梁至潔 賈苗苗 陳 欽 王 靜 鄭 瑛 李玲妹 曹旭晨
·臨床研究與應(yīng)用·
術(shù)后放療對T1~2期伴1~3枚淋巴結(jié)轉(zhuǎn)移乳腺癌患者預(yù)后的影響*
梁至潔①賈苗苗①陳 欽①王 靜②鄭 瑛①李玲妹③曹旭晨①
目的:研究T1~2期伴1~3枚淋巴結(jié)轉(zhuǎn)移乳腺癌患者的預(yù)后危險(xiǎn)因素,并分析術(shù)后放療對帶有不同危險(xiǎn)因素患者局部復(fù)發(fā)及生存的影響。方法:回顧性分析2000年1月至2002年6月457例于天津醫(yī)科大學(xué)腫瘤醫(yī)院診治的T1~2期伴1~3枚淋巴結(jié)轉(zhuǎn)移乳腺癌患者的生存預(yù)后。通過Cox比例風(fēng)險(xiǎn)模型分析明確患者的獨(dú)立預(yù)后因素,并以這些因素進(jìn)行分層,通過生存分析探究放療對不同亞組患者預(yù)后的影響。結(jié)果:放療對整體患者的生存(HR=0.949,95%CI:0.435~2.074,P=0.896)與復(fù)發(fā)(HR= 0.611,95%CI:0.231~1.614,P=0.320)不是獨(dú)立有益因素,結(jié)外浸潤(ECE)和組織學(xué)Ⅲ級是預(yù)后的獨(dú)立危險(xiǎn)因素。以這兩個(gè)危險(xiǎn)因素分別進(jìn)行分層分析后發(fā)現(xiàn)放療對具危險(xiǎn)因素患者的預(yù)后有統(tǒng)計(jì)學(xué)意義(ECE+組OS:P=0.020,LRRFS:P=0.014;GradeⅢ組OS:P=0.002,LRRFS:P<0.001;)對無危險(xiǎn)因素組患者的預(yù)后無顯著性差異(ECE-亞組OS:P=0.353,LRRFS:P=0.796;GradeⅠ~Ⅱ亞組OS:P=0.267,LRRFS:P=0.589)。結(jié)論:結(jié)外浸潤和組織學(xué)Ⅲ級是T1~2期伴1~3枚陽性淋巴結(jié)乳腺癌患者預(yù)后的危險(xiǎn)因素,放療可以明顯改善這些帶危險(xiǎn)因素患者的無局部復(fù)發(fā)生存和總生存,而對于未發(fā)生結(jié)外浸潤及組織學(xué)級Ⅰ~Ⅱ的患者,放療對預(yù)后的影響無顯著性差異。
乳腺癌 放療 結(jié)外浸潤 組織學(xué)分級 預(yù)后
1The First Department of Breast Cancer,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research
Center of Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,Key Laboratory of Breast Cancer Prevention and
Therapy,Tianjin Medical University,Ministry of Education,Tianjin 300060,China;2Department of Radiation,Tianjin Medical
University Cancer Institute and Hospital,Tianjin National Clinical Research Center of Cancer,Key Laboratory of Cancer Preven
tion and Therapy,Tianjin,Tianjin 300060,China;3Department of Pathology,Tianjin Medical University Cancer Institute and Hos
pital,Tianjin National Clinical Research Center of Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,Tianjin
300060,China
This work was supported by The Tianjin Natural Science Foundation(No.11JCZDJC28000)
放療是乳腺癌患者術(shù)后的重要輔助治療之一,可改善患者的局部控制率及總生存率。目前對于T1~2期乳腺癌改良根治術(shù)后腋窩淋巴結(jié)轉(zhuǎn)移>3枚的患者或腋窩清掃不徹底的1~3枚淋巴結(jié)轉(zhuǎn)移的患者,術(shù)后行胸壁及鎖骨上淋巴引流區(qū)的預(yù)防性放療;而對伴有1~3枚淋巴結(jié)轉(zhuǎn)移的腋窩清掃相對徹底的乳腺癌患者改良根治術(shù)后是否放療一直存有爭議。最新的NCCN指南對T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者術(shù)后放療的選擇已由“考慮”改為“強(qiáng)烈推薦”。然而仍有臨床學(xué)者不建議在低復(fù)發(fā)率的情況下選擇放療[1],另有部分學(xué)者則認(rèn)為應(yīng)對此群組中帶有高危因素的患者進(jìn)行放療[2-4]。目前正在進(jìn)行的前瞻性臨床試驗(yàn),MRC/EORTC/SUPREMO試驗(yàn),其入組對象包括T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者,入組患者隨機(jī)進(jìn)入胸壁放療組或未放療組,但目前未有完善結(jié)果[5]。本研究回顧性分析457例T1~2期1~3枚轉(zhuǎn)移淋巴結(jié)乳腺癌患者的預(yù)后因素并初步探討放療在具不同危險(xiǎn)因素患者中的應(yīng)用價(jià)值。
1.1 一般資料
收集2000年1月至2002年6月在天津醫(yī)科大學(xué)腫瘤醫(yī)院診治的552例術(shù)后病理證實(shí)腋窩淋巴結(jié)轉(zhuǎn)移1~3枚乳腺癌病例,其中T1~2期457例納入本研究,全組患者中位年齡51(26~79)歲,均行改良根治術(shù),平均切檢淋巴結(jié)17(4~53)枚,基本資料見表1。
1.2 術(shù)后治療
術(shù)后行輔助化療,采用CAF/CEF/CMF方案,4~6個(gè)周期。381例激素受體(ER/PR)陽性患者均接受內(nèi)分泌治療,采用他莫西芬或芳香化酶抑制劑治療5年。346例患者接受術(shù)后放療,放療方案為患側(cè)胸壁野+/-同側(cè)淋巴引流區(qū)(鎖上野、內(nèi)乳野及腋窩野),胸壁采用6MEV電子線,DT(總劑量)45~50 Gy/25F,切口加量小野6MEV電子線加量,DT10~16 Gy。鎖上野、內(nèi)乳野采用6MEV電子線和6MV X線混合照射,DT50 Gy。
1.3 隨訪
患者在術(shù)后前2年門診復(fù)查4次/年,以后2次/年,復(fù)查內(nèi)容包括體格檢查,血常規(guī)等,由門診醫(yī)生視情況決定是否行影像學(xué)檢查。所有病例均有完整隨訪信息,由本院病案室進(jìn)行電訪或信訪,隨訪間隔半年,直至患者死亡,本研究中位隨訪時(shí)間123(15~155)個(gè)月。局部復(fù)發(fā)定義為同側(cè)乳腺、胸壁復(fù)發(fā)或腋窩、鎖骨上及內(nèi)乳淋巴結(jié)復(fù)發(fā)。無局部復(fù)發(fā)生存期(LRRFS)為手術(shù)之日至局部復(fù)發(fā)之日;總生存期(OS)為手術(shù)之日至死亡之日。
1.4 統(tǒng)計(jì)學(xué)方法
采用SPSS 19.0統(tǒng)計(jì)軟件進(jìn)行計(jì)算,用Kaplan-Meier法進(jìn)行生存分析,Log-rank進(jìn)行組間對比,用Cox比例風(fēng)險(xiǎn)模型進(jìn)行預(yù)后的多因素分析。P<0.05為差異有統(tǒng)計(jì)意義。
隨訪過程中,19(4.16%)例患者發(fā)生局部復(fù)發(fā),32(7.00%)例死亡。多因素分析結(jié)果顯示,結(jié)外浸潤(extracapsular extension,ECE)和組織學(xué)Ⅲ級分別為患者局部復(fù)發(fā)和死亡的獨(dú)立危險(xiǎn)因素,放療不是改善局部復(fù)發(fā)和生存的獨(dú)立因素(表2~3)。根據(jù)患者是否發(fā)生ECE和放療分為為ECE-PMRT-組、ECE-PMRT+組ECE+PMRT-組及ECE+PMRT+組;根據(jù)病理組織學(xué)分級及是否放療將患者分為GradeⅠ~ⅡPMRT-組、GradeⅠ~ⅡPMRT+組、GradeⅢPMRT-組及GradeⅢPMRT+組,各組局部復(fù)發(fā)及死亡情況見表4~5。分層分析發(fā)現(xiàn),放療對ECE-組患者生存及局部復(fù)發(fā)影響無統(tǒng)計(jì)學(xué)差異(OS:P=0.353,LRRFS:P=0.796),對ECE+組患者生存及局部復(fù)發(fā)皆有統(tǒng)計(jì)學(xué)差異(OS:P=0.020,LRRFS:P=0.014);放療對GradeⅠ~Ⅱ組患者生存及復(fù)發(fā)影響無統(tǒng)計(jì)學(xué)意義(OS:P=0.267,LRRFS:P=0.589),對GradeⅢ組患者生存及復(fù)發(fā)皆有統(tǒng)計(jì)學(xué)意義(OS:P=0.002,LRRFS:P<0.001)。
Rangan等[6]曾報(bào)道,1~3個(gè)淋巴結(jié)轉(zhuǎn)移乳腺癌患者術(shù)后在不接受放療情況下,經(jīng)化療及(或)內(nèi)分泌治療后局部復(fù)發(fā)率可控制在10%左右,然而近幾年的報(bào)道則傾向于放療可改善這些患者的局部控制[2-3,7]。Huang等[2]對318例T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移乳腺癌患者預(yù)后分析發(fā)現(xiàn),放療可以改善局部復(fù)發(fā)(P= 0.004)和無病生存率(P=0.001),但不能控制遠(yuǎn)處轉(zhuǎn)移率(P=0.074)和總生存率(P=0.239),Cosar等[7]的報(bào)道亦指出放療對局部復(fù)發(fā)控制有統(tǒng)計(jì)學(xué)意義(P= 0.038),對總生存無顯著影響(P=0.087)。安德森腫瘤中心(M.D.Anderson Cancer Center)[1]報(bào)道近年T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者10年復(fù)發(fā)率為4.3%,與本組總復(fù)發(fā)率(4.16%)相符。Olivotto等[8]及Taylor等[9]建議,若總體復(fù)發(fā)率低于10%,則不推薦放療作為常規(guī)治療。而本研究亦發(fā)現(xiàn),放療并不能改善整體生存率及局部控制,與國內(nèi)一些報(bào)道不完全相符[10-11]。吳冬梅等[10]報(bào)道,放療對T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者的5年生存率和復(fù)發(fā)率影響皆有統(tǒng)計(jì)學(xué)差異(OS:P=0.047,LRRS:P=0.034),郝建磊等[11]則報(bào)道在T2期1~3枚淋巴結(jié)轉(zhuǎn)移患者中放療雖然可以控制整體的10年局部復(fù)發(fā)(P=0.035),但對總體生存率無影響(P=0.094)。本研究進(jìn)一步分析發(fā)現(xiàn)放療在局部高危亞組,即ECE+或gradeⅢ的患者中可以影響局部復(fù)發(fā)及總生存率。本研究與其它報(bào)道發(fā)現(xiàn)的不符考慮可能是不同樣本之間高風(fēng)險(xiǎn)患者組成比例差異所致。
ECE是一種在腋窩淋巴結(jié)轉(zhuǎn)移乳腺癌患者中常見的病理特征,是局部復(fù)發(fā)危險(xiǎn)因素之一,在國外已受到不少學(xué)者關(guān)注[12-13]。Ilknur等[12]發(fā)現(xiàn),ECE顯著降低Ⅰ~Ⅲ期乳腺癌患者的無病生存率(P=0.040)和無遠(yuǎn)處轉(zhuǎn)移率(P=0.002),Neri[13]等通過對376名T1~3期患者的分析后發(fā)現(xiàn),ECE對無病生存率、局部無復(fù)發(fā)率、無遠(yuǎn)處轉(zhuǎn)移率和總生存率的影響皆有統(tǒng)計(jì)學(xué)差異(DFS:P<0.001,LRRFS:P=0.037,DMFS:P<0.001,OS:P<0.001)。然而國內(nèi)對ECE研究極少,宋艷群等[14]發(fā)現(xiàn),ECE對4~9枚淋巴結(jié)轉(zhuǎn)移患者的局部復(fù)發(fā)及生存率影響顯著;Geng等[15]報(bào)道ECE是1~3枚淋巴結(jié)轉(zhuǎn)移患者局部復(fù)發(fā)的危險(xiǎn)因素(P= 0.006),卻未分析其在T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者對放療反應(yīng)的影響。本研究發(fā)現(xiàn)ECE是T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者局部復(fù)發(fā)(HR=1.197,95% CI:1.097~3.6101,P=0.039)和死亡(HR=1.471,95% CI:1.121~3.475,P=0.009)的危險(xiǎn)因素,雖然本文中ECE+患者的局部復(fù)發(fā)率小于10%(ECE+:8.0%vs. ECE-:3.3%),但分層分析發(fā)現(xiàn)放療在ECE+患者中確實(shí)可以影響局部復(fù)發(fā)及總生存率,值得注意的是,若單獨(dú)考慮未接受放療ECE+患者,其復(fù)發(fā)率可高達(dá)25.4%,而另一方面,放療對于ECE-患者的預(yù)后的影響并無統(tǒng)計(jì)學(xué)差異。Hamamoto等[16]分析248例未行放療的T1~2期1~3枚淋巴結(jié)陽性患者局部復(fù)發(fā)率后發(fā)現(xiàn),合并淋巴血管浸潤陽性的激素受體陰性患者10年復(fù)發(fā)率由總體激素受體陰性患者的10%升至17%。基于Olivotto等[8]及Taylor等[9]的建議,Hamamoto認(rèn)為應(yīng)對激素受體陰性伴淋巴血管浸潤陽性T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者進(jìn)行放療。本研究數(shù)據(jù)顯示ECE+患者未經(jīng)放療干預(yù)的復(fù)發(fā)率為25.4%,亦符合放療的指證。此外,放療同樣能逆轉(zhuǎn)組織學(xué)Ⅲ級對預(yù)后的影響,而對gradeⅠ~Ⅱ患者預(yù)后無影響,而gradeⅢ組的總體局部復(fù)發(fā)率為20.0%,未經(jīng)放療干預(yù)的gradeⅢ患者的局部復(fù)發(fā)率高達(dá)54.5%。
隨著對T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移患者高危因素的深入認(rèn)識,對該類患者是否選擇放療的爭論演變?yōu)閼?yīng)對何種患者放療。目前各學(xué)者對高危因素的看法并不統(tǒng)一,淋巴血管浸潤、陽性淋巴結(jié)比率,受體狀態(tài)等因素亦在各家討論范圍[2-4,6],但因缺乏大樣本的報(bào)道,故尚無定論。本研究亦存在一定的局限性,由于樣本量限制,患者死亡及復(fù)發(fā)率很低,且屬于回顧性研究,對各組患者的放療選擇不能控制,因此本文結(jié)果有待大樣本前瞻性試驗(yàn)證實(shí)。
本研究顯示,放療僅對部分T1~2期1~3枚淋巴結(jié)轉(zhuǎn)移乳腺癌患者的預(yù)后有影響,ECE+和(或)組織學(xué)Ⅲ級的患者強(qiáng)烈建議接受放療以獲得更好的局部控制及生存率。
1 Sharma R,Bedrosian I,Lucci A,et al.Present-day locoregional control in patients with t1 or t2 breast cancer with 0 and 1 to 3 positive lymph nodes after mastectomy without radiotherapy[J].Ann Surg Oncol,2010,17(11):2899-2908.
2 Huang CJ,Hou MF,Chuang HY,et al.Comparison of clinical outcome of breast cancer patients with T1-2 tumor and one to three positive nodes with or without postmastectomy radiation therapy [J].Jpn J Clin Oncol,2012,42(8):711-720.
3 Duraker N,Demir D,Bati B,et al.Survival benefit of post-mastectomy radiotherapy in breast carcinoma patients with T1-2 tumor and 1-3 axillary lymph node(s)metastasis[J].Jpn J Clin Oncol, 2012,42(7):601-608.
4 Yang PS,Chen CM,Liu MC,et al.Radiotherapy can decrease locoregional recurrence and increase survival in mastectomy patients with T1 to T2 breast cancer and one to three positive nodes with negative estrogen receptor and positive lymphovascular invasion status[J].Int J Radiat Oncol Biol Phys,2010,77(2):516-522.
5 Kunkler IH,Canney P,van Tienhoven G,et al.Elucidating the role of chest wall irradiation in'intermediate-risk'breast cancer:the MRC/EORTC SUPREMO trial[J].Clin Oncol,2008 20(1):31-34.
6 Rangan AM,Ahern V,Yip D,et al.Local recurrence after mastectomy and adjuvant CMF:implications for adjuvant radiation therapy [J].Aust N Z Surg,2000,70(9):649-655.
7 Cosar R,Uzal C,Tokatli F,et al.Postmastectomy irradiation in breast in breast cancer patients with T1-2 and 1-3 positive axillary lymph nodes:is there a role for radiation therapy[J]?Radiat Oncol, 2011,6:28.
8 Olivotto IA,Truong PT,Chua B.Postmastectomy radiation therapy:who needs it[J]?J Clin Oncol,2004,22(21):4237-4239.
9 Taylor ME,Haffty BG,Rabinovitch R,et al.ACR appropriateness criteria on postmastectomy radiotherapy expert panel on radiation oncology-breast[J].Int J Radiat Oncol Biol Phys,2009,73(4):997-1002.
10 Wu DM,Liu GJ.The Analysis of Clinical Value and Prognostic Factors of Postmastectomy Radiotherapy in Bresat Cancer Patients with 1-3 Positive Axillary Lymph Nodes[J].The Journal of Practical Medicine,2013,29(2):230-232.[吳冬梅,劉冠軍.術(shù)后放療對早期伴有1~3個(gè)陽性淋巴結(jié)乳腺癌患者的臨床價(jià)值及其預(yù)后因素分析[J].實(shí)用醫(yī)學(xué)雜志,2013,29(2):230-232.]
11 Hao JL,Xu LM,Gao QL,et al.Value of Postmastectomy Radiotherapy in T2 Bresat Cancer Patients with 1~3 Positive Axillary Lymph Nodes[J].Chin J of Clin Oncol,2010,37(2):113-116.[郝建磊,徐利明,高秋玲,等.術(shù)后放療在伴有腋窩淋巴結(jié)1~3枚陽性T2期乳腺癌中的作用[J].中國腫瘤臨床,2010,37(2):113-116.]
12 Ilknur GB,Hilmi A,Tülay C,et al.The importance of extracapsular extension of axillary lymph node metastases in breast cancer[J]. Tumori,2004,90(1):107-111.
13 Neri A,Marrelli D,Roviello F,et al.Prognostic value of extracapsular extension of axillary lymph node metastases in T1 to T3 breast cancer[J].Ann Surg Oncol,2005,12(3):246-253.
14 Shong YQ,Zhang Bin,Zhang HM,et al.The Effect of Extracapsular Extension on the Prognosis of Different Pathologically-Positive Axillary Lymph Node Levels in Breast Cancer[J].Chin J of Clin Oncol,2010,37(15):862-865.[宋艷群,張 斌,趙洪猛,等.乳腺癌結(jié)外浸潤對不同水平腋窩淋巴結(jié)受累患者預(yù)后的影響[J].中國腫瘤臨床,2010,37(15):862-865.]
15 Geng W,Zhang B,Li D,et al.The effects of ECE on the benefits of PMRT for breast cancer patients with positive axillary nodes[J].J Radiat Res,2013,54(4):712-718.
16 Hamamoto Y,Ohsumi S,Aogi K,et al.Are there high-risk subgroups for isolated locoregional failure in patients who had T1/2 breast cancer with one to three positive lymph nodes and received mastectomy without radiotherapy[J]?Breast Cancer,2012,[Epub ahead of print]
(2013-09-05收稿)
(2014-01-25修回)
(本文編輯:周曉穎)
Effects of post-mastectomy radiation therapy on T1-2 stage and one to three positive lymph node breast cancer patients with different risk factors
Zhijie LIANG1,Miaomiao JIA1,Qin CHEN1,Jing WANG2,Ying ZHENG1,Lingmei LI3,Xuchen CAO1
Correspondence to:Xunchen Cao;E-mail:cxc@medmail.com.cn
Objective:To retrospectively evaluate the prognostic risk factors of T1-2 stage breast cancer patients with one to three positive node(s)and their effects on the benefits of post-mastectomy radiation therapy(PMRT).Methods:We retrospectively analyzed 457 breast cancer patients with T1-2 stage and one to three positive axillary lymph nodes treated in our hospital between 2000 and 2002.The independent prognostic factors of the patients were calculated by the Cox proportional hazards model.The patients were further classified into high-risk and low-risk subgroups according to the risk factors to explore the benefit of PMRT on the prognosis of different subgroups using survival analysis.Results:PMRT was not an independent beneficial factor of overall survival(OS)(HR=0.949; CI:0.435-2.074;P=0.896)or loco-regional recurrent free survival(LRRFS)(HR=0.611;CI:0.231-1.614;P=0.320)in all patients.Extracapsular extension(ECE)and pathological grades were independent prognostic risk factors,and the benefits of PMRT were significantly different on the prognosis of high-risk subgroup patients(group ECE+OS:P=0.020,LRRFS:P=0.014;group GradeⅢOS:P= 0.002,LRRFS:P<0.001).Meanwhile,PMRT failed to prolong the OS and LRRFS of low-risk subgroup patients(group ECE+OS:P= 0.353,LRRFS:P=0.796;group GradeⅠtoⅡOS:P=0.267,LRRFS:P=0.589).Conclusion:ECE and gradeⅢwere the independentrisk factors of death and loco-regional recurrence in the T1-2 breast cancer patients with one to three positive lymph node(s).PMRT was an effective adjuvant therapy to improve the prognosis of patients with high-risk factors.However,the benefit of PMRT had no significance in patients with ECE-or gradeⅠ-Ⅱ.
breast neoplasm,PMRT,ECE,histological grade,prognosis
10.3969/j.issn.1000-8179.20131490
梁至潔 碩士研究生。研究方向?yàn)槿橄偻饪啤?/p>
①天津醫(yī)科大學(xué)腫瘤醫(yī)院乳腺一科,國家腫瘤臨床醫(yī)學(xué)研究中心,天津市腫瘤防治重點(diǎn)實(shí)驗(yàn)室,乳腺癌防治教育部重點(diǎn)實(shí)驗(yàn)室(天津市300060);②放療科;③病理科
*本文課題受天津市自然科學(xué)基金項(xiàng)目(編號:11JCZDJC28000)資助
曹旭晨 cxc@medmail.com.cn
E-mail:lzjmed@163.com