主要治疗

局部-区域治疗

I、II、IIIA及可手术的IIIC期乳腺癌往往需要综合性治疗。无论最终选择哪种治疗措施,诊断性活检和手术治疗作为主要治疗应分两次进行。在许多病例中,乳腺癌的诊断均由空心针活检完成。一旦确诊乳腺癌,应在选择治疗方案前与患者积极沟通。应确定原发肿瘤的雌激素受体(ER)、孕激素受体(PR)及人类表皮生长因子受体2(HER2/neu)的表达情况[1]。其他病理学特点,包括分级和增殖能力也可能具有重要意义[2][3][4][5]

原发肿瘤的手术治疗包括保乳手术联合放疗、乳房单纯切除术+乳房再造术、乳房单纯切除术。腋窝淋巴结手术分期也是必要的。随机前瞻性临床研究(包括欧洲癌症研究及治疗组织发起的临床试验[ EORTC-10801])表明不同术式的生存率相似[6][7][8][9][10][11][12][13]。局部治疗方案的选择依赖于病变的部位及大小、钼靶分析结果、乳房大小和患者对于保乳的态度。 多灶性病变或胶原血管病病史是保乳手术的相对禁忌症。 [14]一项回顾性研究纳入了753例患者,根据肿瘤受体表达情况将患者分为三组(即ER+或PR+;ER-、PR-、 HER2/neu+;ER-、PR-、 HER2/neu- [三阴性]),经过标准保乳手术治疗三组的预后未表现出显著差异;然而目前尚无充分数据支持这一结论[15]

所有组织学类型的浸润癌均可采用保乳手术联合放疗的治疗方案。 [16]保守治疗的局部复发率低,可能由于手术方式(例如局部病灶切除、四分之一切除、区段切除及其他)的选择而略有不同。是否需要切缘完全阴性仍有争议[17][18][19]

回顾性研究表明以下肿瘤特点与再切除时肿瘤持续存在可能性增高相关:

​肿瘤较大(T2期病变)。

淋巴结转移阳性。

​伴有大量导管内癌成分[20]

​肿瘤可触及。

​小叶组织学。

拥有以上特点的患者应于首次即行较为广泛的切除以避免二次手术[21][22]

放疗(保乳局部治疗的一部分)指总剂量45-50 Gy的术后全乳体外放射治疗(EBRT),平均每日治疗剂量1.8-2.0 Gy,共持续5周。短暂低剂量分次模式亦可获得类似疗效[23][24][25]。通常还需给予肿瘤床加量照射。欧洲两项随机试验表明肿瘤床加量照射10-16 Gy可使3年和5年局部复发风险分别由4.6%和7.3%降至3.6%( P=0.044)[26][ 证据等级:1iiDiii]和4.3%( P<0.001)[27][ 证据等级:1iiDiii]。加量照射既可采用EBRT(一般使用电子)也可采用组织间植入放射性粒子实现。 [28]

在选择保乳手术或乳房单纯切除术时年龄并非决定因素。一项研究表明局部病灶切除联合放疗的生存率和无复发率在年龄≥65岁和<65岁组间无显著差异[29]。关于具有种系突变或明确家族史的女性患者是否是行保乳手术的合适候选者仍有争议。回顾性研究表明保乳手术的局部失败率或总体生存率(OS)在有明确家族史和无明确家族史的患者间无显著差异[30][31]。 [ 证据等级:3iiiDii]然而,具有阳性家族史的患者5年内发生对侧乳腺癌的风险似乎较高[30]。对于BRCA1和BRCA2基因突变的女性来说这一风险甚至更高[32]。[ 证据等级:3iiiDii]鉴于目前可用的数据表明结局无显著差异,有明确家族史的女性可以考虑作为保乳手术的候选者。而对于具有BRCA1和BRCA2种系突变的女性来说,是否可行保乳手术仍需进一步研究。

  6项前瞻性研究(包括美国全国乳腺及肠道外科辅助治疗项目组的研究[ NSABP-B-06]、癌症和白血病B组的研究[ CLB-9343])对比了单纯保乳手术和保乳手术联合放疗的疗效[6][33][34][35][36][37]。其中2项研究里所有患者同时接受了他莫昔芬的辅助治疗[36][37]。每项研究均表明联合放疗乳内肿瘤复发率更低,并且在所有患者亚组中结果类似。例如在一些亚组中,患者肿瘤较小、受体阳性[36]或患者年龄超过70岁[38],复发率降低的绝对值本身即偏低(<5%)。在一项利用监控、流行病学和终点事件(SEER)-医疗保健数据库进行的确证观察研究中这些亚组的患者乳内复发率在接受放疗后仍有降低[39]。研究进一步证实与80岁及以上的患者和存在合并症(需要治疗以预防乳腺癌事件的人数[NNT]=61-125例 )的患者相比,70-79岁(NNT=21-22例)的患者从放疗中获益最大[39]。接受放疗可能与短期死亡率、操作不便和潜在的长期并发症相关[38]

腋窝淋巴结手术

应对腋窝淋巴结分组以协助判断预后和选择治疗方案。对浸润癌患者而言,前哨淋巴结(SLN)活检是首要标准的腋窝淋巴结分期操作。SLN定义为任何接受原发肿瘤淋巴回流的淋巴结;因此,SLN数量往往多于1枚。研究表明通过在肿瘤或活检腔周围注射锝标记的硫胶体、活化蓝染料或同时使用两种试剂并观察这些试剂向腋窝淋巴结引流的情况,可以发现92%-98%患者的SLN[40][41]。这些报告显示SLN活检和全腋窝淋巴结清扫(ALND)结果的一致性高达97.5%-100%[42][43][44][45]

一项多中心随机III期临床试验共纳入5611例乳腺癌患者,这些患者被随机分为接受SLN+ALND和仅接受SLN或仅当SLN阳性时接受ALND两组,结果表明两组在OS、无病生存率(DFS)和区域淋巴结控制方面均无显著差异。两组的OS分别为91.8%和90.3%。(P=0.12)[46]。[ 证据等级:1iiA]

与之类似,一项单中心随机试验共纳入532例T1期乳腺癌患者,同样分为SLN活检+全腋窝淋巴结清扫和仅行SLN活检组,中位随访时间78个月,结果显示两组的5年DFS没有显著差异(分别为92.9%和88.9%,P=0.1)[47]。[ 证据等级:1iiDii]

  以腋窝淋巴结清扫为金标准统计的SLN活检假阴性率介于0-15%,平均8.8%[48]。成功率因外科医生的经验和原发肿瘤特点而有所差异。总体而言,目前研究将SLN活检严格限制在无多病灶或临床阳性淋巴结转移证据的T1和T2期患者。与全腋窝淋巴结清扫相比,仅行SLN活检可以降低致残率。一项纳入1031例乳腺癌患者的随机试验比较了SLN活检阳性者再行全腋窝淋巴结清扫和直接行腋窝淋巴结清扫两种治疗方案,前者1年生活质量(根据肿瘤治疗功能评估试验结果指数-乳腺癌量表患者自觉临床功能减退的频率来评价)优于后者(分别为23%和35%;P=0.001)[49]。[ 证据等级:1iiC]SLN组患者的上肢功能也明显更好。 NSABP-B-32研究共纳入5611例乳腺癌患者,该研究在结果准确性和技术成功方面也获得了同样的结果[50]。这些结果奠定了SLN活检作为浸润癌患者腋窝淋巴结分期的标准首要手术操作。

一项多中心随机临床试验试图确定在SLN活检显示存在乳腺癌的SLN转移后是否需行ALND[51]。这一III期非劣效性临床试验计划将1900例无可触及肿块的腺病、由冰冻切片证实存在1-2枚SLN转移的临床T1-T2期乳腺癌患者分为接受ALND和不进行进一步腋窝淋巴结清扫治疗两组。所有患者均接受局部病灶切除、切向全乳照射和恰当的全身治疗,以OS为主要终点。由于纳入标准过于严格,该研究最终仅筛选出891例患者参与试验。中位随访时间6.3年,ALND组和仅接受SLN活检组5年OS分别为91.8%(95%置信区间[CI],89.1%-94.5%)和92.5%(95%CI,90.0-95.1%)。ALND组和仅接受SLN活检组的次要终点-5年无病生存率(DFS)分别为82.2%(95%CI,78.3%-86.3%)和83.9%(95%CI,80.2%-87.9%)[51]。[ 证据等级:1iiA]另一项设计类似的临床试验共纳入929例肿瘤小于5cm、SLN转移灶小于2mm的乳腺癌患者,随机将其分为接受与不接受全腋窝淋巴结清扫两组。未接受全腋窝淋巴结清扫的患者DFS事件发生率更低(风险比[HR],0.78;95%CI,0.55-1.11)。两组OS无显著差异[52]。[ 证据等级:1iiA]根据这些研究结果,在仅存在有限SLN阳性转移的乳腺癌患者中行保乳、放疗和全身治疗后是否有必要进一步行全腋窝淋巴结清扫值得商榷。

对于需要行ALND的患者,标准评估通常只需清扫I、II站淋巴结,即切除满足要求的一定数目的淋巴结(即至少6-10枚)同时降低因手术操作可能带来的致残率。若干组织试图找出淋巴结转移可能性较低而无需行腋窝淋巴结活检的患者亚群。在这些单机构病例研究中,T1a期乳腺癌患者淋巴结转移阳性率约为9-16%。[53,54]而在另一项类似研究中,未行ALND的T1a期乳腺癌患者腋窝淋巴结复发率为2%[55]。[ 证据等级:3iiiA]鉴于腋窝淋巴结转移情况仍为乳腺癌最重要的预后指标,目前尚无足够证据表明浸润癌患者可以不行淋巴结分期。

乳房再造

对于选择全乳切除术的患者,可以在乳房切除时(即时再造)或之后(推迟再造)行乳房再造术[56][57][58][59]。乳房轮廓再造可以通过在胸大肌下放入人工移植物(盐水填充)或腹直肌或其它皮瓣。如果采用盐水植入物,可以在胸肌下方放入组织扩张器。在扩张器内连续数周至数月注入盐水以使组织充分伸展直至达到目标体积。然后再用永久植入物替换扩张器。(可访问 FDA网站​以获取更多关于乳腺植入物的信息。)腹直肌皮瓣需要更复杂、更长时间的手术操作,必要时可能需要输血支持。

完成乳房再造后,可以行胸壁和区域淋巴结放疗以行辅助治疗或消除局部复发病灶。乳房假体植入的乳房再造术后行放疗可能会影响整形的效果,同时发生囊性纤维化、疼痛或需要去除假体的风险也可能增加[60]

辅助放疗

保乳手术后需常规行放疗。全乳切除术后也可能需要行放疗。辅助放疗的主要目的在于根除残余病灶从而降低局部复发率[61]

保乳术后

对于接受保乳手术的女性,最常见的局部复发部位为保留的乳腺本身。如果保乳术后不行放疗,即使腋窝淋巴结阴性,保留的乳腺复发风险也很高(>20%)。因此,推荐保乳术后行全乳照射治疗[62]

尽管所有评估放疗对保乳术作用的试验均发现放疗后局部复发率在统计学上极为显著地降低了,但其中任何一项试验均未证实死亡率显著降低。2005年早期乳腺癌试验者协作组(EBCTCG)将所有相关试验进行汇总,发现接受放疗的女性的乳腺癌相关死亡率从39.5%下降到30.5%(绝对降幅5.4%;95%CI,2.1%-8.7%;乳腺癌死亡率比值0.83;95%CI,0.75-0.91;P=0.002)。发现放疗对全因死亡率有相似影响[61]

虽然辅助全乳放疗是标准疗法,但目前尚无试验评估这种情况下区域淋巴结放疗的作用。国家癌症研究所加拿大研究(CAN-NCIC-MA20[NCT00005957])已经完成,但在结果报道之前,关于某一病变是否应用此类治疗的决策必须依靠乳腺切除术后的情况推测,也必须对基于保乳加腋窝淋巴结清扫术后局部区域复发率的了解。

乳房切除术后

放疗的迟发毒性作用

放疗的迟发毒性作用少见,包括放射性肺炎、心脏事件、上肢水肿、臂丛神经病和继发肿瘤风险。通过现有的放疗技术和谨慎的目标锚定,这类毒性作用可以最大程度降低。

一项回顾性研究共纳入来自单中心的1,624例接受保乳手术和辅助放疗乳腺癌患者,中位随访77个月,总体上,有症状的放射性肺炎发生率为1.0%[71]。采用锁骨上照射野放疗后肺炎发生率上升至3.0%,同时加用化疗其发生率则上升至8.8%。而接受序贯化疗者肺炎发生率仅为1.3%[68]

关于在左侧胸壁或乳腺及局部淋巴结行辅助放疗是否会增加心脏相关死亡率仍有争议。1980年以前接受放疗的乳腺癌患者与未接受放疗或仅接受右侧放疗的乳腺癌患者相比,其10-15年心脏相关死亡率有所增加[63][69][70][71]。这可能是由于左侧心肌接受部分射线所致。

20世纪90年代兴起的现代放疗技术最大程度地降低了左侧胸壁或左侧乳腺放疗对深部心肌组织的辐射量。心脏相关死亡率随之下降[72][73]。与此同时,美国心脏相关死亡率也有所下降。

对乳腺癌患者而言继发于肿瘤治疗的淋巴水肿仍为影响生活质量的重要问题之一。腋窝淋巴结单一治疗(手术或放疗)后上肢水肿发生率很低。相比于单纯腋窝淋巴结清扫,术后辅助放疗可使患者上肢水肿发生率由2-10%增加至13-18%[76][77][78]。(具体可参见 淋巴水肿​PDQ总结。)

臂丛神经的放射性损伤是一类罕见的乳腺癌放疗并发症。一项单中心研究共纳入449例乳腺癌患者,这些患者均接受术后乳腺及区域淋巴结放疗,研究采用现有放疗技术,随访5.5年以评估臂丛神经损伤的发生率[79]。该疾病依靠临床确诊,同时采用计算机断层扫描技术以除外肿瘤复发。区域淋巴结总剂量54Gy(分30次)放疗组与总剂量45Gy(分15次)放疗组的症状性臂丛神经损伤发生率分别为1.0%和5.9%。

辅助全身治疗

乳腺癌分期和肿瘤分子学特征决定了是否有必要行全身辅助治疗以及应该选择何种治疗方案。例如,ER+和/或PR+患者需接受内分泌治疗。HER2过表达患者应接受辅助曲妥珠单抗治疗,往往还需联合化疗。如果既无HER2过表达,也无激素受体表达,则辅助治疗依赖于化疗,通常还需联合试验性靶向治疗。

内分泌治疗

绝经前女性乳腺癌患者他莫昔芬辅助治疗的最佳疗程是5年还是10年尚有争议。 NSABP-B-14研究比较了早期乳腺癌患者分别接受5年和10年他莫昔芬辅助治疗的疗效,结果表明对于淋巴结转移阴性、ER+的乳腺癌患者,他莫昔芬治疗5年后继续治疗没有额外获益[88]。[ 证据等级:1iA]另一项研究则显示他莫昔芬治疗5年和10年疗效等价[89]。[ 证据等级:1iiDii]同时两项研究均表明,随着治疗时间延长,不良事件的发生率增加。

EST-5181研究中,淋巴结转移阳性的乳腺癌患者在化疗后完成5年的他莫昔芬治疗,这些患者被随机分入继续他莫昔芬治疗组和观察组[90]。在ER+亚组中,继续他莫昔芬治疗与更长时间的疾病缓解相关,但OS无明显改善。

长期与短期他莫昔芬辅助治疗( ATLAS​)试验对12,894例早期乳腺癌患者进行了1996-2005年间长期随访,结果表明连续10年使用他莫昔芬降低乳腺癌的复发风险(分别为617例和711例,P=0.002)、乳腺癌死亡数(分别为331例和397例,P=0.01)和整体死亡数(分别为639例和722例,P=0.01)[91]。[ 证据等级:1iiA]值得注意的是,从乳腺癌首次确诊算起,他莫昔芬治疗10年的获益在10年后较10年内更为显著。在乳腺癌诊断15年后,他莫昔芬治疗10年和5年的乳腺癌死亡率分别为15%和12.2%。与他莫昔芬治疗5年相比,治疗10年增加了以下事件的风险:

肺栓塞相对风险(RR),1.87(95%CI,1.13-3.07,P=0.01)。

卒中RR,1.06(0.83-1.36)。

缺血性心脏病RR,0.76(0.6-0.95,P=0.02)。

子宫内膜癌RR,1.74(1.30-2.34,P=0.0002)。

值得注意的是,乳腺癌确诊后的5-14年间子宫内膜癌的累积风险在他莫昔芬治疗10年和5年患者中分别为3.1%和1.6%,死亡率分别为12.2%和15%,绝对差值2.8%。

这些临床试验都提出了关于内分泌治疗最佳疗程的重要问题。值得注意的是,长期ATLAS为我们提供了在接受5年他莫昔芬治疗后仍未绝经的女性乳腺癌患者相关数据。随机临床试验数据支持在绝经后女性乳腺癌患者中使用芳香酶抑制剂。(具体可参见本总结 芳香酶抑制剂​部分)对于接受5年他莫昔芬治疗后仍未绝经的女性乳腺癌患者,应就延长他莫昔芬治疗的风险与获益与其深入沟通。由于现有数据存在冲突,因此他莫昔芬治疗的最佳疗程仍有待商榷。

(具体可参见本总结 芳香酶抑制剂部分 来曲唑​一节。)

化疗

目前可手术的乳腺癌辅助治疗中标准化疗方案见 表6​所述。尚无证据表明某种方案优于其他方案。因此这些标准方案均为可接受的方案。

一些非常重要的辅助化疗获益证据来自于EBCTCG,该组织每5年对全球乳腺癌试验数据进行一次综述。2000年综述分析(发表于2005年)总结了1995年之前启动的所有随机辅助治疗试验的结果[86]。该辅助化疗分析共纳入来自60项联合化疗(多药化疗)和非化疗对比性试验的28,764例女性、来自17项含蒽环类药物和CMF类化疗对比性试验的14,470例女性、及来自11项长期化疗与短期化疗对比性试验的6,125例女性。

对于年龄小于50岁女性,多药化疗使得乳腺癌年复发风险降低37%,乳腺癌相关死亡风险降低30%,相当于15年生存率绝对增加10%(HR,42%与32%)。对于50-69岁女性,乳腺癌年复发风险降低19%,乳腺癌相关死亡率降低12%,相当于15年生存率绝对增加3%(HR,50%与47%)。对于年龄小于50岁的女性,多药化疗相较于不行辅助化疗可使得生存率增加,15年生存率绝对增幅为5年生存率增幅的2倍(分别10%与4.7%),而多药化疗降低疾病复发率的效果主要在初始5年[86]。对于年龄小于50岁的女性,含蒽环类药物化疗方案(例如氟尿嘧啶、阿霉素、环磷酰胺[FAC]或氟尿嘧啶、表柔比星、环磷酰胺[FEC])治疗6个月后15年累计死亡率降低38%,对50-60岁女性,该数据为20%。该荟萃分析也发现无论患者年龄多大(小于50岁或50-69岁),加用他莫昔芬和不用他莫昔芬的复发风险降低程度相似,但该结果对于年龄小于50岁的女性无统计学显著性。然而,此结果很可能是参与化疗-内分泌联合治疗试验的年轻女性人数较少所致。临床试验中很少纳入年龄大于70岁的女性患者,因此对该年龄群无特殊结论。需注意,这些数据均来自于临床试验,并未根据患者的ER情况选择辅助治疗,且这些试验均在含紫杉烷类剂量密集化疗或含曲妥珠单抗治疗问世前进行[86]。在一些新疗法问世之后,这些结果并不能反映最新的治疗结局。

各项临床试验的结果基本与荟萃分析结论相符。 NSABP-B-13试验发现甲氨蝶呤与5-FU序贯治疗和单独手术相比,前者对淋巴结阴性、ER阴性肿瘤患者更有益[94][95][162][163]。[ 证据等级:1iiA​]

表6. I、II、IIIA期与可手术的IIIC期 HER2/neu非过表达乳腺癌的标准辅助化疗方案
表6. I、II、IIIA期与可手术的IIIC期 HER2/neu非过表达乳腺癌的标准辅助化疗方案
方案 疗程数与持续时间(天) 环磷酰胺(mg/m²) 5-FU (mg/m²) 阿霉素(mg/m²) 紫杉醇/多西他赛(mg/m²)
AC=环磷酰胺,阿霉素;AC-T=环磷酰胺、阿霉素、紫杉酚;CAF=环磷酰胺、阿霉素、氟尿嘧啶;d=天;D=多西他赛;P=紫杉醇;T=紫杉酚;TAC=多西他赛、阿霉素与环磷酰胺;TC=多西他赛与环磷酰胺;5-FU=氟尿嘧啶。
CAF [163] 6 × 21 500, IV d 1 500, IV d 1 50, IV d 1
AC [166] 4 × 21 600, IV d 1 60, IV d 1
剂量密集AC-T[179] 4 (AC), 4 (T) ×14 600, IV d 1 60, IV d 1 P: 175, IV d 1
TAC [193, 194] 6 × 21 500, IV d 1 50, IV d 1 D: 75, IV d 1
TC [195] 4 x 21 600, IV d 1 D: 75, IV d 1

EBCTCG荟萃分析总结了1976-1989年之间启动的11项临床试验,其中女性患者被随机分组接受含蒽环类药物(例如阿霉素或表柔比星)化疗或单行CMF治疗。EBCTCG概况分析直接比较了含蒽环类药物化疗方案(多数为6月FEC方案或FAC方案)与CMF(口服或静脉用)对约14,000例女性的作用,其中64%女性年龄小于50岁[86]。与CMF相比,以蒽环类药物为基础的化疗方案组乳腺癌年复发率约降低11%,幅度不大但具有统计学显著性,死亡年风险降低16%。无论是复发率还是死亡率,含蒽环类药物方案和CMF类化疗方案的5年结局绝对差异约为3%,10年结局绝对差异约为4%[164]。[ 证据等级:1iiA​]

一项美国组间研究( SWOG-8897)为迄今直接比较环磷酰胺、阿霉素、5-FU(CAF)(6程)与CMF(6程)的最大规模研究,未被纳入上述荟萃分析[165]。该研究中2,691例患者被随机分组接受CAF或CMF治疗,二次随机分组接受5年他莫昔芬和无他莫昔芬治疗。10年随访估计值表明CAF组的主要结局DFS并不显著优于CMF(分别为77%与75%;HR,1.09;95%CI,0.94-1.27)(P=0.13)。CAF组OS略优于CMF组(分别为85%与82%,CMF与CAF相比HR,1.19;95%CI,0.99-1.43),但计划进行的单边检验中该差异具有显著统计学差异(P=0.03)。CAF组毒性反应发生率增加,但他莫昔芬治疗后毒性反应发生率未增加。他莫昔芬在总人群中不增加获益(DFS,P=0.16;OS,P=0.37),但高危人群中他莫昔芬效应较为显著。他莫昔芬有益于淋巴结阳性的高危患者群(无他莫昔芬治疗与他莫昔芬治疗相比,DFS:HR,1.32;95%CI,1.09-1.61;P=0.003;OS:HR,1.26;95%CI,0.99-1.61;P=0.03),但淋巴结阴性的高危人群并不得益于他莫昔芬治疗(无他莫昔芬治疗与他莫昔芬治疗相比,DFS:HR,0.81;95%CI,0.64-1.03;P=0.003;OS:HR,0.79;95%CI,0.60-1.05;P=0.03)。该试验结论为,CAF与CMF相比并不改善DFS,但略微影响OS。因CAF毒性反应较大,总体上看CAF并不优于CMF。他莫昔芬对淋巴结阳性的高危人群有益,但对淋巴结阴性的高危人群无效[165]。[ 证据等级:1iiA​]

一些研究者试图通过联用CMF与含蒽环类化疗方案改善患者结局。两项意大利试验比较了这些方案的效果[166][167]。一项试验将490例有1-3枚阳性腋窝淋巴结的绝经前和绝经后女性随机分组,行CMF(12程)治疗或先行CMF(8程)再行阿霉素(4程)治疗[166]。经过17.5年中位观察期之后,第一项研究并未观察到统计学显著差异(无复发生存率[RFS],HR,1.06;总生存率,HR,1.03)。而先行阿霉素再行CMF治疗与现行CMF再行阿霉素治疗相比,前者显著降低疾病复发风险(HR,0.68;95%CI,0.54-0.87;P=0.0017)和死亡风险(HR,0.74;95%CI,0.57-0.95;P=0.018)。第二项试验将403例有4枚或更多阳性腋窝淋巴结的绝经前和绝经后女性随机分组,一组先行阿霉素(4程)再行CMF(8程)治疗,另一组行CMF(2程)与阿霉素(1程)交替治疗,总计12程[167]。先行阿霉素再行CMF治疗组的女性RFS(分别为42%与28%,P=0.002)与OS(分别为58%与44%,P=0.002)均优于另一组[167]。[ 证据等级:1iiA​]

NSABP-B-15试验将腋窝淋巴结阳性且对他莫西芬无反应的2,194例患者随机分为3组,一组接受阿霉素与环磷酰胺(AC)(4程)治疗,一组接受CMF(6程)治疗,一组接受先AC(4程)间隔6月后再CMF(3程)治疗[168]。这三组的DFS与OS无差异[168]。[ 证据等级:1iiA​]该研究也显示4程AC与6程CMF治疗后复发率无差异。

这些CMF联合含蒽环类方案的对比性研究的结果表明蒽环类方案对绝经前和绝经后女性有轻微益处,但关于联用两种方案是否有益仍不确定。

证据表明某些肿瘤特征可预测对蒽环类药物的反应。一些随机临床试验回顾性分析数据表明,对于淋巴结阳性乳腺癌患者,标准剂量辅助性CAF与低剂量辅助性CAF相比的获益[2]或向辅助化疗方案中增加阿霉素的获益[3]仅限于过量表达HER2/neu的肿瘤患者。[ 证据等级:1iiA]一项回顾性分析对710例绝经后淋巴结转移阳性患者的HER2/neu状态进行总结,以评估CMF或环磷酰胺、表柔比星联合氟尿嘧啶(CEF)的效果[169]。[ 证据等级:2A​]HER2/neu状态的评估使用荧光原位杂交法、聚合酶链式反应和免疫组化法。该试验证实了既往数据,即HER2/neu的扩增与RFS、OS降低相关。对于过量表达HER2/neu的患者,CEF可增加RFS与OS。无HER2/neu扩增的患者,CEF与CMF的RFS(复发HR,0.91;95%CI,0.71-1.18;P=0.049)和OS(死亡HR,1.06;95%CI,0.83-1.44;P=0.68)相似。一篇总结了8项随机临床试验(包括上述一项研究)的荟萃分析中也见到类似结果,所纳入的试验共评估了5,354例患者的HER2状态,比较了含蒽环类方案与不含蒽环类方案的效果[170]

许多临床试验评估了向以蒽环类药物为基础的辅助化疗方案中增加紫杉烷(紫杉醇或多西他赛)的益处。一篇文献荟萃分析共纳入13项此类研究,发现加入紫杉烷可提高DFS与OS(DFS:HR,0.83;95% CI,0.79-0.87;P<0.0001;OS:HR,0.85;95%CI,0.79-0.91;P<0.0001)[171]。[[ 证据等级:1iiA]5年绝对生存差异为:DFS 5%,OS 3%,含紫杉烷方案较优。对不同淋巴结情况、雌激素受体情况或年龄/月经情况分组的患者,获益无明显差异。两种药物的有效性亦无明显差异,但这些研究均未直接比较紫杉醇与多西他赛的效果。

东部肿瘤协作组主导的组间试验( E1199[NCT00004125])共纳入4,950例患者,以多因素设计、两药(多西他赛与紫杉醇)双方案(每周一次、每三周一次)开展,患者先行每三周一次标准剂量AC化疗,再行多西他赛或紫杉醇治疗[172]。[ 证据等级:1iiA​]总体比较分析发现多西他赛与紫杉醇组的DFS无差异(比值比[OR],1.03;95%CI,0.91-1.16;P=0.61),每周一次与每三周一次方案的DFS业务差异(OR,1.06;95%CI,0.94-1.20;P=0.33)。但药物与方案之间存在显著的相互作用,DFS(0.003)和OS(0.01)评估中均可见此相互作用。紫杉醇每周一次给药的DFS(OR,1.27;95%CI,1.01-1.57;P=0.006)与OS(OR,1.32;95%CI,1.02-1.72;P=0.01)大于紫杉醇每三周一次给药。多西他赛每三周一次给药的DFS大于紫杉醇每三周一次给药(OR,1.23;95%CI,1.00-1.52;P=0.02),但这两种方案的OS无统计学显著差异(OR,1.13;95%CI,0.88-1.46;P=0.25)。多西他赛每周一次给药不优于紫杉醇每三周一次给药。该试验并未预先设想到两种药物不同的给药方案可能会产生相反效果。因此这些结果成为一些假说的基础,需待证实。

一项美国组间研究( CLB-9344)随机将淋巴结阳性女性乳腺癌患者分组,接受3种剂量的阿霉素(60、75与90mg/m2)联合固定剂量环磷酰胺(600mg/m2)治疗,每三周给药一次,共4程。AC化疗后,再次将患者随机分组,接受紫杉醇(175mg/m2)治疗,每三周一次,共4程,或不再治疗。ER阳性肿瘤患者另外接受5年他莫昔芬治疗。尽管阿霉素剂量增加并无额外获益,但增加紫杉醇治疗显著提高DFS(5%)与OS(3%)[173]。[ 证据等级:1iiA]第二项试验 NSABP-B-28的结果也已报道[174]。该试验将3,060例淋巴结阳性女性乳腺癌患者随机分组,术后接受4程AC化疗或先4程AC化疗再4程紫杉醇化疗。所有年龄大于50岁的女性和年龄小于50岁但受体阳性的女性均接受他莫昔芬治疗。该试验中,增加紫杉醇之后DFS显著改善(风险比[HR],0.83;95%CI,0.72-0.96;P=0.006;5年DFS分别为76%和72%)。但OS差异较小(HR,0.93),不具有统计学意义(P=0.46)[174]。[ 证据等级:1iiA]

乳腺癌国际研究组(BCIRG-001)试验在1,491例淋巴结阳性女性乳腺癌患者中比较了5-FU、阿霉素和环磷酰胺(FAC)与多西他赛、阿霉素和环磷酰胺(TAC)的效果。TAC组5年DFS率为75%,FAC组为68%(P=0.001)。TAC组死亡总风险比FAC组低30%(绝对差异5%)(HR,0.70;98%CI,0.53-0.91;P<0 .008)。TAC组的贫血、中性粒细胞减少症、发热性中性粒细胞减少症和感染的发生率更高。两组均无感染所致死亡病例[175][176]。[ 证据等级:1iiA](贫血信息请参考PDQ总结 乏力。)

回顾性数据和一些前瞻性数据支持医师不应强制减少剂量强度[177][178]。但关于剂量递增对乳腺癌的益处数据则更具争议。 CLB-8541​试验在1,550例淋巴结阳性乳腺癌女性患者中比较了三种剂量CAF的作用。该试验中患者被分入CAF小剂量组(300/30/300 mg/m2,每4周一次,共4程)、CAF中等剂量组(400/40/400 mg/m2,每4周一次,共6程)或CAF大剂量组(600/60/600 mg/m2,每4周一次,共4程)。大剂量组的剂量强度和药物剂量是小剂量组的2倍。中等剂量组的剂量强度是大剂量组的66%,但两组总剂量相等。经过中位时间为9年的随访期之后,大剂量组与中等剂量组的DFS与OS优于小剂量组(P=0.001),而大剂量组和中等剂量组之间的测量指标无差异[177]。[ 证据等级:1iiA]本试验中所用的较大剂量实际上为标准剂量,因此无法明确该试验是支持较大剂量强度有益于治疗,还是证实了强度“阈值”概念,低于该强度阈值的治疗无效。

其他试验所用递增剂量明显大于标准范围。例如, NSABP-B-22NSABP-B-25试验中,环磷酰胺剂量增加到1,200 mg/m2(不加粒细胞集落刺激因子[G-CSF])和2,400 mg/m2(加G-CSF),发现这些剂量递增方案与标准剂量600 mg/m2相比,DFS或OS均无显著提高[179][180]。[ 证据等级:1iiA​]

一项美国组间研究( CLB-9344)将淋巴结阳性女性乳腺癌患者随机分为3组,接受三种剂量的阿霉素治疗(分别60、75、90 mg/m2)。阿霉素治疗后,将患者再次随机分组接受紫杉醇治疗或不接受其他治疗。化疗后,ER阳性乳腺癌患者将接受他莫昔芬5年治疗。三个阿霉素剂量组的DFS无显著差异[173]。但一项加拿大试验( CAN-NCIC-MA5)中,环磷酰胺、表柔比星与5-FU(CEF)的总剂量为720 mg/m2,每程4周,共6程,研究发现对存活患者进行中位时间10年的随访后,CEF组患者的10年RFS为52%,CMF组患者的10年RFS为45%(CMF与CEF相比的HR为1.31;分层秩和检验,P=0.007)[181]。CEF与CMF组患者的10年OS分别为62%与58%(CMF与CEF相比的HR为1.18;分层秩和检验,P=0.085)。和最初报告相比,急性白血病发生率并无改变,但充血性心力衰竭发生率略微升高(CEF组4例患者[1.1%],CMF组1例患者[0.3%])[181]。[ 证据等级:1iiA]该试验设计使得我们无法判断效果的改善归因于蒽环类药物、剂量强度还是二者兼有之。一项法国研究显示表柔比星剂量增加后,预后较差的女性生存率提高[182]。一项随机临床试验延长了淋巴结阳性的绝经前女性接受表柔比星的治疗时间,10年生存率并未增加[183]

一项美国组间研究( CLB-9741)在2,005例淋巴结阳性的绝经前和绝经后女性患者中按2×2因素设计比较了阿霉素、环磷酰胺与紫杉醇(先阿霉素和环磷酰胺,再紫杉醇)与序贯给药(先阿霉素、再紫杉醇、再环磷酰胺)联合非格司亭的效果,每3周或每2周一程[184]。经过中位时间为68个月的随访期之后,观察到剂量密集治疗改善了总患者群的主要终点,DFS(HR,0.80;P=0.018),但OS并无改善(HR,085;P=0.12)。剂量密度和顺序之间无相互作用。剂量密度治疗方案组的患者中,重度中性粒细胞减少症的发生率较低[184][185]。先阿霉素与环磷酰胺再紫杉醇,每2周一程方案组的2级贫血(血红蛋白<10g/dL)的发生率最高(P<0.001)。在第5程化疗时观察到这一组的血红蛋白含量达到最低点,平均为10.7 g/dL,低于另一组。此外,该组所用的红细胞生成素α剂量也高于其他三组(P=0.013)。总之,先阿霉素与环磷酰胺,再紫杉醇,每2周一程的剂量密集方案组中度贫血的发生率较高,红细胞生成素α的使用量更大,红细胞输血量也大于其他组[186]。[ 证据等级:1iiA]

一些临床试验(包括 EST-2190)研究了大剂量化疗加骨髓移植(BMT)或干细胞支持对超过10枚淋巴结阳性的和4-9枚淋巴结阳性的女性患者的作用[187][188][189][190][191][192][193][194]。一项前瞻性随机临床试验纳入403例患者,评估了两种大剂量化疗方案的区别,经过中位时间为49个月的随访期之后,两个方案组的5年生存率(分别为75%与70%)统计学有显著差异(P=0.02)[193]。[ 证据等级:1iiA]其他试验在高危人群中比较了传统化疗和大剂量化疗联合BMT或干细胞支持的作用,发现大剂量化疗加BMT或干细胞支持并不增加OS或EFS获益[187][188][189][190][191][192][194][195][196]。[ 证据等级:1iiA]目前的信息不支持在非随机临床试验条件下使用大剂量化疗。

将比较大剂量化疗联合自体移植与传统化疗对早期预后较差女性乳腺癌患者作用的9项随机对照临床试验进行系统性回顾[194]。共1,758例女性被随机分组接受大剂量化疗联合自体移植,1,767例女性接受传统化疗。大剂量组有48例非癌症相关死亡病例,传统剂量组为4例(RR,7.74;95%CI,3.43-17.50)。大剂量化疗联合自体移植组女性与传统化疗组女性的3年OS(RR,1.02;95%CI,0.98-1.06)和5年OS均无统计学显著差异(RR,0.98;95%CI,0.93-1.05)。大剂量化疗组的3年EFS在统计学上显著优于传统化疗组(RR,1.11;95%CI,1.05-1.18)。但5年EFS无显著差异(RR,1.00;95%CI,0.92-1.08)[194]

一研究比较了多西他赛联合环磷酰胺(TC)方案与阿霉素联合环磷酰胺(AC)治疗1,016例I期或II期浸润性乳腺癌女性患者的作用。这些患者被随机分组接受4程TC或AC术后辅助化疗。TC组的5年DFS显著优于AC组(分别为86%与80%,HR,0.67;95%CI,0.50-0.94;P=0.015)[197]。[ 证据等级:1iiA]初始报告中OS无统计学显著改善。但7年DFS与OS更新结果发现患者接受4程TC治疗后的DFS与OS优于AC治疗[198]。[ 证据等级:1iiA​]TC组的7年DFS显著优于AC组(分别为81%与75%,HR,0.74;95%CI,0.56-0.98;P=0.033)。TC组的7年OS也显著优于AC组(分别为87%与82%,HR,0.69;95%CI,0.50-0.97;P=0.032)。TC组患者的心脏毒性反应低于AC组,但其他毒性反应,包括肌痛、关节痛、水肿、发热性中性粒细胞减少症的发生率大于AC组。

双磷酸盐

辅助治疗中增加双磷酸盐对早期乳腺癌的作用尚不明确。 ABCSG-12(NCT00295646)试验为2×2因素随机对照试验,将1,803例ER+绝经前乳腺癌女性患者随机分组,接受戈舍瑞林抑制卵巢功能加他莫昔芬治疗或戈舍瑞林加阿那曲唑治疗。这些患者随后经二次随机分组,接受唑来膦酸(4 mg静脉用,每6个月一次)和无唑来膦酸治疗[199]。[ 证据等级:1iiA]阿那曲唑与他莫昔芬组患者的DFS无显著差异。但内分泌治疗加唑来膦酸与单纯内分泌治疗相比,疾病进展风险相对降低36%(HR,0.64;P=0.01),但死亡风险并不显著降低。另一项试验( NCT00171340)观察到类似结果,该试验中1,065例绝经后女性接受来曲唑治疗后被随机分组,即刻接受唑来膦酸治疗(4 mg静脉用,每6个月一次)或仅在发生骨质疏松或骨折后应用唑来膦酸治疗。即刻唑来膦酸用药组的DFS提高了34%(HR,0.66;95%CI,0.44-0.97;P=0.035),但OS不受影响[200]。[ 证据等级:1iiA]

虽然双磷酸盐似乎能够提高低-中危乳腺癌患者的DFS,但该获益并不见于所有乳腺癌患者。 AZURE试验为一项随机、III期临床试验,共纳入3,660例II或III期乳腺癌患者,接受化疗联合(或)激素治疗加或不加唑来膦酸[201]。[ 证据等级:1iiA]经过中位时间为59个月的随访之后,两组的DFS均无显著获益(分别各为77%;HR,0.98;P=0.79)。OS结果也类似,唑来膦酸组为85.4%,对照组为83.1%(校正后HR,0.85;P=0.07)。

基于这些不一致的试验结果,双磷酸盐作为乳腺癌辅助治疗的确切作用仍有争议。一项正在进行之中的III期临床试验( NCT01077154)评估了骨调节剂地诺单抗对II期和III期乳腺癌患者的作用。

单克隆抗体

一些III期临床试验评估了抗HER2/neu抗体曲妥珠单抗辅助治疗对HER2过度表达型肿瘤患者的作用。

赫赛汀辅助治疗(HERA)试验( BIG-01-01[NCT00045032])为迄今的最大规模曲妥珠单抗试验,共5,090例患者在完成7周主要治疗后接受每3周一次曲妥珠单抗治疗。多数患者的主要治疗为术前或术后含蒽环类药物化疗,联合或不联合局部放疗[202]。[ 证据等级:1iiA]另外一项对照试验招募了3,387例患者,接受1年曲妥珠单抗治疗(1,694例)或仅观察(1,693例患者)[202]。这些患者的中位年龄为49岁,约有33%的患者淋巴结阴性,近50%患者激素受体(ER与PR)阴性。接受曲妥珠单抗治疗1年组的首例不良事件发生率降低46%(风险比[HR],0.54;95%CI,0.43-0.67;P<0.001),与2年组的DFS绝对获益8.4%一致?(95%CI,2.1-14.8)。经过23.5个月随访,更新的结果显示曲妥珠单抗组与观察组相比,死亡风险的非校正HR为0.66(95%CI,0.47-0.91;P=0.0115),相当于绝对OS获益为2.7%[203]。曲妥珠单抗组共218例DFS事件,观察组321例DFS事件。曲妥珠单抗组事件风险的非校正HR为0.64(0.54-0.76;P<0.001),相当于DFS绝对获益为6.3%。经过中位时间为8年的随访,对曲妥珠单抗治疗1年和2年的效果进行分析[204]。两组的DFS无差异(HR,0.99;95%CI,0.85-1.14;P=0.86)[204]。[ 证据等级:1iiA]1年曲妥珠单抗治疗与仅观察相比的获益持续存在,尽管观察组有52%患者交叉到曲妥珠单抗组(HR,0.76;95%CI,0.65-0.88;P=0.0005)[204]。[ 证据等级:1iiA]

NSABP-B-31(NCT00004067)与组间试验 NCCTG-N9831联合分析评估了曲妥珠单抗每周一次,与AC联合紫杉醇方案中的紫杉醇同时给药或在紫杉醇之后立即给药的效果[205]。[ 证据等级:1iiA]联合分析进一步证实了HERA结果。联合分析总计纳入3,676例患者,发现DFS(HR,0.48;P<0.001;3年DFS分别为87%和75%)与OS(HR,0.67;P=0.015;3年OS分别为94.3%与91.7%,4年OS分别为91.4%与86.6%)均有显著改善[206]。曲妥珠单抗组患者的DFS延长,DFS事件风险降低52%(HR,0.48;95%CI,0.39-0.59;P<0.001),相当于3年DFS绝对相差11.8%,4年DFS绝对相差18%。曲妥珠单抗治疗的患者发生远处复发的风险降低53%(HR,0.47;95%CI,0.37-0.61;P<0.001),死亡风险降低33%(HR,0.67;95%CI,0.48-0.93;P=0.015)。

BCIRG-006(NCT00021255)试验将3,222例早期HER2过度表达型乳腺癌患者随机分组,接受先AC再多西他赛(AC-T)治疗或先AC再多西他赛加曲妥珠单抗(AC-T加曲妥珠单抗)或多西他赛、卡铂联合曲妥珠单抗(TCH,一种非蒽环类方案)治疗[207]。[ 证据等级:1iiA​]含曲妥珠单抗的2个方案组与不含曲妥珠单抗的对照组相比,DFS与OS均有显著获益。对照组的5年DFS率为75%,OS率为87%。AC-T加曲妥珠单抗组的5年DFS率为84%(与AC-T组相比的HR为0.64;P<0.001),OS率为92%(HR,0.63;P<0.001)。TCH组5年DFS率为81%(HR,0.75;P=0.04),OS率为91%(HR,0.77;P=0.04)。

作者认为两个含曲妥珠单抗方案的DFS与OS无显著差异。但该研究效力不足以检测出两个含曲妥珠单抗方案的等效性。AC-T加曲妥珠单抗组的充血性心力衰竭与心功能不全发生率显著高于多西他赛、卡铂加52周曲妥珠单抗(TCH)治疗组(P<0.001)。这些试验结果不禁让人产生疑问,即HER2过度表达型乳腺癌的辅助治疗是否必须含蒽环类药物。AC-T组患者人数较少,但与TCH组相比无统计学显著获益。该试验支持以TCH作为早期HER2过度表达型乳腺癌女性患者的辅助治疗替代方案,尤其可用于有心脏毒性反应顾虑的患者。

AVENTIS-TAX-GMA-302​试验为一项三组大型临床试验,包括两个蒽环类方案组(AC-D:阿霉素、环磷酰胺、多西他赛或AC-DH:阿霉素、环磷酰胺、多西他赛、曲妥珠单抗)和1个非蒽环类方案组(DCbH:多西他赛、卡铂、曲妥珠单抗)[208]。经过中位时间为36个月的随访,第二次中期有效性分析共发现462例DFS事件与185例死亡。对于DFS,AC-DH组与AC-D组相比的HR为0.61(95%CI,0.48-0.76;P<0.001),DCbH组与AC-D组相比的HR为0.67(95%CI,0.54-0.83;P=0.003),相当于增加曲妥珠单抗后(2年-4年)的绝对获益分别为6%与5%。但DCbH组患者仍需延长随访时间,以确保这些患者未接受蒽环类药物治疗。

芬兰赫赛汀(FINHER)研究评估了短程曲妥珠单抗治疗的作用[209]。该试验中,232例年龄小于67岁、淋巴结阳性或淋巴结阴性但高危(肿瘤>50px)的HER2过度表达型乳腺癌患者接受每9周一次曲妥珠单抗联合多西他赛或长春瑞滨加FEC治疗。经过中位时间为3年的随访期之后,曲妥珠单抗用药者的复发和(或)死亡风险显著降低(HR,0.41;P=0.01;95%CI,0.21-0.83;3年DFS分别为89%与78%)。OS差异(HR,0.41)无统计学意义(P=0.07;95%CI,0.16-1.08)[209]。[ 证据等级:1iiA]

拉帕替尼是一种小分子酪氨酸激酶抑制剂,能够抑制EGFR与HER2两种受体。拉帕替尼和(或)曲妥珠单抗优化辅助治疗( ALTTO[NCT00553358])评估了拉帕替尼(联合、序贯、对比或替代曲妥珠单抗)在辅助治疗中的作用。在I、II期研究中,多种含曲妥珠单抗方案治疗后疾病进展的ER2阳性患者经过拉帕替尼单药治疗的客观缓解率在4.3%-7.8%之间,疾病稳定至少4个月(34%-41%)和6个月(18%-21%)的患者不在少数[210]。一项III期临床试验( GSK-EGF100151​)发现对于含蒽环类药物、紫杉烷和曲妥珠单抗方案治疗后进展的HER2阳性晚期乳腺癌患者,拉帕替尼联合卡培他滨的效果优于单用卡培他滨[211]。疾病进展风险比为0.49(95%CI,0.34-0.71;P<0.001),联合治疗组有49例进展,单药治疗组有72例进展。联合治疗组的进展时间中位数为8.4个月,单药治疗组为4.4个月。

ALTTO试验支持了拉帕替尼联合曲妥珠单抗治疗,该试验发现对于既往含曲妥珠单抗治疗后疾病进展的转移性乳腺癌患者,拉帕替尼联合曲妥珠单抗较曲妥珠单抗单药治疗相比,显著改善无进展生存期[212]

2011年9月,ALTTO试验停止了拉帕替尼单药治疗。该试验的独立数据审核委员会认为拉帕替尼单药治疗组患者的结局不如曲妥珠单抗单药治疗对照组。该试验最终结果尚未公布。

在HERA试验( BIG-01-01)中,曲妥珠单抗治疗后0.6%患者出现重度充血性心力衰竭(CHF NYHA分级III-IV级)[202]。曲妥珠单抗组与观察组发生CHF症状的患者比例分别为1.7%与0.06%。曲妥珠单抗治疗组51例患者左心室射血分数(LVEF)下降(EF与基线相比降低至少10点至LVEF<50%),其中86%的患者经过初步治疗后病情在3-6周后康复或稳定。 NSABP B-31(NCT00004067)试验中,曲妥珠单抗组850例患者汇总31例出现心脏事件症状,而对照组814例患者中仅5例出现此类症状[213]。曲妥珠单抗组患者的3年累计心脏事件发生率为4.1%,对照组为0.8%(95%CI,1.7%-4.9%)。曲妥珠单抗组17%(95%CI,15%-20%)患者出现无症状的LVEF下降(定义为EF降低超过10%或低于55%),对照组的相应比例为34%(95%CI,31%-38%),HR为2.1(95%CI,1.7-2.6;P<0.001)。 NCCTG-N9831​试验中,三组在3年时间内共发生39例心脏事件。A组(无曲妥珠单抗)、B组(先紫杉醇再曲妥珠单抗)和C组(紫杉醇与曲妥珠单抗同期给药)的心脏事件3年累计发生率分别为0.35%、3.5%与2.5%。

AVENTIS-TAX-GMA-302​(BCIRG 006)试验中,AC-D组有临床症状性心脏事件的发生率为0.38%,AC-DH组为1.87%,DCbH组为0.37%[208]。AC-DH组无症状性LVEF持续下降事件的发生率显著高于AC-D组或DCbH组。AVENTIS-TAX-GMA-302试验中无心源性死亡报道。

FINHER试验中,所有接受曲妥珠单抗治疗的患者均未发生临床上显著的心脏事件。实际上,所有接受曲妥珠单抗治疗的女性LVEF均未降低,但接受曲妥珠单抗辅助治疗的患者人数很少。

标准治疗为1年曲妥珠单抗辅助治疗。HERA试验中1年与2年曲妥珠单抗治疗的对比结果尚未公布,赫赛汀辅助治疗剂量减少方案(INCA-PHARE​[NCT00381901])试验比较了1年和6个月曲妥珠单抗治疗的效果,结果也尚未公布。

主要治疗和辅助治疗的时机

术后辅助化疗

开始辅助治疗的最优时机仍有争议。一项研究在淋巴结阳性患者中评估了术前辅助化疗的作用,显示在术后4周开始的标准治疗基础上增加1程术前化疗并不改善DFS[214]。术后立即给予1程化疗具有劣效性[215]

术前新辅助化疗

一项随机临床试验( NSABP-B-18​)评估了I期或II期乳腺癌患者接受术前化疗的效果[216]。经过4程阿霉素联合环磷酰胺术前化疗之后,80%的可评估患者肿瘤体积缩小至少50%,36%的患者达到临床完全缓解。术前化疗组能够行保乳术的患者比例高于术后化疗组(分别为68%与60%)。术前化疗组中27%患者原计划行全乳房切除术,最终仅行肿瘤切除术。但术前化疗组和术后化疗组的DFS、远处DFS或OS无统计学显著差异[216][217][218]。[ 证据等级:1iiA]

EORTC随机试验( EORTC-10902)也证实术前FEC化疗与术后FEC化疗相比,DFS或OS没有改善,但保乳手术率增加[219]。[ 证据等级:1iiA ]术前化疗对有保乳意愿但因肿瘤大小原本无法行保乳手术的患者有益。一项荟萃分析总结了所有比较相同术前、术后化疗方案的研究,发现术前化疗的局部复发率较高[22]。虽然术前化疗影响SLN活检结果,但一项小规模研究发现这种情况下仍然可以进行SLN活检操作[221]。然而,两项前瞻性研究( NCT02031042NCT00881361)发现新辅助化疗后淋巴结临床评估从阳性转为阴性的患者行SLN活检的假阴性率分别为14.2%与12.6%[222][223]。[ 证据等级:3iiD]这些假阴性率均高于辅助化疗前的SLN活检。新辅助治疗中SLN活检的作用尚不明确。

HER2导向治疗

对于HER2过度表达型肿瘤患者,一些初步研究证实了在术前进行曲妥珠单抗联合化疗后产生显著的临床和病理缓解效果[224]。在HER2阳性局部晚期或炎症性乳腺癌患者中开展了一项随机临床研究,证实了在阿霉素加紫杉醇继而CMF序贯的新辅助化疗方案中增加曲妥珠单抗不仅改善临床缓解率(分别为87%与74%)和病理缓解率(分别为38%与19%),也改善主要结局,即无事件生存率(EFS)[225]。EFS定义为从随机分组到疾病复发或进展(无论是局部、区域、远处或对侧)或任何原因死亡的时间。

在所有患者中,用曲妥珠单抗组的3年EFS(71%;95%CI,61%-78%)高于无曲妥珠单抗组(56%;95%CI,46%-65%)(HR,0.59;95%CI,0.38-0.90,P=0.013),由此证明增加曲妥珠单抗的效果更优。报告时两组的3年OS分别为87%与79%(P=0.114,无意义)。阿霉素与曲妥珠单抗联合治疗2程后2例患者发生有症状的心力衰竭。密切监测患者的左心室射血分数(LVEF)及阿霉素总剂量不超过180 mg/m2是LVEF下降的患者比例相对较少且仅有2例心脏事件的原因。(详见本总结 曲妥珠单抗辅助治疗的心脏毒性反应部分。)[225][ 证据等级:1iiD]

两项临床试验评估了帕妥珠单抗联合曲妥珠单抗加或不加化疗的效果。 NeoSPHERE试验(NCT00545688)为一项开放、随机的II期试验[226],417例肿瘤大于50px或淋巴结阳性的HER2阳性女性乳腺癌患者被随机分到下列四个术前治疗组中:

四组的病理完全缓解率(pCR)分别为29%、46%、17%与24%[226]。[ 证据等级:1iiDiv]即术前双重HER2阻断加化疗组的pCR率最高。多西他赛联合曲妥珠单抗方案中增加帕妥珠单抗没有表现出增加毒性反应风险,包括心脏不良事件风险。

TRYPHAENA试验(NCT00976989)为一项开放、随机的II期临床试验,力图评估曲妥珠单抗与帕妥珠单抗的耐受性和有效性[227]。[ 证据等级:1iiDiv]纳入的患者为225例肿瘤大于50px或淋巴结阳性且可行手术、局部晚期或HER2阳性炎性乳腺癌患者,被随机分到三个术前治疗组中:

这三组的pCR率相近(分别为62%、57%和66%)。三组的心脏不良事件发生率均不超过5%。

基于这些研究,FDA同意了加速审批帕妥珠单抗用于HER2阳性的早期女性乳腺癌患者的新辅助治疗。FDA批准帕妥珠单抗使用不超过3-6个疗程。目前正在进行的 APHINITY试验(NCT01358877)是针对HER2阳性的女性乳腺癌患者进行的一项随机、III期辅助研究,是为了此次加速审批的验证性试验。预期将在2016年公布结果。

GeparQuinto[NCT00567554]评估了拉帕替尼在新辅助治疗中的作用[228]。该试验为III期随机临床试验,将HER2阳性的早期女性乳腺癌患者随机分组接受化疗联合曲妥珠单抗治疗或化疗联合拉帕替尼治疗,该研究的主要终点为病理完全缓解率(pCR)[228]。[ 证据等级:1iiDiv]化疗联合拉帕替尼组的pCR显著低于化疗联合曲妥珠单抗组(分别为22.7%与30.3%;P=0.04)。其他终点,如DFS、无复发生存率(RFS)与OS尚未报道。这些结果并不支持在新辅助治疗中单独使用拉帕替尼联合化疗。

NeoALTTO[NCT00553358]试验进行了双重HER2抑制作为新辅助治疗的研究[229]。[ 证据等级:1iiDiv]该试验为III期随机临床试验,将455例HER2阳性的早期女性乳腺癌(肿瘤体积>50px)患者随机分组,接受拉帕替尼新辅助治疗,或曲妥珠单抗新辅助治疗,或拉帕替尼联合曲妥珠单抗新辅助治疗。对于所有入组患者,这种抗HER2治疗单独进行6周后,增加紫杉醇每周一次治疗,再持续12周。该研究的主要终点为pCR。拉帕替尼联合曲妥珠单抗组的pCR(51.3%;95%CI,43.1%-59.5%)显著高于单行曲妥珠单抗组(29.5%;95%CI,22.4%-37.5%)。拉帕替尼组(24.7%;95%CI,18.1%-32.3%)与曲妥珠单抗组的pCR无显著差异(相差-4.8%;95%CI,-17.6%-8.2%;P=0.034)。

应注意到该试验并未报道DFS、RFS和OS。虽然pCR率有助于推测其他指标,但并不能替代这些有效性终点。然而该研究结果提示我们,应继续探索单克隆抗体联合酪氨酸激酶双重抑制HER2用于治疗HER2阳性早期乳腺癌患者。一项设计类似的试验 CALGB-40601(NCT00770809)仍在进行之中,结果尚无定论。ALLTO III期试验将女性随机分组接受曲妥珠单抗或曲妥珠单抗联合拉帕替尼辅助治疗,将可能提供更多确切的有效性数据。

贝伐单抗

目前关于将贝伐单抗纳入新辅助化疗方案对乳腺癌患者的作用尚无定论。贝伐单抗是一种单克隆抗体,拮抗血管内皮生长因子A,在一定程度上对转移癌有效。两项化疗联合或不联合贝伐单抗的随机、III期临床试验结果已有报道[230][231]

一项试验将1,206例原发可切除的、HER2阴性的乳腺癌患者随机分组,接受化疗联合贝伐单抗或单纯化疗[230]。增加贝伐单抗显著改善pCR率(无贝伐单抗组与有贝伐单抗组的pCR率分别为28.2%与34.5%;P=0.02)[230]。[ 证据等级:1iiDiv]但增加贝伐单抗增加高血压、心脏毒性、手足综合征和黏膜炎的发生率。

另一项研究将1,948例可手术行HER2阴性乳腺癌患者随机分组,接受表柔比星联合环磷酰胺、多西他赛的新辅助化疗,加或不加贝伐单抗[231]。增加贝伐单抗显著改善pCR率(无贝伐单抗组与有贝伐单抗组的pCR率分别为14.9%与18.4%;P=0.003)[231]。[ 证据等级:1iiDiv]与其他临床试验相似,加入贝伐单抗增加毒性事件发生率,例如发热性中性粒细胞减少症、黏膜炎、受阻综合征、感染、高血压等,但并不增加手术并发症。一项预先计划的亚组分析随后发现向新辅助化疗方案中增加贝伐单抗可使得三阴性乳腺癌的pCR率从27.9%显著增加到39.3%(P=0.003)[232]。[ 证据等级:1iiDii​]

需注意,这两项临床试验均未报道OS与DFS结果[230][231]。根据这些结果,贝伐单抗不应用于可手术乳腺癌的治疗。以pCR作为主要临床结局时必须谨慎。但关于贝伐单抗用于治疗可手术乳腺癌的进一步研究可能是很有道理的。

辅助放疗与化疗

一项随机临床试验评估了保乳术后辅助化疗与放疗的最优次序[233]。该试验中患者先接受化疗再行乳腺放疗(n=122),或先行乳腺放疗再行化疗(n=122),所用化疗方案为CMFP联合阿霉素,每21天为一程,共4程。经过中位时间为5年的随访期,先放疗组的OS为73%,先化疗组的OS为81%(P=0.11)[233]。[ 证据等级:1iiA]先放疗组和先化疗组5年首次复发率粗略估值为:局部复发分别为5%和14%,远处或区域复发或二者兼有分别为32%和20%。复发率上的差异仅具边缘统计学意义(P=0.07)。进一步的分析发现多数亚组均有这种复发率差异,但肿瘤切缘阴性患者或1-3枚阳性淋巴结患者除外。这两组患者接受不同的放疗与化疗顺序后,局部或远处复发率几乎无差异,但这两项亚组分析的统计学效力较低。先放疗组的远处复发率较高的一个原因可能是化疗推迟到术后中位时间17周再进行,因骨髓抑制发生率增高,该组的化疗剂量也降低。

另有2项随机试验虽然并未专门研究放疗和辅助化疗的时机,仍提供了一些有效信息[168][234]NSABP-B-15试验中,保乳术后患者接受1程CMF治疗(n=194)后行放疗,再行5程CMF治疗,或接受4程AC治疗(n=199)后行放疗。两组的DFS、远处DFS和OS无差异[168]。[ 证据等级:1iiA​]国际乳腺癌研究组试验VI和VII也评估了CMF辅助化疗联合不同时间的放疗[234]。这些研究发现术后放疗延迟2-7个月不影响局部复发率。

基于上述研究,保乳术后推迟放疗,直至完成辅助化疗后再行放疗似乎对总结局无负面影响。此外,对于远处播散风险较高的患者,保乳术后早期行化疗为首选。

一项III期试验在HER2/neu阳性乳腺癌患者中进行,以评估增加曲妥珠单抗的获益。该试验的一项未预期计划分析发现辅助放疗联合同期曲妥珠单抗治疗组的患者中,急性不良事件(AE)或心脏事件发生率并未增加[235]。因此放疗与曲妥珠单抗治疗同期进行似乎具有良好的安全性,可避免推迟放疗。

手术时机

一些回顾性综述发现,淋巴结阳性的绝经前乳腺癌女性患者在黄体期(第15-36天)进行手术的DFS显著优于在卵泡期(第0-14天)进行手术[236][237][238]。[ 证据等级:1iiA][239]但也有一些研究未得出类似结果,或得到相反结果[240][241][242][243]。[ 证据等级:1iiA]因这些研究的结果不一致,现在根据患者的月经周期调整乳腺癌手术时机仍为时尚早。一项前瞻性对照试验( UCLA-9810046​)已经结束,但数据分析尚未完成。

化疗风险

辅助化疗与一些重度毒性反应相关,每种方案所用药物不同,产生的毒性反应也不同。常见的毒性反应包括恶心呕吐、骨髓抑制、脱发和黏膜炎等。较为罕见但严重的毒性反应包括心力衰竭(如果使用了蒽环类药物)、血栓栓塞事件[244]和提前绝经[245]。(请参考PDQ总结 恶心与呕吐,黏膜炎相关信息请参考PDQ总结 化疗与头颈部放疗的口腔并发症,提前绝经的症状信息请参考PDQ总结 出汗与潮热​。)

一些患者接受化疗后出现认知损害[246]。但该事件缺乏前瞻性随机研究数据的支持。

EBCTCG荟萃分析显示接受辅助联合化疗的女性患者对侧乳腺癌年发生率降低20%(标准差=10)[164]。这一小比例下降转化为绝对获益仅有边界统计学意义,但提示化疗不增加对侧乳腺癌风险。此外,分析显示所有接受化疗的女性死于其他癌症或血管源性死亡的风险并不显著升高。但含蒽环类药物方案,尤其是接受大剂量环磷酰胺治疗的患者,发生急性白血病的5年累计风险从0.2%上升到1.7%[247][248]。接受较大累积剂量表柔比星(>720 mg/m2)联合环磷酰胺(>6,300mg/m2)治疗的患者相应风险上升至超过4%[249]

化疗联合他莫昔芬的风险

他莫昔芬联合同期辅助化疗增加有效性的同时也增加毒性反应。一项研究将淋巴结阳性、ER阳性的绝经后乳腺癌女性患者随机分组,接受他莫昔芬(30mg/天,共2年)加CMF(静脉用6个月)治疗(n=353)或仅他莫昔芬治疗(n=352)[244]。在接受化疗激素联合治疗的女性患者中,13.6%发生至少一项血栓栓塞事件,仅他莫昔芬组该比例为2.6%(P<0.001)。此外,联合治疗组血栓栓塞事件(3-5级)中,多数事件发生在患者接受化疗时(39/54例)。并非所有对比化疗联合他莫昔芬与单纯他莫昔芬治疗的研究都报道了如此高的血栓栓塞事件率。 NSABP-B-16研究对比了他莫昔芬(20mg/天,5年)联合化疗(阿霉素加环磷酰胺,4程)和单纯他莫昔芬治疗,联合治疗组的血栓栓塞事件发生率为4.9%,单纯他莫昔芬治疗组为2.1%[94]。一项组间试验( INT-0100[NCT00929591],曾用名SWOG-8814)评估了应当在化疗同期进行他莫昔芬治疗,还是应当在化疗结束后进行他莫昔芬治疗,该试验对比了CAF与他莫昔芬同期或序贯治疗对激素受体阳性绝经后乳腺癌患者的作用。序贯给药组8年DFS显著优于对组(分别为67%与62%;P=0.045)[250]。[ 证据等级:1iiDii​]

不一定需行辅助治疗的患者包括肿瘤体积较小(<1cm)和腋窝淋巴结阴性、预后较佳的患者。一项病例分析显示此类患者20年无病生存率近90%[251]。一项美国组间研究( SWOG-8897​)观察到低危患者(肿瘤过小,无法进行ER/PR生化分析)和危险度不明的患者(肿瘤<2cm,ER阳性与PR阳性,S期分数低)不接受治疗的情况。这些低危患者与危险度不明的患者不接受辅助治疗的情况下,5年生存率为96%。从他莫昔芬的辅助作用或预防作用来看,此类患者是否可得益于他莫昔芬长期治疗尚不明确。但此类患者存在新发乳腺癌的风险,可能符合乳腺癌预防试验的入选标准,该试验证实了他莫昔芬治疗的益处。

曾有人提出不行手术、单纯使用他莫昔芬治疗老龄患者。该方法因局部失败率较高而被弃置,除临床试验之外,仅可用于不适合行乳房切除术或保乳术加放疗的患者,或拒绝这些手术治疗的患者[252][253][254]

治疗选择

主要治疗

局部-区域性治疗:

保乳治疗(肿瘤切除术、乳腺放疗、腋窝手术分期)。

改良根治性乳房切除术(切除全乳,行I-II级腋窝淋巴结清扫)伴或不伴乳房重建。

前哨淋巴结活检。

腋窝淋巴结阳性患者在乳房切除术后行辅助放疗:

1-3枚阳性淋巴结:区域治疗(锁骨上、锁骨下淋巴结、内乳淋巴结、腋窝淋巴结和胸壁)的作用不明。

4枚或更多阳性淋巴结或结外受累:建议行区域放疗。

国际共识专家组建议对腋窝淋巴结阴性的患者进行三层危险度分级[55]。该分类及其改良分类标准见下表:

表7. 淋巴结阴性乳腺癌女性患者的危险度分类
表7. 淋巴结阴性乳腺癌女性患者的危险度分类
低危(满足下列所有条件) 中危(危险度介于低危与高危之间) 高危(满足下列至少一项条件)
ER=雌激素受体;PR=孕激素受体
肿瘤大小 = 1 cm 1–2 cm >2 cm
ER或PR状态 阳性 阳性 阴性
肿瘤分级 1级 1-2级 2-3级

最初的共识专家组分类要求低危组女性年龄应大于等于35岁,高危组女性年龄小于等于35岁,此要求显然是根据间接证据作出。通常一些罕见的组织学(例如,管状、髓样和粘液性癌)预后较好,可视为低危因素。其他肿瘤特征也有助于对淋巴结阴性患者的预后进行评估,包括肿瘤增殖分数(S-期)和HER2/neu表达情况。

无论如何确定淋巴结阴性患者的预后,来自临床试验的证据表明多种辅助治疗可以使得某些肿瘤特征的患者获益。这同样适用于淋巴结阳性乳腺癌患者。根据多项乳腺癌治疗试验的结果,人们逐渐认可激素治疗与化疗对女性患者的获益程度相当,而无论有无阳性淋巴结。如何选择治疗还需取决于对肿瘤复发的个体化风险评估和辅助治疗的短期与长期风险的权衡。临床医师经过这种权衡考量,将能够帮助患者判断当下最优治疗的预期获益。下表所列的一些治疗选择应根据患者和肿瘤特征个体化裁量。

表8. 腋窝淋巴结阴性乳腺癌女性患者的全身辅助治疗选择
表8. 腋窝淋巴结阴性乳腺癌女性患者的全身辅助治疗选择
患者分组 低危 中危 高危
AI=芳香化酶抑制剂;ER=雌激素受体;GnRH=促性腺激素释放激素;PR=孕激素受体
a注:该治疗方法目前正在接受临床评估。
绝经前,ER阳性或PR阳性 无,或他莫昔芬 他莫昔芬联合化疗,单独他莫昔芬治疗,卵巢去势,GnRH类似物a 化疗联合他莫昔芬,化疗联合卵巢去势或GnRH类似物*,化疗联合他莫昔芬加卵巢趋势或GnHR*,或单纯卵巢趋势,或卵巢趋势联合他莫昔芬,或单纯GnRH,或GnRH联合他莫昔芬。
绝经前,ER阴性或PR阴性 化疗
绝经后,ER阳性或PR阳性 无,或AI起始方案,或先他莫昔芬再AI AI起始方案或他莫昔芬加AI+/-化疗 AI起始方案或他莫昔芬加AI+/-化疗
绝经后,ER阴性或PR阴性 化疗

表9. 腋窝淋巴结阳性乳腺癌女性患者的治疗选择
表9. 腋窝淋巴结阳性乳腺癌女性患者的治疗选择
患者分组 治疗
AI=芳香化酶抑制剂;ER=雌激素受体;GnRH=促性腺激素释放激素;PR=孕激素受体
a注:该治疗方法目前正在接受临床评估。
绝经前,ER阳性或PR阳性 化疗联合他莫昔芬,化疗联合卵巢趋势/GnRH类似物,化疗联合他莫昔芬联合卵巢趋势/GnRH类似物a,单纯卵巢趋势,或卵巢趋势联合他莫昔芬,或单纯GnRH,或GnRH联合他莫昔芬。
绝经前,ER阴性或PR阴性 化疗
绝经后,ER阳性或PR阳性 AI起始方案,或他莫昔芬加AI加化疗,AI起始方案或他莫昔芬加AI。
绝经后,ER阴性或PR阴性 化疗

目前开展的临床试验

现招募 I期乳腺癌II期乳腺癌IIIA期乳腺癌IIIC期乳腺癌​患者的美国临床试验请参见美国NCI癌症临床试验列表,可根据部位、药物、干预或其他标准进行筛选。

NCI网站提供关于临床试验的基本信息。

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