胃癌原發(fā)灶體積改變?cè)谖赴┬g(shù)前化療療效評(píng)價(jià)中的應(yīng)用價(jià)值

劉 坤, 李國立, 范朝剛, 湯黎明, 許 建

(1. 南京醫(yī)科大學(xué)附屬常州第二人民醫(yī)院 普外科, 江蘇 常州, 213003;南京軍區(qū)南京總醫(yī)院, 2. 普通外科研究所; 3. 醫(yī)學(xué)影像科, 江蘇 南京, 210002)

?

胃癌原發(fā)灶體積改變?cè)谖赴┬g(shù)前化療療效評(píng)價(jià)中的應(yīng)用價(jià)值

劉 坤1, 李國立2, 范朝剛2, 湯黎明1, 許 建3

(1. 南京醫(yī)科大學(xué)附屬常州第二人民醫(yī)院 普外科, 江蘇 常州, 213003;南京軍區(qū)南京總醫(yī)院, 2. 普通外科研究所; 3. 醫(yī)學(xué)影像科, 江蘇 南京, 210002)

目的 觀察胃癌原發(fā)灶體積改變?cè)谖赴┬g(shù)前化療療效評(píng)價(jià)中的應(yīng)用價(jià)值。方法 回顧性分析150例接受術(shù)前化療和D2胃癌根治術(shù)的患者的臨床資料。參照Becker評(píng)分行病理學(xué)化療反應(yīng)評(píng)價(jià)。采用Kaplan-Meier法繪制生存曲線。觀察化療前后胃癌原發(fā)灶體積減小百分率與Becker評(píng)分及患者生存的關(guān)系。結(jié)果 化療后胃癌原發(fā)灶體積較化療前顯著減小(P<0.001)?；熀笤l(fā)灶體積減少百分率與Becker評(píng)分密切相關(guān)(R=0.5672,P=0.002)。ROC曲線分析提示，化療前后原發(fā)灶體積減少百分率對(duì)鑒別化療有效與無效的患者有重要價(jià)值，曲線下面積(AUC)為0.845, 評(píng)價(jià)化療有效的界值點(diǎn)被設(shè)定為體積減少達(dá)到55%。結(jié)論 胃癌原發(fā)灶體積減少程度可以應(yīng)用于評(píng)價(jià)胃癌化療療效。

胃癌; 術(shù)前化療; 體積測(cè)量; RECIST標(biāo)準(zhǔn)

胃癌居全球惡性腫瘤發(fā)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(shù)胃癌患者在確診時(shí)已處于進(jìn)展期[2]。與傳統(tǒng)的術(shù)后化療相比，術(shù)前新輔助化療具有諸多優(yōu)勢(shì)[3]。實(shí)體瘤評(píng)效標(biāo)準(zhǔn)(RECIST)是目前最為常用的影像學(xué)療效評(píng)價(jià)標(biāo)準(zhǔn)[4]。根據(jù)化療前后靶病灶直徑的改變，RECIST標(biāo)準(zhǔn)將化療療效分為完全緩解(CR)、部分緩解(PR)、疾病穩(wěn)定(SD)和疾病進(jìn)展(PD)4個(gè)等級(jí)。本研究通過回顧性分析胃癌患者的影像學(xué)資料、病理學(xué)資料及生存隨訪數(shù)據(jù)，觀察胃癌原發(fā)灶體積改變?cè)谛螺o助化療療效評(píng)價(jià)中的應(yīng)用價(jià)值，現(xiàn)報(bào)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(shù)前化療和胃癌根治術(shù)患者的基本資料。入選標(biāo)準(zhǔn): ① 經(jīng)組織學(xué)檢查證實(shí)的胃癌患者; ② 年齡30～70歲; ③ 明確診斷時(shí)腫瘤臨床分期為T2～4N≥1M0; ④ ECOG體力狀態(tài)評(píng)分為0或1; ⑤ 所有患者需完成2～3個(gè)療程的術(shù)前化療，并在化療結(jié)束后3周內(nèi)接受D2胃癌根治術(shù); ⑥ 患者無嚴(yán)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(shù)前CT、手術(shù)切除標(biāo)本的病理學(xué)資料及隨訪資料。

1.2 影像學(xué)評(píng)價(jià)

所有患者均在第一次化療前及接受手術(shù)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(dòng)，檢查前5 min快速飲水1 000 mL使胃膨脹。常規(guī)仰臥位平掃+增強(qiáng)(西門子64排螺旋CT)，以西門子公司Volume軟件測(cè)量化療前后胃癌原發(fā)灶的體積，并計(jì)算體積變化百分率。

1.3 病理學(xué)評(píng)價(jià)

對(duì)術(shù)前化療的病理學(xué)療效評(píng)價(jià)參照Becker等在2003年提出的Becker評(píng)分進(jìn)行[13]。根據(jù)化療后殘余腫瘤占整個(gè)腫瘤原發(fā)灶的比例，Becker評(píng)分1級(jí)(<10%腫瘤殘余)和2級(jí)(10～50%腫瘤殘余)視為化療有效，3級(jí)(>50%腫瘤殘余)判定為化療無效。

1.4 統(tǒng)計(jì)學(xué)分析

采用SPSS 17.0軟件進(jìn)行統(tǒng)計(jì)分析，化療前后原發(fā)灶體積變化采用Wilcoxon(配對(duì)樣本)秩和檢驗(yàn)。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(yàn)。體積變化百分率與Becker評(píng)分之間的相關(guān)性采用Spearman相關(guān)性檢驗(yàn)。應(yīng)用ROC曲線分析的方法評(píng)價(jià)體積變化百分率在化療有效性鑒別中的價(jià)值。Kaplan-Meier法繪制生存曲線，生存率的差異以Log-rank法檢驗(yàn)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義

2 結(jié) 果

2.1 化療前后原發(fā)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(fā)灶的體積分別為(74.2±59.6) cm3及(41.5±23.1) cm3, 化療后原發(fā)灶體積較化療前減小，差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。

2.2 病理學(xué)化療療效評(píng)價(jià)結(jié)果

150例手術(shù)切除標(biāo)本的Becker評(píng)分結(jié)果如下: 1級(jí)36例，2級(jí)74例，3級(jí)40例，共計(jì)化療有效110例，無效40例。對(duì)化療有效組患者而言，化療前后原發(fā)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(guān)性分析提示，化療前后原發(fā)灶體積減少百分率與Becker評(píng)分密切相關(guān)(R=0.5672,P=0.002)。ROC曲線分析提示，化療前后原發(fā)灶體積減少百分率對(duì)于鑒別化療有效與無效的患者有重要價(jià)值，曲線面積(AUC)為0.845 (95% CI: 0.778～0.913)。見圖1。當(dāng)界值點(diǎn)設(shè)定為體積減少55%時(shí)，約登指數(shù)可獲得最大值，此時(shí)對(duì)應(yīng)的敏感度為82.7%，特異性為67.5%。

2.3 生存分析

根據(jù)ROC曲線分析結(jié)果，作者將化療后原發(fā)灶體積減小55%作為化療有效的影像學(xué)標(biāo)準(zhǔn)。由此, 104位患者評(píng)判為化療有效, 46位患者評(píng)判為化療無效?；熡行У幕颊叩目傮w生存顯著優(yōu)于化療無效的患者(P=0.0138)。見圖2。

圖1 ROC曲線分析評(píng)價(jià)胃癌原發(fā)灶體積變化百分率在化療有效性的價(jià)值

圖2 化療有效組與化療無效組患者術(shù)后生存率比較

3 討 論

RECIST標(biāo)準(zhǔn)在評(píng)價(jià)胃腸道腫瘤化療療效時(shí)有著明顯缺陷。首先，腫瘤并非標(biāo)準(zhǔn)的球體，因此某一方向直徑的變化不能準(zhǔn)確反映化療前后腫瘤大小的改變[5]。其次，對(duì)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(biāo)準(zhǔn)建議將胃腸道腫瘤原發(fā)灶納入為“不可測(cè)量的病灶”，僅將轉(zhuǎn)移灶(包括轉(zhuǎn)移淋巴結(jié)和遠(yuǎn)處轉(zhuǎn)移病灶)化療前后的直徑改變作為評(píng)價(jià)化療療效的依據(jù)[6-8]。由此，難以對(duì)無轉(zhuǎn)移灶的T3～4N0M0患者進(jìn)行準(zhǔn)確的療效評(píng)價(jià)。第三，臨床上淋巴結(jié)反應(yīng)性增生并非罕見，對(duì)于無遠(yuǎn)處轉(zhuǎn)移灶的局部進(jìn)展期胃癌患者而言，僅考慮淋巴結(jié)直徑的變化而忽略化療對(duì)腫瘤原發(fā)灶的影響，往往難以準(zhǔn)確衡量化療療效。因此，對(duì)RECIST標(biāo)準(zhǔn)進(jìn)行改進(jìn)，建立更適合胃癌患者的影像學(xué)化療評(píng)價(jià)標(biāo)準(zhǔn)有著重要意義[9-13]。

理想的影像學(xué)評(píng)價(jià)標(biāo)準(zhǔn)應(yīng)同時(shí)具備準(zhǔn)確、穩(wěn)定和及時(shí)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(yīng)用于直腸癌[16]、肺轉(zhuǎn)移灶[10]、肝轉(zhuǎn)移灶[17]、膀胱癌[18]、及頭頸部腫瘤[19]，并獲得良好的臨床評(píng)價(jià)。

本研究觀察了局部進(jìn)展期胃癌患者新輔助化療后原發(fā)灶的體積變化。作者發(fā)現(xiàn): ① 化療后胃癌原發(fā)灶體積較化療前明顯減小; ② 原發(fā)灶體積減少百分率對(duì)于鑒別化療有效與無效的患者有重要價(jià)值; ③ 化療后原發(fā)灶體積減少百分率與患者預(yù)后有關(guān)。上述結(jié)果提示，原發(fā)灶體積減少程度可以應(yīng)用于評(píng)價(jià)胃癌化療療效。

與RECISDT標(biāo)準(zhǔn)相比，以原發(fā)灶體積變化來評(píng)價(jià)化療療效有以下優(yōu)勢(shì): ① 擴(kuò)大了應(yīng)用范圍。對(duì)于T3～4N0M0的患者，雖然沒有可測(cè)量的淋巴結(jié)和轉(zhuǎn)移灶，作者可以通過胃癌原發(fā)灶的體積改變來評(píng)價(jià)新輔助化療的效果。② 提高了準(zhǔn)確度。首先，將原發(fā)灶納入測(cè)量范圍，而不是僅僅測(cè)量靶淋巴結(jié)和轉(zhuǎn)移灶，有助于提高療效評(píng)價(jià)的準(zhǔn)確度；其次，腫瘤不是標(biāo)準(zhǔn)的球體，因此體積測(cè)量較RECIST標(biāo)準(zhǔn)的直徑測(cè)量更準(zhǔn)確反映腫瘤大小的變化。③ 與直徑測(cè)量相比，體積測(cè)量有更好的穩(wěn)定性(測(cè)量結(jié)果的可重復(fù)性)。④ 與直徑測(cè)量相比，體積測(cè)量能更早地檢測(cè)出腫瘤對(duì)化療的反應(yīng)。

[1] Karimi P, Islami F, Anandasabapathy S, et al. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention[J]. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2014, 23(5): 700-13.

[2] Jackson C, Cunningham D, Oliveira J, et al. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up[J]. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO, 2009, 20(Suppl 4): 34-6.

[3] Yoshikawa T, Rino Y, Yukawa N, et al. Neoadjuvant chemotherapy for gastric cancer in Japan: a standing position by comparing with adjuvant chemotherapy[J]. Surg Today, 2014, 44(1): 11-21.

[4] Therasse P, Arbuck S G, Eisenhauer E A, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada[J]. J Natl Cancer Inst, 2000, 92(3): 205-216.

[5] Prasad S R, Jhaveri K S, Saini S, et al. CT tumor measurement for therapeutic response assessment: comparison of unidimensional, bidimensional, and volumetric techniques initial observations[J]. Radiology, 2002, 225: 416-9.

[6] Eisenhauer E A, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1) [J]. Eur J Cancer, 2009, 45: 228-47.

[7] Ott K, Lordick F, Herrmann K, et al. The new credo: induction chemotherapy in locally advanced gastric cancer: consequences for surgical strategies[J]. Gastric Cancer, 2008, 11: 1-9.

[8] Lee S M, Kim S H, Lee J M, et al. Usefulness of CT volumetry for primary gastric lesions in predicting pathologic response to neoadjuvant chemotherapy in advanced gastric cancer[J]. Abdom Imaging, 2009, 34: 430-40.

[9] Zhao B, Oxnard G R, Moskowitz C S, et al. A pilot study of volume measurement as a method of tumor response evaluation to aid biomarker development[J]. Clin Cancer Res, 2010: 4647-4653.

[10] Marten K, Auer F, Schmidt S, et al. Inadequacy of manual measurements compared to automated CT volumetry in assessment of treatment response of pulmonary metastases using RECIST criteria[J]. Eur Radiol, 2006, 16: 781-790.

[11] Hallinan J T, Venkatesh S K, Peter L, et al. CT volumetry for gastric carcinoma: association with TNM stage[J]. European radiology, 2014, 24(12): 3105-14.

[12] Kikuchi S, Sakuramoto S, Kobayashi N, et al. Tumor volumetry: proposal of a new concept to predict lymph node metastasis in early gastric cancer[J]. Anticancer research, 2000, 20(5C): 3669-74.

[13] Becker K, Mueller J D, Schulmacher C, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy[J]. Cancer, 2003, 98(7): 1521-1530.

[14] Zhao B, James L P, Moskowitz C S, et al. Evaluating variability in tumor measurements from same-day repeat CT scans of patients with non-small cell lung cancer[J]. Radiology, 2009, 252(1): 263-72.

[15] Beer AJ, Wieder HA, Lordick F, et al. Adenocarcinomas of esophagogastric junction: multi-detector row CT to evaluate early response to neoadjuvant chemotherapy[J]. Radiology, 2006, 239: 472-80.

[16] Martens M H, van Heeswijk M M, van den Broek JJ, et al. Prospective, Multicenter Validation Study of Magnetic Resonance Volumetry for Response Assessment After Preoperative Chemoradiation in Rectal Cancer: Can the Results in the Literature be Reproduced？[J]. International journal of radiation oncology, biology, physics, 2015, 93(5): 1005-14.

[17] Rao S X, Lambregts D M, Schnerr R S, et al. CT texture analysis in colorectal liver metastases: A better way than size and volume measurements to assess response to chemotherapy？[J]. United European gastroenterology journal, 2016, 4(2): 257-63.

[18] Hadjiiski L, Weizer A Z, Alva A, et al. Treatment Response Assessment for Bladder Cancer on CT Based on Computerized Volume Analysis, World Health Organization Criteria, and RECIST[J]. AJR American journal of roentgenology, 2015, 205(2): 348-52.

[19] Hou J, Guerrero M, Suntharalingam M, et al. Response assessment in locally advanced head and neck cancer based on RECIST and volume measurements using cone beam CT images[J]. Technology in cancer research & treatment, 2015, 14(1): 19-27.

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(yīng)用基礎(chǔ)研究計(jì)劃(CJ20130024); 解放軍南京軍區(qū)面上課題(12ma087)

R 735.2

A

1672-2353(2016)24-060-03

10.7619/jcmp.201624017