IV期或复发转移性乳腺癌的细胞毒化疗NCCN2016V1

Cytotoxic Chemotherapy for Stage IV or Recurrent Metastatic Disease IV期或复发转移性疾病的细胞毒化疗山东省肿瘤医院呼吸肿瘤内科张品良

Women with hormone receptor-negative tumors not localized to the bone or soft tissue only, that are associated with symptomatic visceral metastasis, or that have hormone receptor-positive tumors that are refractory to endocrine therapy should receive chemotherapy. A variety of chemotherapy regimens are felt to be appropriate, as outlined in the treatment algorithm. Combination chemotherapy generally provides higher rates of objective response and longer time to progression, in comparison to single-agent chemotherapy. Combination chemotherapy is, however, associated with an increase in toxicity and is of little survival benefit. Furthermore, administering single agents sequentially decreases the likelihood that dose reductions will be needed. Thus, the panel finds little compelling evidence that combination chemotherapy is superior to sequential single agents. Standard clinical practice is to continue first-line chemotherapy until progression. Adverse effects may require dose reduction and cessation of chemotherapy prior to disease progression. Limited information suggests that PFS can be prolonged with the use of continuous chemotherapy versus shorter-course chemotherapy. Due to the lack of consistent OS differences, the use of prolonged versus shorter chemotherapy needs to be weighed against the detrimental effects of continuous chemotherapy on overall quality of life.
激素受体阴性肿瘤不是仅局限于骨或软组织、具有有症状的内脏转移或肿瘤激素受体阳性对内分泌治疗耐药的女性，应该接受化疗。正如治疗原则所概述的，认为各种化疗方案都是合理的。与单药化疗相比，联合化疗一般具有更高的客观反应率和更长的疾病进展时间。然而，联合化疗毒性增加且几乎没有生存受益。此外，序贯单药用药将减少可能需要的减量。因此，小组发现几乎没有强有力的证据证明联合化疗优于序贯单药。标准的临床实践是继续一线化疗直至疾病进展。在病情进展之前的不良反应可能需要减量或停止化疗。有限的资料表明，与短程化疗相比持续使用化疗可以延长PFS。由于缺乏一致的OS差异，与更短的化疗相比延长的化疗需要权衡克服持续化疗对总体生活质量的不利影响。

Single cytotoxic agents and combination chemotherapy regimens recommended by the panel for the treatment of patients with metastatic disease are listed in the NCCN Guidelines. Single Agents Single agents are categorized as either preferred or other single agents based on a balance of the efficacy, toxicity, and treatment schedules of the drugs. Among preferred single agents, the panel includes: the anthracyclines, doxorubicin, epirubicin, and pegylated liposomal doxorubicin; the taxanes, paclitaxel, docetaxel, and albumin-bound paclitaxel; anti-metabolites, capecitabine and gemcitabine; and non-taxane microtubule inhibitors, eribulin and vinorelbine.
小组推荐的用于转移性疾病患者单一细胞毒性药物和联合化疗方案在NCCN指南中列出。单药 根据平衡疗效、毒性及药物治疗方案单药可分为首选或其他的单药。首选单药中，小组收录了：蒽环类药物，阿霉素，表阿霉素，和聚乙二醇脂质体阿霉素；紫杉烷：紫杉醇、多西他赛和白蛋白结合型紫杉醇；抗代谢物，卡培他滨和吉西他滨；和非紫杉类微管抑制剂：艾日布林和长春瑞滨。

Eribulin is a non-taxane microtubule inhibitor used for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. In a phase III trial, 762 patients with metastatic breast cancer were randomized 2:1 to eribulin or treatment of physicians’ choice. One-year OS was 53.9% for patients receiving eribulin versus 43.7% for the control arm, and median OS was 13.12 versus 10.65 months, representing a 19% statistically significant risk reduction (P = .041). Time to progression was greater with eribulin 3.7 versus 2.2 months for patients in the control arm (P = .14).
艾日布林是一个非紫杉类微管抑制剂用于治疗既往针对转移性疾病接受过至少两种化疗方案治疗的转移性乳腺癌患者。无论是在辅助背景下还是转移性背景下，既往治疗均应该包括一种蒽环类和一种紫杉类。在一项III期试验中，转移性乳腺癌患者按2:1随机分为艾日布林治疗或医师选择的治疗。一年OS接受艾日布林的患者是53.9%而对照组是43.7%，中位OS分别是13.12个月和10.65个月，风险降低19%统计学上有显著意义（P = .041）。疾病进展时间艾日布林组为3.7个月而对照组患者是2.2个月（P = .14）。

Several studies have demonstrated that eribulin is active in metastatic breast cancer. A large randomized trial of heavily pre-treated patients with metastatic breast cancer compared treatment with eribulin versus therapy of physician’s choice. Eribulin demonstrated significant improvement in OS with 2.5-month prolongation of median OS (median OS for patients treated with eribulin was 13.1 months compared with 10.6 months for those receiving other treatments. HR, 0.81; 95% CI, 0.66–0.99; P = .041).
一些研究已经证明艾日布林治疗转移性乳腺癌是有效的。一项既往强烈治疗过的转移性乳腺癌患者的大型随机试验对比艾日布林治疗与医生选择的治疗。证明艾日布林显著改善OS，中位OS延长2.5个月（艾日布林治疗的患者中位OS为13.1个月，而那些接受其他治疗者10.6个月。HR，0.81；95% CI，0.66-0.99；P = .041）。

A phase III trial compared eribulin with capecitabine in patients with metastatic breast cancer. While a small survival advantage was observed with eribulin treatment in all subgroups of patients, there was a significant survival advantage observed with eribulin over capecitabine among patients with triple-negative breast cancer (15.9 vs. 13.5 months; HR, 0.838; 95% CI, 0.715–0.983; P =.030).
一项III期试验在转移性乳腺癌患者中比较了艾日布林与卡培他滨。而在所有亚组的患者中观察到艾日布林治疗具有些许生存优势，在三阴性乳腺癌患者中观察到艾日布林生存优势显著超过卡培他滨（15.9对13.5个月；HR，0.838；95% CI，0.715-0.983；P = .030）。

Among other single agents, the panel includes: cyclophosphamide, carboplatin, docetaxel, albumin-bound paclitaxel, cisplatin, ixabepilone, and epirubicin.
在其他单药中，小组收录了：环磷酰胺，卡铂，多西他赛，白蛋白结合型紫杉醇，顺铂，伊沙匹隆，和表柔比星。

Ixabepilone, an epothilone B analogue, is also used for treatment of recurrent or metastatic breast cancer as a single agent. Use of ixabepilone as monotherapy has been evaluated in several phase II trials of women with metastatic breast cancer: in a first-line setting in patients previously treated with anthracycline chemotherapy; in patients with taxane-resistant metastatic breast cancer; and in patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. In the phase II trials, objective response rate, median duration of response, and median OS duration were 41.5% (95% CI, 29.4%–54.4%), 8.2 months (95% CI, 5.7–10.2 months), and 22.0 months (95% CI, 15.6–27.0 months) in the first-line setting; 12% (95% CI, 4.7%– 26.5%), 10.4 months, and 7.9 months for the taxane-resistant patients; and 11.5% (95% CI, 6.3%–18.9%), 5.7 months, and 8.6 months for the patients previously treated with an anthracycline, a taxane, and capecitabine. In the study by Perez et al, grade 3/4 treatment-related toxicities included peripheral sensory neuropathy (14%) and neutropenia (54%).
伊沙匹隆，一种埃博霉素B的类似物，也可用于复发或转移性乳腺癌的单药治疗。使用伊沙匹隆单药治疗已在一些转移性乳腺癌患者的II期试验中进行了评估：既往一线接受蒽环类化疗的患者；紫杉类耐药的转移性乳腺癌患者；和对蒽环类、紫杉类和卡培他滨耐药的晚期乳腺癌患者。在II期试验中，在一线情况下客观有效率、中位有效持续时间、和中位OS分别为41.5%（95% CI，29.4% - 54.4%）、8.2个月（95% CI，5.7-10.2月），和22个月（95% CI，15.6-27.0月）；他莫昔芬耐药的患者12%（95% CI，4.7%– 26.5%），10.4个月和7.9个月；而既往蒽环类、紫杉类、卡培他滨治疗的患者为11.5%（95% CI，6.3% - 18.9%）、5.7个月和8.6个月。在Perez等人的研究中，3/4度治疗相关毒性为外周感觉神经病变（14%）和中性粒细胞减少（54%）。

Combination Regimens
联合方案

Among combination regimens, the panel includes FAC/CAF; FEC; AC; EC; CMF; docetaxel, capecitabine; gemcitabine, paclitaxel; gemcitabine, carboplatin; and paclitaxel, bevacizumab.
在联合方案中，小组收录了FAC/CAF；FEC；AC；EC；CMF；多西他赛，卡培他滨；吉西他滨，紫杉醇；吉西他滨，卡铂；以及紫杉醇，贝伐单抗。

A series of trials have sought to define the role for bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor in the treatment of metastatic breast cancer. The E2100 trial randomized 722 women with recurrent or metastatic breast cancer to first-line chemotherapy with paclitaxel with or without bevacizumab. This trial documented superior PFS (11.8 months vs. 5.9 months; HR 0.60; P <.001) favoring bevacizumab plus paclitaxel compared with paclitaxel alone. A similar trial enrolled 736 patients who were randomized to treatment with docetaxel and bevacizumab or docetaxel and placebo. This trial also documented increased PFS in the arm containing bevacizumab (10.1 months vs. 8.2 months with docetaxel alone; HR 0.77; P = .006). An additional trial, RIBBON-1, combined bevacizumab with capecitabine, with a taxane (docetaxel, nab-paclitaxel), with anthracyclines (FEC, CAF, AC, or EC), or with the same chemotherapy alone. Results of this trial show a statistically significant increase in PFS with bevacizumab and capecitabine (8.6 months vs. 5.7 months; HR, 0.69; P < .001) and taxane- or anthracycline- (9.2 months vs. 8.0 months; HR, 0.64; P < .001) containing arms. None of these studies demonstrates an increase in OS or quality of life when analyzed alone or in a meta-analysis combining the trials. The increase in PFS with bevacizumab is modest, and appears the greatest in combination with paclitaxel, especially as reported in an unpublished analysis provided to the FDA.
一系列试验试图确定贝伐单抗——一种人源化抗血管内皮生长因子单克隆抗体在治疗转移性乳腺癌中的地位。E2100试验将722例复发或转移性乳腺癌女性随机分入紫杉醇加或不加贝伐单抗一线化疗。该试验证明，与单纯紫杉醇相比，贝伐单抗加紫杉醇PFS更优越（11.8个月对 5.9个月；HR 0.60；P <.001)。一项相似的试验纳入了736例患者随机分为多西他赛联合贝伐单抗或多西他赛联合安慰剂治疗。这项试验也证明含贝伐单抗组改善PFS（10.1个月对多西他赛单药8.2个月；HR 0.77；P = .006）。另外一项试验，RIBBON-1，贝伐单抗联合卡培他滨、紫杉烷（多西他赛、纳米白蛋白紫杉醇）、蒽环类（FEC、CAF、AC或EC）或同样的单纯化疗。当单独分析或这些试验联合荟萃分析时，这些研究均未证明改善OS或生活质量。联合贝伐单抗适度改善PFS，并且与紫杉醇联合似乎是最大的，特别是在提供给FDA的一个未发表的分析报告中。

As with endocrine therapy, sequential responses are often observed with chemotherapy, supporting the use of sequential single agents and combination chemotherapy regimens. The current guidelines include doses and schedules of these single agents and combination regimens for metastatic breast cancer. Failure to achieve a tumor response to 3 sequential chemotherapy regimens or ECOG performance status of 3 or greater is an indication for supportive therapy only. In this context, failure to respond to a chemotherapy regimen means the absence of even a marginal response to the use of a given chemotherapy regimen. Response to a chemotherapy regimen followed by progression of disease is not considered a failure to experience response.
因为与联合化疗一样联合内分泌治疗也经常观察到相继的应答，支持使用单药序贯以及联合化疗方案。目前的指南包括这些单药及联合化疗方案治疗转移性乳腺癌的剂量与给药计划表。对3个序贯化疗方案未能获得肿瘤应答或ECOG功能状态评分≥3是仅用支持疗法的一个指征。在这种情况下，对化疗方案无应答意味着对给予的化疗方案缺乏即便是临界的应答。对化疗方案应答然后疾病进展不认为是实际上无应答。

Patients with metastatic breast cancer frequently develop many anatomically localized problems that may benefit from local irradiation, surgery, or regional chemotherapy (eg, intrathecal methotrexate for leptomeningeal carcinomatosis).
转移性乳腺癌患者经常出现许多局部的解剖问题，可以从局部照射、手术或区域化疗（如软脑膜癌病鞘内注射甲氨蝶呤）中受益。

Breast Cancer NCCN Guidelines Version 1.2016
乳腺癌NCCN指南2016年第1版