The primary objective of the study is to investigate the effect of sunitinib on endothelial function, insulin sensitivity, renal function and renal blood flow.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Renal and urinary tract neoplasms malignant and unspecified
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
In group A: forearm vasomotor response to increasing doses of intra-arterially
administered acetylcholine and nitroglycerine before and after start of
treatment with sunitinib.
In group B: insulin sensitivity measured by hyperinsulinemic euglycemic clamp
before and after start of treatment with sunitinib.
In group C: GFR and RPF measured by PAH and inulin clearance before and after
start of treatment with sunitinib.
Secondary outcome
1. To investigate the effect of sunitinib on body weight and blood pressure
2. To investigate the effect of sunitinib on levels of VEGF, soluble VEGFR,
renin, aldosteron, endothelin-1 and renal function in relation to blood pressure
3. To investigate the effect of sunitinib on levels of glucose, total
cholesterol, HDL, LDL, triglycerides, insulin, C-peptide, IGF-I, pro-IGF-II,
TSH, FT4, leptin, ghrelin, adiponectin, IL-6, IL-18, TNF-α, IFN-γ.
4. To investigate the effect of oral daily sunitinib dosing on insulin
requirement in the diabetic subpopulation.
Background summary
Hypertension
Decreased production of nitric oxide (NO) seems to be part of the mechanism
inducing hypertension in patients treated with angiogenesis inhibitors. NO
causes vasodilatation, inhibits proliferation of vascular smooth muscle cells
and diminishes endothelial adhesion of platelets and leucocytes. Decreased NO
synthesis promotes vasoconstriction, increases peripheral resistance, decreases
renal excretion of sodium ion and increases blood pressure 1. One of the main
targets of angiogenesis inhibitors is vascular endothelial growth factor
(VEGF). VEGF plays an important role in the proliferation of new blood vessels
necessary for tumor growth 2, 3. In animal experiments, VEGF induces
hypotension due to synthesis and/or release of NO 4. In human umbilical vein
endothelial cells treatment with VEGF resulted in both an acute (1 h) and
chronic (>24 h) stimulation of NO production 5. In animal experiments it is
shown that vasodilator properties of endogenous VEGF may play a role in normal
vascular tone. Theoretically inhibition of VEGF or VEGFr in humans would
decrease NO production and thereby induce vasoconstriction and hypertension.
Another proposed mechanism of angiogenesis inhibitor-induced hypertension is
vascular rarefaction, which is a reduction in the density of micro vessels.
Rarefaction is a normal component of aging and has been demonstrated to occur
to a greater degree in hypertensive adults.
Other possible factors contributing to elevated blood pressure in patients
treated with angiogenesis inhibitors are adrenergic, renal or renovascular
mechanisms.
The appearance of hypertension, particularly grade 3, was associated with
higher treatment response to sunitinib in metastatic Renal Cell Carcinoma
(mRCC)6. Discontinuation of treatment with sunitinib because of hypertension
should therefore be avoided and early and adequate treatment of elevated blood
pressure seems to be essential. Moreover, insight in the pathogenesis of this
side effect could give us insight in how these angiogenesis inhibitors affect
the tumor and thereby give us opportunities to optimize this type of therapy.
The pathogenesis of hypertension caused by treatment with angiogenesis
inhibitors remains unclear. Understanding the pathogenesis of this type of
hypertension is essential for optimal treatment with antiangiogenic therapy.
In a retrospective study of 200 patients with metastatic renal cell carcinoma
It has been described that sunitinib lowers blood glucose levels, even so that
in a diabetic patient blood glucose lowering medication could be withdrawn 8. A
non-significant decrease of IGF-1 was observed at week 4 in five diabetic
patients. Moreover for sunitinib, a case of a patient with diabetes mellitus
type 1 and renal cell carcinoma with a decrease in insulin requirements has
been reported9.
This could imply that sunitinib could reduce insulin resistance, possibly by
interfering with the IGF-1 pathway. Alternatively, intestinal toxicity could
have reduced absorption of oral glucose reducing the need for glucose lowering
drugs. Systematically prospective research regarding the effect of angiogenesis
inhibitors on insulin resistance has not yet been performed.
Study objective
The primary objective of the study is to investigate the effect of sunitinib on
endothelial function, insulin sensitivity, renal function and renal blood flow.
Study design
Single-centre non randomized observational study
Study burden and risks
Patients will not benefit from participating in this study. The intentional
treatment of their disease, i.e. treatment with sunitinib, will not change. In
group A plethysmography will cause numbness and discomfort in both hands due to
inflation of the wrist-cuffs. This is temporarily and completely reversible.
Sometimes there can be some numbness or tingling of fingers due to a hematoma
caused by the intra-arterial cannule for a few weeks after the experiment.
Finally in Group A/B/C, bruising may occur after venapuncture or removal of the
intra-arterial 27 G needle. Measures like pressure bandage will be taken to
minimize the risk.
Side effects due to the euglycemic hyperinsulinemic clamp or PAH/inuline
clearance are infrequent.
Postbus 9101
6500HB Nijmegen
NL
Postbus 9101
6500HB Nijmegen
NL
Listed location countries
Age
Inclusion criteria
• Subject is able and willing to sign the Informed Consent Form
• Age 18 years or older
• WHO performance status 0-2
• Life expectancy >= 12 weeks
• mRCC patients in which the treatment of choice is sunitinib
Exclusion criteria
1) Use of corticosteroids
2) Any evidence of severe or uncontrolled diseases other than renal cell carcinoma eg, unstable or uncompensated respiratory, cardiac, hepatic or renal disease.
3) Known risk of the patient transmitting HIV, hepatitis B or C via infected blood
4) Patients being treated with oral anticoagulants if to be included in group A.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL33069.091.10 |