丁柱良 吳智勇
·綜述·
乳腺癌孤立性局部區(qū)域復(fù)發(fā)的診斷和治療
丁柱良 吳智勇*
乳腺癌孤立性局部區(qū)域復(fù)發(fā)受多種危險(xiǎn)因素影響,雖然預(yù)示著隨后可能出現(xiàn)遠(yuǎn)處轉(zhuǎn)移,然而經(jīng)過(guò)規(guī)范的診斷和治療,仍可獲得較好的局部控制率和遠(yuǎn)期生存率。其復(fù)發(fā)具有較大的臨床異質(zhì)性,因而治療也應(yīng)根據(jù)不同的情況選擇合理的局部治療和全身治療手段,達(dá)到改善患者生活質(zhì)量和提高遠(yuǎn)期生存的目的。
乳腺腫瘤;腫瘤復(fù)發(fā),局部;診療
乳腺癌局部復(fù)發(fā)是指早期乳腺癌保乳或全乳切除術(shù)后同側(cè)乳腺和(或)胸壁再次出現(xiàn)腫瘤,區(qū)域復(fù)發(fā)是指患側(cè)的淋巴引流區(qū)域再次出現(xiàn)腫瘤,范圍包括鎖骨上下、腋窩及內(nèi)乳淋巴結(jié)區(qū)域。孤立性局部區(qū)域復(fù)發(fā)(isolated local?regional recur?rence,ILRR)是指局部?區(qū)域復(fù)發(fā)時(shí),通過(guò)常規(guī)檢查手段沒(méi)有發(fā)現(xiàn)其他部位的轉(zhuǎn)移。
早期乳腺癌試驗(yàn)協(xié)作組(EBCTCG)的研究表明,早期乳腺癌保乳術(shù)后10年局部區(qū)域復(fù)發(fā)率在放療組和非放療組中分別為8.0%和25.0%[1],全乳切除術(shù)后淋巴結(jié)陰性患者中10年局部區(qū)域復(fù)發(fā)率在放療組和非放療組中分別為1.6%和3.0%,而在淋巴結(jié)陽(yáng)性患者中分別為8.1%和26.0%[2]??傮w而言,保乳術(shù)后的孤立性局部復(fù)發(fā)率明顯高于全乳切除術(shù)后,歐洲癌癥治療研究組織(EORTC)[3]對(duì)3602名早期乳腺癌患者的多因素分析結(jié)果表明,保乳手術(shù)是孤立性局部區(qū)域復(fù)發(fā)的危險(xiǎn)因素,其風(fēng)險(xiǎn)比為1.82(95%CI,1.17 to 2.86)。乳腺癌術(shù)后局部區(qū)域復(fù)發(fā)受多種因素的影響,不同的研究得到的危險(xiǎn)因素也不盡相同,較為公認(rèn)的危險(xiǎn)因素為低齡、較晚的分期、脈管浸潤(rùn)、分子分型等。Veronesi等[4]報(bào)導(dǎo)了一項(xiàng)米蘭癌癥中心2233名患者的回顧性研究,對(duì)比年齡大于65歲的患者,年齡小于35歲的乳腺癌患者局部區(qū)域復(fù)發(fā)的風(fēng)險(xiǎn)比為3.777,腫瘤直徑大于2 cm對(duì)比小于0.5 cm的風(fēng)險(xiǎn)比為3.159,同時(shí)復(fù)發(fā)的風(fēng)險(xiǎn)與淋巴結(jié)轉(zhuǎn)移的數(shù)量呈正相關(guān)。Buchanan等[5]的另一項(xiàng)回顧性研究表明,Ⅱ期、Ⅲ期對(duì)比Ⅰ期乳腺癌分別增加了4%和10%的絕對(duì)LRR率,脈管浸潤(rùn)患者增加了9%的復(fù)發(fā)率,小于35歲患者增加了7%的絕對(duì)LRR率。Nguyen等[6]通過(guò)793名保乳術(shù)后患者的多因素發(fā)現(xiàn)HER?2過(guò)表達(dá)型(HR=9.2;95%CI,1.6 to 51;P=0.012)和三陰型(HR=7.1;95%CI,1.6 to 31;P=0.009)顯著增加了局部?區(qū)域復(fù)發(fā)率。一項(xiàng)入組了12592名乳腺癌術(shù)后患者的meta分析證實(shí),對(duì)于保乳術(shù)后患者,luminal型對(duì)比三陰型和Her?2過(guò)表達(dá)型降低了60%以上的LRR率,而全切術(shù)后患者,亦可降低30%以上的LRR率[7],同時(shí)其無(wú)病間隔亦遠(yuǎn)遠(yuǎn)長(zhǎng)于其它分子分型患者[8]。目前,對(duì)于21基因復(fù)發(fā)指數(shù)能否預(yù)測(cè)LRR率仍有較大爭(zhēng)議,盡管有部分回顧性研究發(fā)現(xiàn)高RS患者有著更高的局部域復(fù)發(fā)率[9],但一項(xiàng)前瞻性隨機(jī)對(duì)照試驗(yàn)[10]顯示,RS作為L(zhǎng)RR獨(dú)立危險(xiǎn)因素仍缺乏令人信服的證據(jù)。
及時(shí)地發(fā)現(xiàn)乳腺癌孤立性局部區(qū)域復(fù)發(fā),有助于及早處理復(fù)發(fā),改善患者生存。病人和醫(yī)生定期的視診和觸診是必不可少的,體表的復(fù)發(fā)結(jié)節(jié)往往可以通過(guò)視診和觸診發(fā)現(xiàn)。然而,大約有40%的無(wú)癥狀孤立性局部復(fù)發(fā)患者是在常規(guī)影像檢查中發(fā)現(xiàn)的[11],因而定期的檢查對(duì)發(fā)現(xiàn)ILRR患者十分重要,常規(guī)的影像檢查包括乳腺鉬靶檢查(保乳患者)和超聲檢查。盡管上述方法能夠發(fā)現(xiàn)大部分的復(fù)發(fā)患者,然而仍然有少部分人會(huì)出現(xiàn)假陰性,乳腺M(fèi)RI能夠提高LRR患者的檢出率,尤其是保乳術(shù)后患者,MRI對(duì)復(fù)發(fā)結(jié)節(jié)與術(shù)后或放療后組織的正常改變的鑒別優(yōu)于鉬靶[12,13]。
凡是臨床發(fā)現(xiàn)可疑結(jié)節(jié)的患者,均應(yīng)通過(guò)穿刺活檢或手術(shù)切除活檢[14]確定是否為復(fù)發(fā)結(jié)節(jié),B超引導(dǎo)下穿刺活檢在保乳術(shù)后同側(cè)乳房出現(xiàn)可疑結(jié)節(jié)或鈣化點(diǎn)的鑒別診斷很有意義。應(yīng)常規(guī)測(cè)定復(fù)發(fā)結(jié)節(jié)的激素受體狀態(tài)和HER?2狀態(tài),尤其是初發(fā)病灶分子分型不確定的患者。確定為腫瘤局部區(qū)域復(fù)發(fā)的患者,進(jìn)行完整全面的檢查以評(píng)估有無(wú)合并遠(yuǎn)處轉(zhuǎn)移是必須的,因?yàn)楹喜⑦h(yuǎn)處轉(zhuǎn)移的局部區(qū)域復(fù)發(fā)患者,其局部治療的價(jià)值和ILLR是完全不同的。
乳腺癌術(shù)后孤立性局部區(qū)域復(fù)發(fā)有較大的臨床異質(zhì)性,因既往手術(shù)方式、系統(tǒng)治療、是否放療、復(fù)發(fā)范圍和復(fù)發(fā)時(shí)間間隔等不同而不同,因而治療也應(yīng)根據(jù)不同的情況區(qū)別對(duì)待。
3.1 保乳手術(shù)后同側(cè)乳房復(fù)發(fā)的局部治療
對(duì)于可手術(shù)的保乳術(shù)后孤立性局部復(fù)發(fā)患者,挽救性乳房全切術(shù)是標(biāo)準(zhǔn)的局部治療手段,可以獲得69%~98%的5年局部控制率和約53%~85%的總生存率[15;16]。如果初次手術(shù)時(shí)未行腋窩淋巴結(jié)清掃術(shù),可同時(shí)清掃I、II組淋巴結(jié)。
盡管挽救性乳房全切術(shù)是簡(jiǎn)單可靠的處理措施,然而越來(lái)越多的臨床試驗(yàn)證實(shí),在經(jīng)過(guò)嚴(yán)格選擇的病人中,二次保乳手術(shù)加術(shù)后部分乳房照射代替乳房全切術(shù)可以獲得與全乳切除相似的局部控制率和生存率[17?20],進(jìn)行二次保乳應(yīng)該嚴(yán)格挑選局部復(fù)發(fā)風(fēng)險(xiǎn)相對(duì)較低的患者。Gentilini[21]對(duì)161名孤立性局部區(qū)域復(fù)發(fā)后接受二次保乳手術(shù)的患者進(jìn)行了回顧性分析發(fā)現(xiàn),復(fù)發(fā)腫瘤≤2 cm和無(wú)病間隔大于48個(gè)月的患者能夠獲得更好的局部控制率,其HR分別為3.3和1.9。目前對(duì)于哪一部分的病人可以進(jìn)行二次保乳,仍缺乏明確的標(biāo)準(zhǔn),有待進(jìn)一步的研究。
二次保乳后必須予術(shù)后乳房照射減少術(shù)后復(fù)發(fā),然而二次放療帶來(lái)的副作用也在一定程度上影響了患者的生活質(zhì)量。為減少二次放療的副作用,目前傾向于使用近距離照射技術(shù),其中歐洲GEC?ESTRO的多中心研究入組了217名患者,采用了多管插植近距離治療獲得良好的治療效果,中位隨訪(fǎng)時(shí)間46.8月,其10年保險(xiǎn)統(tǒng)計(jì)局部控制率為93%,OS為76%,放療3~4度并發(fā)癥發(fā)生率僅為11%[22]。
3.2 乳房切除術(shù)后胸壁復(fù)發(fā)的局部治療
乳房切除術(shù)后胸壁復(fù)發(fā)可分為局限性復(fù)發(fā)和彌漫性復(fù)發(fā),對(duì)于可手術(shù)的局限性復(fù)發(fā)患者,如果以前未行放療的,最佳治療方式是根治性切除加放療,術(shù)后放療對(duì)比單純放療,其局部控制率和5年生存率均有明顯獲益[23]。首次復(fù)發(fā)患者,如果僅僅行小野照射仍有64%的5年胸壁復(fù)發(fā)率,而行全胸壁照射胸壁復(fù)發(fā)率僅為25%[24],因而,放療范圍應(yīng)包括患側(cè)全胸壁和鎖骨上/下淋巴引流區(qū),其5年局部控制率為77%,5年DFS和OS分別為41%和55%[25],在標(biāo)準(zhǔn)放療方案的50GY/25次分割基礎(chǔ)上增加劑量沒(méi)有帶來(lái)明顯的獲益[25]。
目前,乳房切除術(shù)后胸壁復(fù)發(fā)再次放療的價(jià)值仍需進(jìn)一步探索。應(yīng)慎重考慮兩次放療的間隔,正常組織的改變程度,衡量再次放療的獲益與風(fēng)險(xiǎn),再行決定。Wahl等[26]對(duì)81例乳房切除術(shù)后胸壁復(fù)發(fā)予再次放療,中位隨訪(fǎng)時(shí)間12個(gè)月,無(wú)一例出現(xiàn)治療相關(guān)性死亡,僅有4例出現(xiàn)3/4級(jí)不良事件,總體反應(yīng)率為57%。同時(shí)再次放療聯(lián)合局部熱療能進(jìn)一步提高局部反應(yīng)率[27]。對(duì)于不可手術(shù)的局限性復(fù)發(fā)或彌漫性復(fù)發(fā)患者,全身治療是首選的治療方法,部分患者全身治療后可以獲得手術(shù)機(jī)會(huì)。
3.3 孤立性腋窩淋巴結(jié)復(fù)發(fā)的局部治療
腋窩清掃是主要的治療手段,若既往已行腋窩清掃,則對(duì)復(fù)發(fā)灶切除即可,可以獲得較好的局部控制率和遠(yuǎn)期生存[28]。既往未行術(shù)后放療的患者,需對(duì)鎖骨上下引流區(qū)和胸壁進(jìn)行預(yù)防性照射。
3.4 孤立性鎖骨上淋巴結(jié)復(fù)發(fā)的局部治療
鎖骨上淋巴結(jié)轉(zhuǎn)移對(duì)比其它局部區(qū)域復(fù)發(fā)患者預(yù)后較差[29]。Pergolizzi等[29]發(fā)現(xiàn)對(duì)比單純化療,化療結(jié)合鎖骨上下引流區(qū)的放療能夠帶好更好的無(wú)進(jìn)展生存和總生存獲益。丹麥乳腺癌合作組的305名無(wú)合并遠(yuǎn)處轉(zhuǎn)移的的鎖骨上淋巴結(jié)復(fù)發(fā)患者的中位25個(gè)月隨訪(fǎng)資料表明,局部治療聯(lián)合全身治療對(duì)比單純?nèi)碇委?,其完全緩解率分別為67%和48%,其中手術(shù)清掃鎖骨上淋巴結(jié)的完全緩解率為76%,結(jié)果表明局部治療聯(lián)合全身治療能夠帶來(lái)更好的PFS和OS[30]
3.5 全身治療
可手術(shù)的孤立性復(fù)發(fā)患者,過(guò)去對(duì)于全身化療的獲益是有較大爭(zhēng)議的,因此由Aebi等發(fā)起一項(xiàng)前瞻性隨機(jī)對(duì)照CALOR試驗(yàn)[31]旨在評(píng)估孤立性復(fù)發(fā)患者根治術(shù)后放療后全身化療的價(jià)值,化療組推薦使用3~6個(gè)月的聯(lián)合化療方案,結(jié)果顯示聯(lián)合化療對(duì)比非化療組顯著提高了5年DFS(HR,0.59;95%CI,0.35 to 0.99;P=0.046)和OS(HR,0.41;95%CI,0.19 to 0.89;P=0.02)。亞組分析顯示全身化療顯著提高了復(fù)發(fā)腫瘤ER受體陰性患者的5年DFS(HR,0.32;95%CI,0.14 to 0.73)和OS(HR,0.43;95%CI,0.15 to 1.24),而在復(fù)發(fā)腫瘤ER受體陽(yáng)性患者,化療組沒(méi)有明顯獲益。該試驗(yàn)證實(shí)了全身化療在可手術(shù)的孤立性復(fù)發(fā)患者中的作用。
SAKK的一項(xiàng)三期隨機(jī)試驗(yàn)[32]表明,復(fù)發(fā)腫瘤根治術(shù)后放療后激素受體陽(yáng)性患者使用他莫昔芬內(nèi)分泌治療,明顯改善了絕經(jīng)后患者的5年DFS(P=0.006),但是DFS獲益沒(méi)有轉(zhuǎn)變?yōu)榭偵娅@益,這可能與絕經(jīng)后患者的死亡原因更多是非乳腺癌相關(guān)的因素。令人意外絕經(jīng)前的婦女沒(méi)有從應(yīng)用TAM中獲益,這可能是受限于入組人數(shù)的原因,仍待進(jìn)一步的研究。
孤立性局部區(qū)域復(fù)發(fā)HER?2陽(yáng)性患者的抗HER?2治療目前的研究極少,對(duì)于曲妥珠單抗的應(yīng)用可以參考Her?2復(fù)發(fā)轉(zhuǎn)移乳腺癌的治療,沒(méi)有曲妥珠單抗耐藥的情況上,推薦使用曲妥珠單抗治療,聯(lián)合紫杉類(lèi)化療療效更佳[33]。
乳腺癌孤立性局部區(qū)域復(fù)發(fā)的預(yù)后受多種因素影響。保乳術(shù)后同側(cè)乳房復(fù)發(fā)患者預(yù)后較好,而全乳切除術(shù)后胸壁復(fù)發(fā)預(yù)后則相對(duì)較差,往往提示著隨后可能出現(xiàn)遠(yuǎn)處轉(zhuǎn)移。Shenouda等[34]對(duì)220名ILRR患者進(jìn)行了長(zhǎng)期的隨訪(fǎng),其中保乳術(shù)后ILRR患者治療后其中位無(wú)病間隔為79個(gè)月,而全乳切除術(shù)后ILRR患者僅為38個(gè)月,前者的5年和8年OS分別為81%和69%,而后者為61%和46%。兩者5年無(wú)遠(yuǎn)處轉(zhuǎn)移(DMFS)率分別為84%和60%。
Schmoor[35]對(duì)來(lái)自四個(gè)前瞻性研究的337名ILRR患者進(jìn)行了分析,中位隨訪(fǎng)時(shí)間為4.5年,結(jié)果顯示首診時(shí)淋巴結(jié)轉(zhuǎn)移個(gè)數(shù)較少、原發(fā)腫瘤的腫瘤分級(jí)較低、雌激素受體陽(yáng)性和無(wú)病間隔較長(zhǎng)的患者能夠獲得更好的DFS和OS。Monique[36]的一項(xiàng)研究通過(guò)多因素分析發(fā)現(xiàn)影響ILRR患者死亡的三個(gè)獨(dú)立預(yù)后因素是:腫瘤的組織學(xué)分級(jí),初診乳腺癌時(shí)的年齡和無(wú)病間隔。
規(guī)范的術(shù)后隨訪(fǎng)復(fù)查有助于及早發(fā)現(xiàn)乳腺癌孤立性局部區(qū)域復(fù)發(fā)。乳腺癌孤立性局部區(qū)域復(fù)發(fā)具有顯著的臨床異質(zhì)性,治療上應(yīng)根據(jù)不同的臨床指標(biāo)選擇個(gè)體化的局部治療和全身治療。局部治療是孤立性局部區(qū)域復(fù)發(fā)的重要手段,CAL?OR試驗(yàn)首次證實(shí)了孤立性復(fù)發(fā)患者根治術(shù)后化療的價(jià)值,分子靶向和內(nèi)分泌治療對(duì)表達(dá)相應(yīng)生物標(biāo)記物的個(gè)體不可或缺。全乳切除術(shù)后孤立性局部區(qū)域復(fù)發(fā)比保乳術(shù)后復(fù)發(fā)預(yù)后差,前者的最佳治療策略值得深入研究。
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Diagnosis and treatment of isolated locoregional breast cancer recurrences
DING Zhuliang,WU Zhiyong.Department ofDiagnosisand Treatment Center ofBreast Disease,Shantou Central Hospital,Shantou 51500,China.Corresponding author:WU Zhiyong,stwuzy@163.com
Isolated Locoregional Breast Cancer Recurrences is subject to various risk factors. While it indicates the potential of distantmetastasis,favorable local control rate and long?term survival rate could be expected with standard diagnosis and treatment.Given the high clinical heterogeneity of such recurrence,local and systemic therapies should be selected as appropriate for the patient's specific condition,in an effort to improve patient’s quality of life and long?term survival.
breastneoplasms;neoplasm recurrence,local;diagnosis and treatment
R737.9
A
10.3969/j.issn.1009?976X.2017.03.031
2017-04-18
廣東省2014年揚(yáng)帆計(jì)劃項(xiàng)目(粵財(cái)教(2014)171號(hào))
515000廣東汕頭汕頭市中心醫(yī)院乳腺疾病診療中心
*通訊作者:吳智勇,Email:stwuzy@163.com