{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:28:30Z","timestamp":1785403710670,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Navarra University Clinic"},{"id":[{"id":"https:\/\/ror.org\/03phm3r45","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Photon re-irradiation in previously treated head and neck cancer (HNC) is constrained by cumulative normal-tissue toxicity. Pencil-beam scanning intensity-modulated proton therapy (PBS-IMPT) allows for a sharper dose conformation than conventional photon techniques, which may widen the therapeutic window in previously irradiated tissue. Methods: Sixty-five patients with recurrent or second primary HNC were enrolled in a prospective single-institution registry and re-irradiated with PBS-IMPT between January 2020 and December 2025. Forty-five were treated with radical intent (69.2%), and 20 were treated postoperatively (30.8%), with a median prescribed dose of 66 Gy (RBE) in 30 fractions. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Locoregional control (LRC), adverse events and the prognostic impact of anatomical extent were secondary endpoints. Results: The median follow-up was 9.3 months. The median OS was 17.2 months (95% CI 13.9\u2013NR), with a 12-month rate of 67.1%. The median PFS was 10.1 months and the median LRC was 28.1 months. Central\/skull-base involvement was associated with a non-significant trend toward worse OS (14.3 vs. 35.2 months; p = 0.062) and with significantly worse PFS (9.1 vs. 14.7 months; p = 0.037) than peripheral disease, but LRC did not differ between the groups (p = 0.240). Grade \u2265 3 oral mucositis occurred in 7.7%, with no grade 4\u20135 acute events. Within a median follow-up of 9.3 months, late osteoradionecrosis affected 6.2%, but late toxicity data remain preliminary given the short follow-up. Ninety-two percent of patients completed treatment. Conclusions: PBS-IMPT re-irradiation provided adequate survival with low acute toxicity. T3\u2013T4 stage at re-irradiation was the only variable retaining significance for PFS on multivariable analysis (HR 4.32, 95% CI 1.24\u201315.13; p = 0.022). The poor survival observed for central\/skull-base disease on Kaplan\u2013Meier curves disappeared after T-stage adjustment, indicating the higher concentration of advanced disease in that compartment. Multicentre prospective data and longer follow-up are needed.<\/jats:p>","DOI":"10.3390\/cancers18142207","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:50:56Z","timestamp":1783587056000},"page":"2207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Salvage Proton Therapy Re-Irradiation in Recurrent Head and Neck Cancer: Outcomes and Adverse Events by Re-Irradiated Target Site"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9055-6859","authenticated-orcid":false,"given":"Enrique","family":"Amaya","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8746-6844","authenticated-orcid":false,"given":"Jacobo","family":"Palma","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8250-854X","authenticated-orcid":false,"given":"Roser","family":"Fay\u00f3s-Sol\u00e0","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-7145","authenticated-orcid":false,"given":"Rosa","family":"Meiri\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5959-7380","authenticated-orcid":false,"given":"Mauricio","family":"Cambeiro","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1542-7724","authenticated-orcid":false,"given":"Ana","family":"Navarrete","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2768-6316","authenticated-orcid":false,"given":"Pablo","family":"Cabello-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9158-7932","authenticated-orcid":false,"given":"Alberto","family":"Vi\u00f1als","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0536-5127","authenticated-orcid":false,"given":"Diego","family":"Pedrero","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-546X","authenticated-orcid":false,"given":"Felipe A.","family":"Calvo","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-2363","authenticated-orcid":false,"given":"Javier","family":"Aristu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0322-7863","authenticated-orcid":false,"given":"Javier","family":"Serrano","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1002\/hed.23542","article-title":"Recurrent and Second Primary Squamous Cell Carcinoma of the Head and Neck: When and How to Reirradiate","volume":"37","author":"Strojan","year":"2015","journal-title":"Head Neck"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.6004\/jnccn.2025.0007","article-title":"NCCN Guidelines\u00ae Insights: Head and Neck Cancers, Version 2.2025: Featured Updates to the NCCN Guidelines","volume":"23","author":"Colevas","year":"2025","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.radonc.2014.04.018","article-title":"High-Dose Reirradiation with Intensity-Modulated Radiotherapy for Recurrent Head-and-Neck Cancer: Disease Control, Survival and Toxicity","volume":"111","author":"Duprez","year":"2014","journal-title":"Radiother. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1002\/hed.26264","article-title":"Reirradiation with Intensity-modulated Radiation Therapy for Recurrent or Secondary Head and Neck Cancer: Meta-analysis and Systematic Review","volume":"42","author":"Lee","year":"2020","journal-title":"Head Neck"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.radonc.2009.10.012","article-title":"Intensity-Modulated Radiotherapy for Recurrent and Second Primary Head and Neck Cancer in Previously Irradiated Territory","volume":"93","author":"Duprez","year":"2009","journal-title":"Radiother. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.ijrobp.2016.03.015","article-title":"Reirradiation of Head and Neck Cancers with Intensity Modulated Radiation Therapy: Outcomes and Analyses","volume":"95","author":"Takiar","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.ijrobp.2008.04.021","article-title":"IMRT Reirradiation of Head and Neck Cancer\u2014Disease Control and Morbidity Outcomes","volume":"73","author":"Sulman","year":"2009","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.ijrobp.2017.06.012","article-title":"Refining Patient Selection for Reirradiation of Head and Neck Squamous Carcinoma in the IMRT Era: A Multi-Institution Cohort Study by the MIRI Collaborative","volume":"100","author":"Ward","year":"2018","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0360-3016(02)02754-2","article-title":"Relative Biological Effectiveness (RBE) Values for Proton Beam Therapy","volume":"53","author":"Paganetti","year":"2002","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.semradonc.2017.08.004","article-title":"Proton Therapy for Head and Neck Cancers","volume":"28","author":"Blanchard","year":"2018","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.ijrobp.2016.02.036","article-title":"Proton Beam Re-Irradiation for Recurrent Head and Neck Cancer: Multi-Institutional Report on Feasibility and Early Outcomes","volume":"95","author":"Romesser","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ijrobp.2016.03.053","article-title":"Reirradiation of Head and Neck Cancers with Proton Therapy: Outcomes and Analyses","volume":"96","author":"Phan","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.ijrobp.2016.07.037","article-title":"Reirradiation of Recurrent and Second Primary Head and Neck Cancer with Proton Therapy","volume":"96","author":"McDonald","year":"2016","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2250607","DOI":"10.1001\/jamanetworkopen.2022.50607","article-title":"Evaluation of Proton Therapy Reirradiation for Patients with Recurrent Head and Neck Squamous Cell Carcinoma","volume":"6","author":"Lee","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"84","DOI":"10.14338\/IJPT-20-00071.1","article-title":"PTCOG Head and Neck Subcommittee Consensus Guidelines on Particle Therapy for the Management of Head and Neck Tumors","volume":"8","author":"Lin","year":"2021","journal-title":"Int. J. Part. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"131","DOI":"10.14338\/IJPT-20-00064.1","article-title":"A Systematic Review on Re-Irradiation with Charged Particle Beam Therapy in the Management of Locally Recurrent Skull Base and Head and Neck Tumors","volume":"8","author":"Gamez","year":"2021","journal-title":"Int. J. Part. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1053\/j.seminoncol.2019.07.002","article-title":"Modern Radiotherapy for Head and Neck Cancer","volume":"46","author":"Alterio","year":"2019","journal-title":"Semin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"203","DOI":"10.5603\/RPOR.a2021.0029","article-title":"Proton Re-Irradiation of Unresectable Recurrent Head and Neck Cancers","volume":"26","author":"Gordon","year":"2021","journal-title":"Rep. Pract. Oncol. Radiother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"051711","DOI":"10.1118\/1.4801899","article-title":"Effectiveness of Robust Optimization in Intensity-Modulated Proton Therapy Planning for Head and Neck Cancers","volume":"40","author":"Liu","year":"2013","journal-title":"Med. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Embring, A., Onjukka, E., Mercke, C., Lax, I., Berglund, A., Bornedal, S., Wennberg, B., Dalqvist, E., and Friesland, S. (2021). Re-Irradiation for Head and Neck Cancer: Cumulative Dose to Organs at Risk and Late Side Effects. Cancers, 13.","DOI":"10.3390\/cancers13133173"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1186\/s13014-023-02342-0","article-title":"Advancements of Radiotherapy for Recurrent Head and Neck Cancer in Modern Era","volume":"18","author":"Zhang","year":"2023","journal-title":"Radiat. Oncol."},{"key":"ref_23","first-page":"331","article-title":"Common Terminology Criteria for Adverse Events (CTCAE)","volume":"784","author":"Shah","year":"2022","journal-title":"Natl. Cancer Inst. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1002\/hed.27153","article-title":"Curative High-Dose Reirradiation for Patients with Recurrent Head and Neck Squamous Cell Carcinoma Using IMRT or Proton Therapy: Outcomes and Analysis of Patterns of Failure","volume":"44","author":"Beddok","year":"2022","journal-title":"Head Neck"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107309","DOI":"10.1016\/j.oraloncology.2025.107309","article-title":"Proton Therapy for Primary and Recurrent HPV-Related Oropharyngeal Cancer","volume":"165","author":"Beddok","year":"2025","journal-title":"Oral Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.radonc.2016.05.022","article-title":"Intensity-Modulated Proton Beam Therapy (IMPT) versus Intensity-Modulated Photon Therapy (IMRT) for Patients with Oropharynx Cancer\u2014A Case Matched Analysis","volume":"120","author":"Blanchard","year":"2016","journal-title":"Radiother. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00066-023-02080-y","article-title":"Predictors of Toxicity after Curative Reirradiation with Intensity Modulated Radiotherapy or Proton Therapy for Recurrent Head and Neck Carcinoma: New Dose Constraints for Pharyngeal Constrictors Muscles and Oral Cavity","volume":"199","author":"Beddok","year":"2023","journal-title":"Strahlenther. Onkol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104482","DOI":"10.1016\/j.amjoto.2024.104482","article-title":"Reirradiation in Head and Neck Squamous Cell Carcinoma; Prognostic Indicators, Oncologic and Functional Outcomes","volume":"45","author":"Slater","year":"2024","journal-title":"Am. J. Otolaryngol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.oraloncology.2016.07.012","article-title":"Patterns of Failure after Reirradiation with Intensity-Modulated Radiation Therapy and the Competing Risk of out-of-Field Recurrences","volume":"61","author":"Margalit","year":"2016","journal-title":"Oral Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17887","DOI":"10.1038\/s41598-024-68676-1","article-title":"Failure Patterns and Individualized Treatment Plans of Reirradiation for Inoperable Locally Recurrent Nasopharyngeal Carcinoma","volume":"14","author":"Lin","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ijrobp.2024.01.012","article-title":"Disease Control and Late Toxicity in Adaptive Dose Painting by Numbers Versus Nonadaptive Radiation Therapy for Head and Neck Cancer: A Randomized Controlled Phase 2 Trial","volume":"120","author":"Bruycker","year":"2024","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s40336-023-00607-y","article-title":"Is There a Role for [18F]-FMISO PET to Guide Dose Adaptive Radiotherapy in Head and Neck Cancer? A Review of the Literature","volume":"12","author":"Sambasivan","year":"2024","journal-title":"Clin. Transl. Imaging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.semradonc.2025.02.009","article-title":"Reirradiation for Locally Recurrent Head and Neck Cancer: State-of-the-Art and Future Directions","volume":"35","author":"Phan","year":"2025","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1001\/jamaoncol.2024.1143","article-title":"Intensity-Modulated Reirradiation Therapy with Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial","volume":"10","author":"Saba","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109380","DOI":"10.1016\/j.radonc.2022.10.007","article-title":"Dose-Escalated Re-Irradiation Improves Outcome in Locally Recurrent Head and Neck Cancer\u2014Results of a Large Multicenter Analysis","volume":"181","author":"Roesch","year":"2023","journal-title":"Radiother. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.canrad.2022.08.008","article-title":"Effect of Lymphoid Volume Irradiation on Radiation-Induced Lymphopenia in Head and Neck Cancers","volume":"27","author":"Rambeau","year":"2023","journal-title":"Cancer\/Radioth\u00e9rapie"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Jin, J.-Y., Hu, C., Xiao, Y., Zhang, H., Paulus, R., Ellsworth, S.G., Schild, S.E., Bogart, J.A., Dobelbower, M.C., and Kavadi, V.S. (2021). Higher Radiation Dose to the Immune Cells Correlates with Worse Tumor Control and Overall Survival in Patients with Stage III NSCLC: A Secondary Analysis of RTOG0617. Cancers, 13.","DOI":"10.3390\/cancers13246193"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.adro.2020.03.021","article-title":"Lymphopenia and Radiation Dose to Circulating Lymphocytes with Neoadjuvant Chemoradiation in Esophageal Squamous Cell Carcinoma","volume":"5","author":"So","year":"2020","journal-title":"Adv. Radiat. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.ijrobp.2019.05.064","article-title":"Impact of Radiation Dose to the Host Immune System on Tumor Control and Survival for Stage III Non-Small Cell Lung Cancer Treated with Definitive Radiation Therapy","volume":"105","author":"Ladbury","year":"2019","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.radonc.2022.01.003","article-title":"The Impact of Radiation Induced Lymphopenia in the Prognosis of Head and Neck Cancer: A Systematic Review and Meta-Analysis","volume":"168","author":"Dai","year":"2022","journal-title":"Radiother. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s00262-026-04389-w","article-title":"Radiation-Induced Remodeling of the T Cell Landscape in Head and Neck Cancer","volume":"75","author":"Memon","year":"2026","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1002\/hed.25180","article-title":"Reirradiation of Head and Neck Cancer Using Modern Highly Conformal Techniques","volume":"40","author":"Ho","year":"2018","journal-title":"Head Neck"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2207\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T07:06:27Z","timestamp":1784185587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":42,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18142207"],"URL":"https:\/\/doi.org\/10.3390\/cancers18142207","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]}}}