Oncology Frontier: Which factors do you consider when selecting the first-line systemic chemotherapy regimen for pancreatic cancer patients?

　　《肿瘤瞭望》：您在为胰腺癌患者选择一线化疗方案时会考虑哪些因素？

　　Dr Kenneth H. Yu: The approach to treating pancreatic cancer has changed a lot over the last five years. There are now two very effective chemotherapy combinations that we use. One is FOLFIRINOX， a combination of 5-FU， leucovor， irinotecan and oxaliplatin. Another effective combination is gemcitabine plus nab-paclitaxel (Abraxane). For the most part， both regimens seem to be active but most patients seem to have more side effects on the FOLFIRINOX regimen， so we usually reserve that regimen for very fit patients and patients who are younger (<76). Patients receiving gemcitabine and Abraxane tend to also be quite fit but we allow for patients to be a little more debilitated from their cancer and we are also willing to treat patients who are a bit older with that particular regimen.

　　Dr Kenneth H. Yu：在过去的五年里，胰腺癌的治疗方法发生了很大的变化。我们用到了两种非常有效联合化疗方案，一种方案是5-FU、叶酸、伊立替康和奥沙利铂联合使用的FOLFIRINOX方案，另一个有效的方案是吉西他滨加白蛋白结合型紫杉醇的联合化疗。在大多数情况下，这两个方案似乎都是有效的。但对于大多数患者，FOLFIRINOX方案似乎有更多的副作用，所以我们通常只对非常健壮的较年轻患者（76岁以下）采用此种化疗方案。接受吉西他滨和白蛋白结合型紫杉醇联合化疗的患者也往往较为健壮，但我们也允许那些被肿瘤折磨地比较虚弱的患者以及较为年老的患者接受此方案治疗。

　　Oncology Frontier: Beyond classical cytotoxic agents administered in different formulations and combinations， could you outline other kinds of novel therapeutic approaches that offer substantial promise for improving the outlook of patients with advanced pancreatic cancer?

　　《肿瘤瞭望》：除了传统的化疗方案以不同的治疗模式或者组合之外，您能告诉我们一些其他的具有潜在治疗前景的可以提高晚期胰腺癌患者预后的新治疗措施吗？

　　Dr Kenneth H. Yu: An important study that was presented at this year’s meeting was a study looking at combining standard chemotherapy (gemcitabine plus nab-paclitaxel) with an investigational agent called PEGPH20. This agent dissolves an important component of the tumor microenvironment. Preliminary studies suggest that for patients whose tumors have very high levels of the target of this drug seem to have significantly prolonged survival. That’s a very interesting targeted agent that is being pursued in clinical research. Another targeted agent is MM-398， a novel formulation of an old drug called irinotecan. There is evidence that this drug combined with 5-FU chemotherapy can be effective in patients as second-line treatment for pancreatic cancer. There is another targeted agent in late stage development called ruxolitinib. It is approved for myelofibrosis but it appears that patients with high C-reactive protein， a marker of inflammation， can also benefit in the second-line from this targeted agent.

　　Dr Kenneth H. Yu：在今年的会议上提出了一个重要的研究，这项研究主要观察标准化疗方案（吉西他滨联合白蛋白结合型紫杉醇）结合一种临床试用药剂PEGPH20的治疗疗效。这个药剂能够溶解肿瘤微环境的重要组成部分。初步研究表明，当患者的肿瘤含有较高水平的药物靶点的时候，其生存期显著延长。这是我们非常感兴趣且一直在临床研究中探索的一个靶向药物。另一个靶向药物是MM-398，这其实是伊立替康这种旧药的一种新的构型。有证据表明，该药联合5-FU的化疗可作为胰腺癌患者二线治疗的有效方案。还有另一个处于后期开发阶段的靶向药叫做ruxolitinib。这种药物被批准用于治疗骨髓纤维化症，但高C反应蛋白（一种炎症标志）患者也可从该靶向药的二线治疗中获益。

　　Oncology Frontier: The identification of predictive biomarkers remains a major challenge in pancreatic cancer. By which methods can we look for predictive or prognostic biomarkers for pancreatic cancer and which factors do you think have more predictive value?

　　《肿瘤瞭望》：识别胰腺癌的预测生物标志物仍然是一个很大的挑战。您认为我们可以通过哪些方式寻找胰腺癌预测生物标记物或预后生物标记物？您认为哪种因子比较有预测价值？

　　Dr Kenneth H. Yu: I don’t think there is going to be one single biomarker that is going to be effective at predicting treatment response and prognosis. There are likely to be a number of them. The ones that seem to be most promising right now are biomarkers such as genomic profiles consisting of BRCA mutations. Even if the patient doesn’t have a BRCA mutation， it seems up to a quarter of patients have a genomic profile consistent with that. That can be predictive for treatment with drugs such as platinum agents as well as PARP inhibitors. A second important biomarker from the ruxolitinib study is high C-reactive protein. And then from a study that was presented here today looking at tumor hyaluronic acid levels， there are tumors that are targets for the drug PEGPH20. There is a lot of active research looking at other biomarkers but they still remain exploratory. These include things like circulating tumor cells and circulating DNA.

　　Dr Kenneth H. Yu：我不认为将会有一个单一的生物标志物来有效地预测患者的治疗反应和预后。但是有可能是多种生物标志物结合预测。现在最有前途的生物标志物似乎是含有BRCA突变的基因组谱。即使患者没有BRCA突变，似乎多达四分之一的患者有与其一致的基因组谱。这可以用来预测铂类药物和PARP抑制剂等治疗的效果。另一个在ruxolitinib研究中重要的生物标志物就是高C反应蛋白。今天的大会报告中也有一项研究，观察了肿瘤的透明质酸水平，发现有一些肿瘤是药物PEGPH20的靶点。有很多正在进行的研究在探索其他生物标志物，这里面包括就包括了循环肿瘤细胞和循环DNA。

　　Oncology Frontier: Considering the prognosis of metastasis pancreatic cancer is poor， what do you think are the challenges in pancreatic cancer treatment and clinical trial design?

　　《肿瘤瞭望》：目前转移性胰腺癌的预后很差，您认为在胰腺癌的治疗及临床试验设计方面，我们临床科研工作者面临哪些挑战？

　　Dr Kenneth H. Yu: The challenges in treating pancreatic cancer are many and include factors such as very complex genetic mutations making it difficult to target any one mutation， on top of the fact the tumor has developed the ability to evade the immune system much better than other cancers. Trial designs that look promising are combining different immunotherapy agents to try and overcome these problems with pancreas cancer as well as strategies looking at multiple targeted agents acting on important pathways in the progression of pancreatic cancer.

　　Dr Kenneth H. Yu：治疗胰腺癌的挑战因素有很多，其中之一就是，由于胰腺癌逃避免疫系统的能力比其他癌症都要强，极其复杂的基因突变使得难以针对单一突变来靶向治疗。较有前景的试验设计是将不同的免疫靶向药物结合使用，探索作用于胰腺癌进展过程中重要通路的多个靶向药物，以期克服胰腺癌及其治疗策略中的诸多问题。