Oncology Frontier: As we learned from the NSABP-CO8 study， there is no significant effect on disease-free survival (DFS) or overall survival (OS) when bevacizumab is combined with FOLFOX6 group compared with FOLFOX6 alone group， in stage II or stage III colorectal patients. However， a post hoc analysis of the NSABP-CO8 population by mismatch repair status suggested a benefit from bevacizumab in the mismatch deficient cohort. Could you tell us how do we choose for a stage II/III colorectal patient with defective DNA mismatch repair (dMMR)?

　　《肿瘤瞭望》：从NSABP-CO8研究，我们得知，贝伐珠单抗联合FOLFOX6 与单用FOLFOX6相比在II/III期结直肠癌患者中不能带来DFS和OS的显著性差异。然而，通过对错配修复状态的亚组分析发现错配修复低的患者可以从联合贝伐珠单抗组中获益。那么对于一个存在肿瘤低度错配修复状态的II/III期的结直肠癌患者，您会选择怎么样的治疗方式？

　　Dr Fakih: We know that patients with stage II and stage III disease can have mismatch repair deficiency. Those patients will usually have microsatellite instability (MSI)， more commonly in stage II disease than stage III disease. About 15-20% of patients with stage II disease will have microsatellite instability while around 10-15% of patients with stage III disease will have microsatellite instability. Historically and as shown in several studies， we know that fluoropyrimidine， either as 5-FU alone or with capecitabine， does not result in any benefit in stage II disease in patients with microsatellite instability. Those patients have an excellent prognosis and they are followed-up with observation and the risk of relapse is very low. In fact， there are some suggestions that chemotherapy with fluoropyrimidine alone in stage II disease with microsatellite instability may be harmful. The question is more regarding stage III disease. Those patients have a better prognosis than those without microsatellite instability with what we call a microsatellite stable tumor. We know from the NSABP study and the MOSAIC clinical trial that these patients do well with chemotherapy. The MOSAIC trial found there is benefit to adding oxaliplatin plus fluoropyrimidine as a FOLFOX backbone in stage III colorectal cancer with MSI is helpful in preventing a relapse. What the NSABP study has shown further by a post hoc analysis of subgroups is that patients with microsatellite instability who received FOLFOX plus bevacizumab did better than those given FOLFOX. That is an important finding but we have to remember that this was found in an analysis after the fact and not part of the trial. So， at best， it is a hypothesis-generating result. I don’t think at this point， that it will impact standard of care for patients with microsatellite instability in stage III disease. At this point， for patients with stage III disease with microsatellite instability， we still recommend those patients receive FOLFOX chemotherapy or oxaliplatin/fluoropyrimidine as standard of care in adjuvant treatment.

　　Dr Fakih：我们知道，II期和III期疾病患者可能出现低度错配修复。这些患者通常会有微卫星不稳定性（MSI），这在Ⅱ期疾病中比Ⅲ期疾病中更常出现。Ⅱ期疾病患者中约15-20%出现微卫星不稳定性，而这在III期疾病患者中出现的比率约为10-15%。既往几项研究显示，氟嘧啶类，无论是5-FU单药还是5-FU联合卡培他滨，均未给存在微卫星不稳定性的II期疾病患者带来获益。这些患者的预后良好，对这些患者进行观察随访发现其复发风险非常低。事实上，有些研究表明，单独使用氟嘧啶类化疗对于存在微卫星不稳定性的II期疾病患者是有危害的。因而这一提问更多是关于III期疾病。相比那些没有微卫星不稳定性的患者，也就是我们称之为带有“微卫星稳定肿瘤”的患者而言，存在微卫星不稳定性的III期疾病患者的预后较好。从NSABP研究和MOSAIC临床试验中我们得知，这些患者对化疗反应好。MOSAIC试验发现增加奥沙利铂联合氟嘧啶类作为FOLFOX基础用药能带来获益，对于预防带有MSI的III期结直肠癌的复发有帮助。NSABP研究事后亚组分析显示，存在微卫星不稳定性的患者接受FOLFOX联合贝伐单抗治疗的效果优于只接受FOLFOX治疗的效果。这的确是一个重要的发现，然而我们也不要忘了，这是事后分析的结果，而不是在试验过程中的分析项目。所以，这至多是一个基于假设的结果。在这一点上，我认为它不会对存在微卫星不稳定性的III期疾病患者的诊疗标准产生影响。对于存在微卫星不稳定性的III期疾病患者，我们还是建议他们接受FOLFOX化疗或奥沙利铂/氟嘧啶类化疗，以之作为辅助治疗的标准治疗方案。

　　Oncology Frontier: Any hypothesis that could explain the favorable trends noted with bevacizumab in tumors with MSI would warrant further investigation. Could you tell us which hypothesis you personally support?

　　《肿瘤瞭望》：目前可以解释贝伐珠单抗使得MSI的肿瘤患者获益的假说需要进一步研究，您能告诉我们您个人支持哪些假说吗？

　　Dr Fakih: It is not very clear why patients with MSI may benefit from bevacizumab. There is another study called the Quick and Simple and Reliable 2 study (QUASAR2) which looks at capecitabine versus capecitabine plus bevacizumab. An interesting finding of that study is that bevacizumab resulted in harm when added to capecitabine in patients with stage II or III colorectal cancer who did not have microsatellite instability. Clearly we will not be using bevacizumab in those cases but why it increases the risk of relapse in the QUASAR2 trial is really not very clear. But there are theories as to why patients with microsatellite instability do better with bevacizumab. We know that VEGF-A， which is inhibited by bevacizumab， may have an immunosuppressive function. We know that increased levels of VEGF-A may be associated withincreases in Tregs， which are immunosuppressive T-cells. They may also help to reduce the activity of dendritic cells in the tumor. So， in a way， VEGF-A may be an immunosuppressive factor. We know that microsatellite instability tumors are highly mutated tumors which are associated with a high involvement of T-lymphocytes， which improves the outcomes of patients with these types of tumors. If you suppress these lymphocytes that are already pre-existing in tumors with microsatellite instability with higher levels of VEGF-A， there will be a reduced immune response to the tumor. So it is very possible that what bevacizumab is doing is giving an extra immune boost to the system by suppressing VEGF-A within the tumor so that the tumor is exposed to an even better immune response than the pre-existing response and therefore reducing the risk of relapse. The QUASAR2 study did give some signs of improvements in survival for capecitabine plus bevacizumab versus capecitabine alone in that study， but without reaching statistical significance. However， it does parallel what we have seen in the NASBP trial.

　　Dr Fakih：目前，有关MSI的患者可从贝伐珠单抗治疗中获益的原因尚不清楚。另外有一项研究叫做“Quick and Simple and Reliable 2研究”（QUASAR2），该研究比较卡培他滨与卡培他滨联合贝伐珠单抗。这项研究的一个有趣的发现是，对于不存在微卫星不稳定性的II期或III结直肠癌患者，在卡培他滨治疗中加入贝伐珠单抗会带来危害。显然，对这些病例我们不会去使用贝伐珠单抗，但在QUASAR2试验中贝伐珠单抗为何会增加复发风险目前尚不清楚。但是，有一些理论可用来解释为何存在微卫星不稳定性的患者对贝伐珠单抗治疗的获益更高。我们知道，贝伐珠单抗可抑制VEGF-A，而后者可能具有免疫抑制功能。VEGF-A水平的上调可能使得Tregs，即免疫抑制性T细胞增加。它们也可有助于降低树突状细胞在肿瘤中的活性。所以在某种程度上，VEGF-A可能是一种免疫抑制因子。我们知道，微卫星不稳定性的肿瘤具有高度突变性，这与T淋巴细胞的高度参与有关，T淋巴细胞可改善此类型肿瘤患者的治疗效果。这些预先存在于VEGF-A高水平的微卫星不稳定性肿瘤中的淋巴细胞如果受到抑制，对肿瘤的免疫反应则会降低。因此，很有可能是，贝伐珠单抗通过抑制肿瘤中的VEGF-A，使机体免疫进一步加强，从而使肿瘤处于更强的免疫反应下，相比原有的免疫反应而言，降低了复发风险。QUASAR2研究确实显示出卡培他滨联合贝伐珠单抗相比卡培他滨单药能改善生存的迹象，但差异不具有统计学意义。但是，其结果确实与我们在NASBP试验中观察到的结果是平行的。

　　Oncology Frontier: Patients with metastatic CRC can benefit from anti-EGFR therapy both in front-line chemotherapy and in downstaging in potentially resectable disease， but patients with CRC in stage II/III respond differently with cetuximab. What do you think is the reason for this disconnect in benefits from anti-EGFR therapy between adjuvant and metastatic disease studies?

　　《肿瘤瞭望》：正如我们所知，转移性结直肠癌患者从抗EGFR治疗中，无论是在一线化疗还是潜在可切除病灶的降期中，均可获益。但II/III期结直肠癌患者却不能受益于西妥昔单抗的辅助治疗，您觉得抗EGFR治疗在辅助治疗和转移性疾病治疗中作用不一致的原因是什么？

　　Dr Fakih: It is very clear that adding anti-EGFR therapy such as cetuximab to chemotherapy as first-line treatment for metastatic colorectal cancer improves the response rate， improves progression-free survival and improves overall survival. However， we also know， based on two randomized clinical trials in the stage III setting， that adding cetuximab to FOLFOX chemotherapy did not improve response rate. So there is indeed a contradiction of the impact of cetuximab per se on outcomes between metastatic colorectal cancer and patients with stage III disease. There are different theories as to why that occurs， but there is really no firm conclusion. One possibility is that while cetuximab increases the response rate， it may not improve the complete pathological response. If we look at studies where cetuximab is added to FOLFIRI or where anti-EGFR therapy is added to FOLFOX， while that improves the response rate， the incidence of complete pathological response is still very low. We may not be able to completely eradicate the disease by adding anti-EGFR therapy to chemotherapy. It is also important to know that the tumors are very heterogeneous. It is possible that anti-EGFR therapy may be effective in differentiating out certain clones of disease that are less important in recurrence but important enough in patients with metastatic disease to induce a response and improve the overall outcomes. We are seeing this over and over again where something that works in the metastatic setting does not always work in the adjuvant setting. This has been the case in other agents， such as irinotecan. Adding irinotecan， a cytotoxic chemotherapy， to 5-FU improves response rate， overall survival and progression-free survival in stage IV disease， but does nothing for stage III disease. That probably has to do with eradication of micrometastatic disease.

　　Dr Fakih：毋庸置疑的一点是，在转移性结直肠癌的化疗中加入抗EGFR治疗（如西妥昔单抗）作为一线治疗，可提高缓解率、无进展生存期和总生存期。但是， 我们也从研究III期治疗方案的两项随机临床试验的结果得知 ，向FOLFOX化疗中加入西妥昔单抗并没有提高缓解率。因此，西妥昔单抗对转移性结直肠癌患者和对III期疾病患者的疗效之间确实存在矛盾。对此存在一些不同的理论来解释，但目前尚无定论。一种可能是，西妥昔单抗提高缓解率的同时并不提高病理学完全缓解率。我们从那些向FOLFIRI治疗中加入西妥昔单抗或抗EGFR治疗的研究中可以看到，虽然缓解率得到了提高，但是病理学完全缓解率依旧很低。我们可能无法通过在化疗中添加抗EGFR治疗来完全根除此疾病。同样重要的是要知道，肿瘤是十分异质性的。有可能抗EGFR治疗可以鉴别出疾病的某些克隆，这可能对防止疾病复发的作用不是很大，但足以促进转移性疾病患者对治疗起反应并改善其总体治疗结果。我们总能看到有些药物在转移性疾病治疗中有效而在辅助治疗中却不总是有效。这种情况在其他药物中也遇到过，如伊立替康。向5-FU治疗中加入细胞毒性化疗药物伊立替康，可提高IV期疾病患者的缓解率、总生存期和无进展生存期，但对于III期疾病患者却没有作用。这可能是由于消灭了微转移病灶的缘故。