趙紅霞，董艷雙，蔡友治，朱穎軍

·論著·

18F-氟脫氧葡萄糖的最大標(biāo)準(zhǔn)攝取值評估宮頸癌伴淋巴結(jié)轉(zhuǎn)移患者預(yù)后的價值

趙紅霞1，董艷雙1，蔡友治2，朱穎軍3*

背景 淋巴結(jié)轉(zhuǎn)移是影響宮頸癌預(yù)后的主要因素，早期診斷可以有效提高患者的生存率。目的 探討18F-氟脫氧葡萄糖(18F-FDG)的最大標(biāo)準(zhǔn)攝取值(SUVmax)評估宮頸癌伴淋巴結(jié)轉(zhuǎn)移患者預(yù)后的價值，并分析患者生存率的影響因素。方法 收集2004年12月—2011年8月天津市第四中心醫(yī)院婦產(chǎn)科經(jīng)活組織檢查證實(shí)的伴盆腔淋巴結(jié)轉(zhuǎn)移和/或腹主動脈旁淋巴結(jié)轉(zhuǎn)移宮頸癌患者70例為研究對象?；颊呔姓娮影l(fā)射斷層聯(lián)合計算機(jī)斷層掃描術(shù)(PET/CT)檢查，記錄18F-FDG的SUVmax，患者均接受放、化療，從患者接受治療開始隨訪，隨訪至患者復(fù)發(fā)或死亡，隨訪截止日期為2015-06-30。結(jié)果 SUVmax預(yù)測患者復(fù)發(fā)的受試者工作特征(ROC)曲線下面積(AUC)為0.703，95%CI(0.542，0.838)，臨界值為7.5，靈敏度為85.7%，特異度為98.2%，陽性預(yù)測值為92.3%，陰性預(yù)測值為96.5%，約登指數(shù)為0.8。SUVmax<7.5 13例，SUVmax≥7.5 57例。SUVmax<7.5患者與SUVmax≥7.5患者總生存率(OS)比較，差異無統(tǒng)計學(xué)意義(χ2=2.934，P=0.087)。SUVmax<7.5患者無病生存率(DFS)高于SUVmax≥7.5患者(χ2=4.791，P=0.035)。多元Cox比例風(fēng)險回歸分析結(jié)果顯示，SUVmax、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)是OS的影響因素(P<0.05)；SUVmax、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)是DFS的影響因素(P<0.05)。結(jié)論18F-FDG的SUVmax可以較好地評估宮頸癌伴淋巴結(jié)轉(zhuǎn)移患者預(yù)后；18F-FDG的SUVmax較大、伴盆腔淋巴結(jié)轉(zhuǎn)移、完全反應(yīng)宮頸癌患者生存率較差。

宮頸腫瘤；淋巴轉(zhuǎn)移；氟脫氧葡萄糖F18；最大標(biāo)準(zhǔn)攝入值

趙紅霞，董艷雙，蔡友治，等.18F-氟脫氧葡萄糖的最大標(biāo)準(zhǔn)攝取值評估宮頸癌伴淋巴結(jié)轉(zhuǎn)移患者預(yù)后的價值[J].中國全科醫(yī)學(xué)，2017，20(6)：668-672.[www.chinagp.net]

ZHAO H X,DONG Y S,CAI Y Z,et al. Prognostic value of18F-FDG SUVmax in pelvic lymph nodes metastases of patients with cervical cancer[J].Chinese General Practice，2017，20(6)：668-672.

宮頸癌臨床癥狀隱匿、分化程度低、易累及淋巴結(jié)、高頻復(fù)發(fā)等特點(diǎn)造成其病死率居高不下，宮頸癌也是臨床治療上最棘手的惡性腫瘤[1]。年齡、腫瘤分期、淋巴結(jié)的累及情況等是宮頸癌患者預(yù)后的影響因素，其中盆腔淋巴結(jié)轉(zhuǎn)移及腹主動脈旁淋巴結(jié)轉(zhuǎn)移與宮頸癌的臨床治療和患者預(yù)后有密切關(guān)系[2-3]。18F-氟脫氧葡萄糖(18F-FDG)正電子發(fā)射斷層聯(lián)合計算機(jī)斷層掃描術(shù)(PET/CT)是一種將解剖位置與代謝功能相結(jié)合的檢查方法，用于探測腫瘤的定位及生物學(xué)特征[4]。目前，PET/CT可以觀察腫瘤浸潤范圍，受累淋巴結(jié)的大小、遠(yuǎn)近等，逐漸成為分析腫瘤分級的重要方法[5-6]。研究證實(shí)，原發(fā)腫瘤18F-FDG的最大標(biāo)準(zhǔn)攝取值(maximim standardized uptake，SUVmax)與腫瘤大小、淋巴結(jié)轉(zhuǎn)移率、療效反應(yīng)、治療后總生存率(OS)及無病生存率(DFS)有一定相關(guān)性[7]。但是，18F-FDG的SUVmax對宮頸癌患者預(yù)后的價值尚未明確。本研究分析70例宮頸癌伴盆腔淋巴結(jié)轉(zhuǎn)移和/或腹主動脈旁淋巴結(jié)轉(zhuǎn)移患者18F-FDG的SUVmax，探討其評估宮頸癌伴淋巴結(jié)轉(zhuǎn)移患者預(yù)后的價值，為臨床上調(diào)整治療方案及康復(fù)監(jiān)測提供依據(jù)。

1 對象與方法

1.1 納入與排除標(biāo)準(zhǔn) 納入標(biāo)準(zhǔn)：(1)經(jīng)PET/CT進(jìn)行診斷、分級及放/化療治療；(2)臨床診斷資料齊全；(3)伴盆腔淋巴結(jié)轉(zhuǎn)移和/或腹主動脈旁淋巴結(jié)轉(zhuǎn)移；(4)患者均已根據(jù)國際婦產(chǎn)科聯(lián)盟(FIGO)標(biāo)準(zhǔn)分期[8]。排除標(biāo)準(zhǔn)：(1)病史、體格檢查、婦科檢查、血液生化檢查、腹部和盆腔的磁共振成像或CT檢查資料缺失的患者；(2)無淋巴結(jié)轉(zhuǎn)移患者；(3)未進(jìn)行PET/CT診斷的患者。

1.2 研究對象 收集2004年12月—2011年8月天津市第四中心醫(yī)院婦產(chǎn)科經(jīng)活組織檢查證實(shí)的宮頸癌患者70例為研究對象。所有患者及其家屬簽署知情同意書。本研究通過天津市第四中心醫(yī)院倫理審查委員會批準(zhǔn)。

1.3 PET/CT檢查[9]

1.3.1 檢查方法 (1)所有患者禁食至少6 h，注射18F-FDG前檢測空腹血糖水平(要求≤15 mg/L)，靜脈注射370～555 MBq(10～15 mCi)的18F-FDG，患者仰臥位以確保18F-FDG全身均勻分布，60 min后采集PET/CT資料。(2)非增強(qiáng)CT掃描顱骨底至盆腔下緣，電壓140 kV，電流80 mA，層厚5 mm。(3)PET按照相對應(yīng)的CT掃描區(qū)采集圖像，3 min/床位，共6～7個床位。(4)采集的所有數(shù)據(jù)經(jīng)衰減校正。

1.3.2 PET/CT圖像分析 PET/CT圖像均由同一資深影像學(xué)診斷醫(yī)師雙盲法閱片，根據(jù)18F-FDG分布的位置、強(qiáng)度、形狀、大小、與CT圖像的相關(guān)性等綜合判斷攝入的18F-FDG水平與定位。由計算機(jī)分析出18F-FDG的SUVmax。

1.4 治療方案 盆腔淋巴結(jié)轉(zhuǎn)移患者患者行三維適形放射治療(3-dimensional conformal external beam RT，3DCRT)同步聯(lián)合順鉑和高劑量(HDR)近距離放射治療(BRT)方案。其中，3DCRT條件是18-MV光子，1.8 Gy/次(周一至周五連續(xù)放療)，共計50.4 Gy；靜脈注射順鉑，40 mg/m2，1次/周；BRT條件是7.0 Gy/次。腹主動脈淋巴結(jié)轉(zhuǎn)移患者，除上述治療方案外，在腹主動脈旁淋巴結(jié)進(jìn)行額外放射，1.8 Gy/次，共計45.0 Gy，若發(fā)現(xiàn)淋巴結(jié)腫大，額外增加9.0 Gy的放射劑量。

1.5 隨訪 從患者接受治療開始電話或門診隨訪，治療后≤3年，3個月隨訪1次；治療后>3年，6個月隨訪1次，隨訪至患者復(fù)發(fā)或死亡，隨訪截止日期為2015-06-30，隨訪時間為6～70個月。療效反應(yīng)：完全反應(yīng)(complete response，CR)為所有目標(biāo)病灶消失；局部反應(yīng)(partial response，PR)為基線病灶最大徑之和至少減少30%；病變進(jìn)展(progressive disease，PD)為基線病灶最大徑之和至少增加20%或出現(xiàn)新病灶。發(fā)生遠(yuǎn)端轉(zhuǎn)移定義為復(fù)發(fā)。

2 結(jié)果

2.1 基本情況 70例患者年齡30～89歲，平均年齡(55.7±17.8)歲；FIGO臨床分期：ⅠB2期5例，ⅡA期1例，ⅡB期34例，ⅢA期8例，ⅢB期20例，ⅣA期2例；鱗癌55例，腺癌14例，鱗腺癌1例；單純盆腔淋巴結(jié)轉(zhuǎn)移48例，盆腔淋巴結(jié)轉(zhuǎn)移及腹主動脈旁淋巴結(jié)轉(zhuǎn)移22例；療效反應(yīng)：CR50例，PR18例，PD2例；平均SUVmax(7.6±0.5)；疾病復(fù)發(fā)14例，存活30例，死亡26例(其中24例死于宮頸癌，2例死于其他疾病)。

2.2SUVmax預(yù)測患者復(fù)發(fā)的價值SUVmax預(yù)測患者復(fù)發(fā)的AUC為0.703，95%CI(0.542，0.838)，臨界值為7.5，靈敏度為85.7%，特異度為98.2%，陽性預(yù)測值為92.3%，陰性預(yù)測值為96.5%，約登指數(shù)為0.8(見表1)。

表1 SUVmax預(yù)測患者復(fù)發(fā)的價值

注：SUVmax=最大標(biāo)準(zhǔn)攝取值

2.3 OS、DFS比較 SUVmax<7.5 57例，SUVmax≥7.5 13例。SUVmax<7.5患者與SUVmax≥7.5患者OS比較，差異無統(tǒng)計學(xué)意義(χ2=2.934，P=0.087，見圖1)。SUVmax<7.5患者DFS高于SUVmax≥7.5患者，差異有統(tǒng)計學(xué)意義(χ2=4.791，P=0.035，見圖2)。

2.4 OS、DFS影響因素的多元Cox比例風(fēng)險回歸分析 以生存時間、OS為因變量，SUVmax、臨床分期、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)為自變量(見表2)，進(jìn)行多元Cox比例風(fēng)險回歸分析，結(jié)果顯示，SUVmax、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)是OS的影響因素(P<0.05，見表3)。

以生存時間、DFS為因變量，SUVmax、臨床分期、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)為自變量(見表2)，進(jìn)行多元Cox比例風(fēng)險回歸分析，結(jié)果顯示，SUVmax、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)是DFS的影響因素(P<0.05，見表4)。

注：OS=總生存率

圖1 SUVmax<7.5患者與SUVmax≥7.5患者OS比較

Figure 1 Comparison of OS of patients of SUVmax<7.5 and SUVmax≥7.5

注：DFS=無病生存率

圖2 SUVmax<7.5患者與SUVmax≥7.5患者DFS比較

Figure 2 Comparison of DFS of patients of SUVmax<7.5 and SUVmax≥7.5

表2 OS、DFS影響因素的多元Cox比例風(fēng)險回歸分析賦值表

Table 2 Assignment of multivariate Cox proportional hazard regression analysis of influencing factors for OS and DFS

變量賦值SUVmax<7.5=0;≥7.5=1臨床分期(期)<ⅡB=0;≥ⅡB=1淋巴結(jié)轉(zhuǎn)移部位單獨(dú)盆腔淋巴結(jié)轉(zhuǎn)移=0;盆腔淋巴結(jié)轉(zhuǎn)移及腹主動脈旁淋巴結(jié)轉(zhuǎn)移=1療效反應(yīng)CR=0;PR/PD=1OS(%)<40=0;≥40=1DFS(%)<40=0;≥40=1

注：CR=完全反應(yīng)，PR=局部反應(yīng)，PD=疾病進(jìn)展

表3 OS影響因素的多元Cox比例風(fēng)險回歸分析

Table 3 Multivariate Cox proportional hazard regression analysis of influencing factors for OS

變量BSEWaldχ2值P值HR值95%CISUVmax0.1160.1531.3670.0082.12(2.03,2.21)臨床分期1.2760.1782.8310.0522.86(0.91,8.97)淋巴結(jié)轉(zhuǎn)移部位0.0980.0111.8930.0372.02(1.10,3.70)療效反應(yīng)-1.3420.0031.9340.0212.29(1.32,3.97)

表4 DFS影響因素的多元Cox比例風(fēng)險回歸分析

Table 4 Multivariate Cox proportional hazard regression analysis of influencing factors for DFS

變量BSEWaldχ2值P值HR值95%CISUVmax0.9340.1344.2810.0022.12(2.04,2.21)臨床分期1.0240.0012.7810.1672.71(0.93,7.99)淋巴結(jié)轉(zhuǎn)移部位3.1340.2912.1030.0412.05(1.15,3.64)療效反應(yīng)-1.2310.0211.9330.0042.32(1.92,2.80)

3 討論

多項研究表明，早期、精確、高效診斷淋巴結(jié)轉(zhuǎn)移是解決宮頸癌的治療及疾病控制的重要前提[9]。淋巴結(jié)的轉(zhuǎn)移基本上遵循著從盆腔淋巴結(jié)、腹主動脈旁淋巴結(jié)，到鎖骨淋巴結(jié)，后期至縱隔淋巴結(jié)這一過程。作為淋巴結(jié)轉(zhuǎn)移的首站，盆腔淋巴結(jié)轉(zhuǎn)移的探查是決定宮頸癌治療策略和評估預(yù)后的主要因素。PET/CT能夠綜合病灶的解剖位置和代謝水平，有效評估宮頸癌患者腫瘤分期[10]，但關(guān)于其對疾病的進(jìn)展及預(yù)后評估的研究較少。本研究采用PET/CT檢查手段，探討18F-FDG的SUVmax評估宮頸癌伴淋巴結(jié)轉(zhuǎn)移患者預(yù)后的價值。

本研究結(jié)果顯示，SUVmax預(yù)測患者復(fù)發(fā)的AUC為0.703，95%CI(0.542，0.838)，臨界值為7.5，靈敏度為85.7%，特異度為98.2%，陽性預(yù)測值為92.3%，陰性預(yù)測值為96.5%，約登指數(shù)為0.8；SUVmax<7.5患者與SUVmax≥7.5患者OS無差異，SUVmax<7.5患者DFS高于SUVmax≥7.5患者。有研究證實(shí)，與無淋巴結(jié)轉(zhuǎn)移的宮頸癌患者相比，有淋巴結(jié)轉(zhuǎn)移的宮頸癌患者5年生存率降低了30%～40%；而伴有盆腔淋巴結(jié)轉(zhuǎn)移及腹主動脈旁淋巴結(jié)轉(zhuǎn)移的宮頸癌患者5年生存率降低了20%～60%[11]。GRIGSBY等[12]發(fā)現(xiàn)，淋巴結(jié)18F-FDG攝入與DFS顯著相關(guān)。YOON等[13]發(fā)現(xiàn)，18F-FDG低攝入其療效反應(yīng)好，CR患者的DFS和OS高于無反應(yīng)患者或PR患者。有研究表明，83例FIGO臨床分期為ⅠB期～ⅢB期的宮頸癌患者，SUVmax≥4.3患者復(fù)發(fā)率高、OS和DFS低、預(yù)后差[14]。另一項研究表明，SUVmax≥2.36的宮頸癌患者OS及DFS相對于SUVmax<2.36差[15]。此外，OH等[16]發(fā)現(xiàn)，60例宮頸癌患者經(jīng)放、化療后，18F-FDG的SUVmax減少≥60%時其療效反應(yīng)好，疾病無快速進(jìn)展。結(jié)合以上研究數(shù)據(jù)和本研究結(jié)果，提示18F-FDG的攝入水平與宮頸癌進(jìn)展程度、療效低反應(yīng)、低生存率有關(guān)。

有關(guān)宮頸癌的預(yù)后因素很多，包括臨床腫瘤分級、腫瘤浸潤范圍、分化程度、鱗狀上皮細(xì)胞癌抗原(squamous cell carcinoma antigen，SCC-Ag)水平、淋巴結(jié)轉(zhuǎn)移率等。KIDD等[17]結(jié)合Cox比例風(fēng)險回歸分析發(fā)現(xiàn)，盆腔淋巴結(jié)18F-FDG的SUVmax增高(≥4.3)可作為宮頸癌的獨(dú)立預(yù)后因子；CHUNG等[18]研究顯示，盆腔淋巴結(jié)18F-FDG的SUVmax和宮旁浸潤程度是宮頸癌復(fù)發(fā)的危險因素。本研究結(jié)果顯示，SUVmax、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)是OS的影響因素，SUVmax、淋巴結(jié)轉(zhuǎn)移部位、療效反應(yīng)是DFS的影響因素，與其他研究結(jié)果[19]不一致，可能的原因是本研究篩選的資料多數(shù)是單純盆腔淋巴結(jié)轉(zhuǎn)移的宮頸癌患者，且ROC曲線分析得到的SUVmax預(yù)測患者復(fù)發(fā)的臨界值也高于其他研究[20]。

本研究有一些局限性。首先，本研究樣本量有限。其次，PET/CT本身有部分容積效應(yīng)，在探查淋巴結(jié)時，降低了分辨率，低估了淋巴結(jié)轉(zhuǎn)移率。增加樣本量和提高PET/CT及儀器的分辨率能更準(zhǔn)確地分析18F-FDG的SUVmax對宮頸癌診斷、治療及預(yù)后的臨床意義。本研究并未涉及遠(yuǎn)端淋巴結(jié)轉(zhuǎn)移的患者，仍需進(jìn)一步研究。

綜上所述，18F-FDG的SUVmax可以較好地評估宮頸癌伴淋巴結(jié)轉(zhuǎn)移患者預(yù)后；18F-FDG的SUVmax較大、伴盆腔淋巴結(jié)轉(zhuǎn)移、完全反應(yīng)宮頸癌患者生存率較差。

作者貢獻(xiàn)：趙紅霞進(jìn)行試驗(yàn)設(shè)計與實(shí)施、資料收集整理、撰寫論文并對文章負(fù)責(zé)；趙紅霞、董艷雙、蔡友治、朱穎軍進(jìn)行試驗(yàn)實(shí)施、評估、資料收集；朱穎軍進(jìn)行質(zhì)量控制及審校。

本文無利益沖突。

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(本文編輯：崔麗紅)

Prognostic Value of18F-FDG SUVmax in Pelvic Lymph Nodes Metastases of Patients with Cervical Cancer

ZHAOHong-xia1,DONGYan-shuang1,CAIYou-zhi2,ZHUYing-jun3*

1.DepartmentofObstetricsandGynecology,TianjinForthCenterHospital,Tianjin300143,China2.DepartmentofOrthopedics,theFirstHospitalofZhejiangProvince,Hangzhou310003,China3.DepartmentofObstetricsandGynecology,TianjinCentralHospitalofGynecologyObstetrics,Tianjin300052,China

Background Lymph nodes metastasis is the main factor that affects the prognosis of cervical cancer. Early diagnosis can effectively improve the survival rate of patients with cervical cancer. Objective To evaluate the prognostic value of the18F-FDG maximum standardized uptake value(SUVmax) in pelvic lymph nodes metastases of patients with cervical cancer and analyze the impact factors of survival. Methods A total of 70 cervical carcinoma patients with pelvic and/or paraaortic lymph nodes metastases confirmed by biopsy in Department of Obstetrics and Gynecology of Tianjin Forth Center Hospital were enrolled in this study from December 2004 to August 2011. All patients accepted PET/CT examination and18F-FDG SUVmax was recorded. All patients received radiotherapy and chemotherapy. Patients were followed up when the treatment began. The follow-up ended when patients relapsed or died. The deadline of follow-up was 2015-06-30. Results The AUC of SUVmax for predicting patients′ recurrence was 0.703,95%CI(0.542,0.838),the cut-off value was 7.5,the sensitivity was 85.7%,the specificity was 98.2%,the positive predictive value was 92.3% and the negative predictive value was 96.5%,the Youden index was 0.8. There were 13 cases with SUVmax<7.5 and 57 cases with SUVmax≥7.5. There was no statistically significant differences in overall survival(OS) between patients with SUVmax<7.5 and SUVmax≥7.5(χ2=2.934,P=0.087). The disease-free survival(DFS) of patients with SUVmax<7.5 was higher than that of patients with SUVmax≥7.5(χ2=4.791,P=0.035). Multivariate Cox proportional hazards regression analysis showed that SUVmax,sites of lymph nodes metastases and therapeutic response were the impact factors of OS(P<0.05);SUVmax,sites of lymph nodes metastases and therapeutic response were the impact factors of DFS(P<0.05).Conclusion SUVmax of18F-FDG can be used to well evaluate the prognosis of cervical cancer patients with lymph nodes metastases. The survival rate of patients with cervical cancer is poor when they have higher SUVmax of18F-FDG,pelvic lymph nodes metastases and complete therapeutic response.

Uterine cervical neoplasms;Lymphatic metastasis;Fluorodeoxyglucose F18;Maximum standardized uptake value

國家自然科學(xué)青年基金資助項目(81201395)

R 737.33

A

10.3969/j.issn.1007-9572.2017.06.007

2016-08-01；

2016-12-02)

1.300143 天津市第四中心醫(yī)院婦產(chǎn)科

2.310003 浙江省杭州市，浙江省第一醫(yī)院骨科

3.300052 天津市中心婦產(chǎn)科醫(yī)院婦產(chǎn)科

*通信作者：朱穎軍，副主任醫(yī)師；E-mail：zhuyingjun5009@sina.com

*Correspondingauthor:ZHUYing-jun,Associatechiefphysician;E-mail:zhuyingjun5009@sina.com