彭健宏 潘志忠
結(jié)直腸癌肝轉(zhuǎn)移精準(zhǔn)治療進(jìn)展
彭健宏 潘志忠
肝轉(zhuǎn)移是結(jié)直腸癌治療失敗的主要原因之一,提高肝轉(zhuǎn)移療效的關(guān)鍵是精準(zhǔn)化治療。寡轉(zhuǎn)移分類標(biāo)準(zhǔn)不僅明確了不同肝轉(zhuǎn)移的治療手段和治療目標(biāo),且進(jìn)一步提升了局部非手術(shù)治療的地位。尋找RAS基因以外具有預(yù)后及療效預(yù)測(cè)價(jià)值的分子標(biāo)志物,對(duì)結(jié)直腸癌肝轉(zhuǎn)移(colorectal liver metastases,CRLM)精準(zhǔn)治療意義重大。精準(zhǔn)化治療貫穿CRLM治療全程優(yōu)化管理的各個(gè)環(huán)節(jié),包括初始可切除肝轉(zhuǎn)移治療順序的優(yōu)化、KRAS基因?qū)Ω吻谐g(shù)的療效預(yù)測(cè)、轉(zhuǎn)化治療敏感人群的選擇、最佳隨訪策略的應(yīng)用及個(gè)體化綜合治療方案的制定。本文就CRLM精準(zhǔn)治療的最新進(jìn)展進(jìn)行綜述。
結(jié)直腸癌肝轉(zhuǎn)移精準(zhǔn)治療進(jìn)展
肝轉(zhuǎn)移是結(jié)直腸癌治療失敗的主要原因之一。約25%結(jié)直腸癌患者初診時(shí)已發(fā)現(xiàn)肝轉(zhuǎn)移,在疾病發(fā)展的過程中約50%患者最終發(fā)生肝轉(zhuǎn)移[1-2]。肝轉(zhuǎn)移灶經(jīng)手術(shù)切除后,部分患者預(yù)后獲得明顯改善[3]。除治療因素外,腫瘤生物學(xué)行為對(duì)療效及預(yù)后的影響起著關(guān)鍵性的作用。結(jié)直腸癌的“精準(zhǔn)醫(yī)學(xué)”精髓是有針對(duì)性地實(shí)施個(gè)體化治療,其基本內(nèi)涵包括臨床和分子層面上的精準(zhǔn)診斷、精準(zhǔn)分類以及精準(zhǔn)治療。本文就結(jié)直腸癌肝轉(zhuǎn)移(colorectal liver metastase,CRLM)精準(zhǔn)治療的最新進(jìn)展進(jìn)行綜述。
2014年版歐洲腫瘤內(nèi)科學(xué)會(huì)(ESMO)指南根據(jù)轉(zhuǎn)移瘤是否可手術(shù)切除為核心,以疾病進(jìn)展的速度與患者對(duì)治療的耐受程度為依據(jù),將患者分為0~3組,分別制定不同的預(yù)期目標(biāo)及治療策略[4]。然而該分組標(biāo)準(zhǔn)欠清晰,臨床操作性較差;本質(zhì)與預(yù)后的預(yù)判不準(zhǔn)確,技術(shù)上幾乎所有肝轉(zhuǎn)移均可切除,但臨床治愈僅30%左右。鑒于上述局限性,2016年版ESMO指南根據(jù)疾病特征維度將CRLM分成寡轉(zhuǎn)移性疾病和廣泛轉(zhuǎn)移性疾病兩類[5]。寡轉(zhuǎn)移定義為介于局限性原發(fā)瘤及廣泛性轉(zhuǎn)移瘤之間的生物侵襲性較溫和的中間狀態(tài),轉(zhuǎn)移瘤數(shù)量有限且局限于一個(gè)器官[6]。寡轉(zhuǎn)移分類的提出帶來(lái)治療策略的更新,對(duì)于寡轉(zhuǎn)移性疾病,應(yīng)積極采取包括手術(shù)或非手術(shù)局部治療方式,力求達(dá)到治愈性的無(wú)瘤狀態(tài)(no evidence of disease,NED);但對(duì)于廣泛性轉(zhuǎn)移性疾病,其目標(biāo)是要達(dá)到疾病的最大控制,限制擴(kuò)大化的手術(shù)適應(yīng)證。新分類標(biāo)準(zhǔn)更加突出射頻消融、立體定向放射治療及肝動(dòng)脈灌注化療等非手術(shù)局部治療的重要性。綜上所述,新的疾病分類更為客觀體現(xiàn)腫瘤預(yù)后,具有更強(qiáng)的臨床指導(dǎo)作用。
盡管越來(lái)越多的基因被證實(shí)與CRLM相關(guān),但真正能夠運(yùn)用到臨床的分子標(biāo)記物仍十分有限。RAS突變患者接受抗EGFR靶向治療已被證實(shí)無(wú)生存獲益,即使是對(duì)抗EGFR靶向治療相對(duì)敏感的RAS野生型患者,仍有近半數(shù)患者對(duì)治療無(wú)效[7-8]。尋找RAS以外的具有預(yù)后及療效預(yù)測(cè)價(jià)值的分子標(biāo)志物對(duì)CRLM精準(zhǔn)治療意義重大。
2.1 PIK3CA基因20外顯子的突變意義
PIK3CA 20外顯子突變是KRAS野生型轉(zhuǎn)移性結(jié)直腸癌(metastatic colorectal cancer,mCRC)抗EGFR靶向治療的潛在不良預(yù)后標(biāo)志[9]。在KRAS野生型的mCRC中,有3.2%~4.5%的患者發(fā)生PIK3CA 20外顯子突變[10-11]。因此,在檢測(cè)RAS基因狀態(tài)的同時(shí)加入PIK3CA 20外顯子突變檢測(cè)有助于進(jìn)一步富集抗EGFR靶向治療獲益人群。
2.2 循環(huán)腫瘤細(xì)胞DNA的臨床價(jià)值
研究發(fā)現(xiàn)循環(huán)腫瘤細(xì)胞DNA(ctDNA)水平與結(jié)直腸癌預(yù)后呈負(fù)相關(guān),在mCRC更為明顯[12]。突變型ctDNA明顯升高的患者,預(yù)后更差[13]。Spindler等[14]研究將配對(duì)的血漿ctDNA與腸癌組織的基因檢測(cè)結(jié)果進(jìn)行對(duì)比,發(fā)現(xiàn)KRAS基因狀態(tài)一致性高達(dá)85%。在無(wú)法獲取活檢腫瘤組織的情況下,通過血液檢測(cè)ctDNA的狀態(tài)獲取基因突變信息亦可行。由于ctDNA檢測(cè)只需提供患者的血液,能實(shí)時(shí)反映腫瘤負(fù)荷水平及基因突變的動(dòng)態(tài)變化,可作為抗腫瘤治療療效實(shí)時(shí)監(jiān)測(cè)的有效手段;同時(shí),ctDNA突變狀態(tài)的變化也能為靶向藥物的選擇提供重要的依據(jù)。
2.3 擴(kuò)大BRAF基因突變位點(diǎn)的檢測(cè)意義
BRAF 15外顯子V600E突變已證實(shí)是結(jié)直腸癌非常強(qiáng)的負(fù)性預(yù)后影響因子[15]。然而,最新的研究發(fā)現(xiàn)BRAF密碼子594、596突變患者比BRAF V600E突變患者預(yù)后更好。雖然突變率僅為1.6%,但具有這種新突變的腫瘤通常位于直腸,病理為非黏液腺癌,腹膜轉(zhuǎn)移較少[16]。擴(kuò)大BRAF基因的突變檢測(cè)位點(diǎn),有利于進(jìn)一步認(rèn)識(shí)BRAF突變亞型的預(yù)后價(jià)值。
3.1 初始可切除CRLM治療順序的優(yōu)化
理論上,新輔助化療能有效縮小腫瘤病灶,及早治療微小轉(zhuǎn)移,有助于判斷腫瘤的生物學(xué)行為,篩選出治療反應(yīng)較差的患者,避免過度損毀性治療[17]。EORTC 40983研究提示圍手術(shù)期化療(手術(shù)前后各6個(gè)周期FOLFOX4方案)聯(lián)合手術(shù)對(duì)比單純手術(shù)未能改善初始可切除CRLM患者的5年總生存期(overall survival,OS)[18],即新輔助化療未能給初始可切除肝轉(zhuǎn)移患者帶來(lái)長(zhǎng)期生存獲益。近期,越來(lái)越多研究嘗試將患者分層,旨在篩選出對(duì)新輔助化療真正獲益的人群。一項(xiàng)回顧性研究比較可切除CRLM患者分別接受新輔助化療和直接手術(shù)的OS,根據(jù)CRS系統(tǒng)評(píng)分(表1),將入組患者分為高復(fù)發(fā)風(fēng)險(xiǎn)和低復(fù)發(fā)風(fēng)險(xiǎn)組。結(jié)果顯示,新輔助化療雖然對(duì)低復(fù)發(fā)風(fēng)險(xiǎn)組的OS沒有顯著影響(65個(gè)月vs.54個(gè)月,P=0.310),但可顯著延長(zhǎng)高復(fù)發(fā)風(fēng)險(xiǎn)組術(shù)后OS(46個(gè)月vs.33個(gè)月,P=0.004)[19]。此外,一項(xiàng)納入18項(xiàng)研究的薈萃分析也表明,高復(fù)發(fā)風(fēng)險(xiǎn)患者才能從新輔助化療中生存獲益(HR=0.69,95%CI:0.55~0.87;P=0.001)[20]。綜上所述,在治療之初,首先應(yīng)將患者根據(jù)預(yù)后風(fēng)險(xiǎn)分層,再?zèng)Q定治療策略,對(duì)于低復(fù)發(fā)風(fēng)險(xiǎn)的患者,可以選擇直接手術(shù),而對(duì)于高復(fù)發(fā)風(fēng)險(xiǎn)者,可先完成新輔助化療后再行手術(shù)治療(表1)。
表1 臨床復(fù)發(fā)風(fēng)險(xiǎn)評(píng)分標(biāo)準(zhǔn)(CRS)Table 1Clinical risk score criteria for predicting recurrence after hepatic resection for metastatic colorectal cancer
3.2 KRAS基因?qū)Ω吻谐g(shù)的療效預(yù)測(cè)
部分肝轉(zhuǎn)移灶經(jīng)一系列新輔助治療后,肝轉(zhuǎn)移瘤顯著縮小,隨后進(jìn)行肝切除術(shù),可以獲得根治機(jī)會(huì)。即使接受肝切除手術(shù),仍有部分患者因術(shù)后腫瘤復(fù)發(fā)未能從中獲益[21]。越來(lái)越多研究提示,KRAS基因不僅可以預(yù)測(cè)抗EGFR靶向治療的療效,還可應(yīng)用于評(píng)估CRLM患者行肝切除術(shù)的預(yù)后。維也納醫(yī)科大學(xué)的一項(xiàng)Ⅱ期臨床研究入組60例初始可切除CRLM患者,給予奧沙利鉑聯(lián)合貝伐單抗的新輔助化療,隨后行肝切除手術(shù),研究表明KRAS突變是OS及無(wú)復(fù)發(fā)生存期(relapse free survival,RFS)的負(fù)性預(yù)后因子[22]。M.D.安德森癌癥中心對(duì)納入的193例初始可切除CLRM患者在治療前進(jìn)行全RAS基因檢測(cè),術(shù)前給予聯(lián)合貝伐單抗的新輔助化療,隨后進(jìn)行肝轉(zhuǎn)移瘤根治性切除。結(jié)果提示RAS突變型患者的3年OS顯著低于RAS野生型患者(52.2%vs.81.0%,P= 0.002)[23]。同樣來(lái)自M.D.安德森癌癥中心的薈萃分析綜合8項(xiàng)臨床研究的KRAS突變狀態(tài)及長(zhǎng)期生存數(shù)據(jù),發(fā)現(xiàn)KRAS基因突變的患者OS和RFS更差[24]。雖然僅憑KRAS基因狀態(tài)難以完全將突變型患者排除在肝切除術(shù)外,但對(duì)于野生型患者,因預(yù)后較好,應(yīng)積極治療,爭(zhēng)取肝轉(zhuǎn)移瘤完全切除。同時(shí)臨床在進(jìn)行術(shù)前評(píng)估時(shí),應(yīng)納入KRAS基因狀態(tài)并聯(lián)合臨床病理因素對(duì)患者術(shù)后復(fù)發(fā)轉(zhuǎn)移風(fēng)險(xiǎn)進(jìn)行充分考量,更有利于篩選出真正適合肝切除術(shù)的患者。
3.3 轉(zhuǎn)化治療敏感人群的選擇
目前,RAS基因是否可作為貝伐單抗的療效預(yù)測(cè)因子之一仍存在爭(zhēng)議。Bencsikova等[25]的回顧性研究納入1 622例mCRC患者,均接受奧沙利鉑或伊立替康聯(lián)合貝伐單抗的一線治療,分析未見KRAS基因突變狀態(tài)影響貝伐單抗作為一線靶向藥物對(duì)mCRC的療效。意大利的一項(xiàng)薈萃分析則認(rèn)為KRAS野生型是貝伐單抗療效良好的預(yù)測(cè)因子。無(wú)論是客觀緩解率(objective response rate,ORR)、無(wú)進(jìn)展生存期(progression-free survival,PFS)還是OS,KRAS野生型患者接受貝伐單抗治療都有更好的臨床獲益[26]。TRIBE研究表明RAS及BRAF突變的患者無(wú)論接受聯(lián)合貝伐單抗的FOLFIRI方案的雙藥治療或FOLFOXIRI 3藥治療,其治療效果均較野生型差。在RAS突變患者中,3藥聯(lián)合貝伐單抗較FOLFIRI聯(lián)合貝伐單抗的PFS顯著延長(zhǎng)(12.0個(gè)月vs.9.5個(gè)月,HR= 0.82,95%CI:0.63~1.07),且也有OS獲益趨勢(shì)(27.3個(gè)月vs.23.9個(gè)月,HR=0.88,95%CI:0.65~1.18)[27]。為增強(qiáng)RAS突變型患者的臨床療效,2016版ESMO指南將3藥化療聯(lián)合貝伐珠單抗作為RAS突變患者優(yōu)先推薦的轉(zhuǎn)化治療方案[5]。
3.4 最佳隨訪策略的應(yīng)用
3.4.1 最佳隨訪間隔結(jié)直腸癌肝轉(zhuǎn)移灶即使完全切除(R0)后,仍有62%患者術(shù)后復(fù)發(fā),其中75%患者集中在術(shù)后2年內(nèi)復(fù)發(fā),而肝內(nèi)復(fù)發(fā)是最常見的復(fù)發(fā)形式之一。因此,肝內(nèi)復(fù)發(fā)病灶的早期發(fā)現(xiàn)是術(shù)后隨訪的重要環(huán)節(jié),目的是為了再次爭(zhēng)取肝切除或局部治療,改善預(yù)后[28-29]。2016年版美國(guó)國(guó)立綜合癌癥網(wǎng)絡(luò)(NCCN)指南推薦接受根治術(shù)達(dá)到NED的mCRC患者,影像學(xué)檢查應(yīng)比早期結(jié)腸癌患者更頻繁。專家組推薦這些患者在結(jié)束輔助治療的最初2年內(nèi)每3~6個(gè)月行胸、腹、盆腔CT增強(qiáng)掃描1次,然后每6~12個(gè)月1次,共5年。Hyder等[30]一項(xiàng)回顧性研究對(duì)比肝轉(zhuǎn)移灶切除術(shù)后每年行3~4、2和1次影像學(xué)檢查對(duì)于二次手術(shù)干預(yù)時(shí)間間隔和OS的影響。結(jié)果發(fā)現(xiàn)每年行3~4次影像學(xué)檢查并沒有明顯縮短二次手術(shù)干預(yù)時(shí)間間隔(11.5、13.0和13.0個(gè)月;P=0.690),OS也無(wú)顯著提高(43.1、56.7和53.7個(gè)月;P=0.080),研究認(rèn)為該群體患者中每年行1次CT掃描即可。選取恰當(dāng)?shù)碾S訪間隔應(yīng)充分考慮患者的病期及成本效益原則,過度頻密的檢查非但未帶來(lái)術(shù)后生存獲益,反而帶來(lái)更多放射性傷害。因此,本研究認(rèn)為達(dá)到NED狀態(tài)的患者2年內(nèi)影像學(xué)最佳隨訪的時(shí)間間隔為6個(gè)月。
3.4.2 影像學(xué)檢查的優(yōu)化2015年版NCCN指南并未將腹、盆增強(qiáng)MRI作為首選檢查方法,僅在患者不能完成腹、盆CT時(shí)才推薦使用。一項(xiàng)薈萃分析發(fā)現(xiàn)腹、盆增強(qiáng)MRI和增強(qiáng)CT發(fā)現(xiàn)肝轉(zhuǎn)移灶敏感性分別是81.1%和74.8%,特異性分別為97.2%和95.6%。因此,增強(qiáng)MRI對(duì)于判斷肝轉(zhuǎn)移灶的敏感性明顯優(yōu)于增強(qiáng)CT(OR=0.66;95%CI:0.55~0.80;P<0.000 1)[31]。此外,增強(qiáng)MRI在判斷<10 mm轉(zhuǎn)移灶的敏感性比增強(qiáng)CT更高,對(duì)于早期發(fā)現(xiàn)肝切除術(shù)后復(fù)發(fā)具有重要的臨床意義[32]。一項(xiàng)多中心前瞻性臨床研究對(duì)比釓塞酸增強(qiáng)顯影MRI,傳統(tǒng)細(xì)胞外增強(qiáng)顯影MRI以及增強(qiáng)CT對(duì)結(jié)直腸肝轉(zhuǎn)移瘤診斷的敏感性,分別為98.3%、85.7%和65.2%,表明釓塞酸增強(qiáng)顯影MRI在肝轉(zhuǎn)移瘤的診斷方面具有更高的準(zhǔn)確性[33]。因此,釓塞酸增強(qiáng)顯影劑(普美顯)能進(jìn)一步提高M(jìn)RI對(duì)肝臟微小轉(zhuǎn)移灶的檢出率,有利于早期發(fā)現(xiàn)肝轉(zhuǎn)移切除術(shù)后的肝內(nèi)復(fù)發(fā)病灶。故推薦結(jié)直腸癌肝轉(zhuǎn)移切除術(shù)后2年內(nèi)的患者應(yīng)用腹、盆普美顯增強(qiáng)MRI作為每6~12個(gè)月常規(guī)復(fù)查的影像學(xué)方式。
3.5 個(gè)體化綜合治療方案的制定
CRLM的綜合治療牽涉到多個(gè)臨床學(xué)科,傳統(tǒng)的“1對(duì)1”診療模式難以滿足最優(yōu)的治療策略要求,多學(xué)科團(tuán)隊(duì)綜合診治模式(multidisciplinary team,MDT)是踐行CRLM規(guī)范化診療的最佳模式[34]。MDT是一項(xiàng)多個(gè)學(xué)科參與并長(zhǎng)期磨合的診治模式,各學(xué)科均需對(duì)疾病發(fā)生發(fā)展的規(guī)律、疾病異質(zhì)性的認(rèn)識(shí)、相關(guān)信息的掌握程度、診療規(guī)范的理解程度以及對(duì)應(yīng)治療策略的制定等方面達(dá)成一致共識(shí),診療過程體現(xiàn)個(gè)體化與精準(zhǔn)化。這是長(zhǎng)期而連續(xù)的,目標(biāo)是確保最佳療效及安全性,最大程度保證生存質(zhì)量,避免過度或無(wú)效治療。近年來(lái),MDT診療模式已被運(yùn)用到CRLM的個(gè)體化實(shí)踐之中。英國(guó)的一項(xiàng)前瞻性臨床試驗(yàn)入組331例CRLM患者,對(duì)MDT的療效進(jìn)行為期10年的研究。結(jié)果表明MDT診療模式能使CRLM患者生存獲益[35]。國(guó)內(nèi)的一項(xiàng)回顧性研究也提示,應(yīng)用MDT治療的結(jié)直腸癌患者能在術(shù)前更早發(fā)現(xiàn)肝轉(zhuǎn)移灶,更多MDT診療的患者早期接受肝切除手術(shù),肝切除率明顯提高(40%vs.10%,P=0.046),進(jìn)而轉(zhuǎn)化為生存延長(zhǎng)[36]。然而,目前國(guó)內(nèi)MDT普及率較低,推廣過程尚存在規(guī)范程度及質(zhì)量不高的問題,這直接影響MDT的作用和患者的療效。為了改善目前現(xiàn)狀,本課題組已開展針對(duì)中國(guó)結(jié)直腸癌肝轉(zhuǎn)移MDT的相關(guān)研究,旨在為MDT診療模式提供可操作性的實(shí)踐藍(lán)本,以期推動(dòng)我國(guó)結(jié)直腸癌肝轉(zhuǎn)移MDT診療實(shí)踐規(guī)范化的發(fā)展。
近年來(lái),CRLM研究領(lǐng)域雖然已取得一定進(jìn)展,但精準(zhǔn)化進(jìn)程仍存在一些亟待解決的難題:如新的疾病分類對(duì)于寡轉(zhuǎn)移中轉(zhuǎn)移瘤的數(shù)量仍未明確,是否以5個(gè)為標(biāo)準(zhǔn),尚需進(jìn)一步探討;傳統(tǒng)檢查方法難以準(zhǔn)確評(píng)估腫瘤的切除范圍,重要器官的保護(hù)還有賴于精準(zhǔn)外科技術(shù)的支持。醫(yī)學(xué)圖像三維重建可視化系統(tǒng)、手術(shù)導(dǎo)航系統(tǒng)、分子影像、醫(yī)學(xué)3D打印技術(shù)和達(dá)芬奇機(jī)器人輔助手術(shù)有望克服傳統(tǒng)外科手術(shù)的缺陷。目前,真正應(yīng)用到臨床的CRLM相關(guān)分子標(biāo)記物仍十分有限,更多預(yù)后標(biāo)記物及治療靶點(diǎn)的臨床應(yīng)用價(jià)值有待進(jìn)一步探索。
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(2016-08-30收稿)
(2016-12-06修回)
(編輯:武斌 校對(duì):孫喜佳)
Advances in the precision treatment of colorectal liver metastases
Jianhong PENG,Zhizhong PAN
Zhizhong PAN;E-mail:panzhzh@sysucc.org.cn
Department of Colorectal Tumor,Sun Yat-sen University Cancer Prevention and Control Center,South China State Key Laboratory of
Oncology,Tumor Medical Cooperative Innovation Center,Guangzhou 510060,China
Liver metastasis is one of the main causes of treatment failure in colorectal cancer,and the key to improve the efficacy of treatment is to adopt precision therapy.Oligometastatic classification clearly defines the treatment methods and goals for distinguishing liver metastases,as well as promotes nonsurgical methods for local treatments.In addition to RAS oncogene,other biomarkers with prognostic and therapeutic predictive values urgently need to be identified.Precision therapy encompasses the entire course of optimal treatment in colorectal liver metastases(CRLM)including the following:optimization of therapy sequence for initial resectable liver metastases,treatment predictive value of KRAS oncogene for liver resection,selection of sensitive subgroups for conversion therapy,application of the optimal follow-up strategy,and formulation of individual comprehensive treatment regimens.This review focuses on the recent progress of precision treatment for CRLM.
colorectal cancer,liver metastass,precision treatment,advance
10.3969/j.issn.1000-8179.2016.24.015
中山大學(xué)腫瘤防治中心結(jié)直腸科,華南腫瘤學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室,腫瘤醫(yī)學(xué)協(xié)同創(chuàng)新中心(廣州市510060)
潘志忠panzhzh@sysucc.org.cn
彭健宏專業(yè)方向?yàn)榻Y(jié)直腸癌分子診斷及綜合治療。
E-mail:pengjh@sysucc.org.cn