编者按：在第20届全国临床肿瘤学大会暨2017年CSCO学术年会（CSCO 2017）的CSCO-ASCO联合论坛，中外知名专家就消化系统肿瘤的临床治疗及研究进展进行了交流和讨论。而近十年来，消化系统的新药研究迅速进展。《肿瘤瞭望》记者特别邀请到CSCO-ASCO联合论坛共同主席、美国梅奥诊所Ramesh Ramanathan教授和中国医学科学院肿瘤医院的黄镜教授，就近年来消化道肿瘤如胰腺癌、食管癌、结直肠癌等的新药研发进展和临床决策进行了探讨。

 

　　全球化时代下的消化道肿瘤临床决策：中外差异日趋缩小

 

　　Ramanathan教授：过去，中外专家在消化道肿瘤的临床决策方面可能存在很多分歧，但现在外科肿瘤学家和放射肿瘤学家正越来越多地以同样的方式进行实践。我知道中国同行们参考NCCN和ESMO指南，这也是我们在美国参考的指南。就外科手术而言，中外专家可能在选择适合手术患者的方法、应用化疗药物和联合治疗方面存在一些差异，但我相信我们在实践中正日趋一致。这是一个全球化的时代，我们可通过国际会议交流观点，所以我相信其实并不存在本质差异，而且在如何更好治疗患者上正逐渐达成共识。

 

　　黄镜教授：是的。在临床实践中，这种差异越来越小；但在临床试验中，可能存在一些差异。

 

　　Ramanathan教授：现在的临床试验也越来越全球化。当我们开展Ⅲ期临床试验时，中国是我们全球多中心研究的重要合作者。当然，有一些药物已经在中国获准上市，而尚未在美国获得通过（如阿帕替尼、S-1）。在中国，因为胃癌和肝癌患者众多，一些大型的单中心研究能够很快完成，而这在美国很难实现。

 

　　黄镜教授：中国的肿瘤患者数量庞大，这是我们能够在短期内募集到大量患者的主要原因。

 

　　Oncology Frontier: Chinese and foreign experts had discussed the current clinical treatment of gastrointestinal cancer in the CSCO-ASCO forum. As a forum Chairperson and invited speaker on this topic， what is your viewpoint? Do you think is there a difference in the clinical decision-making for gastrointestinal tumors between China and abroad?

 

　　Dr Ramanathan: I think in the past there may have been differences， but increasingly， surgical oncologists and radiological oncologists are practicing in the same way. I have seen my Chinese colleagues make reference to the NCCN and ESMO Guidelines， which is what we follow in the United States. I think as far as surgery goes， there may be some differences in approaches to selecting patients， and treating patients with chemotherapy and multimodality therapy， but I think we are increasingly practicing the same way. Everything is becoming globalized. We have international meetings to exchange ideas， and I don’t see any major differences. Slowly， we are reaching consensus on how to treat patients in the best manner.

　　Dr Huang: I agree. In clinical practice， the differences for patients are getting smaller and smaller. But perhaps in clinical trials， there are differences.

 

　　Dr Ramanathan: Clinical trials are now also more global. When we come to phase III clinical trials， China is a very big player in global multinational studies. There are obviously some drugs that China has access to and the US does not (apatinib and S-1， as examples). Also in China， there can be very large， single institution studies performed very quickly， which we have difficulty doing in the United States. For gastric cancer and liver cancer， China is number one in terms of clinical trials because of the sheer volume of patients.

 

　　Dr Huang: The population of Chinese patients is huge， and that is the main reason we are able to enroll large numbers of patients in a short time.

 

　　Ramanathan教授：我研究胰腺癌已超过20年，胰腺癌新药研发的确非常困难。在某些方面，胰腺癌研究落后于其他肿瘤研究。胰腺癌进展迅速，生存率低并且难以早期诊断。大部分胰腺癌患者在明确诊断时已经有转移灶。我认为鲜有新药批准上市是因为其分子生物学机制尤其不同，我们很难确定癌症的突变基因。对于胰腺癌的治疗，尽管细胞毒药物（如吉西他滨、紫杉醇、FOLFIRINOX方案和S-1）已被批准并广泛应用于临床，但其活性有限。因此，本质上胰腺癌对化疗耐药，作为单一药物的免疫疗法通常不起作用。目前很多研究正致力于克服障碍和研发新药。我参与的其中一项研究是靶向于细胞基质，可应用细胞毒药物、缺氧诱导药物及酶类降解细胞基质，像聚乙二醇化的透明质酸酶一样。免疫疗法通过免疫识别同样靶向于并且清除细胞基质。这是评估检查点抑制剂免疫疗法应用于胰腺癌治疗的一个途径。食管癌则有些不同。无论是食管鳞状细胞癌还是食管腺癌，其诱发因素不同，因此治疗方法也各不相同。即使在能够采取手术治疗时，这些癌症通常都需联合治疗。我再次强调，理解分子生物学机制必不可少，在实验室做好临床前研究并将其转化至临床至关重要。

 

　　黄镜教授：过去十年间，我认为在胰腺癌化疗方面取得了一些进展。十年前，我们治疗胰腺癌只能选择吉西他滨，而现在我们有了更多选择。除了吉西他滨，我们还可以选择FULFIRINOX治疗方案、白蛋白结合型紫杉醇以及替吉奥等其他新方案治疗患者，其中部分患者可达到部分缓解，这也是胰腺癌治疗上的重大进展。除特罗凯（厄洛替尼）外我们并没有其他获批的靶向治疗方案，而厄洛替尼的优势非常有限。就食管癌而言，其有两种病理分型，一种是鳞状细胞癌，一种是腺癌，二者迥然不同。近年来，食管鳞状细胞癌发病率有所下降，而食管胃结合部腺癌发病率有所上升。过去五年中，对于食管鳞状细胞癌的系统性药物治疗取得了一些有希望的进展，如抗PD-1抗体和VEGF信号通路抑制剂等。对于食管胃结合部腺癌，一些靶向治疗已在近几年获批。

 

　　Oncology Frontier: The drug therapy choices for pancreatic cancer and esophageal cancer are limited. Researchers are continuing to explore and making some achievements. Can you outline the alternative drug strategies for each of those cancers?

 

　　Dr Ramanathan: I have been working in pancreatic cancer for twenty years， and it has been very difficult to discover new agents. Pancreatic cancer has always lagged behind other cancers to some extent. They are very aggressive cancers with poor survival and typically diagnosed late. Most patients have metastatic disease at diagnosis. I think the reason that we have few approved drugs is that the molecular biology， in particular， is different. We don’t see actionable mutations in these cancers to a large degree. In pancreatic cancer especially， cytotoxic drugs， although approved and widely used (gemcitabine with nab-paclitaxel， FOLFIRINOX， and S-1)， they have limited activity. So pancreatic cancers are intrinsically resistant to chemotherapy， and immunotherapy as a single agent typically does not work. There is a lot of research ongoing looking at how to circumvent these barriers and develop new drugs. One that I am involved in as my research area is targeting the stroma. That can be done with cytotoxic drugs， hypoxia-activated drugs and enzymes that degrade the stroma like pegylated hyaluronidase. Immunotherapy can also target and deplete the stroma allowing immune recognition. That is one way of evaluating checkpoint inhibitor immune  therapy for pancreatic cancer. Esophageal cancer is somewhat different. The precipitating factors are different， whether squamous cell or adenocarcinoma， and the treatments vary. Those cancers are typically treated with multimodality therapy， even if surgically operable. Again， I think understanding the molecular biology is essential. It is important to do good preclinical studies in the laboratory and translate those to the clinic.

 

　　Dr Huang: In pancreatic cancer， I think chemotherapy has seen some progress in the last ten years. Ten years ago， we only had gemcitabine for the treatment of pancreatic cancer， but nowadays， we have more choice. Besides gemcitabine， we have FULFIRINOX and albumin-bound paclitaxel and other new regimens for treating patients. If a patient can achieve even a partial response， then it is great progress in the treatment of pancreatic cancer. We don’t have targeted treatment approved other than Tarceva (erlotinib)， which has only very limited advantages. As for esophageal cancer， there are two types of esophageal cancer. One is squamous cell carcinoma， and the other is adenocarcinoma， which are two totally different diseases. For esophageal squamous cell carcinoma， the incidence has decreased in recent years. But for gastro-esophageal junction cancer， the incidence has increased. Systemic treatment in the past five years for esophageal squamous cell carcinoma has seen some promising advances， such as the PD-1 inhibitors and VEGF pathway inhibitors. For GE-junction cancer， some targeted therapy has been approved in recent years.

 

　　消化道肿瘤新药研发进展

 

　　Ramanathan教授：胰腺癌和结直肠癌是复杂难治的肿瘤，无论在美国还是在中国其治疗都越来越多地采用综合治疗的专家团队模式。我认为外科手术是唯一的治愈式方式，胰腺和食道手术非常复杂，需要这方面的专家。在美国，我们越来越倾向于将患者推荐到有经验的专科中心，我们知道其结果可能会更好（专科中心的致死率和致残率要低得多）。在过去，胰腺癌新药试验后并未得到更多的科学证据。如果某个新药治疗其他疾病有效，我们会尝试将其用于治疗胰腺癌，但通常都以失败告终。目前，有大量胰腺癌临床试验，需要很多患者和大量资源。我们必须后退一步，并尤其应该在将新药用于Ⅲ期临床试验时非常谨慎，这就是有效的临床前研究之意义所在。转化研究很重要，而这正是我们致力于所做的。若没有取得确实有效的临床前数据前，我们是不会开展临床试验的。尽管临床前数据也并不意味着一定成功，但它至关重要。药物越来越昂贵，开展大型Ⅲ期临床试验更加困难。

 

　　黄镜教授：我很同意Ramanathan教授的观点，临床前数据是非常重要的。我们可以聚焦一些驱动基因开展Ⅰ期和Ⅱ期临床试验。如果我们能够明确某一个驱动基因，就能够针对一些特定的患者开展研究。如果没有前景光明、预示良好结果的前期数据，通常我们不建议贸然开展Ⅲ期临床试验。

 

　　中国制药企业已经生产出自主研发成功的有效治疗消化道肿瘤的新药，比如被批准用于胃癌三线治疗的阿帕替尼。这种新药为VEGF抑制剂。另外，今年的ASCO会议上就报道了另一种VEGF抑制剂――呋喹替尼的研究结果，我相信在不久的将来，其将很可能被批准用于结直肠癌的治疗。另一种TKI抑制剂安罗替尼也在肺癌治疗方面显示出良好结果。在中国，我们在进行一项安罗替尼治疗食管鳞状细胞癌的研究，为随机安慰剂对照Ⅱ期临床试验，尽管这项临床试验目前仍在招募患者，但其已显示出一些很有希望的结果，安罗替尼将来可能有望获批治疗食管癌。

 

　　Oncology Frontier: Can you tell us about the current progress in this regard? what is the current state of development of new drugs for digestive tract tumors in China? What lessons can you learn from the world?

 

　　Dr Ramanathan: These cancers are complex cancers to treat， and increasingly in the United States as well as China， they have been treated by a team of specialists with multimodality therapy. I do think surgery is the only curative modality， and pancreatic and esophageal surgeries are complex and require specialists. Increasingly in the US， we tend to refer patients to specialist centers with experience， because we know the outcomes will be better (mortality and morbidity are much lower in specialist centers). In the past， there has not been much science behind testing new drugs for pancreatic cancer. If a new drug is seen to work in other diseases， we try to use it in pancreatic cancer， and typically， it fails. Currently there are a large number of clinical trials in pancreatic cancer， which will require many patients and require tremendous resources. We need to take a step back and be very careful in taking drugs into the phase III setting especially. This is where good preclinical studies come in. Translational research is very important， and that is what we try to do. We don’t do a clinical trial unless we are convinced there is good preclinical evidence that it may work. Preclinical data doesn’t mean success all the time obviously， but it is very important. Drugs are becoming more and more expensive and it is more difficult to do large phase III studies.

 

　　Dr Huang: I agree. I think preclinical data is very important. We can also do phase I and phase II trials to focus on driver genes. If we can identify a driver gene， then we can concentrate on certain patients. Phase III trials are not commonly suggested before there is sufficient promising data indicative of good outcomes.

 

　　Chinese pharmaceutical companies have produced new agents which have proven effective in the treatment of digestive tract cancer， such as apatinib， approved as third-line treatment for gastric cancer. These new drugs are VEGF inhibitors. At this year’s ASCO Meeting， the results were presented for one of these VEGF inhibitors （Fruquintinib）and I think it will be approved for the treatment of colorectal cancer in the near future. Another VEGF-TK inhibitor， Anlotinib， also showed good results in the treatment of lung cancer， and we conducted a randomized placebo-controlled phase II clinical trial here in China in esophageal squamous cell carcinoma. The trial is still enrolling patients but is showing some promising results already， which may lead to approval in the future in the treatment of GI cancer.