{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:25:59Z","timestamp":1792290359841,"version":"4.4.0"},"reference-count":28,"publisher":"Harborside Press, LLC","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Although VEGFR tyrosine kinase inhibitors (TKIs) are a preferred systemic treatment approach for patients with advanced renal cell carcinoma (RCC) and thyroid carcinoma (TC), treatment-related cardiovascular (CV) toxicity is an important contributor to morbidity. However, the clinical risk assessment and impact of CV toxicities, including early significant hypertension, among real-world advanced cancer populations receiving VEGFR TKI therapies remain understudied. <jats:bold>Methods:<\/jats:bold> In a multicenter, retrospective cohort study across 3 large and diverse US health systems, we characterized baseline hypertension and CV comorbidity in patients with RCC and those with TC who are newly initiating VEGFR TKI therapy. We also evaluated baseline patient-, treatment-, and disease-related factors associated with the risk for treatment-related early hypertension (within 6 weeks of TKI initiation) and major adverse CV events (MACE), accounting for the competing risk of death in an advanced cancer population, after VEGFR TKI initiation. <jats:bold>Results:<\/jats:bold> Between 2008 and 2020, 987 patients (80.3% with RCC, 19.7% with TC) initiated VEGFR TKI therapy. The baseline prevalence of hypertension was high (61.5% and 53.6% in patients with RCC and TC, respectively). Adverse CV events, including heart failure and cerebrovascular accident, were common (occurring in 14.9% of patients) and frequently occurred early (46.3% occurred within 1 year of VEGFR TKI initiation). Baseline hypertension and Black race were the primary clinical factors associated with increased acute hypertensive risk within 6 weeks of VEGFR TKI initiation. However, early significant \u201con-treatment\u201d hypertension was not associated with MACE. <jats:bold>Conclusions:<\/jats:bold> These multicenter, real-world findings indicate that hypertensive and CV morbidities are highly prevalent among patients initiating VEGFR TKI therapies, and baseline hypertension and Black race represent the primary clinical factors associated with VEGFR TKI\u2013related early significant hypertension. However, early on-treatment hypertension was not associated with MACE, and cancer-specific CV risk algorithms may be warranted for patients initiating VEGFR TKIs.<\/jats:p>","DOI":"10.6004\/jnccn.2023.7047","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T19:27:24Z","timestamp":1697138844000},"page":"1039-1049.e10","source":"Crossref","is-referenced-by-count":15,"title":["Early Increases in Blood Pressure and Major Adverse Cardiovascular Events in Patients With Renal Cell Carcinoma and Thyroid Cancer Treated With VEGFR TKIs"],"prefix":"10.6004","volume":"21","author":[{"given":"Vivek","family":"Narayan","sequence":"first","affiliation":[{"name":"Division of Hematology\/Medical Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Statistical Sciences, Department of Biostatistics, Brown University School of Public Health, Providence, Rhode Island"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjie","family":"Song","sequence":"additional","affiliation":[{"name":"Center for Statistical Sciences, Department of Biostatistics, Brown University School of Public Health, Providence, Rhode Island"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Cardio-Oncology Center of Excellence, Washington University in St. Louis, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JoRean","family":"Sicks","sequence":"additional","affiliation":[{"name":"Center for Statistical Sciences, Department of Biostatistics, Brown University School of Public Health, Providence, Rhode Island"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilana","family":"Gareen","sequence":"additional","affiliation":[{"name":"Center for Statistical Sciences, Department of Biostatistics, Brown University School of Public Health, Providence, Rhode Island"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lova","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Medical Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas","family":"Denduluri","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciaran","family":"Fisher","sequence":"additional","affiliation":[{"name":"Geisinger Cancer Institute, Geisinger Medical Center, Danville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Manikowski","sequence":"additional","affiliation":[{"name":"Geisinger Cancer Institute, Geisinger Medical Center, Danville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Wojtowicz","sequence":"additional","affiliation":[{"name":"Geisinger Cancer Institute, Geisinger Medical Center, Danville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Vadakara","sequence":"additional","affiliation":[{"name":"Geisinger Cancer Institute, Geisinger Medical Center, Danville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Haas","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Medical Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth B.","family":"Margulies","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie","family":"Ky","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Department of 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J Am Coll Cardiol 2015;66:1160\u20131178."},{"key":"B2","series-title":"Clin Adv Hematol Oncol","first-page":"7","article-title":"Sequencing of tyrosine kinase inhibitors in progressive differentiated thyroid cancer","volume":"14","author":"Brose MS","year":"2016","unstructured":"Brose MS. Sequencing of tyrosine kinase inhibitors in progressive differentiated thyroid cancer. Clin Adv Hematol Oncol 2016;14(Suppl 9):7\u201312."},{"key":"B3","series-title":"N Engl J Med","first-page":"829","article-title":"Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma","volume":"384","author":"Choueiri TK","year":"2021","unstructured":"Choueiri TK, Powles T, Burotto M,  Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829\u2013841."},{"key":"B4","series-title":"N Engl J Med","first-page":"1289","article-title":"Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma","volume":"384","author":"Motzer R","year":"2021","unstructured":"Motzer R, Alekseev B, Rha SY,  Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384:1289\u20131300."},{"key":"B5","series-title":"JACC CardioOncol","first-page":"271","article-title":"How to treat renal cell carcinoma: the current treatment landscape and cardiovascular toxicities","volume":"4","author":"Castro DV","year":"2022","unstructured":"Castro DV, Malhotra J, Meza L,  How to treat renal cell carcinoma: the current treatment landscape and cardiovascular toxicities. JACC CardioOncol 2022;4:271\u2013275."},{"key":"B6","series-title":"Annu Rev Med","first-page":"97","article-title":"Common cardiovascular complications of cancer therapy: epidemiology, risk prediction, and prevention","volume":"69","author":"Narayan V","year":"2018","unstructured":"Narayan V, Ky B. Common cardiovascular complications of cancer therapy: epidemiology, risk prediction, and prevention. Annu Rev Med 2018;69:97\u2013111."},{"key":"B7","series-title":"JACC CardioOncol","first-page":"223","article-title":"Major adverse cardiovascular events in patients with renal cell carcinoma treated with targeted therapies","volume":"4","author":"Chen DY","year":"2022","unstructured":"Chen DY, Liu JR, Tseng CN,  Major adverse cardiovascular events in patients with renal cell carcinoma treated with targeted therapies. JACC CardioOncol 2022;4:223\u2013234."},{"key":"B8","series-title":"JACC Heart Fail","first-page":"72","article-title":"The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients","volume":"1","author":"Hall PS","year":"2013","unstructured":"Hall PS, Harshman LC, Srinivas S,  The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail 2013;1:72\u201378."},{"key":"B9","series-title":"N Engl J Med","first-page":"621","article-title":"Lenvatinib versus placebo in radioiodine-refractory thyroid cancer","volume":"372","author":"Schlumberger M","year":"2015","unstructured":"Schlumberger M, Tahara M, Wirth LJ,  Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621\u2013630."},{"key":"B10","series-title":"J Natl Cancer Inst","first-page":"763","article-title":"Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib","volume":"103","author":"Rini BI","year":"2011","unstructured":"Rini BI, Cohen DP, Lu DR,  Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103:763\u2013773."},{"key":"B11","series-title":"Clin Cancer Res","first-page":"3841","article-title":"Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors","volume":"17","author":"Rini BI","year":"2011","unstructured":"Rini BI, Schiller JH, Fruehauf JP,  Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. 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Cancer 2018;124:2365\u20132372."},{"key":"B13","series-title":"JAMA","first-page":"507","article-title":"2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8)","volume":"311","author":"James PA","year":"2014","unstructured":"James PA, Oparil S, Carter BL,  2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507\u2013520."},{"key":"B14","series-title":"Cancer","first-page":"311","article-title":"Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway","volume":"121","author":"Hamnvik OP","year":"2015","unstructured":"Hamnvik OP, Choueiri TK, Turchin A,  Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer 2015;121:311\u2013319."},{"key":"B15","series-title":"ESMO Open","first-page":"100338","article-title":"Major adverse cardiovascular events associated with VEGF-targeted anticancer tyrosine kinase inhibitors: a real-life study and proposed algorithm for proactive management","volume":"7","author":"Vallerio P","year":"2022","unstructured":"Vallerio P, Orenti A, Tosi F,  Major adverse cardiovascular events associated with VEGF-targeted anticancer tyrosine kinase inhibitors: a real-life study and proposed algorithm for proactive management. ESMO Open 2022;7:100338."},{"key":"B16","series-title":"Hypertension","first-page":"539","article-title":"Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification","volume":"35","author":"Ogden LG","year":"2000","unstructured":"Ogden LG, He J, Lydick E,  Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. 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Ann Intern Med 2009;150:604\u2013612."},{"key":"B20","series-title":"J Clin Oncol","first-page":"5794","article-title":"Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study","volume":"27","author":"Heng DY","year":"2009","unstructured":"Heng DY, Xie W, Regan MM,  Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. 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N Engl J Med 2015;373:2103\u20132116."},{"key":"B23","article-title":"Prescribing information for sunitinib malate capsules, oral","year":"2011","unstructured":"Prescribing information for sunitinib malate capsules, oral. 2011. Accessed May 1, 2023. Available at: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2011\/021938s13s17s18lbl.pdf"},{"key":"B24","series-title":"Eur Heart J","first-page":"4229","article-title":"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)","volume":"43","author":"Lyon AR","year":"2022","unstructured":"Lyon AR, L\u00f3pez-Fern\u00e1ndez T, Couch LS,  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). 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