Oncology Frontier: Taxotere in combination with cyclophosphamide improves survival of women with early-stage breast cancer and reduces the risk of cancer recurrence. Could you briefly explain how that works?

　　《肿瘤瞭望》：多西他赛与环磷酰胺联用改善了早期乳腺癌女性患者的生存状况，并降低了肿瘤复发的风险。您能否简要解释一下它的机理？

　　Dr Chan: Docetaxel is the generic drug name of the brand Taxotere. The US Oncology group was the first to establish the efficacy of this combination， largely driven by the understanding that although anthracyclines remain a very important component of chemotherapy for both early and advanced breast cancer， it is ultimately associated with the potential for cardiac toxicities. There is a direct dose-related cumulative toxicity. In an area where we are trying to improve both the quality of life of metastatic patients but also early cure rates in early breast cancer patients， as clinicians we don’t want to be precipitating cardiac morbidities and cardiac deaths. The knowledge that docetaxel is an effective taxane when given with an alkylating agent like cyclophosphamide was evaluated in the early 1990s in the US Oncology trial. A number of further time points have published this to be an effective regimen with a disease-free and overall survival benefit when compared to four cycles of doxorubicin and cyclophosphamide. Clearly this is a doublet which is a very effective option for us to be offering to our patients. In my clinical practice， the group of patients I would generally be recommending docetaxel and cyclophosphamide to are especially those who are elderly with existing cardiac comorbidities. Unless they are hormone unresponsive， I would tend to use docetaxel/cyclophosphamide (TC) irrespective of whether they are stage 1 or 2 with no positive disease. If they are triple-negative elderly patients， I would still generally consider using an anthracycline-based regimen. The second category of patients I would consider using TC for would perhaps be the lower risk patients – those women who might have no positive or grade 3 breast cancer that are hormone positive and where I am a little nervous about offering just hormone treatment， or conversely a young patient like a 25 year old， who has a small tumor with no node involvement who I am going to be able to offer hormone therapy to but as the St. Gallen guidelines have already provided over so many years， that young age is itself a high risk variable for disease recurrence， in a younger patient， I would probably want to avoid anthracyclines and therefore consider using the TC regimen as well. There are a couple of caveats. There are two things with TC that weren’t clearly evaluated through the registration trial of that regimen. One is the unexpected high rates of febrile neutropenia. Within the confines of the pivotal trial， the rates were actually extremely low. In that particular trial， growth stimulating factors were not used prophylactically and they reported rates of febrile neutropenia of <5%. There are a number of publications including one from Australia， which show that in the absence of primary G-CSF prophylaxis， rates of febrile neutropenia can be as high as 25-30%. If you measure first cycle nadir counts， grade 3/4 neutropenia can occur in up to two-thirds of these women. Although it doesn’t have the anthracycline and although it is generally shorter even when used for four cycles， myelosuppression is a significant predictable effect. So if you have patients who are at risk， such as those with post-surgical wound infections or those with other comorbidities that put them at greater risk for infections like diabetes or those with rheumatoid arthritis and who have been on immunosuppressive drug therapy， I would be very keen to consider using primary G-CSF prophylaxis concurrently with the first cycle of TC chemotherapy. The second issue with TC is that at the moment we are awaiting the results of a large American trial showing the duration of treatment. There have been a number of studies that have suggested that in the early breast cancer setting， not only is the choice of agents important but it is also the duration for which those patients are given the treatment. A NSABP trial showed that four cycles of TAC was actually inferior to eight cycles of AC followed by taxanes. The trial that has been conducted by the NSABP， the TIC-TAC trial， will probably be able to provide us with the information as to whether six cycles of TC is superior to four cycles which then offers us yet another regimen to be able to utilize for perhaps our slightly higher risk patients.

　　Chan博士：尽管蒽环类药物在早期和晚期乳腺癌化疗中占有重要地位，但它始终无法摆脱潜在的累积剂量心脏毒性。考虑到蒽环类药物的这一局限性，美国肿瘤研究小组率先对多西他赛与环磷酰胺联用的有效性进行了研究。我们试图改善转移性肿瘤患者的生活质量，提高早期乳腺癌患者的早期治愈率，但作为临床医生，我们不希望同时会导致心脏相关疾病的发病和死亡。20世纪90年代早期，美国肿瘤研究小组的试验证明，多西他赛与烷化剂环磷酰胺共同给药时，是有效的紫杉烷类药物。后续多项报道同样证明了这两种药物联用的有效性。与4个周期的多柔比星和环磷酰胺联用治疗相比，多西他赛与环磷酰胺联用显示出更好的无病生存和总生存获益。我们认为这是一对有明显疗效的联用药物。

　　在临床实践中，我通常会建议年龄较大并且有心脏并发症的患者采用多西他赛与环磷酰胺(TC)联合治疗。只要患者对激素敏感，我就会倾向于使用这种方案，而不考虑患者是否为1期或2期阴性乳腺癌。对于年龄较大的三阴性乳腺癌患者，我通常还是会考虑以蒽环类药物为基础的方案。第二类我会考虑使用TC联合化疗的患者为低风险患者，即阴性乳腺癌或激素阳性的3期乳腺癌，对于这些患者，我认为仅进行激素治疗是不够的。相反地，针对无淋巴结受累、肿瘤较小、年轻（例如25岁）的患者，我计划给予其激素治疗，正如圣加伦大学指南多年来一贯认为的那样，低龄本身就是导致疾病复发的高风险。因此对于年轻患者来说，我可能会避免蒽环类药物的使用，同时考虑TC联合化疗。

　　在TC联合化疗中，有一些问题需要引起注意。在TC疗法的注册试验中，未对以下两个方面进行评价。一个方面是未预料到发热性中性粒细胞减少的高发病率。在关键性试验中，发热性中性粒细胞减少发病率非常低，未使用生长刺激因子预处理，发热性中性粒细胞减少的发生率＜5%。然而在多项包括一项来自澳大利亚的报道称，当未使用粒细胞集落刺激因子预处理时，发热性中性粒细胞减少的发生率高达25%~30%。如果测量第一个治疗周期后的最低值，有高达2/3的女性患者发生3度或4度中性粒细胞减少。尽管未使用蒽环类药物，治疗周期也通常较短，哪怕只进行了4个周期的治疗，骨髓抑制仍是可预见的重要不良反应。因此，如果患者有相关疾病风险，如术后、有糖尿病等可能增加感染风险的并发症、有类风湿性关节炎以及正在进行免疫抑制药物治疗等，我更建议在TC联合化疗第一周期时进行基本的粒细胞集落刺激因子预处理。

　　另一个方面的问题有关TC疗法治疗周期，我们正在等待美国一项大型试验的研究结果。已有多项研究表明，对于早期乳腺癌，化疗周期时间的选择和化疗药物的选择同样重要。美国乳腺与肠道外科辅助治疗研究组（NSABP）的一项研究显示，使用TAC化疗4个周期的治疗效果优于使用AC化疗8个周期后再使用紫杉烷类药物治疗。由NSABP开展的TIC-TAC试验有可能会给我们提供有关信息，证明对于风险略高的患者，TC化疗6个周期的效果是否优于4个周期的治疗。