涂劍楠王新玲張靜雅葉偉軍金華

早期宮頸癌術(shù)后預(yù)后與不同放療方式的療效及并發(fā)癥比較*

涂劍楠①王新玲②張靜雅①葉偉軍③金華①

目的：探討影響早期宮頸癌患者術(shù)后預(yù)后的因素和不同放療方式的療效及并發(fā)癥情況。方法：回顧性分析2013年3月至9月100例新疆醫(yī)科大學(xué)附屬腫瘤醫(yī)院及中山大學(xué)附屬腫瘤醫(yī)院收治的早期宮頸癌術(shù)后患者資料，并對影響患者預(yù)后的因素進(jìn)行分析。根據(jù)放療方式分為常規(guī)放療（conventional radiotherapy，CRT）組50例，圖像引導(dǎo)調(diào)強(qiáng)放療（image guided radiotherapy，IGRT）組50例，并比較兩組的療效和并發(fā)癥情況。結(jié)果：100例患者3年生存率和無瘤生存率分別為89%和78%。CRT組和IGRT組3年生存率分別為78.57%和89.06%，兩組比較差異具有統(tǒng)計學(xué)意義（P=0.034）；CRT組和IGRT組3年無瘤生存率分別為66.67%和87.36%，兩組比較差異具有統(tǒng)計學(xué)意義（P=0.042）。CRT組和IGRT組早期、晚期并發(fā)癥的比較差異具有統(tǒng)計學(xué)意義（P＜0.05）。單因素分析顯示宮旁浸潤、淋巴結(jié)轉(zhuǎn)移、腫瘤浸潤深度、淋巴脈管間隙浸潤、神經(jīng)侵犯、術(shù)后放療與早期宮頸癌3年生存率相關(guān)（P＜0.05）。Cox多因素分析顯示術(shù)后放療方式、宮旁浸潤、淋巴結(jié)轉(zhuǎn)移、淋巴脈管間隙浸潤、神經(jīng)侵犯及腫瘤浸潤深度均為影響早期宮頸癌患者預(yù)后的獨立危險因素。結(jié)論：早期宮頸癌的預(yù)后是多因素相互作用的結(jié)果，術(shù)后IGRT組3年生存率明顯優(yōu)于CRT組，放療不良反應(yīng)小，有益于患者的生存質(zhì)量。

宮頸癌 放射治療 預(yù)后 療效 并發(fā)癥

宮頸癌是全球女性第四大常見惡性腫瘤［1］，我國每年宮頸癌新發(fā)病例約10萬人，居我國女性生殖系統(tǒng)惡性腫瘤首位［2］。早期宮頸癌手術(shù)切除與根治性放療的療效相當(dāng)［3］，其中術(shù)后ⅠB2、ⅡA2期患者多存在高危或中危因素，50%～80%患者需行放療。根據(jù)NCCN宮頸癌臨床實踐指南（2016年），術(shù)后病理切緣陽性、宮旁浸潤、盆腔淋巴結(jié)陽性被認(rèn)為是“高危因素”，對具備任何一項因素者均推薦術(shù)后行盆腔放療，陰道切緣陽性者的陰道近距離放療可增加治療療效。對無“高危因素”的“中危因素”者中的淋巴脈管間隙浸潤、深層間質(zhì)浸潤和原發(fā)腫瘤較大者也需行盆腔放療。本研究探討影響早期宮頸癌患者的術(shù)后預(yù)后因素，及不同放療方式的療效及并發(fā)癥情況。

1 材料與方法

1.1 一般資料

選取新疆醫(yī)科大學(xué)附屬腫瘤醫(yī)院及中山大學(xué)附屬腫瘤醫(yī)院2013年3月至9月收治的100例ⅠB～ⅡA期宮頸癌術(shù)后患者，年齡為34～65歲，中位年齡為40歲，臨床資料完整，術(shù)前未行新輔助治療，無其他部位原發(fā)腫瘤。術(shù)后病理提示具有“高危（和）或中危因素”。根據(jù)放療方式分為常規(guī)放療（conventional ra?diotherapy，CRT）組50例，圖像引導(dǎo)調(diào)強(qiáng)放療（image guided radiotherapy，IGRT）組50例。KPS評分＞80分，具有放療適應(yīng)證，治療前簽署知情同意書。放療期間給予順鉑40 mg/m2，靜脈滴注，1次/周。

1.2 方法

1.2.1 CRT 盆腔基本照射野采用6MVX線前后兩野對穿照射。上界位于第4、5腰椎水平，下界位于閉孔下緣水平，兩側(cè)緣位于真骨盆最大徑旁開2.0 cm，包括髂總、兩側(cè)盆壁、骶前淋巴結(jié)和殘端，放療劑量為45 Gy。

1.2.2 IGRT 采用仰臥位熱塑體膜固定患者的腹、盆腔。按層厚5 mm行CT掃描，從胸10椎體下緣至坐骨結(jié)節(jié)下緣5 cm。掃描前所有患者均行膀胱殘余尿測定。放療醫(yī)師根據(jù)ICRU83號文件完成靶區(qū)勾畫。分割劑量為1.8 Gy/次，處方劑量45 Gy，95%以上的計劃靶區(qū)（planning target volume，PTV）達(dá)到處方劑量，給予危及器官一定條件的劑量限制?；颊咔?次（1次/天）與后4次（1次/周）治療前行Varian直線加速器系統(tǒng)機(jī)載CBCT掃描，CBCT圖像與定位CT圖像進(jìn)行匹配，比對結(jié)果在允許誤差范圍內(nèi)則可進(jìn)行治療，超出誤差允許范圍，系統(tǒng)自動形成新的擺位參數(shù)并直接修正。

1.2.3 隨訪 所有病例通過電話及臨床資料隨訪，隨訪時間截止至2016年12月31日?？偵妫╫verall survival，OS）為從初次治療至死亡或末次隨訪。無瘤生存（disease free survival，DFS）為從初次治療至任何部位出現(xiàn)復(fù)發(fā)、轉(zhuǎn)移或末次隨訪。復(fù)發(fā)、轉(zhuǎn)移主要根據(jù)癥狀、體征、輔助檢查及穿刺活檢病理診斷。并發(fā)癥分級評價標(biāo)準(zhǔn)根據(jù)放射腫瘤協(xié)作組RTOG放射損傷標(biāo)準(zhǔn)（1995年）。

1.3 統(tǒng)計學(xué)分析

采用SPSS 19.0軟件進(jìn)行統(tǒng)計學(xué)分析。計數(shù)資料采用χ2檢驗或Fisher精確概率法檢驗。生存分析采用Kaplan-Meier曲線，單因素分析采用Log rank檢驗，多因素分析采用Cox風(fēng)險回歸模型進(jìn)行。以P＜0.05為差異具有統(tǒng)計學(xué)意義。

2 結(jié)果

2.1 預(yù)后因素分析

本研究對年齡、FIGO分期、宮旁浸潤、淋巴結(jié)轉(zhuǎn)移、腫瘤浸潤深度、淋巴脈管間隙浸潤、神經(jīng)侵犯、腫瘤直徑、術(shù)后放療方式采用Log rank檢驗進(jìn)行單因素分析，結(jié)果顯示術(shù)后放療方式、宮旁浸潤、淋巴結(jié)轉(zhuǎn)移、淋巴脈管間隙浸潤、神經(jīng)侵犯、腫瘤浸潤深度與預(yù)后相關(guān)（P＜0.05，表1）。Cox多因素分析結(jié)果顯示，術(shù)后放療方式、宮旁浸潤、淋巴結(jié)轉(zhuǎn)移、淋巴脈管間隙浸潤、神經(jīng)侵犯及腫瘤浸潤深度均是影響早期宮頸癌患者預(yù)后的獨立危險因素（表2）。

表1 100例早期宮頸癌術(shù)后患者3年生存率的單因素分析Table 1 Univariate analysis of 3-year overall survival rate for 100 postoperative patients of early cervical squamous cell cancer

表1 100例早期宮頸癌術(shù)后患者3年生存率的單因素分析（續(xù)表1）Table 1 Univariate analysis of 3-year overall survival rate for 100 postoperative patients of early cervical squamous cell cancer

表2 100例早期宮頸癌術(shù)后患者3年生存率Cox多因素分析Table 2 Cox multivariate analyses of 3-year overall survival rate for 100 postoperative patients of early cervical squamous cell cancer

2.2 CRT和IGRT組患者的臨床療效比較

所有患者均完成了術(shù)后放化療，100例患者均隨訪了36個月，隨訪率為100%，3年生存率和無瘤生存率分別為89%和78%。其中CRT組患者3年內(nèi)局部復(fù)發(fā)6例，死亡9例（其中2例死于其他疾?。?，3例遠(yuǎn)處轉(zhuǎn)移；IGRT組患者3年內(nèi)局部復(fù)發(fā)1例，2例死亡，1例遠(yuǎn)處轉(zhuǎn)移。CRT組和IGRT組3年生存率為78.57%和89.06%，兩組比較差異具有統(tǒng)計學(xué)意義（P=0.034，圖1）；CRT組和IGRT組3年無瘤生存率為66.67%和87.36%，兩組比較差異具有統(tǒng)計學(xué)意義（P=0.042，圖2）。

2.3 并發(fā)癥比較

CRT組早期骨髓抑制、消化道癥狀、泌尿系癥狀等并發(fā)癥的發(fā)生例數(shù)均高于IGRT組，兩組比較差異具有統(tǒng)計學(xué)意義（P＜0.05，表3）。CRT組晚期放射性直腸炎、放射性膀胱炎、盆腔纖維化等并發(fā)癥的發(fā)生例數(shù)均高于IGRT組，兩組比較差異具有統(tǒng)計學(xué)意義（P＜0.05，表4）。

圖1 CRT組和IGRT組3年OS生存曲線Figure 1 Three-year overall survival curves of the CRT and IGRT groups

圖2 CRT組和IGRT組3年DFS生存曲線Figure 2 Three-year disease-free survival curves of the CRT and IGRT groups

表3 CRT組和IGRT組早期并發(fā)癥發(fā)生例數(shù)比較Table 3 Comparison of the number of cases with early complications in the CRT and IGRT group

表4 CRT組和IGRT組晚期并發(fā)癥發(fā)生例數(shù)比較Table 4 Comparison of the number of cases with late complications in the CRT and IGRT groups

3 討論

宮頸癌是全球常見的婦科惡性腫瘤，全球每年新增宮頸癌病例約50萬，死亡病例超過20萬［4-5］。早期宮頸癌患者術(shù)后規(guī)范化治療的5年無瘤生存率達(dá)90%［6］。宮頸癌的預(yù)后與多種因素相互影響有關(guān)，是一個復(fù)雜且具有研究意義的問題。本研究發(fā)現(xiàn)術(shù)后放療方式、宮旁浸潤、淋巴結(jié)轉(zhuǎn)移、淋巴脈管間隙浸潤、神經(jīng)侵犯及腫瘤浸潤深度均是影響早期宮頸癌患者預(yù)后的獨立危險因素，尚未發(fā)現(xiàn)年齡、FIGO分期對早期宮頸癌預(yù)后有影響。喻晴等［7］對ⅠB～ⅡA期宮頸癌患者術(shù)后進(jìn)行生存評估分析發(fā)現(xiàn)，腫瘤分期并不是早期宮頸癌預(yù)后的獨立風(fēng)險因素，與本研究結(jié)果相似。馬曉雯［8］對156例宮頸癌患者術(shù)后復(fù)發(fā)及預(yù)后相關(guān)因素的分析結(jié)果顯示，臨床分期、病理類型、有無淋巴脈管間隙浸潤、有無盆腔淋巴結(jié)轉(zhuǎn)移是影響宮頸癌術(shù)后復(fù)發(fā)的臨床病理因素；臨床分期、有無淋巴脈管間隙浸潤、有無盆腔淋巴結(jié)轉(zhuǎn)移是影響宮頸癌術(shù)后5年生存率的獨立因素，與本研究結(jié)果相似。岳慧敏等［9］研究發(fā)現(xiàn)，神經(jīng)侵犯與宮頸癌患者預(yù)后有關(guān)，但不能作為判斷宮頸癌預(yù)后的不良指標(biāo)，與本研究結(jié)果不相符。雖然神經(jīng)侵犯并非判斷宮頸癌預(yù)后的不良指標(biāo)，但神經(jīng)轉(zhuǎn)移途徑值得進(jìn)一步關(guān)注和研究。

放療是宮頸癌術(shù)后重要輔助治療手段，在宮頸癌的治療中占有十分重要的地位。宮頸癌術(shù)后患者常出現(xiàn)腸管下移、腸粘連等并發(fā)癥，照射野內(nèi)小腸體積增多，增加放射損傷的危險度。放療過程中的各種不確定性、擺位重復(fù)性、器官運動等均影響放療劑量的準(zhǔn)確性［10］。在宮頸癌的治療中，盆腔CRT取得了一定成效，但靶區(qū)體積大、適形度差，使腫瘤周圍正常組織受累較多，消化系統(tǒng)和泌尿系統(tǒng)等急慢性并發(fā)癥的發(fā)生率較高。Small等［11］在RTOG0116試驗中觀察宮頸癌患者的放療不良反應(yīng)發(fā)現(xiàn)，45例患者3～4級急性非血液系統(tǒng)不良反應(yīng)發(fā)生率為81%，3年隨訪期內(nèi)3～4級遲發(fā)不良反應(yīng)發(fā)生率高達(dá)40%，嚴(yán)重影響了患者的生存質(zhì)量。IGRT定位精確，腫瘤局部劑量高、劑量梯度下降快，并且能夠形成凹形靶區(qū)劑量分布，增加腫瘤局部控制率，減少危及直腸、膀胱、小腸、股骨頭等器官的損傷，從而減輕放療并發(fā)癥，在宮頸癌放療中被廣泛應(yīng)用。

綜上所述，早期宮頸癌術(shù)后患者的預(yù)后與術(shù)后放療方式、宮旁浸潤、淋巴結(jié)轉(zhuǎn)移、淋巴脈管間隙浸潤、神經(jīng)侵犯及腫瘤浸潤深度等因素密切相關(guān)。圖像引導(dǎo)調(diào)強(qiáng)放療［12-14］通過在線校正，實時調(diào)整擺位誤差，提高靶區(qū)的劑量，減少危及器官的受照劑量，及時改善劑量分布［15］，可較好地彌補(bǔ)傳統(tǒng)放療的局限性，具有很好的臨床應(yīng)用價值。由于本研究樣本量較少，后期需要大樣本進(jìn)一步探索，遠(yuǎn)期臨床療效還需進(jìn)一步評估。

[1] Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012[J]. CA Cancer J Clin,2015,65(2):87-108.

[2] Huang MN,An JS,Du XM.Research progress of radiotherapy for cervical cancer[J].Chin J Obstet Gynecol Pediatr(Electronic Ed),2016,12(1):7-15.[黃曼妮,安菊生,杜霄勐.宮頸癌放射治療的研究進(jìn)展[J].中華婦幼臨床醫(yī)學(xué)雜志(電子版),2016,12(1):7-15.]

[3] Mabuchi S,Morishige K,Isohashif,et al.Postoperative concurrent nedaplatin-based chemoradiotherapy improves survival in earlystage cervical cancer patients with adverse risk factors[J].Gynecol Oncol,2009,115(3):482-487.

[4] Shazly SA,Murad MH,Dowdy SC,et al.Robotic radical hysterectomy in early stage cervical cancer:A systematic review and metaanalysis[J].Gynecol Oncol,2015,138(2):457-471.

[5] Zong S,Wang X,Yang Y,et al.The use of cisplatin-loaded mucoadhesive nanofibers for local chemotherapy of cervical cancers in mice[J].Eur J Pharm Biopharm,2015,93:127-135.

[6] Wang XF,Chen YB,Han ZL,et al.Comparison of intensity modulated radiotherapy versus three dimensional conformal radiotherapy combined with brachytherapy in the treatment of advanced cervical cancer[J].Chin J Gerontology,2013,33(17):4119-4121.[王曉斐,陳玉丙,韓志龍,等.調(diào)強(qiáng)放療與三維適形放療聯(lián)合腔內(nèi)放療同步化療治療中晚期宮頸癌的對比[J].中國老年學(xué)雜志,2013,33(17): 4119-4121.]

[7] Yu Q,Lou XM.Establishment and analysis of survival evaluation system in postoperative patients with cervical cancer of stageⅠB andⅡA[J].Zhejiang Clin Med J,2015,17(3):401-402.[喻 晴,樓向明.ⅠB和ⅡA期宮頸癌患者術(shù)后生存評估體系建立與分析[J].浙江臨床醫(yī)學(xué),2015,17(3):401-402.]

[8] Ma XW.Analysis the postoperative recurrence and prognostic factors of 156 patients with the cervical carcinoma[D],Hebei Medical University,2014.[馬曉雯.宮頸癌156例術(shù)后復(fù)發(fā)及預(yù)后相關(guān)因素分析[D],河北醫(yī)科大學(xué),2014.]

[9] Yue HM,Xue XH,Zhang P.Correlation analysis of perineural invasion and prognosis of cervical cancer[J].Chin J Clinicians(Electronic Ed),2015,9(5):731-734.[岳慧敏,薛秀華,張 萍.宮頸癌神經(jīng)侵襲與其預(yù)后的相關(guān)性分析[J].中華臨床醫(yī)師雜志(電子版),2015,9(5): 731-734.]

[10]Ahmad R,Hoogeman MS,Bondar M,et al.Increasing treatment accuracy for cervical cancer patients using correlations between bladder-filling change and cervix-uterus displacements:proof of principle[J].Radiother Oncol,2011,98(3):340-346.

[11]Small W Jr,Winter K,Levenback C,et al.Extended-field irradiation and intracavitary brachytherapy combined with cisplatin and amifostine for cervical cancer with positive para-aorticor high common iliac lymph nodes:result of armⅡof Radiation Therapy Oncology Group(RTOG)0116[J].Int J Gynecol Cancer,2011,21(7):1266-1275.

[12]Bondar ML,Hoogemon MS,Mens JW,et al.Individualized nonadaptive and online-adaptive intensity-modulated radiotherapy treatment strategies for cervical cancer patients based on pretreatment acquired variable bladder filling computer tomography scans[J].Int J Radiat Oncol Biol Phys,2012,83(5):1617-1623.

[13]Langerak T,Heijkoop S,Quint S,et al.Towards automatic plan selection for radiotherapy of cervical cancer by fast automatic segmentation of cone beam CT scans[J].Med Image Comput Assist Interv, 2014,17(Pt1):528-535.

[14]Heijkoop ST,Langerak TR,Quint S,et al.Clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid motion management in locally advanced cervical cancer IMRT[J].Int J Radiat Oncol Biol Phys,2014,90(3):673－679.

[15]Meng QY,Zhang FQ.The influence of new technology on radiation therapy for locally advanced cervical cancer[J].Medical Journal of Peking Union Medical College Hospital,2013,4(4):433-437.[孟慶宇,張福全.放射治療新技術(shù)對局部晚期宮頸癌治療的影響[J].協(xié)和醫(yī)學(xué)雜志,2013,4(4):433-437.]

（2016-12-15收稿）

（2017-03-20修回）

Prognostic analysis and comparison of the efficacy and complication of different radiotherapy techniques for postoperative early cervical squamous cell carcinoma

Jiannan TU1,Xinling WANG2,Jingya ZHANG1,Weijun YE3,Hua JIN1
1Department of Gynecological Radiotherapy,Affiliated Tumor Hospital of Xinjiang Medical University,Urumqi 830011,China;2Department of Gynecology,Affiliated Tumor Hospital of Xinjiang Medical University,Urumqi 830011,China;3Department of Radiotherapy,Affiliated Tumor Hospital of Sun Yat-sen University,Guangzhou 510000,China

Hua JIN;E-mail:jinhua5616@sina.com

Objective:To explore the factors affecting the postoperative prognosis of early cervical squamous cell carcinoma and investigate the different radiotherapy techniques.Methods:A total of 100 postoperative patients of early cervical squamous cell carcinoma treated in Affiliated Tumor Hospital of Xinjiang Medical University and Affiliated Tumor Hospital of Sun Yat-sen University from March to September 2013 were enrolled in our study.The prognostic factors for these patients were analyzed.After being subjected to different postoperative radiotherapy techniques,the efficacy and complications of the techniques were assessed for patients,including 50 cases of conventional radiotherapy(CRT)and 50 cases of image-guided radiotherapy(IGRT).Results:The 3-year overall survival rate was 89%,and the 3-year disease-free survival rate was 78%.The 3-year overall survival rates of the CRT and IGRT groups were 78.57% and 89.06%,respectively.The difference between these rates was statistically significant(P=0.034).The 3-year survival rates of the CRT and IGRT groups were 66.67%and 87.36%,respectively.The difference was statistically significant(P=0.042).The incidence of early and late complications in the CRT group was higher than that in IGRT group,and the difference of P＜0.05 was statistically significant. Multivariate analysis showed that postoperative radiotherapy,parametrial invasion,lymph node metastasis,lymphovascular space invasion,perineural invasion,and deep stromal invasion were the independent risk factors for the prognosis of patients with early stage cervical squamous cell carcinoma.Conclusion:Early prognosis of cervical squamous cell carcinoma results from the interaction of multiple factors.The 3-year survival rate of the IGRT group was significantly better than that of the CRT group in the early stage of cervical squamous cell carcinoma.IGRT alleviates acute and chronic toxicities and helps improve the quality of life of patients.

cervical cancer,radiation therapy,prognosis,curative effect,complication

10.3969/j.issn.1000-8179.2017.06.426

①新疆醫(yī)科大學(xué)附屬腫瘤醫(yī)院婦科放射治療科（烏魯木齊市830011）；②新疆醫(yī)科大學(xué)附屬腫瘤醫(yī)院婦外四科；③中山大學(xué)附屬腫瘤醫(yī)院放療科

*本文課題受新疆維吾爾自治區(qū)科學(xué)技術(shù)廳科技支疆項目（編號：2013911130）資助

金華 jinhua5616@sina.com

This work was supported by the Science and Technology Branch of the Science and Technology Department of Xinjiang Uygur Autonomous Region(No.2013911130)

涂劍楠 專業(yè)方向為婦科惡性腫瘤放化療。

E-mail：13179839110@163.com