FOLFOX方案联合西妥昔单抗治疗转移性结直肠癌的近期疗效及安全性分析

目的：探讨FOLFOX方案联合西妥昔单抗治疗转移性结直肠癌的近期临床疗效及安全性。方法：选择2009年2月～2011年2月本院诊治的42例转移性结直肠癌患者为研究对象,采用随机数字表法将其随机分入对照组与观察组,其中对照组20例,观察组22例。对照组患者接受FOLFOX方案治疗,每2周重复1次,治疗3周期;观察组患者给予FOLFOX方案联合西妥昔单抗治疗。比较两组的近期疗效及毒副反应。结果：观察组的客观缓解率和疾病控制率均显著高于对照组,差别具有统计学意义（P〈0．05）;骨髓抑制、消化道反应、神经毒性是两组常见的毒副反应,两组患者骨髓抑制、消化道反应、神经毒性、脱发及肝功能损害发生率无显著差别（P〉0．05）,观察组痤疮样皮疹的发生率显著高于对照组（36．4％VS0,P〈0．05）。结论：西妥昔单抗联合FOLFOX方案可提高转移性结直肠癌患者的近期疗效,毒副反应可耐受。     

西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌的疗效及其影响因素分析

目的:探讨西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌(mCRC)的疗效及其影响因素。方法:选取2013年1月～2015年1月河北北方学院附属第一医院收治的K-Ras野生型mCRC患者96例,按照随机数字表法将患者分为对照组(n=48)和观察组(n=48)。对照组给予常规化疗方案治疗,观察组在此基础上给予西妥昔单抗治疗。比较两组临床疗效、中位无进展生存期(PFS)、中位总生存期(OS)以及不良反应发生情况,并分析观察组治疗疗效的影响因素。结果:观察组客观有效率(ORR)和疾病控制率(DCR)分别为54.17%和91.67%,均高于对照组的31.25%和81.25%(P0.05)。观察组患者中位PFS和中位OS均较对照组长(P0.05)。观察组皮肤痤疮样病变发生率高于对照组(P0.05)。单因素分析显示,西妥昔单抗联合化疗治疗K-Ras野生型mCRC的ORR、DCR与年龄、肿瘤部位、肿瘤转移部位、肿瘤分化程度以及西妥昔单抗治疗时间有关(P0.05)。结论:西妥昔单抗联合化疗治疗K-Ras野生型mCRC疗效确切,预后较好,患者对不良反应可耐受,患者年龄、肿瘤部位、转移部位、分化程度及西妥昔单抗治疗时间可能是其疗效的影响因素。     

西妥昔单抗联合FOLFIRI 与单用FOLFIRI 方案治疗转移性结直肠癌近期疗效的对照研究

目的:比较西妥昔单抗(爱必妥)联合FOLFIRI化疗方案与单用FOLFIRI化疗方案治疗转移性结直肠癌患者的临床疗效和毒副反应。方法:回顾性分析2008年1月至2011年11月解放军总医院经组织病理学证实的46例转移性结直肠癌患者临床资料,其中西妥昔单抗联合FOLFIRI化疗方案组22例,单用FOLFIRI方案组24例,观察比较两组方案的近期疗效和不良反应。结果:两组方案治疗转移性结直肠癌的客观缓解率(CR+PR)分别为41.6%和12.5%,其中联合治疗方案治疗效果明显优于单用FOLFIRI化疗方案,两组比较差异有统计学意义(P<0.05)。患者出现的不良反应有痤疮样皮疹、腹泻、骨髓抑制、恶心呕吐、脱发等。除痤疮样皮疹和腹泻外,两组患者毒副反应无显著性差异。结论:西妥昔单抗联合FOLFIRI化疗方案治疗K-Ras基因野生型转移性结直肠癌近期疗效显著,毒副反应较单用FOLFIRI方案无明显增加,患者可以耐受。     

西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的有效性和安全性比较

目的:比较西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的有效性和安全性。方法:选取2014年1月～2017年8月我院收治的晚期结直肠癌患者100例,根据患者入院先后顺序随机分为两组,所有患者均给予FOLFIRI方案进行化疗,A组在化疗的基础上给予贝伐珠单抗进行治疗,B组在化疗的基础上给予西妥昔单抗进行治疗。比较两组患者临床治疗的缓解率、控制率及不良反应的发生情况,对所有患者随访1年,记录并比较两组患者的无进展生存期。结果:两组患者的缓解率、控制率、恶心呕吐、头晕、延迟性腹泻、肝肾损伤、白细胞减少、血小板减少和尿蛋白的发生率相比均无统计学差异(P0.05),但B组患者骨髓抑制和皮疹的发生率显著高于A组(P0.05);两组患者的无进展生存期相比无统计学差异(P0.05)。结论:西妥昔单抗和贝伐珠单抗治疗晚期结直肠癌的临床效果相当,且不良反应较轻,以Ⅰ～Ⅱ度为主,患者均可耐受,对症治疗后均有所缓解。西妥昔单抗易引发骨髓抑制和皮疹,在临床应用过程中需注意并进行有效预防和积极处理。     

贝伐单抗二线治疗转移性结直肠癌的临床观察

目的:观察贝伐单抗二线治疗转移性结直肠癌患者的临床疗效和毒副反应。方法:回顾性分析2008年8月至2011年10月我院经组织病理学证实的转移性结直肠癌患者21例,一线治疗进展后,二线治疗方案中加用贝伐单抗,用法为5mg/kg,每2-3周1次,与化疗方案同步。化疗方案以奥沙利铂及伊立替康为基础,完成2-3周期治疗后评定疗效,观察毒副反应。结果:21例患者中PR1例,SD11例,PD9例,客观缓解率为4.8%,疾病控制率为57.1%,中位TTP为3.7个月。患者出现的不良反应有骨髓抑制、皮疹、恶心呕吐、腹泻、肝功能损害、神经毒性等,贝伐单抗所致高血压的发生率为14.3%(3/21),鼻衄发生率为4%(2/21)。结论:二线治疗中使用贝伐单抗,对一线治疗进展后的转移性结直肠癌疗效有限,毒副反应可耐受。     

维罗非尼联合爱必妥对结直肠癌细胞株的作用研究

探讨BRAF抑制剂维罗非尼联合EGFR单克隆抗体西妥昔单抗对BRAF突变型和野生型结直肠癌细胞株的作用。应用MTT法检测,将不同浓度西妥昔单抗、维罗非尼单药以及两药联合分别作用于BRAF突变型结直肠癌细胞株RKO、HT-29和BRAF野生型结直肠癌细胞株DIFI、CACO-2后,观察各细胞株增殖变化;通过集落形成实验,经过长时间培养细胞验证不同处理因素对细胞增殖的抑制作用;Western blot实验检测EGFR下游通路靶蛋白的活性在两药联合后是否出现明显下调。结果显示,单药治疗,西妥昔单抗能一定程度抑制BRAF野生型结直肠癌细胞株增殖,抑制率达26%~40%,而BRAF突变组两种细胞株对西妥昔单抗均耐药。维罗非尼对不同基因状态细胞的增殖均有一定的抑制作用,IC50均小于7μmol/mL,其中BRAF突变细胞更为敏感。对比单药西妥昔单抗,联合维罗非尼后更加明显地抑制了细胞增殖,4种细胞存活率均明显降低(P0.05)。长时间集落形成实验证实两药联合形成集落的面积和数量均明显减少。Western Blot实验显示对比单药,两药联合明显下调了p-EGFR、BRAF、p-ERK的表达。结果显示,BRAF抑制剂维罗非尼无论在BRAF突变型还是野生型结直肠癌细胞株中,均能增强西妥昔单抗作用的敏感性。     

西妥昔单抗联合低温热疗诱导CNE细胞凋亡的研究

目的:观察西妥昔单抗联合低温热疗诱导人鼻咽癌细胞株CNE凋亡的效果,并初步探讨其可能的机制.方法:试验分对照组、单靶组、单热组及热靶组,MTT法测定西妥昔单抗对CNE细胞株48h20～30%抑制的药物浓度;以该浓度药物与低温热疗(43℃,30分钟)联合,Hoechst33258荧光染色法观察细胞凋亡形态学变化;流式细胞术检测24h、48h凋亡率;Western blot检测Bax、Bcl-2、EGFR蛋白的表达.结果:以48h20～30%抑制率的药物浓度(IC20～30)为试验的工作浓度,确定西妥昔单抗对CNE细胞株的工作浓度为10 ug/ml;荧光染色法观察到热靶组CNE细胞发生典型的凋亡形态学改变;流式凋亡检测显示24、48 h热靶组凋亡率显著高于相应单靶组、单热组及对照组(P＜0.05). western blot检测显示各处理组较之对照组都有上调Bax、下调Bcl-2、EGFR蛋白表达的作用,以热靶组最为显著(P＜0.05);热疗后EGFR蛋白表达逐渐下调.结论:西妥昔单抗联合低温热疗能显著增加CNE细胞的凋亡率,这可能与EGFR的下调与受抑,进而上调Bax、下调Bcl-2蛋白的表达促进凋亡有关.     

血清VEGF水平与贝伐珠单抗联合化疗治疗转移性结直肠癌患者疗效的关系研究

目的:研究血清血管内皮生长因子(VEGF)水平与贝伐珠单抗联合化疗治疗转移性结直肠癌患者疗效的关系。方法:选取2015年2月至2016年2月间我院收治的转移性结直肠癌患者80例,按照数字随机表法将患者随机分为观察组(n=40)和对照组(n=40)。对照组给予氟尿嘧啶/奥沙利铂(FOLFOX-6)方案治疗,观察组则在此基础上加用贝伐珠单抗5 mg/kg治疗,d1,两组均进行4个化疗周期,比较两组患者临床疗效及治疗前、治疗后血清VEGF水平,并分析血清VEGF与疗效的相关性。结果:观察组有效率(RR)为52.50%(21/40),高于对照组的30.00%(12/40)(P0.05)。治疗前两组患者血清VEGF水平差异无统计学意义(P0.05),治疗后两组患者血清VEGF水平均较治疗前显著降低,观察组患者血清VEGF水平显著低于对照组患者,观察组VEGF下降幅度显著高于对照组(均P0.05)。经秩相关分析显示,结直肠癌患者治疗后VEGF下降幅度与治疗疗效呈显著正相关(r=0.683,P=0.000)。结论:贝伐珠单抗联合化疗治疗转移性结直肠癌可显著降低患者血清VEGF水平,疗效更佳。     

Ad-FGF-Trap对头颈部鳞癌细胞的抑制及其与西妥昔单抗的联合作用

西妥昔单抗的耐药问题在头颈部鳞癌(head and neck squamous cell carcinoma,HN-SCC)的治疗过程中较为突出,成纤维生长因子受体1(fibroblast growth factor receptor 1,FGFR1)旁路活化是一个重要原因.在抑制FGFR1活性方面,已有的FGFR小分...     

利妥昔单抗联合化疗治疗非霍奇金淋巴瘤的药物经济学评价

目的：系统评价利妥昔单抗联合化疗治疗非霍奇金淋巴瘤的药物经济学价值。方法：用计算机检索PubMed、ScienceDirect、Springer Link、Elsevier 等英文数据库以及CNKI、维普、万方等中文数据库1998—2013 年间公开发表的利妥昔单抗联合化疗治疗非霍奇金淋巴瘤的药物经济学评价文献,对文献质量、研究结果进行系统评价。结果：所有英文文献的 ICER 值均在各国的意愿支付范围内;国内外利妥昔单抗药物经济学评价在数据来源、研究方法等方面存在差异。结论：利妥昔单抗联合化疗治疗非霍奇金淋巴瘤在国外具有成本-效果;需开展高质量的研究来探索利妥昔单抗联合化疗治疗非霍奇金淋巴瘤在我国的经济性。     

No Survival Benefit from Adding Cetuximab or Panitumumab to Oxaliplatin-Based Chemotherapy in the First-Line Treatment of Metastatic Colorectal Cancer in KRAS Wild Type Patients: A Meta-Analysis

Background

The efficacy of combined therapies of oxaliplatin-based chemotherapy and anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MAbs) remains controversial in colorectal cancer (CRC). The aim of this study is to estimate the efficacy and safety of adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first line treatment in KRAS wild type patients with metastatic colorectal cancer (mCRC) through meta-analysis.

Methods

Medline, EMBASE, and Cochrane library, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) were searched. Eligible studies were randomized controlled trials (RCTs) which evaluated oxaliplatin-based chemotherapy with or without anti-EGFR drugs (cetuximab or panitumumab) in untreated KRAS wild type patients with mCRC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. Hazard ratios (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals.

Results

This meta-analysis included four RCTs with 1270 patients, and all of the patients were administered oxaliplatin-based chemotherapy regimens with or without anti-EGFR MAbs. The result of heterogeneity of OS was not significant. Compared with chemotherapy alone, the addition of cetuximab or panitumumab didn’t result in significant improvement in OS (HR = 1.00, 95%CI [0.88, 1.13], P = 0.95) or PFS (HR = 0.86, 95%CI [0.71, 1.04], P = 0.13). The subgroup analysis of cetuximab also revealed no significant benefit in OS (HR = 1.02, 95%CI [0.89, 1.18], P = 0.75) or in PFS (HR = 0.87, 95%CI [0.65, 1.17], P = 0.36). Patients who received combined therapy didn’t have a higher ORR (Risk Ratio = 1.08, 95%CI [0.86, 1.36]). Toxicities slightly increased in anti-EGFR drugs group.

Conclusions

The addition of cetuximab or panitumumab to oxaliplatin-based chemotherapy in first-line treatment of mCRC in wild type KRAS population did not improve efficacy in survival benefit and response rate. More RCTs are warranted to evaluate the combination of chemotherapy and targeted therapy.     

Clinical Efficacy of Chemotherapy Combined with Verapamil in Metastatic Colorectal Patients

In order to determine the clinical efficacy and adverse reactions of chemotherapy and verapamil infusion through a target artery to treat colorectal cancer patients with metastasis after failure with previous conventional treatments. Patients with metastatic colon cancer (n = 36) received an infusion of verapamil, interleukin-2, oxaliplatin (or hydroxy camptothecin or irinotecan hydrochloride), fluorouracil and calcium folinate through target artery using the Seldinger puncture technique. From the second day of infusion, the patients were treated with fluorouracil and calcium folinate via systematic intravenous injection for 2–3 days. Efficacy was evaluated after at least two treatment courses. The objective response including complete or partial response was 58.3% in the 36 patients; clinical benefit rate, evaluated by Karnofsky Performance Status score was 91.7%; by weight was 83.3%; by the amount of painkiller consumed was 80.6%. No patient experienced side effects associated with heart function. Post-treatment, the P–R period, Q–T period, QRS, and heart rate were not significantly different than before treatment. Liver function was significantly improved. Side effects of chemotherapy were minor in comparison to those observed with intravenous chemotherapy. Infusion of verapamil and chemotherapy directly into pelvic tumor tissue can increase treatment efficacy and has been shown to be a relatively safe technique.     

Immunomodulatory Effects in a Phase II Study of Lenalidomide Combined with Cetuximab in Refractory KRAS-Mutant Metastatic Colorectal Cancer Patients

This study assessed the immunomodulatory effects in previously treated KRAS-mutant metastatic colorectal cancer patients participating in a phase II multicenter, open-label clinical trial receiving lenalidomide alone or lenalidomide plus cetuximab. The main findings show the T cell immunostimulatory properties of lenalidomide as the drug induced a decrease in the percentage CD45RA⁺ naïve T cells 3-fold while increasing the percentage HLA-DR⁺ activated T helper cells and percentage total CD45RO⁺ CD8⁺ memory T cytotoxic cells, 2.6- and 2.1-fold respectively (p<0.0001). In addition, lenalidomide decreased the percentage of circulating CD19⁺ B cells 2.6-fold (p<0.0001). Lenalidomide increased a modest, yet significant, 1.4-fold change in the percentage of circulating natural killer cells. Our findings indicate that lenalidomide significantly activates T cells, suggestive of an immunotherapeutic role for this drug in settings of maintenance therapy and tumor immunity. Furthermore, reported for the first time is the effect of lenalidomide in combination with cetuximab on T cell function, including increases in circulating naïve and central memory T cells. In summary, lenalidomide and cetuximab have significant effects on circulating immune cells in patients with colorectal carcinoma.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01032291","term_id":"NCT01032291"}}NCT01032291     

Detection of KRAS Exon 2 Mutations in Circulating Tumor Cells Isolated by the ISET System from Patients with RAS Wild Type Metastatic Colorectal Cancer

INTRODUCTION: The presence of KRAS mutations in patients with metastatic colorectal cancer (mCRC) predicts poor response to agents targeting the EGFR. Even in patients with RAS wild type (WT) tumors, resistance eventually develops due to multiple mechanisms, including the expansion of previously undetected KRAS mutated clones. In this feasibility study, we aimed to detect KRAS exon 2 mutations in serial samples of circulating tumor cells (CTCs) of RAS WT patients with mCRC captured by the Isolation by Size of Epithelial Tumor cells (ISET) system. METHODS: CTC isolation using the ISET system was performed from prospectively collected blood samples obtained from patients with RAS and BRAF WT mCRC prior to first-line therapy initiation, at first imaging assessment and on disease progression. CTCs were enumerated using hematoxylin & eosin and CD45 double stain on a single membrane spot. DNA was extracted from 5 spots and KRAS exon 2 mutations were detected using a custom quantitative Polymerase Chain Reaction (qPCR) assay. RESULTS: Fifteen patients were enrolled and 28 blood samples were analyzed. In 9 (60%) patients, at least one sample was positive for the presence of a KRAS exon 2 mutation. In 11 out of 28 samples (39.2%) with detectable CTCs a KRAS mutation was detected; the corresponding percentages for baseline and on progression samples were 27% and 37.5%, respectively. The most commonly detected mutations were G13D and G12C (n = 3). The presence of KRAS mutated CTCs at baseline was not prognostic for either PFS (P = .950) or OS (P = .383). CTC kinetics did not follow tumor response patterns. CONCLUSION: The results demonstrate that using a qPCR-based assay, KRAS exon 2 mutations could be detected in CTCs captured by the ISET system from patients with RAS WT primary tumors. However, the clinical relevance of these CTCs remains to be determined in future studies.     

西妥昔单抗联合伊立替康对晚期胃癌患者血清肿瘤标志物、T淋巴细胞亚群水平及生活质量的影响

摘要 目的：探讨西妥昔单抗联合伊立替康治疗晚期胃癌对患者血清肿瘤标志物、T淋巴细胞亚群水平及生活质量的影响。方法：选取2018年4月~2020年4月于包头市中心医院接受诊治的104例晚期胃癌患者,按治疗方案不同分为对照组（52例）与观察组（52例）,对照组接受西妥昔单抗治疗,观察组接受西妥昔单抗联合伊立替康治疗,对比两组临床疗效、不良反应、血清肿瘤标志物、生活质量、T淋巴细胞亚群水平及预后情况。结果：观察组的临床有效率为65.38%,高于对照组的25.00%（P＜0.05）;观察组的疾病控制率为71.15%,高于对照组的34.62%（P＜0.05）。与对照组比较,观察组治疗后糖类抗原199（CA199）、糖类抗原724（CA724）和癌胚抗原（CEA）水平更低（P＜0.05）。CD3⁺、CD4⁺、CD4⁺/CD8⁺水平比较,观察组治疗后均高于对照组（P＜0.05）;CD8⁺水平比较,观察组治疗后较对照组低（P＜0.05）。观察组治疗后各项生活质量评分均高于对照组（P＜0.05）。观察组不良反应发生率为13.46%,低于对照组的15.38%,但无明显差异（P＞0.05）。对照组治疗后1年中位生存期为6.16个月,短于观察组的8.34个月,差异有统计学意义（Logrank x²= 4.219,P=0.040）。结论：西妥昔单抗联合伊立替康治疗晚期胃癌,可有效阻止肿瘤进展,提高临床有效率和患者生活质量,改善T淋巴细胞亚群水平,延长患者生存期,且安全性较好。     

术中局部化疗对大肠癌患者预后影响的临床观察

目的:观察术中局部化疗对大肠癌患者的预后影响,探讨提高大肠癌患者临床疗效的辅助治疗方法。方法:选择DuckB期和DuckC期患者76例,根据自愿的原则均分为常规手术组和术中化疗组,常规手术组采取常规手术治疗,术中化疗组在常规手术过程中给予局部化疗治疗,比较两组患者术后第7d血常规、肝肾功能及两组患者术后并发症,并随访两组患者术后12个月和24个月局部复发情况。结果:两组患者在术后血常规、肝肾功能及术后并发症方面比较,差异无统计学意义(P>0.05);术后12个月和24个月局部复发病例比较,差异具有统计学意义(P<0.05),术中化疗组显著少于常规手术组。结论:在DuckB期和DuckC期大肠癌患者外科手术治疗过程中,应积极采取术中化疗的治疗措施。     

术中局部化疗对大肠癌患者预后影响的临床观察

目的：观察术中局部化疗对大肠癌患者的预后影响,探讨提高大肠癌患者临床疗效的辅助治疗方法。方法：选择DuckB期和DuckC期患者76例,根据自愿的原则均分为常规手术组和术中化疗组,常规手术组采取常规手术治疗,术中化疗组在常规手术过程中给予局部化疗治疗,比较两组患者术后第7d血常规、肝肾功能及两组患者术后并发症,并随访两组患者术后12个月和24个月局部复发情况。结果：两组患者在术后血常规、肝肾功能及术后并发症方面比较,差异无统计学意义（P〉0．05）;术后12个月和24个月局部复发病例比较,差异具有统计学意义①〈0．05）,术中化疗组显著少于常规手术组。结论：在DuckB期和DuckC期大肠癌患者外科手术治疗过程中．应积极采取术中化疗的治疗措施。