David Raubach: So, shifting gears, uh that was a a great discussion of telehealth for part one of this episode. And now, this is part two with Dr. McDonald, and I know you have a hard stop here uh at at 4:45 your time. Um but, I do want to make sure that we touch on because this is also been in the news um is the RadComp trial or the radiation or radiotherapy comparative effectiveness trial. Um and you presented at ASTRO in September, um and there were some preliminary results from that trial. So, for those that maybe aren’t familiar, and and I would say specifically maybe for the general audience, not a lot of doctors are familiar with this

David Raubach: trial, but it maybe just the general public that’s curious about what a RadComp trial is and why we’d be doing this, talk about what the trial is, how it was structured, and why a trial like this is important.

Dr. Shannon MacDonald: Yeah, so um so, RadComp is a randomized trial for women or men with locally advanced breast cancer, where you are treating the internal mammary nodes, which brings radiation closer to the heart. So, those are patients that are likely to have a higher mean heart dose or higher doses to the cardiac substructures. So, we chose a population that would be a greater risk of heart disease. We um we opened the trial, and we successfully accrued 1,239

Dr. Shannon MacDonald: patients, patients that were willing to be randomized to photon therapy of any modality or proton therapy. And we collected the all of the DICOM images and plans. We collected lots of information on health-related quality of life. We’re we are still collecting that, and we’re also collecting information on local regional recurrence, which is another endpoint that’s a major endpoint anticipated around 2028. And then our primary endpoint is major cardiovascular events, which is anticipated around 2031, 32, or when we meet that endpoint statistically. But those are That was the what was considered to be most important but from physicians and patients. And though it’s a very late endpoint and takes a long time, um PCORI was willing

Dr. Shannon MacDonald: to fund our study to for that very long endpoint, which is more expensive. And um and that’s the the thing that was most important to to patients. Um couple special things about breast cancer, although protons were used for partial breast radiation, really we didn’t start to treat locally advanced breast cancer, to my knowledge, with the first patient was treated in 2010. That’s when the first pilot study opened and we quickly moved from pilot trial to phase three randomized trial. So for the breast cancer community and the proton breast cancer community, I think we’ve done an excellent job of enrolling patients on studies, um doing it sort of like in a rapid, like really careful way.

Dr. Shannon MacDonald: And um and it’s um and I think it’s a great indication for protons and it’s great to be able to enroll so many patients on trial. And I think that that treatment has really taken off in the past, you know, decade to 15 years. So.

David Raubach: I think one of the challenges that we’ve had with treating breast cancer uh with protons is um this the skin toxicity. Um and cosmetic outcomes are obviously really important to patients. So just talk about in your experience how you’ve thought about approaching this issue of skin toxicity, maybe both with photons and with protons, and how things like pencil beam scanning have helped evolve protons to be able to deal

David Raubach: with these cosmetic issues.

Dr. Shannon MacDonald: Yes, so David, that’s an excellent question because it’s it’s one I would love to address in a formal way and then and informally here. But one one important thing to remember is we started using, you know, protons for breast cancer around 2010. But if other disease for other disease sites, radiation oncologists were contouring routinely, but the first atlas for breast cancer came out in 2008. And most radiation oncologists were treating by just putting fields on, ignoring the contours, not giving full dose to the lymph nodes or the breast or chest wall. And at the same time we started to use protons and you know, some IMRT and 3D. But we

Dr. Shannon MacDonald: went There’s a nice study from MD Anderson that shows that when you were treating with when we were treating with fields for 3D and and not contouring, we basically covered those those targets from the chest wall was covered 70 to 74% for to 45 gray for a dose of 50 gray, essentially. So you were not covering fully. The lymph nodes ranged anywhere from 80s to 90% 90 maybe 92%. So we went from that to contouring. You have to contour for protons. You don’t contour it, it doesn’t get treated. But when you contour it, usually your your dosimetrist is going to cover it completely. And then with with 3D protons, which was all that was available

Dr. Shannon MacDonald: when we started and many of the enrolling institutions on RadCom even were still using 3D. Some Some institutions still have 3D protons. You have to give full skin dose. So that includes where you treat the lymph nodes and the chest wall, which leads to a much higher skin dose. And arguably even when we move to pencil beam scanning where you can control the skin dose better, we don’t do it. We give a higher dose. So I think most of the time we’re giving a higher skin dose and immediate subcutaneous dose with protons than we are with photons and we’re not sort of thinking about the equivalent. Like should we be reducing and driving down the

Dr. Shannon MacDonald: skin dose? And many I do this for my patients. I know other breast radiation oncologists who treat with protons who do it as well, but we still struggle with what is that right number. Um and if you put TLDs like these the measurements for skin on the skin of patients, you know, for chest wall even with bolus, it’s in the it’s in the low 40s for a prescription dose of 50 gray or and it’s or in the low to mid 40s. For intact breast with no bolus, it’s it’s lower than that. So, we really need to I think in think about what do we want to aim with what do we want to aim for

Dr. Shannon MacDonald: with protons for the skin and subcutaneous dose because we may be uh you know, seeing uh cosmetic outcomes or more skin toxicity because we’re intentionally giving a higher dose because you can’t help but spare it with photons. Photons have a skin sparing property. We put bolus on to try to increase that for some breast patients, but not all. But even with the bolus, we’re not getting as high as we did with 3D protons. So, just something to think about.

David Raubach: So, Dr. McDonald, you mentioned contouring. When you say contouring, what do you mean by that?

Dr. Shannon MacDonald: So, I mean we as radiation oncologist, we look at CAT scans and we actually draw what we see

Dr. Shannon MacDonald: on the scan. So, we draw the area that’s at risk for having cancer cells or a tumor that might be present on the skin and we also draw structures that are healthy organs, healthy tissues. So, for a breast cancer patient, that would be the heart and then different chambers of the heart and the vessels of the heart and the lungs. So, all of those things are contoured or drawn and that’s what what we mean by contours.

David Raubach: Yeah, and so the results that that um you presented at ASTRO uh back in September, there was a there was a cosmetic element to those. Is that correct?

Dr. Shannon MacDonald: Yeah, and it was equivalent to those are patient

Dr. Shannon MacDonald: reported outcomes.

David Raubach: Yeah, and they were the same. So, um so that also, you know, it that patients are just as satisfied um when they report their own outcomes.

David Raubach: And that’s even as you mentioned maybe some of the proton centers treating with um I’ll say older techniques um for how to treat how to treat breast cancer. What um so one of the things that you talked about um I I don’t want to I don’t want to say this is a uh criticism necessarily, but um so one of the uh counterpoints to some of the results that came out initially or that I’ve seen with other proton trials is that well if patients know that

David Raubach: they’re going to that they’re getting protons, they’re they think they’re getting a better treatment and so they’re going to there’s a confirmation bias, so they’re going to be inclined to say that the treatment worked better than maybe it would have if the trial was blinded and the patient didn’t know what they were getting, which obviously is basically impossible to do with radiation. Um why do you why do you think that using patient-reported outcomes is okay for this particular trial or why is it an important element of the results of this particular trial?

Dr. Shannon MacDonald: So he said it’s you know, been shown to be a an important result for many trials. Mostly just to learn like

Dr. Shannon MacDonald: what’s the lived experience of our patients because physicians often under report and our patients might not tell us everything, but if they’re filling out a questionnaire, they’ll fill it out honestly. You know, for example, with with um RadCom, we saw a lot more patients reporting not severe shortness of breath, but some shortness of breath and that was surprising. It’s far higher than what physicians report. And um and it and for the RadCom trial, there were items that, you know, I would choose this treatment again, that were that favored protons. So five of the six items in that survey favored protons, but we argued, well, maybe it’s because it wasn’t blinded cuz you can’t blind patients

Dr. Shannon MacDonald: to what treatment they’re getting and they may be more excited about getting proton therapy, but also proton therapy is a greater burden often. They have to drive farther. They there’s machine the machines tend to be delayed more often. There’s less redundancy. So, if if something happens, you might get your treatment canceled or you know, again or or delayed for several hours. So, there’s So, there’s there’s there’s that, but I think that patient reported reported outcomes in oncology are extremely important to give us a better idea of what the patient’s actual experience is and not what we perceive it to be as their doctors or physicians.

David Raubach: Yeah, I think I think that’s a good that’s

David Raubach: a good counter to the counter. That’s a good That’s a good way to put it. Which I think it’s it’s not to say that one is more or less the physician perspective or the patient perspective is necessarily more or less important. It’s that they’re they’re both important. Both should be reported on.

Dr. Shannon MacDonald: Exactly.

David Raubach: Um so So, you uh you have a quote in the press release that says, “Radiation oncologists have debated whether photon or proton therapy is the better choice for treating breast cancer and there has been little high-quality evidence to guide those decisions.” Um how would you define high-quality evidence in the context of that particular quote? And why would

David Raubach: you Why Why did you make that particular statement about breast cancer?

Dr. Shannon MacDonald: So, I think you know, high-quality probably meaning phase three randomized trials looking at protons versus photons. We’re really lucky to have the RadCom trial and to have it be supported by PCORI and to have it completely accrue and to be able to obtain this data. Um you know, data’s never perfect even in the phase three setting. You know, treatment evolves and improves and you know, by the time we reach our endpoint, things will have further improved for modalities modalities of treatment will very likely. But, but I think it’s a great cohort of patients that were randomized and it’s very It’s prospectively collected

Dr. Shannon MacDonald: data. So, it’s it’s excellent data for breast cancer for receiving radiation therapy for breast cancer patients in general, and we did we did accrue a huge number of patients for a randomized trial, and and it’s the largest randomized trial to date for protons versus photon therapy for any disease site. So, I think it’s high-quality evidence by that. It’s also real world. It’s 32 centers, community and academic.

David Raubach: Right.

Dr. Shannon MacDonald: And it’s very And it’s pragmatic, and that’s sort of a a new you know mandate from the NCI that they want more trials like that. That’s what we’re hearing at least in Children’s Oncology Group. So, I think that it’s it’s applicable to to real-world treatment.

Dr. Shannon MacDonald: Um you know, the thing it’s that’s harder to detect is you know, how carefully were those patients selected, cuz I think we all you know, you treat with protons, I treat with protons, they see a lot of breast cancer patients. This enrolled anyone who was getting the IMNs treated, but we all see abnormal anatomy, very young patients, patients that can’t raise their arm above their head, where you have to use protons, patients with you know, with genetic syndromes that make that predispose them to other malignancies, where sparing any tissue is really important. Um so, it’s it’s great data, but there’s always going to be these you know, the that you know, there’s these patients that

Dr. Shannon MacDonald: benefit a lot that is that are high that you need to highly select for. That’s hard to do in a That’s impossible to do in a randomized trial that’s pragmatic.

David Raubach: So, you’ve talked about the primary endpoint being heart toxicity. And again, maybe for a lay audience, would you define what that means? What it When you say When we say heart toxicity or heart complications, what specifically are we talking about for breast cancer?

Dr. Shannon MacDonald: Yeah, so we’re for these patients, we’re talking about major major things with is the endpoint. So, that’s having a heart attack, dying of heart disease, hospitalizations for heart disease. And the And the trial has done you know, the cardiologists on

Dr. Shannon MacDonald: the trial have done an amazing job of being able to collect lots of detailed data about that. And then also, we have all the CAT scans and we’re centrally contouring all the cardiac substructures. So, we’ll have really good data for the dose to the smaller arteries and chambers of the heart, and be able to correlate that with the outcomes, regardless of modality, but between modalities and also and that will be very valuable as well.

David Raubach: So, you you mentioned shortness of breath was an interesting finding, not not necessarily statistically significant with the initial results, but certainly something as you mentioned being worth following up on. Were there other things that came out of this initial

David Raubach: data review that you’re interested in looking at over the next few years, or maybe something that didn’t come out that you’re We have heart toxicity, we have shortness of breath, are there other things that are intriguing to you as a physician to see what happens over the next few years?

Dr. Shannon MacDonald: Yeah, so I think there So, there there are some studies that are part of RadComp that are studies that include a portion of the patients that are enrolled on RadComp, and and and that’s and there’s a couple of studies. One that one that’s looking at strain echo and chest CT and thyroid function, and that’s the PI of that is Dr. Rachel Jimenez. And then

Dr. Shannon MacDonald: Dr. Bonnie Ky is the is a PI, a cardiologist, who’s also looking at strain echo in a slightly different way, but I think the I can’t wait to see the strain echo data and the data for ultra-sensitive troponin, and also to try to correlate that to some of the cardiac substructures to see if we can find dosimetric relationships because we have seen the Darby study, which is a huge study that looked at mean heart dose, but we know that Darby didn’t have the ability to look at the cardiac substructures because the planning was not done with 3D planning. And there have been subsequent studies since, but RadComp will be a prospective huge study um you

Dr. Shannon MacDonald: know, 1,239 patients, different modalities, and different doses that will be very interesting to look at those cardiac substructure doses, the strain echo results, the ultrasensitive troponin, and other cardiac biomarkers. So, I think that’s going to be really interesting to look at before we’re able to look at the major cardiac events. Um so, we’ll we can look at that before that time point, and that will be really interesting to look at.

David Raubach: Right. And so, look at things like the mean heart dose or the dose to the LAD or some specific areas of the heart and and see if there’s any correlation. So, um before we go, I’ll just ask you this um to close out.

David Raubach: So, uh for a breast cancer patient, they get diagnosed or thinking about what to do. I mean, you obviously went through these conversations asking patients to enroll on this clinical trial and consider photons or protons. How How would you advise a patient to think about the radiation component of their treatment um and how to just go about that that process of deciding what type of radiation to get.

Dr. Shannon MacDonald: So, I think trusting your physician, specifically your radiation oncologist, to give you an honest opinion about will you benefit from proton therapy or will photon therapy provide just as good a a treatment. And it’s so individualized, in my opinion. It’s very much based on their cardiac

Dr. Shannon MacDonald: anatomy. It’s hard to give an opinion till you see that cat scan um pretty often and and it and so, I think that we need to, you know, be honest as physicians who’s going to benefit most, um have our patients trust in us, have, you know, physicians respect the radiation oncologist’s opinion about who will benefit most because, you know, I know you’ve seen patients, I’ve seen patients where their heart’s pulled away from the chest wall, and they’re going to do great probably with either treatment. And then other patients where deep inspiration doesn’t do anything or they’re unable to do it, and and it’s just right up against, you know, their IMNs or their chest wall,

Dr. Shannon MacDonald: and you and you need a modality that can do a better job and and so I think that patients need to trust in their radiation oncologist to guide them towards what will be the best treatment for them.

David Raubach: And I’m going to add to that if you’re in Florida go talk to Dr. McDonald.

Dr. Shannon MacDonald: Thank you.

David Raubach: Because she is an expert in breast cancer for Southwest Florida I guess. And and then hopefully soon if you’re in Georgia or Alabama or Louisiana and all those states they can talk to you as well. Well thank you so much for your time Dr. McDonald. I really appreciate the conversation and bring Franklin on next time.

Dr. Shannon MacDonald: I

Dr. Shannon MacDonald: will try. He’s going to be jealous of my dog.

David Raubach: If he will sit if he will sit still. Yeah, right. Exactly. So.

Dr. Shannon MacDonald: Thank you David and thank you for having me and for your time and interest in those topics.

David Raubach: Yeah. Thank you. Have a great day.

Dr. Shannon MacDonald: You too. Bye-bye.

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