Management of hypertension during lenvatinib for advanced thyroid cancer: a suggested diagnostic and therapeutic algorithm

Figures

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  Figure 1. Prevalence and grade of hypertension (HTN) in patients treated with lenvatinib (LEN). 22/29 patients developed HTN during treatment. Considering severity according to Common Terminology Criteria for Adverse Events (CTCAE) v.5.0, 1/22 (5%) had HTN of grade 1, 11/22 (50%) of grade 2 and 10/22 (45%) of grade 3.

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  Figure 2. (A) Correlation between hypertension (HTN) and lenvatinib (LEN) dosage. Linear regression analysis showed that the grade of HTN positively correlated with LEN dose (P = 0.011). (B) Correlation between HTN, proteinuria and diarrhoea during treatment with LEN. There was no significant correlation between HTN and proteinuria (P = 0.187), while LEN-induced HTN had a significant positive correlation with diarrhoea (P = 0.025).

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  Figure 3. Patients who developed hypertension (HTN) during lenvatinib (LEN) treatment did not have a significant higher prevalence of cardiovascular disease (pre-existing HTN and/or myocardial infarction and/or valvulopathies) prior to the start of the drug compared with patients who did not develop HTN (8 out of 22, 36% vs 5 out of 7, 71%; P = 0.104). A response to LEN treatment (measured according to RECIST criteria) was not different between patients who developed or did not develop HTN (82% and 100%, respectively). In particular, complete response, partial response and stable disease were observed in 0%, 64% and 18% of patients with HTN and in 0%, 86% and 14% of patients without HTN, respectively (P = NS). In addition, there was no significant correlation between HTN and other clinico-pathological features analysed. AJCC, American Joint Committee on Cancer eighth edition staging system; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; NS, not significant.

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  Figure 4. Panel A: (a) 21/22 (95%) patients were on anti-hypertensive treatment: 1/21 in monotherapy and 20/21 in polytherapy; (b) the only patient in monotherapy was on calcium channel blocker (CCB); (c) four of five patients treated with two drugs were well controlled with CCB + angiotensin-converting inhibitor (ACE-i)/beta-blocker (BB) (three cases) or with ACE-i/BB (one case); (d) nine of ten patients controlled with three drugs were on CCB + angiotensin receptor blocker (ARB)/ACE-i and other drug; (e) only three of five patients treated with more than four drugs were controlled. Panel B: CCBs were the most common drugs, used in 17/21 patients, either in monotherapy (5% of cases) or, in case of poor pressure control, in association with other anti-hypertensive drugs as ACE-i or BB (14%), with ARB/ACE-i + other anti-hypertensive drug (43%) or with a total of four anti-hypertensive drugs in 24% of patients.

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  Figure 5. Graphical illustrations of the potential mechanisms underlying multityrosine kinase inhibitor (MKI)-induced hypertension (HTN) and proteinuria and the deriving suggested treatments in patients developing these adverse events. In addition, a diagnostic and therapeutic algorithm is suggested to be applied in clinical practice in the management of patients with MKI-induced HTN. AB, alpha-blockers; ACE-i, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BP, blood pressure; Ca, calcium; CCB, calcium channel blockers; D, diuretics; NO, nitric oxide; VEGF, vascular endothelial growth factor; VGCC, voltage-gated calcium channels.