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。     

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]。     

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、腹腔镜下肝转移灶切除的影响及优势,肝移植在结直肠癌肝转移患者中的应用等.本文旨在结合结直肠肝转移的手术进展和患者的实际情况,为患者选择最佳的治疗方案,从而提高患者的生存时间.     

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。     

结直肠癌肝转移同期肝切除的原则剖析

结直肠癌(CRC)是常见的消化系统恶性肿瘤,其发病率及病死率逐年升高,肝脏是其最常见转移部位。手术治疗是目前治疗结直肠癌肝转移最有效的方法。对于结直肠癌肝转移同期肝切除的手术时机的选择一直是外科医生争论的话题。诸如围手术期化疗或者一些其他新的方法,都可以影响手术时机的选择。随着对结直肠癌肝转移研究的不断深入以及外科手术技巧的不断进步,目前对于同期肝切除的原则仍在很大程度上依赖于新辅助化疗、外科医生对于可切除性的判断以及病人的体质。笔者综述了近些年来对于结直肠癌肝转移同期肝切除的原则剖析,并加以分析。     

结直肠癌肝转移治疗的研究进展

结直肠癌肝转移的发生率和死亡率很高,是影响结直肠癌预后的重要因素.因此,找到合理的治疗方案显得尤为重要.目前手术切除仍被认为是唯一可能有效的治愈手段,但能手术根治的患者仅占少数.因此,随着医疗技术的发展,肝转移癌治疗经验的积累,多学科综合治疗理念逐渐被广泛应用,是确保结直肠癌肝转移患者获得最佳治疗策略的根本,亦是今后结直肠癌肝转移治疗的发展方向.多学科综合治疗方案包括手术切除、新辅助化疗、肝动脉化疗栓塞、放射疗法、射频消融术、冷冻疗法、无水乙醇注射术及中医药治疗等,一种或多种方法联合应用可明显提高患者的生存率并改善生活质量,本文对结直肠癌肝转移的综合治疗进展作一综述.     

结直肠癌肝转移的预后因素

目的:评价结直肠癌肝转移的临床预后因素及治疗方案对预后的影响.方法:收集71例结直肠癌肝转移患者的临床资料及预后情况,用Kaplan-Meier生存分析及Log-rank检验进行单因素分析,将有统计学意义的预后因素纳入Cox回归模型进行多因素分析.结果:Kaplan-Meier单因素分析及Log-rank检验显示,肝转移灶最大直径、有无区域淋巴结转移及诊断肝转移时碱性磷酸酶(ALP)最高值3个因素对其预后影响有显著意义;将这3个预后因素纳入Cox回归多因素分析显示,有无区域淋巴结转移、诊断肝转移时ALP最高值是结直肠癌肝转移的独立预后因素.全组3种治疗方式比较差别无统计学意义,但对手术切除组和化疗组两组进行比较,差异有统计学意义(P<0.05),而局部治疗组和手术组之间,局部治疗组和化疗组之间差别无统计学意义.结论:肝转移灶最大直径、原发病灶有无区域淋巴结转移、诊断肝转移时最高ALP值是结直肠癌肝转移患者的预后因素;肝转移灶最大直径越小、无区域淋巴结转移、诊断肝转移时最高ALP值正常的患者预后越好;手术切除联合化疗目前是结直肠癌肝转移的首选治疗方案,可获得较好的远期生存.     

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。     

同期切除结直肠癌并肝转移灶的可行性探讨

肝转移是结直肠癌的晚期病变 ,约 2 0 %的结直肠癌患者初次就诊时就发现有肝转移 ,其中未经治疗者中位生存期为 7～ 1 0个月[1] ,而行根治性结直肠癌手术后又切除肝转移灶者 ,5年生存率达 2 5 %～3 9%[2 ] 。对部分结直肠癌并肝转移的患者手术切除是获得长期生存的惟一手段[2～ 5] 。但能否同期切除结直肠癌及肝转移灶 ,目前尚有争论 [5]。 1 997～ 2 0 0 2年 ,我院对 8例患者同期切除结直肠癌并肝转移灶 ,取得了良好效果。现对其临床资料进行分析 ,以探讨同期切除结直肠癌并肝转移灶的可行性。1　资料与方法本组 8例中 ,男 5例 ,女 3例 ;年…     

Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements

Selection of the optimal surgical and interventional therapies for advanced colorectal cancer liver metastases (CRLM) requires multidisciplinary discussion of treatment strategies early in the trajectory of the individual patient''s care. This paper reports on expert consensus on locoregional and interventional therapies for the treatment of advanced CRLM. Resection remains the reference treatment for patients with bilateral CRLM and synchronous presentation of primary and metastatic cancer. Patients with oligonodular bilateral CRLM may be candidates for one-stage multiple segmentectomies; two-stage resection with or without portal vein embolization may allow complete resection in patients with more advanced disease. After downsizing with preoperative systemic and/or regional therapy, curative-intent hepatectomy requires resection of all initial and currently known sites of disease; debulking procedures are not recommended. Many patients with synchronous primary disease and CRLM can safely undergo simultaneous resection of all disease. Staged resections should be considered for patients in whom the volume of the future liver remnant is anticipated to be marginal or inadequate, who have significant medical comorbid condition(s), or in whom extensive resections are required for the primary cancer and/or CRLM. Priority for liver-first or primary-first resection should depend on primary tumour-related symptoms or concern for the progression of marginally resectable CRLM during treatment of the primary disease. Chemotherapy delivered by hepatic arterial infusion represents a valid option in patients with liver-only disease, although it is best delivered in experienced centres. Ablation strategies are not recommended as first-line treatments for resectable CRLM alone or in combination with resection because of high local failure rates and limitations related to tumour size, multiplicity and intrahepatic location.     

Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement

Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3 months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.     

Resectable colorectal liver metastases: pro neoadjuvant therapy - contra neoadjuvant therapy

Approximately one third of patients with colorectal cancer (CRC) present with metastases confined to the liver only. In 15 % of these patients the metastases are primarily resectable. After resection of colorectal liver metastases the 5-year survival rate is 25 - 40 %. The EORTC trial of Nordlinger et al. has examined the role of perioperative/neoadjuvant chemotherapy of resectable liver metastases and found in the subgroup of resected patients a significant improvement in disease-free survival through chemotherapy. The results were not significant in the intent-to-treat population. Possible arguments pro neoadjuvant therapy of resectable liver metastases are the early eradication of disseminated tumour cells, the identification of a worse prognosis tumour biology in the individual patient and the higher dose density which can be achieved preoperatively versus postoperatively. Arguments against preoperative chemotherapy are the chemotherapy-induced hepatotoxicity and related increase in perioperative morbidity, the risk of achieving a complete remission of lesions which then cannot be detected intraoperatively and the uncertain optimal duration of chemotherapy. Especially surgical oncologists in Germany do not consider the neoadjuvant treatment of resectable liver metastases as a standard of care. In summary, because of the lack of level 1 evidence, patients with resectable liver metastases of colorectal cancer should be discussed within interdisciplinary tumour boards together with surgeons, gastroenterologists and medical oncologists. Potentially, overall survival data of the EORTC trial which is expected for late 2010 could change the level of evidence.     

从NCCN指南更新看靶向药物在结直肠癌肝转移新辅助治疗中的地位

手术切除是结直肠癌肝转移（CRLM）唯一有治愈可能的治疗方式,但有约70%的CRLM患者会在肝切除后出现复发。新辅助化疗是降低术后复发率并延长患者生存期的有效手段,靶向药物问世后更是以其高有效率而被广泛应用于新辅助治疗中。但是由于目前缺乏靶向药物在新辅助治疗中应用的临床证据,2017年新版NCCN指南将新辅助化疗联合靶向治疗的推荐修改为仅推荐新辅助单纯化疗。如何客观地看待NCCN指南推荐意见的变化对于指导临床实践具有重要意义。因此,本文将重点探讨靶向药物在新辅助治疗中的作用和地位。     

Therapeutic strategies for hepatic metastasis of colorectal cancer: overview

To determine the treatment strategy for hepatic metastases of colorectal cancer, it is important to take into account whether metastases are still localized in the liver, or whether the tumor has metastasized throughout the body. For liver-limited metastasis, hepatectomy is the therapeutic strategy that offers the best prospect of improving a patient's prognosis if the case is deemed resectable. In cases when surgery is not indicated for hepatic metastases of colorectal cancer, chemotherapy is the first-choice treatment. Chemotherapy for colorectal cancer has made vast strides in recent years through advances such as the development of molecular targeted drugs. In cases where chemotherapy is effective and surgical resection becomes possible (conversion chemotherapy), the long-term prognosis may be good. The value of preoperative chemotherapy in resectable cases (neoadjuvant chemotherapy) has also been reported. The improvement in prognosis achieved by eradicating tiny latent metastases is important in conversion therapy, as well as in neoadjuvant chemotherapy. It will be important to achieve further improvements in the prognoses of patients with hepatic metastases of colorectal cancer through a combination of advances in diagnostic imaging, improvements in surgical techniques, and more effective chemotherapy treatments.     

Multimodale Therapie des kolorektalen Karzinoms

Adjuvant chemotherapy for resected stage III colon cancer is indicated for all patients, including elderly patients >70 years. In general, adjuvant oxaliplatin-fluoropyrimidine chemotherapy should be started within 6 weeks after tumor resection and should be given for a period of 6 months. However, patients aged >70 should receive fluoropyrimidine mono-chemotherapy. This mono-therapy, but not an oxaliplatin-based combination, can also be considered for patients with standard risk stage II tumors without microsatellite instability. In stage II patients with a high risk constellation adjuvant oxaliplatin-fluoropyrimidine combination therapy should be considered. Patients with stage II and III rectal cancer require neoadjuvant radiochemotherapy with fluoropyrimidine followed by adjuvant fluoropyrimidine treatment. There is no role for the use of VEGF- or EGFR-antibodies in the adjuvant therapy of colon cancer or in neoadjuvant therapy of rectal cancer. The prognosis of patients with primary resectable colorectal liver metastases may be improved by adjuvant or perioperative chemotherapy, while neoadjuvant systemic chemotherapy frequently facilitates potential curative resection of initially non-resectable liver metastases.     

Preoperative selection of patients with colorectal cancer liver metastasis for hepatic resection

Surgical resection of colorectal liver metastases(CRLM) has a well-documented improvement in survival. To benefit from this intervention, proper selection of patients who would be adequate surgical candidates becomes vital. A combination of imaging techniques may be utilized in the detection of the lesions. The criteria for resection are continuously evolving; currently, the requirements that need be met to undergo resection of CRLM are: the anticipation of attaining a negative margin(R0 resection), whilst maintaining an adequate functioning future liver remnant. The timing of hepatectomy in regards to resection of the primary remains controversial; before, after, or simultaneously. This depends mainly on the tumor burden and symptoms from the primary tumor. The role of chemotherapy differs according to the resectability of the liver lesion(s); no evidence of improved survival was shown in patients with resectable disease who received preoperative chemotherapy. Presence of extrahepatic disease in itself is no longer considered a reason to preclude patients from resection of their CRLM, providing limited extra-hepatic disease, although this currently is an area of active investigations. In conclusion, we review the indications, the adequate selection of patients and perioperative factors to be considered for resection of colorectal liver metastasis.     

Recurrence and survival following microwave,radiofrequency ablation,and hepatic resection of colorectal liver metastases: A systematic review and network meta-analysis

Background: Gold standard for colorectal liver metastases(CRLM) remains hepatic resection(HR). However, patients with severe comorbidities, unresectable or deep-situated resectable CRLM are candidates for ablation. The aim of the study was to compare recurrence rate and survival benefit of the microwave ablation(MWA), radiofrequency ablation(RFA) and HR by conducting the first network meta-analysis. Data sources: Systematic search of the literature was conducted in the electronic databases. Both updated traditional and network meta-analyses were conducted and the results were compared between them. Results: HR cohort demonstrated significantly less local recurrence rate and better 3-and 5-year diseasefree(DFS) and overall survival(OS) compared to MWA and RFA cohorts. HR cohort included significantly younger patients and with significantly lower preoperative carcinoembryonic antigen(CEA) by 10.28 ng/m L compared to RFA cohort. Subgroup analysis of local recurrence and OS of solitary and ≤3 cm CRLMs did not demonstrate any discrepancies when compared with the whole sample. Conclusions: For resectable CRLM the treatment of choice still remains HR. MWA and RFA can be used as a single or adjunct treatment in patients with unresectable CRLM and/or prohibitive comorbidities.     

Resection margin influences the outcome of patients with bilobar colorectal liver metastases

AIM To evaluate the outcome of patients with bilobar colorectal liver metastases(CRLM) and identify clinicopathological variables that influenced survival.METHODS Patients with bilobar CRLM were identified from a prospectively maintained hepatobiliary database during the study period(January 2010-June 2014). Collated data included demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome. Down-staging therapy included Oxaliplatinor Irinotecan- based regimens, and Cetuximab was also used in patients that were K-RAS wild-type. Response to neo-adjuvant therapy was assessed at the multidisciplinary team meeting and considered for surgery if all macroscopic CRLM were resectable with a clear margin while preserving sufficient liver parenchyma.RESULTS Of the 136 patients included, thirty-two(23.5%) patients were considered inoperable and referred for palliative chemotherapy, and thirty-four(25%) patients underwent liver resection. Seventy(51.4%) patients underwent down-staging therapy, of which 37(52.8%) patients responded sufficiently to undergo liver resection. Patients that failed to respond to down-staging therapy(n = 33, 47.1%) were referred for palliative therapy. There was a significant difference in overall survival between the three groups(surgery vs down-staging therapy vs inoperable disease, P 0.001). All patients that underwent hepatic resection, including patients that had down-staging therapy, had a significantly better overall survival compared to patients that were inoperable(P 0.001). On univariate analysis, only resection margin significantly influenced disease-free survival(P = 0.017). On multi-variate analysis, R0 resection(P = 0.030) and female(P = 0.036) gender significantly influenced overall survival. CONCLUSION Patients undergoing liver resection with bilobar CRLM have a significantly better survival outcome. R0 resection is associated with improved disease-free and overall survival in this patient group.