Wu S, Chen JJ, Kudelka A, Lu J, Zhu XIncidence and risk of hypertension with sorafenib in patients with cancer: A systematic review and meta-analysis. Lancet Oncol 9: 117-123
Division of Medical Oncology, Department of Medicine, State University of New York, Stony Brook, NY 11794-9447, USA. The Lancet Oncology
(Impact Factor: 24.69).
03/2008; 9(2):117-23. DOI: 10.1016/S1470-2045(08)70003-2
Sorafenib is used in patients with advanced renal-cell carcinoma (RCC) or hepatocellular cancer, and its application in other types of cancers is also undergoing extensive clinical assessment. Hypertension is one of the major side-effects of this drug, and reported incidences vary substantially between clinical trials. We did a systematic review and meta-analysis of published clinical trials to establish the incidence of hypertension associated with sorafenib. The aim of this study is to gain a better understanding of the overall risk of hypertension in patients with cancer who receive sorafenib.
Databases, including Medline (July, 1966, to July, 2007), and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 to 2007 were searched to identify relevant studies. Eligible studies were prospective clinical trials of patients with cancer assigned single-drug sorafenib at 400 mg twice daily with data on hypertension available. Incidence and relative risk (RR) of hypertension were calculated using a random-effects or fixed-effects model, depending on the heterogeneity of the included studies.
Nine studies published between January, 2006, and July, 2007, which included a total of 4599 patients with RCC or other solid tumours, were selected from 223 articles screened for analysis. For patients assigned sorafenib, the overall incidence of all-grade and high-grade (ie, grade 3 or 4) hypertension were 23.4% (95% CI 16.0-32.9%) and 5.7% (2.5-12.6%), respectively. No significant difference was noted between patients with RCC or a non-RCC malignancy (all grade: RR 1.03 [95% CI 0.73-1.45], p=0.89; high-grade: RR 1.23 [0.76-1.99], p=0.40) who were assigned sorafenib. Sorafenib was associated with a significantly increased risk of all-grade hypertension in patients with cancer with an RR of 6.11 (2.44-15.32], p<0.001) compared with controls.
Patients with cancer assigned sorafenib have a significant risk of developing hypertension. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.
Available from: Feng Xu
- "Furthermore, clinical efficacy was also found for sorafenib in phase II clinical trials for other malignant diseases such as advanced melanoma, breast cancer, nonsmall cell lung cancer, urothelial cancer, prostate cancer, carcinoma of the head and neck, gastrointestinal stromal tumours and thyroid cancer. With the wider usage in clinical practice, side-effects of sorafenib began to be recognized and some of which may be potentially life threatening, such as congestive heart failure (CHF), arterial thrombosis, wound dehiscence, haemorrhage, hypertension, and renal dysfunction (Chu et al., 2008; Wu et al., 2008; Chu et al., 2009; Je et al., 2009; Kerkela et al., 2009; Choueiri et al., 2010; Ewer et al., 2010; Hutson et al., 2010). Fatal adverse events (FAEs) are deaths that related to use of the pharmaceutical agent. "
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Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib.
Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen.
13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumour type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%).
It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.
Available from: Javier De Castro Carpeño
- "Potential overlapping toxicities between axitinib and the chemotherapeutic agents, such as fatigue, nausea, diarrhoea and stomatitis, did not appear to be appreciably exacerbated. Patients receiving anti-VEGF therapies have an increased risk of developing hypertension (Jain and Townsend, 2007; Zhu et al, 2007; Wu et al, 2008), and the incidence of hypertension in this study was consistent with previous axitinib trials (Rixe et al, 2007; Cohen et al, 2008; Rini et al, 2009; Schiller et al, 2009). Moreover, grade X3 hypertension reported here was comparable to that reported in phase III studies in various advanced solid tumours treated with the VEGF inhibitor bevacizumab plus chemotherapy (4–14.8%) "
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This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.
In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.
Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade⩾3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.
Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.
Available from: Yasuhide Yamada
- "The AEs reported for BMS-690514 are typical for TKIs that inhibit EGFR, HER2, or VEGFR2. Diarrhea and skin rash are considered class effects associated with EGFR inhibition , while hypertension, proteinuria, and bleeding events are well-established class effects of anti-VEGF therapy [13–15]. Importantly, the side effects observed with BMS-690514 did not appear to be greater than those observed with single-targeted therapies . "
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ABSTRACT: BMS-690514 is a novel oral tyrosine kinase inhibitor of ErbB and vascular endothelial growth factor receptor. This open-label phase I dose-escalation study (ClinicalTrials.gov Identifier: NCT00516451) aimed to assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients with advanced or metastatic solid tumors.
Patients with advanced or metastatic solid tumors received oral BMS-690514 once daily continuously until disease progression or intolerable toxicity occurred. Dose-limiting toxicity (DLT) was evaluated from the first dose to Day 29. Dose levels at 100 and 200 mg were investigated. Assessments included adverse events, tumor response, pharmacokinetics, pharmacodynamics, 2 [18F] fluoro-2-deoxyglucose positron-emitting tomography, and epidermal growth factor receptor and K-ras mutations.
BMS-690514 at the dose of 100 mg (n = 3) or 200 mg (n = 3) was administered once daily to totally nine patients and was well tolerated up to 200 mg. No treatment-related serious adverse events or DLTs were reported. Frequently observed treatment-related AEs were acne, diarrhea, dry skin, hypertension, stomatitis, blood fibrinogen increased, hemoglobin decreased, pruritus, and hypoalbuminemia. These were generally reported as Grade 1 and 2. Five of 9 patients (56 %) had stable disease. Plasma concentrations of BMS-690514 reached Cmax within 3 h and declined with an effective half-life of approximately 10 and 12 h at 100 and 200 mg, respectively.
Oral BMS-690514 was well tolerated in Japanese patients with advanced or metastatic solid tumors up to 200 mg.
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