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. 2018 Dec 28;11(1):30.
doi: 10.3390/cancers11010030.

Effects of Antiangiogenetic Drugs on Microcirculation and Macrocirculation in Patients with Advanced-Stage Renal Cancer

Andrea Dalbeni  1 , Chiara Ciccarese  2   3 , Michele Bevilacqua  4 , Marco Benati  5 , Cristian Caimmi  6 , Luca Cerrito  7 , Federico Famà  8 , Roberto Iacovelli  9   10 , Anna Mantovani  11 , Francesco Massari Alessandra Meneguzzi  12   13 , Pietro Minuz  14 , Martina Montagnana  15 , Giovanni Orsolini  16 , Maurizio Rossini  17 , Gianpaolo Tortora  18   19 , Ombretta Viapiana  20 , Cristiano Fava  21
Affiliations

Effects of Antiangiogenetic Drugs on Microcirculation and Macrocirculation in Patients with Advanced-Stage Renal Cancer

Andrea Dalbeni et al. Cancers (Basel). .

Abstract

Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1⁻T0 ≥10 and/or SBP ≥140 mmHg and/or diastolic blood pressure (DBP) T1⁻T0 ≥5 and/or DBP ≥90 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population.

Keywords: NO (Nitric Oxide); TKI; VEGF; angiogenesis; capillaroscopy; endothelin-1; hypertension; renal cancer.

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Conflict of interest statement

The authors have nothing to declare; in particular any financial support or other benefits from commercial sources for the work reported on in the manuscript, or any other financial interests that any of the authors may have, which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work.

Figures

Figure 1
Figure 1
Nitrate/creatinine ratio at baseline and at T1 in the whole sample and in the two subgroups defined according to the sensitivity of BP to TKI therapy. TKI SENS = TKI-sensitive patients; TKI INS = TKI-insensitive patients, BP: blood pressure, n.s: no significant.
Figure 2
Figure 2
Protein/creatinine ratio at baseline and at T1 in the whole sample and in the two subgroups defined according to the sensitivity of BP to TKI therapy. n.s: no significant.
Figure 3
Figure 3
Endothelin-1 (ET-1) at baseline and at T1 in the whole sample and in the two subgroups defined according to the sensitivity of BP to TKI therapy n.s: no significant.
Figure 4
Figure 4
Representative capillaroscopic images at the beginning of antiangiogenic therapy (a) and at T1 (b): tortuosity and architectural disorder are shown after one month of therapy (magnification: 100× to 1000×)
Figure 5
Figure 5
Effects of antiangiogenic therapy in terms of moderate dimensional reduction of pulmonary metastasis (in patients from December 2016 to March 2017).
Figure 6
Figure 6
Kaplan–Meier curve of progression-free survival (PFS) (a) and overall survival (OS) (b) in participants treated with first-line therapy.
See this image and copyright information in PMC

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