Oncology Frontier : When considering internal mammary nodes in irradiation can you talk about that in association with the survival of breast cancer patients?

　　《肿瘤瞭望》：乳腺内淋巴结放疗是否可改善乳腺癌患者的生存期？

　　Dr. Ollivotto: The number of evolving studies， big studies， big randomized studies， one done in Europe and one done in North America and Australia and New Zealand， and then a big cohort study from Denmark that have all looked at the issue of more extensive radiation than less extensive radiation. This goes back to the 1997 (or there about) when 2 studies， one from Denmark one from British Columbia (Canada) were published looking at women who have been treated with mastectomy and they had positive nodes. Most of them had 1 to 3 positive nodes and the patients were randomized between just mastectomy and they all had chemotherapy or hormone therapy or no radiation. When we looked at 10 and 15 year follow up， at 5 years there was really no difference in survival. But by 10 or 15 years follow up， there was statistically significant survival gains in the 5 to 8% range in young women with positive nodes that got radiation of the chest wall and lymph node areas. That was in 1997 when the New England Journal of Medicine had a couple of publications， which had a big impact in some places. It demonstrated that radiation not only improved local control， which had been known for years and years， but it also improves survival. Today， most women are treated with lumpectomy and radiation where you are treating already， the chest wall， most of that as post mastectomy volume. There were a number of studies launched in the late 90s to address the issue of whether adding radiation to internal mammary nodes and medial supraclavicular nodes improves survival. These are now getting to mature enough to have 10 year follow up and these data was not presented at the current meeting but the final analyses of those big studies， 1800 patients in North America and Australia， and 4000 from Europe， when you pool them together， and this has just been done recently and they have been submitted for publication. I am aware of that. It has to go through the peer review process but they do show small but potentially important survival gains with long term follow up. Both the studies show very consistent effect of decreasing local recurrence， which is to radiate something to prevent it from growing. Both of these have a statistically significant improvement in avoiding distant metastases. The risk of distant metastases is definitely reduced about 5% in these studies， and we do not have curative treatment for distant metastases. If we develop and prevent distance metastases for 5 to 7 years， we eventually are going to be preventing death at 10 and 15 years. So we have 10 year follow up on these big studies now， but the time we have 15 year follow up I think the avoidance of distant metastases will translate into improved survival. Right now there are small differences， 1 or 2% survival at 10 years and they are just bordering on statistical significance. In the European study with 4000 patients， it is statistically different; it is statistically higher by treating. Now is it the internal mammary nodes or is it the supraclavicular nodes， it is difficult to tease apart. In many of the old historical post mastectomy studies， the studies that did not include internal mammary nodes did not demonstrate an improvement to survival. The other thing that has recently come into the literature and is in the process of being published and presented at meetings is a big cohort study and was discussed at this meeting yesterday， that there was a big study in Denmark in which up until 2003 when they began to be concerned about left sided radiation effecting the heart and increasing the risk of heart attacks， up until 2003 the Danish policy and everybody followed the policy， was that everybody should have internal mammary radiation. That is just the way they did it and in 2003 they decided that they will not give internal mammary radiation anymore in left sided breast cancer but because we have always given it， we will continue to give it to right sided breast cancer. They have now followed up patients treated under that new policy between 2003 and 2007， a couple of thousand patients， and it wasn’t really discussed at this meeting but it has been discussed elsewhere， that the policy was very well followed， like 97% of the right sided patients got internal mammary radiation and like 3 or 4% of the left sided breast cancer patients got internal mammary radiation so it was like a very discreet， very dramatic difference in the treatment. Otherwise everything else was the same， same chemo， same radiotherapy and all that stuff. There is a 3% improvement in survival with longer term follow up in patient who with right sided breast cancer as opposed to left sided breast cancer. What that says is that if you extend the radiation volume to patients， especially if there are bigger tumors， lymphatic invasion， and medial lesions， so a patient with 1 involved node， or 2 involved nodes in the central to medial part of the breast， especially if they also have lymphatic or vascular invasion around the tumor， they have a 20 or 30% risk of internal mammary involvement. We know that because there was a big study from China that investigated biopsying and removing lymph nodes. Surgery alone to one lymph node area does not improve survival but radiation to a large area including the intramammary nodes improves survival by a few percent. You can say “well， is that worth bothering about?” but that is as large a survival or bigger survival impact than switching from tamoxifen to an aromatase inhibitor or using an aromatase inhibitor in addition to tamoxifen in node negative patients. If you are doing that and if you actually believe that that is an important thing to do in terms of the investment， then if you are given the radiation and extending it to include the intramammary nodes， actually it does not add any cost to the health system. You have to do it and you have to pay attention technically to how you do it especially on the left side， you have to use techniques that now avoid the heart and it is possible to do from a technical perspective so that you do not cause heart damage but it does improve survival by a modest amount， the sort of amount that we now observe and make dramatic changes in treatment policy for systemic disease.

　　Ollivotto教授：一系列相关的大型随机研究正在欧洲、北美、澳大利亚、新西兰开展，丹麦还有一项大型队列研究。这些研究比较广泛放疗与范围较小的放疗效果。1997年共计发表了两项研究（一项在丹麦开展，另一项在加拿大的不列颠哥伦比亚省开展）研究对象是接受乳房切除术但淋巴结受累的乳腺癌患者，其大多数有1~3个淋巴结受累。将其随机分为单纯乳房切除术组或化疗、激素治疗或未放疗组。随访5年时，患者的生存率确无差异，随访10~15年时，胸部、淋巴结放疗过的淋巴结受累年轻患者其生存率提高了5%~8%，具有统计显著性。1997年《新英格兰医学杂志》发表了很多这方面的文章并产生了很大的影响。研究表明，放疗不仅能改善癌症局部控制（这一点大家早已熟知），还能提高患者的生存率。现在，大多数乳腺癌患者都接受肿瘤切除术和术后胸壁放疗。上世纪90年代后期的很多关于内乳淋巴结和侧锁骨上淋巴结放疗能否提高乳腺癌患者生存率的研究。现在这方面的内容越来越成熟，相关研究随访时间可达10年之久，不过本次大会上并未发布相关数据。不过最近该研究完成了最终结果分析（北美和澳大利亚1800例、欧洲4000例的患者），并提交发布，现已进入同行评审流程。研究后长期随访发现这种淋巴结放疗可小幅（但可能很重要）提高生存率。这两项研究的结果相当一致，即淋巴结放疗可降低局部复发，在防治远处转移方面，其结果具有统计学的显著性，远处转移的发生风险降低约5%。如果能避免乳腺癌患者术后5~7年内的远处转移，则有望提高10~15年的生存率。这些研究已经随访10年，待随访到第15年，我相信减少远处转移将最终导致生存率改善。目前随访10年患者的生存率提高1%~2%，处在“是否有统计学意义”的边界上。在4000例患者的欧洲研究中，对上述部位进行放疗已经显著改善乳腺癌患者的生存率。但到底是内乳淋巴结放疗还是锁骨上淋巴结放疗发挥了上述作用，我们还不是太清楚。过去很多有关乳房切除术后的研究，未对内乳淋巴结进行放疗，结果未发现放疗可改善患者的生存率。丹麦一项大型队列研究带来了新讯息，该研究昨天在本次大会进行了讨论。过去丹麦的治疗策略是所有患者都进行内乳淋巴放疗，从2003年开始人们开始担心左侧放疗会对心脏有影响，增加心脏病风险，不再对左侧乳腺癌进行内乳淋巴结放疗。该研究并对2003~2007年间新政策实施以来接受治疗的数千例患者进行了随访。虽然本次大会上未对其结果进行讨论，但之前在别的会议上曾讨论过。新政策得到了很好的实施。97%的右侧乳腺癌患者接受了内乳淋巴结放疗，而左侧乳腺癌患者进行内乳淋巴结放疗的比例仅为3%或4%。左右侧乳腺癌的放疗确实存在非常显著的差异。更长期的随访可见，与左侧乳腺癌相比，右侧乳腺癌患者内乳淋巴放疗的生存率显著提高3%。这就是说，患者肿瘤较大、伴有淋巴管浸润及内侧病变，就会有1个或2个受累淋巴结，则内乳淋巴结受累的风险可增加20%或30%，这时需要扩大乳腺癌患者的放疗范围。中国开展的一项关于淋巴结活检和切除的研究发现，单纯手术切除一个淋巴结并未能改善患者的生存率，而扩大范围放疗包括对内乳淋巴结进行放疗则可使患者的生存率提高几个百分点。你可能会说“这是否有意义？”相比未发生淋巴结转移的乳腺癌患者的“他莫昔芬换成芳香化酶抑制剂或他莫昔芬基础上加用芳香化酶抑制剂治疗的效果”，这种放疗的效果要更大。对内乳淋巴结扩大放疗并不增加医疗成本。从技术角度上来说，对左侧乳腺进行内乳淋巴结放疗时，应该选择避免对心脏造成伤害的放疗方案。这样就可以一定程度上提高乳腺癌患者的生存率，并显著改善系统疾病的治疗策略。