结直肠癌肝转移转化治疗的研究进展

结直肠癌患者在全病程中发生肝转移的概率达40%~50%,肝转移是影响结直肠癌患者长期预后的重要不利因素。手术切除肝转移灶是唯一可能达到近似根治效果的治疗选择。对于判断为不可切除的肝转移灶,经过综合治疗,使肿瘤缩小,进而将初始不可切除病灶转化为可切除病灶,称为转化治疗。转化治疗可分为以化疗±靶向为主的系统治疗及局部治疗。本文重点综述近年来结直肠癌肝转移转化治疗相关研究成果:(1)梳理肝转移癌手术可切除性评估标准;(2)探讨疗效评估、手术时机及肿瘤侧性对转化治疗方案选择的影响等临床问题;(3)总结转化治疗方案新进展,包括经典双药方案、三药联合的加强方案、分子靶向药物、免疫检查点抑制剂、多种局部疗法以及门静脉栓塞/两步肝切除、联合肝脏分割和门静脉结扎的分步肝切除术在转化治疗中的应用效果。本综述通过分析结直肠癌肝转移转化治疗现有问题,以期为结直肠癌肝转移的临床治疗发展提供参考。     

分子靶向药物在胃肠道肿瘤综合治疗中的应用

分子靶向药物在晚期胃肠道肿瘤治疗中,被证实可提高患者的客观缓解率并延长总生存期.因此,其在局部进展期胃肠道肿瘤综合治疗中的价值被逐渐重视.曲妥珠单抗用于HER-2基因阳性的局部进展期胃癌新辅助化疗中的临床研究正在进行中,结果值得期待.大量研究证明,西妥昔单抗联合化疗对于KRAS基因野生型潜在可切除的结直肠癌肝转移患者,能提高手术切除率并延长总生存期;而贝伐珠单抗在KRAS基因突变型结直肠癌肝转移术前转化治疗中的作用正在评估中.对于可切除的结直肠癌肝转移,虽现有的证据显示,分子靶向药物在新辅助治疗中未能带来长期生存益处,但最终结论仍存议甚多.对于局部进展期直肠癌患者,新辅助化疗中的西妥昔单抗在二期临床研究中未能显示治疗获益,贝伐珠单抗的作用同样需要在三期临床研究后进一步证实.与晚期肿瘤单一治疗模式不同,在肿瘤综合治疗中,需要系统评估分子靶向药物与细胞毒药物、手术以及放疗之间可能的相互影响及协同作用,制定出科学并适用于临床实践的综合治疗模式.     

转移性结直肠癌药物治疗研究进展

目的 了解化学治疗、靶向治疗和免疫治疗药物对转移性结直肠癌治疗疗效的最新研究进展。方法 检索近年国内外有关研究转移性结直肠癌不同治疗药物疗效的文献并综述。结果 转移性结直肠癌治疗的临床研究较多，新药层出不穷，靶向药物尤为突出，治疗药物的选择及药物联合治疗方案的试验也越来越多。根据患者RAS/RAF基因突变状态及错配修复蛋白表达情况选择不同治疗方式，生存获益有巨大差异。结论 精准医学愈加重要，筛选患者选择适宜的治疗方式可进一步提高生存获益。     

晚期结直肠癌的外科治疗进展

尽管结直肠癌的综合治疗有了很大的进展,但局部晚期(T3期和T4期)以及转移性结直肠癌的治疗仍然是具有挑战性的课题.新辅助放化疗、靶向治疗等研究取得了许多令人鼓舞的结果,但从外科处理的角度,仍然有诸多争议存在.包括对局部晚期结直肠癌多脏器切除的扩大根治指征、对结直肠癌肝转移和肺转移的最优化处理策略等.R0切除是转移病灶的首选处理策略,但仅适用于部分患者.利用化疗联合靶向药物的转化治疗策略将部分不可切除的转移肿瘤转化为可切除,也为进一步的外科治疗创造了机会.本文从局部晚期结直肠癌、结直肠癌肝和肺转移的外科治疗为切入点,简要阐述晚期结直肠癌的治疗进展.     

不可切除结直肠癌肝转移的转化性治疗策略

手术是治疗结直肠癌肝转移最有效的也是惟一有可能治愈的手段,但是大多数结直肠癌肝转移病人并不能够行肝转移灶切除手术。近些年,用各种细胞毒药物和（或）靶向药物等使不可切除的肝转移病灶缩小,转化为可切除,继而行手术切除,从而获得治愈的可能。转化性治疗的目的是获得最佳反应率,而不是获得最大反应率。术前转化性化疗应选择高效化疗方案,并尽量缩短疗程。具体方案选择方面,KRAS野生型病人推荐西妥昔单抗联合FOLFOX/FOLFIRI,其中5-氟尿嘧啶持续给药,而KRAS突变型病人考虑贝伐珠单抗联合两药化疗或者三药化疗方案。在行转化性治疗时,一旦转移灶转化为可切除,应积极手术切除。     

结直肠癌肝转移的转化治疗

对结直肠癌肝转移来说,手术是惟一的治愈手段。但80%的病人初始是不可切除的,将不可切除肝转移转化为可切除是提高结直肠癌总体存活率的关键。目前常用的转化手段有全身化疗（包括单纯化疗、化疗联合靶向药物等）、肝动脉灌注（HAI）、射频消融（RFA）、联合门静脉结扎或栓塞的分期肝切除、联合肝脏分隔及门静脉结扎的二步肝切除等。了解各种转化治疗的有效率和适应证是选择合适治疗的前提。     

结直肠癌肝转移消融与外科切除的治疗选择与时机

结直肠癌是全球第三高发恶性肿瘤,易发生肝转移。消融治疗与外科切除是结直肠癌肝转移有效且安全的局部治疗方法,可在全身治疗有效的基础上,有效控制局部病灶,延长患者生存期。药物治疗的进步使很多既往不宜局部治疗的结直肠癌肝转移患者获得了局部转化治疗机会。然而对于不同治疗目标、不同肿瘤负荷的结直肠癌肝转移,消融治疗与外科切除干预的时机以及术式尚没有明确的界限。本文对结直肠癌肝转移消融治疗与外科切除的研究进展以及治疗时机选择进行讨论。     

以经导管动脉化疗栓塞为基础的联合治疗方案在不可切除的结直肠癌肝转移中应用的新进展

目的了解以经导管动脉化疗栓塞(TACE)为基础联合全身化疗、分子靶向治疗、门静脉栓塞、射频消融等多种治疗方案对不可切除的结直肠癌肝转移患者进行治疗的新进展,探索适用于晚期结直肠癌肝转移患者安全、有效的联合治疗方法,从而控制疾病快速进展,改善患者生存质量。方法收集国内外有关以TACE为主导的联合治疗方案应用于结直肠癌肝转移外科治疗新进展的文献,就联合方案应用于结直肠癌肝转移治疗的新进展以及各联合治疗方案的优势与特点进行综述。结果对于晚期原发或继发性肝脏恶性肿瘤,TACE是一种安全、有效的治疗方法,在此基础上联合其他治疗方案与单一的治疗方案相比,在提高患者生活质量、延长生存时间这两方面均具有明显优势。随着各种新的治疗药物的不断涌现,多种介入治疗方式的快速发展,都为改善结直肠癌肝转移患者的远期生存带来利好因素。结论我们应该加强对不可手术切除的结直肠癌肝转移综合治疗的重视,提高对晚期肿瘤个体化治疗的认识,积极推动联合治疗方案在结直肠癌肝转移治疗中的应用。     

循环肿瘤DNA在不可切除转移性结直肠癌中的应用进展

多数转移性结直肠癌患者为不可切除状态, 因其治疗和监测手段有限, 通常预后不佳。随着测序技术和肿瘤基因组学的发展, 循环肿瘤DNA有望成为管理不可切除转移性结直肠癌的潜在生物标志物。本文就循环肿瘤DNA在不可切除转移性结直肠癌中提示肿瘤负荷、预测生存、指导治疗及评估疗效等方面的研究进展进行综述。     

手术在晚期及复发胃肠间质瘤治疗中的价值与评价

晚期及复发胃肠间质瘤（GIST）预后较差。靶向药物治疗是首选,但手术治疗仍然是重要组成部分。对于不能耐受靶向药物治疗的病人,手术治疗是惟一有效的方法。对于局部晚期GIST病人,术前靶向药物治疗联合手术治疗有利于肿瘤的根治性切除、重要器官的保留。对于全身广泛转移的GIST病人,单纯减瘤手术并不能使病人获益。靶向药物治疗后,病灶缓解或稳定的病人,手术切除耐药病灶能使病人的无进展生存时间和总生存时间延长。对于病灶局部进展的病人,手术能否使病人获益仍存在疑问,但可根据病人意愿、术者的经验选择合适的病人进行手术。而对于病灶进展的病人,手术并不能延长其无进展生存时间和总生存时间,故不建议行手术治疗。     

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??The best timing of preoperative chemotherapy for liver metastases of colorectal cancer XING Bao-cai, WANG Hong-wei. Department of Hepato-bilio-pancreatic Surgery I, Peking University School of Oncology??Beijing Cancer Hospital??Beijing 100142, China
Corresponding author??XING Bao-cai, E-mail??xingbaocai88@sina.com
Abstract The combination of surgery and chemotherapy has become the standard treatment for patients with liver metastases of colorectal cancer. There is controversy that preoperative chemotherapy should be considered in patients with resectable liver metastases of colorectal cancer. The patients with prognostic factor of poor survival should be received preoperative chemotherapy. Surgery should be performed after a maximum of 6 cycles of preoperative chemotherapy. In patients with unresectable liver metastases, there is no question regarding the indication of chemotherapy. They should be carefully monitored and performed surgery as soon as the metastases become resectable. Surgery can be performed after 4 weeks from the last cycle of chemotherapy, and 6-8 weeks following chemotherapy plus bevacizumab.     

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??Convertible therapy for unresectable colorectal liver metastases ZHU De-xiang, REN Li, XU Jian-min. Department of General Surgery, Zhongshan Hospital, Fudan University; Institute of General Surgery, Fudan University; Colorectal Cancer Research Center, Fudan University, Shanghai 200032, China
Corresponding author??XU Jian-min, E-mail??xujmin@aliyun.com
Abstract Surgery is the most effective and the only potentially curative treatment for colorectal liver metastases (CRLM). However, most patients with CRLM are not suitable for liver resection. In recent years, a variety of cytotoxic drugs and/or targeted drugs were used to shrink unresectable liver metastases, and some patients were converted to resectable. Thereby they might be cured following surgical resection. Therefore the purpose of convertible chemothrapy is to get the best response rate, not the maximum response rate. It should choose efficient convertible chemotherapy with short courses for preoperative chemotherapy. For KRAS wild-type patients, cetuximab combined with FOLFOX/FOLFIRI, in which 5-fluorouracil is continuous infused, is recommended, and for KRAS-mutant patients, bevacizumab combined with two-drug chemotherapy regimen or three-drug chemotherapy regimen is considered. They should be operated as soon as the metastases become resectable.     

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??Multi-disciplinary team and conversion therapy for colorectal cancer with unresectable liver metastases??A report of 86 patients WEI-Ye*??YE Qing-hai??YU Yi-yi??et al. *Department of General Surgery, Zhongshan Hospital??Fudan University??Shanghai200032??China
Corresponding author??QIN Xin-yu??E-mail??qin.xinyu@zs-hospital.sh.cn
Abstract Objective To analyze safety and effect of the conversion therapy for initially unresectable colorectal liver metastases (CLMs) under the guidance of multi-disciplinary team (MDT). Methods The retrospective analysis was conducted for 86 patients with unresectable CLMs received MDT management and arrived conversion therapy successfully from January 2008 to December 2011 in Zhongshan Hospital of Fudan University. The perioperative and survival outcomes??prognostic factors were evaluated. Results During the mean follow-up of 41 months (24-68 months), according to the finding time of liver metastases of 86 patients??recurrence events were 73 patients??and 39 patients died. The 1 year??2 year and 3 year overall survival rate (OS) was 90.6%??75.6% and 65.1% respectively. The median OS time was ??47.5±3.1?? months. The 1 year??2 year and 3 year disease free survival rate (DFS) was 72.1%??48.8% and 31.4% respectively. The median DFS time was ??22.0±2.9?? months. The OS and DFS were no significant difference when compared 86 patients with initially unresectable CLMs successfully arrived conversion therapy with 99 patients with initial resectable CLMs??P >0.05??. The perioperative mortality rate was 1.5%??and operative complication rate was 24.4%. Tumor regression grade and early tumor shrink could predict the prognosis of CLM patients received conversion therapy. Conclusion The conversion therapy under the guidance of MDT mode is safe and effective for unresectable CLMs. The mid-term survival rate is similar with initially resectable CLMs??and long-term survival is expected.     

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??Advance of chemotherapy and targeted therapy in colorectal liver metastases SHEN Lin. Department of Gastroenterology, Peking University Cancer Hospital, Beijing 100142??China
Abstract Advances in the treatment of colorectal liver metastases (CRLM) have benefited from the development of multidisciplinary treatment. But many problems are still unresolved in clinical practice including optimization of chemotherapy, advantages and disadvantages of combination of targeted therapy with chemotherapy, safety and chemotherapy timing, etc. Especially after the failure of CRLM adjuvant chemotherapy or targeted therapy, there is a growing concern about preoperative treatment and conversion therapy. Effective chemotherapy can provide more opportunities of radical resection and prolonged survival. Rational option of combination of targeted therapy with chemotherapy, correct chemotherapy duration and withdrawal time are the keys to improve management level of CRLM.     

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结直肠癌肝转移手术策略的选择是结直肠癌治疗的热点和难点之一。同期肝切除手术因其具有避免多次手术打击、不会中断连续的系统化疗等优点,受到越来越多学者的青睐。对于一般状况较好,原发灶可切除,肝转移灶小且多位于周边或局限于半肝,肝切除范围较小时,肝外转移可切除的病人,可考虑同期肝切除手术。认真进行术前评估,严格筛选合适病例,提高手术操作水平并加强围术期管理有助于减少并发症的发生,改善病人预后。     

The Role of Preoperative Chemotherapy in Patients with Resectable Colorectal Liver Metastases

Background  Liver metastases develop in 40–50% of patients with colorectal cancer and represent the major cause of death in this disease. Surgical resection remains the only treatment procedure that can ensure long-term survival and provide cure when liver metastases can be totally resected with clear margins, when the primary cancer is controlled, and when there is no nonresectable extrahepatic disease. Five-year survival rate after surgical resection of colorectal metastases varies from 25% to 55%, but cancer relapse is observed in most patients. Aim  To review the potential benefits and disadvantages of neoadjuvant chemotherapy administered before surgery to patients with initially resectable metastases. Results  European Organization for Research and Treatment of Cancer (EORTC) study 40983 has shown that neoadjuvant chemotherapy could reduce the risk of relapse by one-quarter, and allows to test the chemosensitivity of the cancer, to help to determine the appropriateness of further treatments, and to observe progressive disease, which contraindicates immediate surgery. Neoadjuvant chemotherapy can induce damage to the remnant liver. Oxaliplatin-based combination regimen is associated with increased risk of vascular lesions, whereas irinotecan-containing regimens have been associated with increased risks of steatosis and steatohepatitis. Analysis of EORTC study 40983 showed that administration of six cycles of neoadjuvant systemic chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was associated with moderate increase of the risk of reversible complications after surgery, but mortality rate was below 1% and not increased. If patients are not overtreated, chemotherapy before surgery is well tolerated. The integration of novel targeted agents in combination with cytotoxic drugs is a promising way to improve outcome in patients with advanced colorectal cancer. Preliminary trials have shown that targeted agents combined with cytotoxic regimens can increase tumor response rates. Another impact of preoperative chemotherapy is that metastases that respond to treatment may no longer be visible on computed tomography (CT) scan or at surgery. Patients should be carefully monitored and receive surgery before metastases disappear. Conclusion  Treatment of most patients with liver metastases—those with resectable metastases as well as those with initially unresectable metastases—should start with chemotherapy. If drugs are well chosen and the duration of treatment is monitored with care during multidisciplinary meetings, benefits largely outweigh potential disadvantages.     

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??Conversion therapy for unresectable colorectal liver metastases WANG Kun, XING Bao-cai. Hepatobiliary and Pancreatic Surgery Unit I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
Corresponding author: XING Bao-cai??E-mail: xingbaocai88@ sina.com
Abstract For colorectal liver metastases (CRLM), surgery is the only curable treatment. However, 80% of CRLM is initial unresectable. How to transform patients with unresectable CRLM to resectable is the key to improve the overall survival of colorectal cancer. Strategies for conversion include systemic chemotherapy including target therapy, hepatic arterial infusion (HAI), radiofrequency ablation (RFA), portal vein embolization or ligation (PVE/PVL), associating liver partition with portal vein ligation for staged hepatectomy (ALPPS). Understanding the response rate and indications of various strategies is the prerequisite for the selection of appropriate treatment.     

Neoadjuvant chemotherapy as a treatment strategy for multiple bilobar liver metastases from colorectal carcinoma

Hepatic resection remains the only potentially curative therapy for patients with colorectal liver metastases. Because most have multiple bilobar liver metastases, surgical resection is possible in only 25-58% of patients with colorectal liver metastases. Currently, attention is focused on the potential for neoadjuvant chemotherapy to render formerly unresectable patients resectable. The availability of more efficacious chemotherapy agents and an inventive approach to delivery schedules have resulted in an increase in the number of candidates for hepatic resection after neoadjuvant chemotherapy. Although tumor response varies with regimen and/or route of chemotherapy for colorectal liver metastases, with 16-63% tumor response rates, hepatic resection for responders after neoadjuvant chemotherapy gives survival benefits, with 20-48% 5-year survival rates after surgery. Provided that neoadjuvant chemotherapy controls multiple bilobar liver metastases well, aggressive hepatic resection should be considered for patients with those lesions. As a treatment strategy for multiple bilobar liver metastases, neoadjuvant chemotherapy is a useful to increase resection rates and may contribute to the improvement of prognosis in patients with such lesions.