9

IV期与复发性直肠癌

局部控制的治疗选择:

转移性直肠癌

复发性或晚期结直肠癌患者的治疗选择需考虑疾病部位。对于局部复发和(或)仅有肝转移和(或)仅有肺转移灶的患者,如可手术切除,则手术切除是唯一的可能达到治愈的治疗。肝转移灶是否可切除取决于下列因素:[17][21][24][25][26][27]

病变数量有限。

病变位于肝内。

无主要血管受累。

无肝外病灶或肝外病灶局限。

有充分的肝功能储备。

对于肝转移灶可切除的患者,多数非随机研究(例如美国中北部癌症治疗组试验 NCCTG-934653)发现切缘阴性患者的5年生存率为25%-40%[28][29][30][31][32]。[ 证据等级:3iiiDiv​]随着手术、术前影像学技术的进步,对可行手术切除的患者的筛选也更合理。并且多项多药联合化疗临床研究显示,一些在过去被诊断为无法行手术切除的独立肝转移病灶,如今在接受化疗后偶可转化为可切除病灶[33]

目前有7种已获批准的活性药物可以行单药治疗或者联合其他药物治疗:

氟尿嘧啶(5-FU)。

卡培他滨。

伊立替康。

奥沙利铂。

贝伐单抗。

西妥昔单抗。

帕尼单抗。

5-FU曾是唯一的活性化疗药,当时临床试验中使用5-FU治疗局部晚期、无法切除或转移性病灶,这些临床试验中,对比最佳支持治疗组[35][36][37],接受化疗的患者部分缓解率、疾病进展时间(TTP)延长[41][42]、生存率和生活质量都得到了改善。一些临床试验分析了不同的5-FU-亚叶酸(5-FU/LV)治疗方案,对比了不同剂量和给药方案的的有效性与毒性,研究显示各项化疗方案疗效基本相当,各组患者的生存时间中位数均在12个月内[38]。再出现多药化疗之前,有2项随机研究发现卡培他滨与梅奥诊所方案5-FU/LV有效性相同[39][40]。[ 证据等级:1iiA​]

本章节将提及的化疗药物联合使用方案包括:

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(卡培他滨与奥沙利铂):第1-14天卡培他滨(1,000mg/m2)输液,每天2次,并且每3周第1-8天奥沙利铂(70mg/m2)输液。

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, 并静脉用负荷剂量的5-FU(400mg/m2),此后每两周第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。

一线多药化疗

静脉推注、输液或卡培他滨联合盐酸伊立替康-塞来昔布( BICC-C)临床试验评估了几项不同的基于伊立替康的化疗方案,用于治疗初治的转移性结直肠癌患者。评估的方案包括FOLFIRI、mIFL和卡培他滨/伊立替康方案(CAPIRI)[46]。此研究中430例患者被随机分配至不同的化疗组,后因患者入组速度过慢,研究提前结束。FOLFIRI化疗组患者的PFS优于mIFL组患者(分别为7.6个月和5.9个月,P=0.004),亦优于CAPIRI组患者(分别为7.6个月和5.8个月,P=0.015)。CAPIRI组患者中最高级(3级或3级以上)恶心、呕吐、腹泻、脱水和手足综合征的发生率最高。贝伐单抗获准使用后, BICC-C临床研究对研究方案进行了修正,新招募的117例患者被随机分组,接受FOLFIRI/贝伐单抗方案或mIFL/贝伐单抗方案治疗。尽管研究中两组的主要终点PFS无显著差异,但FOLFIRI/贝伐单抗组患者OS显著改善(分别为28.0月余19.2月,P=0.037;死亡HR,1.79;95%CI,1.12-2.88)。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[46]。[ 证据等级:1iiDii](参考PDQ总结恶心与呕吐,关于腹泻与脱水的更多信息请参考PDQ总结胃肠道并发症中腹泻章节。)

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[47][48]。AIO结直肠研究组研究将474例患者随机分为FUFOX组和CAPOX组。CAPOX组中位PFS为7.1个月,FUFOX组为8.0个月(HR,1.17;95%CI,0.96-1.43;P=0.117),且HR位于既定的等效性范围内[48]。西班牙协作组研究将348例患者随机分组,接受CAPOX或FUOX方案治疗[47]。两组TTP分别为8.9个月和9.5个月(P=0.153),位于既定的非劣性范围内[55]。[ 证据等级:1iiDii ]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。

​肝转移

约有15%到25%的结直肠癌患者在诊断时已有肝转移,另有25%-50%患者在原发肿瘤切除后发生异时性肝转移[66][67][68]。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。

在以下情况中肝转移可考虑行切除术:[17][21][24][25][26][27]

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。

对于可切除性肝转移患者,多数非随机性临床研究(如NCCTG-934653 )显示,术后切缘阴性者5年生存率可达25%至40%[17][21][24][25][26][27]。随着外科技术、术前影像学的进步,可切除的患者的筛选也更为准确。

初始不可切除性肝转移灶的患者如果有对化疗有良好反应,偶可行切除术。这些患者的5年生存率与初始病灶可切除的患者相似[33]。射频消融术是一种安全的治疗手段(严重并发症发生率2%,死亡率小于1%),可能实现长期控制肿瘤的效果[69][70][71][72][73][74][75]。肿瘤不可切除或禁忌肝切除的患者可以选择接受射频消融或冷冻消融术[76][77][78]

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[79][80][81]。某些局限性肺转移、或同时肝转移者也可考虑手术切除,甚至实现长期生存[82][83][84][85]

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。一项临床研究在进行全身5-FU和亚叶酸化疗的基础上,观察了加用肝动脉氟尿苷与地塞米松化疗的疗效观察,研究显示肝动脉氟尿嘧啶与地塞米松联合全身5-FU和亚叶酸组的2年无进展生存率(PFS)(分别为57%和42%,P=0.07)和总生存率(OS)(分别为86%和72%,P=0.03)相比于单独全身5-FU和亚叶酸组均有改善,但是两组中位生存时间无统计学差异。联合治疗组中位生存时间为72.2个月,而单方案治疗组中位生存时间为59.3个月(P=0.21)[86]。[ 证据等级:1iiA ]

另一项临床研究招募了有1-3处潜在可切除结肠癌肝转移患者,术前所有患者分配至两组,一组在术后不接受其他治疗,另一组术后接受肝动脉氟尿苷联合全身5-FU化疗[87]。这些随机分组的患者中,27%的患者在术前被评估为不适合进行手术,故仅余75名患者可进行复发率和生存率评估。两组患者的肝转移复发率均有减少,但其生存时间中位数和4年生存率并无显著差异。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。

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]。由于局部化疗有效性存在争议,一项大型多中心III期临床试验(CALGB-9481)(NCT00002716)对比了肝动脉灌注治疗与全身化疗的作用。一些研究目前正在评估肝动脉内化疗加肝放疗,尤其是转移瘤的局部放疗效果[93]。一些研究指出,肝脏灌注治疗的局部毒性更高,可导致肝功能异常和致死性胆管硬化。

局部复发性直肠癌

局部复发性直肠癌是有切除机会的,尤其在前次手术切除不彻底的情况下。对于初次根治切除术后局部复发的患者,一些局部侵袭性扩大手术可能获得长期无病生存的治疗效果,如复LAR手术、结肠造瘘、APR、全盆或后盆腔脏器切除术[94][95]。对于无放疗史的局部晚期(盆腔侧壁、骶骨和/或相邻器官受累)患者,诱导放化疗可能增加病灶切除、保留括约肌的机会[96][97]。曾接受外照射的局部复发患者行术中放疗可能增加局部控制率,并发症尚在可接受范围内[3]

与复发相关的肾盂积水是根治性手术禁忌证之一[98]。对某些精心选择的患者,即便合并局限肺转移,或是肝肺转移,如果条件允许也可以考虑手术,甚至获得5年生存的机会[82][83][84]

目前开展的临床试验

现招募 IV期直肠癌复发性直肠癌​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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