{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:16:07Z","timestamp":1776795367643,"version":"3.51.2"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T00:00:00Z","timestamp":1681430400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T00:00:00Z","timestamp":1681430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Democritus University of Thrace"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Transl Oncol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Introduction<\/jats:title>\n                <jats:p>Patients with recurrent inoperable squamous-cell head-neck cancer (HNSCC) after chemo-radiotherapy have an ominous prognosis. Re-irradiation can be applied with some efficacy and high toxicity rates. Anti-PD-1 immunotherapy is effective in 25% of patients. Immunogenic death produced by large radiotherapy (RT) fractions may enhance immune response.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Materials and methods<\/jats:title>\n                <jats:p>We evaluated the efficacy and tolerance of ultra-hypofractionated immuno-radiotherapy (uhypo-IRT) in 17 patients with recurrent HNSCC and 1 with melanoma. Four of HNSCC patients also had oligometastatic disease. Using a dose\/time\/toxicity-based algorithm, 7, 7 and 4 patients received 1, 2 and 3 fractions of 8\u00a0Gy to the tumor, respectively. Nivolumab anti-PD-1 immunotherapy was administered concurrently with RT and continued for 24 cycles, or until disease progression or manifestation of immune-related adverse events (irAEs).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Early and late RT toxicities were minimal. Three patients developed irAEs (16%). After the 12th cycle, 7\/17 (41.2%) and 5\/17 (29.4%) patients with HNSCC showed complete (CR) and partial response (PR), respectively. CR was also achieved in the melanoma patient. The objective response rates in HNSCC patients were 57%, 86% and 66%, after 1, 2 and 3 fractions, respectively (overall response rate 70.6%). Most responders experienced an increase in peripheral lymphocyte counts. The median time to progression was 10\u00a0months. The 3-year projected locoregional progression-free survival was 35%, while the 3-year disease-specific overall survival was 50%.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Anti-PD1 uhypo-IRT is safe and effective in patients with recurrent HNSCC. The high objective response rates and the long survival without evidence of disease support further trials on uhypo-IRT.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s12094-023-03172-y","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T18:02:11Z","timestamp":1681495331000},"page":"3032-3041","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Anti-PD-1 immunotherapy with dose-adjusted ultra-hypofractionated re-irradiation in patients with locoregionally recurrent head and neck cancer"],"prefix":"10.1007","volume":"25","author":[{"given":"Ioannis M.","family":"Koukourakis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axiotis G.","family":"Giakzidis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2324-699X","authenticated-orcid":false,"given":"Michael I.","family":"Koukourakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"3172_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/s0167-8140(97)00094-7","volume":"44","author":"S Dische","year":"1997","unstructured":"Dische S, Saunders M, Barrett A, Harvey A, Gibson D, Parmar M. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol. 1997;44:123\u201336. https:\/\/doi.org\/10.1016\/s0167-8140(97)00094-7.","journal-title":"Radiother Oncol"},{"key":"3172_CR2","doi-asserted-by":"publisher","first-page":"103550","DOI":"10.1016\/j.critrevonc.2021.103550","volume":"169","author":"V Lupato","year":"2022","unstructured":"Lupato V, Giacomarra V, Alfieri S, Fanetti G, Polesel J. Prognostic factors in salvage surgery for recurrent head and neck cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2022;169:103550. https:\/\/doi.org\/10.1016\/j.critrevonc.2021.103550.","journal-title":"Crit Rev Oncol Hematol"},{"key":"3172_CR3","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1002\/hed.26485","volume":"43","author":"M Svajdova","year":"2021","unstructured":"Svajdova M, Dubinsky P, Kazda T. Radical external beam re-irradiation in the treatment of recurrent head and neck cancer: critical review. Head Neck. 2021;43:354\u201366. https:\/\/doi.org\/10.1002\/hed.26485.","journal-title":"Head Neck"},{"key":"3172_CR4","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.oraloncology.2019.08.017","volume":"98","author":"F Dionisi","year":"2019","unstructured":"Dionisi F, Fiorica F, D\u2019Angelo E, Maddalo M, Giacomelli I, Tornari E. Organs at risk\u2019s tolerance and dose limits for head and neck cancer re-irradiation: a literature review. Oral Oncol. 2019;98:35\u201347. https:\/\/doi.org\/10.1016\/j.oraloncology.2019.08.017.","journal-title":"Oral Oncol"},{"key":"3172_CR5","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.clon.2004.10.008","volume":"17","author":"AL Creak","year":"2005","unstructured":"Creak AL, Harrington K, Nutting C. Treatment of recurrent head and neck cancer: re-irradiation or chemotherapy? Clin Oncol (R Coll Radiol). 2005;17:138\u201347. https:\/\/doi.org\/10.1016\/j.clon.2004.10.008.","journal-title":"Clin Oncol (R Coll Radiol)"},{"key":"3172_CR6","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1056\/NEJMoa0802656","volume":"359","author":"JB Vermorken","year":"2008","unstructured":"Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116\u201327. https:\/\/doi.org\/10.1056\/NEJMoa0802656.","journal-title":"N Engl J Med"},{"key":"3172_CR7","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1056\/NEJMoa1602252","volume":"375","author":"RL Ferris","year":"2016","unstructured":"Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856\u201367. https:\/\/doi.org\/10.1056\/NEJMoa1602252.","journal-title":"N Engl J Med"},{"key":"3172_CR8","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/S0140-6736(19)32591-7","volume":"394","author":"B Burtness","year":"2019","unstructured":"Burtness B, Harrington KJ, Greil R, Souli\u00e8res D, Tahara M, de Castro Jr G, 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. 2019;394:1915\u201328. https:\/\/doi.org\/10.1016\/S0140-6736(19)32591-7.","journal-title":"Lancet"},{"key":"3172_CR9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3322\/caac.21358","volume":"67","author":"FG Herrera","year":"2017","unstructured":"Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin. 2017;67:65\u201385. https:\/\/doi.org\/10.3322\/caac.21358.","journal-title":"CA Cancer J Clin"},{"key":"3172_CR10","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.ijrobp.2017.07.028","volume":"99","author":"SC Formenti","year":"2017","unstructured":"Formenti SC. Optimizing dose per fraction: a new chapter in the story of the abscopal effect? Int J Radiat Oncol Biol Phys. 2017;99:677\u20139. https:\/\/doi.org\/10.1016\/j.ijrobp.2017.07.028.","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"3172_CR11","doi-asserted-by":"publisher","first-page":"612072","DOI":"10.3389\/fimmu.2020.612072","volume":"11","author":"Y Wang","year":"2021","unstructured":"Wang Y. Advances in hypofractionated irradiation-induced immunosuppression of tumor microenvironment. Front Immunol. 2021;11:612072. https:\/\/doi.org\/10.3389\/fimmu.2020.612072.","journal-title":"Front Immunol"},{"key":"3172_CR12","doi-asserted-by":"publisher","first-page":"15618","DOI":"10.1038\/ncomms15618","volume":"8","author":"C Vanpouille-Box","year":"2017","unstructured":"Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. https:\/\/doi.org\/10.1038\/ncomms15618.","journal-title":"Nat Commun"},{"key":"3172_CR13","doi-asserted-by":"publisher","first-page":"e000146","DOI":"10.1136\/jitc-2019-000146","volume":"8","author":"F Mulkey","year":"2020","unstructured":"Mulkey F, Theoret MR, Keegan P, Pazdur R, Sridhara R. Comparison of iRECIST versus RECIST V.1.1 in patients treated with an anti-PD-1 or PD-L1 antibody: pooled FDA analysis. J Immunother Cancer. 2020;8:e000146. https:\/\/doi.org\/10.1136\/jitc-2019-000146.","journal-title":"J Immunother Cancer."},{"key":"3172_CR14","unstructured":"https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/docs\/CTCAE_v5_Quick_Reference_5x7.pdf"},{"key":"3172_CR15","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/0167-8140(95)90055-1","volume":"35","author":"LENT Soma tables","year":"1995","unstructured":"LENT Soma tables. Radiother Oncol. 1995;35:17\u201360.","journal-title":"Radiother Oncol"},{"key":"3172_CR16","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/s41467-022-27960-2","volume":"13","author":"M Conroy","year":"2022","unstructured":"Conroy M, Naidoo J. Immune-related adverse events and the balancing act of immunotherapy. Nat Commun. 2022;13:392. https:\/\/doi.org\/10.1038\/s41467-022-27960-2.","journal-title":"Nat Commun"},{"key":"3172_CR17","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1158\/2326-6066.CIR-13-0141","volume":"1","author":"MM Ahmed","year":"2013","unstructured":"Ahmed MM, Hodge JW, Guha C, Bernhard EJ, Vikram B, Coleman CN. Harnessing the potential of radiation-induced immune modulation for cancer therapy. Cancer Immunol Res. 2013;1:280\u20134. https:\/\/doi.org\/10.1158\/2326-6066.CIR-13-0141.","journal-title":"Cancer Immunol Res"},{"key":"3172_CR18","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/S1470-2045(20)30737-3","volume":"22","author":"NY Lee","year":"2021","unstructured":"Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M, Bourhis J, 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. 2021;22:450\u201362. https:\/\/doi.org\/10.1016\/S1470-2045(20)30737-3.","journal-title":"Lancet Oncol"},{"key":"3172_CR19","doi-asserted-by":"publisher","unstructured":"Tao Y, Biau J, Sun XS, Sire C, Martin L, Alfonsi M, et al. Pembrolizumab versus cetuximab, concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase 2 trial. Ann Oncol. 2022 (in press). https:\/\/doi.org\/10.1016\/j.annonc.2022.10.006.","DOI":"10.1016\/j.annonc.2022.10.006"},{"key":"3172_CR20","doi-asserted-by":"publisher","first-page":"e002038","DOI":"10.1136\/jitc-2020-002038","volume":"9","author":"S Demaria","year":"2021","unstructured":"Demaria S, Guha C, Schoenfeld J, Morris Z, Monjazeb A, Sikora A, et al. Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose? J Immunother Cancer. 2021;9:e002038. https:\/\/doi.org\/10.1136\/jitc-2020-002038.","journal-title":"J Immunother Cancer"},{"key":"3172_CR21","doi-asserted-by":"publisher","first-page":"5379","DOI":"10.1158\/1078-0432.CCR-09-0265","volume":"15","author":"MZ Dewan","year":"2009","unstructured":"Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379\u201388. https:\/\/doi.org\/10.1158\/1078-0432.CCR-09-0265.","journal-title":"Clin Cancer Res"},{"key":"3172_CR22","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1016\/j.ijrobp.2011.09.049","volume":"83","author":"D Schaue","year":"2012","unstructured":"Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012;83:1306\u201310. https:\/\/doi.org\/10.1016\/j.ijrobp.2011.09.049.","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"3172_CR23","doi-asserted-by":"publisher","DOI":"10.1080\/09553002.2023.2144960","author":"IM Koukourakis","year":"2022","unstructured":"Koukourakis IM, Tiniakos D, Kouloulias V, Zygogianni A. The molecular basis of immuno-radiotherapy. Int J Radiat Biol. 2022. https:\/\/doi.org\/10.1080\/09553002.2023.2144960.","journal-title":"Int J Radiat Biol"},{"key":"3172_CR24","doi-asserted-by":"publisher","first-page":"188704","DOI":"10.1016\/j.bbcan.2022.188704","volume":"1877","author":"MI Koukourakis","year":"2022","unstructured":"Koukourakis MI, Giatromanolaki A. Tumor draining lymph nodes, immune response, and radiotherapy: towards a revisal of therapeutic principles. Biochim Biophys Acta Rev Cancer. 2022;1877:188704. https:\/\/doi.org\/10.1016\/j.bbcan.2022.188704.","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"3172_CR25","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1200\/JCO.20.00290","volume":"39","author":"S McBride","year":"2021","unstructured":"McBride S, Sherman E, Tsai CJ, Baxi S, Aghalar J, Eng J, et al. Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2021;39:30\u20137. https:\/\/doi.org\/10.1200\/JCO.20.00290.","journal-title":"J Clin Oncol"},{"key":"3172_CR26","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/S2213-2600(20)30391-X","volume":"9","author":"WSME Theelen","year":"2021","unstructured":"Theelen WSME, Chen D, Verma V, Hobbs BP, Peulen HMU, Aerts JGJV, et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med. 2021;9:467\u201375. https:\/\/doi.org\/10.1016\/S2213-2600(20)30391-X.","journal-title":"Lancet Respir Med"},{"key":"3172_CR27","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1200\/OP.21.00059","volume":"17","author":"N Shukla","year":"2021","unstructured":"Shukla N, Hanna N, Durm G. Optimal duration of maintenance checkpoint inhibitor therapy in patients with advanced NSCLC. JCO Oncol Pract. 2021;17:472\u20134. https:\/\/doi.org\/10.1200\/OP.21.00059.","journal-title":"JCO Oncol Pract"},{"key":"3172_CR28","doi-asserted-by":"publisher","first-page":"3863","DOI":"10.1200\/JCO.20.00131","volume":"38","author":"DM Waterhouse","year":"2020","unstructured":"Waterhouse DM, Garon EB, Chandler J, McCleod M, Hussein M, Jotte R, et al. Continuous versus 1-year fixed-duration nivolumab in previously treated advanced non-small-cell lung cancer: CheckMate 153. J Clin Oncol. 2020;38:3863\u201373. https:\/\/doi.org\/10.1200\/JCO.20.00131.","journal-title":"J Clin Oncol"},{"key":"3172_CR29","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1172\/JCI67313","volume":"124","author":"L Deng","year":"2014","unstructured":"Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687\u201395. https:\/\/doi.org\/10.1172\/JCI67313.","journal-title":"J Clin Invest"},{"key":"3172_CR30","doi-asserted-by":"publisher","first-page":"610","DOI":"10.3389\/fimmu.2016.00610","volume":"7","author":"A Derer","year":"2016","unstructured":"Derer A, Spiljar M, B\u00e4umler M, Hecht M, Fietkau R, Frey B, et al. Chemoradiation increases PD-L1 expression in certain melanoma and glioblastoma cells. Front Immunol. 2016;7:610. https:\/\/doi.org\/10.3389\/fimmu.2016.00610.","journal-title":"Front Immunol"},{"key":"3172_CR31","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s40425-018-0395-x","volume":"6","author":"WJ Ho","year":"2018","unstructured":"Ho WJ, Yarchoan M, Hopkins A, Mehra R, Grossman S, Kang H. Association between pre-treatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas. J Immunother Cancer. 2018;6:84. https:\/\/doi.org\/10.1186\/s40425-018-0395-x.","journal-title":"J Immunother Cancer"},{"key":"3172_CR32","doi-asserted-by":"publisher","first-page":"114268","DOI":"10.18632\/oncotarget.23217","volume":"8","author":"A Diehl","year":"2017","unstructured":"Diehl A, Yarchoan M, Hopkins A, Jaffee E, Grossman SA. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget. 2017;8:114268\u201380. https:\/\/doi.org\/10.18632\/oncotarget.23217.","journal-title":"Oncotarget"}],"container-title":["Clinical and Translational Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-023-03172-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12094-023-03172-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-023-03172-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T08:20:34Z","timestamp":1693210834000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12094-023-03172-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,14]]},"references-count":32,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["3172"],"URL":"https:\/\/doi.org\/10.1007\/s12094-023-03172-y","relation":{},"ISSN":["1699-3055"],"issn-type":[{"value":"1699-3055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,14]]},"assertion":[{"value":"19 February 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 March 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"There are no conflicts of interest to report.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study has been approved by the local Ethics and Research Committee (\u039887\/\u0394\u03a315\/13-11-2019). The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent to enter the trial was obtained from all patients before therapy. Patients consent included permission to publish anonymously their clinical and laboratory data for research and educational purposes.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}