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分析

目的 观察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安全性,探讨可能影响疗效及预后的因素。方法 收集2007年5月至2012年5月解放军总医院收治的K Ras野生型转移性结直肠癌患者共90例,采用西妥昔单抗（400mg／m2,静滴,第1周,维持剂量每周250mg／m2或每2周500mg／m2）联合化疗方案,主要为含伊立替康为基础方案（FOLFIRI或XELIRI或单药CPT-11）、含奥沙利铂为基础方案（FOLFOX或XELOX）、5 FU／LV方案或单药卡培他滨。回顾性评估西妥昔单抗联合化疗在治疗中的疗效和安全性,分析患者临床病理特征,并探讨影响疗效的因素以及此类患者预后相关的因素。结果 西妥昔单抗中位治疗时间为16周（6～44周）,客观缓解率（ORR）为45.6％,疾病控制率（DCR）为87.8％。其中一线治疗ORR为51.6％,二线治疗ORR为40.0％,三线治疗ORR为18.2％。单因素分析显示,年龄、原发灶部位、西妥昔单抗治疗时间与疗效有关,差异具有统计学意义（P＜0.05）。90例患者中位随访时间为20.2个月,82例（91.1％）复发转移,60例（66.7％）死亡。患者中位无疾病进展时间（PFS）为7.8个月,中位总生存时间（OS）为22.5个月。其中一线中位PFS为9.1个月,中位OS为27.6个月;二线中位PFS为7.7个月,中位OS为14.5个月;三线中位PFS为2.9个月,中位OS为6.7个月。单因素分析显示：原发灶部位、早期肿瘤缓解者以及西妥昔单抗治疗时间与PFS有关;原发灶部位、早期肿瘤缓解者、西妥昔单抗治疗时间以及转移侵及范围与OS有关。Cox多因素生存分析显示：原发肿瘤病灶部位、早期肿瘤缓解是PFS的独立预后因素,转移侵及范围是OS的独立预后因素。西妥昔单抗相关治疗最常见的不良反应是痤疮样皮疹（78.0％）,化疗相关的不良反应主要为腹泻、恶心呕吐、骨髓抑制,经对症处理后,患者均可耐受。结论 西妥昔单抗联合多种方案化疗治疗晚期转移性结直肠癌患者,各线治疗均能取得较好的疗效,不良反应可耐受;原发灶部位可能是西妥昔单抗联合化疗的疗效预测因素,其与患者预后生存可能相关;早期肿瘤缓解可作为判断患者预后相关指标。     

比较西妥昔单抗双周与每周方案联合FOLFOX/XELOX一线治疗KRAS/RAS野生型转移性结直肠癌的回顾性研究

  目的  比较西妥昔单抗双周和每周方案联合FOLFOX/XELOX一线治疗KRAS/RAS野生型转移性结直肠癌的疗效和安全性。  方法  回顾性收集2010年7月至2017年12月在中国医学科学院肿瘤医院接受FOLFOX/XELOX联合双周或每周西妥昔单抗一线治疗的KRAS/RAS野生型转移性结直肠癌患者的资料。比较两组间治疗的客观缓解率（objective response rate,ORR）、无进展生存期（progression-free survival,PFS）、总生存期（overall survival,OS）和不良反应发生率。  结果  共98例符合入组条件。其中西妥昔单抗双周治疗组55例,每周治疗组43例。双周组的ORR显著高于每周组,分别为76.3%和54.8%（P=0.025）。双周组与每周组的PFS分别为10.3个月和8.8个月（P=0.288）,OS分别33.5个月和27.4个月（P=0.563）,结果差异均无统计学意义。双周组的口腔黏膜炎发生率显著高于每周组（32.7% vs. 14.0%,P=0.032）,痤疮样皮疹（80.0% vs. 62.8%,P=0.058）、白细胞和/或中性粒细胞减少（72.7% vs. 55.8%,P=0.081）等不良反应发生率有升高的趋势。双周组与每周组3/4级皮疹的发生率分别为18.2%和7.0%（P= 0.105）,全部3/4级不良反应发生率差异均无统计学意义（P>0.05）。  结论  双周西妥昔单抗联合化疗一线治疗转移性结直肠癌的疗效与每周方案相当,缓解率可能更高,是临床可选择的治疗方案。治疗过程中应关注一些不良反应的发生率增加。      

西妥昔单抗联合化疗治疗转移性结直肠癌

目的:探讨西妥昔单抗联合化疗治疗转移性结直肠癌的疗效和不良反应.方法:对2例转移性结直肠癌患者应用西妥昔单抗联合伊立替康+CF+5-FU,或西妥昔单抗联合奥沙利铂+CF+5-FU化疗方案进行治疗;西妥昔单抗首次剂量400mg/m2,以后250mg/m2每周一次维持.结果:2例转移性结直肠癌患者均达PR.主要不良反应为痤疮样皮疹、腹泻及骨髓功能抑制.结论:西妥昔单抗联合化疗治疗转移性结直肠癌近期疗效显著,不良反应可以耐受.     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的：观察西妥昔单抗联合含伊立替康或奥沙利铂化疗方案治疗转移性结直肠癌的近期疗效及毒副反应。方法：１０例经病理组织学确诊的转移性结直肠癌患者,给予西妥苷单抗联合ＦＯＬＦＩＲＩ方案或ＦＯＬＦＯＸ方案治疗,西妥昔单抗首次给予负荷剂量４００ｍｇ／ｍ^２,每周给予维持剂量为２５０ｍｇ／ｍ^２。结果：全组１０例患者中,完全缓解（ＣＲ）１例,部分缓解（ＰＲ）４例,稳定（ＳＤ）２例,进展（ＰＤ）３例,有效率为５０％,疾病控制率为７０％,中位肿瘤进展时间（ＴＴＰ）为６.４个月。主要毒副反应为痤疮样皮疹和腹泻。结论：西妥昔单抗联合ＦＯＬＦＩＲＩ方案或ＦＯＬＦＯＸ方案治疗转移性结直肠癌疗效较好,毒副反应可耐受。     

西妥昔单抗联合化疗在晚期结直肠癌一线治疗中的疗效观察

背景与目的:体内、外研究均表明,西妥昔单抗可以抑制表达表皮生长因子的人类肿瘤细胞的增殖并诱导其凋亡以及抑制肿瘤血管形成和转移,并己确立其在一线治疗晚期结直肠癌中的地位.本研究观察其在一线治疗晚期结直肠癌的疗效.方法:2007年2月-2007年12月厦门、泉州、漳州三地共五家医院对9例晚期结直肠癌患者应用西妥昔单抗联合化疗进行一线治疗.结果:一线治疗的9例患者中,完全缓解(CR)1例,部分缓解(PR)3例,稳定(SD)3例,进展(PD)2例,一线治疗的有效率(CR PR)44.4%.疾病控制率(CR PR SD)66.6%.结论:晚期结直肠癌一线治疗使用西妥昔单抗联合化疗有较好的疗效,不良反应可耐受.     

西妥昔单抗在转移性结直肠癌治疗中的地位转变

靶向药物在转移性结直肠癌的应用中取得令人鼓舞的疗效,并成为标准内科治疗。通过对临床研究的回顾,我们归纳了表皮生长因子单抗———西妥昔单抗在治疗中的地位变迁,其与化疗的联合应用目前已成为转移性结直肠癌的一线治疗方案。Ｋ-Ｒａｓ基因类型、治疗相关的皮疹等为患者的个体化治疗提供了疗效预测指标。     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的 观察西妥昔单抗联合含伊立替康或奥沙利铂方案治疗转移性结直肠癌的近期疗效、毒副反应.方法 8例经病理组织学确诊的转移性结直肠癌入组,均联合FOLFIRI方案或FOLFOX方案治疗,西妥昔单抗首次给予负荷剂量400 mg/m2,而后每周维持量为250 mg/m2.结果 全组有7例可评价疗效,PR 3例,SD 4例,有效率42.9%,疾病控制率100%,中位TTP 5.8个月.主要毒副反应为痤疮样皮疹和腹泻.结论 西妥昔单抗联合含伊立替康或奥沙利铂方案治疗转移性结直肠癌安全有效.     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的:观察西妥昔单抗联合FOLFIRI或FOLFOX方案治疗转移性结直肠癌的近期疗效及毒副反应.方法: 2006年11月至2009年1月,我院收治的12例转移性结直肠癌患者,接受西妥昔单抗联合化疗治疗,西妥昔单抗首次给予负荷剂量400mg/m2 ,而后每周维持量为250mg/m2.有7例联合FOLFIRI方案, 4例联合FOLFOX方案,1例联合奥沙利铂+放疗.分别按照RECIST标准和NCI-CTC 3.0评价疗效和毒性.结果:全组12例均可评价疗效, PR 7例,SD 3例,PD 2例,总有效率58.3%,疾病控制率83.3%.疾病进展时间(TTP)1.5个月～15个月.主要毒副反应为痤疮样皮疹和腹泻.结论:西妥昔单抗联合FOLFIRI或FOLFOX方案治疗转移性结直肠癌安全有效,除痤疮样皮疹外,毒副作用无明显增加.     

西妥昔单抗联合化疗治疗转移性结直肠癌疗效与K-ras状态的关系

背景与目的：随着西妥昔单抗联合化疗在转移性结直肠癌患者中的不断应用,预测其治疗疗效的研究也越来越深入。本文旨在探讨转移性结直肠癌患者肿瘤组织中K—ras基因表达状态（野生型或突变型）及其与西妥昔单抗联合化疗疗效之间的关系。方法：2006年3月02008年6月期间应用西妥昔单抗联合化疗治疗转移性结直肠癌27例。采用聚合酶链反应（PCR）技术和直接测序法检测肿瘤组织中K-ras基因表达状态。分析K—ras基因表达状态与西妥昔单抗联合化疗疗效之间的关系。结果：全组27例患者中,K-ras野生型15例（55．6％）,K—FaS突变型12例（44．4％）。在K—FaS野生型中,西妥昔单抗联合化疗的总有效率（ORR）为66．7％,其中cR2例（13．3％）,PR 8例（53．3％）,中位无进展生存期（PFS）8个月。在K—ras突变型中,总有效率为25．0％,PR3例（25．0％）,中位PFS4个月。在K—ras野生型转移性结直肠癌患者中应用西妥昔单抗联合化疗的疗效明显优于K—ras突变型患者。结论：K-ras野生型是西妥昔单抗联合化疗疗效良好的预测指标。在西妥昔单抗联合化疗前明确患者的K—ras基因状态有助于选择合适的患者,获得最佳疗效。     

西妥昔单抗在转移性结直肠癌一线治疗后的后续应用研究进展

表皮生长因子受体（epidermal growth factor receptor，EGFR）单克隆抗体西妥昔单抗联合化疗是RAS野生型转移性结直肠癌（metastatic colorectal cancer，mCRC）患者一线治疗的标准方案，并在后续治疗中也可能有效。一线西妥昔单抗联合化疗后患者病情缓解或稳定，西妥昔单抗继续维持治疗存在很大争议。而当肿瘤对治疗产生耐药性时，就会发生疾病进展。而对于化疗和靶向治疗后疾病进展并不意味着患者对这两类药物同时产生耐药性。多项研究表明，患者可能对化疗药物而不是西妥昔单抗产生耐药性，同时对西妥昔单抗产生耐药性的患者也可能通过化疗转换作用复敏，目前对一线西妥昔单抗联合化疗后进展的RAS野生型患者通过后续使用西妥昔单抗跨线治疗或二线化疗后再挑战治疗能否获益尚无定论。多项研究试图筛选适合于上述治疗策略的优势人群，以期延长这些患者的治疗获益时间，有助于建立其全程治疗策略。就近年来RAS野生型mCRC西妥昔单抗维持、跨线和再挑战治疗方面的研究进展进行综述。     

西妥昔单抗联合化疗治疗晚期结直肠癌的近期疗效观察

目的：观察西妥昔单抗联合化疗治疗晚期结直肠癌的近期疗效和安全性。方法：全组29例患者均经病理组织学证实,治疗方案为西妥昔单抗联合FOLFOX4或FOLFIRI方案治疗,西妥昔单抗首剂400mg／m2,然后250mg／m2每周1次维持。3—4周期后评价疗效和不良反应。结果：29例患者治疗6—8周后取得CR1例,PR13例,SD10例,PD5例,有效率40．6％,疾病控制率69．6％。主要的不良反应是痤疮样皮疹,中性粒细胞降低和腹泻。结论：西妥昔单抗联合化疗对耐药性晚期结直肠癌患者有效。除皮疹外,不良反应较单用化疗无明显增加。     

西妥昔单抗联合化疗治疗晚期结直肠癌的近期疗效观察

目的:观察西妥昔单抗联合化疗治疗晚期结直肠癌的近期疗效和安全性。方法:全组29例患者均经病理组织学证实,治疗方案为西妥昔单抗联合FOLFOX4或FOLFIRI方案治疗,西妥昔单抗首剂400mg/m2,然后250mg/m2每周1次维持。3-4周期后评价疗效和不良反应。结果:29例患者治疗6-8周后取得CR 1例,PR 13例,SD 10例,PD 5例,有效率40.6%,疾病控制率69.6%。主要的不良反应是痤疮样皮疹,中性粒细胞降低和腹泻。结论:西妥昔单抗联合化疗对耐药性晚期结直肠癌患者有效。除皮疹外,不良反应较单用化疗无明显增加。     

Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer

Background:

Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment.

Methods:

We used RT–PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS).

Results:

Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC.

Conclusion:

Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.     

Cost-effectiveness of first-line treatments for patients with KRAS wild-type metastatic colorectal cancer

Background

Combinations of chemotherapy regimens and monoclonal antibodies have been demonstrated to improve clinical outcomes in patients with metastatic colorectal cancer (mcrc). Although these combination treatment strategies are safe and effective in first-line treatment for mcrc, little is known about their economic consequences and resource allocation implications. In the present study, we evaluated the cost-effectiveness of bevacizumab plus folfiri, cetuximab plus folfiri, and panitumumab plus folfiri for patients with KRAS wild-type mcrc.

Methods

A Markov model simulated the lifetime patient outcomes and costs of each first-line treatment strategy and subsequent lines of treatment from the perspective of the health care payer in Ontario. The model was parameterized using data from the Ontario Cancer Registry, Ontario health administrative databases, and published randomized control trials. Patient outcomes were measured in quality-adjusted life years (qalys), and costs were measured in monetary terms. Costs and outcomes were both discounted at 5% and expressed in 2012 Canadian dollars.

Results

For mcrc patients with KRAS wild-type disease, the treatment strategy of bevacizumab plus folfiri was found to dominate the other two first-line treatment strategies. Sensitivity analyses revealed that the incremental cost-effectiveness ratio values were sensitive to the effectiveness of treatment, the costs of bevacizumab and cetuximab, and health utility values.

Conclusions

Evidence from Ontario showed that bevacizumab plus folfiri is the cost-effective first-line treatment strategy for patients with KRAS wild-type mcrc. The panitumumab plus folfiri and cetuximab plus folfiri options were both dominated, but the cetuximab plus folfiri strategy must be further investigated given that, in the sensitivity analyses, the cost-effectiveness of that strategy was found to be superior to that of bevacizumab plus folfiri under certain ranges of parameter values.     

A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt,metastatic colorectal cancer: a pilot phase II trial

Background:

We conducted an open-label, pilot phase II trial to evaluate the efficacy and safety of FOLFOXIRI plus cetuximab as first-line treatment of patients with metastatic colorectal cancer (mCRC).

Methods:

Thirty patients with KRAS wild-type mCRC, <70 years and with performance status 0–1 were included in the trial.

Results:

Complete and partial responses were observed in 4 (13.3%) and 17 (56.7%) patients, respectively (overall response rate (ORR)=70% 95% confidence interval (CI): 53.6%-86.4%); 8 patients (26.7%) had stable disease and 1 had progressive disease. The median time to tumour progression was 10.2 months (95% CI: 7.1–13.4) and the overall median survival time was 30.3 months (95% CI: 18.8–41.9). Secondary R0 resection was performed in 11 (37%) patients. Grade 3 or 4 diarrhoea and neutropenia were observed in 16 (53%) and 7 (23.3%) patients, respectively, and febrile neutropenia observed in 2 (6.6%) patients. Neurotoxicity grade 2 or 3 was reported in 7 (23.3%) and in 2 (6.7%) patients, respectively, and grade 3 rush was reported in 1 patient.

Conclusion:

The FOLFOXIRI/cetuximab combination presented increased activity in terms of response rate and R0 secondary liver metastases resection, and merits further investigation, especially in patients with initially unresectable disease confined to the liver.     

MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab

The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006–2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy (P ≤ 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52–10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50–9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients.     

Raltitrexed plus weekly oxaliplatin as first-line chemotherapy in metastatic colorectal cancer

Aim: The primary aims of this study were activity and toxicity evaluation of a new raltitrexed and oxaliplatin-based regimen, as a first-line chemotherapy, in patients with metastatic colorectal cancer (MCC). Survival evaluation was considered a secondary endpoint. Patients and Methods: Forty-four patients were enrolled into this phase II trial. Treatment consisted of raltitrexed 3 mg/m² iv on d 1 and oxaliplatin 70 mg/m² iv on d 1 and d 8 every 3 wk. Results: Twenty patients (45.5%) achieved a response [95% confidence interval (CI): 30.1% to 54.1%], 18 (40.9%) had stable disease, and only 6 (13.6%) developed progressive disease. After a median follow-up time of 14.7 mo (range 6.3–18.6 mo), the median time to disease progression was 6 mo (range 2.0–16.7) (95% CI: 4.4–7.6) and the overall survival was 14.8 mo (range 3–23) (95% CI: 11.2–18.4). Neutropenia was the most common hematological side effect, while transient AST/ALT increase, neurotoxicity, asthenia, and diarrhea were the most common nonhematological side effects. Conclusions: Our data confirmed that oxaliplatin administered weekly plus raltitrexed is an active combination in newly diagnosed patients with advanced colorectal carcinoma that merits further investigation versus the classic schedule in a randomized, phase III trial.     

西妥昔单抗联合伊立替康为主方案治疗耐药性晚期结直肠癌的临床观察

背景与目的：表皮生长因子受体（EGFR）与结直肠癌密切相关,而西妥昔单抗是一种特异性阻断EGFR的单克隆抗体,本文是观察西妥昔单抗联合伊立替康治疗耐药性晚期结直肠癌的有效性和安全性。方法：全组8例患者,均经病理组织学确诊,均联合伊立替康单药或FOLFIRI方案治疗,西妥昔单抗首剂400mg／m^2,然后250mg／m^2每周1次维持。结果：8例患者治疗后取得PR2例,SD4例,PD2例,有效率为25％,疾病控制率75％,中位TTP 15周。主要的毒性反应是痤疮样皮疹和腹泻。结论：西妥昔单抗联合伊立替康对耐药性晚期结直肠癌患者有效。除皮疹之外,毒副反应较单用伊立替康无明显增加。     

Efficacy of first-line systemic treatment in correlation with BRAF V600E and different KRAS mutations in metastatic colorectal cancer - a single institution retrospective analysis

Background

KRAS mutation status in codons 12 and 13 is recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Despite having a wild type KRAS (wt-KRAS), not all patients with wt-KRAS respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway. Consequently, other molecular markers in colorectal cancer are needed to be evaluated to predict the response to therapy.

Patients and methods

In this retrospective study, objective responses (OR), time to progression (TTP), overall survival (OS) were analyzed in 176 metastatic colorectal cancer (mCRC) patients treated with first-line chemotherapy in combination with monoclonal antibodies in respect of KRAS status in codons 12 and 13 and BRAF mutational status.

Results

The KRAS mutations were found in 63 patients (35.8 %), the KRAS mutation in codon 12 in 53 patients (30.1%) and the KRAS mutation in codon 13 in 10 patients (5.7%). The BRAF V600E mutation was detected in 13 of 176 patients (7.4%). In the subgroup of mCRC patients having wt-KRAS and wild type BRAF (wt-BRAF), the objective response rates were higher (OR 54.0% ,CR 14.7%, PR 39.3%) than in the patients with wt-KRAS and mt-BRAF (OR 38.5%,CR 15.4%, PR 23.1%), the difference was not statistically significant (p= 0.378). Median OS in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 107.4 months and 45 months, respectively. The difference was statistically significant (p= 0.042). TTP in patients with wt-KRAS wt-BRAF, and in patients with wt-KRAS mt-BRAF, was 16 months and 12 months, respectively. The difference was not statistically significant (p= 0.558).

Conclusions

Patients with BRAF V600E mutation have statistically significantly worse prognosis than the patients with wt-BRAF and progress earlier during treatment. The definitive role of the BRAF V600E mutation as a prognostic and predictive factor for the response to anti-EGFR monoclonal antibodies needs to be analyzed in large prospective clinical studies.