{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:01:36Z","timestamp":1789999296909,"version":"4.0.1"},"reference-count":48,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The management of hepatocellular carcinoma has traditionally followed a stage-dependent sequence in which surgery or thermal ablation is prioritized for early disease, transarterial approaches are used for intermediate-stage tumors, and systemic treatment is introduced after progression to advanced disease or loss of suitability for locoregional therapy. This paradigm was developed when systemic treatments had limited antitumor activity. Modern immune checkpoint inhibitors and immune\u2013antiangiogenic combinations have substantially changed these premises. Randomized trials now demonstrate clinical benefit when systemic treatment is integrated with transarterial chemoembolization before conventional locoregional failure, while perioperative studies suggest that systemic treatment can also be moved into selected high-risk resectable disease. Conversely, updated adjuvant data indicate that simply administering systemic therapy at an earlier stage does not necessarily improve outcome after complete tumor eradication. We propose the concept of therapeutic time migration, whereby systemic treatment is introduced at an earlier biological point in selected patients, while hepatic reserve is preserved, occult systemic risk is becoming clinically relevant, and effective local treatment remains feasible. We explicitly distinguish this framework from the established concept of treatment stage migration and therapeutic hierarchy. This framework emphasizes treatment sequence rather than treatment escalation and suggests that timing itself may function as a dynamic therapeutic biomarker. Prospective studies should determine whether changing the order of systemic and locoregional therapy can modify immune activation, preserve liver function, increase conversion to definitive local treatment, and ultimately improve survival.<\/jats:p>","DOI":"10.3390\/cancers18183039","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Time Migration in Hepatocellular Carcinoma: Rethinking the Timing of Systemic Therapy Across the Disease Continuum"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0292-340X","authenticated-orcid":false,"given":"Fausto","family":"Meriggi","sequence":"first","affiliation":[{"name":"Oncology Department, Istituto Ospedaliero Fondazione Poliambulanza, Via Leonida Bissolati 57, 25124 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7861-7882","authenticated-orcid":false,"given":"Ester","family":"Oneda","sequence":"additional","affiliation":[{"name":"Oncology Department, Istituto Ospedaliero Fondazione Poliambulanza, Via Leonida Bissolati 57, 25124 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cherri","sequence":"additional","affiliation":[{"name":"Oncology Department, Istituto Ospedaliero Fondazione Poliambulanza, Via Leonida Bissolati 57, 25124 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0817-4633","authenticated-orcid":false,"given":"Alberto","family":"Zaniboni","sequence":"additional","affiliation":[{"name":"Oncology Department, Istituto Ospedaliero Fondazione Poliambulanza, Via Leonida Bissolati 57, 25124 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","unstructured":"European Association for the Study of the Liver (2025). EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J. Hepatol., 82, 315\u2013374."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.annonc.2025.02.006","article-title":"Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"36","author":"Vogel","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1097\/HEP.0000000000000466","article-title":"AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma","volume":"78","author":"Singal","year":"2023","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.jhep.2021.11.018","article-title":"BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update","volume":"76","author":"Reig","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.jhep.2021.11.030","article-title":"Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab versus sorafenib for unresectable hepatocellular carcinoma","volume":"76","author":"Cheng","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_8","first-page":"EVIDoa2100070","article-title":"Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"1","author":"Lau","year":"2022","journal-title":"NEJM Evid."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.jhep.2025.03.033","article-title":"Five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable HCC","volume":"83","author":"Rimassa","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1016\/S0140-6736(25)00403-9","article-title":"Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): An open-label, randomised, phase 3 trial","volume":"405","author":"Yau","year":"2025","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/S1470-2045(25)00543-1","article-title":"Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): Final analysis of a randomised phase 3 study","volume":"26","author":"Qin","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/S0140-6736(24)02551-0","article-title":"Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): A multiregional, randomised, double-blind, placebo-controlled phase 3 study","volume":"405","author":"Sangro","year":"2025","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0140-6736(24)02575-3","article-title":"Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): A multicentre, randomised, double-blind, phase 3 study","volume":"405","author":"Kudo","year":"2025","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S2468-1253(21)00427-1","article-title":"Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: A randomised open-label phase 2 trial","volume":"7","author":"Kaseb","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S2468-1253(21)00385-X","article-title":"Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: A single-arm open-label phase 2 trial","volume":"7","author":"Marron","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/s43018-021-00234-4","article-title":"Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity","volume":"2","author":"Ho","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1016\/S0140-6736(25)01720-9","article-title":"Perioperative camrelizumab plus rivoceranib versus surgery alone in patients with resectable hepatocellular carcinoma at intermediate or high risk of recurrence (CARES-009): A randomised phase 2\/3 trial","volume":"406","author":"Wang","year":"2025","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/S0140-6736(23)01796-8","article-title":"Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): A randomised, open-label, multicentre phase 3 trial","volume":"402","author":"Qin","year":"2023","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.jhep.2026.01.006","article-title":"Updated data from IMbrave050: Adjuvant atezolizumab plus bevacizumab for high-risk hepatocellular carcinoma","volume":"84","author":"Yopp","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1002\/hep.31187","article-title":"Treatment of hepatocellular carcinoma in the precision medicine era: From treatment stage migration to therapeutic hierarchy","volume":"72","author":"Vitale","year":"2020","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e312","DOI":"10.1016\/S1470-2045(23)00186-9","article-title":"Personalised management of patients with hepatocellular carcinoma: A multiparametric therapeutic hierarchy concept","volume":"24","author":"Vitale","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.1111\/liv.14223","article-title":"Biology and significance of alpha-fetoprotein in hepatocellular carcinoma","volume":"39","author":"Galle","year":"2019","journal-title":"Liver Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1038\/s41590-024-01992-w","article-title":"Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma","volume":"25","author":"Shu","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1200\/JCO.2014.57.9151","article-title":"Assessment of liver function in patients with hepatocellular carcinoma: A new evidence-based approach\u2014The ALBI grade","volume":"33","author":"Johnson","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1159\/000480256","article-title":"Hepatic function during repeated TACE procedures and prognosis after introducing sorafenib in patients with unresectable hepatocellular carcinoma: Multicenter analysis","volume":"35","author":"Hiraoka","year":"2017","journal-title":"Dig. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1159\/000368142","article-title":"Transarterial chemoembolization failure\/refractoriness: JSH-LCSGJ criteria 2014 update","volume":"87","author":"Kudo","year":"2014","journal-title":"Oncology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000343867","article-title":"How to define transarterial chemoembolization failure or refractoriness: A European perspective","volume":"3","author":"Raoul","year":"2014","journal-title":"Liver Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1136\/gutjnl-2019-318934","article-title":"Randomised, multicentre prospective trial of transarterial chemoembolisation plus sorafenib compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial","volume":"69","author":"Kudo","year":"2020","journal-title":"Gut"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1080\/02841850801958890","article-title":"Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization","volume":"49","author":"Wang","year":"2008","journal-title":"Acta Radiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/his.14317","article-title":"Transarterial chemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma","volume":"79","author":"Montasser","year":"2021","journal-title":"Histopathology"},{"key":"ref_31","first-page":"33","article-title":"Interactions between tumor microenvironment and resistance to transarterial and systemic treatments for HCC","volume":"8","author":"Saffioti","year":"2025","journal-title":"Cancer Drug Resist."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yu, S., Yu, M., Keane, B., Mauro, D.M., Helft, P.R., Harris, W.P., Sanoff, H.K., Johnson, M.S., O\u2019Neil, B., and McRee, A.J. (2024). A pilot study of pembrolizumab in combination with Y90 radioembolization in subjects with poor prognosis hepatocellular carcinoma. Oncologist, 29.","DOI":"10.1093\/oncolo\/oyad331"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"72343","DOI":"10.18632\/oncotarget.11644","article-title":"Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma: Systematic review and meta-analyses","volume":"7","author":"Rognoni","year":"2016","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1002\/hep.31819","article-title":"Yttrium-90 radioembolization for the treatment of solitary unresectable HCC: The LEGACY study","volume":"74","author":"Salem","year":"2021","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S2468-1253(20)30290-9","article-title":"Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): A randomised multicentre phase 2 trial","volume":"6","author":"Garin","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"264","DOI":"10.2967\/jnumed.123.266211","article-title":"Long-term overall survival after selective internal radiation therapy for locally advanced hepatocellular carcinomas: Updated analysis of DOSISPHERE-01","volume":"65","author":"Garin","year":"2024","journal-title":"J. Nucl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/S2468-1253(21)00305-8","article-title":"Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): A single-arm phase 2 trial","volume":"6","author":"Tai","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e005457","DOI":"10.1136\/jitc-2022-005457","article-title":"Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: A phase 2, single-arm study","volume":"10","author":"Matilla","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lyu, N., Kong, Y., Li, X., Mu, L., Deng, H., Chen, H., He, M., Lai, J., Li, J., and Tang, H. (2020). Ablation reboots the response in advanced hepatocellular carcinoma with stable or atypical response during PD-1 therapy: A proof-of-concept study. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.580241"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jhep.2024.06.042","article-title":"Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis","volume":"82","author":"Yeo","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1097\/SLA.0000000000006386","article-title":"Tumor mutational burden from circulating tumor DNA predicts recurrence of hepatocellular carcinoma after resection: An emerging biomarker for surveillance","volume":"280","author":"Wehrle","year":"2024","journal-title":"Ann. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2400934","DOI":"10.1200\/PO-24-00934","article-title":"Feasibility of personalized and tumor-informed circulating tumor DNA assay for early recurrence detection in patients with hepatocellular carcinoma","volume":"9","author":"Abdelrahim","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wang, Q., Li, C., Zhang, J., Hu, X., Fan, Y., Ma, K., Sparrelid, E., and Brismar, T.B. (2021). Radiomics models for predicting microvascular invasion in hepatocellular carcinoma: A systematic review and Radiomics Quality Score assessment. Cancers, 13.","DOI":"10.3390\/cancers13225864"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/med4.70044","article-title":"Neuronal reshaping of the tumor microenvironment in tumorigenesis and metastasis: Bench to clinic","volume":"3","author":"Wu","year":"2025","journal-title":"Med. Adv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e70074","DOI":"10.1111\/cpr.70074","article-title":"Tryptophan suppresses FTH1-driven ferritinophagy, a key correlate of prognosis in hepatocellular carcinoma","volume":"59","author":"Cheng","year":"2026","journal-title":"Cell Prolif."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wang, L., Peng, Y., Qin, S., Wan, X., Zeng, X., Li, S., Liu, Q., and Tan, C. (2023). First-line systemic treatment strategies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0279786"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Shomura, M., Okabe, H., Sakakibara, M., Sato, E., Shiraishi, K., Arase, Y., Tsuruya, K., Mishima, Y., Hirose, S., and Kagawa, T. (2024). Impact of atezolizumab + bevacizumab therapy on health-related quality of life in patients with advanced hepatocellular carcinoma. Cancers, 16.","DOI":"10.3390\/cancers16213610"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1038\/s41467-024-47420-3","article-title":"Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: The Notable-HCC phase 1b trial","volume":"15","author":"Li","year":"2024","journal-title":"Nat. Commun."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3039\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:10:19Z","timestamp":1789996219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3039"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":48,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18183039"],"URL":"https:\/\/doi.org\/10.3390\/cancers18183039","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]}}}