復(fù)旦大學(xué)附屬腫瘤醫(yī)院放射治療科,復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系,上海 200032
局部治療在乳腺癌局限性肝轉(zhuǎn)移中的作用
張麗 綜述 郭小毛 審校
復(fù)旦大學(xué)附屬腫瘤醫(yī)院放射治療科,復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系,上海 200032
肝臟是乳腺癌遠(yuǎn)處轉(zhuǎn)移最常見(jiàn)的部位之一。全身治療是乳腺癌肝轉(zhuǎn)移的標(biāo)準(zhǔn)治療,但結(jié)果并不理想。轉(zhuǎn)移性乳腺癌中存在一類特殊的亞群,即局限性轉(zhuǎn)移。局部治療,包括轉(zhuǎn)移灶切除術(shù)、射頻消融、放射治療等,結(jié)合全身治療可給該部分患者帶來(lái)生存獲益。現(xiàn)就近年來(lái)有關(guān)乳腺癌局限性肝轉(zhuǎn)移局部治療的研究結(jié)果作一綜述。
乳腺癌肝轉(zhuǎn)移;局限性轉(zhuǎn)移;局部治療;轉(zhuǎn)移灶切除術(shù);射頻消融;立體定向放射治療
乳腺癌是女性最常見(jiàn)的惡性腫瘤之一,2008年全球確診的新病例約138萬(wàn),占所有癌癥的23%[1]。乳腺癌遠(yuǎn)處轉(zhuǎn)移最常見(jiàn)的部位是骨、肺和肝臟。肝轉(zhuǎn)移占轉(zhuǎn)移性乳腺癌的6%~25%[2]。轉(zhuǎn)移性乳腺癌通常被認(rèn)為是不可治愈的全身性疾病,目前的標(biāo)準(zhǔn)治療是以姑息性治療為目的的全身治療,包括全身化療和內(nèi)分泌治療等。乳腺癌肝轉(zhuǎn)移(breast cancer liver metastases)患者接受以蒽環(huán)類為基礎(chǔ)的聯(lián)合方案化療后,中位生存期僅為6~14個(gè)月,比乳腺癌其他部位轉(zhuǎn)移預(yù)后差[3-5],二線、三線和四線化療的療效更差,客觀緩解率僅為27.8%、16.7%和0[6]。
1995年,Hellman等[7]首次提出了“局限性轉(zhuǎn)移”的觀點(diǎn),認(rèn)為腫瘤轉(zhuǎn)移的類型存在一種轉(zhuǎn)移部位限于特定器官,且轉(zhuǎn)移灶數(shù)量有限的中間狀態(tài),并提出局部治療包括轉(zhuǎn)移灶切除術(shù)、射頻消融、放射治療等可能對(duì)這部分患者有效。近年來(lái),Tait等[8]提出乳腺癌也存在局限性轉(zhuǎn)移的狀態(tài)。目前,局限性轉(zhuǎn)移尚沒(méi)有嚴(yán)格的定義,采用比較多的是轉(zhuǎn)移臟器有限,且單個(gè)臟器轉(zhuǎn)移灶數(shù)目≤5個(gè)[9],也有研究將其定義為不超過(guò)2、3個(gè)轉(zhuǎn)移灶或者孤立性轉(zhuǎn)移灶[10-11]。在所有的局限性轉(zhuǎn)移灶中,肝臟被認(rèn)為是可接受局部治療的最常見(jiàn)部位之一。局限性肝轉(zhuǎn)移是指轉(zhuǎn)移部位局限于肝臟且轉(zhuǎn)移灶數(shù)目有限的轉(zhuǎn)移狀態(tài),同時(shí)伴或不伴其他部位的轉(zhuǎn)移[10]。局限性肝轉(zhuǎn)移的診斷主要依據(jù)CT及MRI提高肝內(nèi)病灶的診斷敏感性,采用PET/CT評(píng)估是否存在肝外疾病[12]。
目前局部治療在結(jié)直腸癌局限性肝轉(zhuǎn)移中的應(yīng)用已獲得認(rèn)可,而其在乳腺癌局限性肝轉(zhuǎn)移中的應(yīng)用仍存在很多爭(zhēng)議,包括如何定義局限性轉(zhuǎn)移,如何選擇局部治療的適宜人群等?,F(xiàn)就近年來(lái)有關(guān)乳腺癌肝轉(zhuǎn)移局部治療的最新結(jié)果進(jìn)行綜述,了解乳腺癌局限性肝轉(zhuǎn)移可能的治療策略,從而為臨床決策提供參考。
腫瘤遠(yuǎn)處轉(zhuǎn)移是癌癥患者死亡的首要原因。在傳統(tǒng)概念中,實(shí)體腫瘤遠(yuǎn)處轉(zhuǎn)移通常轉(zhuǎn)移部位及轉(zhuǎn)移灶的數(shù)量多而廣泛,局部治療對(duì)轉(zhuǎn)移性疾病無(wú)效,全身性的化療及激素治療為標(biāo)準(zhǔn)治療。局限性轉(zhuǎn)移與傳統(tǒng)意義上的轉(zhuǎn)移是不同的,這個(gè)概念的提出對(duì)指導(dǎo)存在局限性轉(zhuǎn)移患者的治療有重要意義,即全身治療的基礎(chǔ)上加用局部治療可能使這部分患者獲益[13]。Pawlik等[14]報(bào)道了557例接受轉(zhuǎn)移灶切除術(shù)的結(jié)直腸癌肝轉(zhuǎn)移患者,其5年生存率可提高至58%。而其他治療損傷比手術(shù)小的局部治療方法如立體定向放射治療、射頻消融、MRI引導(dǎo)下聚焦超聲等的提出及成熟,為局限性轉(zhuǎn)移的治療提供了新選擇。
在轉(zhuǎn)移性乳腺癌中同樣存在一群以僅存在單個(gè)或少量轉(zhuǎn)移灶為特征的患者,被定義為局限性轉(zhuǎn)移[15],占乳腺癌人群的1%~3%[16]。局限性轉(zhuǎn)移的乳腺癌患者生存期較長(zhǎng),明顯優(yōu)于存在廣泛轉(zhuǎn)移的乳腺癌患者,并且有臨床治愈的可能性。前者的10年無(wú)復(fù)發(fā)生存率為27%~42%,而后者僅為1.9%~3.4%[17]。局限性轉(zhuǎn)移的患者,轉(zhuǎn)移灶能被徹底消除并獲得長(zhǎng)期生存,可采用更加積極的綜合治療手段[18]。
目前可采用局部治療的乳腺癌轉(zhuǎn)移灶包括肝、肺、腦、骨等。研究發(fā)現(xiàn),乳腺癌肝轉(zhuǎn)移患者采用轉(zhuǎn)移灶局部治療聯(lián)合全身治療可改善患者的生存結(jié)果。另有研究發(fā)現(xiàn),乳腺癌肝轉(zhuǎn)移患者加用局部治療后的中位生存期顯著長(zhǎng)于僅接受全身治療的患者(33個(gè)月 vs 11個(gè)月,P<0.001)[19]。Lubrano等[20]的研究發(fā)現(xiàn)乳腺癌肝轉(zhuǎn)移患者接受局部治療及化療后的中位生存期長(zhǎng)達(dá)42個(gè)月。這可能是由于轉(zhuǎn)移灶的治療和控制可減少患者全身腫瘤負(fù)荷,使其對(duì)激素和化療更有效,從而改善生存[21]。
以上的研究說(shuō)明乳腺癌局限性轉(zhuǎn)移與傳統(tǒng)意義的轉(zhuǎn)移不同,其預(yù)后較好,局部治療結(jié)合全身治療可能給一部分乳腺癌肝轉(zhuǎn)移患者帶來(lái)生存獲益。
2.1 肝臟轉(zhuǎn)移灶切除術(shù)(hepatic metastasectomy)
肝轉(zhuǎn)移灶切除術(shù)在一部分篩選后大腸癌肝轉(zhuǎn)移患者中是一種公認(rèn)的行之有效的治療方法[22]。Choti等[23]研究發(fā)現(xiàn),轉(zhuǎn)移灶少于3個(gè)的肝轉(zhuǎn)移灶根治性全切術(shù)后生存期明顯延長(zhǎng)。目前關(guān)于肝轉(zhuǎn)移灶切除術(shù)在乳腺癌中應(yīng)用價(jià)值的認(rèn)識(shí)尚不足,報(bào)道的肝切除術(shù)的比率較低,但是乳腺癌肝轉(zhuǎn)移患者肝轉(zhuǎn)移灶切除后的中位生存期可達(dá)40個(gè)月,5年生存率達(dá)40%,術(shù)后死亡率為0~6%,手術(shù)并發(fā)癥的發(fā)生率低,為0~44%[24]。提示肝轉(zhuǎn)移灶切除術(shù)是治療乳腺癌肝轉(zhuǎn)移的有效手段。主要并發(fā)癥包括胸腔積液、胸膜瘺、暫時(shí)性肝功能異常、手術(shù)部位出血需脾切除術(shù)等[25-26]。
可能影響乳腺癌肝轉(zhuǎn)移的轉(zhuǎn)移灶切除術(shù)后患者生存的預(yù)后因素包括無(wú)病間隔時(shí)間、手術(shù)切緣、術(shù)前化療的反應(yīng)情況、激素受體狀態(tài)及是否合并肝外轉(zhuǎn)移等。無(wú)病間隔時(shí)間越長(zhǎng),切除術(shù)后的生存期越長(zhǎng)。Selzner等[27]研究發(fā)現(xiàn),原發(fā)腫瘤手術(shù)后1年以上出現(xiàn)肝轉(zhuǎn)移患者的生存時(shí)間比1年以內(nèi)的長(zhǎng)(27個(gè)月 vs 9個(gè)月)。Pocard等[28]發(fā)現(xiàn),原發(fā)腫瘤術(shù)后48個(gè)月以內(nèi)和48個(gè)月以后出現(xiàn)肝轉(zhuǎn)移患者的3年生存率分別為55%和86%。一些研究認(rèn)為手術(shù)切緣陽(yáng)性與不良預(yù)后相關(guān)[29-31]。Elias等[32]的研究包括54例接受肝切除術(shù)的乳腺癌肝轉(zhuǎn)移患者,發(fā)現(xiàn)受體激素陰性患者的相對(duì)死亡風(fēng)險(xiǎn)是陽(yáng)性患者的3.5倍,與其他研究相比[30-31,33-34],差異無(wú)統(tǒng)計(jì)學(xué)意義。對(duì)同時(shí)存在肝外轉(zhuǎn)移的乳腺癌肝轉(zhuǎn)移患者,手術(shù)治療療效存在爭(zhēng)議,Sakamoto等[33]研究發(fā)現(xiàn)轉(zhuǎn)移灶切除前存在肝外轉(zhuǎn)移是一個(gè)不良預(yù)后因素,而Selzner等[27]、Pocard等[35]和Yoshimoto等[36]的研究結(jié)果提示合并肝外疾病與預(yù)后不相關(guān),認(rèn)為除了合并腦轉(zhuǎn)移或其他威脅生命的轉(zhuǎn)移外,穩(wěn)定的肝外轉(zhuǎn)移特別是骨轉(zhuǎn)移不是轉(zhuǎn)移灶切除術(shù)的禁忌證。
因此,對(duì)一部分高度選擇的乳腺癌肝轉(zhuǎn)移患者,如無(wú)病間隔較長(zhǎng)、激素受體陽(yáng)性等,肝轉(zhuǎn)移灶切除術(shù)是有效且安全的。對(duì)可手術(shù)的乳腺癌肝轉(zhuǎn)移患者,實(shí)施根治性切除術(shù)能夠較大程度地延長(zhǎng)患者生存期,取得比常規(guī)治療更好的效果,且并發(fā)癥發(fā)生率較低。但目前研究結(jié)果大部分基于回顧性臨床分析,存在一定的偏移,且不同研究的入組標(biāo)準(zhǔn)和排除標(biāo)準(zhǔn)差異有統(tǒng)計(jì)學(xué)意義,對(duì)手術(shù)切除的適宜人群無(wú)明確統(tǒng)一的標(biāo)準(zhǔn)。因此,手術(shù)治療在乳腺癌肝轉(zhuǎn)移患者中的應(yīng)用仍有一定的局限性。
2.2 射頻消融(radiofrequency ablation)
射頻消融是一種較新的治療方法。它利用特制的電極探針,在超聲或CT引導(dǎo)下經(jīng)皮穿入腫瘤內(nèi)部,通過(guò)射頻電流發(fā)射器發(fā)出電流,經(jīng)探針在腫瘤組織中震動(dòng)摩擦產(chǎn)生熱能從而誘導(dǎo)腫瘤細(xì)胞發(fā)生凝固性壞死。同時(shí)腫瘤周圍的血管組織凝固形成一圈反應(yīng)帶,使之不能繼續(xù)向腫瘤供血并進(jìn)一步防止腫瘤轉(zhuǎn)移。
射頻消融對(duì)無(wú)法手術(shù)切除的肝臟原發(fā)或轉(zhuǎn)移性腫瘤具有較好的療效[37]。射頻消融治療結(jié)直腸癌肝轉(zhuǎn)移的療效已得到確認(rèn),治療后并發(fā)癥發(fā)生率低且長(zhǎng)期效果良好[38]。
目前,關(guān)于乳腺癌肝轉(zhuǎn)移射頻消融治療的研究大多數(shù)為回顧性臨床分析,大部分研究中患者肝轉(zhuǎn)移灶的數(shù)量為3個(gè)及以下,所有轉(zhuǎn)移灶均予以治療[39-45]。乳腺癌肝轉(zhuǎn)移患者射頻消融治療后的腫瘤局部緩解率為63%~97%[39-43],5年生存率為27%~30%[40,44],中位生存時(shí)間為30~60個(gè)月[40-41,44-45]。最常見(jiàn)的并發(fā)癥是腹腔積液和肝包膜下血腫,但絕大多數(shù)都是自限性過(guò)程,很少需要治療。在多數(shù)研究中均未出現(xiàn)治療相關(guān)的嚴(yán)重并發(fā)癥及死亡[39-40,42-44],僅在Jakobs等[41]的研究中發(fā)現(xiàn)2例(4.6%)嚴(yán)重的肝內(nèi)出血及1例(2.3%)膽管損傷,肝內(nèi)出血在血管造影引導(dǎo)下成功止血,膽管損傷通過(guò)經(jīng)皮引流治愈。
乳腺癌肝轉(zhuǎn)移患者肝臟轉(zhuǎn)移灶射頻消融治療后,病灶局部進(jìn)展發(fā)生率為14%~58%[40-42,45],Gunabushanam等[42]研究發(fā)現(xiàn)射頻消融治療后,50%患者出現(xiàn)新的遠(yuǎn)處轉(zhuǎn)移灶而導(dǎo)致治療失敗。
影響乳腺癌肝轉(zhuǎn)移患者射頻消融治療后的生存的預(yù)后因素包括轉(zhuǎn)移灶的大小、是否存在肝外疾病等[40-41]。Meloni等[40]的研究包括52例患者,共87個(gè)肝轉(zhuǎn)移灶,患者的入組標(biāo)準(zhǔn)包括轉(zhuǎn)移灶<5個(gè)、最大徑≤5 cm、病灶僅限于肝臟或穩(wěn)定,轉(zhuǎn)移灶最大徑超過(guò)2.5 cm的患者預(yù)后比<2.5 cm的患者差(HR=2.1),Jakobs等[41]的研究包括43例患者,共111個(gè)轉(zhuǎn)移灶,發(fā)現(xiàn)合并肝外疾病的患者(骨轉(zhuǎn)移除外)生存較差,而激素受體狀態(tài)、HER-2過(guò)表達(dá)、合并孤立性骨轉(zhuǎn)移對(duì)乳腺癌肝轉(zhuǎn)移患者射頻消融治療后的生存無(wú)影響。
射頻消融是一種比手術(shù)損傷小的的局部治療方法,可以提高的乳腺癌肝轉(zhuǎn)移肝轉(zhuǎn)移的局部控制率,并發(fā)癥較輕。射頻消融可與化療結(jié)合,作為體積較小的肝轉(zhuǎn)移灶切除術(shù)的替代或補(bǔ)充治療。但由于回顧性研究的限制,不同研究對(duì)患者的選擇存在差異,且病灶的異質(zhì)性較高。因此,需要一個(gè)嚴(yán)格設(shè)計(jì)的前瞻性研究來(lái)進(jìn)一步明確射頻消融在乳腺癌肝轉(zhuǎn)移中的應(yīng)用價(jià)值。
2.3 立體定向放射治療(stereotactic body radiation therapy,SBRT)
SBRT是一種采用大劑量、有限照射次數(shù)(1~6次)治療顱外腫瘤的放療技術(shù)。SBRT具有高度適形性,接近周圍正常組織的劑量梯度較陡,因而能精確定位腫瘤,給腫瘤病灶高劑量照射,同時(shí)盡量降低周圍重要正常組織的照射劑量[46]。與手術(shù)相似,SBRT是一種局部治療手段,但SBRT比手術(shù)侵襲性小,可用于無(wú)法耐受(或不愿意接受)侵襲性治療方法的患者,或當(dāng)腫瘤位于某些特殊部位無(wú)法實(shí)施侵襲性治療的患者。
目前,很多Ⅰ、Ⅱ期臨床研究表明,SBRT治療不可手術(shù)切除的肝轉(zhuǎn)移灶是有效而安全的[10,47-53]。2年的局部控制率可達(dá)79%~92%[10,50-51],2年的總生存率為49%~62%[49,51]。其中,結(jié)直腸癌肝轉(zhuǎn)移所占的比例最多。Scorsetti等[53]研究了61例不可切除的肝轉(zhuǎn)移患者接受SBRT的療效,該研究共包括76個(gè)轉(zhuǎn)移灶,每例患者轉(zhuǎn)移灶數(shù)目為1~3個(gè),腫瘤最大徑<6 cm,結(jié)直腸癌來(lái)源的占46%,乳腺癌來(lái)源占18%,肝內(nèi)所有轉(zhuǎn)移灶均包括在SBRT治療范圍內(nèi)。結(jié)果顯示,1年的野內(nèi)局部有效率為94%,1年的總生存率為83%,中位生存期為19個(gè)月,提示SBRT是治療不可手術(shù)切除肝轉(zhuǎn)移灶的有效手段。
目前尚沒(méi)有專門評(píng)價(jià)SBRT治療乳腺癌肝轉(zhuǎn)移的治療效果研究。Lee等[52]研究了68例經(jīng)SBRT治療的不可手術(shù)的肝轉(zhuǎn)移患者,其中乳腺癌12例,放療靶區(qū)包括所有CT或MRI上可見(jiàn)的病灶,結(jié)果顯示乳腺癌、大腸癌、其他來(lái)源的肝轉(zhuǎn)移患者1年生存率分別為79%、63%、38%,提示與原發(fā)其他部位的肝轉(zhuǎn)移相比,乳腺癌肝轉(zhuǎn)移經(jīng)SBRT治療后的生存質(zhì)量更高。Milano等[54]分析了121例經(jīng)SBRT治療的任何來(lái)源的局限性轉(zhuǎn)移的生存效果,放療靶區(qū)包括所有的轉(zhuǎn)移病灶,發(fā)現(xiàn)乳腺癌患者的中位生存時(shí)間為4.5年,2年總生存率和局部控制率分別為74%、87%,非乳腺癌患者的中位生存時(shí)間為1.7年,2年總生存率和局部控制率分別為39%、74%,認(rèn)為SBRT治療局限性轉(zhuǎn)移可帶來(lái)良好的生存效果,尤其是乳腺癌局限性轉(zhuǎn)移的患者。Milano等[55]還研究了51例SBRT治療轉(zhuǎn)移性乳腺癌的效果,肝轉(zhuǎn)移灶占70%,其中給予40例<5個(gè)肝轉(zhuǎn)移灶的患者根治性SBRT治療,結(jié)果顯示,4年的總生存率為59%,無(wú)進(jìn)展生存率為38%,局部控制率為89%,提示SBRT可延長(zhǎng)生存期,甚至可能治愈部分高度選擇的乳腺癌局限性轉(zhuǎn)移患者。
SBRT治療肝轉(zhuǎn)移灶引起的早期不良反應(yīng)包括惡心、腹痛、發(fā)熱、疲勞和十二指腸球部潰瘍,晚期不良反應(yīng)包括消化道潰瘍和(或)出血、放射性皮膚反應(yīng)、肌肉骨骼損傷[56]。SBRT治療肝轉(zhuǎn)移灶最常見(jiàn)的并發(fā)癥是1或2級(jí)不良反應(yīng),嚴(yán)重的不良反應(yīng)(超過(guò)3級(jí))非常罕見(jiàn),腸道及大面積肝臟受到高劑量照射的患者更易發(fā)生不良反應(yīng)[57]。最嚴(yán)重的并發(fā)癥為輻射誘導(dǎo)的肝臟疾病,發(fā)病風(fēng)險(xiǎn)與照射劑量及正常肝組織受照射的的體積呈正比[58]。Hoyer等[50]的研究包括64例患者,發(fā)現(xiàn)1例患者死于肝功能衰竭,輻射誘導(dǎo)的肝臟疾病發(fā)生率很低。Lee等[52]研究了68例接受SBRT的肝轉(zhuǎn)移患者,未出現(xiàn)輻射誘導(dǎo)的肝臟疾病。Rusthoven等[10]的研究中,要求接受超過(guò)15 Gy劑量的肝臟體積不超過(guò)700 mL,分3次照射,同樣未發(fā)現(xiàn)輻射誘導(dǎo)的肝臟疾病。Mendez等[51]的研究包括45例患者,接受的劑量為30.0~30.7 Gy,分3次照射,2例患者出現(xiàn)轉(zhuǎn)氨酶升高(3級(jí)),1例出現(xiàn)乏力癥狀(3級(jí)),1例出現(xiàn)門脈高壓癥伴黑糞(3級(jí)晚期不良反應(yīng))。
研究發(fā)現(xiàn)轉(zhuǎn)移灶最大徑<3 cm患者局部控制更好[10],孤立性轉(zhuǎn)移灶(與2~5個(gè)病灶相比)、腫瘤體積較小、骨轉(zhuǎn)移、病灶穩(wěn)定或退縮的患者可能獲得更好的療效[54]。在不同的研究中,放療總劑量、單次分割劑量和劑量的處方要求均存在顯著的異質(zhì)性。目前大部分研究使用的放療方式為總劑量30~60 Gy,分割次數(shù)為1~6次,但關(guān)于不同分割方式對(duì)局控、生存及不良反應(yīng)報(bào)道尚不統(tǒng)一。Lee等[52]研究認(rèn)為,41.8 Gy/6 f的分割方法是安全的。Rule等[59]比較了3種劑量分割方式的生存效果,分別為30 Gy/3 f、50 Gy/5 f、60 Gy/5 f,結(jié)果60 Gy/5 f和30 Gy/5 f之間的局控率差異有統(tǒng)計(jì)學(xué)意義,另兩組差異則無(wú)統(tǒng)計(jì)學(xué)意義。而Vautravers-Dewas等[60]研究認(rèn)為,劑量并不顯著影響生存質(zhì)量及不良反應(yīng)。
因此,在有效的全身控制前提下,SBRT治療肝轉(zhuǎn)移可獲得良好的局部控制和可接受的治療不良反應(yīng),適用不可手術(shù)患者的局部治療。與其他部位原發(fā)的肝轉(zhuǎn)移相比,SBRT治療乳腺癌肝轉(zhuǎn)移的生存效果更好。目前關(guān)于SBRT治療肝轉(zhuǎn)移的研究結(jié)果主要是基于Ⅰ、Ⅱ期臨床實(shí)驗(yàn),不同研究中對(duì)患者的選擇、腫瘤體積、放療總劑量、分割次數(shù)和劑量的處方要求尚不統(tǒng)一,同時(shí)受呼吸運(yùn)動(dòng)等的影響,肝臟內(nèi)靶區(qū)移動(dòng)性較大,對(duì)SBRT技術(shù)的開(kāi)展也是一個(gè)挑戰(zhàn)。因此,SBRT在乳腺癌肝轉(zhuǎn)移中的應(yīng)用受到一定的限制。
局部治療在乳腺癌局限性肝轉(zhuǎn)移中有重要作用。轉(zhuǎn)移灶切除術(shù)在整個(gè)乳腺癌肝轉(zhuǎn)移患者中所占比例不高,但對(duì)于一部分高度篩選的患者,肝轉(zhuǎn)移灶切除術(shù)是有效且安全的。射頻消融也可給乳腺癌肝轉(zhuǎn)移患者帶來(lái)良好的生存效果,可與全身治療相結(jié)合,作為體積較小的肝轉(zhuǎn)移灶的局部治療。SBRT比手術(shù)侵襲性小,可提高一部分乳腺癌肝轉(zhuǎn)移患者的局控并可能延長(zhǎng)生存,且不良反應(yīng)輕,適用于不可手術(shù)患者的局部治療。但是對(duì)于乳腺癌遠(yuǎn)處轉(zhuǎn)移的患者,需結(jié)合全身治療來(lái)評(píng)價(jià)局部治療療效,局部治療只有在全身治療控制其他微轉(zhuǎn)移灶時(shí)才能影響生存。目前的報(bào)道文獻(xiàn)多為回顧性或小樣本的Ⅰ、Ⅱ期臨床研究,需要嚴(yán)格設(shè)計(jì)的大樣本臨床研究來(lái)明確局部治療在乳腺癌局限性肝轉(zhuǎn)移中的應(yīng)用價(jià)值。
[1] JEMAL A, BRAY F, CENTER M M, et al. Global cancer statistics[J]. CA Cancer J Clin, 2011, 61(2): 69-90.
[2] TAMPELLINI M, BERRUTI A, GERBINO A, et al. Relationship between CA 15-3 serum levels and disease extent in predicting overall survival of breast cancer patients with newly diagnosed metastatic disease[J]. Br J Cancer, 1997, 75(5): 698-702.
[3] KIANG D T, KENNEDY B J, YOUNGER J, et al. Alternating chemotherapy regimens for patients with metastatic breast cancer. A pilot study based on tumor marker kinetics. Cancer and Leukemia Group B[J]. Cancer, 1995, 75(3): 826-830.
[4] PICCART M. Docetaxel: A new defence in the management of breast cancer [J]. Anticancer Drugs, 1995, 64: 7-11.
[5] POUILLART P, JOUVET M, PALANGIE T. Hepatic metastases in cancer of the breast. Analysis of parameters acting response to chemotherapy [J]. Ann Gastroenterol Hepatol, 1985, 21: 87-90.
[6] 胡夕春, 郭海宜, 楊新苗, 等. 乳腺癌肝轉(zhuǎn)移患者預(yù)后的多因素分析[J]. 中國(guó)癌癥雜志, 2005, 15(5): 438-441.
[7] HELLMAN S, WEICHSELBAUM R R. Oligometastases[J]. J Clin Oncol, 1995, 13(1): 8-10.
[8] TAIT C R, WATERWORTH A, LONCASTER J, et al. The oligometastatic state in breast cancer: hypothesis or reality[J]. Breast, 2005, 14(2): 87-93.
[9] SALAMA J K, HASSELLE M D, CHMURA S J, et al. Stereotactic body radiotherapy for multisite extracranial oligometastases: Final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease [J]. Cancer, 2011, 118(11): 2962-2970.
[10] RUSTHOVEN K E, KAVANAGH B D, CARDENES H, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases [J]. J Clin Oncol, 2009, 27(10): 1572-1578.
[11] LEE J H, LEE J H, JANG H S, et al. Hypofractionated radiotherapy with tomotherapy for patients with hepatic oligometastases: retrospective analysis of two institutions[J]. Clin Exp Metastasis, 2013, 30(5): 643-650.
[12] MAINENTI P P, MANCINI M, MAINOLFI C, et al. Detection of colo-rectal liver metastases: prospective comparison of contrast enhanced US, multidetector CT, PET/CT, and 1.5 Tesla MR with extracellular and reticulo-endothelial cell specific contrast agents [J]. Abdom Imaging, 2010, 35(5): 511-521.
[13] WEICHSELBAUM R R, HELLMAN S. Oligometastases revisited [J]. Nat Rev Clin Oncol, 2011, 8(6): 378-382.
[14] PAWLIK T M, SCOGGINS C R, ZORZI D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases [J]. Ann Surg, 2005, 241(5): 715-722, 722-724.
[15] PAGANI O, SENKUS E, WOOD W, et al. International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured?[J]. J Natl Cancer Inst, 2010, 102(7): 456-463.
[16] HORTOBAGYI G N. Can we cure limited metastatic breast cancer? [J]. J Clin Oncol, 2002, 20(3): 620-623.
[17] KOBAYASHI T, ICHIBA T, SAKUYAMA T, et al. Possible clinical cure of metastatic breast cancer: lessons from our 30-year experience with oligometastatic breast cancer patients and literature review [J]. Breast Cancer, 2012, 19(3): 218-237.
[18] Metastatic breast cancer. Recommendations proposal from the European School of Oncology (ESO)-MBC Task Force[J]. Breast, 2007, 16(1): 9-10.
[19] EICHBAUM M H, KALTWASSER M, BRUCKNER T, et al. Prognostic factors for patients with liver metastases from breast cancer[J]. Breast Cancer Res Treat, 2006, 96(1): 53-62.
[20] LUBRANO J, ROMAN H, TARRAB S, et al. Liver resection for breast cancer metastasis: Does it improve survival?[J]. Surg Today, 2008, 38(4): 293-299.
[21] BATHE O F, KAKLAMANOS I G, MOFFAT F L, et al. Metastasectomy as a cytoreductive strategy for treatment of isolated pulmonary and hepatic metastases from breast cancer[J]. Surg Oncol, 1999, 8(1): 35-42.
[22] BLAZER D R, KISHI Y, MARU D M, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases[J]. J Clin Oncol, 2008, 26(33): 5344-5351.
[23] CHOTI M A, SITZMANN J V, TIBURI M F, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases[J]. Ann Surg, 2002, 235(6): 759-766.
[24] CHUA T C, SAXENA A, LIAUW W, et al. Hepatic resection for metastatic breast cancer: a systematic review[J]. Eur J Cancer, 2011, 47(15): 2282-2290.
[25] SEIFERT J K, WEIGEL T F, GONNER U, et al. Liver resection for breast cancer metastases [J]. Hepatogastroenterology, 1999, 46(29): 2935-2940.
[26] CARLINI M, LONARDO M T, CARBONI F, et al. Liver metastases from breast cancer. Results of surgical resection[J]. Hepatogastroenterology, 2002, 49(48): 1597-1601.
[27] SELZNER M, MORSE M A, VREDENBURGH J J, et al. Liver metastases from breast cancer: long-term survival after curative resection[J]. Surgery, 2000, 127(4): 383-389.
[28] POCARD M, VINCENT-SALOMON A, GIRODET J, et al. Effects of preoperative chemotherapy on liver function tests after hepatectomy [J]. Hepatogastroenterology, 2001, 48(41): 1406-1408.
[29] HOFFMANN K, FRANZ C, HINZ U, et al. Liver resection for multimodal treatment of breast cancer metastases: identification of prognostic factors [J]. Ann Surg Oncol, 2010, 17(6): 1546-1554.
[30] THELEN A, BENCKERT C, JONAS S, et al. Liver resection for metastases from breast cancer[J]. J Sur Oncol, 2008, 97(1): 25-29.
[31] ADAM R, ALOIA T, KRISSAT J, et al. Is liver resection justified for patients with hepatic metastases from breast cancer?[J]. Ann Surg, 2006, 244(6): 897-907, 907-908.
[32] ELIAS D, MAISONNETTE F, DRUET-CABANAC M, et al. An attempt to clarify indications for hepatectomy for liver metastases from breast cancer [J]. Am J Surg, 2003, 185(2): 158-164.
[33] SAKAMOTO Y, YAMAMOTO J, YOSHIMOTO M, et al. Hepatic resection for metastatic breast cancer: prognostic analysis of 34 patients[J]. World J Surg, 2005, 29(4): 524-527.
[34] VLASTOS G, SMITH D L, SINGLETARY S E, et al. Longterm survival after an aggressive surgical approach in patients with breast cancer hepatic metastases[J]. Ann Surg Oncol, 2004, 11(9): 869-874.
[35] POCARD M, POUILLART P, ASSELAIN B, et al. Hepatic resection for breast cancer metastases: results and prognosis (65 cases)[J]. Ann Chir, 2001, 126(5): 413-420.
[36] YOSHIMOTO M, TADA T, SAITO M, et al. Surgical treatment of hepatic metastases from breast cancer[J]. Breast Cancer Res Treat, 2000, 59(2): 177-184.
[37] ILLING R, GILLAMS A. Radiofrequency ablation in the treatment of breast cancer liver metastases [J]. Clin Oncol (R Coll Radiol), 2010, 22(9): 781-784.
[38] ABDALLA E K, VAUTHEY J N, ELLIS L M, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases[J]. Ann Surg, 2004, 239(6): 818-825, 825-827.
[39] LIVRAGHI T, GOLDBERG S N, SOLBIATI L, et al. Percutaneous radio-frequency ablation of liver metastases from breast cancer: initial experience in 24 patients [J]. Radiology, 2001, 220(1): 145-149.
[40] MELONI M F, ANDREANO A, LAESEKE P F, et al. Breast cancer liver metastases: US-guided percutaneous radiofrequency ablation--intermediate and long-term survival rates [J]. Radiology, 2009, 253(3): 861-869.
[41] JAKOBS T F, HOFFMANN R T, SCHRADER A, et al. CT-guided radiofrequency ablation in patients with hepatic metastases from breast cancer [J]. Cardiovasc Intervent Radiol, 2009, 32(1): 38-46.
[42] GUNABUSHANAM G, SHARMA S, THULKAR S, et al. Radiofrequency ablation of liver metastases from breast cancer: results in 14 patients [J]. J Vasc Interv Radiol, 2007, 18(1 Pt 1): 67-72.
[43] LAWES D, CHOPADA A, GILLAMS A, et al. Radiofrequency ablation (RFA) as a cytoreductive strategy for hepatic metastasis from breast cancer [J]. Ann R Coll Surg Engl, 2006, 88(7): 639-642.
[44] SOFOCLEOUS C T, NASCIMENTO R G, GONEN M, et al. Radiofrequency ablation in the management of liver metastases from breast cancer [J]. AJR Am J Roentgenol, 2007, 189(4): 883-889.
[45] CARRAFIELLO G, FONTANA F, COTTA E, et al. Ultrasound-guided thermal radiofrequency ablation (RFA) as an adjunct to systemic chemotherapy for breast cancer liver metastases[J]. Radiol Med, 2011, 116(7): 1059-1066.
[46] POTTERS L, KAVANAGH B, GALVIN J M, et al. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy[J]. Int J Radiat Oncol Biol Phys, 2010, 76(2): 326-332.
[47] HERFARTH K K, DEBUS J, WANNENMACHER M. Stereotactic radiation therapy of liver metastases: update of the initial phase-Ⅰ/Ⅱ trial[J]. Front Radiat Ther Oncol, 2004, 38: 100-105.
[48] AMBROSINO G, POLISTINA F, COSTANTIN G, et al. Image-guided robotic stereotactic radiosurgery for unresectable liver metastases: preliminary results [J]. Anticancer Res, 2009, 29(8): 3381-3384.
[49] GOODMAN K A, WIEGNER E A, MATUREN K E, et al. Dose-escalation study of single-fraction stereotactic bodyradiotherapy for liver malignancies [J]. Int J Radiat Oncol Biol Phys, 2010, 78(2): 486-493.
[50] HOYER M, ROED H, TRABERG H A, et al. Phase Ⅱ study on stereotactic body radiotherapy of colorectal metastases[J]. Acta Oncol, 2006, 45(7): 823-830.
[51] MENDEZ R A, WUNDERINK W, HUSSAIN S M, et al. Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase Ⅰ-Ⅱ study [J]. Acta Oncol, 2006, 45(7): 831-837.
[52] LEE M T, KIM J J, DINNIWELL R, et al. Phase Ⅰ study of individualized stereotactic body radiotherapy of liver metastases[J]. J Clin Oncol, 2009, 27(10): 1585-1591.
[53] SCORSETTI M, ARCANGELI S, TOZZI A, et al. Is stereotactic body radiation therapy an attractive option for unresectable liver metastases? A preliminary report from a phase 2 trial [J]. Int J Radiat Oncol Biol Phys, 2013, 86(2): 336-342.
[54] MILANO M T, KATZ A W, ZHANG H, et al. Oligometastases treated with stereotactic body radiotherapy: long-term followup of prospective study [J]. Int J Radiat Oncol Biol Phys, 2011, 83(3): 878-886.
[55] MILANO M T, ZHANG H, METCALFE S K, et al. Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy[J]. Breast Cancer Res Treat, 2009, 115(3): 601-608.
[56] GOODMAN K A, WIEGNER E A, MATUREN K E, et al. Dose-escalation study of single-fraction stereotactic body radiotherapy for liver malignancies [J]. Int J Radiat Oncol Biol Phys, 2010, 78(2): 486-493.
[57] HOYER M, SWAMINATH A, BYDDER S, et al. Radiotherapy for liver metastases: a review of evidence [J]. Int J Radiat Oncol Biol Phys, 2012, 82(3): 1047-1057.
[58] DAWSON L A, NORMOLLE D, BALTER J M, et al. Analysis of radiation-induced liver disease using the Lyman NTCP model [J]. Int J Radiat Oncol Biol Phys, 2002, 53(4): 810-821.
[59] RULE W, TIMMERMAN R, TONG L, et al. Phase I doseescalation study of stereotactic body radiotherapy in patients with hepatic metastases [J]. Ann Surg Oncol, 2011, 18(4): 1081-1087.
[60] VAUTRAVERS-DEWAS C, BONODEAU F, LACORNERIE T, et al. Image-guided robotic stereotactic body radiation therapy for liver metastases: is there a dose response relationship? [J]. Int J Radiat Oncol Biol Phys, 2011, 81 (3): e39-e47.
The role of local therapy in liver oligometastases of breast cancer
ZHANG Li, GUO Xiao-mao (Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China)
GUO Xiao-mao E-mail: guoxm1800@126.com
The liver is one of the most common metastatic sites in patients with breast cancer. Systemic therapy is the standard treatment for breast cancer with liver metastasis, but the results are far from satisfaction. A distinctive subset of metastatic breast cancer is oligometastatic disease. Local therapy including metastasectomy, radiofrequency ablation and radiation therapy combined with systemic therapy can provide survival benefit. This review introduced the latest research results of local therapy in liver oligometastases of breast cancer.
Breast cancer liver metastases; Oligometastases; Local therapy; Hepatic metastasectomy; Radiofrequency ablation; Stereotactic body radiation therapy
10.3969/j.issn.1007-3969.2013.12.013
R737.9
A
1007-3639(2013)12-1007-07
2013-07-08
2013-09-30)
郭小毛 E-mail:guoxm1800@126.com