DR MAMOUNAS: These 2 cooperative group trials, we’ll call them sister trials, because they are addressing exactly the same population of patients. And they’re trials trying to tailor local-regional therapy in general, after neoadjuvant chemotherapy. So the NSABP B-51/RTOG 1304, it’s a simple concept. It takes patients who have positive nodes before neoadjuvant chemotherapy, documented by core needle biopsy or fine needle aspiration. They get the neoadjuvant chemotherapy and, also, if they’re HER2-positive, anti-HER therapy. And then if they become clinically node-negative, they go on to surgery. And if their nodes are pathologically negative at the time, then they’re candidates for the study.

And pathologically, nodes can be by axillary dissection, by sentinel node biopsy or combination. So we don’t dictate what happens at the time of surgery, but we do dictate that we need at least 2 sentinel nodes to be removed, if sentinel node alone is the procedure performed. So we essentially start with T1 to T3N1 breast cancer. And then if they get negative nodes at the time of surgery, they get randomized to either comprehensive radiotherapy or not. And what I mean by that is: If they have mastectomy, the control group gets no radiotherapy at all. And the experimental group gets chest wall and regional node radiotherapy. If they have lumpectomy, the control group gets breast radiotherapy, and the experimental group gets breast plus regional node radiotherapy. Now I say the “experimental group,” although in fact that is the experimental group, because the trial is set up as a superiority trial, not a noninferiority trial.

DR LOVE: Before you go on to the other trial, how do you manage this situation outside a trial setting?

DR MAMOUNAS: Yes. This is a tough situation outside a clinical trial setting because, as we talked earlier, the gestalt is to give radiotherapy to these patients because they’re node-positive. But we and others have generated data to support that if you get a pathologic complete response and if your nodes are negative, your rate of local recurrence is actually lower. And it’s potentially lower in the regional nodes as well. So whether you need radiotherapy or you benefit from radiotherapy remains to be determined.

Now again, we don’t have an exact standard in this setting, although again, the gestalt is to give it. But the trial, the way it’s set up, it’s set up as a superiority trial. We would like to show that radiotherapy improves invasive breast cancer-specific survival — in other words, counting all the events, not only local-regional events, because we know radiotherapy will probably reduce local recurrence. The question is, does it improve survival?

A lot of the node-positive trials included in the overview that have shown the survival benefit, the rate of local recurrence in these trials was significantly higher than we see in our everyday practice, to the point that even with 1 to 3 positive-node patients, 20% of the patients had local recurrence without radiotherapy. And in our current adjuvant trials with taxanes, we achieved half of that, 7% to 10%. So the question is, would we have seen the same survival improvement if we had treated all these patients with comprehensive radiotherapy? So that is the main rationale behind this trial.

The other trial, the Alliance trial, takes exactly the same group of patients, but at the time of surgery, if the sentinel node — they have to get a sentinel node biopsy in that trial — if the sentinel node is positive, then patients intraoperatively get randomized to completion axillary dissection or not. The idea behind this essentially is to revisit the Z11 trial in the postneoadjuvant setting and to show whether indeed you need the completion axillary dissection or not to improve disease-free survival, assuming that the patients will get comprehensive radiotherapy, because they remain node-positive. So that’s the sister trial.

So anybody who gets neoadjuvant chemotherapy with positive nodes up front are potentially candidates for one or the other trial. And so surgeons should keep it in mind when they operate on these patients.

DR LOVE: And again, if you could just review how you manage this outside a trial setting.

DR MAMOUNAS: Outside the trial setting, the standard is to do a completion axillary dissection, if the sentinel nodes are positive.

DR LOVE: And can you just review where we are in terms of the Z11 question that Terry referred to, the adjuvant situation where you have a positive sentinel node, what the Z11 study showed and how that’s been playing out in your tumor board?

DR BLACKWELL: It certainly provokes a lot of discussion in our tumor boards. Z11 was a trial for women undergoing lumpectomy, so that you all knew that all of them were basically going to get Level 1 axillary radiation just simply by the sheer fact that the breast was being radiated. And they were clinically node-negative at the time that they went to surgery. And it allowed for 1 or 2 of the 3 positive lymph nodes to be positive and then women were randomized to either complete the dissection or not. And although the study did not reach its full event rate, what it demonstrated was that there was no difference, at least from my remembrance of the studies, there’s no difference in local-regional recurrence in favor of completing the dissection. And, hence, the conclusion that I and many people have drawn is that for women who are going to get postlumpectomy radiation who have 1 or 2 positive lymph nodes that were not clinically positive at the time they went into the OR, you can omit a completion dissection.

But there’s a lot of “ifs” in that statement I just made. And in particular, the Alliance study should help clarify whether or not we can extrapolate those results on patients who have known positive lymph nodes.

DR MAMOUNAS: Yes. That trial, for example, did not include mastectomy patients and did not include patients after neoadjuvant chemotherapy. And that, hence, the Alliance trial currently. And it did show no difference in overall survival or disease-free survival, but again, it wasn’t accrued to its full extent. However, I think the low recurrence rates that we see in the axilla makes it very unlikely — and lack of difference between the 2 groups — makes it very unlikely that even with about 26% of the patients having residual positive nodes in the nondissected group, very unlikely that we’ll see a survival difference, even if it had fully accrued. And that’s why it was incorporated in our practice and we do that now in patients with a very low number of nodes, like 1 or 2 positive sentinel nodes, having breast-conserving therapy.

DR BLACKWELL: And I realize patients don’t want completion dissections. Surgeons don’t want to have to do completion dissections. And we’ve been doing them under the default that there should be a benefit in more surgery in the axilla when you know there’s cancer there. But the morbidity is quite great. And, in fact, the biggest hurdle that I think many of us are facing accruing to the Alliance study is when you sit down and suggest that there’s this trial of randomization or not, patients automatically say, “I don’t want the completion dissection.” Who would? And so I think that that’s something that we all are struggling with in our tumor boards.

DR MAMOUNAS: So what makes completion axillary dissection less appealing, less practiced, is also the AMAROS trial. This is a trial that was presented in the ASCO meeting a couple of years ago and essentially took patients with positive sentinel nodes and randomized them to completion axillary dissection or axillary radiotherapy. And the bottom line from this trial was, first of all, the local recurrence rate was extremely low, no significant difference between the 2 groups, like half percent and 1%, but, more importantly, that radiotherapy was not only equally good in controlling the disease, but it was also better in causing decreased lymphedema in radiotherapy versus a completion axillary dissection.

So even if you don’t totally abide by the Z11, you can always use the AMAROS concept and not dissect the axilla but extend your radiotherapy to the undissected axilla. If you believe the Z11, you can just do your breast radiotherapy and not extend to the axilla, with the intent that some of it will go there anyways. But the AMAROS trial also included mastectomy patients, so about 17% of the patients had mastectomy. So you could potentially extrapolate, even in the mastectomy setting, as long as you’re going to give radiotherapy, of course.

DR LOVE: So is that a strategy you’re using outside a trial setting?

DR MAMOUNAS: Yes, sometimes we use that study, because it’s hard for me to say that they need to complete the axillary dissection when I know the patient will get radiotherapy. On the other hand, if you can make a decision not to give radiotherapy, as long as there are no more positive nodes, that’s a different situation. Then you can complete the axillary dissection. You can avoid radiotherapy in general after a mastectomy, because the patient has reconstruction and there are other morbidity issues. Then sometimes we’ll use a completion axillary dissection in that setting. But if we can agree that we’ll use radiotherapy, then there’s no reason to complete the axillary dissection, based on the trial.

DR BLACKWELL: Yes, but I think that remains a very important discussion that needs to be happening amongst the team members, because I think people, especially in tumor boards, pick and choose the data that they are arguing for their decision-making. So if someone’s arguing to not complete the dissection on Z11, that can’t be extrapolated to a patient who was facing a mastectomy.

DR MAMOUNAS: Absolutely.

DR BLACKWELL: Or, likewise, if someone’s quoting the AMAROS trial and you would have as a surgeon completed the dissection and you’re relying on the AMAROS data, you need to communicate to the radiation doctor, “I’m not going to complete the dissection, so I need you to include the axillary fields,” or, in our practice, total nodal irradiation for positive nodes. So I think this really speaks to the importance of multidisciplinary team communication, because frequently it involves all 3 of the practices/disciplines to really come up with the best plan to minimize the morbidity of how you manage the axilla.

Local disease control and neoadjuvant treatment

Neoadjuvant treatment of HER2-positive tumors

Neoadjuvant treatment of triple-negative tumors

Neoadjuvant treatment of ER-positive, HER2-negative tumors

Other issues in neoadjuvant treatment