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Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma.

ABSTRACT: Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ?10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time.Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%-17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time.Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601-9. ©2017 AACR.

SUBMITTER: Narayan V

PROVIDER: S-EPMC5516884 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma.

Narayan Vivek V Keefe Stephen S Haas Naomi N Wang Le L Puzanov Igor I Putt Mary M Catino Anna A Fang James J Agarwal Neeraj N Hyman David D Smith Amanda M AM Finkelman Brian S BS Narayan Hari K HK Ewer Steven S ElAmm Chantal C Lenihan Daniel D Ky Bonnie B

Clinical cancer research : an official journal of the American Association for Cancer Research 20170214 14

<b>Purpose:</b> To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.<b>Experimental Design:</b> In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, ...[more]

PMID: 28196874

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Project description:Sunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC).To conduct a randomized phase 2 trial comparing sunitinib and everolimus in non-clear cell RCC (non-ccRCC).Patients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive sunitinib or everolimus with crossover at disease progression.Primary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with sunitinib to 20 wk with everolimus.Interim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with sunitinib and 4.1 mo with everolimus (p=0.6); median overall survival (mOS) was not reached with sunitinib and was 10.5 mo with everolimus, respectively (p=0.014). At final analysis, mOS was 16.2 and 14.9 mo with sunitinib and everolimus, respectively (p=0.18). There were four partial responses (PRs) in first-line therapy (sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors (n=49), mOS was 31.6 mo with sunitinib and 10.5 mo with everolimus (p=0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation.In this trial, everolimus was not superior to sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non-ccRCC.This randomized phase 2 trial provides the first head-to-head comparison of everolimus and sunitinib in patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC.

Project description:BackgroundMetastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr.ObjectiveTo analyze long-term safety with sunitinib in mRCC patients.Design, setting, and participantsData were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g., cytokine refractory or treatment-naïve).Outcome measurements and statistical analysisInterval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment.Results and limitationsAmong long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients.ConclusionsProlonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative.Patient summaryMore than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk.

Project description:PurposeWe identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes.Materials and methodsWe retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression.ResultsA total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p <0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p <0.05).ConclusionsSunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

Project description:BackgroundSunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood.Methods and resultsIn a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time.ConclusionsIn patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.

Project description:Following approval of the oral, multitargeted tyrosine kinase inhibitor sunitinib malate for the treatment of patients with metastatic renal cell carcinoma (mRCC) in Europe and the USA in 2006, the agent has had a substantial impact on the treatment landscape in this setting. Sunitinib is now recommended in international treatment guidelines for the first-line treatment of favourable- or intermediate-risk mRCC and as an alternative option in poor-risk mRCC. In the 6 years since the approval of sunitinib, the range of agents available for the treatment of mRCC has expanded substantially, and this, together with a number of additional therapies in late-stage development, has increased the treatment options available to patients. Results from a phase III trial and a global expanded access study have provided robust data to support the efficacy of sunitinib in mRCC, including in real-world populations. Data also suggest a significant quality of life benefit with sunitinib, with superior patient-reported outcomes observed with this agent compared with interferon-α therapy. Both clinical and real-world study data also support the safety profile of sunitinib; most treatment-associated adverse events are mild to moderate in severity and can be managed effectively with close monitoring and proactive management. Clinical experience with sunitinib has demonstrated that therapy management, involving optimal dosing, maximum treatment duration and prompt and effective adverse event management, supports optimal patient outcomes with sunitinib. In this review we discuss clinical experience with sunitinib in mRCC, with an emphasis on real-world data, and utilize clinical case studies to examine the successful implementation of therapy management strategies for optimal patient outcomes. An increasing body of evidence suggests that side effects associated with sunitinib therapy, including hypertension, hand-foot syndrome and hypothyroidism, may represent effective markers of treatment response, and these will also be discussed.

Dataset Information

Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma.

Publications

Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma.

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