胃癌原發灶體積改變在胃癌術前化療療效評價中的應用價值

劉 坤, 李國立, 范朝剛, 湯黎明, 許 建

(1. 南京醫科大學附屬常州第二人民醫院 普外科, 江蘇 常州, 213003;南京軍區南京總醫院, 2. 普通外科研究所; 3. 醫學影像科, 江蘇 南京, 210002)

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胃癌原發灶體積改變在胃癌術前化療療效評價中的應用價值

劉 坤1, 李國立2, 范朝剛2, 湯黎明1, 許 建3

(1. 南京醫科大學附屬常州第二人民醫院 普外科, 江蘇 常州, 213003;南京軍區南京總醫院, 2. 普通外科研究所; 3. 醫學影像科, 江蘇 南京, 210002)

目的 觀察胃癌原發灶體積改變在胃癌術前化療療效評價中的應用價值。方法 回顧性分析150例接受術前化療和D2胃癌根治術的患者的臨床資料。參照Becker評分行病理學化療反應評價。采用Kaplan-Meier法繪制生存曲線。觀察化療前后胃癌原發灶體積減小百分率與Becker評分及患者生存的關系。結果 化療后胃癌原發灶體積較化療前顯著減小(P<0.001)?；熀笤l灶體積減少百分率與Becker評分密切相關(R=0.5672,P=0.002)。ROC曲線分析提示，化療前后原發灶體積減少百分率對鑒別化療有效與無效的患者有重要價值，曲線下面積(AUC)為0.845, 評價化療有效的界值點被設定為體積減少達到55%。結論 胃癌原發灶體積減少程度可以應用于評價胃癌化療療效。

胃癌; 術前化療; 體積測量; RECIST標準

胃癌居全球惡性腫瘤發病率的第4位和死亡率的第2位，每年新增病例近100萬[1]。由于缺乏早期典型癥狀，大多數胃癌患者在確診時已處于進展期[2]。與傳統的術后化療相比，術前新輔助化療具有諸多優勢[3]。實體瘤評效標準(RECIST)是目前最為常用的影像學療效評價標準[4]。根據化療前后靶病灶直徑的改變，RECIST標準將化療療效分為完全緩解(CR)、部分緩解(PR)、疾病穩定(SD)和疾病進展(PD)4個等級。本研究通過回顧性分析胃癌患者的影像學資料、病理學資料及生存隨訪數據，觀察胃癌原發灶體積改變在新輔助化療療效評價中的應用價值，現報告如下。

1 資料與方法

1.1 一般資料

回顧性分析2006年6月—2012年12月150例接受術前化療和胃癌根治術患者的基本資料。入選標準: ① 經組織學檢查證實的胃癌患者; ② 年齡30～70歲; ③ 明確診斷時腫瘤臨床分期為T2～4N≥1M0; ④ ECOG體力狀態評分為0或1; ⑤ 所有患者需完成2～3個療程的術前化療，并在化療結束后3周內接受D2胃癌根治術; ⑥ 患者無嚴重的心、肝、腎功能障礙，無其他臟器惡性腫瘤; ⑦ 有完整的臨床資料，包括化療開始前CT、手術前CT、手術切除標本的病理學資料及隨訪資料。

1.2 影像學評價

所有患者均在第一次化療前及接受手術治療前行CT檢查。檢查前夜禁食、禁水，檢查前0.5 h肌注東莨菪堿10 mg以減少胃腸蠕動，檢查前5 min快速飲水1 000 mL使胃膨脹。常規仰臥位平掃+增強(西門子64排螺旋CT)，以西門子公司Volume軟件測量化療前后胃癌原發灶的體積，并計算體積變化百分率。

1.3 病理學評價

對術前化療的病理學療效評價參照Becker等在2003年提出的Becker評分進行[13]。根據化療后殘余腫瘤占整個腫瘤原發灶的比例，Becker評分1級(<10%腫瘤殘余)和2級(10～50%腫瘤殘余)視為化療有效，3級(>50%腫瘤殘余)判定為化療無效。

1.4 統計學分析

采用SPSS 17.0軟件進行統計分析，化療前后原發灶體積變化采用Wilcoxon(配對樣本)秩和檢驗。不同組別之間體積變化百分率的差異比較采用Mann-Whitney U檢驗。體積變化百分率與Becker評分之間的相關性采用Spearman相關性檢驗。應用ROC曲線分析的方法評價體積變化百分率在化療有效性鑒別中的價值。Kaplan-Meier法繪制生存曲線，生存率的差異以Log-rank法檢驗。P<0.05為差異有統計學意義

2 結 果

2.1 化療前后原發灶體積變化

2006年6月—2012年12月共150例符合條件的患者納入該研究?；熐昂笪赴┰l灶的體積分別為(74.2±59.6) cm3及(41.5±23.1) cm3, 化療后原發灶體積較化療前減小，差異有統計學意義(P<0.01)。

2.2 病理學化療療效評價結果

150例手術切除標本的Becker評分結果如下: 1級36例，2級74例，3級40例，共計化療有效110例，無效40例。對化療有效組患者而言，化療前后原發灶體積減少百分率為(61.8±24.6)%，顯著高于化療無效組患者(29.4±21.7)%(P<0.01)。Spearman相關性分析提示，化療前后原發灶體積減少百分率與Becker評分密切相關(R=0.5672,P=0.002)。ROC曲線分析提示，化療前后原發灶體積減少百分率對于鑒別化療有效與無效的患者有重要價值，曲線面積(AUC)為0.845 (95% CI: 0.778～0.913)。見圖1。當界值點設定為體積減少55%時，約登指數可獲得最大值，此時對應的敏感度為82.7%，特異性為67.5%。

2.3 生存分析

根據ROC曲線分析結果，作者將化療后原發灶體積減小55%作為化療有效的影像學標準。由此, 104位患者評判為化療有效, 46位患者評判為化療無效?；熡行У幕颊叩目傮w生存顯著優于化療無效的患者(P=0.0138)。見圖2。

圖1 ROC曲線分析評價胃癌原發灶體積變化百分率在化療有效性的價值

圖2 化療有效組與化療無效組患者術后生存率比較

3 討 論

RECIST標準在評價胃腸道腫瘤化療療效時有著明顯缺陷。首先，腫瘤并非標準的球體，因此某一方向直徑的變化不能準確反映化療前后腫瘤大小的改變[5]。其次，對胃腸道等空腔臟器而言，CT上其厚度及最大徑隨著胃腸充盈程度不同而改變，因此RECIST標準建議將胃腸道腫瘤原發灶納入為“不可測量的病灶”，僅將轉移灶(包括轉移淋巴結和遠處轉移病灶)化療前后的直徑改變作為評價化療療效的依據[6-8]。由此，難以對無轉移灶的T3～4N0M0患者進行準確的療效評價。第三，臨床上淋巴結反應性增生并非罕見，對于無遠處轉移灶的局部進展期胃癌患者而言，僅考慮淋巴結直徑的變化而忽略化療對腫瘤原發灶的影響，往往難以準確衡量化療療效。因此，對RECIST標準進行改進，建立更適合胃癌患者的影像學化療評價標準有著重要意義[9-13]。

理想的影像學評價標準應同時具備準確、穩定和及時快速等要素。Beer等[14-15]揭示，化療后2周左右病灶體積即可有明顯變化，而直徑變化一般需要7～8周。以體積變化來衡量化療療效已被應用于直腸癌[16]、肺轉移灶[10]、肝轉移灶[17]、膀胱癌[18]、及頭頸部腫瘤[19]，并獲得良好的臨床評價。

本研究觀察了局部進展期胃癌患者新輔助化療后原發灶的體積變化。作者發現: ① 化療后胃癌原發灶體積較化療前明顯減小; ② 原發灶體積減少百分率對于鑒別化療有效與無效的患者有重要價值; ③ 化療后原發灶體積減少百分率與患者預后有關。上述結果提示，原發灶體積減少程度可以應用于評價胃癌化療療效。

與RECISDT標準相比，以原發灶體積變化來評價化療療效有以下優勢: ① 擴大了應用范圍。對于T3～4N0M0的患者，雖然沒有可測量的淋巴結和轉移灶，作者可以通過胃癌原發灶的體積改變來評價新輔助化療的效果。② 提高了準確度。首先，將原發灶納入測量范圍，而不是僅僅測量靶淋巴結和轉移灶，有助于提高療效評價的準確度；其次，腫瘤不是標準的球體，因此體積測量較RECIST標準的直徑測量更準確反映腫瘤大小的變化。③ 與直徑測量相比，體積測量有更好的穩定性(測量結果的可重復性)。④ 與直徑測量相比，體積測量能更早地檢測出腫瘤對化療的反應。

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Value of primary tumor volumetry in predicting tumor response to preoperative chemotherapy in patients with gastric cancer

LIU Kun1, LI Guoli2, FAN Chaogang2, TANG Liming1, XU Jian3

(1.DepartmentofGeneralSurgery,ChangzhouSecondPeople′sHospitalAffiliatedtoNanjingMedicalUniversity,Changzhou,Jiangsu, 213003; 2.InstituateofGeneralSurgery; 3.DepartmentofMedicalImaging,NanjingGeneralHospitalofNanjingMilitaryCommand,Nanjing,Jiangsu, 210002)

Objective To observe the value of primary tumor volumetry in predicting tumor response to preoperative chemotherapy in gastric cancer patients. Methods A total of 150 gastric cancer patients who received preoperative chemotherapy and D2 radical resection were analyzed retrospectively. Pathologic tumor response was evaluated according to Becker score. The percentage change in primary tumor volume between pre-and post-chemotherapy was calculated, and correlation between pathologic tumor regression and survival quality was analyzed. Ability of primary tumor volumetry to distinguish pathologic responders and non-responders was evaluated by receiver operating characteristic (ROC) curve analysis. Results The volume of primary gastric lesion significantly decreased after neo-adjuvant chemotherapy (P<0.001). Percentage reduction rate of primary tumor volume in the pathologic responder group was significantly larger than the non-responder group. There was a significant association between primary tumor volume reduction rate and pathologic tumor regression grade (Becker score). ROC curve analysis showed that volume change of primary gastric lesion was a potential parameter to differentiate pathologic responders from non-responders (AUC=0.845), and the optimal cutoff level was determined to be a reduction of ≥ 55%. Furthermore, responders based on the volumetric criteria had a better overall survival than non-responders. Conclusion Primary tumor volumetry could be used to assess tumor response to preoperative chemotherapy in gastric cancer patients.

gastric cancer; preoperative chemotherapy; volumetric measurement; RECIST criteria

2016-09-27

江蘇省常州市應用基礎研究計劃(CJ20130024); 解放軍南京軍區面上課題(12ma087)

R 735.2

A

1672-2353(2016)24-060-03

10.7619/jcmp.201624017