编者按:当地时间2017年6月2~6日，第53届美国临床肿瘤学会（2017 ASCO）年会在芝加哥盛大召开。大会特设“II/III期结直肠癌个体化辅助治疗”专场，探讨结直肠癌辅助治疗领域最新最热的研究进展。美国西北大学罗伯特.卢里综合癌症中心临床研究部主任、美国国立综合癌症网络（NCCN）结直肠癌专家组主席Al Bowen Benson教授担任本专场的特邀主持，会后，《肿瘤瞭望》对Benson教授作了现场专访！
What are the main controversies in the field of colon cancer adjuvant therapies?
Prof. Benson: One of the problems we have in selecting patients for adjuvant therapy for colon cancer is identifying those patients who are at greatest risk of recurrence. So there are many stage II patients who are cured with surgical resection. Whoever， we know that there some who are not cured and it is a challenge to identify which patients are at higher risk. Currently we tend to recommend adjuvant therapy for T4N0 patient but whether that is always appropriate is still controversial and so we need better molecular characterization of patients to define particularly for stage II patients who might benefit from additional therapy after surgery we do know that the MSI stage II patients do very well and so we are very comfortable recommending no adjuvant therapy for that group. For the stage III MSI patients is still not clear whether they all need adjuvant therapy or not. And that is an area of investigation， in fact there are clinical trials being design looking at the role of immunotherapy for MSI-positive patients in the adjuvant setting. For rectal cancer there is much more controversy because we tend to extrapolate from colon cancer data particularly from stage III patients and apply that to rectal cancer which may not be appropriate. We do not have really good data to define what is the optimal strategy and the treatment of rectal cancer is evolving for example there are trials looking at giving chemotherapy and chemoradiation before surgery thus avoiding adjuvant therapy all together. There are patients who get a complete response from therapy who may not need adjuvant therapy after neoadjuvant therapy. And there are even patients who receive neoadjuvant chemoradiation who may not need surgery at all and certainly no further chemotherapy. So there is still a lot we need to sort out and we are hopeful that as we understand more about the molecular biology and looking at subsets of patients we will have better approaches. It is also a challenge we haven’t move beyond oxaliplatin and fluorouracil perimeter. Outside perhaps the role of immunotherapy for MSI patients we still do not have new drugs for this group. So this is a big challenge and we are hopeful over time we can identify new agents that will improve outcomes.
Whether has the molecular classification of colorectal cancer made an impact on their adjuvant treatment of clinical decision-making ?
Prof. Benson: I think we are making some progress， we need to make more. But for example the very exciting development of immunotherapy for MSI patients and that strategy of immunotherapy is being looked at in the adjuvant setting for MSI-positive patients particularly for the stage III patients. And metastatic disease in incidence of MSI-positivity is quite low， but nonetheless there are data that certainly support the use of immunotherapy for these patients. And there are ongoing trials and the recommendation for use of immunotherapy for stage IV MSI patients is now being incorporated in guidelines such NCCN. Also in the metastatic disease setting we are learning more and more about left vs right-sided tumors and the difference in prognosis and we are getting a better understanding of the biological differences in left versus right tumors. And these are important because there has been the identification of different prognostic factors， as well as ability to respond to therapy. And this is going to need more work， but we hope in clinical trials now that people will take into account these biological differences and identify people who perhaps need a totally differently approach for therapy. There is also work looking at patients with HER2 expression， that is again a small percentage of people with metastatic disease， but it is important to do this work to understand if patients will benefit from therapies such as trastuzumab. In addition there has been some recent work for the BRAF population， patients who have BRAF mutations， that is about 8-10% of metastatic patients and they have a poor prognosis， they need a different strategy and combination therapies including the integration of therapies to target BRAF are showing some promise. So we are making some headway and we are hopeful with the growing database and molecular classification of patients that will make more in route.
The General Assembly on advanced colorectal cancer adjuvant treatment of the latest research progress? What is the future direction of research?
Prof. Benson: I think the most important trial in colorectal cancer that was presented at ASCO this year， was at the Plenary Session looking to determine if 3 months of adjuvant oxaliplatin + fluorouracil XX perimeter in therapy was non-inferior to the standard of care which is 6 months of adjuvant therapy. And unfortunately there results are not a clear-cut. The overall study did not prove non-inferiority， so some people argue that 6 months of therapy is still the standard of care. But there are maybe subsets of patients， so for example we heard about some of the subset analysis， so there a lower risk patients who may do equally well with 3 months versus 6 months. And of course what this study showed is predicted that there are far less neurotoxicity for patients who get 3 months versus 6 months. For the higher risk patients， it does seem that 6 months of therapy must still be given. So these results are mixed， I think somewhat disappointing but I think as the data from this presentation matures and certainly as we develop a survivorship data we may have more guidance as to which patients may actually be fine with 3 months of adjuvant therapy. So there is more work to do and this was a study of great interest. But I am afraid a little bit disappointing. And at this meeting in GI in general there has been so much looking at immunotherapy both in terms of single agent and combination treatments， as well as more information trying to expand our databases in terms of molecular characterization. So I think the field of GI oncology is increasingly exciting. We have been able to identify newer strategies which we hope on the long run will improve our selection of patients for treatment and certainly result in better outcomes.
Prof.Al Bowen Benso:筛选适用于结肠癌辅助治疗的患者关键问题之一就是确定具有高复发风险的结肠癌患者。临床上有许多II期结肠癌患者能够通过手术切除达到治愈，而具有较高复发风险的患者则不然，因此如何筛选出这类患者是一大挑战。目前，我们倾向于推荐T4N0患者接受辅助治疗，但是这种推荐是否合理仍然存在争议，我们还需要明确患者的分子特征以确定结肠癌患者，特别是II期结肠癌患者能否从手术后额外治疗中获益。目前普遍认为II期MSI阳性结肠癌患者的预后较好，因此这类患者不建议给予辅助治疗。而对于III期MSI阳性患者是否需要辅助治疗尚无定论，还有待探索研究。实际上有一项正在进行中的临床试验旨在评估免疫治疗作为MSI阳性患者辅助治疗的疗效。直肠癌辅助治疗领域存在的争议更多，因为临床医生倾向于推断结肠癌，特别是III期结肠癌患者的数据，并将之应用于可能并不适用的直肠癌患者。目前我们缺乏临床数据来定义直肠癌的最佳治疗策略，并且直肠癌的治疗也正在不断发展当中，例如，有试验正在评估针对直肠癌患者，手术前进行化疗或放化疗能够避免给予患者辅助治疗。对于新辅助治疗后达到疾病完全缓解的患者，可能并不需要辅助治疗。甚至有些接受新辅助放化疗的患者根本不需要进行手术治疗，当然也就没有必要再进行下一步的化疗。总而言之，对于结直肠癌的辅助治疗，我们还有许多有待解决的问题。将来希望能够通过更多地了解肿瘤分子生物学和患者亚型，优化结直肠癌的辅助治疗。此外，结直肠癌辅助治疗药物仍然没有超越奥沙利铂和氟尿嘧啶类药物的范畴。除了免疫治疗对于MSI型患者有潜在疗效之外，我们还没有发现新的药物，这也是一个很大的挑战。相信随着时间的推移，我们有希望开发出能够改善患者预后的新治疗药物。
Prof.Al Bowen Benso:今年ASCO提交的结直肠癌领域中最重要的研究是在全体大会上报告的IDEA研究，旨在评估3个月奥沙利铂+氟尿嘧啶类药物的疗效是否非劣效于6个月标准辅助治疗。令人遗憾的是，该研究的结果并不明确。整体研究并没有证明非劣性，因此有人认为6个月治疗仍然是标准治疗方案。但是对患者进行亚组分析显示，在风险较低的结肠癌患者中，3个月和6个月方案在无疾病进展生存方面可能一致。这项研究还显示，相比于6个月方案，接受3个月辅助治疗的患者神经毒性明显降低。而对于较高风险结肠癌患者，似乎仍然需要6个月标准辅助治疗。因此这些结果是存在争议性的，但是我认为随着该研究数据的不断成熟，我们可能能够从生存数据中获得指南以确定3个月辅助治疗的获益人群。这将是一个很有意思的研究领域，还有待更多探索。在本次会议的胃肠肿瘤领域，免疫治疗单一或联合应用一直备受关注，且有越来越多的研究企图在结直肠癌分子表征方面取得突破。因此，我认为胃肠肿瘤学领域的进展越来越激动人心，我们已经能够确定更新的策略以优化患者的治疗，并改善患者的预后。
Prof.Al Bowen Benso:我们在结直肠癌的分子分型方面正在取得一些进展，例如MSI型患者的免疫治疗有了非常令人兴奋的发展。有研究正在探讨免疫治疗作为MSI阳性结直肠患者辅助治疗的治疗策略，特别是对于III期患者。尽管 MSI阳性的发生率在转移性结直肠癌患者中的概率很低，但仍有数据支持针对这些患者使用免疫治疗，而且正在进行这方面的临床试验。此外，NCCN指南还推荐IV期MSI患者使用免疫治疗。另外在转移性疾病中，我们越来越多地了解左侧和右侧结肠癌的生物学以及预后差异，这些发现具有重要的意义，因为已经有研究明确了左右侧结肠癌不同的预后因素以及对治疗的反应差异。我希望今后的临床试验能够考虑到这些生物学差异，并筛选适用于不同治疗方案的人群。转移性结直肠癌患者中有一部分存在HER2过表达，有研究正在评估这类患者能否从西妥昔单抗治疗中获益。此外，约8-10％的转移性患者表现为BRAF突变，预后很差，他们需要不同的治疗策略，例如联合BRAF靶向药物具有一定的前景。将来随着越来越多的数据库和分子亚型的建立，这方面的进展值得期待