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Adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis.
Yin, X, Zhao, Z, Yin, Y, Shen, C, Chen, X, Cai, Z, Wang, J, Chen, Z, Yin, Y, Zhang, B
Clinical and translational science. 2021;(3):919-933
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Abstract
The efficacy of agents targeting epidermal growth factor receptor (EGFR) in patients with various cancers was well elucidated. However, the safety profile of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has not been systematically investigated. This meta-analysis aimed to evaluate the safety profile of EGFR-TKIs in patients with cancer. A systematic search of PubMed, EMBASE, Cochrane Library databases, ASCO, and ESMO abstracts were conducted. Randomized controlled trials (RCTs) that compared safety profile of EGFR-TKIs with placebo were included. The end points included treatment-related adverse events (AEs), treatment discontinuation, and toxic death. Twenty-eight RCTs containing 17,800 patients were included. The analyses showed that the most frequently observed all-grade AEs in patients treated with EGFR-TKIs were diarrhea (53.7%), rash (48.6%), mucositis (46.5%), alanine aminotransferase (ALT) increased (38.9%), and skin reaction (35.2%). The most common high-grade (grade ≥3) AEs were mucositis (14.8%), pain (8.2%,), metabolism and nutrition disorders (7.4%), diarrhea (6.2%), dyspnea (6.1%), and hypertension (6.1%). The incidence of serious AEs, treatment discontinuation, and toxic death due to AEs were 18.2%, 12.36%, and 3.0%, respectively. Pooled risk ratio (RR) showed that the use of EGFR-TKIs was associated with an increased risk of developing AEs. Subgroup analysis indicated that the risk of AEs varied significantly according to tumor type, generation line, and drug type. Our meta-analysis indicates EGFR-TKIs was associated with a significant increased risk of a series of unique AEs. Early detection and proper management of AEs are important to reduce morbidity, avoid treatment discontinuation, and improve patient quality of life. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? The safety profile of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) varied in different trials, and has not been systemically investigated. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted this meta-analysis of randomized control trials (RCTs) to provide a comprehensive evaluation of adverse event in patients with cancer receiving EGFR-TKIs. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our meta-analysis indicates EGFR-TKIs was associated with a significant increased risk of a series of unique adverse events (AEs). HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The integrated understanding of safety profile of EGFR-TKIs will help in the future design of new EGFR-TKIs with a better safety profile.
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Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
Cheng, AL, Kang, YK, Chen, Z, Tsao, CJ, Qin, S, Kim, JS, Luo, R, Feng, J, Ye, S, Yang, TS, et al
The Lancet. Oncology. 2009;(1):25-34
Abstract
BACKGROUND Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. METHODS Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. FINDINGS 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. INTERPRETATION Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.