不可手术的IIIB期或IIIC期或炎性乳腺癌

对于临床分期为IIIB期乳腺癌的患者,根治性的综合治疗是标准治疗。一项回顾性病例发现,同侧锁骨上淋巴结受累但无远处转移证据的患者(pN3c期)中,约有32%的患者经过综合治疗,长期无病生存时间可达10年[1]。尽管其他病例分析未能重复这一结果,但这一结果仍提示此类患者应同样接受以治愈为目的的治疗。

初次手术通常仅限于进行活检,以评估组织学、雌激素受体(ER)和孕激素受体(PR)水平及人类表皮生长因子受体2(HER2/neu)是否过表达。蒽环类化疗和(或)紫杉烷治疗为标准初步治疗[2][3]。一项病例分析纳入178例炎性乳腺癌患者,发现经联合治疗,15年DFS达到28%[2]。[ 证据等级:3iiiDii]对于新辅助化疗有效的患者,局部治疗包括全乳房切除术加腋窝淋巴结清扫术和术后胸壁及区域淋巴放疗。对新辅助化疗有良好的部分缓解或完全缓解反应的患者可考虑行保乳术[3]。后续全身治疗可包括进一步化疗。ER阳性或ER状态不明的患者应接受激素治疗。所有患者均应考虑参与临床试验,以评估综合治疗的最佳方式。

目前开展的临床试验

现招募 IIIB期乳腺癌IIIC期乳腺癌炎性乳腺癌​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。

IV期、复发性与转移性乳腺癌

复发性乳腺癌通常对治疗的反应较佳,尽管这一期别的患者很少达到治愈效果。但局部乳腺或胸壁复发的患者通过适当的治疗可能达到长期生存。在治疗复发性或转移性乳腺癌患者之前需重新对疾病分期,评估侵犯程度。应尽可能记录复发性或转移性乳腺癌的细胞学或组织学类型。选择适当的治疗时注意复发时的ER水平、PR水平、HER2/neu阳性率和既往治疗史。复发时的ER状态可能改变。癌症与白血病B组进行的一项小规模研究( MDA-MBDT-8081)发现36%的激素受体阳性肿瘤在复发之后,活检标本提示受体阴性[4]。该研究中的患者接受了无间歇治疗。如果ER与PR状态不明,复发部位、无病间期、对既往治疗的反应和绝经情况则有助于选择化疗还是激素治疗[5]

局部-区域复发性乳腺癌

局部-区域性乳腺癌复发患者经过适当的治疗可长期生存。一项临床试验指出10%-20%的患者在保乳术联合放疗后的1-9年之间出现局部复发[6]。其中9%-25%的患者在复发时合并远处转移或局部扩散[7][8][9]。局部-区域性复发的患者应考虑进一步行局部治疗(例如乳房切除术)。一项病例分析发现,保乳术联合化疗后出现浸润性复发患者五年精确复发率为52%[8]。一项III期、随机研究发现可外用米替福新局部控制皮肤转移灶,但该药未在美国上市[10]。[ 证据等级:1iiDiii]

乳房切除术后局部胸壁复发通常意味着存在广泛转移。但少数患者可能仅有胸壁复发,对于此类患者,可通过手术与(或)放疗达到治愈目的[11][12]。胸壁复发灶小于3cm、腋窝和内乳淋巴结复发(不包括预后较差的锁骨上淋巴结)、复发前无病生存时间超过2年的患者可有机会实现长期生存[12]。一项病例分析提示此类患者的5年DFS率为25%,10年DFS率为15%[13]。10年局部-区域控制率为57%。局部区域复发的患者应考虑接受全身治疗,因继续转移的风险较高[14]。尚无随机对照临床试验为这种情况下的患者治疗提供指南。

IV期与转移性乳腺癌

全身转移的治疗应以缓解症状为目标。治疗目的包括改善生活质量和延长寿命。虽然据报道中位生存期为18-24个月[15],但也有一些患者可长期生存。一家医院1973-1982年间接受全身化疗的患者中,263例患者(16.6%)完全缓解。其中49例患者(占总数的3.1%)完全缓解超过5年,26例患者(1.5%)完全缓解超过16年[16]。[ 证据等级:3iiDiiii​]

转移性乳腺癌的治疗通常包括激素治疗和(或)化疗加或不加曲妥珠单抗。症状局限的转移癌患者可考虑放疗和(或)手术。所有转移性或复发性乳腺癌患者均应考虑进入目前正在进行的临床试验。

手术可能适用于一些患者,例如出现乳腺病变有真菌感染或疼痛明显、脑实质或椎体转移压迫脊髓、孤立性肺转移、病理性(或危及生命的)骨折或胸腔积液、心包积液等情况的患者。(关于疼痛的更多信息请参考PDQ总结 疼痛,关于胸腔积液和心包积液的更多信息请参考PDQ总结 心肺综合征​。)

放疗对缓解局部转移症状有重要作用。适应证包括骨转移疼痛、无法切除的中枢神经系统转移(例如脑、脑膜和脊髓)、支气管梗阻、乳腺或胸壁病变真菌感染或疼痛。应在手术解除颅内或脊髓转移的压迫症状和病理性骨折固定之后,再行放疗。一些临床试验(包括已经完成的放疗肿瘤组(RTOG)试验[ RTOG-9714])探索了最优的分次放疗方案。锶89是一种全身用的放射性核素,可用于缓解弥漫性骨转移[17][18]。(更多信息请参考PDQ总结 疼痛​。)

目前开展的临床试验

现招募 IV期乳腺癌复发性乳腺癌​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。

全身治疗

双磷酸盐

对于有骨转移的患者,可考虑使用双磷酸盐减少骨骼并发症[19]。帕米磷酸盐和氯膦酸盐治疗骨转移患者的随机临床试验结果显示,患者骨骼并发症减少[20][21][22]。[ 证据等级:1iC​]唑来膦酸的有效性至少等同于帕米膦酸盐[23]。[双磷酸盐的更多信息请参考PDQ总结 疼痛。]

激素治疗

对新诊断癌症转移的ER阳性、PR阳性或ER/PR状态不明的绝经后女性,初步治疗应考虑激素治疗。如果肿瘤仅累及骨和软组织,且患者未接受过辅助性抗雌激素治疗或停用此类治疗已超过1年,则更应考虑激素治疗。他莫昔芬被应用于治疗此类患者已有多年,一些随机临床试验提示芳香化酶抑制剂与他莫昔芬相比,缓解率和无进展生存率(PFS)等效或优于后者[24][25][26]。[ 证据等级:1iiDiii]一项荟萃分析纳入接受芳香化酶抑制剂作为一线或二线激素治疗的转移性乳腺癌患者,这些患者被随机分组接受第三代药物治疗(阿那曲唑、来曲唑、依西美坦或伏罗唑)或标准治疗(他莫昔芬或孕激素治疗),发现第三代药物治疗组患者生存时间长于标准治疗组(死亡风险比[HR],0.87;95%置信区间[CI],0.82-0.93)[27]。[ 证据等级:1iA​]

一些效力欠佳的随机临床试验曾尝试评估对于绝经前女性,激素联合治疗(促黄体激素释放激素[LHRH]拮抗剂+他莫昔芬)是否优于单药治疗。研究结果并不一致[28][29][30]。最佳的研究设计对比了布舍瑞林(一种LHRH拮抗剂)、他莫昔芬或二者联合对161例激素受体阳性的绝经前乳腺癌患者的作用[31]。接受布舍瑞林联合他莫昔芬治疗的患者生存时间中位数为3.7年,而仅接受他莫昔芬或布舍瑞林治疗的患者生存时间中位数分别为2.9和2.5年(P=0.01)[31]。[ 证据等级:1iiA​]该试验中几乎没有女性接受过他莫昔芬辅助治疗,因此很难评估这些结果是否适用于他莫昔芬辅助治疗后复发的女性。

ER阳性或状态不明、仅有骨转移或软组织转移、过去1年内曾接受抗雌激素治疗的女性患者应采用二线激素治疗。适用于绝经后女性的二线激素治疗包括:选择性芳香化酶抑制剂,例如阿那曲唑、来曲唑或依西美坦;醋酸甲地孕酮;雌激素;雄激素;[32][33][34][35][36][37][38][39][40]和下调ER的药物氟维司群[41][42]。所有现在市售的三种芳香化酶抑制剂均有前瞻性随机临床试验证实,与醋酸甲地孕酮相比,有效性至少相等,而耐受性更佳[32][33][34][35][36][37][38][43]。一项荟萃分析纳入接受芳香化酶抑制剂作为一线或二线激素治疗的转移性乳腺癌患者,这些患者被随机分组接受第三代药物治疗(阿那曲唑、来曲唑、依西美坦或伏罗唑)或标准治疗(他莫昔芬或孕激素治疗),发现第三代药物治疗组患者生存时间长于标准治疗组(死亡风险比[HR],0.87;95%置信区间[CI],0.82-0.93)[27]。[ 证据等级:1iA​]两项随机临床试验分别招募了400例与451例他莫昔芬治疗后疾病进展的患者,研究发现氟维司群对PFS的影响与阿那曲唑相当[44][45]。这些治疗的最优顺序目前不明[43][46]。虽然氟维司群联合第三代芳香化酶抑制剂治疗复发性或转移性乳腺癌存在生物学合理性,但这种联合治疗的获益未经临床试验证实[47]

绝经前女性应行卵巢去势治疗(手术,外部照射,或LHRH拮抗剂)[48]。淋巴管炎性肺转移、大部肝转移和(或)中枢神经系统受累的患者不应仅接受激素治疗。承重骨结构受损的患者除全身治疗之外,还应考虑接受手术和(或)放疗。对于椎体受累的患者,即便无神经系统症状,也需评估脊髓压迫情况。激素治疗后数周内出现骨痛加重和碱性磷酸酶升高并不一定意味着疾病进展[49]。有广泛骨转移的患者在激素治疗早期发生高钙血症症状的风险较高[49]。激素治疗早期失败(<6个月)提示下一种治疗方法应考虑细胞毒性化疗。

mTOR抑制剂

建议激素受体阳性(HR+)的乳腺癌转移患者采用内分泌治疗。但患者不可避免会发生内分泌治疗耐药。临床前模型和临床研究均提示此时可用mTOR抑制剂增强激素治疗的有效性。

BOLERO-2[NCT00863655]是一项随机、III期、安慰剂对照临床试验,将对非甾体类芳香化酶抑制剂耐药的HR+转移性乳腺癌患者随机分组,接受mTOR抑制剂依维莫司联合依西美坦或安慰剂联合依西美坦治疗[50]。[ 证据等级:1iDiii​]中期分析显示,依维莫司联合依西美坦组的PFS中位数为6.9个月,安慰剂联合依西美坦组为2.8个月(HR,0.43;95%CI,0.35-0.54;P<0.001)。依维莫司加依西美坦组最常见的3级或4级不良事件(AE)发生率增加,包括胃炎(两组分别为8%和1%)、贫血(6%和<1%)、呼吸困难(4%和1%)、高血糖(4%和<1%)、乏力(4%和1%)及肺炎(3%和0%)。该研究结果提示mTOR抑制剂联合内分泌治疗改善PFS,但增加不良反应。该试验的总体生存率(OS)结论尚未公布。

曲妥珠单抗

约有25%乳腺癌患者肿瘤过量表达HER2/neu[51]。曲妥珠单抗为人源化单克隆抗体,结合HER2/neu受体[51]。曾接受细胞毒性化疗的HER2/neu过量表达型肿瘤患者使用曲妥珠单抗单药治疗的缓解率达21%[52]。[ 证据等级:3iiiDiv]一项回顾性试验将肿瘤转移患者随机分组,接受单独化疗(阿霉素加环磷酰胺或紫杉醇)或相同化疗方案联合曲妥珠单抗治疗。化疗联合曲妥珠单抗组的OS优于对组(分别为25.1个月和20.3个月,P=0.05)[53]。[ 证据等级:1iiA​]曲妥珠单抗联合阿霉素治疗与显著的心脏毒性相关[54]。因此HER2/neu过量表达型转移性乳腺癌患者可考虑联用曲妥珠单抗与紫杉醇治疗,或在临床研究中应用曲妥珠单抗联合紫杉烷及其他化疗药[55]

一些临床试验对比了多药化疗联合曲妥珠单抗与单药化疗的有效性,结果并不一致。一项随机研究对转移性乳腺癌患者采用曲妥珠单抗、紫杉醇联合卡铂治疗或单纯曲妥珠单抗联合紫杉醇治疗,前组患者对联合方案的耐受性良好,至进展时间延长[56]。[ 证据等级:1iDiii]但一项III期临床试验( BCIRG-007[NCT00047255])比较了卡铂联合多西他赛加曲妥珠单抗和多西他赛加曲妥珠单抗作为转移性HER2过量表达型乳腺癌患者一线化疗的作用,发现两组患者的OS、至进展时间或缓解率均无差异[57]。[ 证据等级:1iiA​]非临床试验情况下,转移性HER2过度表达型乳腺癌的标准一线治疗应包括单药化疗加曲妥珠单抗。

拉帕替尼

拉帕替尼是一种口服酪氨酸激酶抑制剂,能够抑制EGFR与HER2/neu两种受体。

一项III期临床试验( GSK-EGF100151)共纳入324例含蒽环类药物、紫杉烷和曲妥珠单抗方案治疗后局部进展或转移的乳腺癌患者,对比了拉帕替尼联合卡培他滨和单用卡培他滨的效果,发现对于曲妥珠单抗治疗后进展的HER2阳性转移性乳腺癌患者,拉帕替尼联合卡培他滨的效果较优[58]。该试验首次中期分析发现联合治疗组的主要终点至进展时间显著优于对组(至进展时间中位数分别为8.4个月和4.4个月;HR,0.49;95%CI,0.34-0.71;P<0.001)。两组的OS无差异(HR,0.92;95%CI,0.58-1.46;P=0.72)[58]。[ 证据等级:1iiA]联合治疗组的患者腹泻、皮疹和消化不良的发生率较高。尚无可用的生活质量或进展后治疗相关数据。(腹泻的更多信息请参考PDQ总结 胃肠道并发症​。)

一项III期试验曾评估过拉帕替尼联合曲妥珠单抗治疗曲妥珠单抗治疗后疾病进展的HER2阳性转移性乳腺癌患者[59]。[ 证据等级:1iiA​]共291例患者被随机分组接受拉帕替尼单药治疗或拉帕替尼联合曲妥珠单抗治疗。与拉帕替尼单药治疗相比,拉帕替尼联合曲妥珠单抗显著改善PFS(HR,0.74;95%CI,0.58-0.94;中位时间,11周与8周)和OS(HR,0.74;95%CI,0.57-0.97;中位时间,14个月与10个月)。拉帕替尼单药治疗对照组并非标准对照组。这些数据为曾接受积极治疗的HER2阳性乳腺癌转移患者提供了一种无化疗替代治疗,即双重HER2阻滞。

一项双盲、随机、III期临床研究比较了紫杉醇、拉帕替尼和紫杉醇联合拉帕替尼作为转移性乳腺癌患者一线治疗的作用[60]。在意图治疗人群里发现,联合治疗并不增加获益。但该研究仅回顾性地评估了标本的HER2/neu状态。紫杉醇联合拉帕替尼治疗HER2/neu阳性患者时改善进展时间、无事件生存率、缓解率和临床获益率,但并不改善OS。HER2/neu阳性患者接受拉帕替尼治疗后毒性反应发生率较高,尤其是脱发、腹泻和皮疹。两组的AE发生率均较低,分布情况相似[60]。[ 证据等级:1iDiii]

帕妥珠单抗

帕妥珠单抗是一种人源化的单克隆抗体,与曲妥珠单抗分别结合HER2细胞外域的不同表位。帕妥珠单抗与HER2结合后阻止HER2与其他配体活化的HER2受体(主要为HER3)形成二聚体。因其潜在互补的作用机制,一项III期临床试验 CLEOPATRA[NCT00567190]评估了帕妥珠单抗联合曲妥珠单抗与多西他赛和安慰剂联合曲妥珠单抗与多西他赛作为HER2阳性转移癌患者一线治疗的作用[61]。[ 证据等级:1iA​]对照组的中位PFS为12.4个月,帕妥珠单抗组为18.5个月(HR,0.62;95%CI,0.51-0.75;P<0.001)。最终OS结果仍未公布。两组的毒性特征相似,帕妥珠单抗联合治疗组的心脏毒性反应发生率并不增加。

Ado-Trastuzumab Emtansine

Ado-trastuzumab emtansine(T-DM1)是一种抗体药物结合物,具有曲妥珠单抗的HER2靶向抗肿瘤活性和微球抑制剂DM1的细胞毒性活性。T-DM1能够将特定的细胞内药物传送至HER2过量表达型细胞中,可能提高治疗指数,减少正常组织的暴露。III期临床试验 EMILIA,也称为TDM4370g(NCT00829166)是一项随机、开放临床试验,共招募了991例HER2过量表达型、不可切除、局部高分期或转移性乳腺癌患者,这些患者既往接受过曲妥珠单抗和紫杉醇治疗[62]。[ 证据等级:1iiA]

患者被随机分组,接受T-DM1治疗,或拉帕替尼联合卡培他滨治疗。T-DM1组PFS中位时间为9.6个月,拉帕替尼联合卡培他滨组为6.4个月(HR,0.65;95%CI,0.55-0.77;P<0.001)。第二次中期分析时OS中位数超过了针对有效性设置的终止边界(分别为30.9个月和25.1个月;HR,0.68;95%CI,0.55-0.85;P<0.001)。血小板减少症和血清转氨酶升高的发生率在T-DM1组更高,而 腹泻、恶性、呕吐、手足综合征的发生率在拉帕替尼联合卡培他滨组更高。

一项II期试验对比了T-DM1与曲妥珠单抗联合多西他赛,为T-DM1在转移性HER2过量表达型乳腺癌中的作用提供了更多证据[63]。[ 证据等级:1iiDiii​]该试验将137例HER2过度表达型乳腺癌随机分组接受一线转移癌治疗。经过中位时间为14个月的随访期,曲妥珠单抗联合多西他赛组与T-DM1组的PFS中位时间分别为9.2个月和14.2个月(HR,0.59;95%CI,0.36-0.97)。T-DM1的安全性优于曲妥珠单抗联合多西他赛。T-DM1组的3级不良事件发生率(分别为46.4%和90.9%)、致停药不良事件发生率(分别为7.2%和40.9%)和严重不良事件发生率(分别为20.3%和25.8%)均低于曲妥珠单抗联合多西他赛组。两组的初步OS结果相似。

细胞毒性化疗

经过激素治疗后肿瘤进展的患者可考虑进行细胞毒性化疗。激素受体阴性肿瘤和脏器转移肿瘤患者也可考虑细胞毒性化疗[64]

对转移性乳腺癌有效的单药包括下列:

蒽环类药物阿霉素表柔比星脂质体阿霉素[65][66][67][68]米托蒽醌

​紫杉烷类紫杉醇[69][70]多西他赛白蛋白结合纳米颗粒紫杉醇(ABI-007或Abraxane)[71][72]

烷化剂环磷酰胺

氟尿嘧啶卡培他滨[73][74][75]5-FU

抗代谢药​甲氨喋呤

长春碱类长春瑞滨[76]长春花碱长春新碱

铂类卡铂顺铂

其他吉西他滨[77]丝裂霉素C甲磺酸艾瑞布林[78][79]

对转移癌有效的联合方案:

CA:环磷酰胺,阿霉素[80]

多西他赛联合阿霉素[81]

CAF:环磷酰胺,阿霉素,5-氟尿嘧啶[82]

CMF:环磷酰胺,甲胺蝶呤,5-氟尿嘧啶[83]

阿霉素联合紫杉醇[84][85]

多西他赛联合卡培他滨[86]

长春瑞滨联合表柔比星[87]

卡培他滨联合伊沙匹隆[88]

尚不明确单药化疗与联合化疗哪种更适合一线治疗。东部肿瘤协作组组间研究( E-1193)将患者随机分组接受紫杉醇联合阿霉素或紫杉醇、阿霉素序贯治疗[89]。尽管联合组的缓解率和进展时间优于序贯组,但两组的生存率相同[89]。[ 证据等级:1iiA][90][91]疾病进展率、是否存在合并症和医师/患者的偏好影响了个例患者的治疗选择。目前尚无数据提示某一具体方案的有效性。单药序贯治疗或联合治疗可以用于复发患者。化疗联合激素治疗的OS获益可能不及细胞毒性化疗药序贯治疗[15][92]。对17项随机临床试验进行系统性回顾,发现向化疗方案中增加一种或多种化疗药以强化治疗可能提高肿瘤缓解率,但并不改善OS[93]。[ 证据等级:1iiA]

一些组织研究了肿瘤缓解或病情稳定患者的最佳治疗持续时间。两项随机临床试验发现,对于初步治疗后完全缓解的患者,立即换用一种化疗方案治疗和仅观察直至肿瘤复发相比,前者的DFS延长[94][95]。[ 证据等级:1iiA]但这些研究均显示患者立即接受下一种治疗并不改善OS,其中一项研究显示[95],立即治疗组的生存率实际上低于对组。类似地,经过初步治疗后部分缓解或病情稳定的患者被随机分组,接受另一种化疗方案治疗,或仅观察[96],或接受另一种剂量更大或更小的化疗方案[97],[ 证据等级:1iiA​]患者的生存率并无差别。这四项研究说明,患者对诱导化疗产生最佳反应之后,立即开始其他化疗的不同组合方案并不改善OS。因缺乏标准治疗方法上,故需二线化疗的患者是临床试验的良好备选受试者。

在针对患者个体化选择化疗方案时需考虑阿霉素诱导心脏毒性反应的风险。已知的心脏毒性危险因素包括:高龄、既往胸壁放疗史、既往蒽环类药物用药史、高血压、糖尿病和已知有基础心脏病。一些对照研究发现心脏保护药右雷佐生降低阿霉素诱导的心脏毒性。右雷佐生的应用使得患者能够有机会接受更大累积剂量的阿霉素治疗,同时一些有心脏危险因素的患者也可以接受阿霉素治疗[98][99][100][101]。右雷佐生对表柔比星用药者有相似的保护作用[102]。阿霉素通过持续静脉输注给药可能降低心脏毒性风险[103]

一些临床研究对比了大剂量化疗联合干细胞支持与传统化疗对转移癌患者的应用,发现接受大剂量化疗联合干细胞支持的患者并无OS或无复发生存获益[104][105]。[ 证据等级:1iiA​]无数据支持大剂量化疗联合干细胞支持的益处,这一领域仍需进行更多的临床评估[106][107]

贝伐单抗

贝伐单抗是一种人源化单克隆抗体,拮抗所有亚型的血管内皮生长因子A,对转移性乳腺癌的作用仍有争议。一项单中心、开放、随机临床试验研究了贝伐单抗作为二线或三线药物治疗转移性乳腺癌的有效性与安全性[108]。该研究共纳入462例曾接受蒽环类药物与紫杉醇治疗的患者,将她们随机分组接受卡培他滨联合或不联合贝伐单抗治疗。该研究发现联合贝伐单抗并不显著改善PFS(两组分别为4.86个月和4.17个月;HR,0.98)或OS(两组分别为15.1个月和14.5个月)[108]。[ 证据等级:1iiA​]

ECOG-2100(NCT00028990)是一项已经完成的开放、随机、IIII期临床试验,该试验证实,对于转移性乳腺癌患者,与单用紫杉醇作为初步治疗相比,贝伐单抗联合紫杉醇显著延长PFS中位数(分别为11.8个月和5.9个月;HR,0.60;P<0.001)[109]。[ 证据等级:1iiA​]但增加贝伐单抗并不改善OS(分别为26.7个月和25.2个月;P=0.16)。需注意,贝伐单抗联合紫杉醇组患者中重度高血压、蛋白尿、脑血管缺血和感染的发生率显著升高。

AVADO试验(NCT00333775)将736例患者随机分组,接受多西他赛联合安慰剂或多西他赛联合贝伐单抗(7.5 mg/kg或15 mg/kg,每三周一次)作为转移性乳腺癌的起始治疗。多西他赛联合贝伐单抗15 mg/kg组较安慰剂组相比,PFS中位时间轻度延长(两组分别为10.1个月和8.1个月),多西他赛联合贝伐单抗7.5 mg/kg组PFS中位时间不优于安慰剂组。但多西他赛联合贝伐单抗15 mg/kg组较安慰剂组相比,OS并无改善(两组分别为30.2个月和31.9个月;P=0.85)[110]。[ 证据等级:1iiA​]含贝伐单抗组的毒性反应发生率显著高于安慰剂组,包括出血和高血压等。

类似地, RIBBON 1(NCT00262067)试验将1,237例患者以2:1随机分组,接受标准化疗联合贝伐单抗或标准化疗联合安慰剂[111]。含贝伐单抗方案的中位PFS延长(卡培他滨队列:从5.7个月增加到8.6个月;HR,0.79;95%CI,0.56-0.84;秩和检验P<0.001;紫杉醇/蒽环类药物队列:从8.0个月增加到9.2个月;HR,0.64;95%CI,0.52-0.80;秩和检验,P<0.001)[111]。[ 证据等级:1iiA​]然而,安慰剂组与含贝伐单抗组的OS无统计学显著差异。贝伐单抗相关毒性反应与既往贝伐单抗临床试验相似。

RIBBON-2试验(NCT00281697)研究了贝伐单抗作为二线药物治疗转移性乳腺癌患者的有效性[112]。该试验将684例患者以2:1随机分组,接受标准化疗联合贝伐单抗或标准化疗联合安慰剂。含贝伐单抗组的中位PFS从5.1个月延长到7.2个月(PFS的分层HR,0.78;95%CI,0.64-0.93;P=0.0072)。但OS无统计学显著差异(化疗联合安慰剂组与化疗联合贝伐单抗组的OS分别为16.4个月和18.0个月;P=0.3741)[112]。[ 证据等级:1iiA​]贝伐单抗相关毒性反应与既往贝伐单抗临床试验相似。

2011年11月,基于现有的结果,贝伐单抗仅轻度改善PFS,但不改善OS,考虑到贝伐单抗的显著毒性,美国食品药品监督管理局(FDA)对贝伐单抗用于转移性乳腺癌 撤销批准​。

目前开展的临床试验

现招募 IIIB期乳腺癌IIIC期乳腺癌IV期乳腺癌复发性乳腺癌转移癌​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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