Efficacy comparison of fruquintinib,regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer

BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.

新型多激酶抑制药regorafenib作用机制及临床研究概述

Regorafenib是一种新型的多激酶抑制药,对干细胞因子受体（KTT）、原癌基因（RET）、血小板源性生长因子受体（PDGFR）、成纤维细胞生长因子受体（FGFR）和血管内皮生成因子（VEGFR）等多个肿瘤通路均有抑制作用,临床试验证实对多种实体瘤有效,美国FDA已批准用于晚期直肠癌治疗,是第一个在晚期结直肠癌中被证实有效的口服多激酶抑制药。本文就其药理学、药动学、不良反应、相互作用及临床试验做一综述。1药理学Regorafenib为小分子多激酶抑制药,对正常细胞,

Regorafenib-loaded poly(lactide-co-glycolide) microspheres designed to improve transarterial chemoembolization therapy for hepatocellular carcinoma

Transarterial chemoembolization(TACE)has been widely introduced to treat hepatocellular carcinoma(HCC)especially for unresectable patients for decades.However,TACE evokes an angiogenic response due to the secretion of vascular endothelial growth factor(VEGF),resulting in the formation of new blood vessels and eventually tumor recurrence.Thus,we aimed to develop regorafenib(REGO)-loaded poly(lactide-co-glycolide)(PLGA)microspheres that enabled localized and sustained drug delivery to limit proangiogenic responses following TACE in HCC treatment.REGO-loaded PLGA microspheres were prepared using the emulsion-solvent evaporation/extraction method,in which DMF was selected as an organic phase co-solvent.Accordingly,we optimized the proportion of DMF,which the optimal ratio to DCM was 1:9(v/v).After preparation,the microspheres provided high drug loading capacity of 28.6%,high loading efficiency of 91.5%,and the average particle size of 149μm for TACE.IR spectra and XRD were applied to confirming sufficient REGO entrapment.The in vitro release profiles demonstrated sustained drug release of microspheres for more than 30 d To confirm the role of REGO-loaded microspheres in TACE,the cell cytotoxic activity on HepG2 cells and anti-angiogenic effects in HUVECs Tube-formation assay were studied in combination with miriplatin.Moreover,the microspheres indicated the potential of antagonizing miriplatin resistance of HepG2 cells in vitro.Pharmacokinetics preliminary studies exhibited that REGO could be sustainably released from microspheres for more than 30d after TACE in vivo.In vivo anti-tumor efficacy was further determined in HepG2 xenograft tumor mouse model,demonstrating that REGO microspheres could improve the antitumor efficacy of miriplatin remarkably compared with miriplatin monotherapy.In conclusion,the obtained REGO microspheres demonstrated promising therapeutic effects against HCC when combined with TACE.

Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization

AIM:To evaluate the inhibitory effects of regorafenib(BAY 73-4506),a multikinase inhibitor,on corneal neovascularization(NV).METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g,were used.Corneal NV was induced by NaOH in the left eyes of each rat.Following the establishment of alkali burn,the animals were randomized into five groups according to topical treatment.Group 1(n=6)received 0.9%NaCl,Group 2(n=6)received dimethyl sulfoxide,Group 3(n=6)received regorafenib 1 mg/mL,Group 4(n=6)received bevacizumab 5 mg/mL and Group 5(n=6)received 0.1%dexamethasone phosphate.On the 7d,the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea’s total area using computer-imaging analysis.The corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by immunostaining.RESULTS:A statistically significant difference in the percent area of corneal NV was found among the groups(P【0.001).Although the Group 5 had the smallest percent area of corneal NV,there was no difference among Groups 3,4 and 5(P】0.005).There was a statistically significant difference among the groups in apoptotic cell density(P=0.002).The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups(P【0.05).The staining intensity of epithelial and endothelial vascular endothelial growth factor was significantly weaker in Groups 3,4 and 5 thanin Groups 1 and 2.CONCLUSION:Topical administration of regorafenib 1mg/mL is partly effective for preventing alkali-induced corneal NV in rats.

Regorafenib联合PD⁃1抑制剂在晚期微卫星稳定型结直肠癌中的疗效和安全性

目的评估瑞戈非尼(Regorafenib)联合PD-1抑制剂三线及以上治疗晚期微卫星稳定(microsatellite stable,MSS)型结直肠癌(colorectal cancer,CRC)的疗效和安全性。方法选择2019年1月至2022年3月在武汉大学人民医院肿瘤中心接受Regorafenib联合PD-1抑制剂或Regorafenib单药三线及以上治疗的22例晚期MSS型CRC患者为研究对象,其中联合治疗组10例,Regorafenib单药组12例。比较两组的无疾病进展生存期(progression-free survival,PFS)、总生存期(overall survival,OS)、客观缓解率(objective response rate,ORR)、疾病控制率(disease control rate,DCR)及不良反应发生情况。结果Kaplan-Meier生存分析显示,联合治疗组和单药组中位OS差异无统计学意义(6.10个月vs 6.13个月,P=0.827);但联合治疗组的中位PFS优于单药组(4.00个月vs 1.63个月,P=0.025)。相比单药组,联合治疗组在DCR(70.0%vs 25.0%,P=0.084)表现出优势,但差异无统计学意义。两组均未出现4级及以上不良反应,联合治疗组和单药组不良反应总发生率(100.0%vs 91.7%)以及≥3级不良反应发生率(30.0%vs 25.0%)比较差异均无统计学意义(均P>0.05)。结论相比于Regorafenib单药治疗,Regorafenib联合PD-1抑制剂作为晚期MSS型CRC三线及以上治疗方案可能在PFS方面带来获益,值得进一步开展临床试验研究。

Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib:Multicenter French clinical experience in real-life after matching

BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma(HCC)is a common situation.The only therapeutic options in France are two broadspectrum tyrosine kinase inhibitors(TKIs),regorafenib(REG)and cabozantinib(CBZ),but no comparative real-life studies are available.AIM To evaluate the progression-free survival(PFS)of patients treated with REG or CBZ,we investigated the disease control rate(DCR),overall survival(OS),and safety of both drugs.To identify the variables associated with disease progression over time.METHODS A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers(Avignon,Marseille,and Nice)between January 2017 and March 2021 using propensity score matching.PFS and OS were assessed using the Kaplan-Meier method.Multivariate analysis(MA)of progression risk factors over time was performed in matched-pair groups.RESULTS Fifty-eight patients 68(62-74)years old with HCC,Barcelona clinic liver cancer(BCLC)B/C(86%),Child-Pugh(CP)-A/B(24%)received REG for 3.4(1.4-10.5)mo as second-line therapy.Twentyeight patients 68(60-73)years,BCLC B/C(75%),CP-A/B(25%)received CBZ for 3.7(1.8-4.9)mo after first-line treatment with sorafenib[3(2-4)(CBZ)vs 4(2.9-11.8)mo(REG),P=0.0226].Twenty percent of patients received third-line therapy.After matching,PFS and DCR were not significantly different after a median follow-up of 6.2(2.7-11.7)mo(REG)vs 5.2(4-7.2)mo(CBZ),P=0.6925.There was no difference in grade 3/4 toxicities,dose reductions,or interruptions.The OS of CP-A patients was 8.3(5.2-24.8)vs 4.9(1.6-11.7)mo(CP-B),P=0.0468.The MA of risk factors for progression over time identified C-reactive protein(CRP)>10 mg/L,neutrophil-to-lymphocyte ratio(NLR)>3,and aspartate aminotransferase(AST)>45 IU as predictive factors.CONCLUSION This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC.Elevated levels of inflammatory markers(CRP and NLR)and AST were associated with non-control of TKIs over time.A 2-mo online progression risk calculation is proposed.

Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness

BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal capillary proliferation(n=1),transaminase elevation(n=1),and hand-foot syndrome(n=2).No grade 4 or higher toxicity was observed.CONCLUSION Regorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC.The PLR might be a prediction of the patient response to this therapy.

Effects of sorafenib and regorafenib on the expression of hypoxia-inducible factors in hepatocellular carcinoma-transplanted nude mice

Objective The objective of this study was to investigate the inhibitory effects of sorafenib and regorafenib on the growth of hepatocellular carcinoma(HCC)using a subcutaneous transplantation tumor model in nude mice and exploring the effects of sorafenib and regorafenib on the expression of hypoxia-inducible factor(HIF)-1α,HIF-2α,and HIF-1βin HCC tissues collected from HCC-transplanted nude mice.Methods HepG2 cells were inoculated intradermally into nude mice.The mice were randomly assigned to either sorafenib treatment(100 mg/kg),regorafenib treatment(20 mg/kg),or solvent control group(dimethylsulfoxide)(n=8 per group)and received once-daily treatment for 14 days.The tumor volumes were recorded every 3 days after the initiation of treatment.The expression levels of HIF-1α,HIF-1β,HIF-2α,and SART1 in the HCC tissues were examined via quantitative real-time PCR(qRT-PCR)analysis and Western blotting.Results The tumors in the sorafenib and regorafenib treatment groups grew slower and smaller than did the tumors in the solvent control group.qPCR analysis and western blotting demonstrated that the mRNA and protein expressions of HIF-1αand HIF-1βwere down-regulated.The expression of HIF-2αand SART1 was up-regulated in the sorafenib treatment group(P<0.05);meanwhile,the expression of HIF-1αand HIF-1βwas up-regulated,and that of HIF-2αand SART1 was down-regulated in the regorafenib treatment group(P<0.05).Conclusion The expression of hypoxia-associated factor is up-regulated by sorafenib and down-regulated by regorafenib,which may induce the different effects of sorafenib on the expression of HIFs.

Case Report: Bilateral Pneumothoraces due to Targeted Tumor Therapy with Regorafenib in a Young Woman with Metastatic Colorectal Cancer

Background: Colorectal cancer is one of the most common cancer types, frequently metastasizing into the lungs. Treatment options have been vastly improved over the last years. With the increasing use of targeted therapies, novel and rare adverse effects can be seen. Case Presentation: A 43-year-old woman presented in our oncology department with chest pain and dyspnea. The patient was diagnosed with colorectal cancer seven years earlier and had received chemoradiation, surgery, and multiple chemotherapies before she was started on regorafenib because of progressive pulmonary metastases. Computed tomography scans demonstrated cavitation of former nodular bilateral pulmonary metastases. After drainage and resolution of the right-sided pneumothorax, the patient returned eleven days later with recurrent symptoms caused by left-sided tension pneumothorax. Video-assisted thoracoscopy and bilateral pleurodeses were performed. Persistent air leaks with severe pain and pulmonary infiltrates led to the death of the patient. Conclusions: This case demonstrates the efficacy of oral antiangiogenetic therapy in advanced metastatic colorectal cancer. Nevertheless, it also depicts an important potential side effect by transforming multiple solid lung metastases into cavitations which led to recurrent pneumothoraces. Special attention should be paid to this phenomenon as treatment of these complications can be challenging.

小分子酪氨酸激酶抑制剂regorafenib研究进展

regorafenib(BAY 73-4506,Stivarga&#174;)是新型的口服小分子多激酶抑制剂,可广泛抑制与血管生成和肿瘤发生相关的靶激酶。该药影响的作用通路以及用于监测该药物疗效的生物标记物是研究的热点之一。同时由于其广谱的激酶抑制活性,对该药多种适应症的研究也在广泛开展。鉴于regorafenib被批准时同时带框警告,其副作用也不容忽视。

瑞格拉非尼(Regorafenib)的合成

瑞格拉非尼(Regorafenib)是新型多激酶抑制剂类抗癌药物,主要用于转移性结直肠癌的治疗。笔者以2-吡啶甲酸为原料,经氯化、醇解、酰胺化、与4-氨基-3-氟苯酚发生亲核取代反应得到中间体4-(4-氨基-3-氟苯氧基)-2-(甲基氨甲酰基)吡啶,再与4-氯-3-三氟甲基苯异氰酸酯和缩合得到瑞格拉非尼(Regorafenib)。瑞格拉非尼(Regorafenib)的总收率为38%(以2-吡啶甲酸计)。

Regorafenib联合TAS102新策略治疗肝细胞癌的研究

背景与目的:瑞格菲尼(regorafenib,REG)和TAS102是治疗消化道肿瘤的新型药物。嘧啶类药物5-氟尿嘧啶(5-fluorouracil,5-FU)联合REG可抑制多药耐药转移性结肠癌的进展。肿瘤干细胞(cancer stem cell,CSC)决定肿瘤的自我更新,异质性及治疗耐受等,靶向CSC为治愈肿瘤提供了可能途径。探讨REG联合TAS102治疗肝细胞癌(hepatocellular carcinoma,HCC)的联合效应及潜在机制。方法:以人HepG2、Huh7和SK-Hep1肝癌细胞系为实验对象。REG和TAS102单药或联合处理肝癌细胞及荷瘤动物。采用细胞计数试剂盒(cell counting kit-8,CCK-8)检测肝癌细胞活力;流式细胞术分析肝癌细胞中CD133阳性细胞亚群比例;采用蛋白质印迹法(Western blot)分析不同药物处理后肝癌细胞中蛋白表达差异;含不同药物的干细胞培养基培养肝癌干细胞球(HCC sphere);荷瘤动物实验评估药物联合治疗效果。结果:REG及TAS102单药显著抑制肝癌细胞活力。TAS102联合使用减低REG单药时诱导增加的CD133阳性细胞亚群比例及干细胞标志分子SRY相关的高迁移率族盒蛋白-2(SRY-related high mobility group box protein-2,SOX2)和乙醛脱氢酶1A(aldehyde dehydrogenase 1A,ALDH1A)的蛋白水平。同时REG的联合使用下调TAS102单药处理时诱导活化的抗凋亡蛋白髓细胞白血病-1蛋白(myeloid cell leukemia-1,MCL1)信号。REG联合TAS102显著抑制了HCC sphere的形成。动物实验证实REG联合TAS102显著抑制肝癌瘤体的生长。结论:REG联合TAS102通过调控肝癌细胞的干细胞性及抗凋亡信号,发挥联合用药增强抗HCC的活性,为临床治疗难治性HCC提供了一种新的治疗策略。

Regorafenib对Aβ_(1-42)诱导的阿尔兹海默病细胞与动物模型的保护作用与机制探究

研究Regorafenib对阿尔兹海默病(Alzheimer’s disease, AD)的保护作用及机制,本研究采用Aβ_(1-42)损伤造模建立AD细胞模型与AD动物模型,并使用Regorafenib进行干预。使用Western blot法、免疫组化以及qRT-PCR法考察Regorafenib对模型小鼠脑内AD病理的影响,进一步使用Western blot法、Hoechst/PI染色法、JC-1探针法探究Regorafenib对AD细胞损伤模型的改善作用,最后深入分析Regorafenib对AD细胞与动物模型发挥保护作用的分子机制。结果显示,Regorafenib能显著缓解AD小鼠脑中tau蛋白的异常磷酸化,并改善脑内小胶质细胞和星形胶质细胞的异常活化,降低炎症因子表达水平。同时,Regorafenib可以有效缓解Aβ_(1-42)致SH-SY5Y损伤的细胞模型中tau蛋白异常磷酸化水平;改善细胞凋亡情况及线粒体膜电位的异常下降,并且Regorafenib主要通过调节AMPK/MEK/ERK通路改善Aβ_(1-42)诱导的阿尔兹海默病模型的病理进展。

Regorafenib

Regorafenib是由德国Bayer Healthcare公司开发的多靶点酪氨酸激酶抑制剂类抗肿瘤药，主要用于治疗转移性结肠直肠癌，商品名称为Stivarga。该药为薄膜衣片，药用成分为其一水合物，于2012年9月27日获美国FDA批准上市。

1例转移性结直肠癌患者三线治疗的综合药学照护

目的探讨1例转移性结直肠癌患者(mCRC)三线治疗的综合药学照护,为mCRC患者三线治疗的药学照护提供参考建议。方法以临床病例为依据,依托在线离线(O2O)药学服务新模式,对患者实施综合药学照护;结合mCRC患者三线治疗现状,探索药物治疗管理方法。结果患者在临床医师与临床药师的协作下顺利完成3个周期的治疗,获得了实验室指标上的改善。结论临床药师通过综合药学照护可以协助临床医师诊疗,促进临床用药合理化和个体化,达到安全、有效、经济的治疗目标。

瑞戈非尼联合健脾消癌方对结直肠癌的临床疗效及免疫功能的影响

目的研究瑞戈非尼联合健脾消癌方治疗结直肠癌的临床疗效及其对免疫功能的影响。方法采用随机数字表法将2022年2月至2023年12月南京中医药大学附属南京医院(南京市第二医院)肿瘤科接收的结直肠癌患者70例进行分组,观察组(35例)服用瑞戈非尼联合健脾消癌方,对照组(35例)予以瑞戈非尼口服,均用药28 d。评价总有效率;检测治疗前后T淋巴细胞(CD3^(+))、辅助性T细胞(CD4^(+))、CD4^(+)/细胞毒性T细胞(CD8^(+))、糖类抗原(CA125、CA19-9、CA242)、癌胚抗原(carcinoembryonic antigen,CEA)、白细胞介素(interleukin,IL)-6、IL-10、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α);统计不良反应(恶心呕吐、手足皮肤反应、腹泻、肝肾功能等)。结果观察组总有效率为57.14%,高于对照组的42.86%(P<0.05)。治疗后,两组患者CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)水平均明显高于治疗前(P<0.05),且观察组CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)均高于对照组(P<0.05)。治疗后,两组CA125、CA19-9、CA242、CEA水平均低于治疗前(P<0.05),且观察组CA125、CA19-9、CA242、CEA水平均低于对照组(P<0.05)。治疗后,两组血清IL-6、IL-10、TNF-α水平均低于治疗前(P<0.05),且观察组IL-6、IL-10、TNF-α均低于对照组(P<0.05)。治疗期间,两组不良反应总发生率比较,差异无统计学意义(P>0.05)。结论瑞戈非尼联合健脾消癌方对结直肠癌有较好疗效,可减轻炎性反应、调节免疫能力、降低肿瘤标志物水平,且不良反应少,值得临床推广。

基于OpenVigil对索拉非尼和瑞戈非尼不良事件的信号挖掘与分析

目的对索拉非尼和瑞戈非尼两种多激酶抑制剂进行药品不良事件(ADE)信号挖掘和分析评价,为临床用药提供参考。方法检索OpenVigil 2.1数据库索拉非尼和瑞戈非尼的ADE报告,时间截至2022年第2季度。使用报告比值比法(ROR)、比例报告比法(PRR)和综合标准法(MHRA)进行信号挖掘,评价ADE信号特点。结果收集到索拉非尼ADE报告11391例,瑞戈非尼4941例。ADE信号929个,其中索拉非尼579个,瑞戈非尼350个。索拉非尼报告数最多的是腹泻,有1363例(11.97%),关联性最强的是维生素K缺乏或拮抗剂Ⅱ诱导产生的蛋白升高(ROR=502.46,PRR=502.064),瑞戈非尼报告数最多的疲劳,有598例(12.1%),关联性最强的是掌跖角化病(ROR=185.378,PRR=185.08)。索拉非尼ADE信号累及系统器官分类(SOC)为25个,瑞戈非尼22个。索拉非尼药品说明书未载明的ADE信号有2种,瑞戈非尼3种。结论索拉非尼与瑞戈非尼作为结构相似的抗肿瘤药物,筛选得到的ADE信号大多重叠,在报告数、涉及系统器官和关联强度上发现新信号,提示临床使用需注意相关ADE。两种药物ADE信号报告数和关联强度的差异可为其临床使用提供参考,建议临床根据信号偏倚合理使用。

1例小剂量瑞戈非尼致晚期软组织肉瘤患者精神异常的药学监护

临床药师参与1例非脂肪软组织肉瘤患者使用小剂量瑞戈非尼致精神异常的临床实践。该患者合并低蛋白血症、肝功能不全、脑白质病等多种疾病,治疗前精神正常,使用瑞戈非尼40 mg,po,qd,用药5 d后突发意识不清。临床药师通过分析排除了肿瘤脑转移、脑白质病变加重或肝性脑病等疾病及合并用药引起精神异常的可能,评定患者精神异常与瑞戈非尼的关联性为“很可能”,考虑精神异常为瑞戈非尼所致不良反应,立即停药,同时给予对症处理,5 d后患者精神状态好转。此外,临床药师监护患者治疗,并结合循证证据提供合适的抗肿瘤药物治疗建议。该病例提示临床使用瑞戈非尼时应警惕精神异常不良反应,做好药学监护,发生不良反应后及时进行用药分析和对症处理。

瑞戈非尼、呋喹替尼、TAS-102治疗转移性结直肠癌的疗效及安全性的Meta分析

目的 系统评价瑞戈非尼、呋喹替尼、曲氟尿苷替匹嘧啶(TAS-102)治疗转移性结直肠癌(mCRC)的疗效及安全性,以有效指导临床医师进行合理用药。方法 利用计算机检索Cochrane Library、PubMed、Google school、Embase、中国知网等数据库,检索时限为建库至2022年12月30日。收集瑞戈非尼、呋喹替尼、TAS-102治疗mCRC疗效及安全性的随机对照试验,采用Cochrane 6.1评分系统对文献进行系统评估,提取总生存期(OS)、无进展生存期(PFS)、客观缓解率(ORR)、疾病控制率(DCR)及药品不良反应(ADR)信息,采用RevMan 5.3、ITC软件进行分析。结果 纳入文献6篇,其中瑞戈非尼相关文献2篇,包括瑞戈非尼组641例,对照组323例;呋喹替尼相关文献2篇,包括呋喹替尼组325例,对照组162例;TAS-102相关文献2篇,包括TAS-102组805例,对照组401例。Meta分析结果显示,瑞戈非尼组、呋喹替尼组、TAS-102组的OS、PFS长于对照组,DCR高于对照组(P<0.01);瑞戈非尼组、呋喹替尼组、TAS-102组的ORR与对照组比较差异无统计学意义(P>0.05);瑞戈非尼组、呋喹替尼组3级以上ADR发生率高于对照组(P<0.05),TAS-102组3级以上ADR发生率与对照组比较差异无统计学意义(P>0.05)。瑞戈非尼组、呋喹替尼组、TAS-102组的OS、ORR、DCR及3级以上ADR发生率比较差异均无统计学意义(P>0.05),但呋喹替尼组的PFS长于TAS-102组(P<0.05)。结论 瑞戈非尼、呋喹替尼、TAS-102作为治疗mCRC的新型化疗药物,其临床抗癌活性均较为可观,且均存在ADR,但呋喹替尼的PFS更优。

广谱激酶抑制剂类抗肿瘤药Regorafenib

由拜耳公司开发的抗肿瘤药regorafenib（BAY73-4506）是一种具口服活性的新型二苯脲类广谱激酶抑制剂,可广泛抑制与血管生成和肿瘤发生相关的靶激酶,如血管内皮生长因子受体VEGFR-2和-3、酪氨酸蛋白激酶受体TIE-2和Ret、血小板衍生生长因子受体PDGFR-β、原癌基因编码的酪氨酸蛋白激酶c-Kit和丝氨酸/苏氨酸蛋白激酶c-Raf、