Oncology Frontier: What criteria do you use to define the patients requiring chemotherapy treatment?

　　《肿瘤瞭望》：您用什么标准来判断哪些患者需要进行化疗？

　　Dr Chan: In the adjuvant setting， there are a number of options clinicians can use. Those include using the St Gallen Guideline Consensus which looks at patient and tumor characteristics with respect to those patients who would benefit from receiving chemotherapy. It essentially categorizes patients into endocrine-responsive and endocrine-unresponsive. Others， particularly in North America， will use gene expression profiles. The use of Oncotype DX has dramatically impacted on the use of chemotherapy for ER-positive early breast cancers. I had a communication from a colleague saying that with the advent of Oncotype DX， there has been a 40% reduction in the use of adjuvant chemotherapy for this group of ER-positive early breast cancer patients. Other countries where gene expression profiling is not funded and it is an additional financial burden on patients， will probably still use algorithms such as Adjuvant! Online to be able to individually decide the prognostic risk to a given patient based on tumor characteristics and then use that information to make a recommendation as to whether patients require chemotherapy or not. In the metastatic setting， it is a completely different story. The factors that you then need to look at in the patient are: has this patient had breast cancer previously? And， has this patient received adjuvant chemotherapy in the past? If so， how long ago was it? What was the experience? Has she developed any long-term sequelae complications such as anthracycline cardiac toxicity or taxane-related neuropathy? The next question we need to ask， if the patient has or hasn’t had prior adjuvant chemotherapy exposure is， what is the patient’s tumor burden? How quickly do we need to obtain a response? And then linked with the tumor burden is the tumor biology. Can we predict on the basis of tumor biology whether this patient is going to respond well to chemotherapy or more likely do just fine with endocrine therapy? If you have a patient who has a strongly endocrine-responsive metastatic tumor biology coupled with low tumor burden and the patient is relatively asymptomatic， really irrespective of the site of metastatic disease， that would be a very clear situation to avoid chemotherapy and deliver endocrine treatment first. On the other end of the spectrum， you may have a patient with triple-negative disease where they are very symptomatic， there has been constitutional weight loss and a reduced performance status， maybe some dysfunction of organ functionality with elevated calcium or transaminase abnormalities， and in these patients you really need to have a response to the very first systemic treatment you offer these patients. Clearly chemotherapy would be the treatment of choice. As to which drug to use， then there is the complex evaluation of what treatment the patient may have had before. Are the higher objective response rates generally seen with combination chemotherapy needed or will the patient do well on monotherapy? Depending on what patients have had before， in the first-line setting， either anthracyclines alone (if patients have never received chemotherapy) or taxanes alone (if they have had prior anthracycline in the adjuvant setting) would be an appropriate option. We have a lot of data from a number of trials showing an overall survival benefit with the use of either anthracycline and/or taxanes in that setting. What we are a little less fortunate to have in terms of a body of evidence is a second-， third-， fourth， fifth-line. The decision that faces any oncologist is really based on what drugs are accessible， what side effects are most likely from those accessible drugs， and are those side effects going to be particularly problematic for the patient? Essentially though， we have a lot of different options. I would summarize the general principles as: assess your patient’s needs and understand the disease first and foremost; assess the patient’s symptoms based on tumor burden; very importantly， make sure you know the tumor biology that you are testing and I am a great proponent of re-biopsying metastatic lesions even if a patient has had a breast cancer of a particular phenotype in the past (you don’t know if it has the same tumor characteristics in the metastatic disease); and then in any given nation， you need to know what drugs are available whether they be reimbursed by the national health system or the patient will need to fund themselves. These four aspects of evaluation will direct you towards making an appropriate decision as to which chemotherapy to use where required.

　　Dr Chan: An important aspect of the schemes of chemotherapy for different patients is that because there are so many choices of treatment for metastatic breast cancer per se， it is important for any clinician to be working within an institutional or clinical setting where there is the ability to develop multidisciplinary approaches so that patients are being treated in a uniform pattern. Secondly， specifically with drug therapy， is to actually establish protocols. Sadly， a number of studies have shown that in the early breast cancer setting， although clinicians recommend and administer treatment regimens that have been established in clinical trials， very often the schedule， doses and duration of that effective regimen is not necessarily delivered at the clinical level. The delivery of adjuvant chemotherapy doses at what is required and thought to be effective is about 85% of what is actually planned for that patient. A number of studies published from the US and Canada and elsewhere have demonstrated that outside of the clinical trial setting， often patients in the adjuvant setting are dose reduced. Therefore， if there is not optimal dose delivery， it is highly likely that the breast cancer outcomes that were hoped for will not match those that are seen in the trials that established those regimens. So apart from drug therapy， if oncologists can develop protocols and algorithms that allow them and their colleagues within their department to treat patients consistently， I have no hesitation in thinking this will improve patient outcomes. It also allows for the ability of institutions and clinics to do quality assurance and by comparing their own figures to the clinical trials， it can be seen whether the adherence to protocol actually performs as well as it was intended.

　　Chan博士：在辅助治疗中，临床医生可以通过多种方法来判断，包括按照圣加伦大学指南共识，根据患者和肿瘤的特征评估哪些患者能够从化疗中受益。本质上可将乳腺癌患者分为内分泌治疗敏感型和内分泌治疗不敏感型两种。其他学者，特别是在北美，常使用基因表达谱对患者进行分类。名为Oncotype DX的基因检测技术对雌激素受体阳性的早期乳腺癌患者化疗方案产生了重要的影响。我的一位同事曾认为，随着Oncotype DX的到来，辅助化疗在雌激素受体阳性早期乳腺癌患者中的使用率降低了40%。在其他一些不能为基因表达检测提供资金，从而可能给患者带来额外经济负担的国家，可使用“Adjuvant! Online”系统，根据肿瘤特性对个别患者进行风险预测，并根据已有信息给出该患者是否需要进行化疗的建议。

　　但对于转移性乳腺癌患者，情况则完全不同。这时候需要考虑的问题是：该患者之前是否得过乳腺癌？该患者之前是否接受过辅助化疗？该治疗是多久前进行的？具体治疗情况如何？是否发生了例如蒽环药物相关的心脏毒性或紫杉烷药物相关的神经病变等长期后遗并发症？随后我们需要了解的问题是，如果该患者先前接受或未接受过辅助化疗，该患者的肿瘤负荷情况如何？我们需要在多短的时间内实现疾病应答？然后再将肿瘤生物学与肿瘤负荷联系起来，基于肿瘤生物学预测患者对化疗或结合内分泌治疗的化疗是否能产生良好应答。

　　若有一名转移性乳腺癌患者对内分泌治疗有明显应答、肿瘤负荷较轻、症状较少，则无论转移性肿瘤实际位置在哪，此种情况下显然应避免使用化疗，而应首先进行内分泌治疗。另一种相反的情况是，若该患者为三阴性乳腺癌、症状明显、体重明显减少、活动状态减弱，或许还出现器官功能障碍，如血钙升高或转氨酶异常，对于这些患者，我们所给予的首个系统治疗方案必须能使患者产生应答。显然，此时应选择化疗。

　　至于用药的选择，则需要对患者之前的用药情况进行综合评价。患者是使用联合化疗的客观应答率更高，还是使用单一治疗的效果更好？基于患者之前的用药情况，一线用药，包括蒽环类药物单一治疗（如果患者之前未接受过化疗）和紫杉烷类药物单一治疗（如果患者在先前的辅助疗法中使用过蒽环类药物），都是比较合适的选择。很多试验得出的大量数据显示，此时使用蒽环类药物和（或）紫杉烷类药物治疗能获得总生存改善。在二线、三线、四线或五线治疗中，我们就没有这么好的运气了。肿瘤医生们做出选择的依据通常为有哪些药物，这些药物最可能产生哪些副作用，这些副作用是否会对患者造成特殊干扰等。实际上，我们有很多不同的选择。我把一般的规则总结为：首先也是最重要的是对患者的需求进行评估，了解疾病特征；然后是基于肿瘤负荷对患者临床症状进行评估；接下来重要的一点是，确保你对你正在做的肿瘤生物学检查有清晰的认识，而且我非常支持对转移性病灶进行重复活检，即使患者过去已经确定了乳腺癌的特异表型（因为你并不知道转移病灶是否具有相同的肿瘤特性）；最后，在任何国家，你都需要知道有哪些药物可用，是否能够报销，还是需要自费。这四个方面的评估将指导我们做出合适的化疗方案。

　　对于不同患者，化疗方案中很重要的一个方面是由于有如此多的转移性乳腺癌的治疗方案，在有能力开展多学科合作的机构或医疗场所开展化疗对临床医生来说显得尤为重要，这样患者能在统一的模式下接受治疗。其次，特别是药物治疗，有必要确立操作流程。遗憾的是，许多研究表明在早期乳腺癌的治疗中，尽管临床医生建议采用临床试验中建立的治疗方案，但这些有效治疗方案中的给药日程、剂量及治疗周期等往往在临床水平上未必能达到。一般认为，要产生疗效的辅助化疗给药剂量应达到计划给药剂量的85%。但美国、加拿大及其他地方发表的许多研究表明，除临床试验以外，其他进行辅助治疗的患者通常都降低了给药剂量。因此，在给药剂量达不到最佳条件时，使用推荐方案进行治疗所期望达到的治疗效果极有可能与试验中的结果不符。所以除了药物治疗，如果肿瘤学家能开发出一种能让他们和同事始终如一治疗患者的操作步骤或流程，我肯定这将改善患者的治疗效果。同时，这也将有利于诊所等机构实施质量保证，并且通过比较自己的数据和临床试验的数据，能看到依照方案执行治疗是否得到了预期效果。