Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: A comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events
Michael S. EwerThomas M. SuterDaniel J. LenihanLiviu NiculescuAurora BreaznaGeorge D. DemetriRobert J. Motzer
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Competing Endogenous RNA
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The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic–pharmacodynamic analysis of sunitinib-induced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethyl-sunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic–pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic–pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.
Pharmacodynamics
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We investigated the relationship between clinically assessed left ventricular ejection fraction (LVEF) and survival in a large, heterogeneous clinical cohort.
Fraction (chemistry)
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Background/Aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study examined the potential role of p53 in sunitinib resistance and as a predictive marker in mRCC. Materials and Methods: We analysed the effects of p53 knockout on sunitinib resistance. p53 expression in 53 mRCC patients receiving first-line sunitinib was determined immunohistochemically. We performed in silico analysis to examine the predictive value of p53 in mRCC. Results: WST-1 assays showed that p53 knockout decreased sensitivity to sunitinib. Sunitinib and nutlin-3 together suppressed cell growth. Immunohistochemistry revealed 11 p53-positive cases among 53 patients with mRCC. Kaplan–Meier analysis showed that p53-positive cases tended to be associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, TP53 mutation was significantly associated with poor PFS after sunitinib treatment. Conclusion: p53 may be involved in sunitinib resistance and represent a valuable marker for sunitinib treatment in mRCC.
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목적: Sunitinib 치료 후 발생하는 갑상선기능저하증은 흔한 부작용이다. 발병 기전으로 sunitinib에 의한 파괴성 갑상선염, 갑상선으로의 요오드 운반 억제, 갑상선호르몬 합성과정의 억제 등이 제시되었다. 이는 요오드 섭취 정도에 따라서도 sunitinib에 의한 갑상선기능이상의 발생률이나 임상적 특성이 다를 수 있음을 시사한다. 이에 본 연구에서는 요오드 풍부 지역의 하나인 한국인에서 sunitinib 투여로 인한 갑상선기능저하증의 발생률 및 특성에 대해 조사해 보고자 하였다. 방법: 2005년 11월부터 2007년 7월까지 서울대학교병원에서 sunitinib을 투약했던 환자 중 sunitinib 치료 기간 혹은 후에 갑상선호르몬을 측정한 환자 25명을 대상으로 하였다. 13명은 sunitinib 투여 기간 혹은 후에 갑상선기능저하증을 의심할 수 있는 임상상을 보여 갑상선호르몬을 측정하였고, 12명은 임상상에 관계없이 추적관찰 위해 sunitinib 치료 기간 동안 갑상선호르몬을 측정하였다. 결과: 갑상선기능저하증을 의심할 수 있는 임상상을 보여 갑상선호르몬을 측정한 13명에서는 모두 갑상선기능저하증 소견을 보였으며(현성 9명, 무증상 4명), 임상상에 관계없이 sunitinib 투여 기간 중 갑상선호르몬을 측정한 12명에서는 6명이 갑상선기능저하증 소견을 보였고(현성 2명, 무증상 4명), 2명이 갑상선중독증 소견을 보였다. 19명의 갑상선기능저하증 환자들을 현성과 무증상 갑상선기능저하증으로 나누어 비교해 본 결과 갑상선자극호르몬 상승이 발견된 시기가 현성 갑상선기능저하증 환자들에서 유의하게 늦게 나타났고(44.5 대. 14.8주, p<0.05), sunitinib 누적 투여량은 유의하게 높게 나타났다(8050±3211 대. 3718±1961 mg, p<0.05). 19명의 환자에서 갑상선자극호르몬 수치와 갑상선자극호르몬 상승시까지의 sunitinib 투여 기간 및 투여 누적량 사이에는 상관성이 있는 것으로 나타났다. 결론: Sunitinib 투여 후 갑상선기능저하증의 발생률은 50% 이상일 것으로 예상되었으며, 다른 지역에서 시행된 연구와 비교해 볼 때 요오드 섭취 정도가 sunitinib에 의한 갑상선기능저하증 발병에 영향을 준다고 말하기는 어려운 결과를 보였다. 갑상선 기능저하증 정도는 sunitinib 투여기간 및 용량에 비례하였다. 향후 전향적 연구를 통해 정확한 발생률 및 요오드 섭취에 의한 영향을 평가해 보는 것이 필요하겠다.
Sunitinib malate
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Sunitinib is one of first targeted agents and tyrosine kinase inhibitors of vascular endothelial growth factor receptor (VEGFR) that approved for therapy of metastatic renal cell carcinoma. -Moreover it is among the first compounds in oncology registered after Phase 2 of clinical trials. Sunitinib was used in the United States since January 2006. For the past 10 years a wide experience of sunitinib administration has been accumulated both in practice and in clinical trials. This review summarizes the results of sunitinib studies.
Targeted Therapy
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Of the many targeted therapies introduced since 2006, sunitinib has carved its way to become the most commonly used first-line therapy for the treatment of metastatic renal cell carcinoma (RCC). Despite significant improvements in progression-free survival, 30% of the patients are intrinsically resistant to sunitinib and the remaining 70% who respond initially will eventually become resistant in 6-15 months. While the molecular mechanisms of acquired resistance to sunitinib have been unravelling at a rapid rate, the mechanisms of intrinsic resistance remain elusive. Combination therapy, sunitinib rechallenge and sequential therapy have been investigated as means to overcome resistance to sunitinib. Of these, sequential therapy appears to be the most promising strategy. This mini review summarises our emerging understanding of the molecular mechanisms, and the strategies employed to overcome sunitinib resistance.
Acquired resistance
Targeted Therapy
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Renal cell carcinoma (RCC) is a treatment resistant cancer. The identification of the link between the von Hippel Lindau (VHL) gene and the vascular endothelial growth factor (VEGF) pathway has led to development of the multi-tyrosine kinase inhibitor sunitinib. The introduction of sunitinib in clinical practice for the treatment of metastatic RCC has significantly increased the overall survival of patients. However resistance to sunitinib is emerging as a challenge. About 30% of patients are intrinsically resistant to sunitinib and almost all patients who show initial response to sunitinib develop extrinsic (acquired) resistance after a median of 6-15 months. While the molecular mechanisms of sunitinib resistance are multifactorial, the emerging consensus is that, sustained VEGF/VEGF receptor (VEGFR) inhibition by sunitinib 'resets' the tumor microenvironment leading to the development of VEGF/VEGFRindependent alternate angiogenic pathways. This chapter summarises the advances in understanding of the molecular mechanisms of sunitinib resistance in RCC.
Kidney cancer
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Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention.
Acquired resistance
Transient (computer programming)
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