<p>Sequential immune checkpoint inhibition after palliative radiotherapy in patients with advanced head and neck squamous cell carcinoma: A retrospective cohort study</p>

Katano,Atsuto; Oka,Akiko; Minamitani,Masanari; Ito,Yusuke; Yamamura,Koji; Kobayashi,Kenya; Yamashita,Hideomi; Saito,Yuki

doi:10.3892/mco.2026.2931

April-2026 Volume 24 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

April-2026 Volume 24 Issue 4

Full Size Image

Article

Sequential immune checkpoint inhibition after palliative radiotherapy in patients with advanced head and neck squamous cell carcinoma: A retrospective cohort study

Authors:
- Atsuto Katano
- Akiko Oka
- Masanari Minamitani
- Yusuke Ito
- Koji Yamamura
- Kenya Kobayashi
- Hideomi Yamashita
- Yuki Saito
View Affiliations / Copyright

Affiliations: Department of Radiology, The University of Tokyo Hospital, Tokyo 113‑0033, Japan, Department of Otolaryngology‑Head and Neck Surgery, The University of Tokyo Hospital, Tokyo 113‑0033, Japan
Article Number: 22
|
Published online on: February 6, 2026

https://doi.org/10.3892/mco.2026.2931
Expand metrics +

Abstract

Head and neck squamous cell carcinoma (HNSCC) frequently presents at an advanced stage, where curative options are often not feasible. Palliative radiotherapy (RT) can relieve symptoms and improve performance status, potentially enabling systemic therapy. Immune checkpoint inhibitors (ICIs) have a survival benefit in recurrent and metastatic HNSCC; however, the optimal sequencing of RT and ICIs remains to be elucidated. The present study aimed to evaluate the clinical outcomes of ICI therapy administered after palliative RT in patients with advanced HNSCC. Consecutive patients with advanced HNSCC treated at The University of Tokyo Hospital (Tokyo, Japan) between January 2017 and December 2024 were retrospectively reviewed. Eligible patients received initial palliative RT, with or without subsequent ICIs within 6 months (RT‑ICI vs. RT groups). Clinical data, including demographics, RT parameters, treatment regimens and outcomes, were collected. Overall survival (OS) and progression‑free survival (PFS) analyses were performed using the Kaplan‑Meier method and Cox proportional hazards models. Among 74 patients (median age, 75 years; 82% male), 17 received ICIs following RT. The RT‑ICI group achieved a 2‑year OS rate of 55.8% compared with 5.7% in the RT group (P<0.001). Median PFS time in the RT‑ICI group was 12.7 months, with a 2‑year PFS rate of 20.9%. Multivariate analysis confirmed RT‑ICI treatment [hazard ratio (HR) 0.22, 95% confidence interval (CI) 0.09‑0.55; P=0.001], higher biologically effective dose (≥39 Gy; HR 0.46, 95% CI 0.24‑0.91; P=0.025) and preserved performance status (HR 1.99, 95% CI 1.02‑3.88; P=0.043) as independent predictors of OS. Grade 3 or higher immune‑related adverse events occurred in three patients (17.6%). In conclusion, sequential ICI therapy after palliative RT was revealed to be associated with improved survival outcomes in patients with advanced HNSCC. Higher RT dose was also associated with a better survival; however, no causal or mechanistic conclusions can be drawn from this observation. Further prospective studies are warranted to confirm these findings, and to clarify the optimal sequencing and dosing strategies.

View Figures

View References

1	Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I and Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74:229–263. 2024.PubMed/NCBI View Article : Google Scholar
2	Nenclares P, Rullan A, Tam K, Dunn LA, St John M and Harrington KJ: Introducing checkpoint inhibitors into the curative setting of head and neck cancers: Lessons learned, future considerations. Am Soc Clin Oncol Educ Book. 42:1–16. 2022.PubMed/NCBI View Article : Google Scholar
3	Kim SS, Liu HC and Mell LK: Treatment considerations for patients with locoregionally advanced head and neck cancer with a contraindication to cisplatin. Curr Treat Options Oncol. 24:147–161. 2023.PubMed/NCBI View Article : Google Scholar
4	Grewal AS, Jones J and Lin A: Palliative radiation therapy for head and neck cancers. Int J Radiat Oncol Biol Phys. 105:254–266. 2019.PubMed/NCBI View Article : Google Scholar
5	Weiss ML, Domschikowski J, Krug D, Sonnhoff M, Nitsche M, Hoffmann W, Becker-Schiebe M, Bock F, Hoffmann M, Schmalz C, et al: The impact of palliative radiotherapy on health-related quality of life in patients with head and neck cancer-results of a multicenter prospective cohort study. Clin Transl Radiat Oncol. 41(100633)2023.PubMed/NCBI View Article : Google Scholar
6	Fabian A, Domschikowski J, Hoffmann M, Weiner O, Schmalz C, Dunst J and Krug D: Patient-reported outcomes assessing the impact of palliative radiotherapy on quality of life and symptom burden in head and neck cancer patients: A systematic review. Front Oncol. 11(683042)2021.PubMed/NCBI View Article : Google Scholar
7	Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al: Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 375:1856–1867. 2016.PubMed/NCBI View Article : Google Scholar
8	Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet. 394:1915–1928. 2019.PubMed/NCBI View Article : Google Scholar
9	Machiels JP, Tao Y, Licitra L, Burtness B, Tahara M, Rischin D, Alves G, Lima IPF, Hughes BGM, Pointreau Y, et al: 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. 2024.PubMed/NCBI View Article : Google Scholar
10	Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M, Bourhis J, Harrington K, Chang PM, Lin JC, Razaq MA, et al: Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: A randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 22:450–462. 2021.PubMed/NCBI View Article : Google Scholar
11	Zandberg DP, Vujanovic L, Clump DA, Isett BP, Wang H, Sica G, Bao R, Li H, Ohr J, Skinner HD, et al: Randomized phase II study of concurrent versus sequential pembrolizumab in combination with chemoradiation in locally advanced head and neck cancer. J Clin Oncol. 43:2572–2582. 2025.PubMed/NCBI View Article : Google Scholar
12	Katano A and Yamashita H: Early-stage hypopharyngeal squamous cell carcinoma treated with radical radiotherapy at a uniform dose of 70 Gy in 35 fractions: A single-center study. Eur Arch Otorhinolaryngol. 281:4401–4407. 2024.PubMed/NCBI View Article : Google Scholar
13	Pandey KC, Revannasiddaiah S, Pant NK, Nautiyal V, Rastogi M and Gupta MK: Palliative radiotherapy in locally advanced head and neck cancer after failure of induction chemotherapy: Comparison of two fractionation schemes. Indian J Palliat Care. 19:139–145. 2013.PubMed/NCBI View Article : Google Scholar
14	Katano A, Minamitani M, Tongyu G, Ohira S and Yamashita H: Survival following palliative radiotherapy for head and neck squamous cell carcinoma: Examining treatment indications in elderly patients. Cancer Diagn Progn. 4:46–50. 2024.PubMed/NCBI View Article : Google Scholar
15	Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Basté N, Neupane P, et al: Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: Updated results of the phase III KEYNOTE-048 study. J Clin Oncol. 41:790–802. 2023.PubMed/NCBI View Article : Google Scholar
16	Cheng Y, Wang J, Sun J, Zhong Y and Wu Q: Radiotherapy improves the clinical outcomes of recurrent or metastatic head and neck cancers treated with immunotherapy. Discov Oncol. 16(988)2025.PubMed/NCBI View Article : Google Scholar
17	Krombach J, Hennel R, Brix N, Orth M, Schoetz U, Ernst A, Schuster J, Zuchtriegel G, Reichel CA, Bierschenk S, et al: Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells. Oncoimmunology. 8(e1523097)2018.PubMed/NCBI View Article : Google Scholar
18	Liao Y, Deng J, Yang X, Wang D and Du X: Advances in radiotherapy enhancing the efficacy of immune checkpoint inhibitors in malignant. Front Oncol. 15(1611036)2025.
19	Liu S, Wang W, Hu S, Jia B, Tuo B, Sun H, Wang Q, Liu Y and Sun Z: Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity. Cell Death Dis. 14(679)2023.
20	Wang Y, Berg T, Verona AW and Morris ZS: NImmuno-radiobiology: Effects of radiation therapy on immune cells, tumor microenvironment, susceptibility of tumor cells to immune-mediated destruction, and anti-tumor immunity. Int J Radiat Oncol Biol Phys: S0360-3016(26)00088-X, 2026 (Epub ahead of print).
21	Lin A, Xiong M, Jiang A, Chen L, Huang L, Li K, Wong HZH, Zhang J, Liu Z, Cheng Q, et al: Tumor immunotherapy and microbiome: From bench-to-bedside applications. MedComm (2020). 7(e70454)2026.
22	Chen C, Liu Y and Cui B: Effect of radiotherapy on T cell and PD-1/PD-L1 blocking therapy in tumor microenvironment. Hum Vaccin Immunother. 17:1555–1567. 2021.
23	Khosravi GR, Mostafavi S, Bastan S, Ebrahimi N, Gharibvand RS and Eskandari N: Immunologic tumor microenvironment modulators for turning cold tumors hot. Cancer Commun (Lond). 44:521–553. 2024.
24	Benoit A, Vogin G, Duhem C, Berchem G and Janji B: Lighting up the fire in the microenvironment of cold tumors: A major challenge to improve cancer immunotherapy. Cells. 12(1787)2023.
25	Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, Vansteenkiste JF, Garassino MC, Hui R, Quantin X, et al: Five-year survival outcomes from the PACIFIC trial: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 40:1301–1311. 2022.
26	Cheng Y, Spigel DR, Cho BC, Laktionov KK, Fang J, Chen Y, Zenke Y, Lee KH, Wang Q, Navarro A, et al: Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer. N Engl J Med. 391:1313–1327. 2024.
27	Pontoriero A, Critelli P, Chillari F, Ferrantelli G, Sciacca M, Brogna A, Parisi S and Pergolizzi S: Modulation of radiation doses and chimeric antigen receptor T cells: A promising new weapon in solid tumors-a narrative review. J Pers Med. 13(1261)2023.
28	Viani GA, Gouveia AG, Matsuura FK, Neves LVF, Marta GN, Chua MLK and Moraes YF: Assessing the efficacy of palliative radiation treatment schemes for locally advanced squamous cell carcinoma of the head and neck: A meta-analysis. Rep Pract Oncol Radiother. 28:137–146. 2023.
29	Katano A, Minamitani M, Ohira S and Yamashita H: Recent advances and challenges in stereotactic body radiotherapy. Technol Cancer Res Treat. 23(15330338241229363)2024.
30	Katano A: Exploring the current challenges and pioneering clinical applications of stereotactic radiotherapy in cancer treatment. Technol Cancer Res Treat. 24(15330338251333658)2025.
31	Mallick S, Dagar A, Ghosh A, Aashita Raj J, Hazarika S, Meena JK, Kumar A, Sharma J, Panda S, et al: Optimum radiation dose for palliation in head and neck squamous cell carcinoma (OpRAH)-A phase 3 randomized controlled trial. Radiother Oncol. 202(110611)2025.