编者按：对于早期乳腺癌患者而言，一些患者接受外科手术和全身治疗后就可以获得较好的长期生存，但对于其他早期乳腺癌患者而言，则需要进行辅助放疗。究竟哪些浸润性乳腺癌患者可在保乳术后省略放疗，哪些患者又需要加用辅助放疗呢？日前，肿瘤瞭望特邀华中科技大学附属协和医院肿瘤中心赵艳霞教授对话爱丁堡癌症中心Ian H Kunkler教授，共同就两国乳腺癌患者保乳术后放疗方案进行介绍。

 

赵艳霞教授：请您介绍一下，您所在国家乳腺癌患者接受保乳术后放射治疗的情况。

Could you please introduce the situation of postoperative radiotherapy for breast cancer patients in your country?

 

Ian H Kunkler教授：在英国，大多数患者在接受保乳治疗、肿瘤边缘安全的条件下手术切除肿块后以及进行适当的系统治疗后都会接受一个疗程的术后放疗。除了被认为疾病风险极低的患者，即65岁以上，ER阳性且肿瘤体积小的患者可以认为不接受放疗也是安全的。由于英国普遍采用低剂量分割放疗，所以放疗时间一般控制在3周内。

In the UK，after breast conserving therapy，surgical removal of the lump with a margin of security，and appropriate systemic therapy，the majority of patients will receive a course of postoperative radiotherapy，perhaps with the exception of those considered very low risk of disease who might be patients over the age of 65 with small ER positive tumors，where it may be considered safe to omit radiation.But for the majority of patients，they will receive a course of radiotherapy，which will normally be over a period of around about 3 weeks since hypofractionation has been adopted widely within the united kingdom.

 

赵艳霞教授：此次苏格兰保乳试验30年随访增加了哪些数据，为我们带来了哪些启示？

What data were added and what were the implications of this 30 year follow-up of the Scottish breast conserving trial（PRIMEⅡ）?

 

Ian H Kunkler教授：苏格兰保乳试验由已故的帕特里克·福雷斯特先生在20世纪80年代领导，该研究招募了585名早期乳腺癌患者（70岁以下、肿瘤大小不超过4厘米的女性），并根据其雌激素受体状态给予系统治疗，患者服用他莫西芬5年治疗，或者服用环磷酰胺、甲氨喋呤和5-氟尿嘧啶治疗，直到疾病复发。然后将患者随机分为手术后放疗组或不放疗组。

The Scottish breast-conserving trial，which was led by the late Sir Patrick Forrest in the 1980s，recruited 585 patients with early breast cancer(women under the age of 70 with tumors up to 4cm in size)，and they received systemic therapy appropriate to their estrogen receptor status，either with tamoxifen for five years or until time of relapse，or systemic therapy with cyclophosphamide，methotrexate and 5FU，and then randomized either to a course of post-operative radiotherapy or no radiotherapy.

 

 

1996年，Patrick Forrest教授及其同事在《柳叶刀》杂志上首次报道了这项试验，结果显示（肿瘤的）局部复发率降低了四倍，从无放疗组的24%以上降至放疗组的6%以下，但总生存率没有差异。我们对同一试验进行了跟踪研究，发现在30年的时间里，患者的复发风险降低了60%，表明放疗对减少复发非常有效。2011年，发表于Oxford overview的数据显示，包括苏格兰保乳试验在内的17项临床试验中，无论是局部复发还是远处复发，10年内首次复发的概率都减少了15%，这相当于15年内乳腺癌死亡人数减少了近4%。

When the trial was initially reported in The Lancet in 1996 by Professor Forrest and colleagues，it showed there was a four-fold reduction in local recurrence from just over 24%in the non-irradiated group down to just less than 6%in the irradiated group.But there was no difference in overall survival.So we undertook a follow-up study of the same trial，and identified that over the 30-year period，there was a 60%reduction in risk of recurrence.The message for patients is that radiotherapy is very effective in reducing recurrence.When the Oxford Overview was published in 2011，what it showed was that in the 17 trials that included the Scottish conservation trial，there was a 15%reduction at ten years in first recurrence，either local recurrence or distant recurrence.That corresponded to just under a 4%reduction in breast cancer deaths at 15 years.

 

该项研究中超过10年的随访数据相对较少。我们在这项分析中发现，放疗减少的局部复发绝大部分发生在前10年内。在10年治疗后，有/无放疗的局部复发率是相同的，每年不到1%，且局部复发率在有/无放疗的患者间差异无显著统计学意义。我想这算是一个惊喜。就临床实践而言，我不认为它改变了术后放疗的适应症，因为这30年间患者在局部复发减少方面有很大的提高。然而我们并没有发现总生存率的差异，这也是一个（与既往研究结果）不一致的点。不过这只是一项临床研究的结果。此外我们也在后续的保乳研究中得去验证减少首次复发和减少乳腺癌死亡之间的关系是否真的成立。

There was relatively little data on what happens after 10 years of follow up.What we showed in this analysis was that most of the reduction in recurrence from radiotherapy occurs within the first 10 years.But after 10 years，the local recurrence rate with/without radiotherapy occurs at the same rate at about less than 1%per year，but there was really no difference in the rates of local recurrence between the irradiated and non irradiated group.And that，I think，was something of a surprise.So in terms of implications for practice，I don’t think it changes the indications for postoperative radiotherapy in the sense that patients gained substantially over the 30 year period in terms of reduction of local recurrence.But we didn’t show any difference in overall survival.And that’s a finding，which is obviously，at variance，would be the findings of the overview，but it’s only one trial.We’ll obviously have to see when the subsequent overview of breast conservation is published，whether that relationship between reduction in first recurrence and reduction in breast cancer deaths actually holds true or not.

 

但我认为患者不应该对这些临床研究的发现而气馁，因为在30年间，患者局部复发率大大减少，只是治疗前10年和10年后的复发模式上存在差异。

So I don’t think patients should be discouraged by the findings，because over the 30 year period，there is a substantial reduction in local recurrence，but the pattern of recurrence differs between the first 10 years and after 10 years.

 

赵艳霞教授：您认为该项临床研究结果会改变您的临床实践吗？

Do you think this clinical trial result can change your clinical practice?

 

Ian H Kunkler教授：我认为它改变的是我们能向病人提供长期复发风险的信息，即我们可以向患者保证，在30年内局部复发率可下降60%。虽然这项研究中，患者的总生存期获益不明显，但仍可以有效避免局部复发，这对许多患者来说是很重要的，（因为）局部复发会让患者十分痛苦。然而，患者的复发模式和局部复发随时间的推移而不同，因此大部分获益都体现在前10年，而后的获益则相对较少。尽管如此，其总体（局部复发）获益仍高于60%。

So I think what it changes is the information that we give to patients about the pattern of recurrence over a long period of time.We can reassure them that over a 30 year period，there is a 60%reduction in local recurrence.It doesn’t confer a benefit in overall survival，but nonetheless avoiding a local recurrence.For many patients is extremely important.And when it occurs causes of distress，but the pattern of recurrence，local recurrence differs over time，so that most of the benefit is conferred in the first 10 years and much less benefit over subsequently，but the overall benefit is higher 60%.

 

我认为该项研究的结果在很长一段时间内对我们向患者传递复发相关的信息有很大的帮助。众所周知，乳腺癌患者的自然发病过程可持续几十年之久，许多病人在首诊40年后才死于乳腺癌。重要的是该研究让患者意识到这些不同的（疾病复发）模式，而且像这样的临床试验应该进行长期的随访研究，而不是如同既往仅仅持续5到10年的随访时长。

I think it contributes to the way we convey information about recurrence over a long period of time.And remember that we all know，obviously that the natural history of breast cancer occurs over many decades.Many patients still die of breast cancer of 40 years after the original diagnosis.It’s important that patients are aware of these different patterns over time，and also that clinical trials like this should be follow up on a long term basis，rather than maybe for 5 or 10 years，which is probably the traditional duration of follow-up.

 

这也涉及到研究赞助者提供的资金。通常情况下，一项临床试验一般会得到5年或10年的资金资助，但很少超过10年。因此，我认为该研究提供了一些与有/无放疗的保乳手术的长期术后情况相关的信息，这些信息鲜为人知，对患者具有宝贵价值。我认为患者需要了解这一点。

That relates to how funders approach the funding of a trial.The funding of a trial.Normally，trials will may be funded over 5 or 10 years，but rarely beyond that.And I think we provided some useful information，which is probably fairly rare about what actually happens after breast conserving surgery with or without radiotherapy in the very long term.And I think patients need to be aware of that.

 

赵艳霞教授：结合苏格兰保乳试验以及您的临床经验，临床中您会选择哪些患者进行保乳术后放疗？

In combination with the Scottish breast-conserving trial and your clinical experience，which patients would you choose for breast-conserving postoperative radiotherapy in the clinic?

 

Ian H Kunkler教授：Prof.Kunkler:目前我们主张对大多数行保乳手术的患者进行术后放疗。来自PRIMEⅡ和其他保乳试验的数据也表明，65岁以上的T1、淋巴结阴性、ER阳性肿瘤患者的复发风险非常低，因此对于这些患者豁免化疗也是相对安全的。

 

At the moment，we would advocate post-operative radiotherapy for the majority of patients who have had breast-conserving surgery.The ones we would consider it safe to omit radiotherapy(based on data from the PRIME II trial and other conservation trials)are patients aged 65 years or older with T1，node-negative，ER-positive tumors where the risk of recurrence is very low.

 

赵艳霞教授：保乳术后放疗也存在一些并发症的风险（皮肤挛缩、上肢水肿等），您在实践中会如何选择放疗方式/方案，降低并发症的风险？

There is also some risk of complications(skin contracture，upper limb lymphedema，etc.)in radiotherapy after breast conserving surgery.How do you choose the radiotherapy method/program in practice to reduce the risk of complications?

 

Ian H Kunkler教授：大多数研究对短期的低剂量分割放疗与传统的大剂量分割放疗（4-6周）进行比较，结果表明低剂量分割放疗对乳房的影响较小。在英国，患者通常会在3周内接受15次剂量为40Gy的分割治疗，且该方案有良好的随机试验数据支持。

Most of the studies that have been done comparing shorter hypofractionated radiotherapy to more traditional longer dose fractionation schedules over 4-6 weeks show that hypofractionation is gentler on the breast.That would be the standard-of-care patients receive in the UK.Patients would normally receive 40 Gy in 15 fractions over 3 weeks，and that is underpinned by good randomized trial data.

 

赵艳霞教授：我们在您这里听到了好消息，并且可以用临床试验数据来指导临床实践。在中国，当患者出现单个淋巴结转移时，医生对是否进行术后放疗犹豫不决。对于这类患者，您会如何对其进行治疗？

We have heard good information from you，and we use clinical trial data to guide clinical practice.In China，when there is a single node metastasis，physicians are hesitant to give post-operative radiotherapy.How do you choose patients to undergo this therapy?

 

Ian H Kunkler教授：通常情况下，如果患者淋巴结转移量少，则可以考虑对乳房和外周淋巴结进行术后放疗。许多患者会先接受前哨淋巴结活检以作为确定腋窝淋巴结状况的诊治基础。对于淋巴结转移量多的患者，通常会给予腋窝淋巴结清扫。但对于大多数淋巴结转移量少的患者，术后放疗仍然是临床治疗标准。

Normally，if there is a low nodal volume，then patients can be considered for post-operative radiotherapy，both to the breast and to the peripheral lymphatics.Many patients would initially undergo a sentinel node biopsy as the basis for establishing nodal status in the axilla.In patients with significant nodal volume，those patients would normally be offered an axillary clearance.But for the majority of patients with low volume disease，post-operative radiotherapy would be standard-of-care.

 

赵艳霞教授：在接受新辅助化疗并达到pCR（病理完全缓解）的患者中，应如何选择放疗方式？

How do you choose radiotherapy in the setting of neoadjuvant chemotherapy where there might be a pCR(pathological complete response)?

 

Ian H Kunkler教授：我认为对于该问题还没有定论，有一些临床试验正在对其进行研究。目前我们对那些淋巴结阳性且病理完全缓解（pCR）的患者长期研究结果知之甚少。我们的政策通常是，如果患者既往有淋巴结受累，考虑手术后对腋窝进行放疗，直到试验结果表明pCR后豁免化疗是安全的。在临床中实践中，我们经常发现患者虽达到pCR，但实际上淋巴结是阳性的情况。

I think this is an area of uncertainty which is being studied in a number of clinical trials.What we don’t know is what the long-term outcomes in patients who are node-positive and have a pCR is.Our policy is normally that if the nodes were originally involved，to consider post-operative radiotherapy to the axilla until the results of the trials show that it is safe to omit axillary radiation after a pCR.We quite often find that there is a pCR within the breast，but the lymph nodes actually remain positive.That is quite a common finding.