Radiation Before Mastectomy: Switching Treatment Order Allows for Immediate Reconstruction

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org senior editor Jamie DePolo.

Jamie DePolo: Hello, thanks for listening.

If early-stage breast cancer has a high risk of occurrence, which means coming back after treatment, nearly all doctors recommend radiation after mastectomy, but when a woman wants to have reconstruction, the timing of radiation after surgery is tricky, because radiation can cause changes in the reconstructed breast’s appearance and up the risk of complications, such as delayed healing.

So, many women have a tissue expander placed during mastectomy surgery and then receive radiation. Once the area has recovered from radiation, reconstruction surgery is done, usually about six or 12 months after radiation is completed.

Our guest today is Dr. Benjamin Smith, who holds the Jay and Lori Eisenberg Distinguished Chair in Radiation Oncology at the University of Texas, MD Anderson Cancer Center. Dr. Smith is a board-certified radiation oncologist.

He and his colleagues published a paper earlier this week on their study, called the SAPHIRe trial, which looked at giving radiation before mastectomy. This allowed women to have immediate reconstruction, meaning the reconstruction was done at the same time as mastectomy surgery, after the breast was removed.

He joins us to explain this study and the benefits switching the order of treatment may offer. Dr. Smith, welcome to the podcast.

Dr. Benjamin Smith: Thanks, Jamie. It's great to be on with you.

Jamie DePolo: So, how did the idea for this SAPHIRe trial come about? What made you think you could switch up the order?

Dr. Benjamin Smith: Yeah, so, giving radiation before surgery was an idea that was initially pioneered by some of our colleagues in the United Kingdom, and several years ago, at MD Anderson, we hired a plastic surgeon who had done some of his training and had been working in the United Kingdom, and so, when he came to MD Anderson, he was interested in seeing if we could start studying this approach in our practice, as well. So, he ended up being the lead author of our study.

And I remember he called me up maybe, like, eight years ago now, and he's like, Ben, you know, I can give you great idea...to, like, start off with radiation, and I was like, Mark, are you crazy? The radiation increases side effects of operative healing. You want me to radiate and make your life harder and worse for you?

But he was persistent, and he convinced me and my colleagues that this was actually a good idea, and so, we were able to incorporate this preoperative component of a clinical trial into a larger clinical trial that myself and my colleague Dr. Karen Hoffman were running called the SAPHIRe trial.

Jamie DePolo: Okay. So, could you summarize your research for us? All the women had external radiation? It wasn't any internal radiation or brachytherapy? That was all external?

Dr. Benjamin Smith: Exactly. So, this was an external beam radiation study, and we were enrolling women who needed to have a mastectomy. Either that was their preferred surgery or they had a large tumor and they had to have a mastectomy, or they had an underlying germline genetic issue, like a BRCA1 or 2 mutation, and they wanted to have a mastectomy to prevent future cancers, as well, as part of treatment for their index cancer.

And so, these are patients, we knew they wanted to have a mastectomy. We knew that they wanted, and generally would be operative candidates for reconstructive surgery, and then, also, based on their cancer characteristics, we knew that radiation was going to be an important part of their care. And so, we knew that if they had a mastectomy, I would be recommending radiation for them after mastectomy. We call that post-mastectomy radiation therapy.

That's been quite standard for about the past 30 years or so. But instead, we sort of like speed up time, and we give them pre-mastectomy radiation therapy, which is a term that we coined in this publication, giving the radiation therapy before their mastectomy. So, when we use the term post-mastectomy radiation or pre-mastectomy radiation, what may not be abundantly clear at first pass is that it implies a lot about where that beam is going.

So, with radiation that's heading into mastectomy, we're talking about more advanced breast cancers. We don't just want to treat a little area around the tumor bed. We want to treat the entirety of the breast, and we also want to treat all the lymph node basins which are draining the breast, and those are the internal mammary, axillary, infraclavicular, and supraclavicular lymph nodes. For your listeners who haven't taken anatomy discipline, that just means...

Jamie DePolo: That's most of us.

Dr. Benjamin Smith: Your armpit lymph nodes, the lymph nodes in your lower neck, and the lymph nodes next to your breastbone. You could think of it as, like, a semicircle above the breast that kind of like sits on top of the breast. The lymph nodes go kind of from the armpit to the breastbone.

Jamie DePolo: I have to ask, sorry to interrupt, would that area of radiation coverage, would that be the same whether it's before or after surgery? I guess what I'm wondering...because we haven't done surgery yet, so you don't know if the cancer is in the lymph nodes. So, is it possible that somebody could have a smaller treatment field after surgery?

Dr. Benjamin Smith: Yeah, it's actually the opposite. So, if you have surgery and your lymph nodes are clear, then we're not going to recommend radiation for you at all after mastectomy, because mastectomy alone is a great treatment for curing that type of breast cancer. So, instead, we're looking at patients where we know up front, essentially, they have lymph node-positive disease and/or a large tumor.

And so, we know what area we need to treat, but actually giving pre-mastectomy radiation or pre-operative radiation, we can treat a smaller area, because when you have a mastectomy, the surgeon, in removing the entire breast, has to go a little bit beyond the imprint or the implant of the breast on your chest in order to be able to have enough skin to close everything and make it look good and smooth.

So, when we give post-mastectomy radiation therapy, I'm treating a bigger area than if I treat pre-mastectomy radiation therapy, because pre-mastectomy, I only have to treat your breast. There's no operative changes that I have to treat, as well. It's a subtle distinction. It's not a huge difference, but in general, I would say that if we do pre-mastectomy radiation with slightly smaller target points that we have to treat, that means the area where we aim our beam, perhaps a little slightly better lung dose, maybe a little better heart dose.

Jamie DePolo: Okay. Okay, well, that's good to know. So, what were the results? Could you summarize those for us? Because, from what I read, they sounded very positive.

Dr. Benjamin Smith: Yeah. So, they were. So, we enrolled 50 patients, and ultimately, 48 patients underwent the whole treatment program of the radiation, followed by the mastectomy with the reconstructive surgery. So, we had two patients who had implant-based reconstruction, and one of them had quite a bit of challenges, so we have not advanced the program, moving forward, for implant-based reconstruction. So, I'm just kind of putting that caveat out there in advance.

However, 46 patients had tissue-based reconstruction. Either what's called a free flap, where we take some tissue from a different part of your body and move it and do microvascular, really fancy, super hard, amazing surgery to connect everything, or a rotational flap, taking some back tissue and moving it to the front. I realize that none of the listeners can see all the nice gestures I'm making right now to explain these procedures, but in any event, for those 46 patients who had a tissue-based reconstruction, they all successfully completed their reconstructive surgery. None of them lost their reconstructive flap. So, all of them are here today with flaps. Their flaps have not died, to the best of our knowledge.

And that was the primary outcome of the study, because we wanted to demonstrate, hey, is it safe for us, in Houston, Texas, with our radiation oncologist and our plastic surgeons, to give radiation first and then still be able to offer the patients a very high likelihood of reconstructive surgery? And so, the answer was a resounding yes, we can do. But there are some other really cool findings, as well. So, the follow-up is still short, around two years or so, but when we did this analysis, none of the patients in the study had had a recurrence. So, that's very encouraging, as well.

So, we don't seem to be taking any, like, major or horrible steps back with regard to cancer control by altering the sequence of treatment. So, that's very encouraging. And then, we were able to look at operative complications, and in essence, the operative complication rate was quite reasonable, and it was very comparable to another group of patients we had on the SAPHIRe trial, who had standard-of-care mastectomy, radiation, and post-radiation reconstructive surgery down the road.

So, I think it's very encouraging that, at least in our hands, we were not hurting patients by giving the radiation first, and we were able to help them quite profoundly by consolidating what, in our practice historically, has been two big surgeries separated by six to 12 months. You know, mastectomy and then your reconstructive surgery, we collapsed them into one surgery, one trip to the operating room, one anesthesia, one post-surgical hospitalization.

So, my patients who were on this trial, they typically got chemotherapy, and then they'd start their radiation about three weeks later. And radiation was three to four weeks or five to six weeks, and then about three weeks after finishing radiation, they go to the hospital. They're put to sleep. They have their mastectomy. They have their axillary lymph node surgery. They have their tissue-based reconstruction. They wake up. They're done with all their local and regional therapy, and they're done with their major reconstructive surgery. They're in the hospital for a few days. They go home.

It takes quite a few weeks to recover, but once they recover, they're done. They're back to life as usual. So, six months after that surgery, those patients, they're literally out dancing and like, having a normal life, you know, being a mom, being a wife, being a partner.

In contrast, the patients treated with standard of care, they're getting ready for big surgery, a three- to five-day hospitalization and six to eight weeks out from work, and so, the differences are just profound.

Jamie DePolo: Okay. I have to ask, did all the women have chemotherapy before they had the surgery? Was that a requirement, and could this work for somebody who wasn't having chemotherapy before?

Dr. Benjamin Smith: You know, the vast majority of patients had chemotherapy. If memory serves correctly, it was about 94% in our study, and the reason for that is the indications for chemotherapy and the indications for post-mastectomy radiation therapy largely overlap. So, this is a population that, typically, they're going to need chemotherapy, and they're going to need a mastectomy, and they're going to need radiation therapy.

With that being said, there are some patients, typically, it's going to be the estrogen receptor-positive post-menopausal breast cancer population, where they may not need chemotherapy, but they may need post-mastectomy radiation therapy. So, in that study, you know, we have these patients occasionally where their first treatment to treat their breast cancer is actually their pre-mastectomy radiation therapy. Then they have their mastectomy and reconstructive surgery, and then they can go on to receive endocrine therapy.

Jamie DePolo: Okay. So, is there any type of early-stage breast cancer that wouldn't be a good candidate for this order?

Dr. Benjamin Smith: Yeah. So, there are definitely patients who need a mastectomy who do not need post-mastectomy radiation therapy or where we don't know for certain until they have the mastectomy and we can look at all their pathologic findings. So, typically, that's going to be in earlier-stage patients, smaller tumor, maybe just a little bit of lymph node disease. We think they may not need radiation therapy.

Those patients should still have up-front mastectomy and axillary lymph node evaluation, because there's a good chance they won't need radiation at all, and so, we would hate for this strategy to result in people who are receiving radiation unnecessarily. In addition, I mentioned this earlier. We didn't have good outcomes in patients who had implant-based reconstruction.

So, if that was the patient's only reconstructive option, or that's the option they really wanted, then I wouldn't favor this approach. There's patients just for whom they have medical contraindications to autologous reconstruction. It's a pretty big surgery. So, if they're older and not a good operative candidate, have significant comorbid disease, or an elevated BMI that would preclude an autologous reconstruction, that would be a patient population where we need to explore other options.

Jamie DePolo: So, I'm wondering if you could explain a little bit more, what is it about implant reconstruction that causes problems with this order?

Dr. Benjamin Smith: Yeah, and I think we're still learning about that. We had a couple challenging outcomes, so we're not going to keep studying that right now, because we don't want to hurt people. We want to offer patients a high likelihood of having a really good outcome, but this is my simplistic, I'm-not-a-plastic-surgeon understanding.

So, when I give radiation, I cause some damage to the normal tissue. That's just a given. When a patient then has a mastectomy and a tissue expander placement, the plastic surgeon, typically, they'll take the tissue expander. They wrap it in a material called AlloDerm, which is cadaveric skin, and then that's placed in the patient and sewn onto their chest wall. Now, for healing to occur, that AlloDerm has to integrate with the undersurface of the skin, essentially.

Jamie DePolo: Basically, they have to grow together, in a sense, right?

Dr. Benjamin Smith: They have to grow together. Exactly. But the radiation that I've given, those skin cells aren't growing as well or as quickly because of the damage I've caused with radiation, and so, it seems like they don't want to integrate with the AlloDerm. So, that creates a potential space where fluid can collect, where infections can develop, and so, we have problems, and we think that's the underlying cause. So, for now, that's not an area that we're actively investigating.

Jamie DePolo: Okay. Thanks for explaining that. You talked about the benefits of switching the order. I'm wondering...and we'll leave the implant reconstruction out of it. Are there any risks at all that you've seen?

Dr. Benjamin Smith: Yeah. So, I would say, like, I treated the most patients of any of our physicians on this study, and like, everybody did really well. I had a patient, actually, with a little bit of some wound healing issues that weren't really that unexpected or bad, but in my personal experience, like, everybody did great, but one risk that we've talked about, and we're still trying to collect data to understand, is does giving radiation before surgery impact the pathologic findings in a way that could impact the overall cancer care?

So, to just unpack that a little bit, let's take the example of HER2-positive breast cancer that's lymph node-positive. Right now, the standard of care would be to give neoadjuvant chemotherapy. We use a common regimen called TCHP, which has Herceptin, which treats the HER2-positive breast cancer, and pertuzumab, which also helps to treat it. Both are targeted biological therapies, and there's a really beautiful clinical trial published a few years ago called the KATHERINE trial, where patients got neoadjuvant chemotherapy for their HER2-positive breast cancer, and then they had surgery.

And the patients who did not have a pathologic complete response, the patients with residual invasive disease in the breast and the lymph nodes, then went on to be randomized to receive a specific targeted agent Kadcyla, or more Herceptin. And what they found was that the patients randomized to get this newer targeted agent Kadcyla, or trastuzumab emtansine, they had about a 50% reduction in their risk of subsequent recurrence anywhere in the body, which is a fabulous finding. Changed practice overnight with regard to HER2-positive breast cancer. Now, we would hate for a patient to miss out on the opportunity to get that medicine if they're going to benefit from it.

So, the theoretical concern, and we don't have great data yet one way or the other to help make a decision, is let's say you got your chemotherapy, and if you're going to have your surgery, you didn't have a path-CR. There's still a little bit of invasive disease in the breast. So, you're going to need this new medicine. But what if you get your chemotherapy and then I give you radiation, and what if the radiation gets rid of the little bad cells that were still left behind?

And now, all of a sudden, you have a pathologic complete response, but it was from me and not from the chemotherapy drugs. We would think that you might actually still benefit from trastuzumab emtansine, but we wouldn't know it. That theoretical concern, I think it's a valid theoretical concern, but I don't know that we have enough data one way or the other to be able to make any decisions about how much of a real-life issue that is for the patient sitting next to me in clinic.

So, that's, I think, one issue that we're still working through. I'm trying to collect more data on that right now. I'm trying to do paired biopsy. Basically, a biopsy after chemo and before we start radiation, and then see, well, if you had a little cancer before I started radiation, does it ever go away with radiation? So, we're actively collecting data in that space and look forward to publishing results probably in about two years, but right now, there's no good data, that I'm aware of, to help with that decision.

Jamie DePolo: Okay. Did any of the women in this study, in the SAPHIRe Trial, did they have HER2-positive disease?

Dr. Benjamin Smith: There were a handful of patients with HER2-positive disease.

Jamie DePolo: Okay. So, did they...yeah, they got chemotherapy, and then I'm assuming they got Herceptin and Perjeta combined with that up front, and then you gave radiation?

Dr. Benjamin Smith: For the most part, yeah, and then adjuvant Herceptin and pertuzumab, also.

Jamie DePolo: Got it. Okay. So, you mentioned your follow-up, which is just about two years, which is great, but I'm wondering, we know that hormone receptor-positive disease, you know, can come back up to 20 years. So, are you continuing to follow these women?

Dr. Benjamin Smith: Yeah. Absolutely. So, we continue to follow these patients. The protocols are to follow them for 10 years after we treat them. It's a challenging time now to do clinical research, because there is so much upheaval in just provision of healthcare and people switching insurance plans and different...you know, giant healthcare entities accepting different plans and not others. So, I would tell you it's a challenge to follow up patients for 10 years, not because of my availability, but just because of all the challenging social factors in our society that cause the fragmentation of healthcare, but we're doing the best we can.

Jamie DePolo: Right, but it's really you plan to...so, just so we can see, at five years, did...

Dr. Benjamin Smith: Absolutely.

Jamie DePolo: ...this group have a higher-than-average risk of occurrence, or maybe they had a lower average recurrence rate? We don't know yet.

Dr. Benjamin Smith: Yeah. Absolutely.

Jamie DePolo: Okay, and then, finally, so, this was a phase II trial, kind of small, 48 women. You're now enrolling women in a phase III trial, which I believe is called the TOPAz trial. So, could you tell us about that study and where we're going from here? I'm assuming a woman could not, right now, ask for radiation before mastectomy, unless she were part of a trial, but I don't know that for sure.

Dr. Benjamin Smith: Yeah. Those are great questions. So, yeah, I'm the PI of our trial, which I named the TOPAz trial. I kind of jokingly say it's the trial of pre-operative zapping, because the Z doesn't really stand for anything, but it's a trial of pre-operative radiation, and it's essentially, a follow-up to the SAPHIRe trial. So, it's actually very similar. It's the same randomization arms as the SAPHIRe trial. It's a little bit more inclusive.

So, we're including women who are a little bit higher risk with regard to their cancer burden, but still non-metastatic, and then they're still randomized to the shorter versus the longer course of radiation therapy, and they undergo their mastectomy with tissue-based reconstruction, and we’re trying to enroll about 124 patients did the trial, and if you were to see me in clinic today and you were a good candidate for preoperative radiation therapy, we would strongly encourage you to enroll in that clinical trial.

You raise a good question. Like, could you get this treatment off-trial? Well, it's standard-of-care radiation. It's standard of care surgery, and really, all you're changing is the sequencing. So, there's no, you know, fundamental structural barrier for me offering this approach to patients outside of the clinical trial. I think it requires careful counseling of the patients to help them understand this is a newer approach to sequencing. We think it's going to be great.

We don't have as much long-term data, and there are some patients who are like, oh, I really don't want to do something if we don't have good long-term data yet. There are others who are like, oh, there is such profound benefits to me. Like, I would really like to do this, even if it wasn't on a trial, because, you know, this is going to help me in X, Y, Z way. So, I think that's where it comes down to a really important conversation with the patient to engage in some shared decision-making around what are the important values that the patient has in deciding about her care.

But fundamentally, there's no reason you couldn't do this outside the clinical trial. I think you really want a good, experienced radiation oncologist and radiation oncology team who can deliver high-quality radiation, and probably even more importantly, a plastic surgeon who's very familiar and comfortable operating on radiated tissues and who has special training in microvascular reconstructive surgery. That's really a must, I would say, in order to safely implement this treatment paradigm.

Jamie DePolo: Okay, and obviously, only flap reconstruction, not implant reconstruction, too? That would be sort of...

Dr. Benjamin Smith: That would be my recommendation, yes.

Jamie DePolo: Okay. Dr. Smith, thank you so much. This is really, really interesting and fascinating, and I am going to be following the TOPAz trial on the clinicaltrials.gov site just to see where you are, how it's going, because this could...I mean, obviously, it's not for everyone, but it could be really a nice way to consolidate treatment for the right folks.

Dr. Benjamin Smith: Absolutely. Thanks so much for your interest in our work, and we'd love to come back and talk about TOPAz in a few years.

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