2015版《中国抗癌协会乳腺癌诊治指南与规范》:药物治疗策略的解读

王碧芸; 龚成成; 胡夕春

doi:10.3877/cma.j.issn.1674-0807.2016.02.001

中华乳腺病杂志(电子版) >

2016 , Vol. 10 >Issue 02: 65 - 70

DOI: https://doi.org/10.3877/cma.j.issn.1674-0807.2016.02.001

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2015版《中国抗癌协会乳腺癌诊治指南与规范》:药物治疗策略的解读

王碧芸 ¹ ,
龚成成 ¹ ,
胡夕春 ^,¹^,^†

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1.200032 上海,复旦大学附属肿瘤医院肿瘤内科

胡夕春, Email:xchu2009@hotmail.com

Hu Xichun, Email: xchu2009@hotmail.com

Copy editor: 刘军兰

收稿日期: 2016-02-25

网络出版日期: 2024-12-07

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版权归中华医学会所有。

未经授权，不得转载、摘编本刊文章，不得使用本刊的版式设计。

除非特别声明，本刊刊出的所有文章不代表中华医学会和本刊编委会的观点。

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Clinical Practice Guidelines in Breast Cancer by Chinese Anti-Cancer Association(2015 version): interpretation of updates in terms of systemic treatment

Biyun Wang ¹ ,
Chengcheng Gong ¹ ,
Xichun Hu ^,¹^,^†

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1.Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

Received date: 2016-02-25

Online published: 2024-12-07

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No content published by the journals of Chinese Medical Association may be reproduced or abridged without authorization. Please do not use or copy the layout and design of the journals without permission.

All articles published represent the opinions of the authors, and do not reflect the official policy of the Chinese Medical Association or the Editorial Board, unless this is clearly specified.

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摘要

为推动中国乳腺癌的规范化诊治,中国抗癌协会乳腺癌专业委员会于2007年发布了第1 版《中国抗癌协会乳腺癌诊治指南与规范》 (简称《指南》),并结合乳腺癌领域最新循证医学进展每2年进行1 次更新,指导中国乳腺癌的诊断与治疗。最新公布的2015 版《指南》从乳腺癌筛查、影像诊断、病理诊断、手术及全身治疗等方面对乳腺癌临床诊治策略进行了规范。本文从乳腺癌的内分泌治疗、抗HER-2 分子靶向治疗、化疗与骨保护治疗的角度出发,对2015 版《指南》药物治疗策略的更新内容进行了解读。

关键词： 乳腺肿瘤; 药物疗法; 实践指南

本文引用格式

王碧芸 , 龚成成 , 胡夕春 . 2015版《中国抗癌协会乳腺癌诊治指南与规范》:药物治疗策略的解读[J]. 中华乳腺病杂志(电子版), 2016 , 10(02) : 65 -70 . DOI: 10.3877/cma.j.issn.1674-0807.2016.02.001

Abstract

In order to standardize the management of breast cancer, Chinese Anti-Cancer Association(CACA) issued the first edition of Clinical Practice Guidelines in Breast Cancer in 2007 and updates it every other year based on latest evidences. The newly published CACA Clinical Practice Guidelines in Breast Cancer in 2015 covers the overall management of breast cancer including screening, imaging, pathology, surgery and systemic treatment. This article mainly focused on the updates of systemic treatment for breast cancer patients in 2015 version, with regard to endocrine therapy, anti-HER-2 molecular targeted therapy, chemotherapy and bone protection.

Key words： Breast neoplasms; Drug therapy; Practice guideline

全世界每年新发乳腺癌病例数稳居女性恶性肿瘤之首,中国近年来的乳腺癌发病率亦逐年升高。为推动中国乳腺癌的规范化诊治,中国抗癌协会乳腺癌专业委员会于2007年发布了《中国抗癌协会乳腺癌诊治指南与规范》(简称《指南》)^[1]。最新公布的2015 版《指南》从乳腺癌筛查、影像诊断、病理诊断、手术及全身治疗等方面分16 个章节对乳腺癌临床诊治策略进行了规范^[2]。笔者就其中乳腺癌药物治疗策略进行了解读。

一、内分泌治疗方案的选择

激素受体(hormone receptor,HR)阳性的乳腺癌约占全部乳腺癌的2/3,内分泌治疗是这部分患者辅助治疗及晚期治疗的重要手段。

1.辅助内分泌治疗

针对HR 阳性乳腺癌的辅助内分泌治疗,他莫昔芬(tamoxifen,TAM)治疗5年一直是标准方案。随着ATLAS^[3]、aTTom^[4]两项大型随机对照研究结果相继公布,延长内分泌治疗时长再次成为关注的焦点。研究提示延长内分泌治疗在10年后显示出生存改善,但目前尚无可靠、可临床推广的评估体系筛选可能从延长内分泌治疗中获益的患者^[3-4]。因此《指南》中仍保留了2013 版的意见,对于服用TAM 5年后仍处于绝经前状态的患者,部分患者(如高危复发)可考虑延长服用至10年。

2013 版《指南》根据EBCTCG 研究结果^[5],将卵巢功能抑制(ovarian function suppression,OFS)放在辅助治疗可选的药物中,但基于ABCSG-12 研究的结果^[6],尚无充分证据显示芳香化酶抑制剂(aromatase inhibitor,AI)联合OFS 优于TAM 联合OFS。 SOFT 和TEXT 两项随机临床试验提供了新的循证医学依据,其联合分析显示,OFS 联合AI 组治疗5年后DFS 为91.1%,明显高于OFS 联合TAM组的87.3%(HR 0.72;95%CI 0.60 ～0.85;P＜0.001),两组OS 差异无统计学意义^[7]。亚组分析提示,具有复发高危因素如淋巴结阳性、肿瘤最大直径＞2 cm(化疗亚组)的患者,OFS+AI 较OFS+TAM的绝对获益更高。该研究验证了OFS,尤其是OFS+AI,在高危患者辅助治疗中的地位和作用。 2015 版《指南》将OFS+AI、OFS+TAM 和TAM 纳入了绝经前乳腺癌辅助治疗方案,在选择方案时须兼顾两个方面:肿瘤方面,复发风险高或需要辅助化疗;患者方面,相对年轻(＜35 岁)、在完成辅助化疗后仍未绝经的病例。同时基于目前最佳循证医学证据,推荐OFS 治疗时间由以往的2 ～3年改为2 ～5年^[2]。

2.转移后内分泌治疗

由于AI 在绝经后患者辅助治疗与转移后一线治疗中的广泛应用,针对晚期乳腺癌内分泌治疗的研究已经进入“后AI 时代”。基于BOLERO-2^[8]、FIRST^[9]及0020^[10]、0021^[11]试验结果,2013 版《指南》建议一类AI 治疗失败患者可选用另外一类AI(加或不加依维莫司) 或氟维司群(500 mg 或250 mg)^[12]。在此基础上,CONFIRM 研究结果显示氟维司群500 mg 较250 mg 能显著延长绝经后晚期HR 阳性患者的无进展生存期(progression-free survival,PFS)(HR 0.80)与OS(HR 0.81)^[13]。这一结论也在中国人群中得到证实,且亚组分析发现在AI 治疗亚组,氟维司群500 mg 组较250 mg 组PFS延长l 倍^[14]。因此,2015 版《指南》着重强调了氟维司群500 mg 在AI 治疗失败患者中的临床优势。

3.卵巢保护问题

卵巢早衰是化疗的一种常见不良反应,是化疗药物对女性卵巢不可逆的损害。 POEMS 临床试验旨在评估ER/PR 均阴性的绝经前乳腺癌患者辅助化疗中联合OFS 能否降低卵巢早衰的发生率^[15]。结果证明通过药物去势保护卵巢,确实改善了患者的月经功能、生育能力,使患者拥有更好的生活质量及预后改善。因此,2015 版《指南》指出HR 阴性的绝经前患者在辅助化疗期间使用OFS 药物可以保护患者的卵巢功能,并且不影响疗效和预后。

二、抗HER-2 分子靶向药物的治疗策略

抗HER-2 分子靶向药物的出现极大改善了HER-2 阳性乳腺癌的预后。基于现有循证医学证据,指南对如何合理使用抗HER-2 靶向治疗药物进行了详细的阐述。

1.标准HER-2 检测和结果判定

参照美国临床肿瘤学会/美国病理学家学会2013 版HER-2 检测指南^[16]及中国《乳腺癌HER-2检测指南(2014 版)》^[17],2015 版《指南》中HER-2阳性的标准为免疫组织化学(+++)或原位杂交法(in situ hybridization, ISH)测到HER-2 基因扩增,即HER-2/CEP(chromosome enumeration probe)17 比值≥2.0 或HER-2 基因拷贝数≥6,HER-2 基因拷贝数4 ～6 定义为“无法判读”。由于基因扩增与染色体拷贝数增加可能引起HER-2 表达增加,当存在染色体拷贝数增加时,即使HER-2/CEP17 比值＜2.0也判定为阳性。

2.HER-2 阳性复发转移乳腺癌治疗原则

HER-2 阳性晚期复发转移乳腺癌首选含曲妥珠单克隆抗体为基础的治疗,曲妥珠单克隆抗体与化疗药物联用效果优于单纯化疗。基于H0648g 研究及M77001 3 期临床研究结果,2013 版《指南》将曲妥珠单克隆抗体联合紫杉类药物作为HER-2 阳性晚期乳腺癌一线治疗^[12,18-19]。

CLEOPATRA 研究证明在紫杉类联合曲妥珠单克隆抗体的标准治疗方案中加入帕妥珠单克隆抗体可进一步延长PFS 和OS(18.5 个月比12.4 个月,P＜0.001;56.5 个月比40.8 个月,P=0.0002)且不增加心脏毒性的风险^[20-22]。该方案迅速被NCCN指南收录为HER-2 阳性转移性乳腺癌的一线治疗首选方案^[23]。由于帕妥珠单克隆抗体尚未在中国内地上市,在帕妥珠单克隆抗体无法获得的情况下,2015 版《指南》建议紫杉醇或多西他赛联合曲妥珠单克隆抗体作为首选的一线方案,在紫杉醇基础上联用卡铂可以进一步提高疗效^[24]。对于紫杉类药物耐药或无法耐受的患者,曲妥珠单克隆抗体联合长春瑞滨、卡培他滨等化疗药物也可用于一线治疗^[25-26]。

近年来,抗HER-2 药物治疗领域最受瞩目的新药即T-DM1 对既往接受过曲妥珠单克隆抗体治疗的HER-2 阳性乳腺癌患者具有良好疗效。 EMILIA试验是在经曲妥珠单克隆抗体治疗后病情进展的HER-2 阳性乳腺癌中进行的3 期临床试验,对比了T-DM1 与拉帕替尼联合卡培他滨方案的疗效与安全性。结果显示T-DM1 可显著延长PFS(独立评估:9.6 个月比6.4 个月)与OS(30.9 个月比25.1 个月),降低了32% 的死亡风险(HR 0.68;95%CI 0.55 ～0.85;P ＜0.001)^[27]。 NCCN 指南将T-DM1作为既往接受过曲妥珠单克隆抗体治疗的HER-2阳性乳腺癌的首选方案^[23]。

结合中国的实际情况,在无法获得该药物的情况下,2015 版《指南》建议曲妥珠单克隆抗体治疗后病情进展患者的治疗策略如下:(1)拉帕替尼联合卡培他滨,患者可能存在不同程度的曲妥珠单克隆抗体耐药,小分子双重酪氨酸激酶抑制剂拉帕替尼可能较好的应对这一问题。研究结果显示,对曲妥珠单克隆抗体为基础的方案治疗失败的乳腺癌,拉帕替尼联合卡培他滨比单用卡培他滨的至疾病进展时间延长近一倍(8.4 个月比4.4 个月,HR 0.49;95%CI 0.34 ～0.71;P＜0.001)^[28]。(2)曲妥珠单克隆抗体联合卡培他滨,有研究显示疾病进展后使用曲妥珠单克隆抗体联合卡培他滨较卡培他滨单药显著提高PFS^[29]。(3)曲妥珠单克隆抗体联合拉帕替尼,双靶向治疗的理论基础为两种靶向药物之间不存在交叉耐药且临床前研究提示两者具有协同作用。这一理论在临床试验中得到了证实,在曲妥珠单克隆抗体治疗失败且经多线治疗后的患者中,拉帕替尼和曲妥珠单克隆抗体联合的双靶向治疗组PFS 为12.0 周,显著高于拉帕替尼单药组的8.1 周(P=0.008)^[30]。且生存分析显示联合治疗组较单药组OS 延长4.5 个月(14.0 个月对9.5 个月,P=0.026)^[31]。这提示在多线曲妥珠单克隆抗体治疗进展的患者中,拉帕替尼联合曲妥珠单克隆抗体仍有较好的疗效,从而为曲妥珠单克隆抗体耐药的患者提供不包含细胞毒性药物的选择。(4)继续使用曲妥珠单克隆抗体,更换其他化疗药物。曲妥珠单克隆抗体作用机制不同于传统药物,临床前研究显示在曲妥珠单克隆抗体治疗进展的细胞模型中,继续应用曲妥珠单克隆抗体联合化疗方案仍具有抗肿瘤活性^[32]。临床一线使用曲妥珠单克隆抗体疾病进展后,继续使用曲妥珠单克隆抗体比停止使用曲妥珠单克隆抗体治疗疗效更好^[33]。

3.HER-2 阳性早期乳腺癌的治疗原则

NSABP B-31 和NCCTG N9831、BCIRG 006 等多项大型随机临床试验奠定了曲妥珠单克隆抗体在HER-2 阳性乳腺癌辅助治疗中的地位^[34-36]。NCCTG N9831/B-31 联合分析表明,在多柔比星联合环磷酰胺序贯紫杉醇方案的基础上加用1年的曲妥珠单克隆抗体(AC-PH)可以显著延长DFS 及OS^[34],其10年随访结果显示曲妥珠单克隆抗体的加入可以降低40% 的复发风险与37% 死亡风险^[37]。 2015 版《指南》中推荐该方案为HER-2 阳性乳腺癌辅助治疗用药首选。 Dang 等^[38]进一步探索了剂量密集型(dose dense,dd)方案ddAC-PH 的安全性,主要研究终点显示并没有增加患者心脏毒性。因此该方案也被纳入HER-2 阳性患者辅助治疗的指南推荐之一。

2015 版《指南》中新增了针对淋巴结阴性、HER-2 阳性早期乳腺癌患者的含曲妥珠单克隆抗体辅助治疗方案——每周紫杉醇80 mg/m²12 次联合曲妥珠单克隆抗体1年。 APT 试验纳入了406 例HER-2 阳性、淋巴结阴性且肿瘤直径≤3 cm 的早期乳腺癌患者,接受了上述不含蒽环类药物的辅助治疗方案,中位随访3.6年结果显示3年DFS 为98.7%(95%CI 97.6 ～99.8, P＜0.0001)^[39]。该研究为淋巴结阴性的小肿瘤患者提供了一个比较有效且安全性好的治疗方案。

在HER-2 阳性乳腺癌的新辅助治疗领域,近年研究热点集中于双靶向治疗能否进一步提高pCR率。 NeoALLTO 研究中紫杉醇联合拉帕替尼、曲妥珠单克隆抗体的双靶向组pCR 率高达51.3%,显著高于紫杉醇联合单靶向组^[40]。而NSABP-41 和CALGB40601 研究却未能证实双靶向的优越性^[41-42]。随后发表的ALLTO 研究在辅助治疗中的初步结果提示拉帕替尼与曲妥珠单克隆抗体pCR率的提高未能转化成生存获益^[43]。对此,2015 版《指南》认为可能存在某些特定患者能从双靶向治疗中获益,而其他患者仅接受单靶向治疗即能获得良好效果,但目前尚无成熟的方法区分这些患者。

NeoSphere 与TRYPHAENA 研究结果均显示帕妥珠单克隆抗体与曲妥珠单克隆抗体联合的双靶向联合化疗方案能显著提高pCR 率^[44-45]。帕妥珠单克隆抗体联合曲妥珠单克隆抗体联合多西他赛已被美国FDA 批准用于肿瘤直径≥2 cm 或淋巴结阳性、HER-2 阳性乳腺癌的新辅助治疗。虽然在辅助治疗领域尚未能证实双靶向治疗能带来DFS 的提高,考虑到帕妥珠单克隆抗体在晚期及新辅助治疗领域所展现的无法忽视的生存获益与pCR 率的显著提高,对于在新辅助治疗中未采用帕妥珠单克隆抗体的患者,NCCN 指南仍将帕妥珠单克隆抗体纳入了辅助治疗方案之一^[23],2015 版《指南》也对此表示认同。

三、化疗方案的优化与探索

蒽环类、紫杉类化疗药物联合或序贯的化疗方案仍是乳腺癌目前新辅助及辅助治疗的主流。根据乳腺癌的类型优化化疗方案使疗效最大化是目前研究的热点。 ECOG1199 试验比较了AC 分别序贯单周或3 周的多西他赛或紫杉醇的疗效,其10年随访结果显示紫杉醇周疗方案与多西他赛3 周方案比紫杉醇3 周方案能显著改善DFS 和OS^[46]。亚组分析提示三阴性乳腺癌(triple negative breast cancer,TNBC)能进一步从紫杉醇周疗中获益^[47]。

提高疗效的另一途径是不断探索新的药物方案,如在化疗方案中联合铂类的疗效。两项大型随机2 期临床试验GeparSixto 与CALGB 40603 均证实在TNBC 新辅助治疗中加入卡铂可以显著提高pCR率^[48-49]。但近期公布的随访数据却不尽如人意:GeparSixto 试验进一步证实卡铂的加入能显著延长TNBC 患者的DFS, 而CALGB 40603 试验中尽管pCR 率明显增高,但含卡铂新辅助方案未能为TNBC 患者带来生存获益^[50-51]。铂类在早期TNBC治疗中的地位尚存争议,因此,2015 版《指南》新辅助化疗推荐方案中并未突出铂类的地位,仅在其他化疗方案中提及。

但是基于最新循证医学结果,2015 版《指南》认可了铂类在晚期TNBC 中的疗效。 O'Shaughnessy等^[52]发起的BSI-201 研究中吉西他滨联合卡铂(GC)在晚期TNBC 展现出良好的疗效与耐受性(PFS 4.1 个月,OS 11.1 个月),使得NCCN 指南最终将GC 方案纳入转移性乳腺癌联合治疗推荐方案之一。胡夕春等^[53]对比了吉西他滨联合顺铂(GP)与吉西他滨联合紫杉醇(GT)方案的疗效,结果显示GP 方案一线治疗晚期TNBC 可使肿瘤进展风险降低31%(PFS 7.73 个月对6.47 个月;HR 0.69,P=0.009)。该项研究得到了国内外专家的广泛认可,GP 方案成为TNBC 转移一线化疗的新选择。 2015 版《指南》推荐TNBC 可选择吉西他滨加卡铂或顺铂。一项进一步比较上述两种含铂方案GP 与GC 一线治疗晚期TNBC 的疗效与安全性的临床试验目前正在进行中,将为肿瘤科医师的临床决策提供更多循证医学证据。

四、骨改良药物的临床应用

双膦酸盐(包括唑来膦酸、伊班膦酸、帕米膦酸二钠)和地诺单克隆抗体可以有效治疗乳腺癌的骨转移,并预防乳腺癌骨转移患者发生骨相关事件(skeletal-related events,SREs)。因此,《指南》建议确诊乳腺癌骨转移的患者,满足预期的生存期≥3 个月且肌酐低于3.0 mg/dl(1 mg/dl=88.41 μmol/L),应在行化疗与内分泌治疗的同时及时予以双膦酸盐或地诺单克隆抗体治疗。

双膦酸盐治疗乳腺癌骨转移患者的最佳用药间隔时间是目前研究的热点。一项3 期临床试验比较了唑来膦酸每12 周用药与目前标准的每4 周用药两种给药方案,结果显示每12 周间隔用药并不会降低唑来膦酸的疗效,两组SREs 的发生率分别为23.2%(12 周方案)与22%(4 周方案)^[54]。目前2015 版《指南》推荐的治疗模式为每4 周1 次,持续1年,后改为每12 周一次持续治疗。

关于骨改良药物治疗的最佳持续时间目前尚无定论:双膦酸盐使用时间多为2年,超过2年的长期安全性数据非常有限^[55-57],延长使用时间可能会增加获益,但尚未得到证实。因此,2015 版《指南》并未对双膦酸盐用药持续时间做出明确指示。

地诺单克隆抗体是一种新型的骨改良药物。一项随机临床试验结果显示,地诺单克隆抗体组首次和后续SREs 时间均显著优于唑来膦酸组(P =0.001),且较唑来膦酸耐受性更好^[58]。地诺单克隆抗体因此被纳入NCCN 临床指南,但目前地诺单克隆抗体的远期毒性尚不明确,其最佳治疗模式还有待探索。

以上为笔者对2015 版《指南》药物治疗策略更新的解读,希望其有助于临床医师更好的理解和掌握《指南》的变更及其所对应的循证医学证据。笔者相信随着《指南》的发布与不断的更新,中国乳腺癌的诊治将逐渐走向规范化的道路,使更多的乳腺癌患者获益。

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