1
Accepted Article
Sunitinib-induced hypertension, neutropenia and thrombocytopenia as predictors of good prognosis in metastatic renal cell carcinoma patients 1 JR JUHANA RAUTIOLA,a,b FD FREDE DONSKOVc, KP KATRIINA PELTOLA,a , HJ
HEIKKI JOENSUU,a,b & PB PETRI BONOa,b
Affiliations: aDepartment of Oncology, Helsinki University Central Hospital, Finland;
b
Laboratory of Molecular Oncology, Molecular Cancer Biology Research Program,
Biomedicum Helsinki, University of Helsinki, Finland; cDepartment of Oncology, Aarhus
University Hospital, Denmark.
E-mail addresses: [email protected]; [email protected]; [email protected]; [email protected]
Address for corresponding author: Petri Bono, MD, Ph.D, Cancer Center, Helsinki
University Central Hospital, P.O. Box 180, HUS, FIN-00029, Helsinki, Finland. E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version
of Record. Please cite this article as doi: 10.1111/bju.12940
This article is protected by copyright. All rights reserved.
2
Accepted Article
Abstract
Objectives: To evaluate the clinical significance of hypertension, neutropenia and thrombocytopenia as possible new biomarkers of sunitinib efficacy in non-trial metastatic renal cell carcinoma (mRCC) patients. Materials and methods: 181 consecutive mRCC patients were treated with sunitinib.
Thirty-nine (22%) patients received sunitinib 50 mg/day 4 weeks on/ 2 weeks off, 80 patients (44%) 37.5 mg/day continuously and 62 (34%) 25 mg/day continuously as their starting dose. Treatment-induced adverse events (AE) and their impact on outcome were analysed on multiple sunitinib doses. Results: During sunitinib treatment 60 patients (33%) developed ≥grade 2 hypertension, 88 (49%) ≥grade 2 neutropenia and 135 (75%) ≥grade 1 thrombocytopenia. These AEs were associated significantly with longer progression-free survival (PFS; 15.7 vs. 6.7; 14.6 vs. 6.9; 10.4 vs. 4.2 months, respectively; P 150mmHg, if previously within normal range.
Statistical Analyses
Progression-free survival (PFS) was calculated according to the Kaplan-Meier method from the date of initiation of sunitinib to the date of documented cancer progression or death. Patients without progression were censored at the time of the last follow-up visit. Overall survival (OS) was calculated from the date of sunitinib initiation to death, censoring patients who were alive on the date of the last follow-up visit. Survival between groups was compared with the log-rank test. Frequency tables were analysed using χ2-test. The landmark survival analysis with the landmark set at 12 weeks after date of initiation of sunitinib therapy was applied to avoid the bias from longer treatment. According to the landmark method, patients with short treatment (i.e less than 12 weeks) were excluded. Progression-free survival and overall survival landmark analyses included those patients who were alive and had no disease progression before the landmark time point. In the landmark analysis, overall survival and progression-free survival were defined as the time from the landmark to the progression or death of any cause.
Multivariate survival analysis was performed with the Cox proportional-hazards model entering the following variables: Hypertension, neutropenia or thrombocytopenia during treatment and Heng criteria (favourable, intermediate or poor). All P-values are two-tailed. All the statistical analyses were performed with IBM SPSS Statistics for Mac, version 20.0, Armonk, NY: IBM Corp.
This article is protected by copyright. All rights reserved.
8
Accepted Article
Results
Sunitinib Administration
One hundred and eighty-one patients were treated with sunitinib. Thirty-nine (22%) patients received sunitinib 50 mg/day 4 weeks on/ 2 weeks off, 80 patients (44%) 37.5 mg/day continuously and 62 (34%) 25 mg/day continuously as their starting dose. The median follow-up time was 33.3 months (range, 1.1-65.3 months). The median duration of sunitinib treatment was 6.5 months (range 0.2-65.3 months) and the median number of 28day cycles given was seven (range, 0.3-69.9). Ten (six patients with 37,5 mg/day, four 25 mg/day) (6%) patients had their sunitinib dose escalated after starting with a reduced sunitinib dose. Eighty-three (46%) patients required dose reduction while on sunitinib. Detailed patient characteristics are shown in Table 1.
The median PFS was 8.6 months (95% CI, 6.9 to 10.3), and overall survival (OS) 20.7 months (95% CI, 17.7 to 23.6). The median PFS among patients with different Heng risk group status (favourable, intermediate, high) was 21.7 vs. 10.0 vs. 5.7 months (95% CIs, 9.6 to 33.8 vs. 6.3 to 13.6 vs. 4.3 to 7.1 months). The median OS of patients according to Heng risk groups was 40.1 vs. 24.3 vs. 9.7 months, respectively (95% CIs, 17.2 to 63.0 vs. 13.0 to 35.7 vs. 3.1 to 16.3). One hundred and eight patients (60%) stopped sunitinib because of progression and 50 patients (47 AE, 3 other) (28%) without progression. The rest of the patients continued sunitinib treatment at the time of data cut-off. There were no treatment-related deaths.
Effect of Hypertension, Neutropenia and Thrombocytopenia on outcome
This article is protected by copyright. All rights reserved.
Accepted Article
9
During sunitinib treatment a total of 60 patients (33%) developed ≥grade 2 hypertension (HTN). The influence of hypertension on outcome is presented in Table 2. Patients who had treatment-related HTN had statistically significantly higher response rate, longer PFS and OS than patients with no HTN (P
Accepted Article
Sunitinib-induced hypertension, neutropenia and thrombocytopenia as predictors of good prognosis in metastatic renal cell carcinoma patients 1 JR JUHANA RAUTIOLA,a,b FD FREDE DONSKOVc, KP KATRIINA PELTOLA,a , HJ
HEIKKI JOENSUU,a,b & PB PETRI BONOa,b
Affiliations: aDepartment of Oncology, Helsinki University Central Hospital, Finland;
b
Laboratory of Molecular Oncology, Molecular Cancer Biology Research Program,
Biomedicum Helsinki, University of Helsinki, Finland; cDepartment of Oncology, Aarhus
University Hospital, Denmark.
E-mail addresses: [email protected]; [email protected]; [email protected]; [email protected]
Address for corresponding author: Petri Bono, MD, Ph.D, Cancer Center, Helsinki
University Central Hospital, P.O. Box 180, HUS, FIN-00029, Helsinki, Finland. E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version
of Record. Please cite this article as doi: 10.1111/bju.12940
This article is protected by copyright. All rights reserved.
2
Accepted Article
Abstract
Objectives: To evaluate the clinical significance of hypertension, neutropenia and thrombocytopenia as possible new biomarkers of sunitinib efficacy in non-trial metastatic renal cell carcinoma (mRCC) patients. Materials and methods: 181 consecutive mRCC patients were treated with sunitinib.
Thirty-nine (22%) patients received sunitinib 50 mg/day 4 weeks on/ 2 weeks off, 80 patients (44%) 37.5 mg/day continuously and 62 (34%) 25 mg/day continuously as their starting dose. Treatment-induced adverse events (AE) and their impact on outcome were analysed on multiple sunitinib doses. Results: During sunitinib treatment 60 patients (33%) developed ≥grade 2 hypertension, 88 (49%) ≥grade 2 neutropenia and 135 (75%) ≥grade 1 thrombocytopenia. These AEs were associated significantly with longer progression-free survival (PFS; 15.7 vs. 6.7; 14.6 vs. 6.9; 10.4 vs. 4.2 months, respectively; P 150mmHg, if previously within normal range.
Statistical Analyses
Progression-free survival (PFS) was calculated according to the Kaplan-Meier method from the date of initiation of sunitinib to the date of documented cancer progression or death. Patients without progression were censored at the time of the last follow-up visit. Overall survival (OS) was calculated from the date of sunitinib initiation to death, censoring patients who were alive on the date of the last follow-up visit. Survival between groups was compared with the log-rank test. Frequency tables were analysed using χ2-test. The landmark survival analysis with the landmark set at 12 weeks after date of initiation of sunitinib therapy was applied to avoid the bias from longer treatment. According to the landmark method, patients with short treatment (i.e less than 12 weeks) were excluded. Progression-free survival and overall survival landmark analyses included those patients who were alive and had no disease progression before the landmark time point. In the landmark analysis, overall survival and progression-free survival were defined as the time from the landmark to the progression or death of any cause.
Multivariate survival analysis was performed with the Cox proportional-hazards model entering the following variables: Hypertension, neutropenia or thrombocytopenia during treatment and Heng criteria (favourable, intermediate or poor). All P-values are two-tailed. All the statistical analyses were performed with IBM SPSS Statistics for Mac, version 20.0, Armonk, NY: IBM Corp.
This article is protected by copyright. All rights reserved.
8
Accepted Article
Results
Sunitinib Administration
One hundred and eighty-one patients were treated with sunitinib. Thirty-nine (22%) patients received sunitinib 50 mg/day 4 weeks on/ 2 weeks off, 80 patients (44%) 37.5 mg/day continuously and 62 (34%) 25 mg/day continuously as their starting dose. The median follow-up time was 33.3 months (range, 1.1-65.3 months). The median duration of sunitinib treatment was 6.5 months (range 0.2-65.3 months) and the median number of 28day cycles given was seven (range, 0.3-69.9). Ten (six patients with 37,5 mg/day, four 25 mg/day) (6%) patients had their sunitinib dose escalated after starting with a reduced sunitinib dose. Eighty-three (46%) patients required dose reduction while on sunitinib. Detailed patient characteristics are shown in Table 1.
The median PFS was 8.6 months (95% CI, 6.9 to 10.3), and overall survival (OS) 20.7 months (95% CI, 17.7 to 23.6). The median PFS among patients with different Heng risk group status (favourable, intermediate, high) was 21.7 vs. 10.0 vs. 5.7 months (95% CIs, 9.6 to 33.8 vs. 6.3 to 13.6 vs. 4.3 to 7.1 months). The median OS of patients according to Heng risk groups was 40.1 vs. 24.3 vs. 9.7 months, respectively (95% CIs, 17.2 to 63.0 vs. 13.0 to 35.7 vs. 3.1 to 16.3). One hundred and eight patients (60%) stopped sunitinib because of progression and 50 patients (47 AE, 3 other) (28%) without progression. The rest of the patients continued sunitinib treatment at the time of data cut-off. There were no treatment-related deaths.
Effect of Hypertension, Neutropenia and Thrombocytopenia on outcome
This article is protected by copyright. All rights reserved.
Accepted Article
9
During sunitinib treatment a total of 60 patients (33%) developed ≥grade 2 hypertension (HTN). The influence of hypertension on outcome is presented in Table 2. Patients who had treatment-related HTN had statistically significantly higher response rate, longer PFS and OS than patients with no HTN (P
