胡飛翔，胡婷丹，童 彤，彭衛(wèi)軍

復(fù)旦大學(xué)附屬腫瘤醫(yī)院放射診斷科，復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系，上海 200032

基于CT圖像紋理分析評價(jià)結(jié)直腸癌肝轉(zhuǎn)移新輔助治療后療效的價(jià)值

胡飛翔，胡婷丹，童 彤，彭衛(wèi)軍

復(fù)旦大學(xué)附屬腫瘤醫(yī)院放射診斷科，復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系，上海 200032

彭衛(wèi)軍，教授，復(fù)旦大學(xué)博士研究生導(dǎo)師，現(xiàn)任復(fù)旦大學(xué)附屬腫瘤醫(yī)院放射診斷科主任，中國抗癌協(xié)會腫瘤影像專業(yè)委員會候任主任委員，上海醫(yī)學(xué)會放射診斷專科委員會副主任委員，上海市抗癌協(xié)會腫瘤影像專業(yè)委員會主任委員，中華醫(yī)學(xué)會放射學(xué)分會乳腺學(xué)組副組長。

目的：探討治療前基線CT門靜脈期圖像的直方圖分析預(yù)測結(jié)直腸癌肝轉(zhuǎn)移(colorectal liver metastasis，CRLM) 新輔助治療后療效的價(jià)值。方法：選取34例CRLM患者，共計(jì)132枚病灶，經(jīng)FOLFOX(氟尿嘧啶+亞葉酸鈣+奧沙利鉑)、FOLFIRI (氟尿嘧啶+亞葉酸鈣+伊立替康)或CapeOX(奧沙利鉑+卡培他濱或卡培他濱單用)方案化療。所有患者均接受至少兩次常規(guī)腹部平掃加增強(qiáng)三期CT掃描，于化療前4周內(nèi)行CT基線掃描，化療開始后2～3個(gè)月內(nèi)行第2次掃描以評估療效。對患者門靜脈期CT圖像進(jìn)行直方圖分析，依據(jù)實(shí)體腫瘤療效評價(jià)標(biāo)準(zhǔn)(Response Evaluation Criteria in Solid Tumors，RECIST)(Version 1.1)進(jìn)行療效評估，獲得相應(yīng)轉(zhuǎn)移瘤的紋理參數(shù)，比較緩解與非緩解組患者治療前基線CT直方圖參數(shù)的差異。采用受試者工作特征(receiver operating characteristic，ROC)曲線分析法計(jì)算各參數(shù)預(yù)測緩解的曲線下面積(area under curve，AUC)、靈敏度、特異度、陽性預(yù)計(jì)值、陰性預(yù)計(jì)值、準(zhǔn)確率及截?cái)嘀?。由兩名放射科醫(yī)師達(dá)成一致意見后勾畫感興趣區(qū)。結(jié)果：34例患者中，緩解組21例，非緩解組13例。緩解組的均值、方差、偏度和百分位數(shù)(10%、50%、90%、99%)低于非緩解組，差異有統(tǒng)計(jì)學(xué)意義(P＜0.05)；但峰度值和1%百分位數(shù)無顯著差異(P=0.769、0.06)。90th百分位數(shù)在截?cái)嘀禐?67時(shí)具有較高的準(zhǔn)確率(81.82%)，此時(shí)靈敏度、特異度、陽性預(yù)計(jì)值、陰性預(yù)計(jì)值及AUC分別為74.42%、95.65%、96.65%、66.97%和0.854。結(jié)論：CT門靜脈期直方圖分析對預(yù)測CRLM患者新輔助療效具有潛在價(jià)值。

紋理分析；直方圖；結(jié)直腸癌肝轉(zhuǎn)移

目前，結(jié)直腸癌(colorectal cancer，CRC)是男性第三高發(fā)、女性第二高發(fā)的腫瘤[1]，且15%～25%的患者在診斷為CRC時(shí)已發(fā)生肝轉(zhuǎn)移。然而，CRC原發(fā)病灶根治性切除手術(shù)后仍有15%～25%的患者發(fā)生肝轉(zhuǎn)移，其中約85%無法做到根治性切除[2-6]，因此CRC肝轉(zhuǎn)移(colorectal liver metastasis，CRLM)也成為CRC患者的最主要死亡原因(60%～71%)[7]。對于無法進(jìn)行根治性手術(shù)切除的CRC患者，往往采用姑息性化療。對于CRC確診后合并同期肝轉(zhuǎn)移患者，若原發(fā)病灶無出血、無梗阻癥狀或無穿孔，除外在技術(shù)上容易切除的肝轉(zhuǎn)移灶且不存在不良預(yù)后的患者，均建議采用新輔助治療[8-11]。全身化療方案包括：FOLFOX (氟尿嘧啶+亞葉酸鈣+奧沙利鉑)、FOLFIRI (氟尿嘧啶+亞葉酸鈣+伊立替康)、CapeOX (奧沙利鉑+卡培他濱或卡培他濱單用)或FOLFOXIRI (氟尿嘧啶+亞葉酸鈣+奧沙利鉑+伊立替康)[12-15]。但一線化療后，仍有約50%的CRC患者表現(xiàn)為無緩解甚至疾病進(jìn)展[16]。對于這部分患者，臨床醫(yī)師可嘗試使用貝伐單抗或西妥昔單抗等靶向治療藥物。為減少化療對肝臟手術(shù)的不利影響，新輔助化療原則上不超過6個(gè)周期[17]，一般建議2～3個(gè)月內(nèi)完成并進(jìn)行手術(shù)[18]。

CRLM新輔助化療后的療效預(yù)測對指導(dǎo)臨床制訂后續(xù)治療方案至關(guān)重要。CT可在形態(tài)學(xué)上對CRLM進(jìn)行療效評價(jià)[19]。圖像紋理分析是近年來新出現(xiàn)的圖像后處理技術(shù)，通過量化分析影像圖像像素灰度值的局部特征、變化規(guī)律及分布模式等紋理特征來反映感興趣區(qū)(region of interest， ROI)內(nèi)生物組織結(jié)構(gòu)的不均質(zhì)性[20-21]。在過去有關(guān)肝臟輔助診斷的紋理分析研究中，多采用平掃圖像[22]。近期CT增強(qiáng)圖像紋理分析的應(yīng)用逐漸廣泛，增強(qiáng)掃描可提供病灶的血供情況及病灶內(nèi)部血流變化特征[23]。影像圖像紋理分析可提供更多肉眼無法觀察到的圖像信息[24]?；叶戎狈綀D分析是紋理分析中的一部分，可幫助量化腫瘤內(nèi)部的異質(zhì)性，在腫瘤診斷及療效評價(jià)中較常規(guī)形態(tài)學(xué)評估具有更多優(yōu)勢[25-27]。

目前，關(guān)于CT增強(qiáng)掃描圖像的灰度直方圖分析預(yù)測CRLM新輔助化療后療效的研究鮮有報(bào)道。本研究采用門靜脈期CT增強(qiáng)圖像的灰度直方圖分析來判斷CRLM患者的近期療效，以期為臨床評估新輔助治療后療效并制訂后續(xù)治療方案提供有效輔助手段。

1 資料和方法

1.1 患者資料

收集復(fù)旦大學(xué)附屬腫瘤醫(yī)院2011年6月—2016年8月期間初診為CRLM的患者共34例，其中＞1 cm的可測量病灶132枚。所有患者均接受CT平掃加三期增強(qiáng)檢查，并于基線檢查結(jié)束后進(jìn)行全身化療。其中男性20例、女性14例；平均年齡(58.85±9.96)歲?；颊叩娜脒x標(biāo)準(zhǔn)為：① 基線CT檢查時(shí)間在新輔助治療開始前4周內(nèi)完成；② 患者在基線檢查前未接受任何CRC及肝臟病灶相關(guān)治療，包括手術(shù)、化療及放療等；③無結(jié)直腸外其他腫瘤相關(guān)病史；④ 第2次評估在新輔助治療后2～3個(gè)月內(nèi)完成。

1.2 檢查方法

CT檢查采用SIEMENS公司Somatom Sensation型螺旋CT掃描儀，層厚8 mm，層距8 mm?；颊邫z查前常規(guī)禁食8～12 h，取平臥位，平掃后行增強(qiáng)掃描。使用碘海醇(300 gI/L)作為造影劑，按1.5 mL/kg體重計(jì)算給藥量。用高壓注射器經(jīng)肘靜脈注射給藥，注射速率為2.5 mL/s。于造影劑注射后30 s、60 s及2～15 min分別行屏氣動脈期、門靜脈期及延遲掃描，掃描范圍包括所有病變區(qū)域。

1.3 圖像分析與評價(jià)標(biāo)準(zhǔn)

采用MaZda軟件(Version 4.6，Instytut Elektroniki)進(jìn)行紋理分析[28]。圖像通過影像歸檔和通信系統(tǒng)(Picture Archiving and Communication Systems，PACS)下載并導(dǎo)入軟件中進(jìn)行分析。對所有患者門靜脈期CT圖像進(jìn)行ROI勾畫，由兩名放射科醫(yī)師達(dá)成一致意見后選取(兩名醫(yī)師分別具有3年和13年以上工作經(jīng)驗(yàn))，均不知道患者預(yù)后情況。ROI選擇于門靜脈期肝轉(zhuǎn)移瘤的最大層面進(jìn)行，以＞1 cm病灶為目標(biāo)，沿病灶邊緣輪廓勾畫ROI，勾畫過程中盡可能避開大血管(包括門靜脈及肝靜脈等)，生成ROI內(nèi)的各個(gè)灰度直方圖參數(shù)值：均值(mean)，方差(variance)，偏度(skewness)，峰度(kurtosis)及第1、20、50、90、99百分位數(shù)(1st、10th，50th，90th，99th percentile)。采用實(shí)體腫瘤療效評價(jià)標(biāo)準(zhǔn)(Response Evaluation Criteria in Solid Tumors，RECIST)(Version 1.1)進(jìn)行療效評估[29]，將完全緩解(complete response，CR)與部分緩解(partial response，PR)患者劃歸于緩解組，將疾病發(fā)展(progressive disease，PD)與疾病穩(wěn)定(stable disease，SD)患者劃歸于非緩解組。然后對各紋理參數(shù)與療效情況進(jìn)行統(tǒng)計(jì)學(xué)分析。

1.4 統(tǒng)計(jì)學(xué)處理

使用SPSS 21.0和MedCalc 12.7.2進(jìn)行統(tǒng)計(jì)學(xué)分析?；颊咭话闾卣鬟B續(xù)性變量符合正態(tài)分布者采用t檢驗(yàn)，用表示；不符合正態(tài)分布者采用Mann-Whitney U檢驗(yàn)，用中位值表示。對具有統(tǒng)計(jì)學(xué)意義的直方圖參數(shù)，進(jìn)行受試者工作特征(receiver operating characteristic，ROC)曲線分析并計(jì)算相應(yīng)的曲線下面積(area under curve， AUC)。截?cái)嘀挡捎米畲蠹s登指數(shù)計(jì)算：約登指數(shù)=靈敏度-(1-特異度)。

2 結(jié) 果

2.1 患者一般特征

根據(jù)RECIST標(biāo)準(zhǔn)，經(jīng)新輔助治療后2～3個(gè)月，將患者分為治療后緩解組(A組，21例)和非緩解組(B組，13例)?；颊呓邮苋砘煼桨赴ǎ篎OLFOX(10例)、FOLFIRI(14例)、CapeOX (10例)。詳見表1。

2.2 灰度直方圖各參數(shù)的診斷效能

結(jié)果顯示，CRLM患者經(jīng)新輔助治療后2～3個(gè)月的療效評估可通過基線CT門靜脈期圖像灰度直方圖分析中的均值、方差、偏度及百分位數(shù)(10%、50%、90%、99%)進(jìn)行有效預(yù)測。緩解組(圖1)中上述紋理參數(shù)顯著低于非緩解組(圖2) (P＜0.05)，但峰度值和1%百分位數(shù)在兩組之間無顯著差異(P=0.769、0.06)(表2)。采用ROC曲線分析CT門靜脈期直方圖各參數(shù)評價(jià)緩解組的診斷效能(圖3)。當(dāng)90th百分位數(shù)≤167時(shí)，可獲得較高的準(zhǔn)確率(81.82%)，此時(shí)靈敏度、特異度、陽性預(yù)計(jì)值(positive predictive value，PPV)、陰性預(yù)計(jì)值(negative predictive value，NPV)及AUC分別為74.42%、95.65%、96.97%、66.67%和0.854 (表3)。

3 討 論

目前，肝轉(zhuǎn)移患者主要采用一線化療方案，但隨訪中發(fā)現(xiàn)約85%患者出現(xiàn)疾病進(jìn)展[30]，且只有不到50%的患者對一線化療敏感[31]。對于一線化療方案療效不理想者，可使用其他治療方案，包括加用分子靶向治療或聯(lián)用肝動脈灌注化療[32]。能否盡早預(yù)測新輔助化療療效對臨床制訂后續(xù)方案至關(guān)重要，已有研究評估了紋理分析評價(jià)療效的潛力。Ganeshan等[33]和Miles等[34]在研究CRC患者肝臟紋理情況時(shí)發(fā)現(xiàn)，肝臟的粗糙紋理與隱匿性惡性腫瘤和不良預(yù)后有關(guān)。本研究發(fā)現(xiàn)，低的均值、方差、偏度和百分位數(shù)(10%、50%、90%、99%)鑒別緩解與非緩解組具有統(tǒng)計(jì)學(xué)意義(P＜0.05)，而峰度值和1%百分位數(shù)鑒別緩解與非緩解組無顯著差異(P=0.769、0.06)。

圖1 新輔助化療后緩解組灰度直方圖及各參數(shù)

圖2 新輔助化療后非緩解組灰度直方圖及各參數(shù)

表1 患者一般特征

表2 緩解組(A組)與非緩解組(B組)之間門靜脈期CT圖像直方圖分析的比較

圖3 門靜脈期基線CT圖像直方圖各參數(shù)的ROC曲線

表3 紋理參數(shù)判斷緩解組與非緩解組的診斷效能

偏度的絕對值越大表示其分布形態(tài)的偏斜程度越大，方差表示平均值的變化情況，偏度和方差值的大小與同質(zhì)均勻性成反比[35]。因此，高的偏度值和方差表示腫瘤具有較高的異質(zhì)性。腫瘤的異質(zhì)性是惡性腫瘤的公認(rèn)特征，反映區(qū)域內(nèi)高細(xì)胞密度、壞死、出血及黏液樣變[36]。腫瘤異質(zhì)性是預(yù)后的重要因素，腫瘤異質(zhì)性越高可能與腫瘤級別越高相關(guān)[37]。本研究結(jié)果與某些研究[34,38-39]相似，他們發(fā)現(xiàn)高偏度值和標(biāo)準(zhǔn)偏差代表腫瘤的異質(zhì)性明顯，預(yù)示患者預(yù)后較差，與本研究中治療后非緩解組的偏度值和方差高相符。本研究顯示，90th百分位數(shù)具有較高的診斷準(zhǔn)確率(81.82%)，AUC值為0.854。90th百分位數(shù)是一個(gè)量度，表示包含了90% CT值的觀測數(shù)據(jù)，并剔除了直方圖中10%的最大值，這些最大值可能代表ROI勾畫過程中無法去除的腫瘤部分供血分支血管。因此，去除這部分10%的最大值，能更準(zhǔn)確地反映腫瘤本身的真實(shí)強(qiáng)化特征。

目前，對于CT圖像紋理分析掃描期相的選擇并無固定標(biāo)準(zhǔn)。Goh等[40]采用動脈期圖像評估腎細(xì)胞癌患者酪氨酸激酶治療后腫瘤紋理的變化。另一些研究使用平掃來評估肝臟腫瘤[41]、肺癌[38]或食管癌[42]。然而，大多數(shù)研究[20]采用門靜脈期圖像的紋理來分析CRLM患者。本研究對門靜脈期圖像進(jìn)行紋理分析，這是因?yàn)镃RC患者監(jiān)視隨訪期間，CT掃描常規(guī)需行門靜脈期檢查；且以往研究指出，CT門靜脈期觀察到的肝臟紋理與生物學(xué)性質(zhì)相關(guān)，如總肝血流量和葡萄糖代謝，可作為CRC患者有價(jià)值的生物標(biāo)記[33]。

本研究存在以下不足之處：首先，是一項(xiàng)回顧性研究，存在選擇偏倚。其次，樣本量較小且為單中心研究，需大樣本、多中心及前瞻性研究來驗(yàn)證。第三，剔除了其他病理類型的CRC(如印戒細(xì)胞癌、黏液腺癌)，最終選擇的患者均為結(jié)直腸腺癌，缺少其他病理類型的轉(zhuǎn)移。但其他病理類型例數(shù)非常少，因此對研究結(jié)果的影響甚微。第四，采用最大層面的方法勾畫ROI，沒有對整個(gè)病灶進(jìn)行分析，可能會對結(jié)果造成一定的影響。但閱讀相關(guān)文獻(xiàn)，發(fā)現(xiàn)2D與3D紋理分析在CRLM患者治療前預(yù)測療效結(jié)果相似[43]。最后，由于統(tǒng)計(jì)數(shù)據(jù)量大及圖像后處理的限制，沒有進(jìn)行其他期圖像的研究，沒有對紋理特征的其他參數(shù)(如灰度共生矩陣、游程矩陣、梯度模型、自回歸模型和基于傅里葉變換的紋理特征)進(jìn)行分析，希望以后能對此進(jìn)行深入研究。

4 結(jié) 語

CRLM患者基線CT門靜脈期灰度直方圖分析可幫助預(yù)測新輔助治療后是否緩解，具有一定的臨床應(yīng)用價(jià)值。

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Value of CT texture analysis in evaluating response to neoadjuvant chemotherapy for colorectal liver metastases

HU Feixiang, HU Tingdan, TONG Tong, PENG Weijun
(Department of Diagnostic Radiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China)

PENG Weijun E-mail: cjr.pengweijun@vip.163.com

Objective:To explore the value of histogram analysis of baseline CT portal images before treatment in predicting the response of patients with colorectal liver metastases (CRLMs) to neoadjuvant chemotherapy.Methods:Thirty-four patients (a total of 132 lesions) diagnosed with CRLM were retrospectively enrolled and underwent contrast-enhanced CT before and after neoadjuvant chemotherapy (FOLFOX, FOLFIRI or CapeOX ). All patients underwent pre-treatment CT baseline scan withinfour weeks for primary tumor assessment and a second CT scan in 2 to 3 months, for response evaluation. Histogram of CT portal images of patients with CRLM was analyzed and response was mainly assessed using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. The texture parameters of the metastatic tumor were analyzed statistically to fi nd the dif f erences in baseline CT histogram parameters between responding group and non-responding group before and after treatment. The receiver operating characteristic (ROC) curves were depicted to characterize each parameter value in evaluating the treatment outcomes. The optimal cutof f value (obtained according to the maximal Youden index = sensitivity + specif i city-1), the corresponding sensitivity, specif i city, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated. Regions of interests (ROIs) were manually drawn on the largest cross-sectional area of the primary lesions by two radiologists in consensus.Results:Twenty-one responding and 13 non-responding patients were evaluated. The values of mean, variance, skewness and percentile (10th, 50th, 90th, 99th) in responding group were much lower than those in non-responding group (P＜0.05). The kurtosis and 1st percentile values between the two groups had no significant difference (P=0.769, P=0.06, respectively). The optimal cutoff value for the accurate identif i cation of responding patients was 167 for 90th percentile (74.42% sensitivity, 95.65% specif i city, 96.97% PPV, 66.67% NPV, 81.82% accuracy, and 0.854 area under curve, respectively).Conclusion:CT histogram analysis of baseline CT portal images before treatment can help to predict the response of patients with CRLM after neoadjuvant chemotherapy.

Texture analysis; Histogram; Colorectal liver metastasis

R445.3

A

1008-617X(2017)02-0106-08

2017-04-01）

國家自然科學(xué)基金項(xiàng)目(No：81501437)

彭衛(wèi)軍 E-mail：cjr.pengweijun@vip.163.com