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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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Anti-Tumor Activity and Safety of Multikinase Inhibitors in Advanced and/or Metastatic Thyroid Cancer: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.
Tsoli, M, Alexandraki, KI, Spei, ME, Kaltsas, GA, Daskalakis, K
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2020;(1):25-31
Abstract
Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03-0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62-2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06-1.24); PFS_HR: 0.99 (95% CI: 0.82-1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05-1.33); PFS_HR: 0.99 (95% CI: 0.81-1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68-16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16-2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22-1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82-5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0-2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians' decisions.
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Trans-catheter arterial chemoembolization plus Sorafenib, an unsuccessful therapy in the treatment of hepatocellular carcinoma?: A systematic review and meta-analysis.
Zhang, T, Huang, W, Dong, H, Chen, Y
Medicine. 2020;(29):e20962
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Abstract
BACKGROUND Trans-catheter arterial chemoembolization (TACE) plus Sorafenib is recommended as one of the primary means for treating hepatocellular carcinoma (HCC). This updated meta-analysis focuses on identifying the efficacy and safety of TACE plus Sorafenib versus TACE, which remains controversial despite years of exploration. METHOD PubMed, Medline, Embase, China Journal Full-text Database, Wanfang Database, and Weipu Database were used to retrieve the studies which are about comparing the clinical efficacy and safety of TACE+Sorafenib with TACE alone. The Review Manager (Version 5. 3) software was used to perform a meta-analysis of the results of studies which met the inclusion criteria recommended by the Cochrane Collaboration. RESULT Compared with TACE for treating primary HCC, TACE combined with Sorafenib can improve the 1 year, 2 years, 3 years, and 5 years overall survival rate (OS) of patients, respectively, and also improve disease control rate (DCR) and objective response rate (ORR). In terms of adverse reactions, the treatment group can lead to more complications significantly, such as hand-foot skin reaction, hypertension, diarrhea, rash, hair loss, and so on, most of which are relevant to Sorafenib related adverse reactions, but most patients have a good prognosis after symptomatic treatment. CONCLUSION The clinical efficacy of TACE combined with Sorafenib in treating primary hepatocellular carcinoma is better than TACE, and the safety is acceptable.
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Which is the best combination of TACE and Sorafenib for advanced hepatocellular carcinoma treatment? A systematic review and network meta-analysis.
Feng, F, Jiang, Q, Jia, H, Sun, H, Chai, Y, Li, X, Rong, G, Zhang, Y, Li, Z
Pharmacological research. 2018;:89-101
Abstract
The aim of this study was to assess the comparative efficacy and safety of combination therapy with transarterial chemoembolization (TACE) and Sorafenib for patients with advanced hepatocellular carcinoma (HCC) through a systematic review and network meta-analysis and identify the best combination of TACE and Sorafenib. We searched databases for publications prior to May 2018. The prespecified efficacy outcomes were the objective response rate, overall survival rate, and time to progression. adverse effects included dermatologic, gastrointestinal, and general disorders. Subgroup analyses, meta-regression, and a network meta-analysis regarding two types of outcomes by different chemotherapy agents in TACE (5-fluorouracil, Adriamycin, Platinum, mitomycin C, hydroxycamptothecin) were included. The study is registered with PROSPERO (CRD42018098541). For efficacy outcomes, subgroups which included 5-fluorouracil and hydroxycamptothecin ranked higher than other chemotherapy agents, while mitomycin C ranked the lowest. For advanced effects, the use of mitomycin C or 5-fluorouracil as the chemotherapy agent ranked higher, while hydroxycamptothecin ranked the lowest. Therefore, we excluded 5-Fu and Mitomycin C in subsequent studies. Additionally, in the evaluation of primary adverse effects by the network meta-analysis, Platinum ranked the highest while hydroxycamptothecin ranked the lowest. Therefore, we excluded Platinum this time. Furthermore, all types of Adriamycin are not same, and some studies included two types of Adriamycin. The network meta-analysis results showed that the TACE (hydroxycamptothecin + pirarubicin) +Sorafenib arm and TACE (hydroxycamptothecin + epirubicin) +Sorafenib arm had significant efficacy differences. In conclusion, for patients with advanced HCC, combination therapy with HCPT plus THP/EPI in TACE and Sorfenib may be used as a first-line treatment.
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Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.
Wang, DY, Salem, JE, Cohen, JV, Chandra, S, Menzer, C, Ye, F, Zhao, S, Das, S, Beckermann, KE, Ha, L, et al
JAMA oncology. 2018;(12):1721-1728
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Abstract
IMPORTANCE Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data. OBJECTIVE To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. DESIGN, SETTING, AND PARTICIPANTS We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. EXPOSURES Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). MAIN OUTCOMES AND MEASURES Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. RESULTS Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). CONCLUSIONS AND RELEVANCE In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.
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Bleeding risk in cancer patients treated with sorafenib: A meta-analysis of randomized controlled trials.
Dai, C, Zhou, F, Shao, JH, Wu, LQ, Yu, X, Yin, XB
Journal of cancer research and therapeutics. 2018;(Supplement):S948-S956
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Abstract
OBJECTIVE Sorafenib, an oral vascular endothelial growth factor receptor tyrosine-kinase inhibitor, has become a cornerstone in the treatment of various malignancies. However, concerns have arisen regarding the risk of hemorrhage with sorafenib use. Nevertheless, the contribution of sorafenib to hemorrhage and the underlying risk factors remains unclear. MATERIALS AND METHODS We performed a meta-analysis to determine the incidence and risk of hemorrhage associated with sorafenib treatment. Multiple databases were searched to identify relevant studies. The analysis included randomized controlled trials (RCTs) that directly compared cancer patients treated with or without sorafenib. Statistical analyses were conducted to determine the overall incidence, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effect models. RESULTS Ten RCTs involving 4720 patients were included in the analysis. Overall, the incidence rates of all- and high-grade hemorrhage in patients receiving sorafenib were 9.89% (95% CI: 8.73-11.18%) and 2.86% (95% CI: 2.25-3.63%), respectively. Sorafenib treatment increased the risk of all-grade hemorrhage in patients compared to control treatment (RR: 1.99; 95% CI: 1.59-2.49; P < 0.00001), but did not increase the incidence of high-grade hemorrhage (RR: 1.42; 95% CI: 0.95-2.12; P = 0.09). Subgroup analysis showed no significant increase in the risk of hemorrhage between patients with various malignancies or concurrent treatment. No evidence of publication bias was observed. CONCLUSION In patients with malignancy, sorafenib treatment combined with standard treatment significantly increases the risk of low-grade hemorrhagic events.
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Hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis.
Kassem, L, Shohdy, KS, Lasheen, S, Abdel-Rahman, O, Bachelot, T
Breast cancer (Tokyo, Japan). 2018;(1):17-27
Abstract
BACKGROUND The introduction of specific cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly improved progression-free survival in hormone receptor-positive metastatic breast cancer. CDK 4/6 inhibitors induce cell cycle arrest via liberating the tumor suppressor retinoblastoma protein from CDK4/6 inhibitory effect. Preliminary studies suggested an increase in the hematological toxicities which might affect the quality of life in such palliative setting. METHODS We searched PubMed, ASCO, ESMO and San Antonio meeting databases for randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors with safety data provided on the incidence of hematological adverse effects. RESULTS Our search identified 1012 citations that were screened for relevance. Thirty-six studies were found to be potentially eligible. After excluding the ineligible studies, six studies were deemed to be eligible for meta-analysis. The risk ratio (RR) was 11.31 [95% confidence interval (CI) 8.06-15.87; p < 0.0001] for all-grade leucopenia, 14.86 (95% CI 11.37-19.41; p < 0.0001) for all-grade neutropenia, 9.04 (95% CI 3.78-21.63; p < 0.0001) for all-grade thrombocytopenia and 3.57 (95% CI 2.65-4.81; p < 0.0001) for all-grade anemia. The RR for grade 3/4 leucopenia was 33.86 (95% CI 14.59-78.57; p < 0.0001), for grade 3/4 neutropenia was 44.00 (95% CI 24.72-78.33; p < 0.0001), for grade 3/4 thrombocytopenia was 5.70 (95% CI 2.03-16.01; p = 0.001) and for grade 3/4 anemia was 2.80 (95% CI 1.45-5.41; p = 0.002). There was no significant increase in the RR of febrile neutropenia with RR of 3.29 (95% CI 0.93-11.57; p = 0.06). CONCLUSION Our analysis provides evidence that the use of CDK 4/6 inhibitors is associated with an increased risk of all-grade and high-grade hematological adverse events, which seems to be a class-effect, but not of febrile neutropenia compared with hormonal therapy alone.