美国西奈山医院肿瘤内科学家Arlene Chan教授

　　Oncology Frontier: What are your go-to strategies for breakthrough chemotherapy regimens for breast cancer?

　　《肿瘤瞭望》：对于乳腺癌化疗的突破性进展你有什么看法？

　　Dr Chan: In the area of chemotherapy， we need to define whether we are talking about the early breast cancer setting for adjuvant treatments versus metastatic. In the adjuvant setting， we have a number of combination regimens that are clearly established with level I evidence coming from large phase III randomized trials. The Oxford Overview has already clearly shown that you have survival benefits when using combinations of anthracyclines and taxanes， and in earlier studies， anthracyclines were also superior to CMF. The days of not using anthracyclines or taxanes is probably fairly rare. I think that is fairly clear and I think physicians around the world have the ability to select from different options based on cost for the institution and the patient， perhaps toxicities that they are particularly concerned with (for example， when using docetaxel， that uniformly requires dexamethasone premedication which can sometimes be a little problematic in patients who are insulin-dependent diabetics) but there are enough choices of established combination regimens that medical oncologists have a number of options to choose from and importantly， these are all evidence-based regimens. When we turn our attention to the metastatic setting， I think clearly again， anthracyclines and taxanes have a strong role to play. In looking at chemotherapy broadly， the usual general principle is that there are two camps of doctors. One camp believes sequential monotherapy is ideal， thus sparing patients from greater toxicities. A number of studies have shown that giving anthracyclines followed by taxanes followed by oral fluoropyrimidines is a very effective treatment. Perhaps the only clinical scenario in the metastatic setting where you might want to consider combination treatment is a very young patient with life-threatening metastatic disease involving the viscera where a quick and rapid assured response is needed. In the second- and third-line setting， there is some data supporting agents like oral fluoropyrimidines such as capecitabine. Eribulin is the only approved drug that has been shown to be effective beyond the second-， third-， fourth- or fifth-line. But in many countries it is not possible to get access to drugs like eribulin. So before I talk about drugs that are accessible， I think probably the most interesting breakthrough chemotherapies are those that can be given with minimal administrative toxicities. For instance， nab-paclitaxel has been developed with that goal in mind and has provided the same degree of efficacy as paclitaxel but it doesn’t require the high doses of steroid premedication. Other drugs such as oral vinorelbine utilizes a very effective drug established in advanced breast cancer but is given in an oral formulation. There are a number of studies now showing pharmacokinetics and clinical efficacy are the same as for the intravenous formulation. That has a place for patients who live in rural areas distant from their treatment center and for women who are very fearful of venous access， this provides an effective alternative. Probably the most exciting breakthrough chemotherapies are those that are going to be designed and given safely and effectively with some of our newer biologics. Instead of just a cytotoxic drug which indiscriminately targets proliferative cells whether they be cancer cells or normal proliferative cells which leads to all of the toxicities， the future will be looking towards smaller doses of those agents but enough to synergize with biologic agents. Biologic agents are those that target HER2 receptors for example. I think the short answer to breakthrough chemotherapy is probably utilizing drugs that are clearly established as being effective but selecting them for the individual patient according to some of the factors I have mentioned. Future research is really trying to harness the efficacy of these chemotherapy drugs， but trying to identify the optimal scheduling to be used with the newer targeted agents.

　　Chan博士：就化疗而言，我们首先要判断是早期乳腺癌的辅助治疗还是转移癌的治疗。辅助治疗方面已建立了很多可信的联合化疗方案，都经过了Ⅲ期临床试验，有循证医学一类证据支持。牛津概论中明确提出，联合使用蒽环类和紫杉类药物有益于患者的长期生存，同时早期研究显示蒽环类药物优于CMF方案。目前的化疗方案中基本都包含蒽环类和紫杉类药物。毋庸置疑，全世界的内科医生都能按照当地机构及患者的治疗花费和需要特别关注的药物毒性而作出适合的治疗方案选择。例如当使用多西他赛时，需要在用药前使用地塞米松，而这对胰岛素依赖性糖尿病患者需谨慎，但是仍有很多疗效肯定的联合化疗方案可供肿瘤内科医生选择，而且这些治疗方案均有循证医学依据。

　　转移癌的化疗方案目前也是肯定的，蒽环类及紫杉类药物占主要地位。总的来看，对化疗基本原则的把握分两个阵营，一方认为单药序贯治疗最为理想，可避免患者产生更多的毒性反应。大量研究显示序贯使用蒽环类、紫杉类药物及口服氟尿嘧啶是十分有效的治疗方案。或许临床上唯一需要考虑联合治疗的情况是当非常年轻的患者发生危及生命的脏器转移时，通常这种情况下要求迅速而有效地产生治疗应答。在乳腺癌的二、三线治疗方面，有研究证实口服单药氟尿嘧啶，如卡培他滨有效。艾瑞布林是唯一一种在二、三、四甚至五线治疗都有效的药物，但是在很多国家购买不到像艾瑞布林这样的药。所以在评论当前的可用药物前，我想最能吸引大家注意的突破性化疗方案是给药毒性最小的方案。例如，白蛋白结合型紫杉醇的开发就基于此目的，它和单纯紫杉醇有相同的有效率，但在用药前无需使用大剂量糖皮质激素。其他药物如长春瑞滨就是在晚期乳腺癌的治疗中十分有效的药物，仅需口服给药。许多研究证实其药代动力学和临床有效率同静脉用药相同。对于那些居住在离治疗中心较远和害怕静脉用药的女性患者，这提供了有效的替代选择。

　　或许化疗方案中最令人激动的突破在于安全有效的新型生物制剂。不同于目前细胞毒药物不加选择地作用于恶性增殖细胞和正常的组织细胞，今后的治疗侧重于小剂量细胞毒药物协同生物制剂，即可产生足够的疗效。所谓生物制剂就是像针对HER-2受体的一类靶向药物。简而言之，化疗的突破性进展就在于针对患者的自身状况在已确定的有效药物中选择合适的治疗方案。今后我们要研究如何利用化疗药物的疗效，同时也要确定化疗药物与新型靶向药物联合应用时的最佳给药方案。