Brain natriuretic peptide precursor (NT-pro-BNP) levels predict for clinical benefit to sunitinib treatment in patients with metastatic renal cell carcinoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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 treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers.

BACKGROUND: Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renal-cell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution. METHODS: We have treated 42 patients with metastatic clear-cell renal carcinoma with sunitinib. Plasma concentrations of VEGF-A, sVEGFR2 and PDGF were determined by ELISA. RESULTS: At the time of analysis 39 patients were evaluable for response and 30 patients had obtained a clinical benefit (CB). Median progression-free survival was 268 days (8.93 months) and median overall survival was 487 days (16.23 months). Interestingly, disease stabilization or objective response resulted in comparable overall survival. Most treatment-related adverse events were of mild-to-moderate intensity with one treatment-related death. Plasma sVEGFR2 and PDGF levels had no predictive value. Fold-increase in plasma VEGF was significantly lower in patients that obtained a CB as compared to patients that progressed after two cycles of treatment. Plasma VEGF did not increase in patients with initial CB at the time of progression. CONCLUSION: Sunitinib showed substantial activity in mRCC. Disease stabilization or objective response resulted in comparable overall survival and both outcomes should be considered positive. Fold-increase in plasma VEGF predicts for CB and could be a candidate marker. Progression after initial CB is not associated with elevated plasma VEGF, implying a different mechanism of resistance.

Adjuvant systemic therapy protocol for Dukes' B2 and C resectable colon carcinoma.

AIMS AND BACKGROUND: Trials of adjuvant systemic therapy in high risk patients with Dukes' B2 and C colon cancer utilizing 5-fluorouracil-based regimens have been ongoing since the 1960s. The aim of this study was to compare the combination of 5-FU and leucovorin with the combination of 5-FU and alfa-2b interferon (IFN) in patients who had undergone "curative" resection foronocarcinoma. STUDY DESIGN: A total of 322 patients with histologically proven adenocarcinoma of the colon, Dukes' stage B2 and C, were entered in the study. They were randomized to A) leucovorin 20 mg/m2 rapid intravenous injection and 5-FU 425 mg/m2 IV days 1-5 every 28 days for six cycles or B) 5-FU 600 mg/m2 24-hour infusion for five days, then 600 mg/m2 IV once a week and IFN 5 MU subcutaneously three times a week for six months. RESULTS: There was no statistically significant difference in either disease-free survival or overall survival. Toxicity was the same in the two groups with the exception of flu-like syndrome, which was universal in IFN-treated patients. CONCLUSIONS: There was no difference in disease-free survival or overall survival between the two combinations in any patient subset. Toxicity was greater with the 5-FU+IFN combination because of the flu-like syndrome. These data do not support the use of IFN in combination with 5-FU as systemic adjuvant therapy for patients with locally advanced colon carcinoma.