Blood pressure elevations post-lenvatinib treatment in hepatocellular carcinoma: a potential marker for better prognosis. - National Genomics Data Center (CNCB-NGDC)

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Blood pressure elevations post-lenvatinib treatment in hepatocellular carcinoma: a potential marker for better prognosis.

Keisuke Shibata, Yuichi Akasaki, Akihiro Tokushige, Mina Nitta, Shin Kawasoe, Takuro Kubozono, Kohei Oda, Kotaro Kumagai, Seiichi Mawatari, Mitsuru Ohishi

Author Information

Keisuke Shibata: Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Yuichi Akasaki: Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. yuichia@m2.kufm.kagoshima-u.ac.jp.
Akihiro Tokushige: Department of Prevention and Analysis of Cardiovascular Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Mina Nitta: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Shin Kawasoe: Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Takuro Kubozono: Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Kohei Oda: Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Kotaro Kumagai: Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Seiichi Mawatari: Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Mitsuru Ohishi: Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

PMID: 39966607 DOI: 10.1038/s41440-025-02149-4

lenvatinib is a tyrosine kinase inhibitor that effectively inhibits vascular endothelial growth factor signaling and is used for treating hepatocellular carcinoma. However, angiogenesis inhibitors often cause hypertension. Although lenvatinib-induced hypertension has been proposed as a potential surrogate marker for better prognosis, studies on Blood pressure elevations and outcomes following lenvatinib initiation are limited. This study included 67 patients who underwent lenvatinib therapy at the Department of Gastroenterology, Kagoshima University Hospital, between May 2018 and December 2023. The median age of the cohort was 71 years, and 82.1% of the patients were male. The median Blood pressure at admission was 128/73��mmHg, which significantly increased to 136/76��mmHg the day after lenvatinib administration. Grade 3 hypertension (��160/100��mmHg) occurred in 37.3% of patients during hospitalization. The median increase in systolic Blood pressure from admission to its peak during hospitalization was 26��mmHg. patients who experienced an increase in Blood pressure of ��26��mmHg were classified into the Blood pressure elevation group, which showed a significantly lower mortality rate than that of the Blood pressure non-elevation group (35.3% vs. 81.8%, log-rank p��=��0.007), even after adjusting for age, sex, disease stage, performance status, and liver reserve function. This study demonstrated that patients who experienced earlier Blood pressure elevation after lenvatinib administration had lower overall mortality rates. These findings suggest that Blood pressure elevations after lenvatinib initiation may serve as valuable prognostic indicators in patients with cancer undergoing lenvatinib therapy. �� Early Blood pressure Elevation Following lenvatinib Administration Significant Blood pressure elevation was observed from the day after lenvatinib administration, with a median systolic Blood pressure increase of 26��mmHg. Grade 3 hypertension (��160/100��mmHg) was observed in 38% of patients during hospitalization. ��Blood pressure Control Antihypertensive therapy was intensified in 39% of patients during hospitalization, yet 12% still had Grade 3 hypertension the day before discharge. �� Association Between Blood pressure Elevation and Prognosis Even after adjusting for age, sex, disease stage, performance status, and liver function reserve, Blood pressure elevation was suggested as a better prognostic factor.

Lenvatinib Onco-Hypertension VEGF Inhibitors

Kidoguchi S, Sugano N, Tokudome G, Yokoo T, Yano Y, Hatake K, et al. New concept of onco-hypertension and future perspectives. Hypertension. 2021;77:16��27. [DOI: 10.1161/HYPERTENSIONAHA.120.16044]
Azegami T, Kaneko H, Minegishi S, Suzuki Y, Morita H, Fujiu K, et al. Current status and future perspective of onco-hypertension. Am J Hypertens. 2024;38:1��6. [DOI: 10.1093/ajh/hpae099]
Stocks T, Van Hemelrijck M, Manjer J, Bj��rge T, Ulmer H, Hallmans G, et al. Blood pressure and risk of cancer incidence and mortality in the metabolic syndrome and cancer project. Hypertension. 2012;59:802��10. [DOI: 10.1161/HYPERTENSIONAHA.111.189258]
Capitanio U, Bensalah K, Bex A, Boorjian SA, Bray F, Coleman J, et al. Epidemiology of renal cell carcinoma. Eur Urol. 2019;75:74��84. [DOI: 10.1016/j.eururo.2018.08.036]
Ikuerowo SO, Ojewuyi OO, Omisanjo OA, Abolarinwa AA, Bioku MJ, Doherty AF. Paraneoplastic syndromes and oncological outcomes in renal cancer. Niger J Clin Pract. 2019;22:1271��5. [DOI: 10.4103/njcp.njcp_35_19]
Cohen JB, Geara AS, Hogan JJ, Townsend RR. Hypertension in cancer patients and survivors: epidemiology, diagnosis, and management. JACC Cardiooncol. 2019;1:238��51. [DOI: 10.1016/j.jaccao.2019.11.009]
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182��6. [DOI: 10.1056/NEJM197111182852108]
Cohen JB, Brown NJ, Brown SA, Dent S, van Dorst DCH, Herrmann SM, et al. Cancer therapy-related hypertension: a scientific statement from the American Heart Association. Hypertension. 2023;80:e46��57. [DOI: 10.1161/HYP.0000000000000224]
van Dorst DCH, Dobbin SJH, Neves KB, Herrmann J, Herrmann SM, Versmissen J, et al. Hypertension and prohypertensive antineoplastic therapies in cancer patients. Circ Res. 2021;128:1040��61. [DOI: 10.1161/CIRCRESAHA.121.318051]
National Cancer Institute. Protocol development. Cancer therapy evaluation program. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm . Accessed 9 Sep 2024.
Kim BH, Yu SJ, Kang W, Cho SB, Park SY, Kim SU, et al. Expert consensus on the management of adverse events in patients receiving lenvatinib for hepatocellular carcinoma. J Gastroenterol Hepatol. 2022;37:428��39. [DOI: 10.1111/jgh.15727]
Lyon AR, L��pez-Fern��ndez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43:4229��361. [DOI: 10.1093/eurheartj/ehac244]
Scartozzi M, Galizia E, Chiorrini S, Giampieri R, Berardi R, Pierantoni C, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol. 2009;20:227��30. [DOI: 10.1093/annonc/mdn637]
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163��73. [DOI: 10.1016/S0140-6736(18)30207-1]
Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020;55:113��22. [DOI: 10.1007/s00535-019-01642-1]
Wirth LJ, Tahara M, Robinson B, Francis S, Brose MS, Habra MA, et al. Treatment-emergent hypertension and efficacy in the phase 3 Study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). Cancer. 2018;124:2365��72. [DOI: 10.1002/cncr.31344]
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649��55. [DOI: 10.1097/00000421-198212000-00014]
Hiraoka A, Kumada T, Tsuji K, Takaguchi K, Itobayashi E, Kariyama K, et al. Validation of modified ALBI grade for more detailed assessment of hepatic function in hepatocellular carcinoma patients: a multicenter analysis. Liver Cancer. 2019;8:121��9. [DOI: 10.1159/000488778]
Li W, Croce K, Steensma DP, McDermott DF, Ben-Yehuda O, Moslehi J. Vascular and metabolic implications of novel targeted cancer therapies: focus on kinase inhibitors. J Am Coll Cardiol. 2015;66:1160��78. [DOI: 10.1016/j.jacc.2015.07.025]
Shibutani Y, Tajiri K, Suzuki S, Enokida T, Sagara A, Okano S, et al. Association between baseline blood pressure and the incidence of lenvatinib-induced hypertension in patients with thyroid cancer. Cancer Med. 2023;12:20773��82. [DOI: 10.1002/cam4.6644]
Piscaglia F, Ikeda K, Cheng AL, Kudo M, Ikeda M, Breder V, et al. Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study. Cancer. 2024;130:1281��91. [DOI: 10.1002/cncr.35185]
Rapposelli IG, Tada T, Shimose S, Burgio V, Kumada T, Iwamoto H, et al. Adverse events as potential predictive factors of activity in patients with advanced hepatocellular carcinoma treated with lenvatinib. Liver Int. 2021;41:2997��3008. [DOI: 10.1111/liv.15014]
Shimose S, Iwamoto H, Niizeki T, Shirono T, Noda Y, Kamachi N, et al. Clinical significance of adverse events for patients with unresectable hepatocellular carcinoma treated with lenvatinib: a multicenter retrospective study. Cancers. 2020;12:1867. [DOI: 10.3390/cancers12071867]
Wang P, Tan G, Zhu M, Li W, Zhai B, Sun X. Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2018;12:1��8. [DOI: 10.1080/17474124.2017.1373018]
Mir O, Ropert S, Alexandre J, Goldwasser F. Hypertension as a surrogate marker for the activity of anti-VEGF agents. Ann Oncol. 2009;20:967��70. [DOI: 10.1093/annonc/mdp206]
Nagahama M, Ozeki T, Suzuki A, Sugino K, Niioka T, Ito K, et al. Association of lenvatinib trough plasma concentrations with lenvatinib-induced toxicities in Japanese patients with thyroid cancer. Med Oncol. 2019;36:39. [DOI: 10.1007/s12032-019-1263-3]
Yang X, Chen B, Wang Y, Wang Y, Long J, Zhang N, et al. Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients. Hepatol Int. 2023;17:709��19. [DOI: 10.1007/s12072-022-10480-y]
Hiraoka A, Kumada T, Atsukawa M, Hirooka M, Tsuji K, Ishikawa T, et al. Prognostic factor of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions-Multicenter analysis. Cancer Med. 2019;8:3719��28. [DOI: 10.1002/cam4.2241]
Dai S, Zhong Y, Cui H, Zhao J, Li S. Aortic dissection induced by vascular endothelial growth factor inhibitors. Front Pharmacol. 2023;14:1189910. [DOI: 10.3389/fphar.2023.1189910]
Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103:763��73. [DOI: 10.1093/jnci/djr128]

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