Eur J Clin Pharmacol (2014) 70:225–231 DOI 10.1007/s00228-013-1598-1
PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis Zexing Wang & Jing Xu & Weiwei Nie & Guichun Huang & Jinhai Tang & Xiaoxiang Guan
Received: 31 July 2013 / Accepted: 30 September 2013 / Published online: 23 October 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Background Regorafenib is a novel multikinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). Hypertension is one of the major adverse events of this agent, but to date the incidence and risk of hypertension with regorafenib have not been systematically investigated. We have conducted a systematic review and meta-analysis of published clinical trials to determine its overall incidence and risk. Methods PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies published up to September 9, 2013. Eligible studies were prospective phase II or III clinical trials using regorafenib in cancer patients with data on hypertension available. The incidence and relative risk (RR) of hypertension were calculated using a random-effects model. Results Data from a total of 1,069 patients (regorafenib n = 750; controls n =319) from five clinical trials were included for analysis. The overall incidence of all-grade and high-grade hypertension were 44.4 % [95 % confidence interval (CI) 30.8–59.0 %) and 12.5 % (95 % CI 5.2–27.1 %), respectively.
Zexing Wang and Jing Xu contributed equally to this work. Z. Wang : J. Xu : G. Huang : X. Guan (*) Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, People’s Republic of China e-mail: [email protected] W. Nie : X. Guan Department of Medical Oncology, Jinling Hospital, School of Medicine, Southern Medical University, Guangzhou 510282, China J. Tang (*) Department of General Surgery, Jiangsu Cancer Hospital–Nanjing Medical University, 42 Baiziting Road, Nanjing 210009, Jiangsu Province, People’s Republic of China e-mail: [email protected]
The use of regorafenib in cancer patients was associated with a significantly increased risk of all-grade (RR 3.76, 95 % CI 2.35– 5.99) and high-grade (RR, 8.39, 95 % CI 3.10–22.71) hypertension. The risk might vary with tumor types (P =0.000). Conclusions Patients with cancer receiving regorafenib have a significantly higher risk of developing hypertension. Close monitoring and appropriate management of this hypertension are strongly recommended. Keywords Regorafenib . Hypertension . Tyrosine kinase inhibitor . Meta-analysis
Introduction Regorafenib (Stivarga; BAY 73-4506) is a novel multikinase inhibitor (MKI) that has demonstrated broad antitumor activity across various solid tumor types in preclinical and clinical studies [1]. Regorafenib inhibits the activity of angiogenic, stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1–3), tyrosine-protein kinase TIE-2, tyrosineprotein kinase receptor Ret, platelet-derived growth factor beta, basic fibroblast growth factor receptor-1, protooncogene c-KIT, RAF-1, BRAF and p38 MAP kinase [2, 3]. Regorafenib has been shown to have significant survival benefits in metastatic colorectal cancer which has progressed following all other standard therapies [4]. Additionally, regorafenib is effective in the treatment of advanced gastrointestinal stromal tumors (GISTs) after the failure of both imatinib and sunitinib [5, 6]. Regorafenib has been approved for the treatment of metastatic colorectal cancer (mCRC) and locally advanced GISTs by the US Food and Drug Administration. At present its utility is being explored for other malignant tumors in more than 30 clinical trials, primarily across North America, Europe, Australia, South America, Middle East, China, Japan and Singapore [7].
226
As with many other approved MKIs (sorafenib, sunitinib, pazopanib, axitinib and vandetanib), regorafenib is associated with substantial side-effects, including hand-foot syndrome, fatigue, diarrhea, among others [8]. Hypertension is also a major side-effect that has been reported in trials, with its incidence ranging from 27.8 to 67.7 % [4, 5]. Previous studies have demonstrated that MKIs are associated with an increased risk of developing hypertension [9–13]. Poorly controlled MKIinduced hypertension may lead to serious cardiovascular events and dose reduction. For example, in the TARGET trial, cardiac ischemia and infarction were more common in patients receiving sorafenib than in those receiving placebo [14]. In addition, in the trial of sunitinib on renal cancer, declined cardiac function was more common in patients assigned sunitinib than in the controls [15]. The left ventricular dysfunction might be partly exacerbated or caused by this hypertension, except for a possible direct cardiomyocyte toxicity from sunitinib [16]. The recognition and management of hypertension might be also an important issue in patients treated with regorafenib because it is a new member of this class of drugs (MKIs). However, because of the limited number of patients in the single trials reported to date, the overall risk of hypertension with regorafenib remains unclear. Therefore, we conducted a systematic review and a meta-analysis to systematically assess this issue.
Eur J Clin Pharmacol (2014) 70:225–231
schedule is 160 mg orally once daily for the first 3 weeks of each 4-week cycle. The clinical trials that met the following criteria were selected for the final analysis: (1) prospective phase II and III clinical trials in cancer patients; (2) participants assigned to treatment with regorafenib at a starting dosage of 160 mg orally once daily, 3 weeks on/ 1 week off; (3) data available on the incidence of hypertension. We reviewed each publication, and only the complete or most recent report of a clinical trial was included when multiple publications of the same trial were identified. We extracted the first author’s name, year of publication, trial phase, numbers of patients for our analysis, treatment arms, median age of patients, primary endpoints of each trial, treatment duration, events of hypertension and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version used to grade toxicities and the targeted cancer diagnosis of the included trials. Clinical endpoints Clinical endpoints extracted from the safety profile of each trial were all-grade (1-4) and high-grade (3-4) hypertension according to the version of NCI-CTCAE used in each trial. Statistical analysis
Methods Data source We searched the PubMed database for relevant studies published between January 1966 and May 2013) using the following keywords: “regorafenib”, “BAY 73-4506” and “stivarga”, respectively. A similar strategy was utilized to query the online database of the American Society of Clinical Oncology (ASCO) meetings’ abstracts from 2004 to 2013. Finally, we conducted an independent search of the Web of Science database for relevant articles published between 1998 and 2013) using the keyword “regorafenib” to ensure that no additional studies were missed. Only full publications (not abstracts) from the Web of Science database were included in the study. The search was restricted to articles published in English. The last search was updated on September 09, 2013. The updated manufacturer package insert of regorafenib was also reviewed for related information. Selection of studies and data extraction Two of the authors independently assessed the eligibility of the articles and abstracts identified by the search, and any discrepancies were resolved by consensus. Regorafenib has been approved for use as a single agent in patients with mCRC and locally advanced GISTs. The recommended dosing
For each trial, the proportion of patients with all-grade and high-grade hypertension was computed and the 95 % confidence interval (CI) derived. For studies with a control arm, the relative risk (RR) of hypertension in patients assigned to regorafenib was also computed and compared only with those assigned to a control treatment in the same trial. For the meta-analysis, the random-effects model was used in view of clinical heterogeneity in the study population (different type of cancer patients). A two-tailed P value of
PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis Zexing Wang & Jing Xu & Weiwei Nie & Guichun Huang & Jinhai Tang & Xiaoxiang Guan
Received: 31 July 2013 / Accepted: 30 September 2013 / Published online: 23 October 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Background Regorafenib is a novel multikinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). Hypertension is one of the major adverse events of this agent, but to date the incidence and risk of hypertension with regorafenib have not been systematically investigated. We have conducted a systematic review and meta-analysis of published clinical trials to determine its overall incidence and risk. Methods PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies published up to September 9, 2013. Eligible studies were prospective phase II or III clinical trials using regorafenib in cancer patients with data on hypertension available. The incidence and relative risk (RR) of hypertension were calculated using a random-effects model. Results Data from a total of 1,069 patients (regorafenib n = 750; controls n =319) from five clinical trials were included for analysis. The overall incidence of all-grade and high-grade hypertension were 44.4 % [95 % confidence interval (CI) 30.8–59.0 %) and 12.5 % (95 % CI 5.2–27.1 %), respectively.
Zexing Wang and Jing Xu contributed equally to this work. Z. Wang : J. Xu : G. Huang : X. Guan (*) Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu Province 210002, People’s Republic of China e-mail: [email protected] W. Nie : X. Guan Department of Medical Oncology, Jinling Hospital, School of Medicine, Southern Medical University, Guangzhou 510282, China J. Tang (*) Department of General Surgery, Jiangsu Cancer Hospital–Nanjing Medical University, 42 Baiziting Road, Nanjing 210009, Jiangsu Province, People’s Republic of China e-mail: [email protected]
The use of regorafenib in cancer patients was associated with a significantly increased risk of all-grade (RR 3.76, 95 % CI 2.35– 5.99) and high-grade (RR, 8.39, 95 % CI 3.10–22.71) hypertension. The risk might vary with tumor types (P =0.000). Conclusions Patients with cancer receiving regorafenib have a significantly higher risk of developing hypertension. Close monitoring and appropriate management of this hypertension are strongly recommended. Keywords Regorafenib . Hypertension . Tyrosine kinase inhibitor . Meta-analysis
Introduction Regorafenib (Stivarga; BAY 73-4506) is a novel multikinase inhibitor (MKI) that has demonstrated broad antitumor activity across various solid tumor types in preclinical and clinical studies [1]. Regorafenib inhibits the activity of angiogenic, stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1–3), tyrosine-protein kinase TIE-2, tyrosineprotein kinase receptor Ret, platelet-derived growth factor beta, basic fibroblast growth factor receptor-1, protooncogene c-KIT, RAF-1, BRAF and p38 MAP kinase [2, 3]. Regorafenib has been shown to have significant survival benefits in metastatic colorectal cancer which has progressed following all other standard therapies [4]. Additionally, regorafenib is effective in the treatment of advanced gastrointestinal stromal tumors (GISTs) after the failure of both imatinib and sunitinib [5, 6]. Regorafenib has been approved for the treatment of metastatic colorectal cancer (mCRC) and locally advanced GISTs by the US Food and Drug Administration. At present its utility is being explored for other malignant tumors in more than 30 clinical trials, primarily across North America, Europe, Australia, South America, Middle East, China, Japan and Singapore [7].
226
As with many other approved MKIs (sorafenib, sunitinib, pazopanib, axitinib and vandetanib), regorafenib is associated with substantial side-effects, including hand-foot syndrome, fatigue, diarrhea, among others [8]. Hypertension is also a major side-effect that has been reported in trials, with its incidence ranging from 27.8 to 67.7 % [4, 5]. Previous studies have demonstrated that MKIs are associated with an increased risk of developing hypertension [9–13]. Poorly controlled MKIinduced hypertension may lead to serious cardiovascular events and dose reduction. For example, in the TARGET trial, cardiac ischemia and infarction were more common in patients receiving sorafenib than in those receiving placebo [14]. In addition, in the trial of sunitinib on renal cancer, declined cardiac function was more common in patients assigned sunitinib than in the controls [15]. The left ventricular dysfunction might be partly exacerbated or caused by this hypertension, except for a possible direct cardiomyocyte toxicity from sunitinib [16]. The recognition and management of hypertension might be also an important issue in patients treated with regorafenib because it is a new member of this class of drugs (MKIs). However, because of the limited number of patients in the single trials reported to date, the overall risk of hypertension with regorafenib remains unclear. Therefore, we conducted a systematic review and a meta-analysis to systematically assess this issue.
Eur J Clin Pharmacol (2014) 70:225–231
schedule is 160 mg orally once daily for the first 3 weeks of each 4-week cycle. The clinical trials that met the following criteria were selected for the final analysis: (1) prospective phase II and III clinical trials in cancer patients; (2) participants assigned to treatment with regorafenib at a starting dosage of 160 mg orally once daily, 3 weeks on/ 1 week off; (3) data available on the incidence of hypertension. We reviewed each publication, and only the complete or most recent report of a clinical trial was included when multiple publications of the same trial were identified. We extracted the first author’s name, year of publication, trial phase, numbers of patients for our analysis, treatment arms, median age of patients, primary endpoints of each trial, treatment duration, events of hypertension and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version used to grade toxicities and the targeted cancer diagnosis of the included trials. Clinical endpoints Clinical endpoints extracted from the safety profile of each trial were all-grade (1-4) and high-grade (3-4) hypertension according to the version of NCI-CTCAE used in each trial. Statistical analysis
Methods Data source We searched the PubMed database for relevant studies published between January 1966 and May 2013) using the following keywords: “regorafenib”, “BAY 73-4506” and “stivarga”, respectively. A similar strategy was utilized to query the online database of the American Society of Clinical Oncology (ASCO) meetings’ abstracts from 2004 to 2013. Finally, we conducted an independent search of the Web of Science database for relevant articles published between 1998 and 2013) using the keyword “regorafenib” to ensure that no additional studies were missed. Only full publications (not abstracts) from the Web of Science database were included in the study. The search was restricted to articles published in English. The last search was updated on September 09, 2013. The updated manufacturer package insert of regorafenib was also reviewed for related information. Selection of studies and data extraction Two of the authors independently assessed the eligibility of the articles and abstracts identified by the search, and any discrepancies were resolved by consensus. Regorafenib has been approved for use as a single agent in patients with mCRC and locally advanced GISTs. The recommended dosing
For each trial, the proportion of patients with all-grade and high-grade hypertension was computed and the 95 % confidence interval (CI) derived. For studies with a control arm, the relative risk (RR) of hypertension in patients assigned to regorafenib was also computed and compared only with those assigned to a control treatment in the same trial. For the meta-analysis, the random-effects model was used in view of clinical heterogeneity in the study population (different type of cancer patients). A two-tailed P value of
