Oncology Frontier:Patients initially diagnosed of colorectal cancer with unresectable liver metastases can be treated with multiple pattern therapies. Targeted therapy combined with chemotherapy can improve liver metastases resection rate. Which treatment modality， anti-EGFR or anti-VEGF， would help liver resection and be the most likely curative? In terms of conversion treatment， which treatment mode would improve the cure rate of the disease?

　　《肿瘤瞭望》：对于初步诊断不可切除的肝转移的结直肠癌患者， 目前多种治疗可以选择，靶向治疗联合化疗可以提高肝转移的切除率，那么对于抗EGFR和抗VEGF，您认为哪种治疗模式可以更好地提高肝切除的几率，从而达到根治的目的？  对于转化治疗，我们通常选择哪种治疗模式可以提高疾病的治愈率？

　　Dr Schwarz: The important thing regarding the systemic therapy options for unresectable liver colorectal metastases is the intrahepatic location and the extent of the disease. These are factors that limit the resectability of the tumor hence the need for a systemic chemotherapy based treatment that is most likely to accomplish a response. This may then present the patient with a potentially resectable tumor. The key question is which regimens or biologic additions to cytotoxic chemotherapy would be most likely to accomplish this. The good news is that we have several options with different combination chemotherapies that all have proven track records (FOLFOX， FOLFIRI and more recently FOLFIRINOX as a more aggressive four-agent combination) all of which are acceptable. FOLFIRINOX tends to be better than FOLFOX and FOLFIRI based on some preliminary trial comparisons. A biologic add-on to FOLFOX or FOLFIRI does better than FOLFOX or FOLFIRI alone. Long-term benefits based on large prospective studies are not clearly or strongly established. My feeling is the field will move in that direction but it requires more study-based data in order to make a clear statement. For more elderly patients， a less aggressive approach， perhaps 5-FU-based， is also acceptable but will have a much lower conversion rate to resectable disease. The biologic agents offer several options now too. The more established options would be either anti-VEGF or anti-angiogenic therapy in the form of bevacizumab， or EGFR-based agents like cetuximab or panitumumab. That choice should be based on the mutation status of the KRAS or extended RAS pathway. If there is a KRAS mutation， it is clear that an anti-EGFR approach is not appropriate. But if there is a wild-type KRAS status， that approach is a reasonable one. It is difficult to say from the available data which one is better than the other. We have good choices， that is clear， but we do not know if there is a clear winner or combination that is superior to another. That is a little bit of bad news. It is up to the treating teams preference as to which agent to choose. The combination of chemotherapy with a biologic tends to have higher response rates. If the greatest response opportunity is what is most likely to render a patient resectable where initially there was unresectable disease， we tend to favor combination therapy. But between anti-EGFR and anti-VEGF therapy， there is really no clear winner when it comes to KRAS wild-type lesions and that the choice has to be an anti-angiogenic， anti-VEGF approach in cases of KRAS mutations or extended RAS mutation findings.

　　Dr Schwarz: 对于结直肠癌不可切除肝转移的系统性治疗选择的重要因素是转移灶在肝脏内的位置以及肝脏的损害程度。肿瘤的可切除性受到很多因素的限制，因此需要最可能有疗效反应的系统性化疗来治疗这样的患者。通过化疗患者可能会有潜在切除肿瘤的机会。现在的关键性问题是哪种细胞毒性的化疗方案最有可能使晚期 肿瘤降期从而具有可切除性。好消息就是我们已经有好几个不同化疗药物联合使用的方案可供选择，这些化疗都是通过临床试验验证过的，主要是FOLFOX，FOLFIRI和最新的FOLFIRINOX方案，这种四种药物联合的化疗方案更具有杀伤力。基于一些临床试验的初步结果比较，相对于FOLFOX和FOLFIRI，FOLFIRINOX方案的疗效显得更好。FOLFOX和FOLFIRI方案联合使用确实比单独使用FOLFOX或者FOLFIRI的疗效要好。但基于大型前瞻性研究的长期获益并不清楚或者确切。我的感觉是在这个问题上会继续朝着这个方向研究但是还需要更多基于研究的数据去做一个清晰的声明。对于那些年纪较大的患者，像5-FU这样的不具有太强杀伤力的化疗方案可能更容易接受，但是这样的化疗方案很难将晚期肿瘤转归到可切除的分期。同时在生物学的靶向药物方面也提供了一些选择的余地。基于抗VEGF 或者抗血管生成的贝伐单抗以及抗EGFR 的西妥昔单抗或者帕尼单抗都是可以选择的靶向药物。而选择是要基于KRAS的突变情况和RAS通路的扩展。如果患者有KRAS的突变，那么抗EGFR的靶向药物治疗就明显不合适了。如果患者是野生型的KRAS，那么抗EGFR的靶向药物治疗就是合适的。现有的数据很难说两种靶向药物哪种更好。我们可以很清楚地做正确的决定，但是我们没办法知道两者中的一个或者联合使用是不是更好。这个看起来像是个不好的消息。选择哪种靶向药物其实还是由治疗团队的选择偏好决定的。化疗方案联合靶向药物更能得到更高的化疗反应率。如果这个好的化疗疗效可以使不可切除的病人获得手术切除的机会，我们将更倾向于这种联合治疗方案。当患者是野生型的KRAS，抗EGFR和抗VEGF的疗效相当，而对于KRAS突变或者RAS突变的患者，我们的选择就必须是抗血管生成或者抗VEGF的靶向药物。

　　Oncology Frontier: In gastroesophageal junction cancer patients， neoadjuvant chemotherapy combined with chemoradiation showed a better prognosis for higher surgical resection rate and higher rate of lymph node-negative than for neoadjuvant chemotherapy alone. When choosing neoadjuvant chemotherapy regimens， besides platinum-fluorouracil based chemotherapy， which else neoadjuvant chemotherapy regimens that are proven in clinical trials can we consider?   What kind of patients would you say are suitable for neoadjuvant chemotherapy with chemoradiation modalities?

　　《肿瘤瞭望》：在胃食管交界的肿瘤患者，术前新辅助化疗联合放化疗比单纯术前新辅助化疗在手术切除率及术后淋巴结阴性率较高，那么，对于术前新辅助化疗方案，除了氟尿嘧啶联合铂类之外，我们还可以选择哪些被临床试验证明了的新辅助诱导化疗方案？另外哪些人群适合术前新辅助化疗联合放化疗的治疗模式？

　　Dr Schwarz: Gastroesophageal (GE) junctional cancer is a challenging situation for which we have some good trial-based options that are setting the standard of care. The field is moving somewhat towards a more individualized targeted approach. The trial options we have embraced in our practice (and that are widely used in the Unites States) is a preoperative chemoradiation regimen that has a limited duration， gives a standard amount of radiation in conjunction with carboplatin and a taxane. Carbotaxel (carboplatin/paclitaxel) is the standard chemotherapy rather than 5-FU/platinum combinations. That is the CROSS trial regimen which is now the standard of care. We would not do prolonged systemic chemotherapy and we are not convinced there is benefit from post-operative adjuvant additional chemotherapy once patients have been treated with that regimen. We know from the MAGIC trial that an ECF-based combination is an acceptable regimen as well. So if we have a situation where a patient has a rare contraindication to radiation， we would probably resort to an ECF- or modified (like an EOX) type chemotherapy regimen to cover that. The MAGIC regimen approach has a built-in planned post-operative component. The point is that this is a six-month treatment (three months pre-op， three months post-op) with the same net benefit of an operation alone， but the CROSS trial regimen uses a much shorter chemotherapy duration. There is no clear evidence that this is superior to anything that the chemoradiation-based CROSS regimen can provide. But the field will change. We don’t have sufficient data now for the identified subtypes with expression of certain target genes such as HER2. I think HER2-positive GE-junctional cancers will likely be expected to benefit from a HER2 targeted therapy approach in addition to chemotherapy. So that is expected to change but we don’t have for the preoperative and ultimately resectable lesions a standard of care that is currently favoring this. This is just the beginning of multiple potential targeted therapies that will start to contribute to this. I think the field will be different in five or ten years time， but where we are currently， we have pretty clear standards for chemoradiation or， where radiation has to be avoided， chemotherapy alone.

　　Dr Schwarz: 对于胃食管连接部的肿瘤，如何根据临床数据的选择来制定标准的治疗方案是个很有挑战的难题。而这个领域正在向个体化靶向治疗的方向前进。在我们的实际操作中所接受的治疗选择包括了现在在美国被广泛使用的术前新辅助化放疗，这个治疗是在有限的时间里给予病人标准剂量的放疗并联合使用卡铂和紫杉醇。卡铂联合紫杉醇是比5-FU联合铂类更标准的化疗方案。CROSS临床研究就是在关注哪种化疗方案更标准。我们不想延长系统性的化疗时间，对于接受术前放化疗的患者术后接受辅助化疗是否受益我们也不是很确信。从MAGIC 研究中我们知道基于ECF的联合化疗同样是被接受的治疗方案。所以如果我们遇到对放疗有很大禁忌症的患者可以使用ECF联合化疗方案或者改进的EOX 化疗方案来替换放疗。MAGIC 研究对于术后治疗有很完善的计划方案。这个计划方案包括6个月的化疗方案（三个月的术前化疗，三个月的术后化疗）结合手术治疗，而 CROSS方案则是采用更短的化疗持续时间。没有很充分的数据能够证实这6个月的化疗方案相对于放化疗的CROSS研究有更好的疗效。但是在这个领域也会产生一些变化。虽然我们还没有充分的证据去明确表达像HER2这样特定目的基因的亚型。但是我认为对于HER2阳性的胃食管连接部肿瘤有望从抗HER2的靶向治疗中获益。所以这是期待被改变的地方，但是现在我们还没有术前或者术中的证据去支持这样的理论。具有潜力的综合靶向治疗才刚刚开始，我们正试图为这个研究做出贡献。我想在5到10年以后，我们现在标准的化放疗将可能变成单纯的化疗而将减少放疗的使用。

　　Oncology Frontier:Hulscher studies showed that， compared with open surgery， laparoscopic surgery has relatively better 5-year overall survival and disease-free survival， and the postoperative mortality rate is lower. Compared with traditional open surgery， what is the role of laparoscopic surgery in the treatment of gastric cancer in the US?

　　《肿瘤瞭望》：Hulscher的研究表明，腹腔镜在胃癌治疗方面，与开腹手术相比，具有相对较好的5年总生存期及无疾病生存期，较低的术后率。在美国，腹腔镜手术与传统的开腹手术相比，腹腔镜在胃癌的治疗效果如何？

　　Dr Schwarz: There is general awareness that the laparoscopic approach to gastric cancer is a different technical approach to the operative treatment of the disease. It is now accepted as not having inferior oncologic outcomes. If it can be done well under good oncologic operative standards， then it is an acceptable way of doing it. The potential for reduced post-operative morbidity is also accepted， although the differences from some experiences in the United States would perhaps be smaller than seen in other countries. Patients don’t necessarily do remarkably well just because they had a laparoscopic procedure and there is still a significant challenge with operative risk and comorbidity which would be different perhaps for the average US patient than for the average patient in other countries where the BMI is lower or the general health status is better. This is maybe part of the reason the US has been somewhat slow to embrace or accept the laparoscopic approach to gastric cancer therapy. There are centers of excellence or higher volume that have moved this forward and it is certainly existent in the US but these are exceptions rather than the norm. From my own experience， I have done these operations but not many of them. I don’t automatically prefer a laparoscopic approach and there are other potential reasons for that as well. I am not convinced that the long-term survival benefits of laparoscopy are a sufficiently proven finding. In a univariate comparison， that may be so， but we know that patients selected for laparoscopic procedures have lower stage disease， better performance status and perhaps a better nutritional status. Those are all things that could and most likely will influence post-operative recovery and long-term survival. One would need to do a very careful study of all of those factors in order to identify if a laparoscopic approach is truly superior when it comes to long-term survival compared to an open resection approach. The moment there is convincing evidence， I think we would expect to see a significant shift in favor of a laparoscopic approach but so far， even good studies， primarily from Eastern Asian countries， have not given us convincing evidence for that. So we are in a holding pattern in that regard. I think convincing evidence of superiority is what is needed for most centers in the United States to embrace the technique because it is a rare disease in the United States， which is part of the reason why developments tend to be slower in terms of operative components for gastric cancer treatment. The magnitude of improvement in recovery time with the less invasive technique is maybe a little smaller than hoped for. If you leave the hospital a day earlier and return to work two weeks sooner， is that enough to now routinely do the procedure that way? The laparoscopic procedures themselves actually take longer to perform using more expensive equipment. So when those factors are added to the value proposal， there may be some quality benefits in terms of patient recovery or reduced morbidity but I am not convinced of a survival or mortality benefit and there may be a downside in terms of cost and equipment. Unfortunately， that is important to several US programs as well. We have not yet seen that laparoscopic gastrectomy is a clear winner in all of these aspects. It has the potential to indeed be superior but I suspect many centers will wait for more convincing evidence before making it the new standard of care.

　　Dr Schwarz: 大家普遍的认识是觉得腹腔镜治疗胃癌是手术治疗这个疾病的一种不同的技术手段。现在腹腔镜相比开腹治疗胃癌具有同等的肿瘤学结果这个一观点被大家所接受。如果腹腔镜技术按照肿瘤学操作标准来完成，它可以成为被我们所接受的治疗方式之一。尽管相比其他国家研究样本要小很多的美国研究得出的结论都不统一，但是腹腔镜手术减少术后并发症的潜力是被认可的。由于相比美国患者，其他国家的患者平均的BMI值要低很多，而且健康状态也相对更好，所以当美国患者接受腹腔镜手术之后，他们的效果可能没有那么显著的好，同时他们还要承受更大的手术风险和并发症的可能。这可能就是为什么美国相对接受腹腔镜这种治疗胃癌的治疗方案较慢的部分原因。在美国确实也是存在腹腔镜治疗胃癌比较优越或者治疗人数较多的中心，但是这可能是例外但不是常态。按照我自己的经验来看，我做过其中的一些手术但不是很多。我不是很倾向于做腹腔镜手术，因为其中有一些潜在的原因。因为我对腹腔镜治疗对于长期生存是否有利还不是很确信。当单因素分析时，这个结论可能是正确的，但是我们知道被选择做腹腔镜手术的患者一般肿瘤分期较早，依从性较好，可能还有更好的营养状况。这些都是很有可能影响到患者的术后康复和长期的生存时间的因素。相比开腹手术，腹腔镜手术对患者的长期生存是否有优势还需要一个涉及到以上所有因素的研究去证实。我们期待确切的证据去证实腹腔镜手术的显著优势，但是即使是做的很好的东亚国家的研究也还没有给出这样确切的证据。所以在这个方面我们还是持一个保守的观点。像美国的大部分机构都需要这样确切的证据去证实腹腔镜的优越性，因为在美国胃癌是一个相对罕见的疾病，所以我们对于腹腔镜手术的接受也相对其他的手术方式要慢一些。腹腔镜手术因为其实种微创技术而使患者术后恢复时间变短的优势并没有我们期望的那么有优势。仅仅因为你可以早一天出院和早两个礼拜回去工作，还不足以完全认为这个操作优于开腹。实际上，腹腔镜手术要使用更多更昂贵的器材以及要更久的手术时间。当将这些因素考虑进来的时候，即使腹腔镜手术在加快患者康复和减少并发症方面有优势，但是却没有确切的证据去证实腹腔镜在总生存以及死亡率上游优势，所以考虑到费用和设备的时候，腹腔镜手术就有它的劣势了。不幸的是，这对一些美国的研究计划也是很重要的。在所有的这些方面，我们并没有看到腹腔镜胃癌手术切除是绝对的赢家。虽然腹腔镜手术确实有潜在的优势，但是我怀疑很多中心在将腹腔镜手术列为他们的常规治疗方案之前都在等待更确切的证据！