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【35under35】彭健宏医生:RAS突变型结直肠癌肝转移转化治疗进展和治疗模式的思考

2022年07月27日
作者:彭健宏
医院:中山大学肿瘤防治中心

   

               
彭健宏
主治医师,硕士研究生导师

中山大学肿瘤防治中心结直肠科主治医师,硕士研究生导师
中山大学肿瘤防治中心住培外科专业基地秘书
广东省抗癌协会大肠癌专业委员会青年委员会秘书
广东省肿瘤性疾病医疗质量控制中心结直肠癌专家委员会委员
广东省精准医学应用学会胃肠肿瘤分会委员 熟练掌握结直肠癌全程管理流程,主攻结直肠癌外科治疗以及结直肠癌肝转移综合治疗
近五年第一/通讯作者发表SCI论文42篇,10分以上5篇,累积影响因子225.4
主持国家自然科学基金青年项目1项
2021年获“叶任高-李幼姬”临床医学专业优秀中青年教师奖

临床挑战

结直肠癌(Colorectal cancer, CRC)是一种高发且发病率上升最快的消化道恶性肿瘤之一,严重威胁人类全球生命健康 [1]。远处转移是结直肠癌致死的主要原因之一。在所有转移途径中,肝转移是最常见的转移模式。大约有25%的结直肠癌患者初诊时已发现肝转移,在疾病发展的过程中超过半数的患者最终发生肝转移 [2]。结直肠癌肠癌肝转移(Colorectal liver metastases, CRLM) 经过局部治疗后达到无疾病状态(No evidence disease, NED)可以延长总生存期,既往研究发现CRLM完全切除后,约30%的患者可以获得10年生存 [3]。不幸的是,初诊时符合手术切除条件的患者比例仅为20%,因此约80%的病例定义为初始不可切除[4]。然而,若该类患者经过转化治疗能够获得根治性切除,部分患者也能获得长期生存 [5]。实际上,临床上对于初始不可切除的CRLM患者最终能否转化成功的初始判断没有清晰的界限,转化治疗和姑息治疗有时候清晰的边界[6]。目前国内外指南建议,如患者在身体情况允许的条件下,尽可能采用高效治疗方案,在最短时间内达到肿瘤的最大程度的退缩,争取通过多种方式的局部治疗手段达到肿瘤的完全损毁,为患者最大可能地创造肿瘤治愈性机会。

作为CRC远处转移的典型表现,CRC肝转移是一个涉及多基因异常、多阶段、多步骤渐进演化的复杂过程。其中KRAS是CRC其中一个最常见的促癌驱动基因,其突变的发生率约为40% [7, 8]。本人既往分析本中心数据发现,在初始不可切除CRLM中,KRAS常见的突变类型依次为G12D占36.17%,G12C占23.4%,G13D 17.2% 。以RAS突变驱动激活的表皮皮生长因子受体(Epidermal Growth Factor Receptor, EGFR) 信号通路是CRLM恶性进展的重要通路。RAS蛋白在EGFR通路上发挥开关分子的门控作用,其下游分子RAF和MEK的激活是依赖于RAS基因的突变状态, RAS 基因一旦突变可持续激活下游的MAPK和PI3K-AKT通路,进而激活下游的转录因子,继而转录调控肿瘤侵袭转移相关蛋白表达水平改变 [9, 10]。大量临床研究证实RAS基因突变是CRLM肝转移切除术后的负性预后因子 [11, 12]。本人既往分析本中心数据发现,KRAS突变的CRLM在接受一线治疗后6个月早期进展的风险是KRAS野生型患者的2倍。此外,RAS突变的结直肠癌肿瘤对抗EGFR 靶向治疗具有原发性耐药,因此该类患者不能从抗EGRR治疗获益 [13]。因此,在以NED为目标的治疗策略框架下,RAS突变的CRLM治疗困境显而易见:首先,肿瘤的生物学性为较差,治疗后肿瘤进展较快,转化治疗成功率较低,治疗难度大;全身转化治疗方案的靶向药物选择局限,如何在有限的靶向治疗条件下优化转化治疗的策略,是摆在每位肿瘤医生的难题。以下是本人对RAS突变CRLM的治疗进展进行梳理并对其治疗策略进行的思考(说明:本文主要针对MSS的CRLM)。

 强化一线治疗,抢占NED先机

临床实践当中,我们发现一线治疗在CRLM的全程管理中发挥关键性的作用。一线治疗强调短时间降低肝脏肿瘤负荷,为局部治疗的实施创造足够的残余肝脏体积条件。复旦大学附属中山医院许剑民教授团队主持的BECOME研究奠定了以贝伐单抗(Bev)作为RAS突变型的初始不可切除CRLM靶向治疗的基础。研究结果显示,与单纯mFOLFOX6组对比,mFOLFOX6联合Bev能够显著提高的肝转移切除率(22.3% vs. 5.8%, P<0.001),此外,mFOLFOX6联合Bev的客观缓解率(ORR)(54.5% vs. 36.7%, P<0.001),无进展生存期(9.5月 vs. 5.6月, P<0.001)和总生存期(25.7月 vs. 20.5月, P=0.031)均有显著提高 [14]。鉴于奥沙利铂和伊利替康的抗肿瘤的机制及化疗毒副反应谱的有一定的差异性,两者联合可到达到抗肿瘤的叠加效应,而经过剂量调整后严重的毒副反应在可控范围,加上贝伐单抗(Bev)临床使用具有良好安全性和耐受性,FOLFOXIRI+Bev方案应运而生。意大利TRIBE研究首次在大规模III期随机对照试验中证实了FOLFOXIRI+Bev的疗效显著优于目前临床标准方案FOLFIRI+Bev,ORR达到71.6%,而总生存比双药方案显著延长4个月,总体患者耐受性良好 [15, 16]。VISNU-1研究进一步填补了FOLFOXIRI+Bev对比FOLFOX+Bev临床疗效数据的空白。研究结果发现FOLFOXIRI+Bev对比FOLFOX+Bev, ORR从57%显著提高到69%(OR=0.61,95%CI 0.38-0.97, P=0.0381),肿瘤反应的中位持续时间显著延长1.8个月(9.9个月比8.1个月,P=0.001)。生存分析显示FOLFOXIRI+Bev带来了3.1个月的PFS延长(12.4个月对比9.3个月,P=0.0006)。在CRLM领域,OLIVIA研究首先表明FOLFOXIRI+Bev对比FOLFOX6+Bev在转化治疗中带来更好的临床结局。FOLFOXIRI+Bev的ORR提高19%(81% vs. 62%),R0切除率提高26%(49% vs. 23%), 中位无进展生存期(PFS)延长7.1个月(18.6个月 vs. 11.5个月) [17]。今年作为ASCO口头汇报的CAIRO5研究将FOLFOXIRI+Bev作为RAS突变CRLM一线治疗的循证依据获得更充分的肯定,夯实了FOLFOXIRI+Bev作为RAS突变型CRLM一线治疗的地位。与双药联合Bev相比,FOLFOXIRI+Bev的ORR提高20.5%(53.5% vs. 33.3%, P<0.001),肝转移瘤R0切除率提高14%(51% vs.37%, P=0.02),疾病进展风险显著降低23%,并显著延迟PFS。从2016年开始,国内外多个指南(NCCN、ESMO、CSCO等)已将FOLFOXIRI+Bev方案作为RAS突变型晚期CRC一线治疗的标准方案。

血管生成抑制剂联合免疫检查点抑制逐渐成为近年来的晚期CRC治疗的研究热点。若在FOLFOXIRI+Bev基础上加入PD-1抑制剂能否进一步增加临床疗效?今年ASCO的 II期单臂NIVACOR研究给我们带来了初步答案。该研究入组73例RAS/BRAF突变的晚期CRC,其中MSS肠癌占83.8%,给予FOLFOXIRI+Bev联合纳武利尤单抗一线治疗8周期。研究结果显示ORR为76.6%,中位PFS为10.1个月。该方案一线治疗未见非预期不良反应。与FOLFOXIRI+Bev的历史数据相比,ORR和中位PFS相当。结合AtezoTRIBE和Checkmate-9X8研究,晚期CRC一线“免疫+靶向+化疗“方案仍需进一步探索。去年,全球范围内首款靶向KRAS G12C突变的抑制剂sotorasib的上市,该药为RAS突变实体瘤的治疗注入了新生血液。CodeBreaK100 II期临床研究发现, sotorasib治疗晚期结直肠癌的ORR为9.7%,疾病控制率达到51%,肿瘤反应持续中位时间为4.2个月,总体不良反应可控 [18]。虽然ORR并未达到预期,该研究结果仍然提示KRAS G12C突变抑制剂联合一线的FOLFOXIRI+Bev治疗可能成为未来值得探索的研究方向。

 积极使用局部区域治疗,争取最后NED机会

目前CRLM的临床治疗面临的最大挑战是一线治疗后获得性耐药导致治疗失败。本人在也在临床中发现约25%的初始不可切除CRLM接受一线治疗期间发生肿瘤进展 [19]。LiverMetSurvey研究回顾性分析6415例CRLM治疗结局,发现一线治疗后局灶性进展接受二线治疗后肝切除仍可获得与一线治疗肝切除相当的长期生存 [20]。然而,包括RAISE和AXEPT在内的众多前瞻性临床研究发现晚期CRC二线治疗的ORR仅为12%-24% [21, 22]。值得注意的是,RAS突变型晚期CRC接受二线线治疗的缩瘤失败风险比RAS野生型患者有升高趋势 [23]。因此,RAS突变型CRLM一旦接受一线转化治疗失败,二线全身治疗难以达到更显著的缩瘤效果,这些患者往往失去获得NED的机会。在药物治疗难以达到肝脏肿瘤满意的退缩效果时,基于肝脏的双重供血模式,肝脏区域治疗是值得考虑的,它有望成为耐药性CRLM获得转化治疗机会的救命稻草。目前ESMO指南推荐的肝脏区域治疗包括肝动脉灌注化疗(HAI),栓塞化疗(DEBIRI)以及选择性内放射治疗(SIRT) [24]。

一项来自MSKCC中心的II期临床研究已证实了HAI在CRLM转化治疗的疗效, HAI联合全身治疗初始不可切除CRLM,ORR高达到 76%, 转化率可达47% [25]。我们中心李宇红教授团队在中国人群中首次开展了氟尿苷肝动HAI联合m-FOLFOX6系统化疗治疗初始不可切除CRLM患者的I期临床试验,发现了该治疗方案的ORR高达68.6%,转化率为28.6%,并确定了该治疗方案中氟尿苷肝动脉灌注的最大耐受剂量为0.12 mg/kg/天。该研究首次在中国人群中评估了氟尿苷肝动脉灌注的耐受性和治疗效应,为肝动脉灌注化疗在初始不可切除CRLM中的标准化应用奠定了基础 [26]。对于一线转化治疗失败的患者,法国的HEARTO II期临床研究应用雷替曲塞和奥沙利铂HAI治疗全身系统治疗失败的CRLM患者,16例患者经过治疗以后,ORR达到43.8% [27]。由于样本量较少,后续需要更多的样本量证实HAI在耐药性CRLM的临床疗效。  目前正在进行的SULTAN UCGI 30/PRODIGE 53 (NCT03164655)研究旨在评估基于奥沙利铂HAI联合全身化疗的强化治疗策略作为对一线转化治疗2个月后疗效不佳的不可切除的CRLM患者挽救治疗的疗效 [28],期待该研究结果能够进一步夯实HAI在耐药性CLRM转化治疗中的应用价值。目前临床研究较多的主要是伊立替康载药微球的DEBIRI。已有小样本随机对照临床研究研究报道了DEBIRI对CRLM的ORR为66%-75%,与单纯FOLFIRI化疗相比,DEBIRI延长了显著PFS 3个月,延长了总生存7个月,同时减少了伊立替康全身应用的不良反应 [29-31]。然而,DEBIRI在耐药性CRLM的转化治疗领域尚未有大样本的III期临床研究报道。同时,DEBIRI应用后的栓塞综合征较常见,特别是肝区疼痛,因此,其在临床上广泛应用受到一定的限制。

HAI和DEBIRI已经在国内很多中心开展,但相比而言,SIRT受到的关注较少,这可能是由于既往SIRT需要用到的90Y放射微球还没进入中国大陆市场。SIRT对于CLRM的治疗具有以下三个方面的突出优势:1.选择性强,肿瘤覆盖率高:利用肝脏供血的特点,放射性微球可以通过动脉最终沉积在肿瘤组织的末端分支,最低限度减少对于正常组织的损伤;2. 对肝脏恶性肿瘤的治疗作用显著,尤其适合合并门脉癌栓的患者,使肿瘤退缩转化可性根治性手术,并有可能达到病理完全坏死,延缓肿瘤进展;3. 安全性良好且操作方便,栓塞后综合症发生率甚微,所需治疗次数多为一次,对患者周围人群无需做特别防护。SIRFLOX研究首次证实了SIRT在CRLM转化治疗作用。研究纳入了530例初始不可切除CRLM, 实验组给予SIRT联合mFOLFOX6±Bev治疗,对照组给予单纯mFOLFOX6±Bev一线治疗。研究结果表明,联用SIRT显著提高接近10%的ORR(78.7% vs. 68.8%,P = 0.042),最终提高9.2%肝切除(治愈)机会 (38.1% vs 28.9% ,P < 0.001)。此外SIRT联合FOLFOX治疗能够显著延长肝脏的无进展生存时间达8个月 [32]。而综合FOXFIRE, SIRFLOX, 和 FOXFIRE 三项临床试验的荟萃分析显示:虽然化疗基础上联合SIRT与单纯化疗相比没能显著改善生存,这主要由于三项研究中纳入了超过35%的肝外转移的患者,但可以降低49%的肝内肿瘤进展风险 [33]。一项意大利多中心II期前瞻性临床研究纳入50例既往接受过3线及以上化疗的CRLM,  其中60%患者肝脏肿瘤负荷为25%-50%。这些患者接受SIRT治疗后6周后进行CT评估,肿瘤ORR为26.1%,疾病控制率达到52.2% [34]。本人认为,对于经典全身治疗失败的CRLM患者,SIRT可作为全身治疗耐药的后线治疗不失为一个理想的选择。2021年9月董家鸿院士团队在中国大陆实施了首例特许准入的SIRT治疗,开创了SIRT造福中国肝脏恶性肿瘤患者的新纪元,具有里程碑式的意义。

 合理使用局部治疗工具箱,打开NED大门

CLRM的治疗理念近年来已发生了改变,由既往以手术治疗为中心转变成以NED为中心。NED概念的提出实质是扩展了CRLM根治性治疗的范畴,则是由传统的单纯R0肝切除模式扩展到以手术切除为主,联合各种消融损毁,立体定向放疗等局部治疗丛而达到彻底消灭所有肉眼或影像可见病灶的治疗模式。因此,NED的治疗理念更加强调局部治疗工具箱的合理应用。

既往大样本研究发现只要保证切缘大于1mm,可以达到肝切除的根治性 [35]。因此,目前手术基本原则采用保留肝实质手术(PSH)切除方式,如肿瘤局部切除,亚肝段切除,在保证根治性的情况下,尽可能地保留有功能的正常肝组织。日本一项回顾性研究纳入145例CLRM进行分析,其中113例应用PSH,32例应用解剖性肝切除,术后随访,两组单纯肝内复发率相当(43.4% vs.50.0%,P=0.505),但在仅肝内复发的情况下,PSH组进行挽救性肝切除术更容易获得实施 [36]。MD Anderson的回顾性研究则发现PSH组比解剖性肝切除组的术中中位失血量明显减少(100ml vs.200ml, P<0.01),在肝内复发的情况下,PSH组有显著更多患者接受了二次肝切除手术(68% vs. 24%, P<0.001),预后显著延长 [37]。因此保留肝实质对于复发后进行挽救性肝切除术至关重要,挽救性肝切除有利于提高患者预后。然而,对于RAS突变型的肝脏转移瘤,切缘为1mm,是否足够?MD Anderson纳入633例接受肝切除的CRLM,其中404例为RAS野生型,229例为RAS突变型,术后病理分析肝转移瘤的切缘的状态,结果发现RAS突变型的切缘阳性率比RAS野生型显著升高(11.4% vs.5.4%, P=0.007)。进一步分析发现虽然两类型肿瘤的最大肝转移瘤平均直径无明显差异,但RAS突变型的肝转移瘤的中位切缘距离显著比RAS野生型短(4mm vs.7mm, P=0.031)。研究结果给我们的提示:RAS突变型的肝转移瘤浸润范围更广,故应应保证更充足的切缘范围,降低切缘阳性率。对于RAS突变型的肿瘤,肝脏肿瘤切缘应尽量做到>10mm。

此外,术中还应注意寻找潜在化疗后消失的肝转移灶(DLM),其发生率约为4%~38% [38, 39]。DLM不等于病理完全缓解,文献报道DLM病灶经过手术切除后病理仍发现35-100%的病例有肿瘤残留[40]。韩国一项回顾性研究提示,DLM如果在后续未进行局部处理,1年内累积原位复发率高达10.9%,2年内高达15.7% [41]。外科手术切除临床完全缓解(cCR)转移灶虽然无显著改善总生存,但提高了3年肝内无复发生存率[39],因此,对于DLM的积极干预还是有必要的。然而DLM的采用常规检查手段去甄别是非常困难的。研究发现示卓安造影剂对肝脏病灶的敏感性高于普通超声和增强CT。尤其对于<1cm的病灶,示卓安超声造影敏感度达88.9%,远高于增强CT和一般彩超 [42]。我们中心的经验是使用术中B超和示卓安超声造影进行肝脏探查,以发现更多潜在的DLM,及时予以切除或局部损毁,降低术后肝内复发率。

然而临床上经常发现,对于超声发现的肝脏肿瘤,往往深在位于肝实质内,虽然肿瘤不大,但若进行肝切除,必然牺牲较多的正常肝脏组织。因此,目前的肝转移瘤手术模式已经发生根本性的改变,即有必要联合局部治疗工具箱,由单一手术模式转变为以手术为主的LATs模式。射频消融的优势十分明显,其治疗创伤小,能够深入肝实质,对于肿瘤位于肝实质内,直径小于 3cm,经射频消融后可达到根治效果 [43]。MSKCC回顾性研究发现手术联合RFA与双叶肝切除对比,能够显著减少术中出血,CRLM患者长期生存未见明显受损(5年OS :联合消融组 56% vs.单纯肝切除组 49%, P=0.16) [44]。然而对于临近大血管,胆总管以及重要结构的肝脏肿瘤,手术切除风险较高,射频消融容易损伤临近结构,因此该类肿瘤可借助立体定向放疗(SBRT)进行局部损毁。SBRT具有单次剂量高,肿瘤周围剂量梯度变化大,正常组织受照剂量低,可提高肿瘤区剂量而不增加周围正常肝组织剂量等优势,因此对于技术处理难度较大的肿瘤,SRBT是理想选择。既往多项临床研究发现CRLM接受SBRT治疗是安全而有效的,2年局部控制率为60%~90%,2年总生存(OS)率为38%~70%,且无严重放射性肝病发生 [45, 46]。

 总结

RAS突变使CRC细胞获得更高的恶性侵袭转移能力,该类CRLM生物学行为较差,转化治疗难度大,给临床医生带来巨大挑战。若患者一般情况能耐受,治疗意愿强烈,其治疗策略应该在NED的为目标的框架下进行。目前国内外指南中,三药联合Bev已成为RAS突变型晚期CRC的常规推荐方案。随着KRAS靶向抑制剂上市,三药+Bev+KRAS抑制剂联合转化治疗方案的临床价值值得进一步探索。在全身转化治疗疗效欠佳的情况下,肝脏局域治疗的加入能够提高肝转移瘤的退缩率,最大限度为患者创造NED的机会。手术联合局部损毁性治疗的联合治疗模式,打破了单一手术模式,目的是以最小肝损伤代价,达到肿瘤根治性治疗效果。期待未来有更多新型药物和局部损毁技术加入到CLRM转化治疗策略中,进一步丰富CRLM 的NED治疗内涵,为患者带来更多福音。

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