中国结直肠癌肝转移诊断和综合治疗指南(2020版)

肝脏是结直肠癌血行转移最主要的靶器官[1-2]。结直肠癌肝转移是结直肠癌治疗的重点和难点之一。有15%~25%结直肠癌患者在确诊时即合并有肝转移,而另有15%~25%患者在结直肠癌原发灶根治术后可发生肝转移,其中绝大多数(80%~90%)的肝转移灶初始无法获得根治性切除[3-7]。肝转移也是结直肠癌患者最主要的死亡原因[2],未经治疗的肝转移患者的中位生存期仅6.9个月,无法切除患者的5年生存率低于5%[8-9],而肝转移灶完全切除[或可以达到“无疾病证据(no evidence of disease,NED)”状态]患者的中位生存期为35个月,5年生存率为30%~57%[10-14]。有一部分最初肝转移灶无法根除的患者经治疗后可以转化为可切除[15]或达到NED状态。因此,通过多学科团队(multidisciplinary team,MDT)对结直肠癌肝转移患者病情进行全面评估,个性化地制定治疗目标,开展相应的综合治疗,以预防结直肠癌肝转移的发生,提高肝转移灶手术切除率和5年生存率[16-17]。     

中山医院结直肠癌MDT讨论治疗策略分析

目的分析结直肠癌多学科诊疗团队（MDT）讨论后制定的治疗策略。 方法回顾性分析2010年7月至2019年2月复旦大学附属中山医院进行MDT讨论的结直肠癌患者的临床资料,对MDT讨论结果进行统计分析。 结果结直肠癌MDT总计为1 953例结直肠癌患者进行4 535人次讨论制定个体化治疗方案。其中,553例患者肝转移灶和111例患者肺转移灶被认为可切除。另有261位最初不可切除的结直肠癌肝转移患者,在接受系统化疗联合分子靶向以及介入等综合治疗后,转化为可切除,建议接受肝转移灶切除手术。实际上总计772位结直肠癌患者接受肝转移灶切除,其中同时性肝转移患者有581例,而接受结直肠癌原发灶和肝转移灶同步切除的患者有248例。肝切除手术中仅有87例患者（11.3%）实施解剖性肝切除,绝大多数实施非解剖性肝切除。肝转移灶切除手术中联合射频消融的有62例（8.0%）。术后病理提示R1切除的有18位（2.3%）。 结论复杂结直肠癌病例推荐行MDT讨论。扩展手术适应证、应用二步肝切除术、联合射频消融等局部毁损治疗可以扩大肝转移灶手术的适应人群。初始无法手术切除的患者,如状况耐受,建议给予强烈的个体化转化治疗,争取转化后手术切除。     

同时性结直肠癌肝转移患者的生存分析

目的分析结直肠癌合并同时性肝转移患者的生存状况和相关影响因素。 方法回顾性分析2000年至2010年复旦大学附属中山医院收治的1061例结直肠癌合并同时性肝转移患者的病例。收集所有患者的临床资料、病理特征、治疗策略、住院费用、随访状况等,进行生存状况分析,并采用单因素和Cox比例风险回归模型等分析影响结直肠癌肝转移生存的相关因素。 结果肝转移灶可切除患者中,同期切除肠道原发灶和肝转移灶与分期切除患者的住院费用分别为25693元、34129元(P<0.05),手术并发症(分别为24.5%、20.5%)和总生存期方面(分别为48.5月、47.0月)无显著差异。肝转移灶不可切除且原发灶无症状的患者中,原发灶切除的患者总体中位生存时间明显好于原发灶未切除的患者(分别为19.0月、9.3月,P<0.001)。肠道原发灶分化Ⅲ～Ⅳ级、肝转移灶≥4个、最大肝转移灶直径≥5 cm、肝外转移、肠道原发灶未手术切除和肝转移灶非手术治疗是影响肠癌同时性肝转移患者预后的独立危险因素。将上述6个危险因素各设定为1分,所有患者分为低风险组(0～1分)、中风险组(2～3分)和高风险组(4～6分),5年存活率分别为51%、16%和0%(P<0.001)。 结论结直肠癌合并同时性肝转移患者中,原发灶和转移灶均可切除的可予以同期切除,原发灶可切除且无出血梗阻症状的不可切除的肝转移仍建议在合适时机切除肠道原发灶。根据上述6个独立预后因素所建立的预测模型可以指导临床采取合适的治疗方案。     

外科治疗策略对结直肠癌同时性肝转移患者预后改善的影响

目的化疗及外科治疗策略的优化使结直肠癌肝转移患者生存期得到了明显改善。本研究拟利用中国国家癌症中心数据库数据评价同时性结直肠癌肝转移患者的生存率变化以及探讨其与治疗策略之间的关系。方法回顾性分析2010年1月~2018年2月在国家癌症中心/中国医学科学院肿瘤医院诊治的结直肠癌同时性肝转移患者临床资料,按确诊年度,分为2010~2011年、2012~2013年、2014~2015年、2016~2017年四组,比较其肿瘤特异性生存时间及外科治疗策的差异。结果本研究共纳入1286例患者,中位生存时间从2010~2011年度的20个月提高到2016~2017年度的33个月。3年肿瘤特异性生存率从23.0%提高到45.3%。5年肿瘤特异性生存率从9.5%提高到35.2%。接受原发灶切除和肝转移灶局部治疗患者生存优于单纯化疗组、单纯原发灶切除组和肝转移灶局部治疗组。结论基于人群的研究显示同时性结直肠癌肝转移患者整体生存得到显著改善。在接受化疗的同时,患者接受外科治疗策略比例的增高与生存率升高有关。     

结直肠癌肺转移的外科治疗

结直肠癌是我国的常见恶性肿瘤,发病率居第三位。约20%的结直肠癌初诊时就伴有远处转移,其中肺是最常见的转移部位之一。大量文献表明,对于结直肠癌伴有局限性肺转移的患者手术切除转移病灶,术后的5年生存率为21%～64%。存在其他可切除转移灶并不是手术禁忌。对于手术耐受良好的肺部转移瘤术后复发的患者,再次手术仍可生存获益。距离病灶0.5cm～1.0cm楔形切除是肺外周型病灶的经典术式。对于结直肠癌肺转移瘤手术胸腔淋巴结清扫仍有不同观点。目前公认的结直肠癌肺转移预后不良的因素包括：多发肺转移瘤、癌胚抗原水平升高、胸内淋巴结转移、无瘤间期较短。基于精准医学的个体化治疗将是未来进一步改善预后的关键。     

结直肠癌肝转移外科治疗的共识与争议

结直肠癌肝转移是导致结直肠癌患者死亡的主要原因。目前,循证医学证据表明手术切除是结直肠癌肝转移患者有效且可能获得长期生存的惟一治疗方式。随着外科技术尤其是微创外科技术的进步,越来越多的患者可从外科手术中获益。化学药物的发展以及贝伐单抗和西妥昔单抗等靶向药物的应用,使不可切除的结直肠癌肝转移转化为可切除,从而使更多患者获得治愈的机会。对于无法根治性切除的患者,外科手术联合射频治疗的方法可延长生存期。多学科合作团队诊治模式的广泛应用,使结直肠癌肝转移的治疗更加精准。     

结直肠癌肝转移的外科治疗

结直肠癌患者容易出现肝转移,肝转移是影响结直肠癌患者预后的主要原因之一.手术是目前治愈结直肠癌肝转移的唯一方法.本文主要总结了近年来结直肠癌肝转移患者肝转移病灶的手术进展情况:包括通过新辅助化疗或分阶段肝切除等方法提高肝转移病灶的手术切除率、肝转移灶切缘对患者预后的影响、同时性结直肠癌肝转移患者手术时机的选择、腹腔镜下...     

直肠癌同时性肝转移的外科治疗

目的探讨直肠癌同时性肝转移外科治疗手术时机及方法。方法对2006年8月至2008年8月在我中心32例直肠癌同时性肝转移患者的诊断和治疗的临床资料进行回顾性分析。结果术前B超、CT、MRI能够明确诊断直肠癌肝转移灶能否手术切除;术前新辅助化疗及靶向治疗可以进一步筛选直肠癌肝转移;治疗模式是以手术为主的综合性治疗。结论可切除的直肠癌肝转移首选手术治疗;采取合适的、个体化综合治疗手段能够提高无瘤生存率和累计生存率。     

结直肠癌肝转移综合治疗进展

虽然手术仍是目前唯一有可能治愈结直肠癌肝转移的手段,但是在结直肠癌肝转移的诊疗方面发展迅速。多学科团队综合治疗和分组治疗逐渐成为诊疗规范。对可切除的结直肠癌肝转移患者,在围手术期也应实施标准化疗,是否加用靶向药物尚无定论。实施转化性化疗时应选择高效化疗方案,并尽量缩短疗程,且一旦转移灶转化为可切除,就应积极安排手术。肝转移灶不可切除的患者,是否切除原发灶也存在争议。在肝转移灶局部治疗方面的新技术发展迅速,可改善患者生存。     

结直肠癌肝转移预后因素分析及治疗方式对生存期的影响

目的研究在原发癌切除术后,结直肠癌肝转移患者的临床特征与预后之间的相关性。方法对118例结直肠癌肝转移患者13个临床病理特征进行单因素生存分析及多因素COX风险回归模型的分析。各种治疗方法对1、3、5 a生存率及中位生存期的影响应用生存寿命表法进行比较。结果手术组的生存期明显长于姑息治疗组和未治疗组。原发癌的TNM分期、术前CEA、肝转移灶的最大径和发现时间、肝外转移的存在以及原发癌切除术后的治疗方式等6个因素对结直肠癌肝转移患者的中位生存期存在显著性影响（P〈0.05）。原发癌的TNM分期、术前CEA、肝转移灶的大小与结直肠癌肝转移长期生存的危险性呈正相关。结论结直肠癌肝转移患者的临床病理特征与患者预后有着密切关系。手术治疗,特别是手术联合全身化疗、肝动脉介入化疗等综合治疗比单纯治疗具有更佳的疗效。     

结直肠癌同时性肝转移患者原发灶切除的预后分析

目的 原发灶切除能否使结直肠癌肝转移患者生存获益,目前仍有争议.本研究探讨接受原发灶切除结直肠癌肝转移患者的生存状况及预后的影响因素.方法 回顾性分析2010年1月～2018年2月在国家癌症中心/中国医学科学院肿瘤医院治疗的371例结直肠癌同时性肝转移患者的病例资料.根据治疗方式分为单纯化疗组和原发灶切除组,分析两组患...     

Treatment of liver metastases from colorectal cancer: what is the best approach today?

Liver is the common site for metastases from colorectal cancer. The 5-year overall survival rate of patients following radical operations is 25%. Surgery can be carried out in only 10-15% of the patients, yet it remains the potential curative treatment for resectable lesions. For the unresectable cancers, only chemotherapy is recommended. New drugs such as Irinotecan prolongs the overall survival of patients affected by advanced disease. In patients with unresectable metastases at diagnosis, pre-surgical treatment with Oxaliplatin leads to reduction of the lesions, allowing resection in 16% of cases. Chemotherapy may be delivered directly into the liver via the hepatic artery. No, clinical trials, to date, have shown convincing survival results in patients treated with this procedure. Combined hepatic artery and systemic treatment may provide a new strategy as adjuvant therapy for patients undergoing resections.     

Role of surgery in colorectal cancer liver metastases

Colorectal carcinoma (CRC) is the third most common cancer, and approximately 35%-55% of patients with CRC will develop hepatic metastases during the course of their disease. Surgical resection represents the only chance of long-term survival. The goal of surgery should be to resect all metastases with negative histological margins while preserving sufficient functional hepatic parenchyma. Although resection remains the only chance of long-term survival, management strategies should be tailored for each case. For patients with extensive metastatic disease who would otherwise be unresectable, the combination of advances in medical therapy, such as systemic chemotherapy (CTX), and the improvement in surgical techniques for metastatic disease, have enhanced prognosis with prolongation of the median survival rate and cure. The use of portal vein embolization and preoperative CTX may also increase the number of patients suitable for surgical treatment. Despite current treatment options, many patients still experience a recurrence after hepatic resection. More active systemic CTX agents are being used increasingly as adjuvant therapy either before or after surgery. Local tumor ablative therapies, such as microwave coagulation therapy and radiofrequency ablation therapy, should be considered as an adjunct to hepatic resection, in which resection cannot deal with all of the tumor lesions. Formulation of an individualized plan, which combines surgery with systemic CTX, is a necessary task of the multidisciplinary team. The aim of this paper is to discuss different approaches for patients that are treated due to CRC liver metastasis.     

Complete resection of unresectable liver metastases from colorectal cancer without deterioration of liver function after cetuximab and irinotecan: two case reports

Complete resection for colorectal metastases is the only treatment that can provide long-term survival and may lead to cure. Recent reports have shown that liver resection following systemic chemotherapy in patients with initially unresectable metastases from colorectal cancer may also result in a good long-term survival, and rescue surgery after chemotherapy has become a strategy of choice. A 29-year-old male and a 35-year-old female with unresectable liver metastases from colorectal cancer underwent complete resection after administration of third-line combination therapy of cetuximab and irinotecan. Although systemic chemotherapy may decrease liver function, which may make liver resection unfeasible, in the two cases reported, liver function did not deteriorate after cetuximab plus irinotecan. The indocyanine green retention rate at 15 minutes, which is useful in deciding the safe limit of hepatectomy, was optimal after the administration of cetuximab plus irinotecan in both patients. Cetuximab plus irinotecan may be beneficial as neoadjuvant chemotherapy for metastatic colorectal cancer, not only because of its oncological efficacy but also for preservation of liver function.     

Cryosurgery as treatment modality for colorectal liver metastases

Liver metastases occur in more than 40% of the patients with colorectal cancer. The best prospect of cure is achieved by resection of the metastases. Only 10-15% of the patients with colorectal metastases are candidates for resection. When resection is impossible, other treatment options are limited. Response rates to chemotherapy are around 40%, but survival benefit is generally limited to a few months. Recently, cryosurgery has provided a new therapeutic approach for unresectable colorectal liver metastases. The metastases are localized by ultrasonography and are subsequently frozen with the aid of cryosurgical equipment. The treatment results in necrosis of the tumor and is characterized by low mortality and acceptable morbidity. Experience with cryosurgery is limited, but the results are promising. Various studies report a 1-year survival of more than 70% and a 2-year survival of > 50%. Disease-free survival after 2 years varies between 20-29%. Recurrences in the liver are usually other lesions than those treated with cryosurgery. Cryosurgery in combination with resection or as sole treatment, can result in radical treatment for patients formerly considered unresectable. Resection of liver metastases, however, remains the gold standard in the treatment of liver metastases. The main indication for cryosurgery may be as a complement to hepatic resection in those patients in whom liver resection can not achieve complete tumor clearance.     

Neoadjuvant and adjuvant therapy in relation to surgery for colorectal liver metastases

Liver resection is associated with prolonged survival in patients with colorectal liver metastases. At diagnosis, 15-20% of patients have resectable colorectal liver metastases whereas other patients have too advanced disease to enable surgical treatment and receive chemotherapy. In patients undergoing resection of colorectal liver metastases, disease relapse occurs in up to 70%. Therefore, a combined approach including preoperative or postoperative chemotherapy or both has been tested to improve outcome after surgery. In patients with unresectable colorectal liver metastases, chemotherapy is initially the sole treatment option. The considerable improvement of the efficacy of anticancer agents has contributed to increase the response rate in patients with advanced colorectal cancer. In case of major response to chemotherapy, surgery with curative intent can be offered to patients with initially unresectable liver metastases.     

Surgical management of recurrence after resection of colorectal liver metastases

The optimal treatment for recurrent lesions after hepatectomy for colorectal liver metastases is controversial. We report the outcome of aggressive surgery for recurrent disease after the initial hepatectomy and the influence on quality of life of such treatment. Forty-five (70%) of the 64 surviving patients developed recurrence after the initial hepatectomy for liver metastases. The determinants of hepatic recurrence were the distribution and the number of liver metastases. Twenty-eight (62%) of patients with recurrence underwent resection. A second hepatectomy was performed in 20 patients, and a third hepatectomy was done in 5 patients. Ten patients with pulmonary metastasis underwent partial lung resection on 14 occasions, while resection of brain metastases was performed in 3 patients on 5 occasions. There were no operative deaths after resection of recurrent disease. The morbidity rate was 28% after repeat hepatectomy, 21% after pulmonary resection, and 0% after resection of brain metastasis. The Karnofsky performance status (PS) after the last surgery was not significantly different from that after the initial hepatectomy. The 3- and 5-year survival rates after the second hepatectomy were 54% and 14%, respectively. The 3-and 5-year survival rates of the patients undergoing resection of extrahepatic recurrence were both 17%. The survival rate after resection of recurrent disease (n=28) was significantly better than that of patients (n=17) with unresectable recurrence (P < 0.05). For the 66 patients with colorectal liver metastases, the 5-year survival rate after initial hepatectomy was 50%. The distribution and the number of liver metastases and the presence of extrahepatic disease, as single factors, significantly affected prognosis after the initial hepatectomy. Multivariate analysis revealed that only the presence of extrahepatic metastasis and a disease-free interval of less than 6 months were independent predictors of survival after the initial and second hepatectomy, respectively. It is concluded that aggressive surgery is an effective strategy for selected patients with recurrence after initial hepatectomy. Careful selection of candidates for repeat surgery will yield increased clinical benefit, including long-term survival.     

Surgical treatment of liver metastases from pancreatic cancer

Pancreatic cancer is a disease with a poor prognosis. Most patients are diagnosed at an advanced and unresectable stage. Even if the primary cancer is radically removed, postoperative recurrence frequently occurs. Generally, metastatic liver tumors from pancreatic cancer are not indicated for surgical treatment. Here we evaluate the results of performing hepatectomy for liver metastases of pancreatic cancer. In our institute, six patients with liver metastases from pancreatic cancer were treated by partial hepatectomy. Overall 1-, 3- and 5-year survival rates of six patients after hepatectomy were 66.7%, 33.3% and 16.7%, respectively, and one patient was alive for 65.4 months. Performing a hepatectomy for liver metastases of pancreatic cancer, when combined with a pancreas resection, was recently considered to be a safe operation, and one that might offer prolonged survival for highly selected patients with curative resection of liver metastases. In the future, it will be necessary to develop new multi-modality therapies to improve the prognosis of pancreatic cancer.     

Xelox (capecitabine plus oxaliplatin) as neoadjuvant chemotherapy of unresectable liver metastases in colorectal cancer patients

Complete resection of liver metastasis may provide long term survival in patients with colorectal cancer. Increased number of studies on successful resection after neoadjuvant chemotherapy with initially unresectable liver metastasis has been reported. We evaluated retrospectively the results of 35 patients with unresectable liver only metastases from colorectal cancer treated with capecitabine plus oxaliplatin combination (XELOX). Treatment consisted of IV oxaliplatin 130 mg/m2 day 1 and oral capecitabine 1000 mg/m2 day twice daily on days 1 to 14 followed by 7 days of rest repeated every 3 weeks. After chemotherapy, 13 (37, 2 %) patients showed partial clinical response. Among them, 7 patients were considered suitable for surgery but 2 patients refused the surgery. While one of 5 patients had unresectable disease at surgery, the remaining 4 patients (11, 4 %) had a complete resection. There was one postoperative mortality due to sepsis within 2 months after surgery. Our data suggests that XELOX regimen seems to be useful in unresectable liver only metastases from colorectal cancer because of its activity, feasibility and tolerability. Further studies of XELOX in combination with bevacizumab and/ or cetuximab are warranted in this setting.