9

IV期结肠癌与复发性结肠癌的治疗

IV期结肠癌表明已存在远处转移。复发性结肠癌的治疗效果取决于体格检查和(或)影像学检查所发现的复发部位。除了标准的影像学检查,放射免疫成像也可以为治疗提供更多的临床信息[1]。然而这些方法并未改善包括生存在内的长期治疗效果。

IV期结肠癌与复发性结肠癌的治疗选择

IV期结肠癌和复发性结肠癌的治疗选择包括:

肝转移治疗

约有50%的结肠癌患者在诊断时已有肝转移病灶,肝转移可以为首发表现,或疾病复发表现。虽然只有小部分肝转移患者适合手术切除,但肿瘤消融、局部和全身化疗的发展提供了更多的治疗选择,包括:

手术​。

新辅助化疗​。

局部消融术​。

辅助化疗​。

动脉内化疗​。

手术

以下情况肝转移可考虑手术切除:[5][7][13][14][15][16]

病灶数量有限。

病变位于肝内。

未累及重要血管。

无肝外病变或肝外病灶数量有限。

充分的肝储备功能。

对于可切除肝转移患者,多数非随机临床研究(如 NCCTG-934653)显示,术后切缘阴性者5年生存率可达25%至40%[5][7][13][14][15][16]。随着外科技术、术前影像学的进步,可切除患者的筛选也更为准确。此外,多项多药联合化疗临床研究显示,一些既往诊断为无法手术切除的孤立肝转移者经过化疗偶可转化为可手术切除[17]

新辅助化疗

初始肝转移不可切除者如果化疗效果理想,偶可外科切除转移灶,术后5年生存率与初始转移灶可切除者相当[17]

局部消融术

射频消融术是一种安全的治疗手段(严重并发症率2%,死亡率小于1%),可能实现长期控制肿瘤的效果[18][19][20][21][22][23][24]。肿瘤不可切除或禁忌肝切除的患者可以选择射频消融或冷冻消融术[25][26][27][28]

其他治疗肝转移病灶的局部消融技术还包括栓塞术和间质放疗[29][30]。某些局限性肺转移、或同时肝肺转移者也可考虑手术切除,甚至实现长期生存[12][31][32]

辅助化疗

对于可能的根治性肝转移切除术后患者,术后辅助化疗的意义尚不确定。

证据(辅助化疗):

此治疗方法的有效性需要进行更多临床研究评估,以对比单独使用更有效力的全身联合化疗的临床结局是否与肝动脉内化疗联合全身化疗类似。

动脉内化疗

肝动脉内氟脲苷化疗可提高肝转移患者的总体缓解率,但与全身化疗相比,动脉内化疗并未获得相似的生存改善[2][35][36][37][38][39]。一项荟萃分析汇总了仅有氟嘧啶作为全身化疗药物时代的多项临床研究,此分析发现患者生存时间并无获益[40]

一些研究指出,肝脏灌注治疗的局部毒性增加更高,如肝功能异常和致命性的胆管硬化。

IV期结肠癌和复发性结肠癌的治疗

手术​。

化疗和靶向治疗​。

二线化疗。

手术

复发性或晚期结肠癌患者的治疗取决于肿瘤病灶位置。对于局部复发、和(或)仅有肝转移、和(或)仅有肺转移的患者,如果可能,则手术切除是其唯一的治愈手段。

化疗和靶向治疗

目前,已有八种有效药物获得批准用于转移性结直肠癌的单独或联合用药:

5-FU​。

卡培他滨​。

伊立替康​。

奥沙利铂​。

贝伐单抗​。

西妥昔单抗​。

阿柏西普​。

帕尼单抗​。

本章节将提及的联合化疗药物方案包括:

德国肿瘤医学协会(AIO)化疗方案(叶酸、5-FU与伊立替康):第1天伊立替康(100mg/m2)输液2小时和亚叶酸(500mg/m2)输液2小时,此后每年(共52周)4周,每周一次静脉(IV)泵入5-FU(2,000mg/m2)24小时。

CAPOX化疗方案:第1-14天卡培他滨(1,000mg/m2)输液,每天2次,并且第1-8天奥沙利铂(70mg/m2)输液。每三周重复一次。

Douillard化疗方案(叶酸、5-FU与伊立替康):第1天伊立替康(180mg/m2)输液2小时。第1天和第2天亚叶酸(200mg/m2)输液2小时。第1天输液后静脉用负荷剂量5-FU(400mg/m2)一次,随后第1天和第2天各连续22小时静脉泵入5-FU(600mg/m2)。每两周重复一次。

FOLFOX4化疗方案(奥沙利铂、亚叶酸和5-FU):第1天奥沙利铂(85mg/m2)输液2小时,第1天和第2天亚叶酸(200mg/m2)输液各2小时, 并静脉用负荷剂量5-FU(400mg/m2)。此外,第1天和第2天各连续22小时静脉泵入5-FU(600mg/m2)。每两周重复一次。

FOLFOX6化疗方案(奥沙利铂、亚叶酸和5-FU):第1天奥沙利铂(85-100mg/m2)输液2小时,亚叶酸(400mg/m2)输液2小时, 并静脉用负荷剂量5-FU(400mg/m2),此后46小时静脉泵入5-FU(2,400-3,000mg/m2)。每两周重复一次。

FOLFIRI化疗方案(叶酸、5-FU和伊立替康):第1天伊立替康(180mg/m2)输液2小时,亚叶酸(400mg/m2)输液2小时,并静脉用负荷剂量5-FU(400mg/m2),此后连续46小时静脉泵入5-FU(2,400-3,000mg/m2)。每两周重复一次。

FUFOX化疗方案:第1、8、22、29天使用奥沙利铂(50mg/m2)、亚叶酸(500mg/m2)和5-FU(2,000mg/m2),连续输液22小时。每36天重复一次。

FUOX化疗方案:第1、8、15、22、29和36天5-FU(2,250mg/m2)连续输液48小时,第1、15、29天奥沙利铂输液(85mg/m2)。每6周重复一次。

IFL(又名Saltz)化疗方案(伊立替康、5-FU和亚叶酸):每周行伊立替康(125mg/m2)输液,静脉推注5-FU(500mg/m2)和亚叶酸(20mg/m2),共四周。每6周重复一次。

XELOX化疗方案:每日口服卡培他滨(1,000mg/m2)2次,连续14天。同时第1天奥沙利铂输液(130mg/m2)。每三周重复一次。

在5-FU是唯一有效化疗药物的时代,使用5-FU治疗局部晚期、无法切除或转移性病灶的临床试验中,相比最佳支持治疗组,化疗后患者的缓解率、疾病进展时间(TTP)、生存时间和生活质量都有改善[43][44][45][41][42]。一些临床试验分析了不同的5-FU-亚叶酸治疗方案,对比了不同剂量和给药方案的有效性与毒性,研究显示各项化疗方案疗效基本相当,中位生存时间12个月左右[46]

在多药联合化疗之前,两项随机临床研究显示卡培他滨的化疗有效性与梅奥诊所方案(5-FU-亚叶酸方案)基本相同[47][48]。[ 证据等级:1iiA]

三项随机临床试验显示,当伊立替康或奥沙利铂与5-FU-亚叶酸联合化疗时,患者缓解率、PFS和OS均有改善[49][50][51]

证据(伊立替康):

研究发表后,FOLFOX或FOLFIRI作为一线方案治疗转移性结直肠癌患者的作用得到认可。

在使用基于伊立替康的化疗方案作为一线方案治疗转移性结直肠癌患者时,优先选用FOLFIRI方案[54]。[ 证据等级:1iiDii​]

III期随机临床试验分析了用卡培他滨代替5-FU输液的有效性。两项III期临床研究对比了FUOX和CAPOX的有效性[55][56]

证据(奥沙利铂):

在使用基于奥沙利铂的化疗方案作为一线治疗方案治疗转移性结直肠癌患者时,CAPOX方案不劣于FUOX方案。

贝伐单抗是一种结合血管内皮生长因子的部分人源化单克隆抗体。贝伐单抗可以合理的加入FOLFIRI或FOLFOX化疗方案,作为一线方案治疗转移性结直肠癌患者。

证据(贝伐单抗):

基于以上研究结果,有理由将贝伐单抗加入FOLFIRI或FOLFOX化疗方案,作为治疗转移性结直肠癌的一线方案。贝伐单抗面临的一个主要问题在于,当贝伐单抗作为一线疗法的一部分时,一线治疗后是否继续使用贝伐单抗尚有争议。2012年美国临床肿瘤学协会年会发表了一些来自随机对照临床试验的数据[62]。这项临床试验招募了820例转移性结直肠癌患者,入组者为已接受含有贝伐单抗的一线化疗后出现疾病进展的病例。研究者将这些患者随机分入单纯化疗组和含贝伐单抗的化疗组。结果显示,相比于单纯化疗组,含贝伐单抗的化疗组OS显著改善。含贝伐单抗化疗组的中位OS为11.2个月,不含贝伐单抗化疗组的中位OS为9.8个月(HR,0.81;95%CI,0.69-0.94;非分层log-rank检验P=0.0062)。含贝伐单抗化疗组的中位PFS为5.7月,不含贝伐单抗化疗组的中位PFS则为4.1个月(HR,0.68;95%CI,0.59-0.78;非分层log-rank检验P<0.0001)[62]。[ 证据等级:1iiA]

阿柏西普是一种新型抗VEGF分子,已有研究评估该药作为二线治疗对转移性结直肠癌患者的有效性。其中一项临床试验招募了1,226例患者,所有患者被随机分组,接受每两周一次阿柏西普(4mg/kg IV)或安慰剂治疗,并联合使用FOLFIRI方案[63]。相较于安慰剂联合FOLXFIRI组,阿柏西普联合FOLFIRI化疗组的OS有显著改善(HR,0.817;95.34%CI,0.713-0.937;P=0.0032),阿柏西普和安慰剂组的中位生存时间分别为13.50月和12.06月。阿柏西普亦显著延长患者的PFS(HR,0.758;95%CI,0.661-0.869;P<0.0001),阿柏西普和安慰剂组的中位PFS分别为6.90月和4.67月。在上述结果基础上,对于既往接受FOLFOX方案治疗的患者,可以将FOLFIRI联合阿柏西普方案作为二线治疗方案[63]。[ 证据等级:1A]对于是否二线治疗中继续使用贝伐单抗,或二线治疗开始即使用阿柏西普的问题,由于目前尚无相关临床试验,因此无相关数据。

西妥昔单抗是抗表皮生长因子受体(EGFR)的部分人源化单克隆抗体。西妥昔单抗的作用机理是在细胞膜表面干扰酪氨酸激酶的信号通路,故导致EGFR下游通路激活的肿瘤突变,如KRAS突变,则对西妥昔单抗不敏感。在多药联合化疗方案中添加西妥昔单抗可改善无KRAS突变(即KRAS基因野生型)的结肠癌患者的生存率。需要注意的是,对于有KRAS突变的肿瘤患者,若在接受含贝伐单抗的多药方案化疗时增加西妥昔单抗治疗,其预后变差。

证据(西妥昔单抗):

帕尼单抗是一种抗EGFR的完全人源化抗体。美国食品药品监督管理局(FDA)已批准帕尼单抗用于治疗化疗耐药的转移性结直肠癌患者[70]。临床试验显示,帕尼单抗单药或联合用药对PFS和OS的作用与西妥昔单抗一致,疑为一致性类效应。

证据(帕尼单抗):

二线化疗

对于以5-FU-亚叶酸作为一线治疗的患者,伊立替康二线化疗与5-FU输液或支持治疗相比,可使患者OS有所改善[74][75][76][77]

类似地,一项III期临床试验以曾接受伊立替康联合5-FU-亚叶酸治疗的患者为研究对象,将他们随机分为5-FU静脉推注与输液联合亚叶酸(LV5FU2方案)、奥沙利铂单药治疗或FOLFOX4方案的患者。FOLFOX4和LV5FU2治疗组患者的中位TTP分别为4.6个月和2.7个月(分层秩和检验,双边P<0.001)[78]。[ 证据等级:1iiDiii]

三线化疗

瑞戈非尼是血管内皮生长因子(VEGF)等多种酪氨酸激酶通路的抑制剂。2012年9月,FDA 批准瑞戈非尼应用于治疗后疾病进展的癌症患者。一项单中心临床研究评估了瑞戈非尼的安全性和有效性,该研究招募了760例曾接受过治疗的转移性结直肠癌患者[79]。这些患者被随机分组,接受瑞戈非尼或安慰剂治疗,且同时接受最佳支持治疗。瑞戈非尼治疗组患者OS得到了统计学显著改善(分别为6.4个月和5个月,HR,0.493,95%CI,0.418-0.581,单边P<0.000001)[79]

处于临床评估阶段的治疗方案

对于IV期结肠癌和复发性结肠癌,目前处于临床评估阶段的治疗方案包括:

目前开展的临床试验

现招募 IV期结肠癌复发性结肠癌​患者的美国临床试验请参见美国NCI癌症临床试验列表,可根据部位、药物、干预或其他标准进行筛选。

NCI网站提供关于临床试验的基本信息。

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