诊治指南
结直肠癌肝转移诊断和综合治疗指南(V 2013)
aa 发布时间:2013/6/25 15:46:33

中华医学会外科学分会胃肠外科学组  中华医学会外科学分会结直肠肛门外科学组
中国抗癌协会大肠癌专业委员会
(执笔整理:许剑民  任黎)

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(colorectal cancer liver metastases)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%的患者将在结直肠癌原发灶根治术后发生肝转移,其中绝大多数(80%~90%)的肝转移灶无法获得根治性切除[3-7]。结直肠癌肝转移也是结直肠癌患者最主要的死亡原因[1]。未经治疗的肝转移灶患者的中位生存期仅6.9,无法切除患者的5年生存率接近0[8-9],而肝转移灶能完全切除患者的中位生存期为35,5年生存率可达30%~ 50%[10-14]。研究表明,有一部分最初肝转移灶无法切除的患者经治疗后可以变为可切除病灶[8]。因此,应通过多学科合作团队对结直肠癌肝转移患者进行全面地评估,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[15-16]
        为了提高我国结直肠癌肝转移的诊断和综合治疗水平,受卫生部临床重点学科项目资助,中华医学会外科学分会胃肠外科学组和结直肠肛门外科学组、中国抗癌协会大肠癌专业委员会自2008年起联合编写了《结直肠癌肝转移诊断和综合治疗指南》(《指南》),并于2010年进行了修订(见本刊2010年第6),以指导我国结直肠癌肝转移的诊断和治疗。20134,进一步总结国内外先进经验和最新研究进展,再次修订了本《指南》。
       
(:本《指南》对结直肠癌肝转移的诊断、预防、外科手术和其他综合治疗提出的建议,请各地医院根据实际情况予以应用。本《指南》中出现的推荐级别、循证医学证据分类的界定,详见附录一)

第一部分  诊疗指南

        一结直肠癌肝转移的诊断与随访

结直肠癌肝转移的定义

按照国际通用分类方法:同时性肝转移(synchronous liver metastases)是指结直肠癌确诊时发现的、或结直肠癌原发灶根治性切除术后6个月内发生的肝转移;而结直肠癌根治术6个月后发生的肝转移称为异时性肝转移(metachronous liver metastases)

由于结直肠癌确诊时合并肝转移与结直肠癌原发灶根治术后的肝转移在诊断和治疗上有较大差异,因此,本《指南》按照结直肠癌确诊时合并肝转移结直肠癌根治术后发生肝转移两方面进行阐述。

      结直肠癌确诊时肝转移的诊断常规

对已确诊结直肠癌的患者,除血清CEACA19-9检查以及病理分期评估外,应常规进行肝脏超声和()增强CT等影像学检查以了解有无肝转移的发生,对于怀疑肝转移的患者可加行血清AFP和肝脏MRI检查[17-18](1a类证据,A级推荐)PET-CT检查不作为常规推荐,可在病情需要时酌情应用[19-20](2a类证据,B级推荐)

肝转移灶的经皮针刺活检仅限于病情需要时应用(4类证据,C级推荐)[21]

结直肠癌手术中必须常规探查肝脏以进一步排除肝转移的可能[22]。对可疑的肝脏结节可考虑术中活检(3a类证据,B级推荐)

结直肠癌原发灶根治术后的随访

结直肠癌根治术后,应对患者密切随访[23-26],了解有无肝转移的发生。

1. 3~6个月进行1次病史询问、体格检查和肝脏超声检查,持续2,以后每6个月1次直至满5年。

2. 3~6个月检测1CEACA19-9等适当的肿瘤标记物,持续2,以后每6个月1次直至满5[27](1a类证据,A级推荐)

3.II期和III期的结直肠癌患者,建议每年进行1次胸盆腔增强CT扫描,3~5[28](1b类证据,A级推荐)。怀疑肝转移的患者应加行MRI检查,PET-CT扫描不作常规推荐。

4.术后1年内应进行电子结肠镜的检查,若发现异常,需在1年内复查[29]。否则,术后第3年复查,以后每51次。如果患者发病年龄小于50,则应适当增加电子结肠镜的检查频度。对于结直肠癌根治术前因梗阻等原因无法行全结肠镜检查的患者,应在术后3~6个月内完成首次电子结肠镜检查[29](1a类证据,A级推荐)

结直肠癌肝转移灶完全切除术后的随访

结直肠癌肝转移灶完全切除(R0)术后,对患者也应进行密切的随访,了解有无肝转移复发。

1.根据术前肿瘤标记物的升高情况,建议术后2年内每3个月随访血清CEACA19-9等肿瘤标记物,以后3~5年内每6个月随访1(1a类证据,A级推荐)

2.术后2年内每3~6个月进行1次胸盆腔增强CT扫描,以后每6~12个月进行1,5[28](1a类证据,A级推荐)。不推荐常规PET-CT扫描。

3.其他随访内容和频次参照结直肠癌原发灶根治术后的随访进行。

结直肠癌及其肝转移的相关基因检测

1.KRAS检测:推荐在所有结直肠癌肝转移的患者中进行KRAS2外显子1213密码子的检测。结直肠癌原发灶和转移灶的KRAS基因状态大多无差别[30-32](1a类证据,A级推荐)

2.BRAF检测:建议在KRAS基因野生型的结直肠癌肝转移患者中进行检测,作为预后的预测指标[33-34](1b类证据,A级推荐)

3.UGT1A1检测:UGT1A1是伊立替康的药物代谢酶,其基因的多样性会显著影响该酶的活性。非野生型的UGT1A1患者接受伊立替康化疗,可能会增加III度以上骨髓抑制以及腹泻的风险。

二、结直肠癌肝转移的预防

结直肠癌原发灶根治性切除术

根治性手术是迄今为止结直肠癌最有效的治愈方法[35]。也是预防肝转移发生的重要环节。

1. 结肠癌根治性手术范围应包括肿瘤全部及其两端足够肠段、周围可能被浸润的组织和器官以及相关系膜、主要供应血管和淋巴引流区,具体手术方式依照肿瘤部位不同而异。

2. 直肠癌根治性手术范围应包括肿瘤全部及其两端足够肠段、周围可能被浸润的组织和器官以及相关的肠系膜和淋巴结。直肠中下段的肿瘤应遵循全直肠系膜切除(total mesorectal excision,TME)原则。

3. 术中发现存在切除范围外的可疑淋巴结,应进行术中活检或切除。

结直肠癌确诊时无肝转移的新辅助治疗

术前通过新辅助治疗杀灭无法被影像学检测到的微小转移灶,可以最大程度地减少根治性手术后的远处转移[36-37]

1. 中低位直肠癌的新辅助治疗(:高位直肠癌,即肿瘤下缘距肛缘12 cm以上者,其新辅助治疗参照结肠癌): 联合放化疗或放疗:直肠为腹膜间位器官,位置相对固定,周围空间狭小,故放疗可作用于肿瘤组织而对周围正常组织损伤较少。建议术前诊断为T3及以上或任何T而淋巴结阳性的直肠癌,在不伴有出血、梗阻、穿孔以及其他远处转移等情况时应用[38-41]联合放化疗:总剂量45~54 Gy的放疗,采用常规分割剂量(通常每周5 d,5),并应用以氟尿嘧啶(5-FU)或卡培他滨为主的化疗。放化疗治疗结束后4~8周行直肠癌根治性手术[40,42](1a类证据,A级推荐)术前放疗与化疗联合,能利用各自的优势达到更好的治疗效果[43]。放疗作用于局部使肿瘤降期甚至缓解,化疗可在术前杀灭微转移灶预防肿瘤远处转移,还能提高放疗的敏感性。术前放化疗可使TME手术更易实施,减少远处转移的概率,取得更佳的预后:对于II期有局部浸润的直肠癌患者,可降低T分期, 对于III期患者则不仅可以降低T分期,更可作用于局部淋巴结,降低N分期[41,44-46]单纯短程放疗:也可考虑直肠癌肿瘤部位及淋巴引流区短程(5 d)总剂量25 Gy的放疗[41,47-49]。并于放疗后1~7 d行根治性手术。但短程放疗不能降期,同时还将增加手术操作难度和吻合口瘘的机会,应予以重视[50](2b类证据,B级推荐) 肝动脉和肿瘤区域动脉联合灌注化疗:术前分期III,且不伴有出血、梗阻或穿孔等,在有条件的单位可考虑应用。5-FU(5-FU前体药物)并可联合奥沙利铂,经肝动脉、肿瘤区域动脉分别灌注,化疗后7~10 d施行根治性切除术。目前的临床试验已取得初步结果,该方案虽不能明显降期,但对预防肝转移有一定的帮助,可在临床研究中予以关注[51]。不作为常规推荐。全身化疗:术前判断为III期的患者,如无出血、梗阻或穿孔等情况时也可应用术前化疗[37]可用的方案有FOLFOX、卡培他滨单药或5-FU/LV,但目前尚无明确的循证医学证据,不作为常规推荐。

2. 结肠癌的新辅助治疗:结直肠癌的新辅助治疗尚无明确的循证医学证据,不作常规推荐。对于术前全身化疗、肝动脉和肿瘤区域动脉联合灌注化疗等方法应进一步临床研究。

无转移结直肠癌患者术中门静脉化疗和腹腔化疗

该治疗方案疗效尚缺乏循证医学数据,不作为常规手段推荐,临床研究可关注。

无转移结直肠癌患者根治术后的辅助治疗

1. 术后辅助化疗对于III期以上结肠癌,T3以上或任何T而淋巴结阳性的直肠癌患者能延长5年无病生存率及总生存率[52-53]。因此,上述结直肠癌患者在手术治疗后应进行6个月的辅助化疗,可选择的治疗方案有FOLFOXCapeOX5-FU/LV或卡培他滨单药[53-56](1a类证据,A级推荐)

II期无转移高危因素的患者,术后辅助化疗在许多临床研究中未见到明显的效果,故建议接受临床观察和随访[57](1b类证据,A级推荐)。但对于高危 II期患者[T4、组织分化差(MSI-H患者除外)、肿瘤周围淋巴管神经侵犯、肠梗阻、或T3伴有局部穿孔、切缘不确定或阳性、淋巴结活检数量少于12]应予以辅助化疗,方案同III期患者[53,58](2a类证据,B级推荐)

2. T3及以上和任何T、淋巴结阳性的中低位直肠癌患者,如术前没有进行放化疗,术后辅助放疗能提高3年无病生存率及降低局部复发率[59-60]。但对于能否减少结直肠癌肝转移方面研究有限,和辅助化疗的结合方式也需更多临床试验验证。术前接受过放疗或联合放化疗的患者,术后也应接受辅助治疗。

三、多学科团队在结直肠癌肝转移诊治中的作用

对于肿瘤性疾病,多学科团队(multidisciplinary team,MDT)治疗模式是特别有效的手段[61-62]。因此,建议所有结直肠癌肝转移的患者均应进入MDT治疗模式[63](1a类证据,A级推荐)。结直肠癌的MDT以患者为中心,成员应包括胃肠外科、肝外科、肿瘤内科、放疗科、放射影像科及其他相关专业的医生[64-65]。尽管目前有关MDT的报道仍较少,但其重要作用已经显现:更精确的疾病分期[66];较少的治疗混乱和延误[67-68];更个性化的评估体系[69];更好的治疗衔接[70];提高生活质量[71];最佳的临床和生存获益[72-76]

MDT通过对结直肠癌肝转移的患者进行全面评估,针对不同的治疗目标,给予患者最合理的检查和最恰当的综合治疗方案[65,77](1a类证据,A级推荐)

1.0患者:其肝转移灶完全可以R0切除,这类患者的治疗目的就是使其获得治愈。应该围绕手术治疗进行相应的新辅助或()辅助治疗,以降低手术后复发的风险。

2.1患者:其肝转移无法切除,但经过一定的治疗有望转为可以R0切除,且全身情况能够接受转移灶的切除手术和高强度的治疗。这类患者的治疗目的主要是最大程度地缩小瘤体或增加残肝体积,应采用最积极的综合治疗。

3.2患者:其肝转移灶可能始终无法切除,同时又快速进展(或有快速进展的风险)()伴有相关症状,但全身情况允许接受较高强度的治疗。这类患者的治疗目的是尽快缩小瘤体或至少控制疾病进展,应该采用较为积极的联合治疗。

4.3患者:其肝转移可能始终无法切除,并无症状或快速进展风险,或伴有严重合并疾病无法进行高强度的治疗。其治疗目的是阻止疾病的进一步进展,应予维持治疗,制定低强度、低毒性的治疗方案。

四、结直肠癌肝转移的手术治疗

手术完全切除肝转移灶仍是目前能治愈结直肠癌肝转移的最佳方法[78-82]。故符合条件的患者均应在适当的时候接受手术治疗。部分最初肝转移灶无法切除的患者,经治疗后转化为可切除病灶时也应适时接受手术治疗。

手术适应证和禁忌证

1.适应证:是否适合手术切除的标准一直在演变,但主要应从以下3方面来判断[8,16,40,83-84](2a类证据,B级推荐):结直肠癌原发灶能够或已经根治性切除;根据肝脏解剖学基础和病灶范围肝转移灶可完全(R0)切除,且要求保留足够的肝脏功能,肝脏残留容积大于或等于30%~50%;患者全身状况允许,没有不可切除的肝外转移病变。

随着技术的进步,肝转移灶的大小、数目、部位和分布等已不再是影响判断结直肠癌肝转移患者是否适宜手术的单一决定因素。另外,新近的文献资料已经将切缘不足1 cm[85-88]、可切除的肝门淋巴结转移[89-90]、可切除的肝外转移病灶(包括肺和腹腔)[91-95]等也纳入了适宜手术切除的范畴(4类证据,C级推荐)

2.禁忌证[8,40,83,96](3a类证据,B级推荐):结直肠癌原发灶不能取得根治性切除;

出现不能切除的肝外转移;预计术后残余肝脏容积不够;患者全身状况不能耐受手术。

结直肠癌确诊时合并肝转移的手术治疗

1. 结直肠癌原发灶和肝转移灶一同步切除:在肝转移灶小、且多位于周边或局限于半肝,肝切除量低于50%,肝门部淋巴结、腹腔或其他远处转移均可手术切除的患者可建议一期同步切除[97-99]

有研究认为,一期同步切除肝转移灶和原发结直肠癌病灶手术患者的并发症和死亡率可能高于二期分阶段手术者[100-104]。能在结肠癌原发灶根治术的同一手术切口或仅适当延长后的切口内完成肝转移灶切除,也是选择一期同步切除的依据之一,但在两切口内(如直肠和乙状结肠癌)一期同步切除并非不允许,只是应更为慎重。

急诊手术由于缺少完备的术前检查资料和较高的感染发生机会,不推荐原发结直肠癌和肝脏转移病灶一期同步切除[105](2c类证据,B级推荐)

2.结直肠癌原发灶和肝转移灶二期分阶段切除:术前评估不能满足二期同步切除条件的患者,可以先手术切除结直肠癌原发病灶,二期分阶段切除肝转移灶,时机选择在结直肠癌根治术后4~6;若在肝转移灶手术前进行治疗,肝转移灶的切除可延至原发灶切除后3个月内进行。可根治的复发性结直肠癌伴有可切除肝转移灶的治疗按结直肠癌确诊时合并肝转移处理,但倾向于进行二期分阶段切除肝转移灶。

二期分阶段或一期同步切除肝转移灶的选择标准仍在不断修订和完善中[100]。二期分阶段切除的弊端在于:肝脏转移灶可能在原发病灶切除后进展;累积住院时间明显延长,费用相对高昂;患者必须接受二次手术,并且在等待肝脏手术时承受较大的心理压力[106]。其优点则在于:手术风险小于一期同步切除;患者能接受肝脏转移灶切除前的化疗。

目前,另一种二期分阶段切除模式(先切除肝转移灶,再切除结直肠原发灶,故也有称作颠倒模式Liver First Approach)已引起多方的关注[107-110]。先行切除肝转移灶可以降低肝转移进展和化疗相关肝脏损害的风险[111]。原发灶(主要是直肠癌)则在经过一定的治疗后再予根治性切除。其手术的并发症和死亡率与传统模式的二期分阶段切除相同[112]。术后5年生存率可达38%[113](3b类证据,B级推荐)

结直肠癌根治术后发生肝转移的手术治疗

既往结直肠原发灶为根治性切除且不伴有原发灶复发,肝转移灶能完全切除且肝切除量低于70%(无肝硬化者),应予以手术切除肝转移灶,也可考虑先行新辅助治疗[114](3b类证据,B级推荐)

诊断结直肠癌根治术后发生肝转移应当有两项以上的影像学检查依据,包括肝脏超声、增强CTMRI,必要时可结合PET-CT扫描以确定病变的范围和有无肝外转移,从而避免不必要的手术治疗[115]

肝转移灶手术方式的选择[114,116-118](3b类证据,B级推荐)

1. 肝转移灶切除后至少保留3根肝静脉中的1根且残肝容积大于或等于50%(同时性肝转移)大于或等于30%(异时性肝转移)

2. 转移灶的手术切除应符合R0原则,切缘至少大于1 mm[85,119-121]

3. 如是局限于左半或右半肝的较大肝转移灶且无肝硬化者,可行规则的半肝切除。

4. 建议肝转移手术时采用术中超声检查,有助于发现术前影像学检查未能诊断的肝转移病灶。

肝转移灶切除术后复发和肝外转移灶的切除

在全身状况和肝脏条件允许的情况下,对于可切除的肝转移灶术后的复发病灶,可进行2次、3次甚至多次的肝转移灶切除。文献报道显示,其手术并发症和死亡率并不高于第1次肝转移灶的切除,而且可获得相同的术后生存率[8,122-124](3b类证据,B级推荐)

同样,在患者全身状况允许时,如果肺[125]和腹腔[126-127]等的肝外转移病灶可完全切除,也应进行同步或分阶段切除(3b类证据,B级推荐)

五、可切除结直肠癌肝转移的新辅助及辅助治疗

新辅助治疗

对可切除的结直肠癌肝转移患者,可考虑进行新辅助治疗[128-129]。主要基于以下几方面原因:新辅助化疗提供了窗口期,观察有无新的无法切除的转移灶的出现,减少没有必要的手术[130];新辅助治疗可提高R0手术的机会,增加术后残余肝脏的体积[131-132];新辅助化疗可作为评价化疗方案敏感性的依据,指导术后化疗方案的选择[133];新辅助化疗的疗效,可作为患者预后评估的一个指标[134-138];新辅助化疗结合辅助化疗,可能改善接受治愈性手术患者的预后[139-143]

然而,新辅助治疗也有一定的弊端: 化疗可能会造成肝脏损伤:如与奥沙利铂治疗相关的肝脏血管性病变[144-148];与伊立替康治疗相关的非酒精性脂肪肝等[149-151]。这些损害均可能增加肝切除术后的并发症[146,151-154]影像学检查消失的转移灶仍应切除[97,134,155-156]。但术者无法在术中给予肝脏转移灶精确定位[109,157]转移灶进展致使无法切除。

1. 结直肠癌确诊时合并肝转移的新辅助治疗:在原发灶无出血、梗阻或穿孔时可考虑应用新辅助治疗[16,158-160](2a类证据,B级推荐),如全身化疗,方案包括FOLFOXFOLFIRICapeOX[161-164]。也可联合分子靶向治疗,但其效果仍有争议[165-169]。且贝伐珠单抗可能会带来肝脏手术中更多的出血和手术后更多的伤口问题[170-172]。故建议手术时机应选择在最后一次使用贝伐珠单抗后6~8[162,173-174]。而西妥昔单抗的治疗只在KRAS基因野生型的患者中应用[175-179]。同时也可以考虑联合肝动脉灌注化疗[180-182]

为减少化疗对肝脏手术的不利影响,新辅助化疗原则上不超过6个周期[54,144,147,153,183] (1a证据,A级推荐)。一般建议2~3个月内完成并进行手术[184]

2. 结直肠癌根治术后发生的肝转移的新辅助治疗:原发灶切除术后未接受过化疗的患者,或者发现肝转移12个月前已完成化疗的患者,可采用新辅助治疗(方法同上),时间2~3个月[54,185](2a证据,B级推荐)。而肝转移发现前12个月内接受过化疗的患者,新辅助化疗作用有限,应考虑直接切除肝转移灶,继而术后辅助治疗[158](2a类证据,B级推荐)。也可考虑术前联合肝动脉灌注化疗[180-182]

肝转移灶切除术后的辅助治疗

建议肝转移灶完全切除的患者接受术后辅助化疗[183-190]。特别是没有进行过术前化疗及辅助化疗的患者,推荐时间为6个月(1a类证据,A级推荐)。已完成术前化疗患者术后的辅助化疗时间可适当缩短(3b类证据,B级推荐),也可考虑同时联合肝动脉灌注化疗[4,191-193]

辅助化疗的药物和持续时间目前尚有争议[194-197]。应继续临床研究探讨。

六、不可切除的结直肠癌肝转移的综合治疗

结直肠癌肝转移的综合治疗包括全身和介入化疗、分子靶向治疗以及针对肝脏病灶的局部治疗如射频消融、无水酒精注射和放射治疗等,治疗方案的选择应基于对患者治疗前的精确评估。部分初诊无法切除的肝转移灶,经过系统的综合治疗后可转为适宜手术切除[79,169]。其术后5年生存率与初始肝转移灶手术切除的患者相似[198-199]。此类患者应当采取较为积极的诱导方案,应用有效的强烈化疗,并考虑联合肝动脉灌注化疗及分子靶向药物治疗。对于肝转移灶始终无法根治性切除的患者,综合治疗也可明显延长中位生存期,控制疾病快速进展,明显改善生存质量[200-203]。因此,积极的综合治疗对于不可切除结直肠癌肝转移患者的意义重大。

㈠治疗策略

1.结直肠癌确诊时合并无法手术切除的肝转移:结直肠癌原发灶存在出血、梗阻或穿孔时,应先行切除结直肠癌原发病灶,继而全身化疗(或加用肝动脉灌注化疗[192,204-206]),可联合应用分子靶向治疗[178,207-208](1b类证据,A级推荐)。治疗后每6~8周进行肝脏超声、增强CT()MRI检查予以评估[151]。如果肝转移灶转变成可切除时,即予以手术治疗;如果肝转移灶仍不能切除,则继续进行综合治疗[183,209] 结直肠癌原发灶无出血、梗阻或穿孔时也可选择先行切除结直肠癌的原发病灶,继而进一步治疗,具体方案同上。或者先行全身化疗(或加用肝动脉灌注化疗),时间为2~3个月,并可联用分子靶向治疗[207](1c类证据,B级推荐)。如果转移灶转化成可切除时,即手术治疗(一期同步切除或分阶段切除原发病灶和肝转移灶);如果肝转移灶仍不能切除,则视具体情况手术切除结直肠癌原发病灶,术后继续对肝转移灶进行综合治疗。

但是,对于结直肠癌原发灶无出血、梗阻或穿孔合并始终无法切除的肝转移灶的患者是否必须切除原发灶,目前仍有争议[210-211]

2.结直肠癌术后发生的无法手术切除的肝转移: 采用5-FU/LV(或卡培他滨)联合奥沙利铂或伊立替康作为一线化疗[9,212-213]。并可加用分子靶向治疗,或联用肝动脉灌注化疗[136](1b类证据,A级推荐) 在肝转移发生前12个月内使用过奥沙利铂为基础的化疗作为辅助治疗的患者,应采用FOLFIRI方案;化疗结束后12个月以上发生肝转移,仍可采用FOLFOX化疗方案,并可加用分子靶向药物治疗,或联用肝动脉灌注化疗[207,214](3a类证据,B级推荐)

治疗后每6~8周检查肝脏超声、CT()MRI,予以评估[150-151,215]。化疗有效,肝转移灶转为可切除的患者,即应接受肝转移灶切除手术,术后再予以辅助化疗;如果肝转移灶仍不能切除,则应继续进行综合治疗[151,183,209]

3.应用门静脉选择性的栓塞或结扎可以使肝转移灶切除术后预期剩余肝脏代偿性增大,增加手术切除的可能。此方法被用于预计手术切除后剩余肝脏体积不足30%的肝转移患者。对于那些剩余肝脏体积在30%~40%、并且接受了强烈化疗而有肝实质损伤的患者,同样也可从中得益[216-220](4类证据,C级推荐)

治疗方法

1.全身化疗和肝动脉灌注化疗:化疗开始前应充分评估患者的身体状况和肿瘤分期,事先规划好患者的后续治疗和预计有严重化疗不良反应时剂量和方案的调整。开始治疗时必须考虑患者的分类(详见多学科团队在结直肠癌肝转移诊治中的作用)、化疗的安全性以及将来手术治疗的可能性[15]

初始化疗:1患者:这类患者的肝转移灶有潜在R0切除可能,对此进行的转化治疗至关重要。转移灶出现的早期退缩(early tumor shrinkage,ETS)更是预后的重要指标之一[221]。研究表明,5-FU/LV(或卡培他滨)联合奥沙利铂或伊立替康的化疗方案具有较高的转化切除率[222-224](1b类证据,A级推荐),应该作为首选。如果化疗联合分子靶向药物可以进一步提高转化率[225-228](1b类证据,A级推荐)。现有的研究数据显示,KRAS野生型患者化疗联合西妥昔单抗治疗,能明显提高肝转移的切除率 [169,178-179,229]。因此,对于KRAS野生型患者应首先考虑化疗联合西妥昔单抗(1b类证据,A级推荐)。而KRAS突变型患者应考虑化疗联合贝伐珠单抗[230]FOLFOXIRI也有较高的切除转化率[202,231-232]。但毒性也大,可以作为5-FU/LV(或卡培他滨)联合奥沙利铂或伊立替康化疗联合分子靶向药物治疗的替代方案,尤其在分子靶向药物无法使用且患者体质较好的情况下应该作为首选(1b类证据,A级推荐)。目前,该方案联合分子靶向药物治疗尚缺乏充分的依据,且不良反应增加,应慎用。2患者:5-FU/LV(或卡培他滨)联合奥沙利铂或伊立替康的化疗方案是首选,也可以联合分子靶向药物治疗(2b类证据,B级推荐)FOLFOXIRI尽管有较高的反应率,但不良反应也较大,是否应在此类患者中应用尚不明确。3患者:一般建议以5-FU/LV或卡培他滨单药开始的序贯治疗,在治疗过程中的某个时刻(如病情进展)再联合奥沙利铂或伊立替康,可能对延长生存有益[233](2a类证据,B级推荐)。也有研究表明,5-FU/LV或卡培他滨单药联合贝伐珠单抗是一种有效且耐受性良好的治疗[234](2b类证据,B级推荐)本类患者也可以在如下情况下选择观察等待:低肿瘤负荷,但仍不适宜手术切除;疾病进展缓慢,无症状;患者充分知情同意。

病情进展后的化疗选择:FOLFOX(CapeOX)FOLFIRI方案或联合分子靶向治疗,如果病情进展可以考虑互为二线,仍可考虑与分子靶向药物的联合[235-237]。如果病情第二次进展,则可以改用西妥昔单抗治疗[238](未用过此类药者)或进行最佳支持治疗[37](2a类证据,B级推荐)5-FU/LV联合分子靶向治疗后如果病情进展,应改用FOLFOXFOLFIRICapeOX(均可联合分子靶向治疗),病情再次进展时进行最佳支持治疗[239](3b类证据,B级推荐)

上述治疗期间可在适当时机联合应用肝动脉灌注化疗,可能有助于延长总体生存期,单纯肝动脉灌注化疗并不比全身化疗更具优势[240-241]

2.分子靶向治疗:在无法切除的结直肠癌肝转移治疗中加入分子靶向药物,其有效性已得到广泛的证实[53,242-244]。目前认为,化疗联合应用靶向分子药物治疗是提高肝转移灶切除率的最有前景的治疗方法。

西妥昔单抗:西妥昔单抗为EGFR的抗体,现有的研究已显示,西妥昔单抗单用或联合化疗治疗结直肠癌肝转移有良好的临床效果[33,179,228,245-246]。其中西妥昔单抗和伊立替康联合应用具有更高的局部缓解率[179,247-248]。有III期临床研究证实,在化疗基础上联合使用西妥昔单抗可以使结直肠癌肝转移灶的反应率提高1倍以上,并明显提高无残留病灶切除率[169,179](1b类证据,A级推荐)。但是,西妥昔单抗的治疗效果与肿瘤组织的KRAS基因的状态密切相关,KRAS基因野生型患者治疗有较好的效果,而在KRAS基因突变型患者中应用并不提高疗效[175-179]。最近的研究提示,KRAS2外显子的第13密码子(G13D)突变并不一定意味着西妥昔单抗治疗的无效[249-251]。但目前临床研究证据不足,所以不推荐G13D突变的患者应用西妥昔单抗治疗。BRAF的突变与西妥昔单抗的治疗效果无关,而是与疾病的不良预后有关[33,246,252-254]

目前认为,可以同西妥昔单抗联合的化疗方案包括FOLFOXFOLFIRI[178-179,255]。不建议其与CapeOX5-FU推注方案联用[33,256]。如果在一线治疗时已使用了西妥昔单抗,在病情进展后也不建议继续使用[176]

贝伐珠单抗:贝伐珠单抗为VEGF的抗体。多项临床研究的结果表明,贝伐珠单抗加5-FU/LV作为不可切除的结直肠肝转移一线治疗有良好的效果[207,239,257-259]。近期的结果还显示,贝伐珠单抗联合奥沙利铂或伊立替康也在一定程度上提高中位生存、局部缓解率和切除率[208,260-263]。同样,贝伐珠单抗在肿瘤进展后的二线治疗上疗效也得到了证实(无论一线是否使用过贝伐珠单抗)[244,264-266](3b类证据,B级推荐)。贝伐珠单抗易引起出血和伤口延迟愈合[170-172]。所以,如在其治疗后需进行手术,建议手术时机选择在最后一次贝伐珠单抗使用后的6~8[162,173-174,267]

尽管分子靶向药物的治疗效果可喜,但目前的研究资料不建议多种靶向药物联合应用[174,268-270]

3.消融治疗: 射频消融:射频消融术使用方便,安全性好[271-273]。且能高效破坏肝转移灶的肿瘤细胞,但其在结直肠肝转移治疗中的地位仍有争议[274-277]。现有资料表明,单独使用射频消融治疗肝转移的生存率仅略微高于其他非手术治疗[278-281]。目前仅作为化疗无效后的治疗选择或肝转移灶术后复发的治疗[281]。建议应用时选择肝转移灶最大直径小于3 cm且一次消融最多3[8,16,282](5类证据,D级推荐)。肝转移灶的解剖位置是制约射频消融应用的另一个方面[283]。肿瘤邻近大血管使瘤内温度下降过快,从而使肝转移灶不能完全消融;同时,也应注意肝外热损伤[284-286]。以下情况也可考虑射频消融:一般情况不适宜、或不愿意接受手术治疗的可切除结直肠癌肝转移患者;预期术后残余肝脏体积过小时,可先切除部分较大的肝转移灶,对剩余直径小于3 cm的转移病灶进行射频消融。 微波消融:高于900 MHz的微波会使组织中的水分子产生振动,并摩擦发热从而使局部的组织凝固坏死,较大功率(70~90 W)的微波会在1 min内产生2 cm左右的凝固消融带[287]。微波消融较之射频消融有一定技术上的优势,如微波的传导不受组织干燥碳化的限制,使肿瘤内部在较短的时间内就可产生较高的温度和更大的消融带,而使肿瘤细胞的坏死更彻底[288]。与单纯化疗相比,结合微波消融治疗经过选择的不可切除的结直肠癌肝转移患者可以更有效地提高生存率[289-290] 冷冻治疗:应用液氮或液氩迅速使肿瘤组织的温度降至-180oC,这时细胞内所形成的冰晶将会造成机械性的损伤,消融带边缘的细胞也会因为脱水或周围小血管的闭塞而发生坏死。尽管冷冻治疗严格挑选的不可切除的结直肠癌肝转移患者在一定程度上提高了生存率[291-293]。但是,较高的局部复发率和并发症发生率(可达35%,包括ARDSDIC)限制了该技术的广泛应用[294]

4.放射治疗:对于无法手术切除的肝转移灶,若全身化疗、肝动脉灌注化疗或射频消融无效,可考虑放射治疗,但不作常规推荐。

由于全肝放射耐受剂量远低于肿瘤细胞所需的致死剂量,常规放射治疗在大的或多发肝转移灶的治疗中仅能起到姑息作用。无肝硬化时的全肝平均安全照射剂量为30 Gy[295]。虽然该剂量可以显著地减轻由于肝转移灶侵犯而引起的疼痛或黄疸[296-299]。但尚没有依据表明能延长生存期。为了减少放射性肝损伤,采用超分割或限制肝脏受照射体积,针对转移灶的局部剂量可提高到60~70 Gy[16,297,300]。如果有足够的正常肝脏组织被保护,肝脏的一部分受高剂量照射将不会产生严重的放射性肝病[16,301](3b类证据,B级推荐)。随着放疗设备的发展,最近出现的诸如射波刀等立体定向放射治疗(SBRT),对小的(直径小于5 cm)不能切除的孤立性肝转移灶进行低分割放疗,结果是安全有效的[302-305]。放疗前肝功能必须正常,肝脏受到射线的剂量必须在安全范围,以防止严重放射性肝损伤出现[303,306-307]

5.其他治疗方法:其他治疗方法包括无水酒精瘤内注射、选择性内放射(selective internal radiotherapy,SIRT)、药物洗提珠(durg-eluting beads,DEB)的动脉灌注化疗和中医中药治疗等,但其疗效并不优于上述各项治疗,仅能作为综合治疗的一部分,单独使用可能会失去其治疗意义。

第二部分   诊疗流程

 

 

 

 

 

第三部分   附录

附录一  推荐级别的分类

推荐分级   证据水平                               证据

A                         1a                        RCTs的系统综述

                                     1b                        单项RCT(95%CI较窄)

                                     1c                        全或无,必须满足以下要求

传统方法治疗全部致残或治疗失败,新方法治疗后,有部分患者存活或治愈;

传统方法治疗许多患者死亡或治疗失败,新方法治疗后,无一死亡或治疗失败。

B                         2a                        队列研究的系统综述

2b                        单项队列研究(包括质量较差的RCT)(如随访率小于80%)

                                     2c                        结局研究

                                     3a                        病例对照研究的系统综述

                                     3b                        单项病例对照研究

C                         4                          系列病例分析及质量较差的病例对照研究

D                         5                          没有分析评价的专家意见


附录二    结直肠癌分期

美国癌症联合委员会 (AJCC)结直肠癌TNM分期系统(第七版,2010)

 

原发肿瘤 (T)

Tx                    原发肿瘤无法评估

T0                    无原发肿瘤

Tis                            原位癌:上皮内或侵犯黏膜固有层

T1                    肿瘤侵犯黏膜下层

T2                    肿瘤侵犯固有肌层

T3                    肿瘤穿透固有肌层抵达浆膜下,或侵犯无腹膜覆盖的结直肠旁组织

T4a                  肿瘤穿透至脏层腹膜

T4b                  肿瘤与其他器官/组织结构粘连,或直接侵犯

区域淋巴结 (N)

Nx         区域淋巴结无法评估

  N0         区域淋巴结无转移                                       

  N1         1~3枚区域淋巴结转移

  N1a            1枚区域淋巴结转移

  N1b            2~3枚区域淋巴结转移

  N1c        无区域淋巴结转移,但肿瘤在浆膜下、肠系膜或无腹膜覆盖的结直肠旁组织中种植

  N2         4枚或4枚以上区域淋巴结转移

  N2a            4~6枚区域淋巴结转移

  N2b            7枚或更多的区域淋巴结转移

远处转移 (M)                                                      

  M0         无远处转移                                                 

  M1         有远处转移

  M1a                 转移局限在单个器官或部位(:肝脏、肺、卵巢,非区域淋巴结转移)

  M1b                转移超过一个器官/部位或腹膜转移

 

 

 

 

分期分组

分期                T                         N                       M                 Dukes分期            MAC

0                      Tis                       N0                       M0                   ——               ——

I                       T1                        N0                       M0                    A                  A

T2                        N0                       M0                    A                      B1  

IIA                  T3                        N0                       M0                         B                     B2

IIB                       T4a                       N0                       M0                         B                     B2

IIC                       T4b                       N0                       M0                         B                     B3

IIIA                 T1~T2                 N1/N1c               M0                         C                     C1

                            T1                        N2a                     M0                         C                     C1

IIIB                 T3~T4a               N1/N1c               M0                         C                C2

                            T2~T3                 N2a                     M0                         C                   C1/C2

                            T1~T2                 N2b                     M0                         C                     C1

IIIC                 T4a                      N2a                     M0                         C                C2

                            T3~T4a               N2b                     M0                         C                     C2

                            T4b                      N1~N2                M0                         C                     C3

IVA                 任何T                 任何N                M1a                       ——                ——

IVB                 任何T                 任何N                M1b                      ——                ——

组织学分级 (G)

Gx        分化程度不能被评估

G1        高度分化

G2        中度分化

G3        低度分化

G4        未分化

 

附录三  化疗方案

l   5-FU/LV

LV 500 mg/m2静脉滴注2 h,每周1×6

5-FU 500 mg/m2LV滴注开始1 h后静脉推注,每周1×6

5-FU 370~400 mg/m2+LV400 mg/m2每日1×5,28 d重复

l   卡培他滨

卡培他滨1250 mg/m2每日2次口服,1~14,3周重复

l   FOLFOX

Ø  FLOX

奥沙利铂85 mg/m2 静脉滴注2 h,135周各1

8周重×3周期

5-FU 500 mg/m2 静脉推+ LV 500 mg/m2 静脉滴注,每周1×6

8周重×3周期

Ø  mFOLFOX6

奥沙利铂85 mg/m2 静脉滴注2 h,1

LV 400 mg/m2 静脉滴注2 h,1

5-FU 400 mg/m2 静脉推注,1,然后1200 mg/m2 /2持续静脉输注 (总量 2400 mg/m2 ,输注46~48 h)

2周重复

l   CapeOX

奥沙利铂130 mg/m2,1

卡培他滨850~1000 mg/m2,每日2,持续14 d

3周重复

l   FOLFIRI

伊立替康180 mg/m2 静脉滴注30~120 min,1

LV 400 mg/m2与伊立替康同时输注,持续时间相同,5-FU之前,1天和第2

5-FU 400 mg/m2 静脉推注,然后600 mg/m2 持续静脉输注22 h,1天和第2

2周重复                                                                                                     

伊立替康180 mg/m2 静脉滴注30~120 min,1

LV 400 mg/m2 与伊立替康同时输注,持续时间相同,1

5-FU 400 mg/m2 静脉推注,1,然后1200 mg/m2 /d×2持续静脉输注 (总量 2400 mg/m2,输注46~48 h)

2周重复

l   FOLFOXIRI

伊立替康165 mg/m2,奥沙利铂85 mg/m2,LV400 mg/m2静脉滴注,1

5-FU3200 mg/m2 48 h持续滴注,1天开始

2周重复

 

附录四  无肝转移的直肠癌的联合放化疗

放疗剂量总量45~54 Gy,采用常规分割剂量(通常为35 d),同时接受如下方案化疗:

l   不伴有肝转移:卡培他滨850~1000 mg/m2,每日2,每周5 d

l   伴有肝转移:

Ø  奥沙利铂 每周60 mg/m2,6;5-FU 200 mg/m2,1~40

Ø  伊立替康 50 mg/m2,181522;5-FU 200 mg/m2,1~33

Ø  奥沙利铂 每周d1 60 mg/m2,卡培他滨650 mg/m2 bid,d1~d5,6

 

附录五  肝动脉和结直肠肿瘤区域联合灌注化疗

奥沙利铂 75 mg/m2,FUDR 650 mg/m2,丝裂霉素 8 mg/m2

采用股动脉穿刺法(Seldinger),经动脉导管超选择插管至结直肠肿瘤主要的滋养动脉内注入化疗1/2剂量;再超选择插管至肝固有动脉或肝肿瘤的滋养动脉注入内注入1/2剂量。

 

附录六  结直肠癌肝转移分子靶向治疗

l   西妥昔单抗5-FU的方案

西妥昔单抗首次剂量400 mg/m2 输注,输注时间为120 min,然后每周250 mg/m2输注时间为60 min,FOLFIRIFOLFOX

西妥昔单抗首次剂量400 mg/m2 输注,输注时间为120 min,然后每2500 mg/m2输注时间为60 min,FOLFIRIFOLFOX

仅结直肠癌检测KRAS基因野生型的患者建议使用。

l   贝伐珠单抗

贝伐珠单抗5 mg/kg 静脉滴注,2周重复,5-FUFOLFOXFOLFIRI

贝伐珠单抗7.5 mg/kg 静脉滴注,3周重复,CapeOX

(执笔整理:许剑民  任黎)  

     

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