胰腺癌与肝癌的三“早”：早预防、早诊断、早治疗

　　Alfa 教授：肝细胞癌（HCC）是世界性常见的恶性肿瘤，大部分患病人群集中在东南亚地区，尤其是中国。肝癌的早期预防和早期诊断非常重要，尤甚，但目前这在许多国家都尚未实现。目前我们所知的导致肝癌发生的危险因素主要有4种，而其中在中国最常见的是HBV病毒感染。因此，实施HBV疫苗计划至关重要，然而这在许多国家还没有广泛开展。患者一旦感染HBV，则需要及时治疗和密切随访以防止疾病进展成肝癌。目前的共识是每年检测甲胎蛋白（AFP）两次，肝脏超声一次，这至少可以早期诊断肝癌，然而，肝癌的预防理念仍然缺乏足够的重视。

　　秦教授：正如Alfa教授所说，HCC是全球常见肿瘤之一，尤其是在中国高发。由于大多数肝癌患者都有乙型肝炎和肝硬化病史。因此，我们要高度重视随访乙肝病毒感染者和乙型肝炎、肝硬化患者，可以通过体格检查、肝功能、肝脏超声检查和AFP血清检测等措施来帮助早期诊断肝癌。需要指出的是：在我国，应政府卫生部门的要求，多年来有关医疗和防疫单位已经对于新生儿和高危人群实施强制性接种乙肝疫苗，而其他人群也提倡进行接种预防，使得乙肝病毒携带者明显减少，取得了显著的成就，未来乙肝病毒感染者相关性肝癌发病率会逐渐降低的。

　　O’Reiley教授：我想补充的就是西方的肝细胞癌主要是由于丙型肝炎病毒所引起的。近年来，抗丙型肝炎的治疗取得了突破性进展， 有望降低肝硬化以及肝细胞癌的发病率，尽管目前正在研究之中，尚缺乏可靠的证据，但其可能具有潜在预防肝细胞癌的价值。

　　Professor Abou-Alfa:Primary liver cancer or hepatocellular carcinoma (HCC) is one of the mostcommon cancers worldwide and especially here in China where most of the patients are from. It will be very important to diagnose it early or more importantly to prevent it. Liver cancer is caused by 4 major risk factors， the most important of which here in China is Hepatitis B.

　　Professor Qin: A hepatitis B vaccination program would be effective， however such a program isvery laborious for a large country like China， and is unfortunately is limited by the vertical transmission from mother to child among already infected people.

　　As far as early detection， the general consensus is to check the alpha-fetoprotein (AFP)level twice a year and have a liver ultrasound once a year.

　　Professor O’Reilly: One other thing to add with the new era of antiviral therapies for hepatitis C that hopefully help reduce the incidence of hepatitis C related primary liver cancer.

　　肝癌与胰腺癌个体化治疗的关键：分子靶向治疗

　　O’Reiley教授：首先我要谈谈靶向治疗在胰腺癌方面的进展。关键是发现新的靶点和靶向治疗药物，现在我们已经有了厄洛替尼，但是它的疗效有限，对K-RAS基因突变的胰腺癌可能无效，因此，并不推荐用于一线治疗。需要寻找新的分子靶向标志物，有报道称白藜芦醇可能有一定疗效。关于胰腺癌的分子标志物，有几个指标具有临床意义：第一， C反应蛋白可作为衡量胰腺癌炎症水平的标志，C反应蛋白升高的胰腺癌患者可能对卡培他滨和JAK激酶抑制剂鲁索替尼有效，这个理念正在二项大型全球III期临床试验中进行评估。第二，某些DNA损伤基因可能与铂类药物的敏感性有关，据我们所知，存在BRCA突变基因的患者可能从铂类化疗药物和PARP抑制剂中获益。相关基因分析表明，该BRCA基因突变亚型胰腺癌患者占总人数的1/4，当然这还存在争议，需要进一步研究和证实。第三，Notch可作为治效不佳的胰腺癌患者的治疗靶点。虽然临床上还没有出现能够明确预测疗效和指导治疗的生物标志物，但将来一些标志物也许能够确认。

　　Alfa 教授：关于分子靶向治疗方面，我非常想听一下秦教授在这方面的看法。毫无疑问，我们都在期待C-MET通路抑制剂在肝癌中的疗效的两项临床试验的结果；另一个热点是免疫药物CTLA-4和PD-L1在原发性肝癌中的潜在应用，当然我们需等待Ⅲ期临床试验的结果。

　　秦教授：我非常同意Alfa教授的观点，多种治疗HCC的新药虽然在I/Ⅱ期临床试验中苗头好，但是随后的Ⅲ期临床试验试验的结果均以失败告终，令人沮丧。一方面与这些药物有关，但是超过50%是临床试验的问题。正如Alfa教授所说的那样，我们要更多地关注分子靶向治疗和系统化疗及其进展，尤其是重视临床研究的设计和质量控制，而且寄希望于免疫治疗将来能在肝癌治疗中占一席重要之地。

　　Professor O’Reilly: I can start with pancreas cancer. Erlotinib， the first targeted agent to be approved for pancreatic cancer has modest efficacy but has sort of fallen out of favor primarily because pancreas cancer is K-ras mutated and probably this drug can’t work effectively. There are hints that resveratrol， a JAK inhibitor， may have potential therapeutic value for patients with pancreatic cancer and elevated CRP level， a sign of systemic inflammation that may benefit from a targeted approach with using capecitabine and ruxolitinib. That concept is being evaluated in two large global phase III studies. Another target of interest relays to the whole area of DNA damage response and susceptibility to platinum therapies. We know there are patients with germline and some patients with somatic mutations in BRCA may benefit from platinum therapies and experimentally PARP inhibitors. Some additional genomic analysis has suggested that that subgroup may represent up to a quarter of patients with pancreas cancer. Of course there is a number of poised targets on the horizon.

　　Professor Abou-Alfa: I will definitely talk about some of the directions and biologics， but then I would very much like to hear Professor Qin reflections on the use of chemotherapy for liver cancer， which he is an expert on. The two latest trials evaluating c-met inhibition， are still awaiting completion and reporting. The other area of great interest is immunomodulation. CTLA 4 and PD-L1 remain potential targets in primary liver cancer， in view of the data that was recently reported and showed quite encouraging results..

　　Professor Qin: I totally agree with Professor Abou Alfa’s opinion. No doubt we should focus on some special targets however a backbone of chemotherapy may be valuable as we have shown in our work of FOLFOX that is now an approved approach for treatment in China.

　　多学科合作模式：优化肿瘤治疗的必由之路

　　Alfa 教授：肿瘤治疗的多学科综合治疗模式（MDT）是个很重要的概念。在世界各地，不论在美国还是中国，HCC都是一种涉及多学科的疾病，其治疗需外科、移植外科、介入放射科、肝胆科、消化科、肿瘤内科、放射科、病理科、感染科及其他支持性科室等多个科室的医生共同参与。有试验证实，多学科治疗确实能够明确提高患者的生存，因为，不同学科可从不同治疗角度为患者提供全面的治疗选择，而非局限于某一学科的专业水平。

　　O’Reiley教授：多学科合作模式（MDT）对于优化胰腺癌患者=的治疗也非常必要，尤其针对局限性的胰腺癌患者。多学科形成的一致意见将有助于为其提供最理想的治疗选择，不管是术前治疗、全身放化疗还是直接进行手术治疗等。此外，如果出现肠道和胆道梗阻，也需要胃肠专家参与诊断和治疗。因此，我认为MDT对于优化胰腺癌的治疗至关重要。

　　秦教授：我们应该借鉴欧美的MDT模式。在中国更习惯按治疗手段将科室分类，如肿瘤外科、化疗科和放疗科，而不是根据疾病将科室分类，如胃癌中心和肝癌中心等。因此，我们需要学习欧美专家，积极开展多学科协作以及规范化综合诊疗模式。

　　O’Reiley教授：实现MDT的途径有很多，如我们可以通过科室内人员以及科室间同事之间的交流和讨论获得有效的治疗意见。

　　Alfa教授：在美国Memorial Sloan Kettering癌症中心，我们是第一个开展多学科协作疾病治疗模式（DMT）的团队。每周，我与O’Reiley医生以及其他学科的同事都会进行一次常规讨论，研究我们已有的项目和患者的病情。来自外科、放射科、肝病学科的医生共同参与疾病治疗，这非常令人振奋且意义重大。我们的门诊中心也采取同样的模式，提供外科和肿瘤内科或外科和放疗科医生共同接诊的服务，事实证明这种MDT方式非常有效且有益。

　　Professor Abou-Alfa: Multidisciplinary treatment is a very important concept which is more noticeable and applied worldwide. Primary liver cancer， is a multidisciplinary disease by excellence: Surgeons， transplant surgeons， interventional radiologists， hepatologists， gastroenterologists， oncologists like us， radiologists， pathologists， infectious diseases specialists， have all a key role to play for every patient with primary liver cancer. By the mere fact of seeing physicians of different disciplines， will improve survival of a certain patient with primary liver cancer.The ability to offer different types of therapy to the patients and seeing it from a different perspective already broaden their horizons rather than simply dependent on one specific aspect that a specialist might know and they are repeating the same thing.

　　Professor O’Reilly: The same applies to pancreatic cancer， where multidisciplinary treatment have shown to optimize outcomes for patients. This is particularly true for the spectrum of localized pancreas cancer and that includes resectable patients， the newly defined entity of borderline disease and patients with locally advanced disease. A multidisciplinary consensus can be helpful in terms of guiding whether a patient should be treated with preoperative therapy or best served by systemic therapy followed by radiation or upfront surgery.

　　Professor Qin: Here in China， we need to acknowledge and learn from the experience of our American colleagues， as in China， it is more common to divide departments according to the treatment method， not the according to the needs of the patient，Undoubtedly we need to transition to a multidisciplinary cooperation and a comprehensive treatment approach.

　　Professor Abou-Alfa: Memorial Sloan Kettering Cancer Center where Professor O’Reilly and I practice， was first in bring the concept of disease management teams or DMT to cancer care. For example， Professor O’Reilly， myself， and many other colleagues from the different disciplines make up the disease management team for liver， pancreas， and biliary cancers. We meet on a weekly basis and work forone hour on research and another hour and a half on discussing patients and their needs . It is fascinating to see the input of the surgeons， the interventional radiologists， the oncologists and many other coming into play to help define the best approach of care for a specific patient. The way our clinic operate allow same day evaluation by a  surgeon and an oncologist ， or a interventional radiologist an oncologist as needed.

　　术后辅助治疗：在肝癌和胰腺癌中的地位

　　Alfa 教授：众所周知，目前在HCC手术后尚无有效的辅助治疗方案。两项分别来自日本和香港的动脉内灌注栓塞临床试验均显示阴性结果；另外，最近的索拉非尼对照安慰剂试验（STORM研究)的结果也是阴性的。因此，目前我们不支持任何的HCC辅助治疗方案。尽管如此，一些新的治疗领域，如免疫治疗也许能够打开新的局面。由于肝脏非常脆弱，可能不适合术后进行肝动脉灌注化疗。目前正在进行一项由美国NCI赞助的立体定向放疗联合索拉非尼治疗进展期HCC的临床试验，也许有一天这会给HCC的靶向治疗带来突破，不过这还很难说。与O’Reilly医生将要提到的辅助治疗在胰腺癌方面的积极作用不同，当前辅助治疗在肝癌中的价值有限。。

　　O’Reiley教授：辅助治疗在胰腺癌中疗效确切，胰腺癌术后全身化疗能成倍延长各个阶段胰腺癌患者的生存。然而胰腺癌复发的风险仍然比较高，我们需更研究更为有效的方案。吉西他滨是国际通用的标准方案，现在有临床试验正在研究卡培他滨与其他药物如白蛋白紫杉醇等联合能否改善胰腺癌术后患者的预后。2年前，我们完成了第一项胰腺癌的免疫治疗研究，该试验利用癌胚抗原激活患者的免疫力，目前正在等待其更为成熟的数据发表。放疗是否用于胰腺癌术后患者辅助治疗一直存在争议，欧亚国家似乎倾向于不采用，而北美则存在分歧，目前有临床试验正在评估新辅助放化疗能否延长胰腺癌患者的生存，目前结果尚未可知。

　　秦教授：HCC目前尚无可行的抗肿瘤辅助治疗方案。我们普遍认为肝癌是一种异质性强、恶性程度高和具有基础肝病的肿瘤。多项试验业已表明，积极应用抗病毒治疗药物能够减少肝细胞癌的术后复发率，但是采用系统化疗和靶向药物辅助治疗尚无充分数据加以支持。在胰腺癌方面，已有大型的临床研究证据支持给予吉西他滨和／或S-1的方案作为辅助化疗。在不久的将来，我们应该更多地关注免疫治疗及其他的新药物。

　　Professor Abou-Alfa: In regard to primary liver cancer there is no adjuvant therapy established yet. There has been several genuine efforts， they key ones of which is the retinoic acid studies， done by our Japanese colleagues， and iodine 131 intra-arterial infusion done in Hong Kong. Lately a sorafenib versus placebo adjuvant study was reported negative. So at the moment no one can vouch or support any adjuvant treatment for HCC， With the advent of immunotherapy， a new ear of potential therapies in the adjuvant therapies may evolve.

　　Professor Qin: I concur with Professor Abou-Alfa， talking about HCC there is no standard adjuvant drug proven for therapy but we commonly said HCC is a special tumor， it can be very malignant and affect liver function. So we have to pay a lot of attention to antivirus drugs. Some studies show that we use anti-HBV virus drug to decrease the likelihood of relapse after resection.

　　Professor O’Reilly: Speaking to the role of adjuvant therapy and pancreas cancer， it definitely is established and postoperative and systemic therapy has been shown to double the number of people who will be alive at any point and time that you pick. However， the risk of reccurrence remains substantial in this disease and the need for more effective therapies remains pressing. Gemcitabine is an acceptable standard of care. Current trials are investigating whether adding a second drug， may improve on outcome. We have the first completed study of an immune therapy in pancreas cancer， which is an oncofetal antigen used to immunize patients. We are waiting for maturation of the data. Radiation though is a controversial consideration， European and Asian to a greater extent has moved away from the routine use of radiation in the adjuvant setting in pancreas cancer. Now the American opinion remains divided and one of our ongoing national studies is designed to answer the question whether adjuvant chemo-radiation will add to systemic therapy in terms of both situation and overall survival. We do not know the answer to that yet.

　　国际视野之背景链接

　　秦叔逵教授

　　解放军八一医院副院长兼全军肿瘤中心主任

　　中国临床肿瘤学会（CSCO）副理事长，CSCO基金会理事长; 国家卫生计生委肝癌、胃肠间质瘤和癌痛控制三个专家组的组长；长期从事肿瘤内科工作，擅长消化道肿瘤（特别是肝癌）的诊治和研究。获得国家科技进步一等奖和二等奖各1项，省部级科技成果一等奖4项、二等奖3项、三等奖9项及4等奖2项。

　　Eileen M. O’Reilly， MD

　　纽约纪念斯隆凯特琳癌症中心胰腺癌首席专家

　　美国国家癌症研究所（NCI）胰腺癌专家组组长，胃肠道联盟核心委员会委员，还在胰腺癌行动网络科学顾问委员会、美国国家综合癌症网络（NCCN)胰腺癌专家组、国家胰腺癌研究基金会理事会以及ASCO IMT委员会任职，在多项Ⅰ、Ⅱ、Ⅲ期胰腺癌大型临床研究中担任主要研究者（PI）。

　　Ghassan K. Abou-Alfa， MD

　　美国纪念斯隆凯特琳癌症中心肝癌首席专家

　　美国NCI肝胆癌专家组组长。多次组织和牵头一系列大型国际临床研究，在全世界率先研究和报道索拉非尼治疗原发性肝癌，担任其Ⅰ、Ⅱ临床研究主要研究者（PI）。