Sunitinib-induced Hypertension Research Articles

Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension.

Antiangiogenic tyrosine kinases inhibitors induce hypertension, which may increase the incidents of cardiovascular complications and limit their use. However, the mechanisms by which usage of TKIs results in hypertension have not been fully understood. Here, we report the potential mechanisms of how sunitinib, a widely used TKI, induces hypertension. Male SD rats were randomly divided into control group and sunitinib-administrated group. We show that sunitinib administration for seven days caused a significant increase in artery blood pressure, along with glycerolipid metabolism abnormalities including decreased food intake and low body weight, hypoglycemia, hyperinsulinemia. Sunitinib administration also resulted in a significant increase in the levels of insulin autoantibody (IAA), cyclic adenosine monophosphate and free fatty acid in serum; whereas, sunitinib administration had no effects on serum glucagon levels. Sunitinib led to the decreased insulin sensitivity as determined by insulin tolerance test (ITT) and glucose tolerance test (GTT), reflecting insulin resistance occurred in sunitinib-treated rats. The results obtained from wire myograph assay in the mesenteric arteries show that endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired by sunitinib. Furthermore, western blot analysis revealed that the expressions levels of phosphorylated IRS-1, Pellino-1, AKT and eNOS were significantly attenuated by sunitinib in rat mesenteric artery tissues and in the sunitinib-treated primary cultured mesenteric artery endothelial cells. The levels of serum and endothelium-derived nitric oxide were also significantly decreased by sunitinib. Moreover, sunitinib-induced decrease in the expression levels of phosphorylated AKT and eNOS was further reduced by knocking down of Pellino-1 in MAECs. Our results suggest that sunitinib causes vascular dysfunction and hypertension, which are associated with insulin resistance- and Pellino-1-mediated inhibition of AKT/eNOS/NO signaling. Our results may provide a rational for preventing and/or treating sunitinib-induced endothelial dysfunction and hypertension.

Meta-Analysis of ABCG2 and ABCB1 Polymorphisms With Sunitinib-Induced Toxicity and Efficacy in Renal Cell Carcinoma.

Background: ABCG2 and ABCB1 are genes related to the pharmacokinetics of sunitinib and have been associated with its toxicity and efficacy. However, the results have been controversial. This study aimed to evaluate the associations of ABCG2 and ABCB1 polymorphisms with sunitinib-induced toxicity and efficacy in renal cell carcinoma (RCC) by meta-analysis. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for studies investigating the associations of the ABCG2 rs2231142 polymorphism with sunitinib-induced toxicity and the associations of the ABCB1 rs1128503 and ABCB1 rs2032582 polymorphisms with sunitinib-induced toxicity and clinical outcomes. The associations were evaluated by effect size (ES) with 95% confidence intervals (CIs). Results: Eight and five studies were included in the toxicity and efficacy analysis, respectively, including a total of 1081 RCC patients. The ABCG2 rs2231142 A allele was associated with an increased risk of sunitinib-induced thrombocytopenia and hand-foot syndrome (HFS) in Asians (ES = 1.65, 95% CI = 1.15–2.36, p = 0.006; ES = 1.52, 95% CI = 1.02–2.27, p = 0.041). However, the ABCG2 rs2231142 polymorphism was not associated with sunitinib-induced hypertension or neutropenia (ES = 1.09, 95% CI = 0.69–1.73, p = 0.701; ES = 0.87, 95% CI = 0.57–1.31, p = 0.501). Compared with the C allele, the ABCB1 rs1128503 T allele was associated with a decreased risk of sunitinib-induced hypertension but worse progression-free survival (PFS) (ES = 0.44, 95% CI = 0.26–0.77, p = 0.004; ES = 1.36, 95% CI = 1.07–1.73, p = 0.011). There was no significant association between the T allele or C allele of ABCB1 rs1128503 and overall survival (OS) (ES = 0.82, 95% CI = 0.61–1.10, p = 0.184). The ABCB1 rs2032582 T allele was associated with worse PFS than the other alleles (ES = 1.46, 95% CI = 1.14–1.87, p = 0.003), while there was no significant association between the T allele or other alleles and sunitinib-induced hypertension, HFS, or OS (ES = 0.77, 95% CI = 0.46–1.29, p = 0.326; ES = 1.02, 95% CI = 0.65–1.62, p = 0.919; ES = 1.32, 95% CI = 0.85–2.05, p = 0.215). Conclusion: The results indicate that the ABCG2 rs2231142 polymorphism may serve as a predictor of sunitinib-induced thrombocytopenia and HFS in Asians, while the ABCB1 rs1128503 polymorphism may serve as a predictor of sunitinib-induced hypertension, and both the ABCB1 rs1128503 and rs2032582 polymorphisms may serve as predictors of PFS in RCC. These results suggest a possible application of individualized use of sunitinib according to the genetic background of patients.

Sunitinib-induced cardiac hypertrophy and the endothelin axis.

Anti-angiogenics drugs in clinical use for cancer treatment induce cardiotoxic side effects. The endothelin axis is involved in hypertension and cardiac remodelling, and addition of an endothelin receptor antagonist to the anti-angiogenic sunitinib was shown to reduce cardiotoxicity of sunitinib in mice. Here, we explored further the antidote effect of the endothelin receptor antagonist macitentan in sunitinib-treated animals on cardiac remodeling.Methods: Tumor-bearing mice treated per os daily by sunitinib or vehicle were imaged before and after 1, 3 and 6 weeks of treatment by positron emission tomography using [18F]fluorodeoxyglucose and by echocardiography. Non-tumor-bearing animals were randomly assigned to be treated per os daily by vehicle or sunitinib or macitentan or sunitinib+macitentan, and imaged by echocardiography after 5 weeks. Hearts were harvested for histology and molecular analysis at the end of in vivo exploration.Results: Sunitinib treatment increases left ventricular mass and ejection fraction and induces cardiac fibrosis. Sunitinib also induces an early increase in cardiac uptake of [18F]fluorodeoxyglucose, which is significantly correlated with increased left ventricular mass at the end of treatment. Co-administration of macitentan prevents sunitinib-induced hypertension, increase in ejection fraction and cardiac fibrosis, but fails to prevent increase of the left ventricular mass.Conclusion: Early metabolic changes predict sunitinib-induced cardiac remodeling. Endothelin blockade can prevent some but not all cardiotoxic side-effects of sunitinib, in particular left ventricle hypertrophy that appears to be induced by sunitinib through an endothelin-independent mechanism.

PK/PD modeling based on NO-ET homeostasis for improving management of sunitinib-induced hypertension in rats

Sunitinib is an oral small molecule multitargeted tyrosine kinase inhibitor, which is currently used to treat severe cancers. Clinical research has shown that patients treated with sunitinib develop hypertension. As soon as sunitinib-induced hypertension appears, it is usual to administer anti-hypertension agent. But this treatment may cause acute blood pressure fluctuation which may lead to additional cardiovascular risk. The aim of this study is to establish a mathematical model for managing sunitinib-induced hypertension and blood pressure fluctuation. A mechanism-based PK/PD model was developed based on animal experiments. Then this model was used to perform simulations, thus to propose an anti-hypertension indication, according to which the anti-hypertension treatment might yield relative low-level AUC and fluctuation of blood pressure. The simulation results suggest that the anti-hypertension agent may yield low-level AUC and fluctuation of blood pressure when relative ET-1 level ranges from −15% to 5% and relative NO level is more than 10% compared to control group. Finally, animal experiments were conducted to verify the simulation results. Macitentan (30 mg/kg) was administered based on the above anti-hypertension indication. Compared with the untreated group, the optimized treatment significantly reduced the AUC of blood pressure; meanwhile the fluctuation of blood pressure in optimized treatment group was 70% less than that in immediate treatment group. This work provides a novel model with potential translational value for managing sunitinib-induced hypertension.

The role of distal tubule and collecting duct sodium reabsorption in sunitinib-induced hypertension.

Antiangiogenic receptor tyrosine kinase inhibitors (RTKI) induce arterial hypertension which may limit their use. Renal fractional sodium excretion (FENa) is reduced in early RTKI-induced hypertension, whereas fractional lithium excretion is unaltered. Therefore, we tested the hypothesis that activated distal tubule and collecting duct sodium reabsorption contributes to RTKI-induced hypertension. Amiloride-sensitive and hydrochlorothiazide (HCTZ)-sensitive fractional sodium reabsorption (FRNa) and renal epithelial sodium channel (ENaC) as well as sodium chloride cotransporter (NCC) abundances were determined in sunitinib-treated and control rats. The antihypertensive effects of amiloride and HCTZ were investigated by radiotelemery. After 4 days of treatment, mean arterial pressure was 20 mmHg higher, FENa was lower (0.32 ± 0.08% vs. 0.65 ± 0.14%; P < 0.05), and renal medullary-ENaC protein abundance was higher in sunitinib-treated rats than in controls. Amiloride-sensitive FRNa was 2.37 ± 0.52% in sunitinib-treated rats vs. 2.66 ± 0.44% in controls (n.s.). HCTZ increased FENa by a similar magnitude without affecting amiloride-sensitive FRNa in both groups. After 14 days of treatment, renal medullary β-ENaC protein abundance was higher in rats that received sunitinib than in controls, whereas α-ENaC, γ-ENaC, and NCC abundances were similar in both groups. Amiloride and HCTZ reduced the sunitinib-induced mean arterial pressure rise by 8 ± 3 mmHg (P < 0.05) and 12 ± 2 mmHg (P < 0.05), respectively, without additive effects when combined. ENaC-dependent and thiazide-sensitive sodium-retaining mechanisms are not overactive in sunitinib-induced hypertension but ENaC blockers and in particular thiazides may be suitable for its treatment.

Abstract P186: Selective ET A Receptor Antagonism versus Dual ET A /ET B Receptor Blockade for Preventing Angiogenesis Inhibitor-induced Hypertension

Angiogenesis inhibitors are a mainstay treatment for cancer. While effective in preventing tumor growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin-1 (ET-1) upregulation. ET-1 via stimulation of the ET A receptor causes pro-hypertensive effects whereas stimulation of the ET B receptor can elicit both pro- or anti-hypertensive effects. In the present study, we hypothesized that selective ET A receptor blockade versus dual ET A /ET B blockade provides better cardiovascular protection from angiogenesis inhibitor-induced hypertension. Male WKY rats were treated with vehicle, sunitinib (VEGF inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ET A/B receptor antagonist; 30 mg/kg/day) or sitaxentan (ET A receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry at baseline and days 1-6 of treatment. Vasoreactivity to acetylcholine (ACh) and ET-1 was assessed in iliac vessels. Compared to vehicle treatment, sunitinib treatment caused a rapid and sustained increase in MAP (1±1 versus 23±2 mmHg on day 6 of treatment, respectively, P&lt;0.001). Co-treatment with macitentan blunted the pressor response to sunitinib, such that on day 6 of treatment the increase in MAP was 7±4 mmHg (P&lt;0.01 versus sunitinib-treated). Similar results were observed for co-treatment with 30 mg/kg/day of sitaxentan. Conversely, co-treatment with 100 mg/kg/day sitaxentan, which has been shown to induce a depressor response in normotensive Wistar rats, completely abolished sunitinib-induced hypertension, with MAP actually decreasing before returning to near baseline level (-1±1 mmHg on day 6 of treatment, P&lt;0.001 versus sunitinib-treated). Compared to vehicle treatment, ET B receptor stimulation yielded a constrictor response after 8 days of sunitinib treatment, while the response to ACh was unaltered. Both macitentan and sitaxentan reversed the constrictor ET B receptor response. Our results support a key role for the ET-1 system in the development of sunitinib-induced hypertension and suggest that selective ET A receptor blockade is sufficient to block this effect.

PP.27.18] EFFECTS OF SUNITINIB TREATMENT ON PITUITARY-ADRENAL AXIS IN NEOPLASTIC PATIENTS

Objective: Hypertension is a frequent side effect of antiangiogenic treatment with tyrosine kinase inhibitors (TKIs) in neoplastic patients; the pathogenetic mechanism of hypertension, in particular the role of pituitary-adrenal axis, is still controversial. In a clinical study, indeed, increased circulating levels of ACTH and cortisol have been observed during Vandetanib treatment; conversely, adrenal toxicity and necrosis has been documented in experimental animals treated with Sunitinib. In this clinical study we measured blood pressure (BP) and circulating levels of ACTH and cortisol during Sunitinib treatment in patients with metastatic renal cell carcinoma (mRCC). Design and method: In 8 patients with mRCC (M/F 5/3) we performed 24 h Blood Pressure (BP) Monitoring and measured plasma ACTH and cortisol (by radioimmunoassay and electrochemiluminescence immunoassay, respectively) in peripheral venous blood sampled in the morning in supine patients. Hemodynamic and humoral parameters were measured at baseline, after Sunitinib (50 mg/day for 4 weeks, first cycle) and after 2 weeks of recovery. Results: Data are shown as means±SD*p < 0.01 vs baseline Baseline body weight (83.5 ± 12.6 kg) and serum glucose (89.1 ± 10.8 mg/dL) were unchanged after Sunitinib. Conclusions: In front of marked increments of systolic/diastolic BP, plasma ACTH and cortisol levels were not significantly affected by Sunitinib treatment in neoplastic patients. These data do not support an increased glucocorticoid activity as pathogenetic mechanism of Sunitinib-induced hypertension.

Salt Sensitivity of Angiogenesis Inhibition-Induced Blood Pressure Rise: Role of Interstitial Sodium Accumulation?

In response to salt loading, Na+ and Cl- accumulate in the skin in excess of water, stimulating skin lymphangiogenesis via activation of the mononuclear phagocyte system cell-derived vascular endothelial growth factor-C-vascular endothelial growth factor type 3 receptor signaling pathway. Inhibition of this pathway results in salt-sensitive hypertension. Sunitinib is an antiangiogenic, anticancer agent that blocks all 3 vascular endothelial growth factor receptors and increases blood pressure. We explored the salt dependency of sunitinib-induced hypertension and whether impairment of skin lymphangiogenesis is an underlying mechanism. Normotensive Wistar-Kyoto rats were exposed to a normal or high salt with or without sunitinib administration. Sunitinib induced a 15 mm Hg rise in telemetrically measured blood pressure, which was aggravated by a high-salt diet (HSD), resulting in a decline of the slope of the pressure-natriuresis curve. Without affecting body weight, plasma Na+ concentration or renal function, Na+ and Cl- skin content increased by 31% and 32% with the high salt and by 49% and 50% with the HSD plus sunitinib, whereas skin water increased by 17% and 24%, respectively. Skin mononuclear phagocyte system cell density increased both during sunitinib and a HSD, but no further increment was seen when HSD and sunitinib were combined. HSD increased skin lymphangiogenesis, while sunitinib tended to decrease lymphangiogenesis, both during a normal-salt diet and HSD. We conclude that sunitinib induces hypertension that is aggravated by high salt intake and not accompanied by impaired skin lymphangiogenesis.

The best objective response of target lesions and the incidence of treatment-related hypertension are associated with the survival of patients with metastatic renal cell carcinoma treated with sunitinib: a Japanese retrospective study

BackgroundThe aim of this study is to investigate the prognostic relevance of the best objective response of metastatic target lesions during sunitinib treatment in patients with metastatic renal cell carcinoma.MethodsRadiographic analysis of the best objective response according to the Response Evaluation Criteria in Solid Tumors was assessed in 50 patients. Clinicopathological characteristics including the Heng risk classification and sunitinib-related adverse reactions were compared among four patient subgroups [complete response or partial response (CR/PR), stable disease (SD), progressive disease (PD), and those without treatment evaluation (NE)]. Kaplan–Meier and Cox proportional regression analyses of progression-free survival and overall survival were performed to identify prognostic variables.ResultsThe best objective response was CR/PR in 12 (24 %) patients, SD in 22 (44 %), PD in 6 (12 %), and NE in 10 (20 %). The incidence of hypertension and hypothyroidism was associated with a better objective response. Progression-free survival was 15.0, 9.2, 6.8, and 2.2 months in the CR/PR, SD, PD, and NE groups, respectively (P = 0.0004, log-rank test), while the corresponding median overall survival was 59.7, 24.2, 17.1, and 18.1 months, respectively (P = 0.007). Multivariate analysis revealed that hazard ratios for risk of death of the SD, PD, and NE groups were 4.51 (P = 0.06), 7.93 (P = 0.02), and 4.88 (P = 0.04), respectively, as compared to the CR/PR group.ConclusionsOur findings suggested that the best objective response of target lesions was a prognostic marker for both progression-free survival and overall survival in sunitinib treatment. Furthermore, the incidence of sunitinib-induced hypertension was associated with a longer progression-free survival.

Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma

The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients. We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2.4, 95% confidence interval: 1.1-5.2, P=0.021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib.

Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are overexpressed in the majority of renal cell carcinomas. This characteristic has supported the rationale of targeting VEGF-driven tumour vascularization, especially in clear cell RCC. VEGF-inhibiting strategies include the use of tyrosine kinase inhibitors (sunitinib, axitinib, pazopanib, and sorafenib) and neutralizing antibodies such as bevacizumab.Hypertension (HTN) is one of the most common adverse effects of angiogenesis inhibitors. HTN observed in clinical trials appears to correlate with the potency of VEGF kinase inhibitor against VEGFR-2: agents with higher potency are associated with a higher incidence of HTN. Although the exact mechanism by tyrosine kinase inhibitors induce HTN has not yet been completely clarified, two key hypotheses have been postulated. First, some studies have pointed to a VEGF inhibitors-induced decrease in nitric oxide synthase (NOS) and nitric oxide (NO) production, that can result in vasoconstriction and increased blood pressure. VEGF, mediated by PI3K/Akt and MAPK pathway, upregulates the endothelial nitric oxide synthase enzyme leading to up-regulation of NO production. So inhibition of signaling through the VEGF pathway would lead to a decrease in NO production, resulting in an increase in vascular resistance and blood pressure. Secondly a decrease in the number of microvascular endothelial cells and subsequent depletion of normal microvessel density (rarefaction) occurs upon VEGF signaling inhibition.NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects.

Rho kinase inhibition mitigates sunitinib-induced rise in arterial pressure and renal vascular resistance but not increased renal sodium reabsorption.

The therapeutic use of the vascular endothelial growth factor (VEGF) antagonist sunitinib is limited by sunitinib-induced hypertension. The hypotheses were tested that sunitinib increases renal vascular resistance (RVR) and renal Na+ reabsorption, and that Rho kinase (ROCK) inhibition blunts sunitinib-induced hypertension. Sunitinib actions on human and rat resistance arteries were investigated by myography. The effects of sunitinib alone or in combination with a ROCK inhibitor on arterial pressure and renal function were investigated in rats by radiotelemetry, renal function and metabolism studies accompanied by biochemical, molecular and histological analyses. Sunitinib blunted agonist-induced vasoconstriction and facilitated endothelium-dependent vasodilation. Within 4 days, sunitinib treatment caused arterial pressure and RVR to rise by 30 mmHg and 5 mmHg × ml × min × g kidney weight, respectively, accompanied by reduced glomerular filtration rate and fractional Na+ excretion with unaffected fractional Li+ excretion. ROCK inhibition blunted sunitinib-induced hypertension and prevented the early rise in RVR, but not the decrease in fractional Na+ excretion, which may explain its modest effect on sunitinib-induced hypertension. Our data indicate that early sunitinib-induced hypertension is associated with modest alterations in renal vascular function, but markedly increased renal sodium reabsorption, probably due to direct actions of the VEGF antagonist on the collecting duct, suggesting that VEGF receptors regulate renal Na+ absorption.

Clinicopathologic factors associated with the development of sunitinib-induced hypertension (HTN) in patients (pts) with metastatic renal cell carcinoma (mRCC).

Clinicopathologic factors associated with the development of sunitinib-induced hypertension (HTN) in patients (pts) with metastatic renal cell carcinoma (mRCC).

Abstract 453: Angiogenesis Inhibition-Induced Hypertension and Nephrotoxicity: Not All Antihypertensives are the Same

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy inducing hypertension and nephrotoxicity. Here we compared the effects of the endothelin antagonist (ET-R) macitentan (30 mg/kg/day, p.o; n=8), the calcium channel blocker (CCB) amlodipine (3 mg/kg/day, p.o; n=9), or the ACE-inhibitor captopril (3 or 12 mg/kg/day, s.c.; n=9) vs. no treatment (n=14) in sunitinib (26.7 mg/kg/day, p.o)-exposed hypertensive WKY rats. Treatment lasted 8 days; mean arterial pressure (MAP) was monitored telemetrically. At the end of the treatment period, 24-hour urine samples for protein and endothelin-1 (ET-1) measurements, and blood samples and kidneys for histological evaluation were collected. With sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p&lt;0.001). Co-administration of macitentan (Δ12.3±1.5 mmHg, p&lt;0.001) or amlodipine (Δ11.4±1.7 mmHg, p&lt;0.001) attenuated the sunitinib-induced MAP rise, whereas low and high captopril doses did not (Δ28.1±2.0 and Δ27.2±1.1 mmHg). With sunitinib, serum creatinine increased from 8.0±2.7 to 29.9±4.6 μmol/l (p&lt;0.01) and proteinuria from 7.5±1.3 to 33.3±4.8 mg/day, p&lt;0.05. Although no agent could prevent the sunitinib-induced rise in creatinine, the induced proteinuria was attenuated by 62% (p&lt;0.01) with macitentan and by 88% with low and 114% (p&lt;0.001) with high dose of captopril, while proteinuria increased by 56% (p=NS) with amlodipine. With sunitinib, urinary ET-1 increased from 3.3±0.5 to 4.8±1.0 pg/day (p&lt;0.05). Macitentan and captopril abolished this increase. Renal histology revealed extensive glomerular ischemia and endothelial cell swelling. Concomitant with the decrease in proteinuria, glomerular intra-epithelial protein deposition decreased with macitentan and captopril. In conclusion, ET-R antagonism and CCB effectively reduced the sunitinib-induced hypertension, whereas ACE-inhibition did not. Both ET-R antagonism and ACE inhibition diminished the sunitinib-induced proteinuria. Since ET-R antagonists are not yet available as anti-hypertensive agents, CCBs are preferred in angiogenesis inhibition-induced hypertension, while adding an ACE-inhibitor might be considered when proteinuria is also present.

Polymorphisms in Endothelial Nitric Oxide Synthase (eNOS) and Vascular Endothelial Growth Factor (VEGF) Predict Sunitinib-Induced Hypertension

Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.

Association of hypothyroidism with improved outcomes in first-line treatment of renal cell carcinoma with sunitinib.

466 Background: Sunitinib, a multitarget tyrosine-kinase inhibitor, has become a standard of care for first-line low and intermediate risk metastatic renal cell carcinoma (mRCC). Sunitinib-induced hypothyroidism and hypertension have been correlated with better outcomes in those patients. Methods: Fifty patients with mRCC, treated in the first-line with sunitinib, were retrospective analyzed at one brazilian institution, for overall survival (OS), progression free survival (PFS), overall response rate (ORR) and toxicity. We evaluated clinical and laboratory parameters, such as hypothyroidism (TSH level &gt; 5,5 mIU/L) and hypertension, to identify prognostic factors. Results: The median age of patients was 58 years (range: 37-73 years), 82% were male, 54% were ECOG 0 or 1, and 76% were classified in low or intermediate risk. Nefrectomy was performed in 96% of cases. Lung and bone were the most common sites of metastases. The incidence of hypothyroidism and hypertension during treatment were 40% and 34%, respectively. ORR for the entire population was 40% and it was statistically superior in patients that developed hypothyroidism during treatment (90% vs. 20%; p&lt;0,0001). Median survival and PFS were 21.7 months (10.65-17.70 months, 95% CI) and 14.2 months (15.77-27.58 months, 95% CI), respectively. In univariate analysis, ECOG (p&lt;0,0001), MSKCC criteria (p&lt;0,0001), hypothyroidism (p&lt;00001) and hypertension (p=0,001) were associated with OS. In multivariate analysis, ECOG (p&lt;0,0001), MSKCC criteria (p&lt;0,0001) and hypothyroidism (p&lt;00001) were independent prognostic factors for OS. The most common severe adverse events (G3-4) were asthenia (14%), diarrhoea (6%), neutropenia (14%), thrombocytopenia (10%), hand-foot syndrome (6%) and hypertension (8%). Conclusions: Efficacy in survival and toxicity profile of sunitinib in first-line treatment of mRCC in patients out of clinical trials were comparable to prior studies. Hypothyroidism, MSKCC criteria and ECOG were independent prognostic factors for survival.

Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib

Biomarkers that predict response or toxicity to antiangiogenic therapy are sought to favorably inform the risk/benefit ratio. This study evaluated the association of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) genetic polymorphisms with the development of hypertension (HTN) and clinical outcome in metastatic clear cell renal cell carcinoma (MCCRCC) patients treated with sunitinib. Sixty-three MCCRCC patients receiving sunitinib (50 mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. A panel of candidate VEGF and VEGFR2 single nucleotide polymorphisms (SNPs) were evaluated for associations with the development of hypertension and clinical outcome. VEGF SNP -634 genotype was associated with the prevalence and duration of sunitinib-induced hypertension (as defined by systolic pressure ≥150 mmHg and/or diastolic pressure ≥90 mmHg) in both univariable analysis (P = .03 and .01, respectively) and multivariable analysis, which adjusted for baseline BP and use of antihypertension medication (P = .05 and .02, respectively). Patients with the GG genotype were estimated to have a greater likelihood of being hypertensive during treatment compared with patients with the CC genotype (odds ratio of 13.62, 95% confidence interval [CI] 3.71-50.04). No single VEGF or VEGFR SNPs were found to correlate with clinical outcome. However, the combination of VEGF SNP 936 and VEGFR2 SNP 889 were associated with overall survival after adjustment for prognostic risk group (P = .03). In MCCRCC patients treated with sunitinib, VEGF SNP -634 is associated with hypertension and a combination of VEGF SNP 936 and VEGFR2 SNP 889 genotypes is associated with overall survival.

The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension.

Single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) and vascular endothelial growth factor (VEGF) and its relationship to sunitinib-induced hypertension.

4611 Background: Hypertension is a common side-effect in patients treated with sunitinib and is likely associated with inhibition of the VEGF/VEGF receptor(R)-2 pathway. SNPs in VEGF-A, VEGFR-2, but also in NOS3and endothelin-1 (EDN1) have been mentioned as possible candidates associated with a higher risk on development of hypertension. METHODS: A retrospective multicenter study was performed in 255 patients with advanced renal cell cancer and gastrointestinal stromal tumor treated with sunitinib 50 mg/day in a 4 weeks on 2 weeks off or 37.5 mg/day continuous schedule. Office systolic (SBP) and diastolic blood pressure (DBP) were measured at baseline and on days 14 and 28 of the first treatment cycle. Hypertension was graded according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). Seven SNPs in genes encoding for VEGF-A (rs2010963, rs833061, rs3025039, rs699947), VEGFR-2 (rs1870377), EDN1 (rs5370) and NOS3 (rs2070744) were selected. SNPs were univariately tested against hypertension grades according to CTCAE. RESULTS: During the first treatment cycle, sunitinib induced a mean increase of 13 ± 23 mmHg and 10 ± 12 mmHg in SBP and DBP (t-test, P < 0.001), respectively. According to CTCAE, 36.5 % of patients developed hypertension. Among these patients, 10.6%, 12.9% and 12.9% had hypertension grade 1, 2, and 3, respectively. Development of grade 3 hypertension was associated with two copies of the C-allele in VEGF-A (rs833061; Chi-square, P = 0.048), two copies of the A-allele in VEGF-A(rs699947; P = 0.053) and a C-allele in NOS3 (rs2070744; P = 0.051). CONCLUSIONS: SNPs in genes of NOS3 and VEGF-A are associated with the development of severe hypertension in patients treated with sunitinib. In particular, the association between the NOS3 pathway and hypertension induced by an inhibitor of the VEGF/VEGFR-2 pathway is a new finding. Hence, SNPs in VEGF-A and NOS3 genes may identify patients predisposed to develop hypertension on sunitinib treatment.

255 mTOR inhibitors, bevacizumab

The therapeutic scenario for metastatic renal cell carcinoma (mRCC) has been evolving rapidly, with sunitinib, sorafenib, bevacizumab, everolimus, pazopanib, and temsirolimus being successfully tested and approved in a short period of time. Oncologists must be familiar with the management of toxicity that these biologic agents cause, as such toxicity is different from that of conventional chemotherapeutic agents.To describe toxic effects associated with targeted therapy of mRCC and their proper management on the basis of currently available evidence.We conducted a systematic analysis of the literature on 15th October 2010 by performing a search of Medical Subject Headings (MeSH) on PubMed using the words sorafenib, sunitinib, bevacizumab, everolimus, pazopanib, or temsirolimus combined with the MeSH term kidney neoplasms. Consideration for inclusion was given to articles providing data concerning (1) incidence and grading and (2) management of targeted therapy–related toxic effects. A separate search was conducted on PubMed to retrieve meta-analyses using each drug name and the word meta-analysis.Hypertension, fatigue, bone marrow toxicity, skin toxicity, and gastrointestinal side-effects are common with the six targeted agents. Everolimus and temsirolimus are associated with immunosuppression, metabolic alterations, and interstitial pneumonitis, while sunitinib is associated with hypothyroidism. Recommendations for treating these conditions usually follow those for the general population because of the lack of experimental data in this setting (eg, for management of sunitinib-induced hypertension).The treating oncologist should try to manage side-effects associated with targeted therapy using supportive and pharmacologic interventions. Severe toxicity requires external specialist consultation and treatment suspension and/or dose reduction. Experimental data about the management of targeted therapy–related toxicity in mRCC is lacking and required in this setting.