重視直腸癌的術(shù)前精準(zhǔn)評(píng)估

徐惠綿 王鵬亮

·述評(píng)·

重視直腸癌的術(shù)前精準(zhǔn)評(píng)估

徐惠綿 王鵬亮

徐惠綿 二級(jí)教授，博士生導(dǎo)師，國務(wù)院特殊津貼專家，現(xiàn)任中國醫(yī)科大學(xué)附屬第一醫(yī)院腫瘤中心主任。中華醫(yī)學(xué)會(huì)腫瘤學(xué)分會(huì)第十屆侯任主委兼胃腸腫瘤學(xué)組組長、中國抗癌協(xié)會(huì)胃癌專業(yè)委員會(huì)侯任主委、中國醫(yī)科大學(xué)胃腸腫瘤首席專家。曾獲第十屆中國醫(yī)師獎(jiǎng)、遼寧省政府優(yōu)秀專家、中央保健委員會(huì)會(huì)診專家、首屆遼寧名醫(yī)等榮譽(yù)稱號(hào)。從醫(yī)三十余年，在胃癌、結(jié)直腸癌診斷及外科治療專業(yè)有較深的造詣。先后主持“863”國家高技術(shù)研究發(fā)展計(jì)劃項(xiàng)目1項(xiàng)、國家自然科學(xué)基金6項(xiàng)、省部級(jí)科研項(xiàng)目11項(xiàng)。在《Annals of Surgery》《Stem cells》《Oncogene》《Annals of Oncology》《Cancer》等著名雜志發(fā)表SCI收錄論文93篇，國內(nèi)核心期刊論文161篇，累計(jì)影響因子300。主編胃癌專著2部。“胃癌三早與現(xiàn)代外科治療研究”和“胃癌及癌前病變分子病理學(xué)機(jī)制研究” 分別榮獲2001年、2006年國家科技進(jìn)步二等獎(jiǎng)；“胃癌轉(zhuǎn)移規(guī)律及亞臨床轉(zhuǎn)移診治研究”獲2016年中國抗癌協(xié)會(huì)科技進(jìn)步一等獎(jiǎng)。

以往對(duì)于直腸癌患者術(shù)前評(píng)估主要關(guān)注的是手術(shù)方式的選擇以及能否達(dá)到根治性切除。而近年來隨著新輔助治療及多學(xué)科診療模式等新技術(shù)在直腸癌臨床實(shí)踐中的應(yīng)用，精準(zhǔn)術(shù)前評(píng)估對(duì)患者也不僅限于手術(shù)方式選擇、預(yù)后評(píng)估，更重要的是指導(dǎo)個(gè)體化綜合治療方案和流程的選擇，使患者生存獲益及生活質(zhì)量提高。因此，精準(zhǔn)的術(shù)前評(píng)估對(duì)于直腸癌患者顯得尤為重要。本文旨在對(duì)直腸癌術(shù)前的精準(zhǔn)評(píng)估做一概述，供臨床醫(yī)生借鑒。

直腸腫瘤； 術(shù)前評(píng)估； 新輔助治療； 精準(zhǔn)醫(yī)學(xué)

近年來，隨著人民生活質(zhì)量的提高以及飲食結(jié)構(gòu)的改變，我國結(jié)直腸癌的發(fā)病率逐年上升；全國癌癥數(shù)據(jù)顯示：2015年我國新發(fā)生結(jié)直腸癌病例約37.6萬人，死亡病例約19.1萬人，發(fā)病率及死亡率在所有腫瘤中均居第五位［1］。同歐美相比，我國直腸癌的比例較高；約占全部結(jié)直腸癌患者的半數(shù)以上［2］。

隨著術(shù)前新輔助放化療的應(yīng)用、直腸癌外科技術(shù)手段的進(jìn)步以及多學(xué)科協(xié)作（multidisciplinary team，MDT）診療模式的開展，使得直腸癌患者的治療方式多樣化個(gè)體化，治療效果得到明顯的提升，特別是保肛率的提高以及局部復(fù)發(fā)率的降低［3］。因此，對(duì)直腸癌患者進(jìn)行術(shù)前精準(zhǔn)評(píng)估，選擇個(gè)體化治療方案和流程，是進(jìn)一步提高療效的關(guān)鍵。

一、術(shù)前T分期的評(píng)估

手術(shù)前對(duì)于直腸癌T分期的評(píng)估是決定后續(xù)治療的重要依據(jù)。根據(jù)直腸癌NCCN治療指南：對(duì)于術(shù)前臨床分期為腫瘤浸潤突破腸壁固有肌層或達(dá)到漿膜下層及以上的患者（cT3-4b），應(yīng)當(dāng)先行術(shù)前放化療或單純放療［4］。目前對(duì)于術(shù)前T分期的診斷，最常用的影像學(xué)檢查方法為直腸核磁共振成像（magnetic resonance imaging，MRI）或直腸內(nèi)鏡超聲（rectal endoscopic ultrasound，EUS）。EUS可顯示正常腸壁不同的解剖層次交替形成三條強(qiáng)回聲帶以及兩條低回聲帶，根據(jù)腫瘤侵犯所形成的回聲中斷來判斷腫瘤的浸潤深度。EUS對(duì)于T1-2期直腸癌診斷的準(zhǔn)確度較高，且優(yōu)于MRI［5］。但存在操作者的技術(shù)差異，腸道準(zhǔn)備情況欠佳，氣體較多及糞渣等都會(huì)影響EUS診斷的準(zhǔn)確性。且有10～20%的T2期的直腸癌由于腫瘤周圍的炎癥反應(yīng)而被高估，10%的T3期患者被低估［6］。此外，當(dāng)腸腔狹窄內(nèi)鏡無法通過也會(huì)限制EUS的使用。

MRI 具有較高的軟組織分辨率，可以在不同的斷面上進(jìn)行成像，因而可以較為清晰地顯示直腸各層的解剖層次。盡管MRI 在T1-2期腫瘤的診斷的準(zhǔn)確度上較EUS低，但由于MRI對(duì)局部解剖結(jié)構(gòu)顯示的更清晰，對(duì)T3-4期直腸癌則更具有優(yōu)勢(shì)［7］。北美放射學(xué)會(huì)利用高分辨率的MRI，將T3期腫瘤進(jìn)一步分為cT3a：腫瘤突破肌層＜5 mm，cT3b：5～10 mm，cT3c ：＞10 mm［8］。盡管這一分類并沒有體現(xiàn)在新版的TNM分期中，但業(yè)內(nèi)認(rèn)為對(duì)預(yù)后評(píng)估更準(zhǔn)確。文獻(xiàn)報(bào)道T3a期直腸癌的5年腫瘤相關(guān)生存率為85%，而T3b-3c期則僅為54%，強(qiáng)調(diào)T3a期同T3b-3c期腫瘤應(yīng)區(qū)別對(duì)待［9］。盡管高分辨率MRI對(duì)于判斷腫瘤浸潤肌層（T3）的誤差在0.5 mm之內(nèi)，但對(duì)于T2期與T3a期的鑒別仍然不理想［10］，而對(duì)于T2期與T3a期的鑒別恰恰是術(shù)前診斷的難點(diǎn)及重點(diǎn)。對(duì)于T4期MRI診斷的準(zhǔn)確性可達(dá)90%以上，并能夠準(zhǔn)確的評(píng)價(jià)腫瘤與直腸周圍器官的關(guān)系［11-12］。

二、術(shù)前N分期的評(píng)估

區(qū)域淋巴結(jié)的轉(zhuǎn)移是影響直腸癌預(yù)后的重要危險(xiǎn)因素，如術(shù)前判斷存在區(qū)域淋巴結(jié)轉(zhuǎn)移的患者需要行新輔助放化療。但目前，MRI，EUS，CT在內(nèi)的多種影像學(xué)手段對(duì)于淋巴結(jié)轉(zhuǎn)移的診斷均不夠理想［13］。因此，對(duì)于N分期的判斷是直腸癌術(shù)前評(píng)估的重點(diǎn)與難點(diǎn)。影像學(xué)診斷淋巴結(jié)轉(zhuǎn)移主要是依據(jù)淋巴結(jié)的大小、形態(tài)、密度等特征。目前常以5 mm作為MRI檢查淋巴結(jié)是否轉(zhuǎn)移的臨界值，但約有15～30%的陽性淋巴結(jié)直徑＜5 mm［14］。亦有文獻(xiàn)報(bào)道當(dāng)淋巴結(jié)直徑≥4 mm，淋巴結(jié)的邊緣不規(guī)則以及低信號(hào)等，有助于提高陽性淋巴結(jié)診斷的準(zhǔn)確率［15］。此外彌散加權(quán)成像技術(shù)（diffusion weighted imaging，DWI），以及應(yīng)用淋巴結(jié)特異性的對(duì)比劑，如超小順磁氧化鐵顆粒及釓磷維司，亦有助于提高M(jìn)RI陽性淋巴結(jié)的診斷率［16-18］。EUS診斷陽性淋巴結(jié)的靈敏度及特異度均較MRI低。近年來有學(xué)者提出，在超聲內(nèi)鏡引導(dǎo)下，通過細(xì)針穿刺活檢［19-20］，可以提高陽性淋巴結(jié)診斷的準(zhǔn)確率，但該檢查屬有創(chuàng)操作，存在并發(fā)癥的風(fēng)險(xiǎn)，并且受到多種因素的影響，其臨床應(yīng)用價(jià)值有待進(jìn)一步驗(yàn)證。

近年來，放射組學(xué)技術(shù)發(fā)展迅速，使影像學(xué)從傳統(tǒng)的圖像時(shí)代深入到大數(shù)據(jù)時(shí)代。從影像檢查圖像中高通量的提取大量的影像學(xué)特征，通過數(shù)學(xué)方法對(duì)其進(jìn)行定量轉(zhuǎn)換后形成數(shù)字影像模式，利用特定的參數(shù)預(yù)測(cè)淋巴結(jié)轉(zhuǎn)移概率。我國學(xué)者利用放射組學(xué)技術(shù)，預(yù)測(cè)結(jié)直腸癌淋巴結(jié)轉(zhuǎn)移的概率，使其準(zhǔn)確性得以提高［21］。期待放射組學(xué)技術(shù)對(duì)提高直腸癌術(shù)前精準(zhǔn)N分期，具有更大的發(fā)展空間。

三、術(shù)前環(huán)周切緣及直腸周圍血管浸潤的評(píng)估

直腸癌環(huán)周切緣（ circumferential resection margin，CRM）是指直腸腫瘤與直腸系膜筋膜（mesorectal fascia，MRF）間的最短距離。CRM是影響預(yù)后的獨(dú)立因素，主要與局部復(fù)發(fā)密切相關(guān)［22-23］。因此CRM的判定對(duì)直腸癌治療策略的選擇具有重要意義，并可避免部分患者接受過度治療［24］。病理CRM陽性的判定為顯微鏡下CRM小于等于1 mm。來自歐洲的MERCURY實(shí)驗(yàn)證明高分辨率的MRI對(duì)CRM的預(yù)測(cè)準(zhǔn)確率可達(dá)到94%［25］。一項(xiàng)薈萃分析顯示：MRI對(duì)診斷CRM的靈敏度為77%，而特異度達(dá)到94%［26］。但是MRI對(duì)于中下段直腸癌診斷的準(zhǔn)確率較低。有研究證明EUS可以輔助MRI更好的判斷中下段直腸癌的CRM［27］。

直腸周圍血管浸潤是指病理檢查發(fā)現(xiàn)直腸壁固有肌層外血管被腫瘤浸潤及壁外的靜脈浸潤（extramural venous invasion，EMVI）。EMVI是預(yù)測(cè)直腸癌預(yù)后及遠(yuǎn)處轉(zhuǎn)移的重要危險(xiǎn)因素［28-29］。目前認(rèn)為MRI是術(shù)前評(píng)價(jià)EVMI最為有效的檢查手段。通過高分辨率MRI建立了EMVI評(píng)分標(biāo)準(zhǔn)，其預(yù)測(cè)敏感度及特異度分別為62%，88%［29］。此外EMVI尚可用于判斷腫瘤對(duì)新輔助放療的療效。因此對(duì)于cT3且MRI-EMVI陽性的病例，可作為采取新輔助放化療的依據(jù)之一［30］。提高M(jìn)RI對(duì)于EMVI診斷的準(zhǔn)確性，也是未來影像學(xué)需關(guān)注和深入研究的。

四、術(shù)前肝轉(zhuǎn)移的評(píng)估

肝臟是結(jié)直腸癌遠(yuǎn)處轉(zhuǎn)移最為常見的部位，約有60～70%結(jié)直腸癌發(fā)生肝轉(zhuǎn)移，其中25%左右的患者出現(xiàn)同時(shí)性肝轉(zhuǎn)移［31-32］。未接受肝轉(zhuǎn)移灶切除的的患者5年生存率幾乎為0，而接受肝轉(zhuǎn)移灶切除的患者5年生存率可達(dá)到30～50%［33］。對(duì)于直腸癌患者，肝轉(zhuǎn)移的定性定量診斷對(duì)決定治療方式和流程至關(guān)重要。一項(xiàng)薈萃分析比較了超聲、CT、 MRI、PET/CT在診斷結(jié)直腸癌肝轉(zhuǎn)移的準(zhǔn)確度，結(jié)果發(fā)現(xiàn)在檢測(cè)的準(zhǔn)確度上MRI均優(yōu)于其余幾種檢查［34］。PET/CT在評(píng)估結(jié)直腸癌肝轉(zhuǎn)移方面具有一定的優(yōu)勢(shì)。但是對(duì)肝轉(zhuǎn)移小于1 cm的病灶，PET/CT存在假陰性的結(jié)果［35］。而MRI對(duì)診斷＜1 cm的病灶時(shí)則較敏感和特異。若使用特異性的對(duì)比劑及DWI-MRI技術(shù)，其診斷更為精準(zhǔn)［36］。因此NCCN指南推薦肝臟MRI作為結(jié)直腸癌肝轉(zhuǎn)移的一線檢查手段，PET/CT作為二線檢查手段。

五、術(shù)前腫瘤標(biāo)志物的評(píng)估

1.癌胚抗原（carcinoembryonic antigen，CEA）是目前最為常用的腫瘤標(biāo)志物。對(duì)結(jié)直腸癌早期發(fā)現(xiàn)，術(shù)后腫瘤復(fù)發(fā)，轉(zhuǎn)移具有良好的監(jiān)測(cè)作用，CEA是目前指南唯一推薦的用于結(jié)直腸癌監(jiān)測(cè)的腫瘤標(biāo)志物。第八版TNM分期將CEA 的重要性提到一個(gè)更高的位置。約有70～90%的結(jié)腸癌患者會(huì)出現(xiàn)血清中CEA的升高［37］。且與腫瘤分期相關(guān)，亦為預(yù)后不良的危險(xiǎn)因素［38-40］。尚有助于對(duì)新輔助治療的療效評(píng)價(jià)，即手術(shù)前后血清CEA升高值變化不大的病例，預(yù)示不易達(dá)到病理上的完全緩解［41-42］。目前，對(duì)于CEA的爭(zhēng)議主要集中在CEA閾值的設(shè)定，閾值過高會(huì)使一部分患者被漏診，過低則可能會(huì)使一部分患者接受過度治療。新近一項(xiàng)薈萃分析顯示［43］：不同閾值的敏感度及特異度均不同，在每1 000例患者中，選取10 ug/L作為閾值相比于選取5 ug/L作為閾值，減少了78例假陽性病例，而僅漏診一例。因此選取10 ug/L作為閾值更加合理。

2.循環(huán)腫瘤細(xì)胞/DNA的術(shù)前評(píng)估

循環(huán)腫瘤細(xì)胞（circulating tumor cell，CTC）是指由腫瘤原發(fā)灶或轉(zhuǎn)移灶釋放入循環(huán)系統(tǒng)中的腫瘤細(xì)胞，并且具有腫瘤特異性抗原或其基因特征［44］。既往研究證實(shí)CTC是評(píng)估結(jié)直腸癌患者預(yù)后的獨(dú)立危險(xiǎn)因素，并且對(duì)術(shù)后的復(fù)發(fā)具有一定的預(yù)測(cè)作用［45］。一項(xiàng)薈萃分析顯示：CTC可以早期預(yù)測(cè)結(jié)直腸癌化療的有效性［46］。還可用于預(yù)測(cè)局部進(jìn)展期直腸癌對(duì)于新輔助放化療的反應(yīng)［47］。

循環(huán)腫瘤DNA （circulating tumor DNA，ctDNA）是指凋亡或壞死的腫瘤細(xì)胞進(jìn)入循環(huán)系統(tǒng)中釋放的腫瘤DNA片段［48］。對(duì)于難以獲得組織標(biāo)本進(jìn)行基因檢測(cè)的患者可以通過對(duì)ctDNA進(jìn)行檢測(cè)來獲取腫瘤相關(guān)的基因特征。對(duì)于術(shù)前患者，ctDNA檢測(cè)可預(yù)估局限性癌或可能出現(xiàn)血行轉(zhuǎn)移的潛在風(fēng)險(xiǎn)。對(duì)于接受化療或靶向治療的患者，ctDNA的檢測(cè)可以幫助了解患者的基因突變情況，對(duì)化療及靶向治療具有重要的指導(dǎo)意義［49-51］。

六、新輔助治療后的再評(píng)估

對(duì)于局部進(jìn)展期直腸癌患者，接受新輔助放化療的主要目的在于減小腫瘤體積，降低分期，提高保肛率、減少術(shù)后復(fù)發(fā)。接受新輔助治療后再分期對(duì)于選擇手術(shù)方式及個(gè)體化治療模式至關(guān)重要。再分期評(píng)價(jià)所采用的影像學(xué)檢查手段通常與初始評(píng)估的檢查方法相一致。近年來隨著MRI技術(shù)的發(fā)展，一些功能成像技術(shù)，例如DWI-MRI，可用于對(duì)新輔助治療后直腸癌的分期的重新評(píng)價(jià)［52-53］。

對(duì)于新輔助治療的患者，腫瘤退縮評(píng)分（tumor regression score，TRG）是療效評(píng)估的重點(diǎn)。TRG主要是依據(jù)腫瘤對(duì)新輔助治療后的病理學(xué)反應(yīng)進(jìn)行分級(jí)。一項(xiàng)薈萃分析結(jié)果顯示，獲得pCR的患者其五年無病生存率為83.3%，并且證明pCR是預(yù)后較好的獨(dú)立預(yù)測(cè)因素［54］。Habr-Gama等［55］對(duì)71例達(dá)到臨床完全緩解的患者未進(jìn)行手術(shù)治療，而采用等待——觀望的策略（wait and see）。結(jié)果顯示其5年總體生存率為100%，無病生存率達(dá)到82%。這為部分達(dá)到臨床完全緩解的病例提供了新的治療思路，其優(yōu)點(diǎn)是免去了手術(shù)治療的風(fēng)險(xiǎn)，尤其是對(duì)于無法保肛的患者獲益最大。因此，對(duì)于術(shù)前判斷患者是否達(dá)到pCR十分重要，目前文獻(xiàn)報(bào)道PET/CT有助于預(yù)測(cè)直腸癌對(duì)于新輔助治療的病理反應(yīng)和緩解程度，但仍有待于更深入的研究和驗(yàn)證［56-58］。

七、低位直腸癌術(shù)前是否保肛的評(píng)估

我國直腸癌患者中約有70%為中低位直腸癌［59］，對(duì)于這部分患者在根治手術(shù)的前提下，應(yīng)盡可能保留肛門，提高患者術(shù)后生活質(zhì)量。低位直腸癌能否保肛取決于腫瘤下緣距齒狀線的距離、浸潤深度、淋巴結(jié)轉(zhuǎn)移情況，腫瘤與肛門括約肌、肛提肌的關(guān)系、組織學(xué)分型等因素。既往提出的保肛手術(shù)適應(yīng)證為：（1）高、中分化腺癌，未浸透肌層。腫瘤環(huán)周＜1/2周，腸管周圍無腫大淋巴結(jié)，距齒狀線1 cm以上；（2） 高中分化腺癌，浸透肌層，環(huán)周＞1/2周，距齒狀線2～3 cm；（3）低分化或粘液腺癌，未浸透肌層，環(huán)周＜1/2周，距齒狀線3～5 cm［60］。利用MRI評(píng)估腫瘤浸潤情況，發(fā)現(xiàn)腫瘤侵及周圍臟器、括約肌或肛提肌時(shí)，保肛手術(shù)則難以實(shí)現(xiàn)。Nougaret等［61］利用MRI對(duì)腫瘤與括約肌及肛提肌關(guān)系進(jìn)行評(píng)價(jià)，提出了不同的分級(jí)標(biāo)準(zhǔn)，為手術(shù)決策提供了依據(jù)。亦有國內(nèi)學(xué)者利用CT模擬盆腔來預(yù)測(cè)直腸癌手術(shù)方式，取得了較為滿意的效果［62］。此外，CRM也是能否保肛的重要因素，應(yīng)當(dāng)確保CRM陰性的情況下行保肛手術(shù)。遠(yuǎn)端切緣距離也是評(píng)估能否保肛的重要依據(jù)之一。目前公認(rèn)的遠(yuǎn)端切緣距離為2 cm［4］，可達(dá)到根治的效果獲得長期生存，并可以保留較為滿意的括約肌功能。新近一項(xiàng)薈萃分析顯示遠(yuǎn)端切緣＞1 cm同≤1 cm在局部復(fù)發(fā)率上無差別［63］。說明傳統(tǒng)的2 cm安全距離正逐漸接受挑戰(zhàn)，而新提出的更加“冒險(xiǎn)”的切緣距離是否真正具有臨床意義尚需要大規(guī)模的臨床試驗(yàn)加以驗(yàn)證。

術(shù)前除判斷影響根治性切除的因素外，對(duì)于直腸肛管功能的評(píng)價(jià)亦是十分重要的。新輔助放化療可使腫瘤縮小，提高患者的保肛率，但有文獻(xiàn)表明這會(huì)對(duì)患者術(shù)后排便功能造成一定的影響［64-65］。因此，術(shù)前應(yīng)在審慎對(duì)患者的括約肌功能評(píng)價(jià)的基礎(chǔ)上，決定是否實(shí)施保肛手術(shù)。

綜上，直腸癌的術(shù)前精準(zhǔn)評(píng)估，對(duì)于直腸癌患者個(gè)體化治療模式和流程的選擇極為重要。目前淋巴結(jié)狀態(tài)是直腸癌術(shù)前評(píng)估中的重點(diǎn)及難點(diǎn)，無論是直接手術(shù)或接受新輔助治療，影像學(xué)對(duì)其預(yù)測(cè)能力均不夠理想。期待放射組學(xué)或分子影像學(xué)進(jìn)一步深入的研究。盡管等待——觀望的治療策略目前的結(jié)果較為樂觀，但是其真正應(yīng)用于臨床實(shí)踐，仍然需要大樣本的臨床研究對(duì)其進(jìn)行驗(yàn)證。保肛手術(shù)應(yīng)堅(jiān)持在根治性切除的前提下，注重患者括約肌功能的保留，這樣才會(huì)給保肛患者帶來真正的獲益。

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Emphasize on rectal cancer preoperative precise assessment

Xu Huimian, Wang Pengliang.
Department of Surgical Oncology, the First Affliated Hospital of China Medical University, Shenyang 110001, China

Xu Huimian, Email: xuhuimian@126.com

In recent years, as some new technology applied in the clinical practice of rectal cancer,such as neoadjuvant therapy, multidisciplinary team (MDT) and so on, the infuence of accurate preoperative assessment for patients is not only associated with operation selection and prognosis assessment, but also related with reasonable choice of personalized comprehensive treatment plan and process. Furthermore, it also can provide survival beneft and improve the quality of life for patients. Therefore, the precision preoperative assessment is critical for patients with rectal cancer. The purpose of this study is to given an overview to precision preoperative assessment of rectal cancer and provide reference for clinical oncologists.

Rectal neoplasms; Preoperative assessment; Neoadjuvant treatment; Precision medicine

2017-06-20）

（本文編輯：劉正）

10.3877/cma.j.issn.2095-3224.2017.05.001

國家自然科學(xué)基金項(xiàng)目（No.81372550）

110001 沈陽，中國醫(yī)科大學(xué)附屬第一醫(yī)院腫瘤外科

徐惠綿，Email：xuhuimian@126.com

徐惠綿, 王鵬亮.重視直腸癌的術(shù)前精準(zhǔn)評(píng)估[J/CD].中華結(jié)直腸疾病電子雜志, 2017, 6(5): 354-359.