Oncology Frontier: Can you tell us about under-represented populations， including non-clear cell carcinoma， as you discussed in your presentation?

　　《肿瘤瞭望》：请您谈谈非透明细胞型癌患者的临床治疗和研究现状，以及未来的研究方向？

　　Dr. Osanto: In general， the pivotal clinical trials that have been done in kidney cancer patients have all included patients with clear cell carcinoma， which is the most prevalent type of kidney cancer (75% of patients). In principle then， we have no firm data if the current drugs that are available and that were designed typically for clear cell carcinoma based on the VHL mutation that is very prominent and important in clear cell carcinoma， have efficacy in the non-clear cell histologies. There are more data becoming available at this moment from very small trials or anecdotes of specific patients with other histologies， and it seems that the same drugs that we are using in classical clear cell carcinoma are also effective， but less effective. In general， patients have fewer good outcomes compared to the larger group of clear cell carcinoma patients.

　　We need a lot of data. What we are seeing is that these studies are being done and most of the patients have papillary renal cell carcinoma which have BAP-1 and BAP-2. We also need data on the biology of the tumors so I think it is important to have preclinical studies on the tissues of these patients but up till now， it has not been helpful because we do not have that many drugs that target the completely different proteins that may be relevant in these types of histologies.

　　It is something we really have to do on the basis of collaboration internationally because of the rarity of patients with these histologies. We need to do these studies globally with many more doctors and maybe centralize the patients to be able to make progress for patients with these more rare histologies. There is a lot of work to do and it will take many years. It may be that we have to use completely different agents but at the moment， we do not have the knowledge to say a protein is extremely important and designing drugs to act on that protein will make a difference in the future.

　　Suzanne Osanto教授：通常情况下，肾癌相关的关键临床试验都是在透明细胞型肾癌患者中进行，因为75％的肾癌患者为透明细胞癌。原则上，我们并没有足够的数据支持目前的药物哪些可用，以及基于VHL基因突变研发的透明细胞癌药物对非透明细胞癌患者是否有效。从小样本的临床试验或其他特定组织类型患者来看，某些在经典的透明细胞癌治疗中有效的药物，在非透明细胞癌患者中也是有效的，但相比之下疗效差一些；相比于绝大多数透明细胞癌患者，非透明细胞癌中预后好的患者较少。

　　我们迫切地需要大量的临床试验数据。目前正在进行的关于非透明细胞型肾癌患者的研究中，大部分的患者为乳头状肾细胞癌，嫌色细胞型肾细胞癌和未分类癌较少。此外，开展临床前研究，以分析非透明细胞型肾癌的肿瘤生物学特性也是非常重要的，尽管到目前为止，组织分型还没有真正发挥作用，因为我们没有那么多靶向不同蛋白（与组织分型相关）的药物。

　　由于拥有这些组织学类型的肾癌患者非常少，所以我们需要加强国际多中心合作，将这些研究全球化，让更多的医生参与，集中更多的罕见组织学类型患者，以寻求非透明细胞型肾癌在治疗上的突破。未来，有很多工作要做，而且可能需要为之奋斗多年。这可能是因为我们必须使用完全不同的药物，但在此刻，我们没有足够的数据认为某种蛋白是非常重要的，设计药物作用于该蛋白将在未来具有非常重要的意义。

　　Oncology Frontier: You were also discussing treating special populations in your sessions. Could you talk about that?

　　《肿瘤瞭望》：请您分享一下特殊人群，如寡转移性肾癌患者的临床治疗经验？

　　Dr. Osanto:One of the topics that came up was patients with oligometastatic disease (i.e. patients with relatively few metastases) and that these metastases can occur in various parts of the body. For instance， we were discussing brain metastases. In general， in any form of cancer， brain metastases usually have a poor outcome. It is difficult to treat them with systemic agents as they do not reach high enough concentrations in the brain， so it is not an easy task.

　　But we do have to make a distinction between patients who have from one to five smaller lesions and the ones with multiple brain metastases. The patient with a limited number of brain metastases can have more complaints compared to someone with multiples because usually the effects of the tumor are not dependent on size itself but from the edema around it. That needs to be taken into consideration.

　　What is very important is if the patient is stable and in good condition， then local treatments like stereotactic radiotherapy can be a great option to attack the brain lesions and then continuing with systemic therapy as long as the other metastases in other parts of the body were responsive to some degree. A patient who presents with multiple lesions in the brain is a much more difficult scenario; the outcome will be poor anyway. The only option at that time will be whole brain irradiation with its side effects and because you have to spare the normal brain tissue， probably not being able to control all of the metastatic sites. To give up with patients with brain metastases at multiple sites is not my recommendation though. I would individualize therapy and see if there are other modalities or even surgery if it is a larger metastasis followed by local radiotherapy.

　　Something that came up in our discussion was if you really wanted to continue systemic treatment， can you irradiate safely concurrently? The answer is we really don’t know for the brain. The half-life of TKIs is one or more day depending on the drug so you can still stop therapy and restart therapy prior to and after irradiation. I would stop 3 days before and restart 3 days after irradiation， for instance.

　　Surgery is more difficult and requires a longer withholding period. There are also patients with oligometastatic disease that may have metastases in the pancreas， for instance. Where there are metastases， you usually start with systemic treatment， but you have to consider at any point in time where the surgical removal of specific lesions could be of benefit to the patient. Another category of patients is those with a large primary tumor and a thrombus in the vena cava. That is a very difficult scenario. If the patient has multiple metastases， I think it is logical to start with systemic treatment if it is just the primary tumor and the vena cava thrombus and the urologists and surgeons are dubious about whether or not that will be able to remove the large renal tumor safely with good resection margins.

　　Suzanne Osanto教授：寡转移是指患者具有相对较少的转移灶，而且这些转移可以发生在身体的各个部位，如脑转移。对于任何类型的癌症，脑转移通常都具有较差的预后，因为血脑屏障的存在，药物在颅内难以达到足够高的浓度。但我们还是应该将转移灶较少者（1～5个）与多发性脑转移瘤患者进行区分。脑转移数量少的患者相比于转移数量多的患者甚至可能有更多的主诉，因为肿瘤的对患者的影响通常不依赖于其本身大小，而是取决于肿瘤周围的水肿情况。这是需要提醒大家注意的一点。

　　对于脑转移灶较少的患者，如果病情稳定且一般状态良好，可以选择立体定向放射治疗，随后进行全身治疗。而多发性脑转移瘤患者，情况要复杂一些，可选择全脑放射治疗。但由于全脑照射的副作用大，在兼顾正常脑组织的同时，可能导致部分转移灶不能得到有效的控制，因而预后很差。我不建议放弃多发性脑转移患者，可以考虑个性化治疗，看看是否有其他的治疗方式，如果转移灶较大，甚至可以考虑手术治疗，而后再进行局部放疗。

　　全身治疗同步放疗可行吗？在本届论坛上，我们也讨论了这一问题，但答案是真的不知道大脑是否可以。酪氨酸激酶抑制剂（TKI）的半衰期≥1天，可以在照射之前停止治疗，照射治疗后重新开始TKI治疗。例如，我会在照射前停止3天，然后在照射后3天再重新开始全身治疗。

　　手术治疗是比较困难的，并且需要较长的停药期。如胰腺转移的寡转移患者，通常先进行全身治疗，但治疗中需要观察并及时考虑手术切除某些病灶是否能使患者获益。另一类是那些具有大的原发肿瘤和腔静脉血栓的患者。如果患者有多处转移灶，我认为首先进行全身治疗是合乎逻辑的，如果它仅仅是原发肿瘤和腔静脉血栓，手术切除肾巨大肿瘤并且获得良好切缘也是可能的。