article-title":"The etiology of treatment-related lymphopenia in patients with Malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells","volume":"31","author":"Yovino","year":"2013","journal-title":"Cancer Invest"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3342\/kjorl-hns.2022.00283","article-title":"Neoadjuvant immunotherapy following definitive surgical treatment for locoregionally advanced head and neck cancer: perioperative complication and surgical outcomes","volume":"65","author":"Park","year":"2022","journal-title":"Korean J Otorhinolaryngology - Head Neck Surg"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.oor.2024.100682","article-title":"Head and neck cancer treatment delays in 2021: estimating distributional effects by site, surgery, and p16-positivity","volume":"4","author":"Semprini","year":"2024","journal-title":"Public Health"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/lary.31990","article-title":"Delayed postoperative radiotherapy in head & neck cancers-a systematic review and meta-analysis","volume":"135","author":"Villemure-Poliquin","year":"2025","journal-title":"Laryngoscope"},{"key":"B43","doi-asserted-by":"publisher","first-page":"6006","DOI":"10.1200\/JCO.2021.39.15_suppl.6006","article-title":"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)","volume":"39","author":"Wise-Draper","year":"2021","journal-title":"J Clin Oncol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-01188-3","article-title":"Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)","volume":"27","author":"Menzies","year":"2021","journal-title":"Nat Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02660-6","article-title":"Association between pathologic response and survival after neoadjuvant therapy in lung cancer","volume":"30","author":"Deutsch","year":"2024","journal-title":"Nat Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2025.4573","article-title":"Pathologic response and survival after neoadjuvant immunotherapy for resectable mucosal HNSCC: a systematic review and meta-analysis","volume":"151","author":"Mastrolonardo","year":"2025","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-0037","article-title":"Response-adaptive surgical timing in neoadjuvant immunotherapy demonstrates enhanced pathologic treatment response in head and neck squamous cell carcinoma","volume":"31","author":"Mastrolonardo","year":"2025","journal-title":"Clin Cancer Res"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.04.001","article-title":"Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study","volume":"31","author":"Ferris","year":"2020","journal-title":"Ann Oncol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.04.474","article-title":"The EAGLE study: two is not always better than one","volume":"31","author":"Merlano","year":"2020","journal-title":"Ann Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.12.008","article-title":"Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study","volume":"34","author":"Psyrri","year":"2023","journal-title":"Ann Oncol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00332","article-title":"Nivolumab plus ipilimumab versus EXTREME regimen as first-line treatment for recurrent\/metastatic squamous cell carcinoma of the head and neck: The final results of CheckMate 651","volume":"41","author":"Haddad","year":"2023","journal-title":"J Clin Oncol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1016\/j.cell.2017.07.024","article-title":"Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade","volume":"170","author":"Wei","year":"2017","journal-title":"Cell"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-01211-7","article-title":"Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma","volume":"27","author":"Rozeman","year":"2021","journal-title":"Nat Med"},{"key":"B54","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/j.ccell.2020.09.001","article-title":"The PD-1\/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes","volume":"38","author":"Dammeijer","year":"2020","journal-title":"Cancer Cell"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1506007","article-title":"Elective versus therapeutic neck dissection in node-negative oral cancer","volume":"373","author":"D\u2019Cruz","year":"2015","journal-title":"N Engl J Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2015.08.023","article-title":"Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer","volume":"51","author":"Schilling","year":"2015","journal-title":"Eur J Cancer"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/hed.26601","article-title":"Effect of preoperative immunotherapy on surgical outcomes for head and neck squamous cell carcinoma patients undergoing free tissue transfer","volume":"43","author":"Mays","year":"2021","journal-title":"Head Neck"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.35045","article-title":"Effect of preoperative programmed death-1 or programmed death ligand-1 immune check point inhibition on complications after surgery for primary head and neck cancer","volume":"130","author":"Philips","year":"2024","journal-title":"Cancer"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-025-03895-0","article-title":"Assessing oral and dental health-related quality of life in head and neck cancer patients at 1, 5, and 10 years: a comparison of the EORTC QLQ43, FACT H&N, and the Orthognathic-QLQ questionnaires","volume":"27","author":"Guedea","year":"2025","journal-title":"Clin Transl Oncol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1001\/jamaoto.2022.2291","article-title":"Association of neoadjuvant pembrolizumab for oral cavity squamous cell carcinoma with adverse events after surgery in treatment-naive patients","volume":"148","author":"Tang","year":"2022","journal-title":"JAMA Otolaryngology\u2013Head Neck Surg"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.194","article-title":"Perioperative events influence cancer recurrence risk after surgery","volume":"15","author":"Hiller","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-008-9890-5","article-title":"Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis","volume":"15","author":"Benish","year":"2008","journal-title":"Ann Surg Oncol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan3464","article-title":"The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy","volume":"10","author":"Krall","year":"2018","journal-title":"Sci Transl Med"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00189","article-title":"Immune checkpoint inhibitor outcomes for patients with non-small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications","volume":"37","author":"Ricciuti","year":"2019","journal-title":"J Clin Oncol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01440","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update","volume":"39","author":"Schneider","year":"2021","journal-title":"J Clin Oncol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0152","article-title":"Perioperative COX-2 and \u03b2-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial","volume":"23","author":"Shaashua","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B67","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ejca.2020.02.047","article-title":"Impact of antibiotic use during curative treatment of locally advanced head and neck cancers with chemotherapy and radiotherapy","volume":"131","author":"Nenclares","year":"2020","journal-title":"Eur J Cancer"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.2785","article-title":"Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer","volume":"5","author":"Pinato","year":"2019","journal-title":"JAMA Oncol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.03.002","article-title":"NSCLC immunotherapy efficacy and antibiotic use: A systematic review and meta-analysis","volume":"15","author":"Lurienne","year":"2020","journal-title":"J Thorac Oncol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2019.104525","article-title":"Relationship between immune-related adverse events and the long-term outcomes in recurrent\/metastatic head and neck squamous cell carcinoma treated with nivolumab","volume":"101","author":"Matsuo","year":"2019","journal-title":"Oral Oncol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.5811\/westjem.20305","article-title":"Immune checkpoint inhibitor-associated pneumonitis: A narrative review","volume":"26","author":"Li","year":"2025","journal-title":"West J Emerg Med"},{"key":"B72","article-title":"Diagnosis and management of immune checkpoint inhibitor colitis","volume":"17","author":"Hashash","year":"2021","journal-title":"Gastroenterol Hepatol (N Y)"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1097\/CMR.0000000000000878","article-title":"Clostridium difficile infection and immune checkpoint inhibitor\u2013induced colitis in melanoma: 18 cases and a review of the literature","volume":"33","author":"Vuillamy","year":"2023","journal-title":"Melanoma Res"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.02.037","article-title":"Myocarditis in patients treated with immune checkpoint inhibitors","volume":"71","author":"Mahmood","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics13071243","article-title":"Immune checkpoint inhibitors-related myocarditis: A review of reported clinical cases","volume":"13","author":"Zotova","year":"2023","journal-title":"Diagn (Basel)"},{"key":"B76","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2478\/jtim-2022-0009","article-title":"Immune checkpoint inhibitor-related endocrinopathies","volume":"10","author":"Lu","year":"2022","journal-title":"J Transl Int Med"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.5811\/cpcem.20448","article-title":"Immune checkpoint inhibitor-induced primary adrenal insufficiency: A case report","volume":"8","author":"Gupta","year":"2024","journal-title":"Clin Pract cases Emerg Med"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2025.0410","article-title":"Neoadjuvant therapy for mucosal head and neck squamous cell carcinoma: A review from the American Head and Neck Society","volume":"151","author":"Contrera","year":"2025","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.77.6385","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline","volume":"36","author":"Brahmer","year":"2018","journal-title":"J Clin Oncol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2022.105906","article-title":"Enhanced recovery after surgery (ERAS) in head and neck oncologic surgery: Impact on return to intended oncologic therapy (RIOT) and survival","volume":"130","author":"Kiong","year":"2022","journal-title":"Oral Oncol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-023-08292-3","article-title":"Enhanced recovery after surgery (ERAS) protocol improves patient outcomes in free flap surgery for head and neck cancer","volume":"281","author":"Nieminen","year":"2024","journal-title":"Eur Arch Otorhinolaryngol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.28526","article-title":"Overall survival, treatment duration, and rechallenge outcomes with ICI therapy for recurrent or metastatic HNSCC","volume":"7","author":"Sun","year":"2024","journal-title":"JAMA Netw Open"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1458479","article-title":"Salvage chemotherapy after progression on immunotherapy in recurrent\/metastatic squamous cell head and neck carcinoma","volume":"14","author":"Llop","year":"2024","journal-title":"Front Oncol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-25-0073","article-title":"INTERLINK-1: A phase III, randomized, placebo-controlled study of monalizumab plus cetuximab in recurrent\/metastatic head and neck squamous cell carcinoma","volume":"31","author":"Fayette","year":"2025","journal-title":"Clin Cancer Res"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1627442","article-title":"Pathological regression patterns following neoadjuvant chemo-immunotherapy in head and neck squamous cell carcinoma: A pilot study","volume":"16","author":"Wang","year":"2025","journal-title":"Front Immunol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002485","article-title":"Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma","volume":"9","author":"Leidner","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.10.018","article-title":"Updated pan-tumor guidelines for neoadjuvant scoring of pathologic response: A joint SITC and INMC effort","volume":"37","author":"Deutsch","year":"2025","journal-title":"Ann Oncol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.12.016","article-title":"Optimizing pathological response assessment after neoadjuvant immunotherapy: Linking clinical practice to drug development","volume":"37","author":"Tawbi","year":"2026","journal-title":"Ann Oncol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14246235","article-title":"Quantitative diffusion-weighted imaging analyses to predict response to neoadjuvant immunotherapy in patients with locally advanced head and neck carcinoma","volume":"14","author":"van der Hulst","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-021-05610-x","article-title":"18F]FDG-PET accurately identifies pathological response early upon neoadjuvant immune checkpoint blockade in head and neck squamous cell carcinoma","volume":"49","author":"Vos","year":"2022","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy218","article-title":"Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: A proposal for quantitative immune-related pathologic response criteria (irPRC)","volume":"29","author":"Cottrell","year":"2018","journal-title":"Ann Oncol"},{"key":"B92","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.jtho.2020.01.005","article-title":"IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens following neoadjuvant therapy","volume":"15","author":"Travis","year":"2020","journal-title":"J Thorac Oncol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci Rep"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.566315","article-title":"Discordant responses between primary head and neck tumors and nodal metastases treated with neoadjuvant nivolumab: Correlation of radiographic and pathologic treatment effect","volume":"10","author":"Merlino","year":"2020","journal-title":"Front Oncol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30074-8","article-title":"iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics","volume":"18","author":"Seymour","year":"2017","journal-title":"Lancet Oncol"},{"key":"B96","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1186\/s12880-025-01806-x","article-title":"MRI-based texture analysis for the evaluation of the response to neoadjuvant chemoimmunotherapy in locally advanced head and neck squamous cell carcinoma","volume":"25","author":"Wei","year":"2025","journal-title":"BMC Med Imaging"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-009616","article-title":"Intratumoral and peritumoral radiomics of MRIs predicts pathologic complete response to neoadjuvant chemoimmunotherapy in patients with head and neck squamous cell carcinoma","volume":"12","author":"Lin","year":"2024","journal-title":"J Immunother Cancer"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000003710","article-title":"Deep learning enhanced MRI radiomics in predicting pathologic response of head and neck squamous carcinoma to neoadjuvant chemoimmunotherapy: A retrospective analysis","volume":"112","author":"Lan","year":"2025","journal-title":"Int J Surg"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1200\/EDBK-25-472464","article-title":"Artificial intelligence for head and neck squamous cell carcinoma: From diagnosis to treatment","volume":"45","author":"Song","year":"2025","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2025.104534","article-title":"Tumor-informed ctDNA assay to predict recurrence in locally advanced squamous-cell carcinoma of the head and neck (SCCHN)","volume":"10","author":"Honor\u00e9","year":"2025","journal-title":"ESMO Open"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-3053","article-title":"A prospective trial of biomarker-guided surveillance for HPV-positive oropharynx cancer using plasma tumor tissue-modified viral HPV DNA","volume":"31","author":"Rettig","year":"2025","journal-title":"Clin Cancer Res"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2025.1606","article-title":"Postoperative cthpvDNA kinetics in patients with HPV-related oropharyngeal cancer","volume":"151","author":"Yin","year":"2025","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.35291","article-title":"Impact of circulating tumor human papillomavirus DNA kinetics on disease outcomes in HPV-associated oropharyngeal cancer","volume":"156","author":"Jhawar","year":"2025","journal-title":"Int J Cancer"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2023.2219591","article-title":"Trial watch: chemotherapy-induced immunogenic cell death in oncology","volume":"12","author":"Sprooten","year":"2023","journal-title":"OncoImmunology"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01851-x","article-title":"Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial","volume":"28","author":"Reijers","year":"2022","journal-title":"Nat Med"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03943-w","article-title":"Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial","volume":"31","author":"Breukers","year":"2025","journal-title":"Nat Med"},{"key":"B107","article-title":"Towards organ preservation and cure via immunotherapy in cutaneous squamous cell carcinoma patients, normally undergoing morbid curative surgery and radiotherapy","volume-title":"The MATISSE 2 trial, an investigator-initiated multicentre phase 2 trial","year":"2025"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2402604","article-title":"Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma","volume":"391","author":"Blank","year":"2024","journal-title":"N Engl J Med"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1576800","article-title":"Neoadjuvant chemoimmunotherapy in patients with locally advanced squamous head and neck cancer: a retrospective study","volume":"15","author":"Huang","year":"2025","journal-title":"Front Oncol"},{"key":"B110","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1186\/s12916-025-04441-z","article-title":"Comparative efficacy and safety of neoadjuvant immunotherapy vs chemotherapy in resectable head and neck squamous cell carcinoma: an umbrella review of randomized controlled trials and single-arm studies","volume":"23","author":"Feng","year":"2025","journal-title":"BMC Med"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003476","article-title":"Antitumor immune effects of preoperative sitravatinib and nivolumab in oral cavity cancer: SNOW window-of-opportunity study","volume":"9","author":"Oliva","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2025.2561223","article-title":"Next-generation immunotherapies for head and neck squamous cell carcinoma: targeting novel immune checkpoints","volume":"57","author":"Tang","year":"2025","journal-title":"Ann Med"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2024.6998","article-title":"Novel combination immunotherapy and clinical activity in patients with HPV-associated cancers","volume":"11","author":"Floudas","year":"2025","journal-title":"JAMA Oncol"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2023.102220","article-title":"Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis","volume":"9","author":"Landr\u00e9","year":"2024","journal-title":"ESMO Open"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2025.107772","article-title":"Impact of time-of-day administration of immune checkpoint inhibitors on survival outcomes in patients with recurrent\/metastatic head and neck cancer (R\/M HNSCC): a retrospective cohort study","volume":"171","author":"Van Loocke","year":"2025","journal-title":"Oral Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1799437\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T09:51:04Z","timestamp":1778838664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1799437\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":115,"alternative-id":["10.3389\/fonc.2026.1799437"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1799437","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]},"article-number":"1799437"}}