FOLFOXIRI方案一线治疗晚期结直肠癌的研究进展

结直肠癌是最常见的恶性肿瘤之一,晚期结直肠癌的主要治疗手段是全身药物治疗。近年来,两药联合化疗方案FOLFOX或FOLFIRI联合靶向药物抗VEGF单抗或抗EGFR单抗已成为晚期结直肠癌的标准一线治疗方案。氟尿嘧啶、奥沙利铂和伊立替康是结直肠癌的3种主要化疗药物。这3种药物的联合方案FOLFOXIRI在晚期结直肠癌的治疗中越来越重要。FOLFOXIRI较两药联合方案可以显著改善晚期结直肠癌患者的预后,但同时也明显增加了不良反应。如何在保证疗效的前提下降低不良反应是临床上亟需解决的问题。本文将对FOLFOXIRI方案一线治疗晚期结直肠癌的研究进展进行综述。      

贝伐珠单抗在结直肠癌治疗中的应用

近年来,随着对肿瘤生物学认识的深入,以贝伐珠单抗、西妥昔单抗为代表的分子靶向治疗药物正逐渐丰富着晚期结直肠癌的治疗选择.贝伐珠单抗是一种人源化、人鼠嵌合抗血管内皮生长因子的单克隆抗体,是第一个被美国FDA批准用于治疗晚期结直肠癌患者的抗血管生成药物,以贝伐珠单抗为基础进行的临床研究也证实了它能改善晚期结直肠癌患者的生存期.全文通过回顾近年来发布的结直肠癌治疗领域有关贝伐珠单抗的临床研究,对其在晚期结直肠癌一线、二线和维持治疗以及在结直肠癌术后辅助治疗领域中的应用做一系统综述.     

结直肠癌辅助治疗现状

在过去的20年结直肠癌辅助治疗有很大改进。辅助性放化疗已成为结直肠癌综合治疗的重要组成部分。本文综述了结直肠癌术后辅助化疗、术前、术后辅助放疗、免疫治疗、局部门静脉灌注化疗的现状。     

2008年转移性结直肠癌个体化治疗进展回顾

含草酸铂或伊立替康的化疗方案作为晚期结直肠癌的标准治疗方案,使得患者总生存期超过20个月,靶向治疗药物西妥昔单抗和贝伐单抗的加入进一步提高了疗效.2008年结直肠癌治疗的重要进展是确定KRAS基因状态与抗EGFR抗体疗效的相关性.CRYSTAL、OPUS和CELIM等随机研究显示,通过K-ras检测可筛选出能从分子靶向治疗药物中获益的人群,西妥昔单抗无论是联合以奥沙利铂为基础、还是联合以伊立替康为基础的一线化疗方案,都能使KRAS野生型患者疗效显著提高,显示出西妥昔单抗在mCRC一线治疗中的优势.     

结直肠癌新辅助化疗患者术后预后的相关影响因素分析

目的 探讨结直肠癌新辅助化疗患者术后预后的相关影响因素。方法 选取接受新辅助化疗与根治术治疗的85例结直肠癌患者作为研究对象,术后随访2年,记录患者随访期间复发情况与患者基线资料,分析结直肠癌新辅助化疗患者预后的影响因素。结果 85例结直肠癌患者术后2年内复发16例(18.82%),未复发69例(81.18%)。复发患者与未复发患者在年龄、吸烟史、肿瘤分化程度、术前癌胚抗原(CEA)方面比较,差异有统计学意义(P<0.05);经Logistic回归分析结果显示,年龄大、有吸烟史、肿瘤分化程度低、术前CEA高表达是导致结直肠癌新辅助化疗患者预后不佳的因素(OR>1,P<0.05)。结论 结直肠癌新辅助化疗患者术后预后情况受患者年龄、吸烟史、肿瘤分化程度、术前CEA水平的影响。     

结直肠癌术后辅助化疗对血脂变化的影响

目的:探讨结直肠癌患者术后辅助化疗前后血脂水平的变化及不同化疗方案对血脂变化的影响。方法:对127例结直肠癌患者术后辅助化疗前后总胆固醇（TC）、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)水平进行测定并比较分析。结果:化疗后,TG、HDL、LDL水平较化疗前升高,差异有统计学意义（P＜0.05）。TC值较化疗前增高,但差异无统计学意义（P＞0.05）。含奥沙利铂的化疗方案与卡培他滨单药方案相比对TC、TG、LDL的影响更加显著,差异有统计学意义（P＜0.05）。结论:结直肠癌患者在术后辅助化疗期间存在血脂代谢紊乱,以血清TG、HDL、LDL升高为特点;不同化疗方案对血脂变化的影响存在差异。     

晚期结直肠癌化疗的研究进展

随着细胞毒药物和分子靶点药物的发展,晚期结直肠癌患者姑息化疗的有效率以及生存期取得了瞩目的成效,患者中位生存期可超过2年。本文通过比较单药化疗与联合化疗以及不同联合化疗方案的优劣,分析卡培他滨能否替代5-FU的作用;阐述打打停停(stop-and-go)的化疗观念,介绍贝伐单抗和西妥昔单抗这两种分子靶点药物在晚期结直肠癌患者中的疗效。旨在对这些问题的综述来阐明奥沙利铂或伊立替康联合5-FU/LV优于5-FU/LV单药;FOLFOX或FOLFIRI联合方案均可作为晚期结直肠癌可耐受化疗患者的一线化疗方案,疾病进展后可互换作为二线方案;卡培他滨可代替5-FU/LV与奥沙利铂联合作为晚期结直肠癌患者的一线化疗方案,但卡培他滨与伊立替康联合不是一个理想的方案;在转移性结直肠癌的化疗中不建议完全停止化疗,可考虑使用5-FU/LV单药维持;贝伐单抗和西妥昔单抗这两种分子靶点药物联合化疗均可有效的提高生存期。从而概述晚期结直肠癌化疗的一些新进展。     

转移性结直肠癌维持治疗的研究现状与治疗策略

结直肠癌是常见的恶性肿瘤之一,其发病率和死亡率分别位于第三位和第四位。大约60%的患者确诊时已处于晚期,其5年生存率在13%左右。近20年来,由于转移性结直肠癌(mCRC)晚期一线化疗方案及靶向药物的规范化应用,mCRC的治疗获得了重大突破。奥沙利铂、卡培他滨、贝伐珠单抗、西妥昔单抗等药物的应用使患者的中位生存期提高了一倍,5年生存率提高了20%。mCRC晚期一线治疗的常规模式是持续用药,直至病情进展或出现不可耐受的毒性。但是由于化疗药物的毒性累积,只有三分之一的患者能够坚持接受治疗直至病情进展。而患者在完成既定的初始化疗周期数,达到CR/PR/SD后,继续采用低剂量、低毒性的药物进行维持治疗,既可以延缓肿瘤的进展和转移,又可以减轻药物的毒副作用。目前,维持治疗已经成为mCRC晚期一线化疗后的主要治疗模式。但是,mCRC的最佳维持治疗方案仍无定论,现有的维持治疗方案仍不能找到最佳疗效与最大生活质量之间的平衡点。本文将回顾mCRC现有的维持治疗方案的临床研究,总结mCRC维持治疗现状,并对个体化的治疗策略进行讨论。     

新辅助化疗在结直肠癌中的应用（附62例报告）

目的：观察新辅助化疗在结直肠癌中的临床疗效。方法：收集2008年6月-2012年6月住院患者资料。对62例进展期结直肠癌患者行术前全身化疗4个周期（ FOL FOX4方案）,并于术后2周行辅助化疗2个周期（ FOL FOX4方案）。结果：经新辅助化疗,病人肿瘤平均直径缩小了32.5％,肿瘤的TNM分期得到降低。本组62例患者行4周期化疗后行腹腔镜辅助下结直肠癌根治术,手术顺利,无中转开腹,平均手术时间180min（120-240min）,平均术中出血150ml（100-300ml）,术后胃肠功能恢复时间1-2d,平均住院时间10d （8-14d）,术中及术后无严重并发症。本组中有3例因术后并发肝肺转移于术后2年内死亡,1例脑转移死亡,失访5例,余53例均存活至今未发现局部复发、远处转移。结论：新辅助化疗在结直肠癌的治疗中,使肿瘤分期得以降期,不同程度缩小了肿瘤体积,减少局部复发,对中晚期结直肠癌有积极意义。     

结直肠癌组织中ERCC1蛋白的表达及其与铂类化疗疗效的关系

目的 探讨核苷酸切除修复交叉互补基因1(ERCC1)蛋白在结直肠癌组织中的表达及其与铂类化疗疗效的关系.方法 采用免疫组化法检测结直肠癌组织中ERCC1蛋白的表达,所有入组患者术后均给予含奥沙利铂的方案辅助化疗,并且随访4年以上.结果 结直肠癌组织中ERCC1蛋白阳性表达率为42.6%,低于两对照组(P<0.01);ERCC1蛋白表达与患者年龄、性别、肿瘤局部浸润、淋巴结转移及TNM分期无关,但与组织病理学分级有关;ERCC1蛋白阴性患者术后经含奥沙利铂的方案化疗后生存期高于阳性患者,差异有统计学意义(P<0.05);Cox回归分析显示ERCC1蛋向表达为结直肠癌患者的独立预后因子.结论 ERCC1蛋白阴性患者应用含奥沙利铂的方案化疗可获得生存获益,ERCC1蛋白表达水平有可能作为指导结直肠癌患者术后化疗方案选择及预后判断的指标.     

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.     

Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer.

BACKGROUND: Mucinous carcinoma of the colon and rectum (mucinous CRC) is a histological subtype of colorectal adenocarcinoma for which there is little data on chemotherapy responsiveness. The purpose of this study was to investigate specifically the efficacy of fluorouracil-based first-line chemotherapy in patients with advanced mucinous CRC. PATIENTS AND METHODS: All patients with advanced mucinous CRC enrolled in three prospective randomized trials evaluating infused 5-fluorouracil as first-line treatment were compared with patients with non-mucinous subtypes enrolled in the same trials in a case-control study. Prognostic factors associated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. RESULTS: The study included 135 patients (45 cases and 90 controls). The response rates for cases and controls were 22% [95% confidence interval (CI), 11% to 38%] and 47% (95% CI, 36.1% to 58.2%), respectively (P=0.0058). Median OS for the mucinous CRC patients was 11.8 months (95% CI, 8.87-14.8) compared with 17.9 months (95% CI, 13.38-22.39) in the control group (univariate analysis, P=0.056); after correcting for significant prognostic factors by multivariate Cox regression analysis, P=0.0372 and hazard ratio (HR)=1.497 (1.02-2.19). CONCLUSION: Patients with advanced mucinous CRC have a poorer response to fluorouracil-based first-line chemotherapy and reduced survival compared with patients with non-mucinous CRC.     

Advanced colonic neoplasia in the first degree relatives of colon cancer patients: A colonoscopy‐based study

We aimed to determine the risk of advanced neoplasms among a cohort of asymptomatic first degree relatives (FDRs) of patients with sporadic colorectal cancer (CRC) compared with matched controls. Data for patients with a diagnosis of CRC made between September 2013 and August 2014 were obtained from a population‐based cancer registry system in Tehran. Screening colonoscopies were done for 342 FDRs and the findings were compared to those from 342 age‐ and gender‐matched healthy controls without a family history of CRC. We reported the association as conditional Odds Ratio (OR) using Mantel Hazel and Logistic regression. The prevalence of advanced neoplasia was 13.2% among FDRs and 3.8% in controls (matched OR [mOR], 4.0, 95% confidence interval [CI], 2.1 – 7.6; p < 0.001). In FDRs aged 40–49 years, the prevalence of advanced neoplasia was significantly higher than in their matched controls (mOR, 6.8, 95% CI, 1.5–31.4; p = 0.01). Family history of CRC in at least one FDR was the strongest predictor of advanced neoplasia (adjusted OR, 4.0, 95% CI: 2.1–7.6; p < 0.001). The age of the index case at diagnosis did not predict the presence of advanced colonic neoplasms in their FDRs. Our study indicates a high risk of advanced neoplasia in FDRs of CRC cases, where only eight colonoscopies are needed to detect one advanced neoplasia. Our data suggest that all FDRs, regardless of the age of CRC diagnosis in their index case, should be considered for a targeted early screening.     

An evaluation and replication of miRNAs with disease stage and colorectal cancer‐specific mortality

MicroRNAs (miRNAs) have been implicated in colorectal cancer (CRC) development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on few individuals and imprecise. In this study, we utilize population‐based data from 1,141 CRC cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage and tumor molecular phenotype. Five miRNAs were associated with more advanced disease stage; hsa‐miR‐145‐5p and hsa‐miR‐31‐5p showed increased expression with more advanced tumor stage, while hsa‐miR‐200b‐3p, hsa‐miR‐215 and hsa‐miR‐451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with CRC mortality among individuals diagnosed with colon cancer while 14 were associated with CRC mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa‐miR‐145‐3p [hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.54, 5.61], and hsa‐miR‐9‐3p (HR 10.28, 95% CI 1.31, 80.84) with colon cancer and hsa‐miR‐335‐5p (HR 0.17, 95% CI 0.05, 0.54) for rectal cancer. hsa‐miR‐374a‐5p, hsa‐miR‐570‐3p and hsa‐miR‐18a‐5p significantly reduced the hazard of dying for all cases, regardless of tumor site. Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.     

The expanding role of PET technology in the management of patients with colorectal cancer.

The therapeutic options and subsequent survival of colorectal cancer (CRC) patients has increased substantially over recent years. While surgical excision of the primary cancer results in cure of approximately 50% of patients, recurrence and metastatic disease still remains a significant cause of death. Although resection of liver or lung metastases can result in cure, relapse rates remain high, indicating that patient selection needs improvement. Positron emission tomography (PET) technology has a great deal to offer with respect to CRC management, particularly in the setting of patient selection for metastasectomy and in the evaluation of possible recurrent disease, however it has not yet become a routine part of the management of all CRC patients. This review article aims to discuss the current and future implications of PET technology in the optimal management of CRC patients throughout their care pathway.     

Raltitrexed: current clinical status and future directions.

Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC), and has single-agent activity in a variety of advanced solid tumours. Although both raltitrexed and 5-FU are thymidylate synthase inhibitors, raltitrexed has a specific mode of action and a toxicity profile distinct from 5-FU. The mechanism of action of raltitrexed is also completely different from that of oxaliplatin, irinotecan and other drugs with which it has been combined. These properties, together with preclinical data, suggested that combinations of raltitrexed with 5-FU, other chemotherapeutic agents, or radiotherapy could result in improved therapies for a variety of advanced solid tumours, including advanced CRC. This review outlines the appropriate management of patients treated with raltitrexed, whether as monotherapy or in combination, and discusses the preliminary results of combination studies with raltitrexed in a range of tumour types including advanced CRC, malignant mesothelioma, gastric, pancreatic, head and neck, and non-small-cell lung cancers. Of particular interest is the combination of raltitrexed and oxaliplatin, which has shown promising antitumour effects in first-line treatment of advanced CRC and malignant mesothelioma, a disease that is refractory to chemotherapy.     

阿帕替尼单药在标准方案治疗失败晚期结直肠癌患者中的疗效及安全性

目的：探讨阿帕替尼单药在标准治疗方案失败晚期结直肠癌（colorectal cancer,CRC）患者中的疗效和安全性。方法：本研究为前瞻性研究设计,用PASS15 软件计算研究所需的样本量,从2017 年7 月到2018 年8 月入组标准方案治疗失败的晚期CRC患者52 例,给予阿帕替尼起始剂量750 mg或500 mg单药治疗;评估患者的客观缓解率（ORR）和疾病控制率（DCR）,随访评价患者的无进展生存期（PFS）和总生存期（OS）,并记录治疗过程中出现的不良反应。主要研究终点为PFS,次要研究终点为ORR、DCR、OS和安全性。结果：纳入研究的52 例CRC患者中45 例可以评价疗效及安全性,其均为既往接受过至少2 次系统性化疗的晚期CRC患者。疗效：完全缓解0 例、部分缓解5 例、疾病稳定30 例、疾病进展10 例,ORR为11.11%、DCR为77.78%;预后：45 例患者的中位PFS 为3.95 个月（95% CI=3.16~4.74）,中位OS为10.3 个月（95% CI=5.70~14.90）;3 级以上不良反应：手足综合征6 例（13.33%）,高血压5 例（11.11%）,蛋白尿5 例（6.67%）,转氨酶升高4 例（8.89%）,腹泻3 例（6.67%）,疲劳2 例（4.44%）,出血1例（2.22%）。结论：阿帕替尼单药治疗标准方案失败的晚期CRC患者具有潜在的临床获益,安全性事件总体可控。     

First clinical experience of orally active epidermal growth factor receptor inhibitor combined with simplified FOLFOX6 as first-line treatment for metastatic colorectal cancer

BACKGROUND: Gefitinib, an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, combined with chemotherapy, has shown efficacy as second-line treatment for advanced colorectal cancer (CRC). Gefitinib combined with FOLFOX6 (oxaliplatin plus folinic acid and 5-fluorouracil) was tested as a first-line therapy. METHODS: Patients with metastatic EGFR-positive CRC received gefitinib at a dose of 250 mg/day combined with simplified FOLFOX6. Gefitinib was continued as maintenance treatment in nonprogressing patients. Responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and adverse events were assessed with the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale. RESULTS: A total of 56 patients were recruited. There were 26 men and 30 women, with a median age of 57.5 years. The Eastern Cooperative Oncology Group (ECOG) performance status was as follows: 0 in 39 patients, 1 in 12 patients, and 2 in 5 patients. Thirty-nine patients (69.6%) had stage IV disease at diagnosis, 92.9% had liver involvement, and 46.4% had > or =2 metastatic sites. All patients were evaluated for safety, and 53 were evaluated for response: 40 patients (71.4%; 95% confidence interval [95% CI], 57.8%-82.6%) had complete or partial responses, and 11 patients (19.6%) had stable disease. Median time to progression was 7 months (range, 2.1-33.0 months; 95% CI, 6.2-9.0 months). Radical surgery or thermoablation of metastatic sites was performed in 14 patients (25%). NCI-CTC grade 3-4 events occurred in 36 patients (64.3%): diarrhea in 9 patients (16.1%), and hematologic toxicity in 13 patients (23.2%). Four patients (7.1%) were withdrawn for drug-related adverse events. CONCLUSIONS: The regimen has shown promising efficacy with manageable toxicity as a first-line treatment for patients with advanced CRC.     

Colorectal cancer surgery in elderly patients 80 years and older: a comparison with younger age groups

BackgroundA reduction in complications and mortality can be observed over the last few decades among elderly patients in the early postoperative period for colorectal cancer (CRC) surgery, but long-term outcomes are largely unknown. This study aimed to investigate the long-term outcomes of elderly patients 80 years and older after CRC surgery in comparison with younger age groups. The influence of clinical, oncological, and physical parameters on outcome were retrospectively analyzed.MethodsA total of 346 patients underwent CRC surgery with curative intent between January 2013 and December 2017. Patients were divided into three age groups: younger than 60 (n=47), between 60 and 79 (n=218), and 80 and older (n=81). Clinicopathological variables including comorbidity, modified frailty index, prognostic nutrition index (PNI), operative/postoperative data, and outcome including cause of death were compared among age groups. To identify factors associated with death from CRC and other causes, univariate and multivariate analyses using the Cox proportional hazards model were performed.ResultsImmediate postoperative morbidity of patients with Clavien-Dindo grades of III or greater (16.0%) and the 30-day mortality rate (2.5%) of patients 80 years and older were not statistically different from those of younger age groups. Long-term disease-free survival was also similar among age groups, suggesting CRC surgery provides oncological benefit to patients irrespective of age. Multivariate analysis revealed that R1 resection, advanced tumor stage, carcinoembryonic antigen (CEA) level of >5 ng/mL, undifferentiated tumor, and longer postoperative hospital stay were risk factors for CRC death. Long-term overall survival was significantly reduced in comparison to younger age groups. Seventy percent of deaths in elderly patients during follow-up were primarily from respiratory failure and cardiovascular disease. Multivariate analysis demonstrated that advanced age, frailty, low PNI, and open procedure were risk factors for other causes of mortality.ConclusionsElderly patients undergoing CRC surgery appeared to enjoy similar oncological benefits as younger age groups. Since both modified frailty index and PNI were correlated with mortality unrelated to CRC, preoperative assessment of these factors can be important for predicting outcome and selecting patients for prehabilitation.