Chapters Transcript Video On Target with Dr Akila Viswanathan – Breast Cancer in the Modern Era for Seminars in Radiation Oncology Dr. Akila Viswanathan and Dr. Jean Wright discuss the most recent recommendations for treating breast cancer with radiation. Hello everyone. Happy New Year. I'm dr Akilah Viswanathan, the director for johns Hopkins radiation oncology and molecular radiation sciences and this is my podcast. You can subscribe to our podcast from wherever you are or find them at Hopkins cancer dot org backsplash podcasts today we're very happy to speak with dr jean right about the latest in breast cancer derived from a seminars in radiation oncology. C series of articles that were recently published, Dr Wright is based at Sibley Memorial Hospital in Washington, D. C. She's the director of the breast cancer program for the Department of radiation Oncology and Molecular radiation Sciences and works closely with a multidisciplinary team of breast cancer experts at johNS Hopkins welcome dr Wright. Thank you. So we're very excited to talk today about all the latest and newest changes and Advil dances that have occurred in breast cancer. And this started with the seminars and radiation Oncology Journal issue that you guest edited with Dr Catherine Park from UCSF. Tell me a little bit about how did you select the theme of biologically driven paradigms and what does that really mean? So when we sat down to think about this issue, we wanted to think about the best way to frame the way we think about breast cancer and specifically radiation therapy for breast cancer in the modern era. And we thought that the most important shift in the way that we think about management, related to our better understanding of the biology of breast tumors and the variability in the biology of breast tumors and how that has really driven the way that we tailor care in the modern era so much differently than we used to, which was more sort of based around the stage of disease and less around biology in terms of the way that you set up the series, it actually really follows a new flow where thinking about times when radiation may actually not be used at all is one of the considerations based on these biological factors. I just wanted to ask, has there been a change in the recommendations of R. T. Overall in the most recent research and some of the findings that you have and what was summarized? I think in one of the articles about using raid or not, there are a couple of really key themes going on in radiation therapy for breast cancer and one of them is the more judicious use of radiation therapy with the lens of avoiding overtreatment and really using only the amount of radiation therapy that's necessary. So in certain cases that looks like avoiding radiation therapy in cases where we might traditionally have used it and in other cases that might look like reducing the volume of tissue that's exposed to radiation such as partial breast radiation therapy or avoiding the use of regional lymph node radiation therapy in cases where we might historically have done it. There's a large theme about reducing the intensity or the target volume or even the use of radiation therapy and all of that really does. Center around biology. Up until recently we've had some national guidelines that allow us to forgo radiation therapy in patients who have low risk breast cancers, primarily defined by age. Looking at the population Of women who are 70 years of age or older. And had low risk features such as lymph node positive disease and estrogen receptor positive, which does play into the biology. But there are quite a few studies that either have early reports or are still in progress that are looking at omitting radiation therapy in patients who have biologically low risk cancers but focusing on that as opposed to the age. So a lot of the studies that are summarized in that chapter are looking at avoiding radiation therapy and patients who are between 50 and 70 years of age. So postmenopausal but under 70. But the biology is assessed using a number of different techniques and I think that's one of the challenges for our field going forward is what is the best or what are the best techniques for doing that, whether its receptor combinations or using tests like the archetype or the Pan 50 tests which some of the studies have used in pre invasive cancer ductal carcinoma in situ or D. C. I. S. We oftentimes have talked about admitting radiation because it's not truly invasive but we now also have in this article the very first article in the journal by Moran at all molecular profiling and how is that? Molecular profiling. Changing the management of the ductal carcinoma insitu group of cancers, interestingly I would say that molecular profiling has really taken hold in the setting of invasive breast cancer, initially directing the use of systemic therapies. And now more and more being evaluated for directing the role of radiation therapy in D. C. I. S. There are a couple of tools that are genomic assays that can be used to try to predict a patient's risk of having a recurrence of DCs within without radiation therapy. But those have not gained as much traction as the ones that are used in invasive cancer. So the chapter by Moran at all does a really good job of just laying out the background data for the various tools that are available and the type of work that we would I need to do to bring them more into the clinical paradigm. I think that one of the challenges with pre invasive cancer is that we know that radiation does not impact survival. It just reduces the risk of an in breast recurrence. And so the issues surrounding whether or not to offer radiation therapy or to receive radiation therapy are more complex just because of the risk benefit ratio. We have not adopted these molecular profiles as much in D. C. I. S. But I think we're looking for the best ways to do that going forward. Excellent. Well that will certainly be something we eagerly await in the future. The patient voice is incredibly important and how patients feel and their choice really. What patients sense is of benefit to them. But then also understanding the incredible challenges that they're facing both in terms of functional and physical emotional and then psychological stressors that are ongoing. You chose to place the patient voice article that is really about treatment decisions in toxicity reporting fairly early in that journal. And I'd be curious to hear a little bit about your thought about this topic and how it integrates in as well with the other journal articles. We thought this was a really important chapter to include because the two previous chapters that focused on D. C. I. S. Where the role of radiation therapy as we said can be debated in many cases. And then on that low risk population where we're also looking at identifying patients who can avoid radiation therapy. Those are two populations where really the decision does come down to a very tailored and very individual balancing of the side effect profile that can be expected with the course of radiation therapy both acute and long term and the benefit and the perceived benefit of treatment and the perceived burden of side effects is going to be variable from patient to patient. So we thought it was very important to bring this chapter early on in order to frame the way that we think about making these decisions. We I think not just in breast cancer but across the field of oncology that we need to be thinking more about toxicity reporting from the patient's perspective and less so from the physician's objective perspective. And so there's a lot of work going on in breast cancer to look at how to bring patient reported outcomes into our understanding of toxicity experiences and therefore into the decision making process. So this chapter was great because it focused on the tools that we have for patient reporting and then also how we can use that information to really carry out a shared decision process, which the majority of our patients really prefer. A shared process rather than being told what to do or being given the information and saying what do you want to do? They really are looking for a shared process and how to carry that out is something that we need to learn how to do better. Absolutely. I'm sure that the patients really appreciate all of the changes occurring in breast cancer, radiation and the evolution of the field and want to be part of the decision making is these are evolving but it gets harder and harder when these things are so new. There's not much information available. Absolutely. So you move on to talking a little bit about regional nodal radiation. Right? So typically we think about treating the breast and the lumpectomy cavity or the region of the breast around where the surgery occurred. But then also considering treating the axillary nodes or the nodes up higher by the soup particular region. And first of all, what do you mean by regional nodal radiation? How is that defined in the modern era? Regional nodal radiation, I'd say can have a number of different meanings because there are different nodal basins that we might consider treating based on the clinical scenario, looking at even what quadrant of the breast the tumor was originally located in and whether or not axillary lymph nodes are involved. So regional nodal radiation is something that has to really be defined from patient to patient. The term that we use when we're thinking about treating all of the lymph nodes that could be treated is comprehensive. Regional lymph node radiation which would include the internal mammary lymph nodes, the supra and in very particular lymph nodes as well as the axillary nodes. But really there is now more and more nuanced as to which of those groups we would include and that would also vary with the extent of surgery that they've had. So I think that the way that we have started to think more and more about regional lymph node management is in relation to biology because biology often determines whether a patient's going to receive systemic therapy before or after surgery. So her two positive tumors and triple negative tumors. Many of those are now treated with preoperative systemic therapy. And it's a real challenge for us as radiation oncologists or it has been because of the fact that all of the early literature that defined the role of regional lymph node radiation looked at patients who had surgery and it was really all based on the number of lymph nodes that were positive and less on the biology and less on response to systemic therapy. There's a great divide in terms of whether a patient has had upfront surgery and we still are basing our recommendations on things like just the number of lymph nodes of pathologic assessment. In addition to biologic factors versus after patients had preoperative systemic therapy. And then we're also including how well the tumor responded to preoperative systemic therapy into the decision process. So I think these two chapters do a very good job of reviewing the factors that would influence our recommendations for regional lymph node radiation therapy, whether that's comprehensive or more limited to, for example, the low and Zilla in certain situations. And also discussing some of the ongoing clinical trials because these are two areas where there actually are ongoing cooperative group studies that are asking the question of, do we need to do regional lymph node radiation therapy? And these two clinical scenarios. The one that looks at the use of the archetype test to see if we can identify patients who have lymph node positive disease but have a low enough risk of recurrence that they don't require regional lymph node radiation therapy. And then the major study that's described in the chapter that addresses nodal management after preoperative systemic therapy. Look at whether or not we can forego lymph node radiation therapy and patients who had no positive disease but become no negative after an excellent response to preoperative systemic therapy. These are two really really rapidly changing areas and a lot to think about from patient to patient know it certainly sounds like patients must get highly individualized recommendations. And one of the things in the past I mentioned earlier lumpectomy followed by radiation was one of the newer paradigms many, many, many years ago. Now that's become standard but that's an alternative to mastectomy. And in some ways sometimes mastectomy has actually become more popular. But you chose not to write so much about postmaster radiation but instead about the integration of radiation with the reconstruction. Is that becoming the new standard that you're seeing very much as radiation after reconstruction. And absolutely I would just say that historically we have thought about radiation after lumpectomy or radiation after mastectomy. But now more and more we really are focusing on the lymph node status as being one of the primary drivers of whether a patient needs either nodal radiation or Postmaster radiation therapy. And in the clinical trials that I just described the eligibility and the randomization really relates to the lymph node status and is agnostic to the type of breast surgery that a patient had. So it really moved to thinking about the lymph nodes as being the main driver of some of these treatment decisions and whether or not the patients had mastectomy really primarily influences the way we would integrate radiation with reconstruction for those patients. So I'd say yes many or I would say most of our patients who have mastectomy have reconstructions, although there's certainly a population of patients that choose not to do any form of reconstruction and value the quality of life of not having to deal with the multiple surgeries that are involved etcetera. But the vast majority of our patients who have mastectomy do have reconstructions and there are a lot of complexities surrounding how we interdigital eight. Those two aspects of their care, the timing and the sequencing of things. And there's also active research going on in that area. One of the ships that will probably get to shortly that's going on is also a movement towards hypo fraction ation and breast cancer and using fewer and fewer radiation sessions. But most of the studies that have looked at hypo fraction ation look at patients who have had radiotherapy to the breast or possibly the breast and the regional lymph nodes. But less so for patients who have had mastectomy with reconstruction. So there are a couple of important ongoing studies looking at short course radiation therapy and patients with reconstructions. And so that's covered in this chapter. Got it when you mentioned short course and hyper fraction ation take me through just the basics of what was a traditional regular course of radiation. How long was it? And then when it moved to like short course who qualified for short course, like was that age based or was it for everybody? And then this hypo fraction ation and ultra fast or a short course radiation. What are the lengths And our bacteria defined for each type of the historical approach to radiation therapy would be 1.8 to 2 great per fraction for a total dose of if you include the breast plus a boost to a total dose of 60 gray. And so that could end up being six weeks, 6.5 weeks of daily radiation therapy. And I'd say about a decade ago or so. We had mature data that compared that approach to what we now use the term moderate hypo fractionated. We used to just call it hyper fraction ation. But now with these ultra short courses we have to add that it's moderate hipaa fraction ation and so those are courses of 3 to 4 weeks. And I would say that that had become the standard for patients who are receiving radiation therapy to just the breast but not the regional lymph nodes about a decade ago or so. And so we have really moved towards doing the moderately hypo fractionated course for those patients that didn't require lymph node radiation therapy I'd say in the last five years we've had more data that shows us that it is reasonable to also offer moderate hypo fraction ation to either patients who've had a mastectomy without reconstructions and or to patients who require lymph node radiation therapy in addition to the whole breast radiation therapy. But that's a relatively new group of patients that we're offering moderate hypo fraction ation too. And there's some nuances to which patients are better suited for the moderate hypo fraction a shin versus conventional. But I'd say now that many of our patients are candidates for this moderately hypo fractionated approach. One thing I'll just but as a caveat is for proton radiation therapy, we still are using conventional fracture nation just because it's a little bit less well studied with the shorter courses. But then what happened in the middle of the pandemic was that there was mature data that was published from a couple of studies looking at whole breast radiation therapy using only five radiation sessions and that's called ultra short course or extremely hypo fractionated regimens and those are generally suitable for patients who do Not require lymph node radiation therapy and who have not had mastectomies. There's some variability across the country as to which patient populations are being offered that here at Hopkins, we do use it for patients with particularly low risk tumors and older patients. The studies that were done looked at an age cut off of 50, but the majority of the patients that were studied were a little bit older. And so we tend to offer the ultra short course to patients who have early stage breast cancer and are about 65 years of age or older. But that's something that as a field we're still really investigating and my suspicion is that this is covered in some of the chapters that will be offering these ultra short course approaches to more and more patients over time as we gain data. And then the other thing is just partial breast radiation therapy is also only five radiation sessions. And so many of our low risk patients are eligible for that. Even if they're under 65 they have small early stage breast cancers. They can often receive only five fractions with partial breast and partial breast means she just to the lumpectomy cavity correct. Are there still varying techniques for how partial breast can be done? I would say that there are there are a lot of different approaches and a lot of different dose fraction ation schedules that have been published and they're all viable, reasonable data supported approaches. One thing that happened with the pandemic is that 10 year follow up was published from a regimen that was developed in Florence italy we called the Florence protocol that was using intensity modulated radiation therapy to do partial breast radiation therapy in five sessions and because of the convenience of that and only once a day because of the convenience of that. I think that when we're using external beam radiation therapy that's really become the preferred regimen. That's what the N. C. C. N. Guidelines now support. And it's just the most convenient and accessible. The early studies that looked at partial breast radiation therapy used these twice daily regimens so 10 fractions twice a day. So they were five day schedules but patients had to come in twice a day for treatment and that was obviously burdensome and inconvenient for patients. So the new five fractions once a day is just really made it much more accessible for a lot of our patients. And with the 10 year data from the Florence study it's become a really good approach obviously in these changes. Some of the ways that we actually draw delineate the areas for treatment which we call contouring have changed. What are some of the most appropriate and best ways that the radiation oncologists should think about what to treat and how to treat. You know in the old era used to be that each region of the country or each big cancer center or site would have its approach. And it was known for that Now we have much more standardized guidelines in the field of radiation oncology. So people tend to be doing things more evenly across institutions. But what are some of those guides and guidelines that we use that are really the best space for radiation oncologist to think about how to go forward with planning treatment. We do have a chapter we call it target delineation contouring for breast cancer and one of the reasons we thought it was important to address that is because there actually are a number of resources that are available. If you just do a pub med search or do a google search for target delineation for breast cancer, you'll find that there are actually a number of different atlases. There's a european atlas and there are two different atlases that are actually sponsored by N r g r T O G oncology depending on the clinical context. One is for use for patients who are receiving proton therapy and the other is our more general atlas that we use for patients receiving photons, radiation therapy, their valuable resources but they can also be confusing because they're not exactly the same. And how do we decide which atlas to use and why this chapter really looks at the differences in the various atlases and how we can sort out when to apply one set of standards versus another because it does actually vary with the modalities, such as whether you're using protons or photons, it varies with the treatment approach, even within photons, if you're using three d informal radiation therapy versus intensity modulated radiation therapy. The way you would approach contouring is a little bit different. The chapter also looks at patterns of failure and you know, where if patients do have, for example regional lymph node recurrences. Where do those occur and what risk factors are associated with that particular pattern of recurrence so that we can really tailor our target delineate to the patient's clinical scenario. That's actually a fairly complex aspect of the decision process in how we carry out our plan. So this chapter I look back at it actually quite frequently. It's just an excellent resource for how to think about things and what to access when and where to get it. The experts teaching the experts basically. Yes, absolutely. So one of the newest things that we hear about all the time is artificial intelligence and it means so many different things in different contexts. But in radiation oncology we apply it to some extent to the use of auto segmentation or contouring for volumes. Using technology that's brand new. What are some of the ways that we're using these ai tools like auto segmentation to help reduce toxicity or side effects from radiation. The most important area for aI application for treatment planning is in cardiac dose symmetry analysis. Historically we identify the heart as just one structure and we say we want to avoid the heart but we're learning more and more that the impact of radiation exposure is different depending on what part of the heart or what sub structure is being assessed. It is very difficult in some cases to really identify, for example where exactly the left anterior descending artery is or the left ventricle, which is considered really important avoidance structure. There's a lot of effort going on right now in terms of auto contouring of these cardiac sub structures, which allows us to number one assess our radiation dose to those structures in a more sophisticated way and then to really learn more about the radiation tolerances of these various sub structures and how that varies with patient cardiac risk factors. We do know that the baseline cardiac risk is associated with a higher risk of radiation induced toxicity. So it's really important to have an understanding of patient's individual risk and then a better understanding of the radiation dose to these various sub structures. The chapter that addresses this also talks a little about proton radiation therapy. The primary potential benefit hypothetical benefit of protons in breast cancer is avoidance of the heart. But there are actually differences in the radiation dose to the various sub structures. When you use protons versus photons. There's a large clinical trial that we're participating in going on right now comparing protons two photons for patients who are receiving lymph node radiotherapy because exposure of the lymph nodes to radiation tends to drive up the car exposure. And so that study will really help us to understand the impact of not only radiation in general to these sub structures, but the differences between the various modalities, but the ability to really auto segment these sub structures so that we can more rapidly access doses is going to be one of the major impacts. I think going forward. Some patients have disease that's limited to the breast and others have disease that it's migrated outside of the breast to the nodes or sometimes to one other site. It's in one site and not in multiple. We tend to call it Allah go metastatic breast cancer and that can be treated as well. There's a nice article on Oliver metastatic breast cancer and I was wondering if you could summarize some of the concepts about whether ah ligo metastatic disease is now considered differently than it used to be. And what are some of the paradigms that we're using to treat patients that might have disease spread to just a limited number of locations. The chapter tackles this really challenging and kind of controversial area of oligarch metastatic breast cancer. As you were describing. Olivo metastatic breast cancer refers to scenarios where a patient has disease outside the breast and the regional lymphatic. But to a relatively limited number of sites, there are a number of studies that are ongoing that have really looked at whether managing these Oliver metastatic sites with radiation therapy typically steri attacked radiation therapy improves outcomes right now in breast cancer in particular, it's considered very controversial and there's no clear evidence that there really is a benefit to offering radiation therapy to all the oligarch metastatic sites for these patients. But the reality is that there's a posse of data and that as we were talking about this entire discussion breast cancer is such a spectrum of diseases and the way that management of Allah go metastatic disease might impact long term outcomes is going to be variable by the subtype and what other systemic agents are available. For example, patients with her two positive disease, fortunately we have a really, really long list of targeted therapies that are available for patients with her two positive disease. That's a disease sort of subset where systemic therapy is particularly, you know, there are particularly wide range of options. Whereas in something like triple negative disease where there are fewer options for targeted systemic therapies. That's a scenario where radiation therapy could have potentially more of a row. There are also a lot of studies that are looking at combining radiation therapy with immunotherapy in particular or with other forms of systemic therapy and either the oligarch metastatic setting or the kind of locally advanced setting. So I'd say that there's really at this point, not like a take home or a known role for radiation therapy in this context, but there's a lot of work going on in a lot of really sort of basic biology that we need to understand to know whether this is something that will be useful for any of our patients down the line. You mentioned immunotherapy. There are quite a number of trials, clinical studies ongoing looking at combining immunotherapy with radiation therapy and using radiation boost even in patients with metastatic disease. So it seems like this is a rapidly evolving field and one in which will have much more information coming out in the next few years. Is there a current accepted standard at this point for how immunotherapy and radiation are combined? No, I mean honestly there isn't. And I think that's one of the hardest things. The keynote five to to study that was published a year or so ago showed an added benefit in terms of pathologic complete response rate for patients with triple negative breast cancer who are receiving preoperative chemotherapy. So it has now become standard of care that patients with triple negative disease who are receiving preoperative chemotherapy have embolism have added to their chemotherapy regimen and that this improves the pathologic complete response rate. But we don't really have a good idea about how the toxicity profile of that regimen relates to radiotherapy because in that study, patients continue on the pebble is a map adamantly as well which is when we deliver the radiation treatment. And so there's a lot of discussion around, do we overlap the radiotherapy with their ongoing immunotherapy or do we stagger them? That's something that we individualize. But we also have one study in particular that looks at adding three fractions of radiation therapy early on in that regimen of chemotherapy plus immunotherapy to see if the addition of radiation therapy would further improve the rate of pathologic complete response in these patients. And it's a really cool study because it randomizes patients to one of three dose levels for radiation, one of those dose levels is zero. So they could get randomized to not receive radiation therapy at all, or they can receive either nine grade or 24 grade based on laboratory analysis. There is some suggestion that this nine gray dose may be sort of the optimal dose in terms of priming the immune system using radiation to prime the immune system. But there are other studies that suggest that 24 great way the right dose. It's kind of cool because patients are randomized to these three different dose levels. And so we'll hopefully be able to get a better understanding of Not only does radiation there be crime, the immune system, but which dose level is the right one to maximize that effect written. And really interesting information that we're going to blame from these trials and these important studies. You mentioned earlier that proton therapy is something that's also being tested. And I know that you treat at simply Memorial Hospital where we have the johns Hopkins proton therapy Center. Are you running any studies related to proton therapy and cancers, breast cancers or other types of cancers that you'd like to bring up? Sure, well, we are participating in this rad comp which is the national study that I mentioned earlier that is randomizing patients to either photon or proton radiation approaches when the primary endpoint of that study is cardiac endpoints. So from the perspective that that study takes is that cancer control or oncological outcomes should be similar between the two approaches, because the radiation itself is equivalent, we have different ways to do it, as I was alluding to before, but we generally target the same areas based on the patient's clinical risk. But we can sometimes achieve lower cardiac doses with the protons versus the photons. And so the question is, a is that clinically impactful in terms of a patient's risk of cardiac events down the line. And then what can we learn more about the specific impact on these cardiac sub structures? So that's a study that we are participating in. And then the other thing that we very recently have started doing in the context of our proton registry is a three treatment, partial breast radiation approach. And we're limiting this to particularly low low risk patients who are considered the astro guidelines have criteria for partial breast radiation therapists that are described as quote, suitable cautionary or unsuitable. So our study is looking at patients who have suitable characteristics for partial breast radiation therapy and again, using three fraction approaches. Just even more convenient than the five fraction one depending on the location in the breast that we're treating. That can be very helpful for again minimized radiation exposure to the heart and in some cases the lungs. And then the last one I'll mention is that we have a study that is for patients with really large symptomatic tumors in the context of metastatic breast cancer. This study is actually open to all histology is not limited to breast cancer, but we have treated quite a few breast cancer patients who have poorly controlled local disease involving the breast and they receive a single fraction of what's called space initially fractionated radiation therapy, which is high dose of radiation therapy to small islands within the tumor surrounded by low dose baths. And we call that the proton grid. So we have, the proton grid study is available for patients with large breast tumors. They receive a single fraction, it's 18 gray and one fraction to these high dose fosse. And then that's followed with a short course of more conventionally fractionated radiation therapy. We've had some very good responses but with a very small patient number at this point. All fascinating and really, really interesting. Well, I'm so glad that we had this opportunity today to review updates in radiation oncology for breast cancer and dr rights leading and guest editing issue of seminars and radiation oncology. So, thank you again for joining us. Dr Right, thank you all for having me today. Remember you can subscribe to all of our podcast from where you're listening from or find them at Hopkins cancer dot org back slash podcast Created by Related Presenters Akila Viswanathan, MD, MPH, MSc, MD Director, Johns Hopkins Radiation Oncology and Molecular Radiation Sciences View full profile Jean Wright, MD Director of Breast Cancer Program, Department of Radiation Oncology and Molecular Radiation Sciences View full profile
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