{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T17:02:29Z","timestamp":1784998949731,"version":"3.55.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Int J Clin Oncol"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Systemic chemotherapy for unresectable or metastatic colorectal cancer (mCRC) has improved clinical outcomes through substantial therapeutic advances. Triplet chemotherapy based on FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) has achieved high response rates and deep tumor shrinkage. In combination with molecularly targeted agents, triplet therapy plus bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, has demonstrated superior efficacy compared with doublet chemotherapy plus bevacizumab. In patients with\n                    <jats:italic>RAS\/BRAF<\/jats:italic>\n                    wild-type tumors, combination therapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab has also shown improved survival outcomes, although toxicity remains a major concern. Although intensified treatment is associated with increased gastrointestinal and hematologic toxicity, improved supportive care and optimized dose-adjustment strategies have enhanced the feasibility of triplet therapy in routine clinical practice. This review outlines the historical development of triplet therapy in mCRC, summarizes the major clinical trials investigating triplet chemotherapy combined with molecularly targeted agents, and discusses direct comparisons between anti-VEGF- and anti-EGFR-based strategies. Particular emphasis is placed on practical considerations for clinical implementation, including toxicity management, dose optimization, and multidisciplinary supportive care.\n                  <\/jats:p>","DOI":"10.1007\/s10147-026-03101-3","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T16:51:14Z","timestamp":1782406274000},"page":"1538-1546","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High therapeutic efficacy of triplet therapy in unresectable or metastatic colorectal cancer and its optimal application strategies"],"prefix":"10.1007","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5844-7830","authenticated-orcid":false,"given":"Hiroki","family":"Sakuyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Okuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoriyuki","family":"Tahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sena","family":"Tsukamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuhiro","family":"Kita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotone","family":"Nomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akitsu","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Okita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironaga","family":"Satake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"issue":"12","key":"3101_CR1","doi-asserted-by":"publisher","first-page":"2410","DOI":"10.1007\/s10147-025-02899-8","volume":"30","author":"Y Kinugasa","year":"2025","unstructured":"Kinugasa Y, Uehara K, Yamaguchi K et al (2025) Japanese society for cancer of the colon and rectum (JSCCR) guidelines 2024 for the treatment of colorectal cancer. Int J Clin Oncol 30(12):2410\u20132463. https:\/\/doi.org\/10.1007\/s10147-025-02899-8","journal-title":"Int J Clin Oncol"},{"issue":"3","key":"3101_CR2","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1200\/JCO.22.01690","volume":"41","author":"VK Morris","year":"2023","unstructured":"Morris VK, Kennedy EB, Baxter NN et al (2023) Treatment of metastatic colorectal cancer: ASCO guideline. J Clin Oncol 41(3):678\u2013700. https:\/\/doi.org\/10.1200\/JCO.22.01690","journal-title":"J Clin Oncol"},{"issue":"2 D","key":"3101_CR3","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2024.0029","volume":"22","author":"AB Benson","year":"2024","unstructured":"Benson AB, Venook AP, Adam M et al (2024) Colon cancer, version 3.2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 22(2 D):e240029. https:\/\/doi.org\/10.6004\/jnccn.2024.0029","journal-title":"J Natl Compr Canc Netw"},{"issue":"1","key":"3101_CR4","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.annonc.2022.10.003","volume":"34","author":"A Cervantes","year":"2023","unstructured":"Cervantes A, Adam R, Rosell\u00f3 S et al (2023) Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 34(1):10\u201332. https:\/\/doi.org\/10.1016\/j.annonc.2022.10.003","journal-title":"Ann Oncol"},{"issue":"13","key":"3101_CR5","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1200\/JCO.2006.09.0928","volume":"25","author":"A Falcone","year":"2007","unstructured":"Falcone A, Ricci S, Brunetti I et al (2007) Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 25(13):1670\u20131676. https:\/\/doi.org\/10.1200\/JCO.2006.09.0928","journal-title":"J Clin Oncol"},{"key":"3101_CR6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.1.301","author":"P Piedbois","year":"1998","unstructured":"Piedbois P, Rougier P, Buyse M et al (1998) Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol. https:\/\/doi.org\/10.1200\/JCO.1998.16.1.301","journal-title":"J Clin Oncol"},{"issue":"9209","key":"3101_CR7","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1016\/s0140-6736(00)02034-1","volume":"355","author":"JY Douillard","year":"2000","unstructured":"Douillard JY, Cunningham D, Roth AD et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041\u20131047. https:\/\/doi.org\/10.1016\/s0140-6736(00)02034-1","journal-title":"Lancet"},{"issue":"16","key":"3101_CR8","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.1200\/JCO.2000.18.16.2938","volume":"18","author":"A de Gramont","year":"2000","unstructured":"de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18(16):2938\u20132947. https:\/\/doi.org\/10.1200\/JCO.2000.18.16.2938","journal-title":"J Clin Oncol"},{"issue":"2","key":"3101_CR9","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1200\/JCO.2004.05.113","volume":"22","author":"C Tournigand","year":"2004","unstructured":"Tournigand C, Andr\u00e9 T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22(2):229\u2013237. https:\/\/doi.org\/10.1200\/JCO.2004.05.113","journal-title":"J Clin Oncol"},{"issue":"11","key":"3101_CR10","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1634\/theoncologist.2011-0141","volume":"16","author":"E Assenat","year":"2011","unstructured":"Assenat E, Desseigne F, Thezenas S et al (2011) Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist 16(11):1557\u20131564. https:\/\/doi.org\/10.1634\/theoncologist.2011-0141","journal-title":"Oncologist"},{"issue":"12","key":"3101_CR11","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1038\/bjc.2012.509","volume":"107","author":"Z Saridaki","year":"2012","unstructured":"Saridaki Z, Androulakis N, Vardakis N et al (2012) A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Br J Cancer 107(12):1932\u20131937. https:\/\/doi.org\/10.1038\/bjc.2012.509","journal-title":"Br J Cancer"},{"issue":"1","key":"3101_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54460-2","volume":"15","author":"M Shiozawa","year":"2024","unstructured":"Shiozawa M, Sunakawa Y, Watanabe T et al (2024) Modified FOLFOXIRI plus cetuximab versus bevacizumab in RAS wild-type metastatic colorectal cancer: a randomized phase II DEEPER trial. Nat Commun 15(1):10217. https:\/\/doi.org\/10.1038\/s41467-024-54460-2","journal-title":"Nat Commun"},{"key":"3101_CR13","doi-asserted-by":"publisher","first-page":"2335","DOI":"10.1056\/NEJMoa032691","volume":"3","author":"H Hurwitz","year":"2004","unstructured":"Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 3:2335\u20132342. https:\/\/doi.org\/10.1056\/NEJMoa032691","journal-title":"N Engl J Med"},{"key":"3101_CR14","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1200\/JCO.2007.14.9930","volume":"20","author":"LB Saltz","year":"2008","unstructured":"Saltz LB, Clarke S, D\u00edaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 20:2013\u20132019. https:\/\/doi.org\/10.1200\/JCO.2007.14.9930","journal-title":"J Clin Oncol"},{"issue":"13","key":"3101_CR15","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1016\/S1470-2045(15)00122-9","volume":"16","author":"C Cremolini","year":"2015","unstructured":"Cremolini C, Loupakis F, Antoniotti C et al (2015) FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 16(13):1306\u20131315. https:\/\/doi.org\/10.1016\/S1470-2045(15)00122-9","journal-title":"Lancet Oncol"},{"issue":"4","key":"3101_CR16","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S1470-2045(19)30862-9","volume":"21","author":"C Cremolini","year":"2020","unstructured":"Cremolini C, Antoniotti C, Rossini D et al (2020) Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 21(4):497\u2013507. https:\/\/doi.org\/10.1016\/S1470-2045(19)30862-9","journal-title":"Lancet Oncol"},{"issue":"2","key":"3101_CR17","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.clcc.2018.01.011","volume":"17","author":"E Oki","year":"2018","unstructured":"Oki E, Kato T, Bando H et al (2018) A multicenter clinical phase II study of FOLFOXIRI plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer: QUATTRO study. Clin Colorectal Cancer 17(2):147\u2013155. https:\/\/doi.org\/10.1016\/j.clcc.2018.01.011","journal-title":"Clin Colorectal Cancer"},{"key":"3101_CR18","doi-asserted-by":"publisher","first-page":"18811","DOI":"10.18632\/oncotarget.24702","volume":"10","author":"H Satake","year":"2018","unstructured":"Satake H, Sunakawa Y, Miyamoto Y et al (2018) A phase II trial of 1st-line modified-FOLFOXIRI plus bevacizumab treatment for metastatic colorectal cancer harboring RAS mutation: JACCRO CC-11. Oncotarget 10:18811\u201318820. https:\/\/doi.org\/10.18632\/oncotarget.24702","journal-title":"Oncotarget"},{"key":"3101_CR19","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1016\/j.medj.2024.05.012","volume":"13","author":"H Bando","year":"2024","unstructured":"Bando H, Kotani D, Satake H et al (2024) QUATTRO-II randomized trial: CAPOXIRI+bevacizumab vs. FOLFOXIRI+bevacizumab as first-line treatment in patients with mCRC. Med 13:1164-1177.e3. https:\/\/doi.org\/10.1016\/j.medj.2024.05.012","journal-title":"Med"},{"key":"3101_CR20","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1038\/sj.bjc.6605940","volume":"9","author":"C Garufi","year":"2010","unstructured":"Garufi C, Torsello A, Tumolo S et al (2010) Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer 9:1542\u20131547. https:\/\/doi.org\/10.1038\/sj.bjc.6605940","journal-title":"Br J Cancer"},{"issue":"35","key":"3101_CR21","doi-asserted-by":"publisher","first-page":"3401","DOI":"10.1200\/JCO.19.01340","volume":"37","author":"DP Modest","year":"2019","unstructured":"Modest DP, Fischer von Weikersthal L, Decker T et al (2019) FOLFOXIRI plus panitumumab as first-line treatment of RAS wild-type metastatic colorectal cancer: the randomized, open-label, phase II VOLFI study (AIO KRK0109). J Clin Oncol 37(35):3401\u20133411. https:\/\/doi.org\/10.1200\/JCO.19.01340","journal-title":"J Clin Oncol"},{"issue":"1","key":"3101_CR22","doi-asserted-by":"publisher","first-page":"e90","DOI":"10.1634\/theoncologist.2020-0563","volume":"26","author":"H Hu","year":"2021","unstructured":"Hu H, Wang K, Huang M et al (2021) Modified FOLFOXIRI with or without cetuximab as conversion therapy in patients with RAS\/BRAF wild-type unresectable liver metastases colorectal cancer: the FOCULM multicenter phase II trial. Oncologist 26(1):e90\u2013e98. https:\/\/doi.org\/10.1634\/theoncologist.2020-0563","journal-title":"Oncologist"},{"key":"3101_CR23","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.1200\/JCO.22.00839","volume":"1","author":"D Rossini","year":"2022","unstructured":"Rossini D, Antoniotti C, Lonardi S et al (2022) Upfront modified fluorouracil, leucovorin, oxaliplatin, and irinotecan plus panitumumab versus fluorouracil, leucovorin, and oxaliplatin plus panitumumab for patients with RAS\/BRAF wild-type metastatic colorectal cancer: the phase III TRIPLETE study by GONO. J Clin Oncol 1:2878\u20132888. https:\/\/doi.org\/10.1200\/JCO.22.00839","journal-title":"J Clin Oncol"},{"key":"3101_CR24","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1200\/JCO-25-01337","volume":"10","author":"V Conca","year":"2026","unstructured":"Conca V, Rossini D, Antoniotti C et al (2026) Upfront modified FOLFOXIRI plus panitumumab for RAS\/BRAF wild-type metastatic colorectal cancer: final results of the phase III TRIPLETE study. J Clin Oncol 10:361\u2013369. https:\/\/doi.org\/10.1200\/JCO-25-01337","journal-title":"J Clin Oncol"},{"key":"3101_CR25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1004389","volume":"10","author":"DS Wang","year":"2024","unstructured":"Wang DS, Ren C, Li SS et al (2024) Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS\/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): a randomized controlled trial. PLoS Med 10:e1004389. https:\/\/doi.org\/10.1371\/journal.pmed.1004389","journal-title":"PLoS Med"},{"issue":"10","key":"3101_CR26","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1016\/S1470-2045(14)70330-4","volume":"15","author":"V Heinemann","year":"2014","unstructured":"Heinemann V, von Weikersthal LF, Decker T et al (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15(10):1065\u20131075. https:\/\/doi.org\/10.1016\/S1470-2045(14)70330-4","journal-title":"Lancet Oncol"},{"issue":"3","key":"3101_CR27","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/s41416-020-01140-9","volume":"124","author":"V Heinemann","year":"2021","unstructured":"Heinemann V, von Weikersthal LF, Decker T et al (2021) FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial. Br J Cancer 124(3):587\u2013594. https:\/\/doi.org\/10.1038\/s41416-020-01140-9","journal-title":"Br J Cancer"},{"issue":"15","key":"3101_CR28","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1001\/jama.2023.4428","volume":"329","author":"J Watanabe","year":"2023","unstructured":"Watanabe J, Muro K, Shitara K et al (2023) Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: a randomized clinical trial. JAMA 329(15):1271\u20131282. https:\/\/doi.org\/10.1001\/jama.2023.4428","journal-title":"JAMA"},{"key":"3101_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2025.115399","volume":"15","author":"L Weiss","year":"2025","unstructured":"Weiss L, Stintzing S, Stahler A et al (2025) Molecular hyperselection for optimal choice of first-line targeted therapy independent of primary tumor sidedness: an exploratory analysis of the randomized FIRE-3 study performed in RAS wild-type metastatic colorectal cancer. Eur J Cancer 15:115399. https:\/\/doi.org\/10.1016\/j.ejca.2025.115399","journal-title":"Eur J Cancer"},{"issue":"3","key":"3101_CR30","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/s41591-023-02791-w","volume":"30","author":"K Shitara","year":"2024","unstructured":"Shitara K, Muro K, Watanabe J et al (2024) Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nat Med 30(3):730\u2013739. https:\/\/doi.org\/10.1038\/s41591-023-02791-w","journal-title":"Nat Med"},{"key":"3101_CR31","doi-asserted-by":"publisher","first-page":"4143","DOI":"10.1200\/JCO.22.01420","volume":"1","author":"S Stintzing","year":"2023","unstructured":"Stintzing S, Heinrich K, Tougeron D et al (2023) FOLFOXIRI plus cetuximab or bevacizumab as first-line treatment of BRAFV600E-mutant metastatic colorectal cancer: the randomized phase II FIRE-4.5 (AIO KRK0116) study. J Clin Oncol 1:4143\u20134153. https:\/\/doi.org\/10.1200\/JCO.22.01420","journal-title":"J Clin Oncol"},{"issue":"24","key":"3101_CR32","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1056\/NEJMoa2501912","volume":"392","author":"E Elez","year":"2025","unstructured":"Elez E, Yoshino T, Shen L et al (2025) Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med 392(24):2425\u20132437. https:\/\/doi.org\/10.1056\/NEJMoa2501912","journal-title":"N Engl J Med"},{"issue":"23","key":"3101_CR33","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1056\/NEJMoa2308795","volume":"389","author":"MG Fakih","year":"2023","unstructured":"Fakih MG, Salvatore L, Esaki T et al (2023) Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. N Engl J Med 389(23):2125\u20132139. https:\/\/doi.org\/10.1056\/NEJMoa2308795","journal-title":"N Engl J Med"}],"container-title":["International Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10147-026-03101-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10147-026-03101-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10147-026-03101-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T16:35:39Z","timestamp":1784997339000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10147-026-03101-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":33,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["3101"],"URL":"https:\/\/doi.org\/10.1007\/s10147-026-03101-3","relation":{},"ISSN":["1341-9625","1437-7772"],"issn-type":[{"value":"1341-9625","type":"print"},{"value":"1437-7772","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]},"assertion":[{"value":"17 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Hiroyuki Okuyama received lecture fees from Miyarisan Pharmaceutical, AstraZeneca, Novartis Pharma, Otsuka Pharmaceutical Factory, Chugai Pharmaceutical, Guardant Health Japan, Nihon Servier, Taiho\u3000Pharmaceutical, MSD, and Incyte. Akitsu Murakami received lecture fees from Terumo Corporation and Daiichi Sankyo. Yoshihiro Okita received lecture fees from Daiichi Sankyo, Eli Lilly Japan, MSD, Bristol-Myers Squibb, Takeda Pharmaceutical, Merck, Eisai, Taiho Pharmaceutical, Chugai Pharmaceutical, and Ono Pharmaceutical. Hironaga Satake reports grants from Asahi KASEI; grants and personal fees from Daiichi Sankyo Co, Ltd; Kyo Diagnostics; MSD Co, Ltd; Ono Pharmaceutical Co, Ltd; Taiho Pharmaceutical Co, Ltd; and Takeda Pharmaceutical Co, Ltd; and personal fees from Astellas Pharma; AstraZeneca plc; Bayer Co, Ltd; Bristol-Myers Squibb Co, Ltd; Chugai Pharmaceutical Co, Ltd; Eli Lilly Japan Co, Ltd; Merck Bio Pharma Co, Ltd; Sanofi Co, Ltd; Yakult Honsha Co, Ltd (Takata Pharmaceutical Co. Ltd.). outside the submitted work. Takeshi Kato received lecture fees from LTT Bio-Pharma Co., Ltd.; Amgen K.K.; Bristol Myers Squibb; Miyarisan Pharmaceutical Co., Ltd.; Asahi Kasei Pharma Corporation; Ono Pharmaceutical Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Eli Lilly Japan K.K.; and Takeda Pharmaceutical Company Limited. Akihito Tsuji received lecture fees from Asahi Kasei Corporation, AstraZeneca, Eisai, Ono Pharmaceutical, Sun Pharmaceutical Industries Limited, Taiho Pharmaceutical, Chugai Pharmaceutical, Terumo Corporation, Nippon Zoki Pharmaceutical, Bayer Yakuhin, Bristol-Myers Squibb, Merck Biopharma, Takata Pharmaceutical, Zeria Pharmaceutical, LTT Bio-Pharma, Astellas Pharma, MSD, Guardant Health Japan, Daiichi Sankyo, Takeda Pharmaceutical, Tsumura, Eli Lilly Japan, Novartis Pharma, Pfizer Japan, MedPeer, Yakult Honsha, Nihon Servier, EA Pharma, and Sawai Pharmaceutical. Akihito Tsuji participated in advisory boards for Shanghai Henlius Biotech and FeliMedix. Hiroki Sakuyama, Yoriyuki Tahara, Sena Tsukamoto, Ikuhiro Kita and Kotone Nomura have no conflicts of interest.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":4,"name":"Ethics","label":"Consent to publish","group":{"name":"EthicsHeading","label":"Declarations"}}]}}