Sorting Therapy Options in Locoregional Breast Cancer

Kathy D. Miller, MD; Richard Zellars, MD


February 05, 2015

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Back When Radiation Therapy Was Simple

Kathy D. Miller, MD: I'm Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis, Indiana. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2014 San Antonio Breast Cancer Symposium.

The treatment options for local-regional therapy have been evolving over the past several years, and many of us have found it challenging to keep up. I have brought in Dr Richard Zellars, associate professor of radiation oncology and molecular radiation sciences, and associate professor of oncology at the Johns Hopkins University School of Medicine in Baltimore, and soon to be my colleague as the new chair of radiation oncology at Indiana University, to go through some of those new data with us.

Let me take you back a few years to when, for the medical oncologist, radiation therapy was simple. You gave whole breast radiation to our patients who had a lumpectomy, and I only bothered you for post-mastectomy radiation in women with inflammatory disease, four or more positive nodes, or a primary tumor greater than 5 cm. Who needs post-mastectomy radiation today? I am often uncertain about whom to refer.

Richard C. Zellars, MD: There is still some uncertainty, but much less today than there used to be. Just to back up a little bit, some of the earliest randomized trials in all of oncology were evaluating post-mastectomy radiation. These trials date back to the 1940s. Those trials concluded pretty much the same thing with respect to local control: Radiation improved local control across the board. However, they did not show an improvement in overall survival.

Dr Miller: I'm going to guess that in the 1940s those trials, by today's standards, were probably pretty small and underpowered to look at overall survival.

Dr Zellars: They tended to be small, but they used old radiation techniques and they did not have the benefit of chemotherapy for those patients. We fast-forward to the 1980s, during which three trials were started, all using radiation techniques current for the time. All patients received systemic therapy, either chemotherapy or tamoxifen. When those studies came out in the 1990s,[1,2,3] we saw not only a local control benefit, which was not a surprise, but also a survival benefit with the addition of radiation.

Positive Nodes: Does Radiation Improve Survival?

Dr Miller: That was hard for medical oncologists to understand and to accept. If they are going to look at overall survival, those trials have a pretty long timeline. The radiation and the chemotherapy techniques were standards for the 1980s. But a lot changed in systemic therapy between the 1980s and the 1990s. Radiation techniques have continued to evolve as well.

Dr Zellars: If you look at those three trials that came out in the 1990s, there were two general critiques. One was that the systemic therapy used at that time was mainly CMF [cyclophosphamide, methotrexate, and fluorouracil], and that's not considered the standard today. The second critique was that there was an issue with local failure. Patients who had one to three positive nodes had a much higher rate of local failure than you would expect, approximately 33% at 5-10 years. In the retrospective analyses of current trials, the local failure rate in patients with one to three nodes is 15% and 13% at 5 and 10 years, respectively.[4,5] There was this disconnect, and that caused a lot of people to have less faith in the results [of radiation therapy] with respect to patients with one to three positive nodes.

However, we have newer data that call into question that concern. We have the meta-analysis from the Early Breast Cancer Trialists' Collaborative Group,[6] which has shown that there was a breast cancer–specific survival benefit with the addition of radiation in the one- to three-node groups. We have had reassessment of those post-mastectomy trials that came out in the 1990s,[7] looking at a more select group—patients with more extensive nodal dissection—and there was a survival benefit in the one- to three-node groups. Now we have some newer trials; of greatest importance is MA.20,[8] a Canadian trial. They randomized patients who had breast-conserving therapy and one to three positive nodes to radiation to the regional nodes or to no radiation. In that study, a disease-free survival benefit was seen as early as 5 years, which is pretty new. We haven't seen the final results of that study.

On the basis of those three trials,[1,2,3] the redo of a couple of those trials,[7] and the Early Breast Cancer Trialists' Collaborative Group,[4] we assume that patients with one to three nodes should at least have a discussion with a radiation oncologist about the potential benefit of radiation on survival.

Dr Miller: There is a pretty consistent story that additional radiation as part of the local therapy, almost regardless of the type of surgical therapy, seems to have some improvement in local control and overall survival.

Dr Zellars: The real hero of this story I would love to say is radiation, but I think it's the benefit from chemotherapy, which the patients in the older studies did not have. They most likely died of systemic disease before local therapy had a chance to improve their survival.

Patient Selection Critical for Partial Breast Irradiation

Dr Miller: The other controversial area in local therapy—and one in which we have seen a shift in enthusiasm lately—is partial breast radiation. It's almost a departure from what we have been talking about. We have been talking about increasing radiation, but this approach is decreasing radiation, irradiating less breast tissue. Five or 6 years ago, there was a lot of enthusiasm for partial breast radiation, so much so that enrolling patients in randomized trials was difficult. Those trials have finished enrollment, and in the past couple of years we have started to see some results that have put a damper on the enthusiasm. Where are we with partial breast radiation?

Dr Zellars: It's important to remember that there are several different ways to deliver partial breast radiation. The most common way is external beam. The second most common method is intracavitary brachytherapy, in which we place a radiation source in the lumpectomy bed. The third is intraoperative radiation therapy in which the radiation is delivered at the time of surgery.

Two large partial breast irradiation trials have been presented. One has been published. One is the TARGIT-A trial,[9] which used intraoperative radiation therapy. The other is the ELIOT trial[10] from Italy; it also used intraoperative radiation therapy. The ELIOT trial showed that patients who had whole breast radiation did significantly better than those who had partial breast radiation with respect to local control. On the whole, one would consider ELIOT a negative trial. The study authors point out that if you remove certain high-risk groups, the outcome would be better. So, they basically concluded that one needs to be very careful about who is offered partial breast irradiation.

The TARGIT-A trial is a more difficult trial to read. It has been published a couple of times with varying follow-ups.[11,12] Many people believe that the follow-up [of 5 years] is not long enough. In that trial, as a whole there was a higher rate of local failure in the partial breast group. However, those study authors said that once you remove the high-risk patients, the local failure rate is acceptable. The TARGIT-A and ELIOT studies came to the same conclusion: that one needs to be very careful about which patients are offered partial breast irradiation.

Awaiting Definitive Answers

Dr Miller: I always worry about those subset analyses, when you have a negative trial of a systemic therapy and then find a subset where it looked like it worked. We have also seen an analysis[13] of a Medicare claims database that suggested there might be increased rates of mastectomy [in women who received brachytherapy]. Yet, the database didn't allow us to know whether more women had mastectomy because of failure of local control, or whether there was a toxicity/infection/cosmesis problem.

Dr Zellars: Right. In that analysis of the Medicare data,[13] the authors show that patients who had partial breast irradiation were twice as likely to have subsequent mastectomy, twice as likely to be hospitalized, and twice as likely to have an infection as patients who had whole breast irradiation. The technique that we assume was overwhelmingly used in this population was not the intraoperative technique, but the intracavitary brachytherapy technique.

Dr Miller: That would be the Mammosite® or the SAVITM (Strut Assisted Volume Implant) device?

Dr Zellars: Or the ConturaTM, yes. That paper caused a lot of people to step back and reevaluate. The idea is fantastic. We treat only part of your breast. We reduce the number of treatments so you finish treatment sooner. And you may have less toxicity because we are treating a smaller area. It's a great idea. It's deserving of study, and it has been studied. I don't think we have enough evidence to say that it should be the standard of care.

Dr Miller: The B-39 study[14] will be definitive, but the results won't be out for a couple of years. Are there patients to whom you would offer partial breast radiation?

Dr Zellars: Ideally, any patient being offered partial breast irradiation should be in a trial so that we can learn from these patients to help future generations of patients. Outside of that, the very lowest-risk patients could be considered for partial breast irradiation. That would be an elderly patient, small tumor, ER/PR positive, wide margins—the standard low-risk category.

Sentinel Nodes: Surgery or Radiation?

Dr Miller: I have to take you to another local therapy area.We talked a lot about partial breast radiation and about what to do with the chest wall. I used to know what to do with the axilla as well. Our surgeons took out the axillary lymph nodes and that was it. They now do less and you do more. When do you think about axillary radiation instead of axillary surgery?

Dr Zellars: That's a huge topic. Let's tackle the easy question, the patients who are receiving neoadjuvant chemotherapy. [There is some controversy about whether a negative sentinel node biopsy after neoadjuvant chemo is reliable.] We have had two studies[15,16] in different countries with very similar results, basically showing that if a patient is clinically node positive or pathologically node positive before neoadjuvant chemotherapy, and undergoes surgery, you can trust the results of the sentinel node biopsy if two or more nodes are removed or two types of tracers are used during the procedure.

Dr Miller: That is a departure, because in the early sentinel node days it was widely listed in the guidelines that if a patient was known to be node positive or had neoadjuvant therapy, sentinel node biopsy was off the table. So have both of those recommendations changed? If a patient is clinically node negative, a sentinel node biopsy is now okay?

Dr Zellars: Given that those criteria are met, more than two nodes [are removed] and/or two tracers are used, yes.

Dr Miller: Then those results are accurate; you can trust them.

Dr Zellars: Yes, which I think is a win for many women.

Dr Miller: It's a huge win. We used to have days when women who needed neoadjuvant therapy would actually go to the operating room, have a sentinel node biopsy, come back and get their chemotherapy, then go back to the operating room again for their breast surgery. We can now make the patient flow easier. What do you do with the results? How do you decide which of those patients needs axillary radiation?

Dr Zellars: In the non-neoadjuvant chemotherapy setting?

Dr Miller: Or in the neoadjuvant setting. You just told me that if they had one to three positive nodes you would want to see them. They had a positive node. I made it go away. Do you still need to see them?

Dr Zellars: If the nodes are negative, the information about this varies. There are basically two camps that I like to consider. There is the NSABP [National Surgical Adjuvant Breast and Bowel Project] camp, which analyzed their neoadjuvant chemotherapy trials, B-18 and B-27,[17] and they basically showed that if someone is node positive before and node negative afterwards, their rate of local-regional recurrence is fairly low. You probably do not need to treat them comprehensively [with radiation] if they have a mastectomy. The MD Anderson data are a little bit more categorized.[18] Their data show that if someone has less than clinical stage III disease at diagnosis and is node negative afterwards, post-mastectomy radiation probably will not be of much benefit. However, if a patient is clinical stage III (and especially clinical stage IIIB), there appears to be a clear benefit of radiation even in patients who have become pathologic node negative after chemotherapy.

Those are the two basic camps I like to discuss. However, we have two great studies now open; one especially will answer some of those questions. NSABP-51 is directly addressing this question of what to do with the node-negative axilla after neoadjuvant chemotherapy.[19] In this trial, women are randomized to comprehensive nodal radiation or not. This is an excellent trial that will help move the field forward.

Radiation After Mastectomy?

Dr Miller: In our last few minutes, let's look at whatmay be the more common situation. A woman who goes directly to the operating room for primary surgery has a sentinel node biopsy, has one or two nodes with microscopic involvement. Should she have axillary surgery? Should she have radiation? Should you do both?

Dr Zellars: We had the great Z11 study[20] which looked at women receiving breast-conserving therapy. Those who were sentinel-node positive were randomized to axillary node dissection or nothing. They showed that the outcomes in those groups were the same. Z11 concluded that an axillary node dissection is equivalent to a sentinel node biopsy in this select group of patients. However, when the data were reanalyzed in Z11, we found that many patients actually received axillary node radiation.[21]

Dr Miller: We were shocked. Radiation oncologists cheated.

Dr Zellars: "Cheated" is a strong word. I would say they were overcome by concern for their patients. They felt uncomfortable, so they enlarged their fields to cover the low axilla, which was what everyone was concerned about. There was an additional field added in almost 20% of those patients. It really caused us to step back and wonder whether we could trust the results of Z11. Additional information has come out since then. A large study in Europe[22] looked at sentinel node biopsy alone vs axillary node radiation, and the outcome was the same in both groups.

That study argued that the options are probably similar, but the really exciting result came from MA.20,[8] in which they looked at patients who had an axillary node dissection; half of whom received regional radiation and the other half did not. This study again reported a disease-free survival benefit in the patients who had an axillary node dissection and radiation as opposed to those who had only an axillary node dissection. Looking at MA.20, one would argue that both arms of the Z11 were inferior treatments. However, [MA.20]* has not been published fully and we don't have much information about the patients to make a better comparison. Of course, there is a need to be cautious when comparing the results of two completely different studies.

Dr Miller: There is still obviously a tremendous amount of work to do in individualizing local therapy.

Dr Zellars: Absolutely.

Dr Miller: The meeting in San Antonio is still going on. Some of the results have not yet been reported. Are there any local therapy trials yet to come from this meeting that you are looking forward to that our listeners should be looking for as well?

Dr Zellars: Absolutely. There is a huge one coming out in which they are looking at ductal carcinoma in situ scoring to see whether that predicts outcomes. We are eager to hear the results of that study.[23]

Dr Miller: Stay tuned. Thank you, Rich.To our listeners, thank you for joining us in this edition of Medscape Oncology Insights. This is Kathy Miller, reporting from San Antonio Breast Cancer Symposium 2014.

*Corrected by Dr Zellars on review.


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