Prof.Wang：As surgeons， we’ve been looking for evidence that locoregional treatment to optimal systemic treatment could improve overall survival in women who present with the novo stage IV breast cancer. However， we have only retrospective studies， with selection bias. This study（ECOG-ACRIN 2108）fills in this gap， it’s a randomized controlled prospective study. Could you please tell us the most important results and conclusion from this research？

 

王嘉教授：作为外科医生，我们一直在寻找从局部区域治疗（LRT）到最佳系统治疗以改善初治IV期乳腺癌患者总体生存的证据。然而，目前仅有回顾性研究且存在选择偏倚，随机、对照、前瞻性研究ECOG-ACRIN 2108填补了空白，请介绍一下该研究的结果和结论?

 

Dr Kahn: The primary endpoint for the study was to assess whether or not the use of locoregional treatment for the intact primary tumor would improve survival in women with newly-diagnosed stage IV breast cancer. The main finding of our study was that among women who received locoregional treatment for the primary tumor， the survival experience was the same as women who did not. We randomized women after they had a period of initial systemic therapy. Those who didn’t progress during that time (their disease was at least somewhat responsive to the treatment they had received) were randomized to locoregional treatment or not. The group that received locoregional treatment survived exactly the same as the group that did not. I think that is the main finding from the study.

 

Kahn教授：该研究的主要终点是评估完整的原发肿瘤（IPT）的局部区域治疗是否会改善初治IV期乳腺癌患者的总生存期（OS）。研究发现，接受原发肿瘤局部区域治疗患者与未接受治疗患者的生存期相同。我们将接受了一段时间系统治疗后无进展或缓解的患者随机分配到LRT组和非LRT组，研究结果显示LRT组和非LRT组两组患者的生存期无显著差异。

 

Prof.Mao：Do you think that if we select cohorts with a partial response for systemic treatment rather than no progression of distant disease following 4-8 months of therapy， maybe we would get a positive result？

 

毛晓韵教授：相对于4-8个月治疗未进展的患者，若在该研究中选择系统治疗后部分缓解（PR）的人群，是否会得到阳性结果?

 

Dr Kahn: We did not distinguish between stable disease and responsive disease， but many women had responsive disease. As you know， the treatment for breast cancer now is associated with response rates in the 70-80% range， so，of the women who were randomized， the majority would have responsive disease. We did have a good proportion of women with HER2-positive disease as well， and HER2-positive disease responds very well to HER2-directed therapy， and these women did receive HER2-directed therapy. At the moment， we don’t have any suggestion that women who responded well to treatment did better with locoregional treatment than women who didn’t respond well. In our subset analyses， we found that women with HER2-positive disease also had no survival benefit from the use of locoregional treatment， and women with hormone receptor-positive disease similarly saw no survival benefit with the use of locoregional treatment. Among women with triple-negative breast cancer， we found that women who received continued systemic therapy who did not receive locoregional treatment seemed to better. But that was a very small number of women， so it is hard to draw any conclusions from that. But among women who generally demonstrate a response to locoregional treatment， whether HER2-positive or hormone receptor-positive， they did not experience and benefit from the locoregional treatment..

 

Kahn教授：在该研究中多数患者系统治疗后出现缓解，但我们并未对疾病稳定或缓解的患者进行区分。目前乳腺癌治疗的缓解率约70～80%，所以入组后参与随机分组的患者多数均为缓解患者。HER2阳性乳腺癌是乳腺癌亚组之一，对靶向抗HER2治疗反应率较高，所以需要抗HER2治疗。目前没有任何证据表明，全身系统治疗后缓解较未缓解患者LRT的反应率高。亚组分析显示，HER2阳性患者、激素受体阳性化安置均未从LRT中获得生存获益；三阴性乳腺癌患者中，接受持续全身治疗后未行LRT的患者可能获益更多，但因为数量较少，很难从中得出任何结论。

 

Prof.Wang： Comparing with the other two prospective studies MF 07-01 and TBCRC 013， The design of this study is more similar to TBCRC013. The screening effective patients (respone patients) for locoregional treatment after systemic treatment negative results were also obtained， while in MF07-01， when we do surgical treatment firstly， then followed by comprehensive treatment， obtained the result that surgical treatment could improve the prognosis. How do we understand this difference.

 

王嘉教授：与MF 07-01和TBCRC013两项前瞻性研究相比，本研究设计和TBCRC013研究更相似，在对患者全身性治疗后进行LRT得到了阴性结果。而MF07-01研究则先对患者进行手术治疗，再综合治疗，结果显示手术治疗可以改善患者预后。我们应如何理解其中的差异?

 

Dr Kahn: It’s a good question. The difference is actually hard to understand， because I think we would all agree that the reason women die with metastatic breast cancer is due to distant disease， not local disease. For the great majority of women， the cause of death is distant disease. In a patient whose distant disease is not responding， the idea that locoregional treatment would provide better benefit is contrary to the way we think about breast cancer biology today. It is a little counterintuitive that studies that use systemic therapy first don’t show a benefit， whereas the study that used locoregional treatment first shows a benefit. I don’t know that we are going to have that question answered for us， unless our Chinese colleagues decide to repeat MF 07-01.

 

If you decide to repeat the study that was done in Turkey and get similar results， that will tell us something new. But in the absence of another study replicating the results of the Turkish trial， I think we are left with a little bit of a quandary， because biologically， it is not rational that the use of locoregional treatment in women who may be non-responsive to treatment would provide a benefit. The problem with randomizing at the beginning when women have not received any systemic therapy， means we don’t know whether systemic therapy is responsive or not. The other thing to remember is that these are all relatively small trials. The way we overcome bias in randomized trials is with large numbers. Unfortunately， we had to cut back on the sample size we had originally planned to recruit 880 women， eventually recruiting 390. But the results are so null， that I think if we had actually enrolled 880 women， I doubt that would have made a difference. There is not even a hint of a benefit to suggest that a larger number would have resulted in statistically significant results. 

 

I think that contradiction between the Tata Memorial study， E2108 on the one side， and the Turkish Federation study on the other side， is a difference that is puzzling. I would challenge our colleagues in China to try to replicate that experience. Although， I have to say that there are questions that have been raised about the design of the Turkish study and the randomization between the two arms. If you remember， there was some imbalance between arms with women who received surgery having better prognostic features than women who didn’t receive surgery at the beginning. We need to break that tie. Our Japanese colleagues have a study that will mature in two years – JCOG1015. The Japanese trial will hopefully provide additional information. Their design is similar to the E2108 design. They are using systemic therapy first and randomizing responders. I think for most of us who looked at this problem and started thinking about designing trials， that seems to be the rational approach. 

 

The other study I would mention as a reminder (although it was very small) was the Austrian study. The Austrians have done the Posytive trial published two years ago. Although they had 40-45 women per arm， their design was similar to the Turkish study. They used surgery first， so their patients did not get an initial period of systemic therapy but were randomized at enrolment to locoregional treatment or systemic therapy. Although small， the trial also pointed in the same direction as the Indian study and E2108， not showing any benefit for the use of early surgery and radiation.

 

Kahn教授：临床实践中这种差异很难解释，众所周知，乳腺癌患者往往死于远处转移，而非局部病灶。对于远处转移未缓解的患者，LRT治疗会给患者带来更好疗效的想法是与我们对乳腺癌生物学的认知相悖的。全身治疗后采用LRT治疗的研究未显示获益，而LRT后再系统治疗却显示出了获益也与之前研究有所违背。所以这点很难解释，除非有中国学者重复MF 07-01研究并得到类似的结果，则可以说明一些问题。

 

ECOG-ACRIN 2108研究未能复制另一项研究的结果也令人困惑，因为从生物学上看，全身治疗后未缓解的患者使用局部治疗却能带来获益是不合理的。若在开始入组就随机的话也存在问题，即在不知道系统治疗是否有效时，就对患者进行了随机化。此外，对于相对规模较小的研究，我们克服偏差的方法是使用大量的数据，所以本研究原计划招募880名患者，但最终只招募到390名，结果显示LRT并未改善初治远处转移乳腺癌伴完整原发肿瘤患者的生存结局。所以我认为若能招募样到880名患者，可能结果会有所不同，但同时也没有迹象表明，更大的样本量会使统计学差异更显著。

 

ECOG-ACRIN 2108研究与MF 07-01研究的矛盾令人费解，可能是研究设计中两组间随机化存在一些问题。所以希望中国学者能尝试挑战复制这一研究，并且打破接受手术比未行手术的患者预后更好的束缚。现在，日本学者已经开启了一项类似于ECOG-ACRIN 2108的研究（JCOG1015），对系统治疗后有效的患者再随机分组治疗，设计更为合理，其结果将在两年内成熟，希望能为我们提供更多的信息。

 

此外，奥地利一项类似MF 07-01的规模相对较小的研究，每组40-45名患者，首先行手术治疗，虽然患者均未接受过初期的系统治疗，但在登记时被随机分配到局部治疗组或系统治疗组。该研究结果与ECOG-ACRIN 2108结果相同，没有显示出LRT的获益。

 

Prof.Mao：A randomized trial with incorporation of exciting correlative science ideas has big potential rewards for our patients. I think ECOG-ACRIN 2108 is just changed my assumptions. Actually I can accept the selection bias of surgery for patients. Can you give us some advices about to promote the quality of life for metastatic breast cancer? 

 

毛晓韵教授：ECOG-ACRIN 2108研究相关理论对患者有巨大的潜在回报，临床中我可以接受对手术患者的选择偏向。您能给我们一些提高转移性乳腺癌患者生活质量的建议吗?

 

Dr Kahn: How do we promote quality of life for women with metastatic breast cancer? There are many aspects to quality of life obviously， and we always have to balance the quality of life effects of the disease (and metastatic breast cancer is a highly symptomatic disease) against the treatment effects on quality of life. That is always the balance we have to try to reach. I think that to the extent that treatment controls metastatic disease， it improves quality of life related to the disease， so the toxicity of that treatment needs to be considered. Clearly， less toxic treatment will have a lesser impact on quality of life. I am not a medical oncologist. I have to make these decisions on a daily basis. I know that in China you also manage chemotherapy， although not in the metastatic therapy if I understand correctly. Chinese breast surgical oncologists manage chemotherapy for adjuvant settings. 

 

I think that is the challenge. Paying attention to the toxicity of treatment while achieving good responses and controlling the symptoms of metastatic breast cancer， specifically in terms of the effects of locoregional treatment on quality of life， should be the goal. The way we set up our quality of life analyses was to anticipate that local progression of the tumor would impair quality of life to some extent (and we know it does that in women with large tumors that fungating， or where there are skin nodules， or where there is pain). There are many aspects of local disease that can impair quality of life， but when applying local treatment (surgery and radiation)， that also has an impact on the quality of life. So ，in our trial， we were not focusing on palliative locoregional treatment. We were focusing on locoregional treatment that was delivered in the same way it is delivered to women who do not have metastatic disease. It was also delivered to women who had no symptoms from their tumors. In that setting， where the local tumor is not causing symptoms， it seems， at least on our initial analyses， that the symptoms related to treatment also have a significant impact.

 

In the asymptomatic patients， adding those symptoms related to treatment (the side effects of surgery and radiation) does have an impact on quality of life. The biggest impact we observed was at 18 months. We had expected that women would have recovered from their surgery and radiation by 18 months， so the immediate short-term impact of locoregional treatment would have resolved. What we saw was that the only time point where quality of life was different in the two arms in terms of the locoregional area was at 18 months.  So， we still have to explore that further and look at the details of the quality of life responses. I think these conclusions are somewhat tentative at the moment， because the number of women who completed the quality of life surveys was not ideal. There was a fall-off in the submission of quality of life surveys as the trial progressed. Fewer women completed the quality of life surveys towards the end than at the beginning. The firm conclusion that we can reach is that locoregional treatment does not improve quality of life， at least for locoregional symptoms， but whether there is a difference between arms is bit more questionable.

 

Khan 教授：提高生活质量包括很多方面，转移性乳腺癌症状较多，我们必须平衡疾病与治疗对生活质量的影响。就转移性疾病的治疗而言，在改善疾病相关生活质量影响时也要考虑治疗的毒性，低毒性治疗对患者生活质量的影响较小。即便我不是肿瘤学家，也仍需要每天做这些决定，而中国的乳腺外科医生则更精通化疗，除了转移性患者的治疗外，也会参与到辅助化疗中。

 

在控制好转移性乳腺癌的症状取得良好疗效的同时更要关注治疗相关的毒性，尤其是局部治疗对生活质量的影响是我们管理的目标。我们用预测的方式对患者生活质量进行分析，在一定程度上局部的肿瘤进展会给患者生活质量带来影响，如肿瘤较大、皮肤结节、疼痛均会影响患者生存质量。局部病变和局部治疗（如手术和放疗）也会对患者生活质量产生影响。因此，在ECOG-ACRIN 2108研究中，我们更多关注于对未转移和无肿瘤相关症状的患者提供局部治疗，而非姑息治疗。在这种情况下，初步分析显示，疾病相关影响较小，而治疗相关的症状较为明显。对于无症状患者，治疗相关的症状会影响患者生活质量。目前两组唯一的不同是接受早期LRT的患者在随访时间达18个月时的HRQoL明显较差，我们预计在18个月时，患者将从LRT中康复。所以，还需要进一步对生活质量其他细节进行探索。目前这些结论尚未确定，因为完成生活质量调查的患者并不理想。且随着试验的进行，生活质量调查问卷表现呈下降趋势，患者数也在不断减少。所以目前明确的结论是，局部治疗并不能改善生活质量，但两组患者之间是否存在差异则值得怀疑。

 

Prof.Wang：In my clinical experience， the responses at the primary site and of distant tumors are sometimes very different. Where distant disease is well controlled with systemic therapy， but the primary tumor is progressing， local surgery should then be considered? 

 

王嘉教授：根据我的临床经验，原发部位和远处转移肿瘤存在异质性，若患者通过全身治疗远端肿瘤得到很好控制后，原发肿瘤仍在进展时，是否应该考虑局部手术?

 

Dr Kahn: That is a reasonable strategy. Clearly， we have all seen women with metastatic breast cancer whose locoregional treatment is causing them problems. We have also seen， as demonstrated by our data and also the other two trials that have been completed， that for the majority of women who are responding to systemic therapy， they respond at both distant sites and locally. If the local tumor is ulcerated， it will often heal. If it is large， it will often shrink. Successful systemic therapy can control the local tumor as well， in terms of symptoms at least. So women who receive effective systemic therapy often don’t have symptomatic local disease. 

 

If the distant disease is responding， the local disease also responds. There is a small group of women though， where the distant disease seems well controlled， but the local disease is progressing. I have seen that， and I am sure you have too. In that situation， offering women local treatment would be reasonable. But we must remember that women with metastatic breast cancer are seeking treatment that they think will extend survival， so when talking to women about locoregional treatment for the primary tumor， it needs to made clear that we cannot anticipate improved survival as a consequence. What it might offer them is longer-term better control if the local tumor is progressing. But if the local tumor is well controlled with systemic therapy， I don’t think there is a survival advantage in offering locoregional treatment.

 

Khan 教授：该策略十分合理，虽然转移性乳腺癌患者局部治疗仍存在问题，但我们应看到已完成的研究中，大多数对系统治疗缓解的患者，远端和原发灶均缓解，使肿瘤体积缩小甚至痊愈。通常全身治疗有效的患者，局部病灶也会有效，若全身治疗能很好地控制局部肿瘤，再行局部治疗不一定能提供生存优势。但也存在转移灶缓解局部病灶恶化的情况，此时局部病灶的治疗非常重要。但我们必须明确，转移性乳腺癌的患者需要可以延长生存的治疗。因此，当我们与患者讨论原发性灶的局部治疗时，需要让其明确该疗法不一定可以延长生存，但可以对病灶进展提供更好的控制。

 

Prof.Wang：Some researchers suggest that if we resect primary tumor， the judgement whether the subsequent systematic treatment is effective may be not accurate comparing with no resection. Could you give me some information about this point.（24:44～25:28）

 

王嘉教授：一些研究者认为与不切除相比，如果切除原发肿瘤，后续患者系统治疗是否有效的判断可能不准确。您如何看待这一问题?

 

Dr Kahn: The primary tumor is an indicator of response， so it is a site that we can follow to assess response. You are asking whether if the primary tumor is removed， can we assess response as well if it were not resected? It is true that a responding primary tumor does tell us that a treatment is working， and， in general， the response at the primary site corresponds to the response at distant sites. But as you have said， that is not always true. When we are treating women for metastatic disease， we can follow the intact primary tumor for response， but we also generally follow the distant disease response. The responding distant disease has to be assessed separately from the responding primary tumor. They often go together， but they can be different. Each disease site， distant and primary， needs to be assessed. The primary tumor response will often be concordant with the distant response， but not in every patient.

 

Khan 教授：原发肿瘤是缓解的指标，可以通过观察原发肿瘤来评估缓解程度，通常原发灶与转移灶的对治疗的反应是一致，但并非完全可靠。当我们治疗转移性乳腺癌患者时，既要观察完整的原发肿瘤的反应，也要观察转移灶的反应，但必须分开评估，以确定患者不同病灶对治疗的反应。

 

Prof. Wang: Is following the response to therapy for 4-8 months sufficient?

 

王嘉教授： 4～8个月的治疗及随访是否足够？

 

Dr Kahn: That is a good question. We actually struggled with how long to define that interval of initial treatment. If we let it go too long， then we are not using local therapy early in the course of disease. One of the theoretical premises that the trial was built on was the idea of reseeding – that the primary tumor site was a place where circulating tumor cells could recirculate through the tumor and become more competent to set up new sites. If we leave the primary tumor alone for a long time， then we may not see the benefit of resecting the primary tumor. If we don’t treat long enough， particularly with hormone receptor-positive disease， it can take a while to see responses. The shorter end of the limit of four months was based on the idea that most chemotherapy regimens need to run for four months in order to declare a response or not. For example， sequential-ACT goes for four months. Most of the medical oncologists in the group felt that four months was a good minimum interval. For the maximum interval， we based on endocrine therapy， because we don’t often see a good response to endocrine therapy in less than six months， and we wanted to allow some flexibility. That is how we set that interval of 4-8 months. 

 

But the intent of the trial was really to assess the value of early local therapy， so we wanted to make it open-ended， so ，patients could be treated for as long as wanted and then be randomized. We needed the interval to make the population relatively homogeneous in terms of treatment duration. That is how we came up with the 4-8 month interval. In practice， however， obviously systemic treatment goes on longer than eight months. It goes as long as necessary. So in practice， that 4-8 month interval is not as important， particularly seeing as our results did not show a value for early local therapy. If we follow the results of the trial， then we won’t have to make these decisions of when to offer local therapy. The trial shows that early local therapy is not beneficial in women whose tumors are asymptomatic.

 

Khan 教授：我们通常很难确定初始治疗的间隔时间，若间隔太久，则不会在病程早期使用局部治疗。该研究重新建立了一种新的理论：原发灶的循环肿瘤细胞可以在肿瘤中再循环，并发展新病灶。所以需要切除原发灶，系统治疗足够长的时间才能看到获益，如激素受体阳性乳腺癌患者需要长期治好了。四个月的治疗下限则是基于大多数化疗方案都需要经过四个月才能确定是否有反应的理论。例如，AC-T序贯治疗持续四个月，大多数肿瘤学家认为四个月是很好的最小间隔。而最大的时间间隔往往以内分泌治疗为基础，因为若内分泌治疗小于六个月，则无法看到疗效。因此结合方案操作的灵活性，将治疗间隔设置为4-8个月。

 

但本研究的目的是评估早期局部治疗的价值，因此我们希望将其设为开放式治疗，以便根据需要对患者进行尽可能长的治疗后再将其随机分组。我们需要使患者在治疗持续时间方面相对均匀，所以我们提出了4-8个月的间隔。但实际操作中全身治疗要持续8个月以上，间隔4-8个月并不重要，特别是本研究结果并未显示出早期局部治疗的价值，若遵循试验结果，则无需决定何时提供局部治疗。

 

Prof.Mao：Your answers have changed some of my viewpoints on local therapy for metastatic breast cancer. I have a final question. I noticed that in your results， FACT-B TOI was significantly lower in patients receiving early local therapy at 18 months post randomization. How we understand this problem. Maybe you can give us more details about it. Thank you so much.

 

毛晓韵教授：在本研究中，随机分组后18个月接受早期局部治疗的患者的FACT-B TOI显著降低。您如何看待这个问题？是否有更多信息？ 

 

Dr Kahn: Unfortunately， we don’t have more details at the moment. We are looking more closely at the quality of life data to try and understand why that 18-month timepoint was different. As I mentioned earlier， the response rate declines during the course of the study. We had fewer women responding with their quality of life surveys， so the information is not as robust as we would have liked. What we had hypothesized was that the side effects of surgery and radiation would have gone away by that timepoint 18 months after randomization. It is possible that in some women， the surgery and radiation was a little delayed， so by 18 months， the acute effects had not subsided. We did， of course， see an improvement in local control. Women who had locoregional treatment were less likely to experience progression at the local site. Despite the lower rate of local progression， we did not see improved quality of life in terms of local symptoms. This may just be a reflection of the tail-end of the acute effects of surgery and radiation. We do need to look at that data more closely， and we hope to be able to report those findings in greater detail in our manuscript.

 

Khan 教授：很遗憾，我们目前没有更多的详细信息。我们正在仔细地研究患者生活质量数据，以试图理解为什么18个月时与以往结果不同。如上所述，随着试验进行，患者缓解率下降，参与生活质量调研的患者不断减少，因此相关信息并不丰富。虽然我们确实看到了局部控制的优势，接受局部治疗的患者进展的可能较小，但就局部症状而言，我们并未发现生活质量得到改善，可能是由手术和放射带来急性影响的末期反应造成的。因此我们提出的假设是，在随机分组后的18个月时，手术和放疗的副作用消失；然而某些患者手术和放疗带来的副作用延续较长，在18个月时并未消失。我们确实需要更仔细地查看这些数据以发现具体原因，希望能在未来进行更详细地报告呈现。