Oncology Frontier: Dr. Yarnold， radiation fibrosis is one of the late effects of breast radiotherapy. Are there any biomarkers that can measure established fibrosis in patients who have undergone radiotherapy for breast cancer?

　　《肿瘤瞭望》：放疗纤维化是乳腺放疗的远期并发症。有没有可测定乳腺癌放疗纤维化程度的生物标志物？

　　Dr. Yarnold: It is a clear question and an interesting one but the simple one is that there are no biomarkers that have been shown， particularly at serum， for example the interleukins and other cytokines which have been shown to be biomarkers in some fibrotic states. I think in terms of the clinical assessment of fibrosis， in our own clinical trials when we have fought hard about how to monitor this， we have found to our surprise that patients are as good as doctors， or ever any machine that we have in actually quantifying the degree of firmness in their breasts. Maybe we should not have been surprised by that， but by just asking them to apply a 4 point gradient scale over a period of years after their radiotherapy treatment or trials， we have been able to discriminate between a 5 and 10% difference in dose intensity. In other words the patients seems to be pretty good at judging that side effect.

　　Yarnold教授：很显然这是一个大家都比较感兴趣的话题，简单来说目前尚无测定乳放疗纤维化程度的生物标志物、特别是血清生物标志物如白介素及其他细胞因子，尽管它们是其他原因所致纤维化的生物标志物。我认为，就纤维化的临床评估而言，我们在临床试验中一直努力探索应如何监测纤维化，并最终惊喜地发现，患者量化乳房硬度的能力和医生、甚至仪器一样好。患者放疗数年后，我们可以通过患者填写的四点梯度量表来区分5~10%放疗强度。对于这点本我们不必惊讶。换句话说，患者似乎能够很好地判断放疗的副作用。

　　Oncology Frontier: Controversy exists in the issue of internal mammary chain irradiation in breast cancer and the benefit is limited， could you please talk about the characteristics of the patients that may benefit from this irradiation?

　　《肿瘤瞭望》：乳腺癌的内乳淋巴结放疗存在争议，并且获益有限，您能否谈一下哪些患者可能从这种放疗中获益？

　　Dr. Yarnold: That controversy is going to continue for a while yet. The 10 years results of the EORTC trial and the updated 10 year results of the Canadian MA.20 trial both testing radiotherapy to the internal mammary chain and the supraclavicular fossa after primary surgery and systemic therapy for breast cancer have been submitted for publication and I guess it will be available to us all for a detailed scrutiny in the next few weeks and months. Even at that stage it may be quite difficult for us to refine our indications for IMC radiation， my hunch is there will be quite wide international differences as to how recommendations are taken up. I think that in the United Kingdom for example， it will only be the highest risk patients for example， those under the age of 40 with heavy node positive tumors and all central or inner quadrant tumors that will be considered for the benefits of treatment. I imagine that other countries may actually implement lower threshold for implementing the treatment. In terms of safe delivery I think our modern techniques of radiotherapy have improved a great deal in the last decade certainly. The current data from those 10 years reports that I just mentioned to you do suggest that the cardiac risk for example is frankly undetectable against the background risk of heart disease in those populations. That is a very positive point.

　　Yarnold教授：这方面的争论还将会继续持续一段时间。EORTC试验十年研究结果及加拿大MA.20最新十年研究数据均探讨了初次手术后内乳淋巴结放疗及锁骨上淋巴结放疗对乳腺癌的影响，其结果已经提交等待发表。我想在几周或几个月后，其详细结果将会发布。但是，即使这些结果发布后，对我们而言，细化IMC放疗的适应证仍有很大难度。我预感，有关那些患者被推荐IMC放疗可能会存在很大的国际差异。例如，英国认为高危患者（如年龄小于40岁、淋巴结强阳性、以及肿瘤位于乳腺中央或内侧象限者）能从内乳淋巴结放疗中获益；而在其他国家可能内乳淋巴结放疗的推荐门槛会比较低。就内乳淋巴结放疗的安全性而言，我认为在过去十年中现代放疗技术有了很大的进步。以上试验的十年研究数据表明，相对于这些患者本身的心脏病潜在风险，内乳淋巴结放疗导致的心脏风险是可以忽略不计，这是个好消息。

　　Oncology Frontier: Cardiac and pulmonary toxicity related to internal mammary chain irradiation in breast cancer is well known， how can we evaluate the potential late toxicity and achieve the accurate dosimetry for critical organs?

　　《肿瘤瞭望》：众所周知，乳腺癌内乳淋巴结放疗可能存在心肺毒性。我们应当如何评估潜在的远期毒性，并且做到准确给予放疗剂量？

　　Dr. Yarnold: In terms of measuring the adverse effects of exposure to the lung and the heart， clearly clinically relevant events are the traditional way， in other words， major cardiac events. As the question hints， you have to wait a long time for those events to accrue. What you really want would be markers that predict that risk. Some of those you collect at baseline before you even treated your patient when you ask her about her smoking history or assess her body mass index and her other comorbidities such as diabetes for which you can actually generate a score that has been published by Caroline Taylor and her colleagues at Oxford. That allows you to at least stratify your patients into those of average， lower than average， or higher than average risk of which you may wish to take account of when deciding your treatment thresholds for patients. In terms of actually monitoring the adverse effects， where lung fibrosis is concerned， then x-ray and CT scanning is about as good as you need and that offers good quantitative measures in the research setting. It would not be relevant to us in the routine setting. Similarly sophisticated measures of cardiac perfusion of the heart using functional MRI offer similarly sophisticated measures of blood flow.

　　Yarnold教授：就放疗所致心肺不良事件而言，主要是指传统的临床相关事件即主要严重心脏不良事件。但问题是其可能在放疗毒性累积很长时间后才发生。我想你真正想问的是，是否有预测放疗心肺毒性风险的生物标志物。其实，按照牛津大学Caroline Taylor及其同事发布的评分系统，我们可根据患者治疗前的基线信息如吸烟史、体重指数（BMI）以及其他合并症（如糖尿病）对其进行风险评分。并以此对患者进行危险分层，将其分为低于平均风险组、平均风险组与高于平均风险组。在进行治疗决策选择时我们可参考上述风险分层结果。就不良反应的实际监测而言，这里说的是肺纤维化，X线检查与CT检查都非常不错，能够实现研究中肺纤维化风险的定量评估，但这还不是临床常规手段。此外，心脏灌注的功能性核磁共振成像也能监测各项复杂的血流指标。

　　Oncology Frontier : Could you please talk about the future perspectives of the radiotherapy techniques，?and how can the development contribute to the treatment of breast cancer?

　　《肿瘤瞭望》：您能否对未来放疗技术发展予以展望？乳腺癌治疗将如何从放疗技术发展中获益？

　　Dr. Yarnold: I am going to address that via the internal mammary chain specially， just as an example because otherwise that question is an extremely broad one although highly relevant. In a discussion we have had at this conference， it was pointed out that advanced techniques of radiotherapy to the internal mammary chain using VMAT or volumetric arc rotation can conform the internal mammary chain extremely well and also practically avoid any kind of heart exposure. The point I wish to make is that the radiation has got to go somewhere and if you avoid the heart then some other organ must get it， to put it crudely. In the context of VMAT to the cancer of the breast， that dose is absorbed by the lungs albeit very low doses. You have very low dose radiation but to large volumes of lung and then really the issue that we all have to face with all tumor sites in the body， not just in the particular one that I am talking to， is how does that trade off against the long term risks of radiation induced cancers? Clearly in the patient at high risk of cancer death from her first cancer， and a large absolute benefit from treatment today， then that decision is easy but where the benefits are down at the 1 or 2% level in terms of improved benefits in 10 year survival as they appear to be for internal mammary chain radiation， my hunch is that techniques like VMAT may not be the best bet and we should stick to what we know now and manage it that way.

　　Yarnold教授：这个问题很宽泛，涉及很多方面，我想以内乳淋巴结放疗为例进行阐述。在本次大会上我们曾专门就此进行讨论，有人认为“容积弧形调强放射治疗技术（VMAT）能够实现精准内乳淋巴结放疗，几乎可以避免对心脏的不良反应”。我想强调的是，辐射总是需要有归处的，如果能够避免心脏不受其影响，则其他器官必将受到影响。就乳腺癌的VMAT放疗而言，尽管其辐射剂量较低，但却需要由肺部来吸收。如果放疗的辐射剂量很小而肺容积很大的话，则我们需要考虑其他肿瘤治疗同样要考虑的问题：即“应如何权衡放疗获益和放疗诱发癌症的远期风险。显然，如果患者原发癌症死亡风险较高，而放疗能为其带来绝对获益，临床决策就非常容易。但是，如果这种放疗的获益仅能使未来十年的生存率提高1%或2%，则VMAT可能并不是患者最佳的治疗选择，我们还是应该坚持现有治疗与管理方法。