郭歡 孔玲玲 邢力剛
乳腺癌改良根治術(shù)后輔助放療(PMRT)的目的是殺滅術(shù)后殘存于胸壁和淋巴引流區(qū)的亞臨床病灶,降低局部區(qū)域復(fù)發(fā)率(LRR)和遠(yuǎn)處轉(zhuǎn)移率[1-2]。乳腺癌PMRT指南建議:原發(fā)腫瘤≥5cm或術(shù)后病理學(xué)檢查證實(shí)淋巴結(jié)轉(zhuǎn)移數(shù)目≥4個(gè)均推薦PMRT;淋巴結(jié)≤3個(gè)時(shí),是否需要PMRT應(yīng)根據(jù)患者復(fù)發(fā)轉(zhuǎn)移的高危因素而定[3-4]。新輔助化療(NAC)最初應(yīng)用于局部晚期乳腺癌患者,以使不可手術(shù)切除患者轉(zhuǎn)變?yōu)榭墒中g(shù)切除患者。近年來,NAC不僅被廣泛用于局部晚期乳腺癌患者,還被應(yīng)用于早期可手術(shù)乳腺患者。由于NAC的降期作用,傳統(tǒng)乳腺癌患者PMRT指南并不能完全適用于NAC后的患者。NAC后有10%~20%原發(fā)灶和腋窩淋巴結(jié)可達(dá)術(shù)后病理完全緩解(pCR)[5],腋窩淋巴結(jié) pCR 率可達(dá)到 20%~40%[6],在Her-2過表達(dá)的患者中,聯(lián)合注射用曲妥珠單抗(商品名:赫賽汀)的NAC方案更可使淋巴結(jié)轉(zhuǎn)陰率達(dá)74%[7]。由于NAC降低了術(shù)后病理學(xué)診斷對(duì)放療的指導(dǎo)價(jià)值,乳腺癌NAC加PMRT的應(yīng)用存在爭(zhēng)議。本文就國(guó)內(nèi)外乳腺癌NAC加PMRT的研究進(jìn)展綜述如下。
臨床Ⅱ期術(shù)后病理學(xué)檢查證實(shí)原發(fā)灶和腋窩淋巴結(jié)皆達(dá)pCR的患者,不推薦PMRT[8]。Cortazar等[9]研究認(rèn)為,可通過NAC后術(shù)后病理學(xué)檢查證實(shí)達(dá)pCR來篩選出預(yù)后較好的患者免行術(shù)后輔助治療;該研究分析了12 000例接受NAC的患者,結(jié)果表明達(dá)pCR者其無病生存(DFS)和總生存(OS)情況明顯好于未達(dá)pCR的患者。安德森腫瘤中心發(fā)現(xiàn),30例臨床Ⅱ期乳腺癌NAC后術(shù)后病理學(xué)檢查證實(shí)達(dá)pCR者無一局部復(fù)發(fā)[10]。有學(xué)者認(rèn)為cT1-2N0-1M0的患者,年齡>40歲、激素受體陽性且 NAC后達(dá)到 pCR或 pN0者其 LRR≤10%[11]。Mamounas等[12]發(fā)現(xiàn),臨床Ⅱ期達(dá)pCR患者不行PMRT,10年LRR<7%。因此對(duì)于初始臨床Ⅱ期NAC后改良根治術(shù)后病理學(xué)檢查證實(shí)達(dá)pCR患者,不推薦PMRT。
臨床Ⅱ期NAC后原發(fā)灶有殘留但達(dá)pN0可不行PMRT。研究表明178例cT2N0M0的患者NAC后術(shù)后病理學(xué)檢查證實(shí)pN0,不放療10年LRR約為6.3%,因此不推薦PMRT;37例cT1-2N1M0達(dá)pN0患者不放療10年LRR約為10.8%;95例cT3N0M0原發(fā)灶有殘留但達(dá)pN0者不放療10年LRR為11.8%[12]。Nagar等[13]研究表明,cT3N0M0術(shù)后病理證實(shí)達(dá)pN0者其5年LRR未能從PMRT中顯著獲益(2%vs 14%,P=0.06);然而,cT1-2N1M0和cT3N0M0兩組患者10年LRR>10%。Garg等[14]發(fā)現(xiàn),對(duì)于年齡<35歲接受NAC的患者,PMRT能夠明顯改善患者的局部控制和生存情況。因此若合并有以下因素可考慮行PMRT:年齡≤35歲,有瘤周脈管侵犯,HER-2基因過表達(dá)。
Le Scodan等[15]回顧性分析了134例臨床Ⅱ~Ⅲ期患者NAC后行改良根治術(shù),78例接受PMRT,56例未行PMRT;結(jié)果發(fā)現(xiàn)兩組患者10年LRR(3.8%vs 13.2%,P=0.18)、DFS(70.9%vs 79.8%,P=0.25) 及 OS(77.2%vs 87.7%,P=0.15)均無統(tǒng)計(jì)學(xué)差異。Shim 等[16]進(jìn)行了相似的研究,151例NAC后改良根治術(shù)后達(dá)pN0的臨床Ⅱ~Ⅲ期患者,其中105例接受PMRT,46例不行 PMRT,兩組患者 5 年 LRR(1.9%vs 7.7%,P=0.148)、5 年 DFS(91.2%vs 83.0%,P=0.441)及 5 年 OS(93.3%vs 89.9%,P=0.443)也均無統(tǒng)計(jì)學(xué)差異,患者的局部控制和生存情況也均未從PMRT中獲益。兩組研究納入的Ⅲ期患者比例不到40%余皆為Ⅱ期患者,因此對(duì)Ⅲ期患者PMRT的決策參考價(jià)值有限,但為Ⅱ期患者PMRT的決策提供了重要的參考[17]。
美國(guó)國(guó)家癌癥研究所建議NAC后pN+的患者需行PMRT[18]。多數(shù)專家認(rèn)為PMRT能改善NAC后pN+的患者局部控制和生存情況[19-21]。研究發(fā)現(xiàn),184例cT1-2N0M0術(shù)后病理學(xué)檢查證實(shí)pN+的患者不行放療10年LRR為12%;143臨床Ⅱ期中cT1-2N0M0術(shù)后病理證實(shí)pN+的患者不行放療患者10年LRR約為17%[12]。鐵劍等[23]發(fā)現(xiàn),136例cT1-2N0M0期、NAC后pN+乳腺癌患者行PMRT獲益顯著(16.5%vs 2.3%,P<0.01)。根據(jù)上述資料認(rèn)為,有必要對(duì)cT1-2N0M0術(shù)后病理證實(shí)達(dá)pN+患者行PMRT。
Nagar等[13]研究發(fā)現(xiàn)cT3N0M0患者NAC后術(shù)后病理學(xué)檢查證實(shí)達(dá)pN+者大約45%,說明臨床N分期很容易誤判。很多臨床ⅢA期患者被判斷為cT3N0M0。分析表明,NAC后pN+、pN0兩組患者不行放療5年LRR分別為53%、14%(P=0.02)。然而,術(shù)后淋巴結(jié)陽性患者放療后5年LRR僅為5%。資料表明,cT3N0M0且pN+的179例患者不行放療10年的LRR>14%;cT3N1M0且pN+的128例患者不行放療10年的LRR>22%[12]。因此,建議NAC后改良根治術(shù)后證實(shí)pN+的cT3N0M0患者行PMRT。
初始臨床ⅢA期除NAC后達(dá)pCR者PMRT仍存有爭(zhēng)議,未達(dá)pCR的患者較為肯定的能從PMRT中獲益[24-25]。臨床分期≥ⅢB期的患者不論是否達(dá)到pCR,PMRT均能改善患者的局部控制和生存情況。
Huang等[26]報(bào)道了一項(xiàng)回顧性研究,發(fā)現(xiàn)臨床Ⅲ期患者即使NAC后達(dá)pCR后仍有行PMRT的必要;676例局部晚期患者接受NAC后行改良根治術(shù),其中542例患者接受PMRT,134例患者未行PMRT,結(jié)果表明PMRT能改善患者10年的LRR(11%vs 22%,P<0.01),并且放療組患者的生存情況也得到了改善。該研究還對(duì)46例初始臨床Ⅲ期,術(shù)后證實(shí)原發(fā)灶和腋窩淋巴結(jié)達(dá)pCR的患者進(jìn)行了亞組分析,35例行PMRT,11例未行PMRT,結(jié)果表明PMRT能改善患者10年的LRR(3%vs 33%,P<0.01)。McGuire等[27]認(rèn)為臨床Ⅲ期不論 NAC后是否達(dá)pCR,PMRT能夠?yàn)榛颊邘砭植亢蜕娅@益。他們回顧性分析了106例術(shù)后病理學(xué)檢查證實(shí)原發(fā)灶和淋巴結(jié)達(dá)pCR的患者,其中72例行PMRT,34例未行PMRT,結(jié)果發(fā)現(xiàn),32例臨床Ⅰ~Ⅱ期患者10年的LRR為0,74例臨床Ⅲ期患者放療組LRR明顯低于未放療組(7.3%vs 33.3%,P=0.04),且放療組的OS也得到了改善(P<0.01)。
研究表明,cT3N1M0亞群11例NAC后達(dá)pCR患者不放療,10年LRR為0,84例達(dá)pN0的患者不放療10年LRR為9.2%。然而,F(xiàn)owble等[28]認(rèn)為,不論臨床Ⅲ期患者NAC后是否達(dá)pCR,LRR>25%,PMRT是綜合治療必不可少的一部分。初始cT4期放療組5年LRR為15%,而不放療5年LRR高達(dá)46%(P=0.002)。NAC后術(shù)后病理學(xué)檢查證實(shí)原發(fā)灶>5 cm,放療組5年LRR僅為2%,而不放療5年LRR為13%(P=0.01)。
總之,初始臨床Ⅱ期NAC后乳腺癌改良根治術(shù)后病理學(xué)檢查證實(shí)達(dá)pCR或pN0的患者,不常規(guī)推薦PMRT;初始臨床Ⅱ期NAC后乳腺癌改良根治術(shù)后pN+的患者,多數(shù)專家認(rèn)為PMRT能改善患者局部控制和生存情況。臨床ⅢA期除NAC后達(dá)pCR者PMRT仍存有爭(zhēng)議,其他患者較為肯定的能從PMRT中獲益。臨床≥ⅢB期的患者不論術(shù)后原發(fā)灶和腋窩淋巴結(jié)是否達(dá)到pCR,PMRT能改善患者的局部控制和生存情況。雖然本文所及研究為NAC后PMRT的決策提供了重要的參考,但關(guān)于NAC后PMRT的決策基本都是回顧性的,結(jié)果受制于回顧性研究的缺陷,包括入組標(biāo)準(zhǔn)各期混合,化療藥物使用類別和強(qiáng)度不一,大部分?jǐn)?shù)據(jù)源于單個(gè)中心且未全面考慮患者分子病理亞型,如ER、PR、Her-2等。因此關(guān)于乳腺癌患者NAC后PMRT的選擇仍需要大樣本的前瞻性臨床病例進(jìn)一步研究。
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