安罗替尼联合替吉奥治疗三线及以上晚期非小细胞肺癌的安全性和有效性

目的:前瞻性应用安罗替尼联合替吉奥治疗三线及以上晚期非小细胞肺癌，观察临床疗效和药物的安全性。方法:均经组织病理或细胞学明确诊断晚期非小细胞肺癌，且二线化疗治疗后疾病进展。口服安罗替尼胶囊8 mg/d，d1~14联合替吉奥胶囊60 mg/m2 bid d1~14，21天为一个周期。治疗终止时间为疾病进展或出现不可接受的毒副反应。结果:本研究结果显示，总体客观缓解率（ORR）可达到26.8%，总体疾病控制率（DCR）可达到80.5%，中位无进展生存期（mPFS）达到5.2个月（95%CI:3.9~6.6个月）。单因素分析，脑转移组患者mPFS（4.8个月）对比无脑转移组患者mPFS（5.9个月），两组差异具有统计学意义（P=0.039）。多变量回归分析显示，ECOG评分(P=0.002)、治疗线数（P=0.015）和疗效(P=0.014)是PFS的独立影响因素。最常见毒副反应为高血压、蛋白尿、骨髓抑制、胃肠道反应、疲乏和口腔黏膜炎。结论:安罗替尼联合替吉奥胶囊在晚期非小细胞肺癌三线及以上治疗中，其总体的疗效确切且药物毒副反应可控。     

放疗联合安罗替尼对小细胞肺癌患者胱天蛋白酶3、多腺苷二磷酸核糖聚合酶表达的影响研究

目的探讨放疗联合安罗替尼对小细胞肺癌(SCLC)患者胱天蛋白酶3(caspase 3)、多腺苷二磷酸核糖聚合酶(PARP)表达的影响。方法将86例SCLC患者随机分为放疗组(n=42)和联合组(放疗联合安罗替尼,n=44),探索两组1年生存率、不良反应发生情况及对caspase 3、PARP表达的影响。结果治疗前两组患者血清caspase 3、PARP水平比较,差异均无统计学意义(P﹥0.05);治疗后联合组患者血清caspase 3水平明显高于放疗组,PARP水平明显低于放疗组,差异均有统计学意义(P﹤0.01)。两组患者白细胞减少、中性粒细胞减少发生率比较,差异均无统计学意义(P﹥0.05)。联合组患者1年生存率高于放疗组,差异有统计学意义(P﹤0.05)。结论放疗联合安罗替尼可以有效提高SCLC患者血清内caspase 3水平,降低PARP水平,延长患者的生存时间,值得临床进一步研究。     

Efficacy and safety of anlotinib plus S-1as thirdly-line or later-line treatmentin advanced non-small cell lung cancer

Objective Anlotinib,an oral vascular endothelial growth factor receptor 2(VEGFR2)inhibitor,has confirmed antitumor activity in lung cancer in both in vitro and in vivo assays,and has been recommended as third-line treatment agent in non-oncogene driven non-small cell lung cancer(NSCLC).This prospective study aimed to investigate the efficacy and safety of anlotinib plus S-1 for third-or later-line treatment in patients with advanced NSCLC.Methods Patients with histologically or cytologically confirmed NSCLC,and documented disease progression following second-line chemotherapy,and/or epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI)treatment were enrolled in this study.The patients were treated anlotinib(8 mg daily d 1–14)and S-1(60 mg/m^2 d 1–14)and the treatment was repeated every 3 weeks.Treatment was continued until disease progression or unacceptable toxicity occurred.The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),and adverse events(AEs)were reviewed and evaluated.Results Forty-one patients were enrolled in the study between June 2018 and December 2018.The total ORR and DCR were 26.8%and 80.5%,respectively.The median PFS was 5.2 months[95%confidence interval(CI),3.9 to 6.6 months].In the univariate analysis,there was a significant difference in the median PFS between patients with brain metastases and those without brain metastases(4.8 months vs 5.9 months,respectively;P=0.039).The Eastern Cooperative Oncology Group(ECOG)performance status(P=0.002),lines of therapy(P=0.015),and therapeutic evaluation(P=0.014)were independent factors that influenced PFS.The most common AEs were hypertension,proteinuria,myelosuppression,gastrointestinal reactions,fatigue,and mucositis.Conclusion Anlotinib plus S-1 is an effective and safe regimen for advanced NSCLC as third-or later-line therapy.     

Anlotinib,a novel TKI,as a third-line or further-line treatment in patients with advanced non-small cell lung cancer in China: A systemic review and meta-analysis of its efficacy and safety

Purpose:In this meta-analysis and systemic review, we focused on the effectiveness and safety of anlotinib in patients with advanced non-small cell lung cancer(NSCLC).Methods:The databases of PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, and CBM were searched by 2 investigators up to April 2020. Titles and abstracts of all records were screened and eligible publications were retrieved in full. Review Manager (version 5.2, Cochrane Library) was used for data analysis. The outcomes of interest were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse event (TRAE). Data was pooled for quantitative analysis and the effect size was reported as hazard ratio for survival outcomes and odds ratio (OR) for safety outcomes, both with a random-effects model.Results:A sum of 1480 patients were included in 11 trials ranging from 2018 to 2020. Substantial improvements of PFS, OS, and DCR were observed in patients treated with anlotinib alone or in combination with other conventional treatment. Accompanied TRAE included statistically significant higher risk for hypertension (OR = 11.05, 95% confidence interval [CI] = 7.85–15.55, P < .001), hepatic dysfunction (OR = 1.96, 95% CI = 1.29–2.68, P < .001), diarrhea (OR = 2.20, 95% CI = 1.17–4.16, P < .05), and hemoptysis (OR = 2.59, 95% CI = 1.71–3.93, P < .01).Conclusions:Our study suggested that anlotinib as maintenance therapy for advanced NSCLC patients is associated with prolonged PFS and OS as well as DCR improvement, but it was accompanied by increased risk of TRAE, such as hypertension, hepatic dysfunction, diarrhea and hemoptysis. Although much effort has been made to clinical trials of anlotinib, further studies are warranted to provide more convincing evidence.     

安罗替尼联合化疗治疗晚期软组织肉瘤的近期疗效及安全性分析

目的:探讨安罗替尼联合化疗治疗晚期软组织肉瘤(STS)的近期疗效及安全性。方法:2018年5至10月,应用安罗替尼联合化疗治疗晚期STS 27例。其中,平滑肌肉瘤11例,去分化脂肪肉瘤3例,滑膜肉瘤3例,其他类型STS 10例。安罗替尼联合化疗一线治疗14例,二、三线治疗13例。化疗方案以蒽环类药物和异环磷酰胺为主,其他药物包括达卡巴嗪、吉西他滨、替莫唑胺、长春新碱、环磷酰胺和紫杉醇等。每治疗2个周期进行疗效和安全性评价。结果:27例患者中,部分缓解(PR)9例,疾病稳定(SD)10例,疾病进展(PD) 8例,总体有效率(overall response rate, ORR)为33.3%(9/27),疾病控制率(DCR)为70.4%(19/27)。常见不良反应有骨髓抑制、恶心、呕吐、高血压和口腔黏膜炎;1例发生严重不良反应,为发热性中性粒细胞减少。无治疗相关死亡。结论:安罗替尼联合化疗治疗晚期STS的近期疗效肯定,不良反应可耐受,值得进一步开展大样本临床研究。     

The relationship between treatment-induced hypertension and efficacy of anlotinib in recurrent or metastatic esophageal squamous cell carcinoma

Objective:In this post-hoc analysis, we evaluated anlotinib treatment-induced hypertension as a potential predictive factor of efficacy in esophageal squamous cell carcinoma (ESCC) patients.Methods:A total of 109 patients enrolled in the anlotinib group in a phase 2 trial were included. The tumor response was assessed by computed tomography at week 3, week 6, and then every 6 weeks until progressive disease was observed. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints included overall survival (OS) and objective response rate (ORR).Results:In all patients, the median PFS was 3.02 months [95% confidence interval (CI): 2.63–3.65 months] and the OS was 6.11 months (95% CI: 4.40–7.79 months). The ORR was 7.34% (95% CI: 3.22%–13.95%). A total of 59 (54%) patients were diagnosed with treatment-induced hypertension (Group A), and the remaining patients (n = 50, 46%) were in Group B. Baseline prognostic factors were similar between the 2 groups. Patients in Group A had a longer PFS and OS and higher ORR. When stratifying patients using a previously known history of hypertension, treatment-induced hypertension was a predictor only for patients without previous hypertension, who had longer PFS [hazard ratio (HR): 0.40, 95% CI: 0.24–0.68] and OS (HR: 0.37, 95% CI: 0.21–0.67).Conclusions:We showed, for the first time, a correlation between treatment-induced hypertension and better prognoses in recurrent or metastatic ESCC patients treated with anlotinib, without a previously known history of hypertension. Treatment-induced hypertension may be a simple and low cost predictor for anlotinib antitumor efficacy in these patients, which may also reflect the intended target inhibition.     

安罗替尼三线以上治疗非小细胞肺癌疗效观察

目的:观察安罗替尼在晚期非小细胞肺癌三线以上治疗中的疗效和不良反应。方法:二线或多线治疗后进展的晚期非小细胞肺癌患者75例（其中55例为二线治疗后,15例为三线治疗后,5例为4线治疗后）。所有患者均给予安罗替尼 12 mg,每天1次口服,连续服用14天,停用1周,每21天重复,直到疾病进展或不能耐受不良反应为止。不能耐受不良反应的患者,根据情况将剂量降至每天10 mg或每天8 mg。每6周复查CT评价疗效。结果:75例患者中,PR 6例,SD 45例,PD 24例,ORR 8.0%,DCR 60.0%,PD 32.0%,PFS和OS分别为5.2个月（95%CI:4.4~6.0）和8.0个月（95%CI:6.1~9.9）。分层结果,45例腺癌中,PR 4例,SD 27例,PD 14例,ORR 8.9%,DCR 68.9%,PD 31.1%。30例鳞状细胞癌中,PR 2例,SD 18例,PD 10例,ORR 6.7%,DCR 66.7%,PD 33.3%。腺癌组与鳞状细胞癌组的DCR比较,P=0.840,无统计学差异,腺癌组与鳞状细胞癌组的PFS分别为4.5个月（95%CI:3.9~5.1）和5.2个月（95%CI:4.2~6.2）,Log-Rank P=0.033,有统计学差异,OS分别为6.7个月（95%CI:3.2~10.2）和8.0个月（95%CI:5.9~10.1）,Log-Rank P=0.057,无统计学差异。不良反应主要是疲劳、食欲减退、手足综合征、头痛和高血压。结论:安罗替尼三线以上治疗非小细胞肺癌有效,鳞状细胞癌患者的PFS显著高于腺癌患者,不良反应可以耐受。     

安罗替尼联合多西他赛二线治疗晚期非小细胞肺癌疗效观察

目的观察晚期非小细胞肺癌患者应用安罗替尼联合多西他赛二线治疗后血清癌胚抗原(carcino-embryonic antigen,CEA)、血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)水平变化,探讨其治疗效果及安全性。方法60例晚期非小细胞肺癌患者依据治疗方法分为观察组和对照组各30例。对照组给予多西他赛75 mg/m2,静脉滴注,第1天,21 d为1个周期;观察组在对照组化疗基础上口服安罗替尼胶囊12 mg/次,1次/d,第1~14天,21 d为1个周期。每2个周期评估1次疗效,至出现严重不良反应或疾病进展停药。比较2组化疗前及化疗4个周期后血清CEA、VEGF水平;化疗4个周期后评定2组疾病控制率、客观有效率;随访观察无进展生存时间;比较2组治疗期间不良反应发生情况。结果观察组、对照组化疗4个周期后血清CEA[(7.25±4.93)、(12.28±5.63)μg/L]和VEGF[(56.12±33.69)、(102.17±44.94)ng/L]水平均低于治疗前[CEA:(50.47±13.49)、(54.15±12.93)μg/L;VEGF:(407.41±147.32)、(411.44±143.56)ng/L](P<0.05),观察组低于对照组(P<0.05)。化疗4个周期,观察组疾病控制率(86.67%)高于对照组(60.00%)(P<0.05),客观有效率(26.67%)与对照组(20.00%)比较差异无统计学意义(P>0.05)。随访至2020年4月30日,观察组中位无进展生存时间(4.8个月)长于对照组(2.8个月)(P<0.05)。治疗期间2组不良反应多为Ⅰ~Ⅱ级,均可耐受,观察组手足综合征、高血压、咯血的发生率(36.67%、33.33%、13.33%)高于对照组(0、6.67%、0)(P<0.05)。结论晚期非小细胞肺癌患者应用安罗替尼联合多西他赛二线治疗可下调肿瘤标志物水平,提高疾病控制率,延长无进展生存时间,不良反应可耐受。     

360例小分子激酶抑制剂不良反应报告分析

目的 分析360例小分子激酶抑制剂不良反应（ADR）发生的一般规律和特点,为临床合理用药提供依据。方法 收集陕西省2016—2020年各级医疗卫生机构上报至陕西省食品药品研究院的360例小分子激酶抑制剂ADR报告,从性别、年龄、给药途径、药物种类、临床转归和ADR累及系统/器官进行统计分析。结果 在360例ADR患者中,男性多于女性,好发于40岁以上的中老年人。ADR累及系统/器官以消化系统为主,其次为皮肤及附件、血液系统、心血管系统。引起ADR最多的药品是伊布替尼。在临床转归方面,痊愈和好转占59.5%。1例“新的”ADR表现为全身皮肤变黑,其是否与该类药物有关有待进一步研究。结论 小分子激酶抑制剂ADR的发生与患者年龄、性别、药物种类等密切关联,并且涉及多个系统或器官,临床使用时应根据具体用药情况采取有效预防措施,以减少或避免ADR的发生,从而优化合理用药,确保患者用药安全。     

影响安罗替尼临床疗效和预后的多因素分析

目的:观察经过安罗替尼治疗的不同瘤种恶性肿瘤患者的相关指标,探索影响安罗替尼临床疗效和预后的因素。方法:2018年7月至2019年12月使用安罗替尼治疗的晚期恶性肿瘤患者101例,取患者治疗过程中的血液,用ELISA法和实时荧光定量PCR法检测血清中VEGF、FGF、c-Kit、Bcl-2、PARP蛋白含量和mRNA相对表达量。另一方面,评价安罗替尼的疗效和随访观察PFS。结果:全部病例的总的中位PFS为4.8月（95%CI:3.8~5.8）,PR 18例（17.82%）,SD 61例（60.40%）,PD 22例(21.78%),ORR 17.82%,DCR 78.22%。TSH升高患者的DCR较未发生者高（P=0.039 0）。既往曾使用铂类化疗者较未使用者具有更长的中位PFS（5.3月 vs 3.6月,Log-rank P=0.038 0）,TSH升高患者较未升高患者的中位PFS显著延长（6.4月 vs 4.0月,Log-rank P=0.046 0）,发生手足综合征者中位PFS较未发生者显著延长（11.4月 vs 4.2月,Log-rank P=0.021 0）。血清bFGF的蛋白含量（P=0.009 0）及Bcl-2 mRNA相对表达量（P=0.012 0）是安罗替尼治疗晚期恶性肿瘤预后的独立影响因子。结论:血清bFGF含量及Bcl-2 mRNA表达量是安罗替尼疗效的独立影响因素;既往曾使用铂类、发生手足综合征和促甲状腺素升高者具有更长的PFS。