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. 2015 Dec 1;113(11):1571-80.
doi: 10.1038/bjc.2015.368. Epub 2015 Oct 22.

Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients

Frede Donskov  1 , M Dror Michaelson  2 , Igor Puzanov  3 , Mellar P Davis  4 , Georg A Bjarnason  5 , Robert J Motzer  6 , David Goldstein  7 , Xun Lin  8 , Darrel P Cohen  8 , Robin Wiltshire  9 , Brian I Rini  10
Affiliations

Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients

Frede Donskov et al. Br J Cancer. .

Abstract

Background: Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities.

Methods: In sunitinib-treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ⩾140 mm Hg), neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points.

Results: On-treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P<0.0001, respectively) and OS (P=0.0014 and P<0.0001, respectively), independent of baseline prognostic factors, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. By 12-week landmark analysis, neutropenia was significantly associated with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand-foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63-0.67) for IMDC classification alone and 0.72 (95% CI: 0.70-0.74) when combined with hypertension and neutropenia. Considering hypertension and neutropenia (developing both vs neither) changed IMDC-predicted median OS in each IMDC risk group (favourable: 45.3 vs 19.5 months; intermediate: 32.5 vs 8.0 months; poor: 21.1 vs 4.8 months).

Conclusions: On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model.

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Conflict of interest statement

F Donskov has received research funding from Pfizer, Novartis, and GlaxoSmithKline. GA Bjarnason has received research funding and consulting fees from Pfizer. RJ Motzer has received research funding and consultant fees from Pfizer and has been compensated for expert testimony by Pfizer. D Goldstein has received research funding from Pfizer and GlaxoSmithKline. X Lin, DP Cohen, and R Wiltshire are full-time employees of Pfizer with Pfizer stock. BI Rini has received research funding and consulting fees from Pfizer. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Prognostic model based on baseline neutrophil status (normal vs elevated) with the addition of on-treatment status of hypertension (HTN; yes vs no) and neutropenia (yes vs no) (‘8-group' analysis). All patients were treated with sunitinib on Schedule 4/2. (A) PFS; (B) OS. ULN=upper limit of normal.
Figure 2
Figure 2
Incorporating on-treatment neutropenia and hypertension into the IMDC model leads to improved prognostic accuracy. Prognostic model based on (A) baseline IMDC status, with the addition of on-treatment status of neutropenia and hypertension in patients with (B) IMDC favourable prognosis, (C) IMDC intermediate prognosis and (D) IMDC poor prognosis.
See this image and copyright information in PMC

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