Oncology Frontier:Could you please talk about the dose and fractionation of radiotherapy in locally advanced non-small cell lung cancer？

　　《肿瘤瞭望》：可以请您介绍一些局部晚期非小细胞肺癌（NSCLC）的放疗剂量及分割方式吗？

　　Dr. Dirk：Certainly. We should distinguish the different situations in sequential chemotherapy & radiotherapy and concurrent chemotherapy & radiotherapy. In sequential chemotherapy and radiotherapy， you first give three or four cycles of chemotherapy， followed by radiotherapy. As effective as local treatment， it has been shown in individual patient-based meta-analysis that overall survival is better at five years when you level the radiation at an accelerated way. That is why we decided that the ESMO guidelines also put forward this type of radiotherapy. The meta-analysis was done with bifractionated or trifractionated radiation schedules， whereas at the moment， we adhere to the RTC（randomized controlled trial）schedule， which is something like 66gy in 24 daily fractions followed by a very high dose， from a biological point of view， 66gy in a short of arm treatment time. We have a phase three trial from the RTC（randomized controlled trial）and a phase two trial by the RTC（randomized controlled trial） which shows that the toxicity of this schedule is very feasible. So， in the sequential schedule it’s really best to first give chemotherapy， then follow with accelerated radiation. On the other hand， if you give concurrent chemo-radiation， we don’t have an argument to give accelerated radial therapy at this time. Then we have the American IMRT study， which was just published， that shows no survival benefit in giving 74Gy in the conventional 2 Gy a day， five times a week fractionation， compared 60Gy in the same fractionation but given concurrently with chemotherapy. On the contrary， the 74 Gy arm had a lower survival rate. Now， the issue as to why this is has not been settled yet. It might be due to an excess of heart toxicity—this is a hypothesis and there are arguments for it—but it may also be due to other unknown factors. What is also strange is that， numerically， there were more local failures in the high dose， 74 Gy arm， than in the 60 Gy arm， which is difficult to understand. So， I think the question as to why the 74 Gy arm had the worse survival rate is still out there. But， the RTOT should be congratulated for doing this type of phase 3 trial as it’s also true that at the moment we don’t have any arguments， or clinical trials， to give 74Gy. Of course， there is a lot of interest to do other kinds of dose escalations instead of adding 2 Gy fractions a day.

　　Dirk教授：当然可以，这要分时序贯放化疗还是同步放化疗的情况。在序贯放化疗中，首先给予3-4周期的化疗，后给予放疗。与其它局部治疗一样，一项meta分析（基于个体患者的数据）显示序贯放化疗较同等水平的超分割放疗有较好的5年生存率。基于这项结果，ESMO的指南中也提出了这种治疗方式。该meta分析中放疗分割方式分为每天照射两次或三次，该分析纳入的RTC（随机对照临床试验）中放疗剂量大部分为66Gy/24次，从肿瘤生物学的角度来讲，如此短的时间内给予66Gy属于较大的剂量，同时该meta分析中也有Ⅲ期及Ⅱ期随机对照临床试验同时显示该放疗剂量引起的毒副作用是可耐受的。所以，在序贯放化疗中，首先给予化疗，接着给予加速超分割放疗是最好的治疗方法。若为同步放化疗中，放疗采用加速超分割方式是无争议的。刚刚发布的来源于美国的研究结果显示常规分割放疗（74Gy，1次/d，5次/周）与同步放化疗（60Gy，1次/d，5次/周）相比并未显示能够带来生存的优势。与此相反，74Gy组还显示了较低的生存率。对这一结果，现在仍无定论，可能是由于较高的放射性心脏损伤导致的，这一个假设尚待进一步研究，也可能是由于其他未知因素引起的。此外，在数据的结果上也令人难以理解，放疗剂量74Gy组较60Gy组却显示了较高的局部失败率。但是，话说回来，RTOG应该庆幸这项Ⅲ期临床试验的结果，也就不会再有争论及临床试验会采用74Gy的放疗剂量。当然，与常规的2Gy/d的放疗相比放疗剂量爬坡试验也是一个有趣的研究方向。

　　Oncology Frontier: Do you recommend 74 Gy dose for the treatment of patients with unresectable stage III NSCLC？Could you please introduce the optimal dose and area of thoracic radiotherapy （TRT）for small cell lung cancer (SCLC)？

　　《肿瘤瞭望》：您是否推荐74Gy放疗剂量用于不可切除Ⅲ期NSCLC的患者？能否请您介绍一下小细胞肺癌（SCLC）的最佳放疗剂量和胸部放疗（TRT）的面积？

　　Dr. Dirk：Yes， for small cell lung cancer we should distinguish the so-called limited stage versus the extensive stage. The limited stage is stage 1， 2， and 3， and stage 4 is the extensive stage. Most patients， of course， have stage 3 disease. We had shown at the Amsterdam World Cancer Congress that， based on randomized studies， and meta-analysis based on individual patient data， when you deliver the radiation in a very short overall treatment time， and deliver it very quickly， then you have a better overall survival rate at five years. At the moment， the standard treatment is 45gy in 3 weeks， twice daily radiation with 1.5gy， and the absolute difference in 5 year survival rate is 10%， based on published data， and 8%， based on individual patient data analysis (8%). Of course， the price to be paid is that you have more acute esophagitis， but it’s temporary and heals a few weeks after the end of radiation. Since there is no increase of late side effects，  accelerated radiation， combined with chemotherapy， is the first choice in treating limited stage small cell lung cancer.In extensive disease small cell lung cancer， there is an RTC trial that shows that survival increases by adding thoracic radiation， wherein patients receive 30gy in 10 daily fractions.

　　Dirk教授：可以，对于小细胞肺癌，我们应该区分所谓的局限期与广泛期。局限期包括1，2，3期，4期属于广泛期，当然了，多数患者，处于第3期。我们在阿姆斯特丹世界癌症大会已经报道了随机研究和meta分析（基于个体患者的数据）的结果，加速超分割方式显示了较好的5年生存率。这样，标准方案给予加速超分割（45 Gy，1.5Gy/次，1天2次）使得并以5年绝对生存率提高10％，基于公布的数据及meta分析（基于个体患者的数据）结果都显示生存率提高8％.当然，所要付出的代价是，会有较高的急性放射性食管炎，但它只是暂时的，在放疗结束后的几个星期后可以治愈。由于没有增加晚期放疗损伤，加速超分割联合化疗，为治疗限期小细胞肺癌的首选。对于广泛期小细胞肺癌，有一项随机对照临床试验显示，30Gy/10次的胸部放疗可以使生存率提高。

　　Oncology Frontier: What is the optimal timing of thoracic radiotherapy in patients receiving chemotherapy for limited stage SCLC？

　　Dirk教授：什么时间是局限期小细胞肺癌化疗期间接受胸部放疗的最佳时机？

　　Dr. Dirk：Well， here we also have stage 3 data from meta-analysis showing that if you deliver the thoracic radiation within 60 days after the beginning of chemotherapy， then survival in the long run is better. While the results of the Korean trial where they administered thoracic radiation in the third cycle is still unknown， it is true that you should give the radiation in the first or second cycle， probably within 60 days. I would like to stress that the chemo component is crucial， so give early accelerated radiation with cisplatin and etoposide at full dose. Then， you will have the best survival rate in the long run， so five years， in stage 3 lung cancer.

　　Dirk教授：来源于meta分析的结果显示，化疗结束后60天内行放疗可以提高长期生存率。来自于韩国的研究表明在化疗的第三个周期给予放疗，但随访的结果尚未可知。在化疗的第一或第二周期给予放疗或在化疗开始的60天内给予放疗是可行的。我想强调的是化疗是非常重要的，所以在早期给予加速超分割与标准剂量的顺铂和依托泊苷联合治疗，可以有较好的长期生存率，3期的肺癌也有较好的5年生存率。

　　Oncology Frontier: There is a controversy surrounding the prophylactic cranial irradiation (PCI) for preventing brain metastases in patients with SCLC， how do you evaluate the benefit and treatment-related toxicities http://www.tlcr.org/article/view/578/1157of PCI？

　　《肿瘤瞭望》：对于小细胞肺癌脑预防照射（PCI）存在争议，您如何看待这种治疗方法给患者带来的获益及毒副作用？

　　Dr. Dirk：Again， we should distinguish between the limited stage and the extensive stage disease small cell lung cancer. In the limited stage， we have an old meta-analysis which shows that PCI improves long term survival.There is also one RTC study that shows the same positive effect on survival by adding PCI in patients with extensive disease small cell lung cancer.Now， I am aware that there was recently an abstract of a Japanese study group that shows that PCI had detrimental effects on survival， but we don’t know the full contents of the paper as the abstract was for the preliminary results.

　　It could be due to a selection bias of the patients， because in no other study， neither in small cell lung cancer， nor in non-small cell lung cancer， has it been shown that PCI has a detrimental effect on survival.At this time， in non-small cell lung cancer， we don’t have arguments that it improves survival， although it decreases the incidences of brain metastasis， but it was never a detrimental effect. So， I would just wait for the full paper， and then we can analyze in detail why there was a detrimental effect. But at this point I would say that PCI is still the gold standard.We have to wait until we have the long term results and the full published result of the Japanese paper to claim otherwise. Having said that， we know that PCI may lead to neuro-cognitive decline， but first of all， this is not in all patients—it’s in about 1/4th of the patients. You do not see dementia， but you see a decrease in learning capacity， which is the same bolt in magnitude and duration as with adjuvant chemotherapy in breast cancer patients. So we know that chemotherapy has about the same effects on the neuro-cognition as PCI. So in order to find out how to decrease the incidence of neuro-cognition， we， together with Jose Belderbos from the Netherlands Cancer Institute， are running a randomized phase 3 trial in Belgium and the Netherlands， where one group of patients receive regular PCI and the other group receives PCI with sparing of the hippocampus， the two nuclei in the brain which presumably are the most important parts for the neuro-cognitive function and for the learning capacity. We will see what the results will be within a few years.

　　Dirk教授：再次，我们还是要区分局限期还是广泛期小细胞肺癌，有一项旧的meta分析结果显示于脑预防照射能够提高患者的长期生存率。对于广泛期小细胞肺癌，也有一项RTC结果显示PCI可以使患者获益。现在，来源于日本的一项研究的摘要显示PCI对患者的生存产生不利影响，但是仅仅只有摘要的初步结果，该研究的全部内容尚不得知。这可能是由于入组患者的选择偏差造成的，因为无任何报道或研究，无论是在小细胞肺癌中还是在非小细胞肺癌中，显示PCI对患者的生存产生不利影响。在非小细胞肺癌，PCI可以降低脑转移的发生率，尽管对生存率的提高尚无定论，但未见其对生存产生不利影响的报道。所以，我们只想等待全文的报道，就可以对这一结果进行详细的分析。但此时，我认为PCI仍然是黄金标准。我们必须等待长期的随访结果及日本研究的更新报道。话虽如此，我们也知道PCI可能导致神经认知功能的下降，但重要的是，不是所有的患者都会出现，只有约1/4的患者可能导致神经认知功能下降。可能不会像痴呆那么严重，但会有学习能力的下降，这与乳腺癌患者化疗后导致的认知功能障碍现象相似。因此，关于PCI对神经认知功能的损害与化疗的影响相似。因此，为了了解如何降低对神经认知功能的损害，我们与来自荷兰癌症研究的Belderbos在比利时及荷兰发起了一项Ⅲ期随机对照临床试验。该研究中，一组患者接受常规的PCI，另一组接受PCI但给予海马区保护，海马区大概是对神经认知功能及学习能力的最重要神经中枢。我们将会在几年之内看到该研究的结果。