Brain natriuretic peptide precursor (NT-pro-BNP) levels predict for clinical benefit to sunitinib treatment in patients with metastatic renal cell carcinoma
- Konstantinos T Papazisis†1, 2Email author,
- Lukas F Kontovinis†1, 2,
- Christos N Papandreou3,
- George Kouvatseas4,
- Christos Lafaras5,
- Evangelos Antonakis6,
- Maria Christopoulou6,
- Charalambos Andreadis1,
- Despoina Mouratidou1 and
- Alexandros H Kortsaris7
© Papazisis et al; licensee BioMed Central Ltd. 2010
Received: 30 March 2009
Accepted: 14 September 2010
Published: 14 September 2010
Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that has been approved for the treatment of metastatic renal cell carcinoma. Although the majority of sunitinib-treated patients receive a clinical benefit, almost a third of the patients will not respond. Currently there is no available marker that can predict for response in these patients.
We estimated the plasma levels of NT-pro-BNP (the N-terminal precursor of brain natriuretic peptide) in 36 patients that were treated with sunitinib for metastatic clear-cell renal carcinoma.
From the 36 patients, 9 had progressive disease and 27 obtained a clinical benefit (objective response or disease stabilization). Increases in plasma NT-pro-BNP were strongly correlated to clinical outcome. Patients with disease progression increased plasma BNP at statistically significant higher levels than patients that obtained a clinical benefit, and this was evident from the first 15 days of treatment (a three-fold increase in patients with progressive disease compared to stable NT-pro-BNP levels in patients with clinical benefit, p < 0.0001). Median progression-free survival was 12.0 months in patients with less than 1.5 fold increases (n = 22) and 3.9 months in patients with more than 1.5 fold increases in plasma NT-pro-BNP (n = 13) (log-rank test, p = 0.001).
This is the first time that a potential "surrogate marker" has been reported with such a clear correlation to clinical benefit at an early time of treatment. Due to the relative small number of accessed patients, this observation needs to be further addressed on larger cohorts. More analyses, including multivariate analyses are needed before such an observation can be used in clinical practice.
Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, Fms-like tyrosine kinase receptor 3 (FLT3), c-KIT (stem-cell factor [SCF] receptor) and PDGFR  that has shown clinical activity in the treatment of metastatic renal cell carcinoma. The majority of sunitinib-treated renal cancer patients obtain a clinical benefit in the form of either objective response or disease stabilization (31% and 48% respectively in the large, phase III trial ). Treatment with sunitinib results in alterations of several plasma proangiogenic factors, as sVEGFR2, VEGF, PDGF and PIGF . However, none of these markers has a predictive value for response and the search for a "surrogate marker" is still ongoing .
Cardiac toxicity is reported to be a common adverse event in sunitinib-treated patients . Schmidinger et al, reported that from 86 renal cancer patients that were treated with sunitinib or sorafenib, 33.6% experienced a cardiac event, 40.5% had ECG changes and 18% were symptomatic . On a report by Rixe and colleagues, patients that developed hypertension during treatment (or other sunitinib-related adverse events) had a better outcome than normotensive ones , but this observation remains to be confirmed. Brain natriuretic peptide (BNP) has been shown to be associated with left ventricular dysfunction . This peptide is secreted by atrial and/or ventricular myocardial cells due to volume or pressure overload, according to the severity of myocardial dysfunction. Pro-BNP, the precursor of BNP may provide the same diagnostic information as BNP, but less is known about its clinical utility. Brain natriuretic peptide (BNP) and N-terminal (NT) pro-BNP are useful as diagnostic objective markers of chronic heart failure (CHF) due to systolic and diastolic dysfunction and important prognostic predictors .
We recently reported on a cohort of patients treated with sunitinib for metastatic clear-cell renal carcinoma in our department . Following-up these data we estimated the plasma levels of NT-pro-BNP in 36 sunitinib-treated patients as a marker for cardiac toxicity. Sunitinib was administrated in the usual scheme (50 mg daily, four weeks on treatment, followed by two weeks off treatment, on a six - week cycle). During the first two cycles, plasma was obtained every 2 weeks with a complete blood count and a full biochemical profile. All patients had an appropriate renal, liver, cardiac and bone marrow function . The plasma levels of NT-pro-BNP were analyzed using Elecsys 2010 automated immunoassay analyzer. The study was approved by the local ethics review board (Theagenion Cancer Hospital Research and Ethics Committee) and was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. All patients had confirmed metastatic disease (CT and/or MRI and bone scan), were informed for their participation and signed the appropriate consent form.
The Chi-square test was used for testing significance of correlation for categorical variables. Univariate comparisons of Plasma NT-pro-BNP levels as well as changes from baseline where performed with the Wilcoxon non-parametric test. Logistic regression analysis was used in order to assess jointly the effects of baseline Plasma NT-pro-BNP levels and day 15 changes on disease progression. The area under the Receiver Operating Characteristic (ROC) curve is also reported. Time to event curves were calculated with the Kaplan-Meier method. Indicative cutpoint determination in PFS analysis was made using the method of Contal and O'Quigley (1999)  but there was no formal assessment of the significance of the cutpoint due to the small size of the sample.
Assessable for response
Median and first and third quartile levels (pg/ml) and medianfold-increase in plasma NT-pro-BNP in patients receiving sunitinib according to clinical outcome after the first two cycles of treatment.
Actual values after baseline
change to baseline
Median PFS was 6.9 months in patients (n = 15) with increases in plasma NT-pro-BNP after 15 days of treatment and 15.8 months in patients (n = 20) where plasma NT-pro-BNP remained at the baseline or lower values (p = 0.036, log-rank test).
NT-pro-BNP levels in healthy population are depended on age and gender . In our cohort of metastatic RCC patients, NT-pro-BNP levels were not statistically significantly different in men than women and in older (> 60 years old) that younger patients. Age and gender had no impact on the differences observed in fold-increase of NT-pro-BNP between PD and CB patients (Additional file 1: Table S1).
Discussion and Conclusions
Plasma NT-pro-BNP levels may reflect volume overload or cardiac dysfunction in patients with heart disease. We observed a high variation in pre-treatment NT-pro-BNP levels that was not associated to disease burden or baseline cardiac function. However, Baseline levels predicted for response and sharp increases in plasma NT-pro-BNP were observed in patients that did not obtain any clinical benefit from treatment, and this was evident from the first 15 days of treatment. BNP is produced by myocardial cells, but it has been reported to be produced by many tissues including renal parenchyma as well . Whether this observation reflects the increasing production of NT-pro-BNP from the non-responding metastatic foci remains yet unanswered. When we assayed Caki-1 and Caki-2 renal cancer cell lines in vitro we did not find any significant BNP production and sunitinib had no effect of on BNP at a protein level (data not shown).
On the other hand, hypoxia in large treatment-refractory tumours is a direct and sufficient stimulus for BNP induction via stabilization of HIF-1 alpha . Sunitinib treatment results in improved blood flow and less hypoxic tumour microenviroment [15, 16] in patients that respond. Disease progression can therefore relate to a more hypoxic tumour environment, higher HIF-1 alpha expression, higher plasma VEGF levels (as we have already shown, ref 10) and, finally, increased HIF-1 alpha-dependent BNP induction.
We report the value of plasma NT-pro-BNP measurement for predicting response to sunitinib treatment in patients with metastatic renal cell carcinoma. This is the first time that a potential "surrogate marker" has been reported with such a clear correlation to clinical benefit at an early time on treatment. Due to the relative small number of assessed patients, this observation needs to be further addressed on larger cohorts. More analyses, including multivariate analyses are needed before such an observation can be used in clinical practice.
We are obliged to the patients that participated in the study as well as to the nurses and clinical staff of "Theagenion" Cancer Hospital for their continuing support in our clinical and experimental work
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