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。     

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]。     

结直肠癌肝转移的可切除性判断

结直肠癌最好发的转移部位是肝脏,手术是治愈结直肠癌肝转移并获得长期生存的唯一可能方式。就目前多学科治疗背景下,高效能的化疗方案联合靶向药物以及多种手术方式,如传统二步肝切除联合门静脉栓塞术/门静脉结扎术（portal vein embolization,PVE/portal vein ligation,PVL）及联合肝脏劈离及门静脉结扎的二期肝切除（associating liver partition and portal vein ligation for staged hepatectomy,ALPPS）的出现,包括各种消融等局部治疗手段拓展了过去对于肝脏可切除性的定义,而依据新的可切除标准对于可切除性的判断仍存在较大差异,本文将就肝脏可切除性判断展开探讨。     

手术切除联合射频消融治疗结肠癌肝转移疗效分析

目的 探讨手术联合射频消融治疗结肠癌肝转移患者的治疗效果。方法 对2008年1月至2014年3月我科诊治的结肠癌肝转移接受结肠癌根治术和肝内肿瘤灶切除治疗的17例和结肠癌根治术后对肝内肿瘤行射频消融（RFA）治疗的12例患者的临床资料进行回顾性分析。绘制Kaplan-Meier生存曲线,进行生存分析。结果 单纯手术治疗的17例患者均于术后20个月内死亡,平均生存时间为（13.412±0.912）月,而手术联合射频消融治疗的12例患者随访6~28个月,平均生存时间为（18.496±2.139）月（P<0.05）;RFA治疗后患者均出现不同程度的恶心、呕吐、胸闷、右上腹痛、发热,血清ALT和AST轻度升高。结论 手术联合射频消融治疗结肠癌肝转移是一种可行的、安全的、有效的方法,可以明显延长患者的生存期。     

结直肠癌肝转移的综合治疗策略

结直肠癌(colorectal cancer,CRC)是世界上常见的消化道肿瘤之一,约有50%的患者最终出现肝转移。对于发生肝转移的患者,若不经治疗,中位生存期仅为6.9个月,5年生存率为0。若肝脏转移灶行根治性手术,则中位生存期为35个月,5年生存率为30～50%,因此手术切除仍是结直肠癌肝转移治疗的首选。对于同时性肝转移的患者,若无肠道梗阻、穿孔、出血等症状,笔者倾向于同时性切除原发灶和转移灶,术中联合应用B超探查、微波、射频等新技术来提高切除率,降低复发率。而临床上只有少部分患者(10%～15%)可以行手术治疗。对于不可切除的肝转移灶,需通过多学科讨论,针对疾病某一时期,制定出详细的个体化综合性治疗方案,如术前新辅助化疗、联合靶向药物治疗、门静脉栓塞术的应用、局部治疗、放疗等,使得一些不可切除的病灶转化为可切除病灶。因此癌肿作为一项全身性疾病,单纯依靠一种治疗手段很难取得理想的效果,需要多学科的合作,通过对疾病的不同时期进行认识、讨论,以便找到针对某一时间段疾病的最佳治疗方法。同时术后需要定期复查及时发现复发和转移以及制定进一步治疗计划,从而提高患者的长期生存率及生活质量。     

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。     

结直肠癌肝转移的治疗进展

结直肠癌的发病率和死亡率逐年上升,肝转移是主要死因。本文阐述了目前临床上使用较多的治疗方式及进展。分为系统性治疗,包括了新辅助化疗、转化治疗和分子靶向治疗;及局部治疗,包括手术切除、放射治疗、射频消融及介入治疗等。各种治疗手段各有优缺点,多学科综合治疗团队模式的推广,将为结直肠癌肝转移患者制定出较适合的方案,实现个体化治疗。     

局部治疗手段在结直肠癌肝转移治疗中的价值

结直肠癌肝转移患者全身治疗是标准治疗,应该作为每一种治疗策略的初始,但局部治疗也发挥着重要价值.手术完全切除肝转移灶仍是目前能治愈结直肠癌和胃肠道神经内分泌肿瘤肝转移的最佳方法 .射频消融主要应用于那些不可切除或术后复发的局限性病灶,但受转移灶大小、数量和解剖位置的制约.立体定向放射治疗作为一种非手术的局部治疗是安全、有效的.微波消融、冷冻消融、高能聚焦超声刀、经皮穿刺瘤内注射无水乙醇、肝动脉栓塞或肝动脉化疗栓塞、肝动脉灌注化疗等也是重要的局部治疗手段,在患者的综合治疗中发挥重要作用.本文就以上内容作一综述.     

胰腺神经内分泌肿瘤伴肝转移的治疗

胰腺神经内分泌肿瘤（pNET）是所有胰腺肿瘤中较少见的一类肿瘤,近些年发病率呈逐渐增加趋势。肝脏是其远处转移的常见器官。对于分化良好、没有肝外转移、可切除的患者,手术仍是首选的治疗方法。对于不可切除的肝转移患者联合肝动脉栓塞化疗、射频消融、化疗和分子靶向药物等多种治疗方法可以延长患者的存活时间。而对于此类患者的肝移植指征则需要根据个体化情况严格掌握。     

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.     

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.     

Treatment of colorectal cancer with synchronous bilobar liver metastases with simultaneous bowel and liver resection plus radiofrequency ablation

Patients with synchronous bilobar colorectal liver metastases usually have an extent or distribution of the metastases that precludes curative resection. Recently radiofrequency ablation has been proved to safely control liver metastases but a combination of radiofrequency ablation with more than liver resection is rarely performed. We report two patients with colorectal primary and synchronous classically unresectable bilobar liver metastases treated with a combination of bowel and liver resection plus radiofrequency ablation. In the first patient we performed left colectomy, left hepatic lobectomy and radiofrequency ablation of lesions in segments I and VII. In the second patient we performed low anterior resection, wedge resections for three superficially placed lesions in segments V and VIII, and radiofrequency ablation of five more deeply located lesions in segments III, IV, VI and VII. Both patients recovered uneventfully. At the eighth month, the first patient developed three new liver metastases that were treated with subsequent radiofrequency ablation and at the tenth and seventh months of follow-up respectively, both patients are disease free. In conclusion, combination of bowel and liver resection plus radiofrequency ablation expands the possibilities to treat more patients with colorectal cancer having synchronous bilobar unresectable liver metastases.     

Short- and-long term results of intraoperative radiofrequency ablation of liver metastases

BACKGROUND: Surgical resection is the only therapeutic option with curative effect on malignant liver tumours, but in over 70% of cases, this is not a feasible option. A prospective study was performed to assess the short- and long-term effects of intraoperative radiofrequency ablation on unresectable liver metastases. PATIENTS: Between 1997 and 2001, 57 patients (mean age 61.9 years; range 31-83 years) with 297 unresectable liver metastases (colorectal adenocarcinoma, n=38; carcinoid tumour, n=4; malignant melanoma, n=3; other metastases, n=12) underwent intraoperative radiofrequency ablation. RESULTS: No mortality was observed in patients managed solely with radiofrequency ablation. Eight postoperative complications occurred in eight patients (14%). Three occurred when radiofrequency ablation was combined with resection. Of the 33 patients completely ablated, 30 patients are still alive and 21 are disease-free after a median follow-up of 18.1 months (range 2-43). Ten patients underwent more than one intraoperative radiofrequency ablation episode. Overall survival was 72.5% at 1 year and 52.5% at 3 years. Complete ablation and the number of lesions were significant independent prognostic factors for survival, with p<0.001 and p<0.0001, respectively. CONCLUSION: Radiofrequency ablation is a safe and effective option for patients with inoperable liver metastases without extra hepatic disease. Prospective controlled trials comparing the results of different treatments are required to assess which patients will benefit best from this emerging new treatment.     

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。     

An 11-year survivor who underwent ten sequential resections of colonic adenocarcinoma metastases

Hepatectomy is an established treatment for colorectal carcinoma liver metastases. However, the benefit of multiple repeat metastasectomies in the management of colorectal carcinoma patients remains uncertain. We report the case of a 47-year-old man who underwent ten sequential resections of intra- and extrahepatic colonic adenocarcinoma metastases. Metastasectomy procedures in this case included: 6 hepatic resections, 2 pulmonary resections, 1 pulmonary resection combined with wide resection of the abdominal wall, and 1 wide resection of the abdominal wall. The patient finally died, from unresectable metastases to the liver and pancreas, 133 months after the initial hepatectomy. The aggressive multiple repeat metastasectomies may have provided this unusual long-term palliation. Colorectal carcinoma patients with sequential resectable recurrences may be candidates for multiple repeat metastasectomies. Surgeons should pursue resection for colorectal carcinoma metastases, regardless of frequent operations and sites involved, as reliable medical treatment remains unestablished.     

Kurativer Ansatz für metastasierte kolorektale Karzinome

Synchronous or metachronous metastases of colorectal cancer (CRC), although being the expression of systemic disease, allow a curative approach for a selected group of patients. Mainly patients presenting with colorectal liver metastases (CLM) should be evaluated for multimodal management with curative intent. Preoperative and/or postoperative systemic chemotherapy show beneficial impact on progression-free and overall survival, without significantly increasing postoperative complication rates. Concerning the complex definition of resectability and the number of patients with ?borderline“ resectable CLM, preoperative chemotherapy plays an important role in both improvement of prognosis and ?conversion“ to a resectable status. Advances in hepatic surgery and the addition of either locally ablative procedures, such as radiofrequency and SIRT are extending resectability to a larger group of patients and have joined the armamentarium for cases of positive resection margins or technically unresectable disease or add to surgery with a large loss of liver parenchyma. Moreover, multimodal approaches should be considered in pulmonary and peritoneal metastases of CRC.     

Secondary hepatic resection as a therapeutic goal in advanced colorectal cancer

Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresectable disease and allow for potentially curative surgery. Standard chemotherapy regimens convert 10%-20% of cases to resectable disease in unselected populations and 30%-40% of those with disease confined to the liver. One strategy to further increase the number of candidates eligible for surgery is the addition of active targeted agents such as cetuximab and bevacizumab to standard chemotherapy. Data from a phase Ⅲ trial indicate that cetuximab increases the number of patients eligible for secondary hepatic resection, as well as the rate of complete resection when combined with first-line treatment with the FOLFIRI regimen. The safety profiles of preoperative cetuximab or bevacizumab have not been thoroughly assessed, but preliminary evidence indicates that these agents do not increase surgical mortality or exacerbate chemotherapyrelated hepatotoxicity, such as steatosis （5-fluorouracil）, steatohepatitis （irinotecan）, and sinusoidal obstruction （oxaliplatin）. Secondary resection is a valid treatment goal for certain patients with initially unresectable liver metastases and an important end point for future clinical trials.     

Current preventive treatment for recurrence after curative hepatectomy for liver metastases of colorectal carcinoma： A literature review of randomized control trials

To review the preventive approaches for recurrence after curative resection of hepatic metastases from colorectal carcinoma, we have summarized all available publications reporting randomized control trials (RCTs) covered in PubMed. The treatment approaches presented above include adjuvant intrahepatic arterial infusion chemotherapy, systemic chemotherapy, neoadjuvant chemotherapy, and immunotherapy. Although no standard treatment has been established, several approaches present promising results, which are both effective and tolerable in post-hepatectomy patients. Intrahepatic arterial infusion chemotherapy should be regarded as effective and tolerable and it increases overall survival (OS) and disease free survival (DFS) of patients, while 5-fluorouracil-based systemic chemotherapy has not shown any significant survival benefit. Fortunately chemotherapy combined with hepatic arterial infusion and intravenous infusion has shown OS and DFS benefit in many researches. Few neoadjuvant RCT studies have been conducted to evaluate its effect on prolonging survivals although many retrospective studies and case reports are published in which unresectable colorectal liver metastases are downstaged and made resectable with neoadjuvant chemotherapy. Liver resection supplemented with immunotherapy is associated with optimal results; however, it is also questioned by others. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence after hepatectomy for liver metastases from colorectal cancer (CRC), but multi-centric RCT is still needed for further evaluation on their efficacy and systemic or local toxicities. In addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with resectable hepatic metastases from CRC.     

Short- and long-term outcomes of hepatectomy combined with intraoperative radiofrequency ablation for patients with multiple primarily unresectable colorectal liver metastases: a propensity matching analysis

BackgroundHepatectomy combined with intraoperative radiofrequency ablation (IORFA) is a strategy to eliminate all tumors in patients with multiple colorectal liver metastases (CRLM). This study aimed to evaluate the surgical and oncological outcomes of hepatectomy + IORFA for multiple unresectable CRLM.MethodsWe included patients who underwent combined hepatectomy and IORFA for multiple unresectable CRLM (n = 67) or hepatectomy alone (n = 268) for CRLM. Patients were matched in a 1:1 propensity score analysis to compare the short- and long-term outcomes between groups.ResultsPatients in hepatectomy + IORFA group had a median number of 10 liver lesions. Postoperative morbidity and the rate of major complications was similar between groups (P = 0.362, P = 1.000). The median overall survival (OS), progression free survival (PFS) and hepatic recurrence free survival (HRFS) was similar between groups (3-year OS: 54.2% versus 60.9%, P = 0.389; 3-year PFS: 7.9% versus 19.6%, P = 0.148; 3-year HRFS: 16.7% versus 31.5%, P = 0.202). Re-hepatectomy or radiofrequency ablation was used to treat 47.5% of hepatic recurrences, and the median OS was significantly higher than for patients treated with systemic treatment alone (P < 0.001).ConclusionsCombining hepatectomy and IORFA could provide comparable survival rates for patients with multiple unresectable CRLM compared to those with resectable CRLM treated with hepatectomy alone.