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指南阅读

Ⅳ期或复发转移性乳腺癌内分泌治疗NCCN指南2015v3

发表者:张品良 711人已读

Endocrine Therapy for Stage IV or Recurrent Metastatic Disease

Ⅳ期或复发转移性疾病的内分泌治疗

Women with recurrent or metastatic disease characterized by tumors that are ER- and/or PR-positive are appropriate candidates for initial endocrine therapy.

复发或转移性疾病的妇女,特征为雌激素受体和/或孕激素阳性者适于初始内分泌治疗。山东省肿瘤医院呼吸内科张品良

In premenopausal women, endocrine therapies include selective ER modulators (tamoxifen or toremifene); LHRH agonists (goserelin and leuprolide); surgical or radiotherapeutic oophorectomy; progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol).

在绝经前女性中,内分泌治疗包括选择性雌激素受体调节剂(他莫昔芬或托瑞米芬);LHRH激动剂(戈舍瑞林和亮丙瑞林);手术或放疗卵巢去势;孕酮(甲地孕酮);雄激素(甲睾酮);和大剂量雌激素(炔雌醇)。

For most premenopausal patients the use of ovarian suppression or ablation in combination with endocrine therapy for postmenopausal women is appropriate.

对于大多数绝经前患者使用卵巢抑制或消融联合内分泌治疗对于绝经后女性是合适的。

In premenopausal women without previous exposure to an antiestrogen, initial treatment is with selective ER modulator alone or ovarian suppression/ablation plus endocrine therapy as for postmenopausal women.

在未暴露于抗雌激素的绝经前女性中,初始治疗单独用选择性雌激素受体调节剂或对绝经后妇女卵巢抑制/消融加内分泌治疗。

In premenopausal women with previous antiestrogen therapy who are within one year of antiestrogen exposure, the preferred second-line therapy is ovarian ablation or suppression followed by endocrine therapy as for postmenopausal women.

在既往抗雌激素治疗、抗雌激素暴露一年内的绝经前女性中,对于绝经后妇女首选的二线治疗是卵巢切除或抑制序贯内分泌治疗。

Endocrine therapies in postmenopausal women include nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); serum ER modulators (tamoxifen or toremifene); ER down-regulators (fulvestrant); progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol) and recently several new combination therapies with novel agents have become available.

绝经后妇女的内分泌治疗包括非甾体芳香酶抑制剂(阿那曲唑和来曲唑);甾体芳香酶抑制剂(依西美坦);血清雌激素受体调节剂(他莫昔芬或托瑞米芬);ER下调剂(氟维司群);孕酮(醋酸甲地孕酮);雄激素(氟甲睾酮);和高剂量雌激素(炔雌醇)以及最近一些新的与已经可获得的新药联合治疗。

According to some studies, aromatase inhibitors appear to have superior outcome compared with tamoxifen, although the differences are modest.

根据一些研究,与他莫昔芬相比,芳香抑制剂似乎有更好的结果,虽然差异不明显。

A Cochrane review has also suggested a survival benefit favoring the aromatase inhibitors over other endocrine therapies, although the advantage is small.

Cochrane综述也提示生存获益芳香酶抑制剂超过其他内分泌治疗,尽管优势很小。

A randomized phase III trial comparing tamoxifen with exemestane as first-line endocrine therapy for postmenopausal women with metastatic breast cancer showed no significant differences in progression-free survival (PFS) or OS between the two arms.

一项随机比较他莫昔芬与依西美坦一线内分泌治疗绝经后转移性乳腺癌女性的III期试验显示两组间无进展生存(PFS)或OS无显著差异。

Fulvestrant appears to be at least as effective as anastrozole in patients whose disease progressed on previous tamoxifen.

在既往他莫昔芬疾病进展的患者中氟维司群似乎至少与阿那曲唑一样有效。

A randomized phase II study compared anastrozole versus fulvestrant in over 200 patients with advanced breast cancer.

在超过200例晚期乳腺癌中的一项随机II期研究比较了阿那曲唑与氟维司群。

In the initial analysis, fulvestrant was as effective as anastrozole in terms of overall response (36.0% vs. 35.5%; odds ratio, 1.02; 95% CI, 0.56 -1.87; P = .947) in 461 evaluable patients (n = 89 for fulvestrant and n = 93 for anastrozole).

在初步分析中,461例可评价的患者中(氟维司群n= 89,阿那曲唑n = 93)总有效率氟维司群与阿那曲唑一样(36%对35.5%;优势比,1.02;95% CI,0.56-1.87;P= .947)。

An improved time to progression was seen with fulvestrant compared to anastrazole (median time to progression was 23.4 months for fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, 0.39- 1.00; P =.0496).

与阿那曲唑相比氟维司群改善至进展时间(中位至疾病进展时间氟维司群是23.4个月而阿那曲唑是13.1个月;风险比,0.63;95% CI,0.39-1.0;P= .0496)。

This study used a higher 500 mg loading dose every 2 weeks for 3 doses and then 500 mg monthly.

该研究使用了更高的500mg负荷量每2周1次共3次,然后500mg每月1次。

The median OS was longer in the fulvestrant group than in the anastrozole group (54.1 463 months vs. 48.4 months; HR, 0.70; P = .041).

氟维司群组比阿那曲唑组中位OS更长(54.1个月对48.4个月;HR,0.70;P = .041)。

A phase II study of fulvestrant in postmenopausal women with advanced breast cancer and disease progression following aromatase inhibitor therapy documented a partial response rate of 14.3% with an additional 20.8% of patients achieving stable disease for at least 6 months.

氟维司群治疗绝经后晚期乳腺癌在芳香化酶抑制剂治疗后疾病进展女性的一项Ⅱ期研究证明,部分缓解率14.3%,另外20.8%的患者达到疾病稳定至少6个月。

The clinical benefit rates of exemestane and fulvestrant observed in a phase III trial of postmenopausal women with hormone receptor-positive advanced breast cancer who experienced disease progression on prior nonsteroidal aromatase inhibitor therapy were comparable (32.2% vs. 31.5%; P = .853).

在既往非甾体芳香酶抑制剂治疗疾病进展的绝经后激素受体阳性晚期乳腺癌女性的一项Ⅲ期试验中观察到依西美坦和氟维司群的临床获益率相似(32.2%对31.5%;P= .853)。

In that study, fulvestrant was administered as a 500 mg loading dose followed by doses of 250 mg on day 14, day 28, and then monthly.

在这项研究中,氟维司群给予500 mg负荷剂量,随后250mg,第14天、28天给药,然后每月1次。

A separate phase III randomized study in postmenopausal women with metastatic ER-positive breast cancer compared fulvestrant 500 mg every 2 weeks for 3 doses followed by 500 mg monthly versus fulvestrant 250 mg monthly.

在绝经后ER阳性的转移性乳腺癌女性的一项独立III期随机研究中比较了氟维司群500mg每2周3次然后每月500 mg与氟维司群250mg每月1次。

The PFS was superior with the fulvestrant 500 mg regimen (HR 0.80; 95% CI, 0.68-0.94; P = .006), indicating an increased duration of response with the higher dose of fulvestrant.

氟维司群500mg方案PFS占优势(HR 0.80;95% CI,0.68-0.94;P = .006),说明较高剂量的氟维司群应答持续时间增加。

The final analyses demonstrated an increase in median OS (4.1 months) and reduced risk of death (19%) with a dose of 500 mg compared with 250 mg.

终末分析表明,与250mg相比,500mg的剂量改善中位OS(4.1个月)并降低死亡风险(19%)。

Median OS was 26.4 versus 22.3 months (HR, 0.81; 95% CI, 0.69-0.96; P = .02).

中位OS为26.4个月对22.3个月(HR,0.81;95% CI,0.69-0.96;P = .02)。

Combination endocrine therapy in postmenopausal women with hormone receptor-positive, previously untreated metastatic breast cancer has been reported from two studies comparing single-agent anastrozole versus anastrozole plus fulvestrant.

已有两项研究报道在绝经后激素受体阳性既往未经治疗的转移性乳腺癌女性中比较了阿那曲唑加氟维司群联合内分泌治疗与单药阿那曲唑。

In one study (FACT), combination endocrine therapy was not superior to single-agent anastrozole (time to progression HR, 0.99; 95% CI, 0.81-1.20; P = .91).

在一项研究(FACT)中,联合内分泌治疗并不优于单药阿那曲唑(疾病进展时间HR,0.99;95% CI,0.81-1.20;P = .91)。

In the second study (S0226), PFS (HR, 0.80; 95% CI, 0.68-0.94; stratified log-rank P = .007) and OS (HR, 0.81; 95% CI, 0.65-1.00; stratified P = .049) were superior with combination anastrozole plus fulvestrant.

在第二项研究(S0226)中,联合阿那曲唑加氟维司群PFS(HR,0.80;95% CI,0.68-0.94;分层秩和检验P = .007)和OS(HR,0.81;95% CI,0.65-1.00;分层P = .049)均占优。

An unplanned subset analysis in this trial suggested that patients without prior adjuvant tamoxifen experienced the greatest benefit.

这项试验的一个计划外亚组分析表明,既往未辅助他莫昔芬的患者获益最大。

The reason for the divergent outcomes in these two studies is not known.

这2项研究结果不同的原因不得而知。

A phase III trial studied the effect of fulvestrant alone or in combination with anastrozole or exemestane in patients with advanced breast cancer and an acquired non-steroidal aromatase inhibitor-resistant disease.

一项III期临床试验研究了氟维司群在非甾体芳香酶抑制剂获得性耐药的晚期乳腺癌患者中单独或与阿那曲唑或依西美坦联合的效果。

An aromatase inhibitor had been given as adjuvant treatment to 18% of patients for a median of 27.9 months, and to 82% of patients for locally advanced/metastatic disease for a median of 19.3 months.

18%已经给予一种芳香化酶抑制剂作为辅助治疗的患者中位数为27.9个月,而82%的局部晚期/转移性疾病患者中位数为19.3个月。

Median PFS was 4.8 months, 4.4 months, and 3.4 months for patients treated with fulvestrant alone, anastrazole plus fulvestrant, and fulvestrant plus exemestane, respectively.

氟维司群单独、阿那曲唑加氟维司群和依西美坦治疗的患者中位PFS分别为4.8个月、4.4个月和3.4个月。

No differences were observed for overall response rate, clinical benefit rate, and OS.

总有效率、临床获益率和OS未观察到差异。

This trial provides no evidence that adding an aromatase inhibitor to fulvestrant in patients with non-steroidal aromatase inhibitor-resistant disease improves the results achieved with fulvestrant alone.

在非甾体芳香酶抑制剂耐药的患者中增加芳香酶抑制剂至氟维司群提高单独氟维司群获得的结果这项试验没有提供证据。。

In postmenopausal women who have received previous antiestrogen therapy and are within one year of antiestrogen exposure, there is evidence supporting the use of a selective aromatase inhibitor as the preferred first-line therapy for their recurrent disease.

在既往已经接受抗雌激素治疗且抗雌激素治疗暴露在1年内的绝经后女性中,有证据支持对于其复发性疾病使用选择性芳香化酶抑制剂作为首选的一线治疗。

New agents, such as palbociclib, a highly selective inhibitor of CDK 4/6 kinase activity, now have a role in treating women with ER-positive metastatic breast cancer in combination with endocrine therapy.

新的药物,如palbociclib,一种高选择性CDK 4/6激酶活性抑制剂,目前在治疗ER阳性转移性乳腺癌女性中联合内分泌治疗有一定作用。

A phase 2, open-label, randomized, multicenter trial evaluated the safety and efficacy of palbociclib in combination with letrozole versus letrozole alone as first-line treatment for patients with advanced ER-positive, HER2- breast cancer.

一项2期、开放标签、随机、多中心临床试验评估了 帕布昔利布联合来曲唑对比来单独曲唑作为ER阳性HER2阴性晚期乳腺癌患者一线治疗的安全性和疗效。

Median PFS reported was double with the combination regimen compared to letrozole alone (20.2 months for the palbociclib plus letrozole group and 10.2 months for the letrozole alone group; HR, 0.488; 95% CI, 0.319-0.748).

报告的中位PFS二联方案对比单纯来曲唑(帕博西尼加来曲唑组20.2个月而单纯来曲唑组10.2个月;HR,0.488;95% CI,0.319-0.748)。

The grade 3/4 adverse reactions reported at a higher incidence in the palbociclib plus letrozole versus letrozole alone included neutropenia (54% vs. 1%) and leukopenia (19% vs. 0%).

帕博西尼加来曲唑对比单纯来曲唑3/4度不良反应发生率较高,中性粒细胞减少(54%对1%)、白细胞减少(19% 对0%)。

Based on this study, the FDA approved palbociclib in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

基于这项研究,FDA批准帕博西尼联合来曲唑用于绝经后ER阳性HER2阴性晚期乳腺癌女性作为其转移性疾病的初始内分泌治疗。

The NCCN Panel has included the combination of palbociclib with letrozole as a first-line endocrine therapy option for postmenopausal patients with ER-positive, HER-negative metastatic breast cancer.

NCCN小组已经收入帕博西尼联合来曲唑作为绝经后ER阳性HER阴性转移性乳腺癌患者一线内分泌治疗的一个选择。

Limited studies document a PFS advantage of adding trastuzumab or lapatinib to aromatase inhibition in postmenopausal women with hormone receptor-positive metastatic breast cancer that is HER2- positive.

有限的研究证明在绝经后激素受体阳性HER2阳性的转移性乳腺癌女性中将曲妥珠单抗或拉帕替尼加入到芳香酶抑制中具有PFS优势。

Resistance to endocrine therapy in women with hormone receptor-positive disease is frequent.

激素受体阳性的女性对内分泌治疗抵抗是常见的。

One mechanism of resistance to endocrine therapy is activation of the mammalian target of rapamycin (mTOR) signal transduction pathway.

对内分泌治疗抵抗的一个机制是激活哺乳动物雷帕霉素靶蛋白(mTOR)信号转导通路。

Several randomized studies have investigated the use of aromatase inhibition in combination with inhibitors of the mTOR pathway.

若干随机研究调查了芳香化酶抑制联合使用mTOR信号通路抑制剂。

A randomized phase II study estimated the efficacy of tamoxifen alone versus tamoxifen combined with everolimus, an oral inhibitor of mTOR, in women with hormone receptor-positive, HER2-negative metastatic breast cancer previously treated with an aromatase inhibitor.

一项随机II期研究评价单独他莫昔芬对比他莫昔芬联合依维莫司——一种口服的mTOR抑制剂用于既往芳香酶抑制剂治疗的激素受体阳性、HER2阴性转移性乳腺癌妇女的疗效。

After a median follow-up of 13 months, an intent-to-treat analysis showed that the clinical benefit was 42.1% (95% CI, 29.1-55.9) with tamoxifen alone and 61.1% (95% CI, 46.9-74.1) with tamoxifen plus everolimus.

在中位随访13个月后,意向治疗分析显示,临床受益率单独他莫昔芬为42.1%(95% CI,29.1-55.9)而他莫昔芬联合依维莫司为61.1%(95% CI,46.9-74.1)。

An improvement in median time to progression was seen when everolimus was combined with tamoxifen compared with tamoxifen alone.

与他莫昔芬相比依维莫司联合他莫昔芬中位进展时间改善。

Median time to progression was 4.5 months (95% CI, 3.7-8.7) with tamoxifen alone versus 8.5 months (95% CI, 6.01-13.9) with everolimus and tamoxifen.

中位疾病进展时间单独他莫昔芬为4.5个月(95% CI,3.7-8.7)而依维莫司加他莫昔芬是8.5个月(95% CI,6.01-13.9)。

A phase III trial in postmenopausal women with advanced, hormone receptor-positive breast cancer with no prior endocrine therapy for advanced disease, randomized subjects to letrozole with or without the mTOR inhibitor temsirolimus has been reported.

绝经后晚期、激素受体阳性、既往未针对转移病变内分泌治疗的乳腺癌女性的一项III期试验报道,受试者随机分为来曲唑加或不加mTOR抑制剂替西罗莫司。

In this study, PFS was not different between the treatment arms (HR, 0.89; 95% CI, 0.75- 1.05; long-rank P = .18).

在这项研究中,治疗组间PFS没有差异(HR,0.89;95% CI,0.75 - 1.05;对数秩和检验P = 18)。

The results of this trial differ from that of the BOLERO-2 trial (described below).

这项试验的结果与BOLERO-2试验不同(如下所述)。

The reasons for the differences in the outcomes of these two randomized phase III studies is uncertain, but may be related to the issues of patient selection and extent of prior endocrine therapy.

这两项随机III期研究结果差异的原因不确定,但可能与病人的选择问题和既往内分泌治疗程度有关。

A phase III study (BOLERO-2) randomized postmenopausal women with hormone receptor-positive advanced breast cancer that had progressed or recurred during treatment with a nonsteroidal aromatase inhibitor to exemestane with or without the mTOR inhibitor everolimus.

一项III期研究(BOLERO-2)随机化绝经后激素受体阳性的晚期乳腺癌在非甾体芳香酶抑制剂依西美坦加或不加mTOR抑制剂依维莫司治疗期间进展或复发的女性。

Final results reported after median 18-month follow-up show that median PFS (by central review) remained significantly longer with everolimus plus exemestane versus placebo plus exemestane at 11.0 versus 4.1 months, respectively; (HR, 0.38; 95% CI, 0.31-0.48; P < 0.001).

在中位随访18个月后报告的最终结果表明,中位PFS(由中心审查)依维莫司加依西美坦仍然比安慰剂加依西美坦明显更长,分别为11个月和4.1个月;(HR,0.38;95% CI,0.31-0.48;P<0.001)。< p="">

The adverse events (all grades) that occurred more frequently in those receiving everolimus included stomatitis, infections, rash, pneumonitis, and hyperglycemia.

不良事件(所有等级)在那些接受依维莫司者中更常见包括口腔炎、感染、皮疹、肺炎、高血糖。

Analysis of safety and efficacy in the elderly patients enrolled in this trial showed that elderly patients treated with an everolimus-containing regimen had similar incidences of these adverse events, but the younger patients had more on-treatment deaths.

在参加这项试验的老年患者中安全性和有效性分析表明,含依维莫司方案治疗的老年人这些不良事件的发生率相似,但较年轻的患者有更多的治疗死亡。

The NCCN Panel agrees that the evidence from the BOLERO-2 trial is compelling enough to consider the addition of everolimus to exemestane in women who fulfill the entry criteria for BOLERO-2.

NCCN小组同意BOLERO-2的证据足以令人信服的考虑在满足BOLERO-2入组标准的女性中将依维莫司加入到依西美坦中。

Many premenopausal and postmenopausal women with hormone-responsive breast cancer benefit from sequential use of endocrine therapies at disease progression.

许多绝经前和绝经后激素敏感性乳腺癌女性在疾病进展时受益于序贯使用内分泌治疗。

Therefore, women with breast cancers who respond to an endocrine maneuver with either shrinkage of the tumor or long-term disease stabilization (clinical benefit) should receive additional endocrine therapy at disease progression.

因此,对内分泌策略应答肿瘤缩小或长期稳定(临床受益)的乳腺癌女性在疾病进展时应该接受其他的内分泌治疗。

After second-line endocrine therapy, little high-level evidence exists to assist in selecting the optimal sequence of endocrine therapy.

二线内分泌治疗后,目前几乎没有高级别的证据来帮助选择内分泌治疗的最佳顺序。

Additional endocrine therapies for second-line and subsequent therapy are listed in the algorithms.

随后列出用于二线及后续治疗的其他内分泌治疗。

Endocrine therapy may be active in patients with negative ER and PR determinations, especially on the primary tumor and in soft tissue disease and/or bone-dominant disease.

对于ER和PR测定阴性的患者内分泌治疗可能是有效的,尤其是对于原发肿瘤和以软组织和/或骨转移为主的疾病。

Endocrine therapy is associated with relatively low toxicity.

内分泌治疗具有相对较低的毒性。

Further false-negative determinations of ER and PR tumor status are not unusual and the hormone receptor status of primary and metastatic sites of disease may differ.

肿瘤ER、PR状态测定进一步假阴性是罕见的而原发灶与转移部位的病变激素受体状况可能不同。

Therefore, the NCCN Breast Cancer Panel recommends consideration of a trial of endocrine therapy for patients with disease characterized as hormone receptor-negative with disease localized to the bone or soft tissue only or with asymptomatic visceral disease, irrespective of HER2 tumor status.

因此,NCCN乳腺癌小组建议对于病变仅局限于骨或软组织或无症状的内脏疾病激素受体阴性的患者考虑试用内分泌治疗,不管肿瘤HER2状态如何。

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发表于:2016-03-02 15:24

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