Treating metastatic CRC with radiotherapy: Dr. Sanford (2021)

Dr. Nina Sanford 0:00
After ASCO, after the GRASP walk through, there were a lot of great questions about when and why radiation is used in the treatment of metastatic colorectal cancer, and it’s definitely an area of controversy and active study. So Manju had reached out to me to talk about it to COLONTOWN, so I’ll give some background. And then I divided the talk into ablative radiotherapy, which I’ll talk a little bit more about, and then sort of palliative radiation therapy. And there is some overlap, but I wanted to, at least in the talk, talk about them a little bit separately. So this is probably very familiar to you guys, but when colorectal cancer spreads, where does it spread? And then there are really two ways that it spreads, the one is through lymph nodes, and as shown in the picture, and those are local- regional lymph nodes are those around the tumor that’s still considered stage three disease. So technically not metastatic disease, even though it’s spread from the primary tumor when it leaves the local area and goes to the bloodstream. Areas that it tends to go are the liver, most likely, followed by the lung and then the bone, and then other things less likely would be things like the brain or other areas, but definitely what we see most common is liver and then lung, and then less likely bone. So the standard of care for cancer when it’s spread through the bloodstream distantly, is chemotherapy. And I would say, you know, 10-20, years ago, that was really the only treatment without counting palliative treatments. However, for patients with limited metastatic disease, we can consider addition of a local therapy, and I’ll define that for two main scenarios.

Dr. Nina Sanford 1:52
One, if they present with metastatic disease, they initially get chemotherapy and they get kind of a good response everywhere, then one can consider treating all of their areas with curative treatment, which could involve radiation. The second main scenario is that the patient previously had curative treatment, and now a new site has appeared. And you know, these are kind of broad scenarios, and when we decide whether or not to treat the areas aggressively, we take a lot of things into account, like time since development of a new area,what their prior lines of chemotherapy are, and a whole host of other factors as well. But these are kind of the two main scenarios where we say, well, this patient has metastatic disease, but does aggressive local therapy make sense? So there are different types of local therapy. So the gold standard is surgery, or resection or metastatectomy, which I find very hard to say, but basically, is surgery to the metastatic site.

Dr. Nina Sanford 2:58
Radiation Therapy. We’ll talk about, obviously, the most other things, like ablation, and then for liver there’s y 90 embolization and also liver transplant, and that their protocol of investigating the use of that for metastaticcolorectal cancer and we have one at our institution. So the liver anatomy is divided into eight segments. The segments are shown here on this picture. They’re really based on blood supply. So you can kind of see how the lines in the picture on the left, like the red line and the blue and they kind of follow the vasculature of the liver. And the reason why they’re divided into blood supply is surgical consideration. So if something is in a certain part of the liver, then they need to think about what blood supply is feeding that, because that could determine what extent of resection. And this becomes important where a spot may be very small, but if taking out that area would then compromise blood supply to the rest of the liver, then, the surgery actually may be more extensive than one might think by just looking at the scans.

Dr. Nina Sanford 4:08
So yeah, basically eight parts of the liver, eight segments of the liver that are divided by blood supply. So for the liver, surgery, again, is the gold standard. The patient needs to be medically operable, meaning they need to be healthy enough to to undergo surgery. They need to have sufficient remnant liver, and a lot of that depends on the blood supply feeding the area that needs to be resected. And then the third criteria for it is that the tumor can’t really be invading a major vessel, like one of the big vessels feeding the liver. Again, if you resected that vessel, the rest of the liver would not have blood supply. So sometimes in tumor board, now I’m a little bit more familiar, obviously, with the liver anatomy, but initially I would say, hey, this spot is so small you can take it out, but they’re like actually, given the location that is a really tough spot to take out, because then the rest of the liver would not have blood supply. The other major options are radio frequency ablation, where the tumor is ablated through very high heat. It’s best for small tumors. Unfortunately, blood vessels are heat sinks, so the heat goes in the blood vessels, so the tumor can’t get as much so if a tumor is near blood vessel, then RFA may not be the best choice. Y90 is a radio isotope, and this is a good treatment for diffuse metastatic disease if patients really have a lot of liver disease burden, sometimes we do Y90 to try to control that disease. And then transplant– like I was saying, we have a protocol for this, but this is certainly an area that there’s definitely a lot of interest. And at least on our protocol, and I don’t remember all the criteria, but patients need to have no other sites of disease. They need to have obviously liver only disease, and it’s an area where there’s a lot of interest. But obviously, a transplant is not a small operation and shouldn’t be taken lightly.

Dr. Nina Sanford 6:13
So I’ll spend the majority of today talking about radiation for liver metastases. So historically, liver radiation was limited by techniques and concern for toxicity. There’s a phenomenon called radiation induced liver disease. Basically, this is caused by high doses of radiation to large parts of the liver, and it can be fatal. Sothose symptoms are transaminitis– which means elevation of your liver enzymes, hepatomegaly– which is enlargement of the liver, or ascites– which is fluid buildup in the abdomen. So because of this phenomenon, people really weren’t excited about radiating the liver for many years. Recently, not even recently, like 15 years ago, there’s been a development of something called SBRT or SABER. They mean the same thing, and I put what they stand for here. So basically, this is the delivery of high doses of radiation to small volumes and a few treatments. And it can be very effective. So the local control rates–and local control refers to the likelihood that this tumor that you are treating doesn’t grow after ,can be upwards of 90%. A big part of that depends onthe size and the location of the tumor. And I’ll talk about that a little bit more.

Dr. Nina Sanford 7:35
SBRT was pioneered in the lung and in the brain. So you can imagine those areas the tumor is kind of isolated. You just want to treat the tumor. So that’s where it’s been pioneered, but now it’s kind of used in many parts of the body, including the liver, the adrenal glands, the bone. Basically, any place that you feel like giving a high dose to a small volume makes sense. So with liver SBRT, there are several additional considerations when kind of designing the best radiation plan and also determining if a patient is eligible for liver SBRT. So the first thing is that the patient, him or herself, needs to be immobilized. The second thing is that the tumor needs to be immobilized as much as possible. So when we breathe, our diaphragm moves up and down, sometimes upwards of a centimeter, and the liver can move with it. The third thing is target localization, meaning that we actually need to see the tumor when we treat every day. So these things can make liver SBRT technically challenging, and are definitely things to consider when designing a radiation plan, and I said that we need to be within millimeters of accuracy, which is true, but not completely true. So you want to be within millimeters of accuracy. You don’t have to be. If you aren’t, then you just have to add a bigger margin and treat more normal tissue, but ideally you should be within millimeters of accuracy, so you’re just treating the tumor and as little healthy liver as possible.

Dr. Nina Sanford 9:19
So how are patients immobilized? Well, there are many ways to do this. In our department, we use what is on the left, which is like a plastic frame on the bottom, and then a back lock bag inside. So that back lock bag, that blue bag, is basically like a bean bag that the patient lies in, and then all the air is sucked out so it’s firm. You can see here it’s kind of molded the patient’s legs, and the patient kind of sits in there every day, and that’s kind of the first check for being in the right spot. And we’ll do additional checks like CT scans and and Cone Beam CTS, but this is what they lie in every day. At MGH, where I did my residency, they actually basically wrapped the patient in saran wrap and suck all the air out. It actually it looks a little bit strange, but it’s actually a great way to both immobilize the patient and also, you can see there’s a little bit more compression on the abdomen to actually limit breathing too. So, these are sort of, it looks kind of silly that we’re doing this in 2021 but these are really the best ways to ensure that patient is in the exact same spot every day as much as possible.

Dr. Nina Sanford 10:38
So the second part I mentioned is tumor mobilization. So with breathing, the liver can move up and down a centimeter or more. And if you don’t take that into account, then, as I was saying, then you have to treat a lot more normal tissue. So there are different ways to to handle this. So the first one, again, sounds barbaric, is just compression. So that is on the left here, basically there’s a pad and like a flat surface that just pushes down on the abdomen. It’s definitely not comfortable, but it’s certainly not painful. It just limits how you breathe, so that you’re actually not moving your diaphragm as much, but you’re more moving the upper part of your chest. You know, if a patient has a colostomy and it’s right in that area, then obviously that is very difficult to do, and we don’t do that. Our preferred method is actually active breathing control with oxygenation. So here the patient has a mouthpiece, and that they are getting oxygen through the mouthpiece to help them hold their breath. There’s a surface marker on their chest that shows how much their chest is kind of rising and falling. And that’s kind of that wave that you see on the screen. And the treatment beam only goes on when they’re fully inspired. So basically, you’re only treating when they’re at a certain point in their respiratory cycle. That is,sort of consistent with what you did at radiation planning, this requires a patient to hold their breath for about 20 to 30 seconds at a time. When I practice with my patients I do it as well, it’s actually not that easy to do that repeatedly. And for each treatment, they have to do that about three or four times. But with practice at home, I found that most patients are able to do it.

Dr. Nina Sanford 12:23
And then the other part is just seeing the tumor itself. So liver tumors are best seen on MRIs. They can be hard to see on a CAT scan. Things that help us are using fiducial markers, which are little radiopaque seeds, basically, that are put in by interventional radiology. Here are three and here you actually can’t even see the tumor, but the tumor is somewhere around these seeds, and if a patient has a stent for some reason that can help as well.I also look at anatomical landmarks, so it’s easier to treat tumors that are near vessels that you can see, or at the top or the bottom of the liver, then I have a lot more confidence that I kind of know where it is by matching to other parts of the liver. For spots that are right in the middle of the liver, and the liver being pretty big, you really need some sort of markers to make sure that you’re seeing the right thing every day.

Dr. Nina Sanford 13:23
All right. So treatment outcomes. So there are a lot of series on this. This was one that I found looking at long term safety and efficacy of SBRT for oligo mets the liver. And they basically showed, and again, the patient characteristics are on the right, just looking at the bottom, colorectal CRC here was the majority of patients. Here are their different doses that they use. So most were in three to five fractions. And this number of centigray is here on the right. And the local control for everything was at 94%, which is very high. That local control rate is completely dependent on the size of the tumor and where it is. So I tell patients, if you have a really small tumor in a really safe location, I’ll talk more about that, there is more than a 90% chance that it’s going to be gone with radiation. If it’s a big tumor, and this is just the biology of radiation, if it’s a big tumor that has just that many more cells, even if you kill 99.99% of those cells, there’s going to be enough cells there to continue growing in the future. So it’s really a function of size and then also where the tumor is. So if the tumor is really close to the stomach or the esophagus or bowel, we can’t get the full dose there that we want to, so that an area the tumor is going to be under dosed. If the tumor is away from everything, if it’s in the middle of the liver, even if it’s near a rib– I talk to patients about the risk of rib injury, but I generally prioritize. I. Coverage of the tumor over the ribs, then your local control rates going to be very high. So, you know, 94% obviously looks good, but it’s really predicated on the size and the location of the tumor. Okay, so here is a patient that I had cared for. So this gentleman was 52 years old. He was diagnosed with colon cancer in 2015 the treatment then was left hemicolectomy, followed by chemotherapy. Two years later, he developed a liver occurrence that was recepted and then got adjuvant chemotherapy, and then a second liver occurrence was in 2020 in the caudate lobe. So caudate lobe is right here. Can you guys see my mouse?

Dr. Nina Sanford 15:45
Okay, so it’s here and and again, this is an area that looks like it’s like small, but because of a vascular, vascular supply that it’s sort of right where all the vessels feed in the liver. This is an area that is really tough to operate on surgically. So this is it on the CAT scan, and then this is it on the MRI. I can see this area of darkening on the MRI is actually just a little bit bigger than on the CAT scan. When a patient has a liver met on a CAT scan, we like to get another MRI, both to better define that spot and also to make sure there are no other spots. So sometimes an MRI can pick up new spots that the CAT scan could not see. So we treated that patient with 50 gray and five fractions. He did really well. And here you can see, you know, what we do is we outline the tumor and we take into account motion, then we put it, put in a small margin around it. This area was a little bit harder to treat because the esophagus is right here, so we had to cool the target a little bit here. So this area is probably not getting full dose because the proximity to the esophagus. And then this is just showing how we evaluate radiation plan. So, you know, patients sometimes ask appropriately. You know how you know you’re getting dose to the right areas, and how do you know what you’re trying to avoid? So we look at these graphs. They’re called dose volume histograms. Each line, each different color line, represents a different structure, either a target structure or an area that we want to avoid. So here the and then they’re all here. So the gross tumor volume is in, is to do the red, sorry that. So the the the ITV, or basically the gross tumor volume plus the margin for movement is here in purple and the and the target. So basically, the target volumes are up in the corner. We want to make sure they get a lot of coverage. So the relative dose here, you know, 100% here. So 100% is reaching about 90% of the target volume. You know, we want that to be 100 ideally, we want basically a completely sharp fall off where this is all getting 100 and then it falls off to zero after 100 we don’t always get that because of the other organs in the area, but basically, the target volumes are getting good coverage, and then we look at the other organs here, the esophagus, the heart, the non target liver, the lung, the stomach, to make sure that they’re also, you know, getting a dose that is safe. Obviously we want these to be zero, but we can’t. That’s not possible, but we consider what is safe for those organs. And then they’re different for different for different organs. Some organs you want you care more about the maximum dose. Some organs you care more about sparing a certain amount of that organ by a certain dose. And we have metrics for every organ, so this is basically how we evaluate every plant to make sure that it’s safe. So the patient had radiation, he did really, really well, and his liver function after was fine. And then you can see on the scan in February, and then to May, the spot is is a lot smaller. And basically, another thing that patients ask is, you know, how do I know that radiation worked? So unlike surgery, the tumor is not taken out. It’s still there. But we basically look for growth of the tumor. If the tumor is not growing, we assume that all the cancer cells are no longer viable. Sometimes immediately after radiation, you can get some swelling that can look like progression. Sometimes we’ve been tricked out by that we’ll maybe do a pet or maybe even biopsy it. But a lot of times we just wait, and over time it gets better.

Dr. Nina Sanford 19:47
This, I think we are. Let me, did we move on to lung radiation? Hold on one second. Yes. Okay, so now we’re moving on to lung so I just wanted. Give a case of a patient who had radiation to the lungs. So this is a patient who is 55 years old, had a colectomy and full Fox in 2018 two, two years later, he developed metastatic disease in the lung, the liver and the pelvis, so both in the primary site and two metastatic sites. He was treated with second line chemotherapy, which is full theory and Avastin, and he had a partial response, meaning that the areas of disease that were there all got smaller and no new areas of disease. So historically, what you would do in this setting is probably just continue chemotherapy, give them a break off of chemotherapy, knowing that, you know, they have a strong likelihood of the disease coming back in the future. Because he was young, and you know, he wanted very aggressive treatment to his cancer, we met as a board and decided that we could go for definitive therapy to all site to disease, to sort of give him a break off of chemotherapy, and thinking that he had sort of proven himself by not blossoming further on treatment. So I was in charge of the lungs, so the patient had two pretty small spots in the lungs, one here and one there. So these are very safe spots to treat in the lung, especially the first one here, it’s just right in the middle of a lung that’s very safe. Areas that are a little bit trickier are when they’re near the central airway. So when they’re near the trachea or the Carina, those carry risk of bleeding or fistula due to injury of the airways. But this is a very safe area for this one that’s more peripheral. I did caution about the risk of rib injury because it is a little bit closer to the to the rib, but again, when you know in talking to the patient, I usually prioritize treating the tumor fully over injury to the rib, which is still pretty rare.

Dr. Nina Sanford 22:07
So two spots in the lungs, this patient got 54 gray and three fractions to both sites. And these are basically isodose lines. So it’s kind of like a topographic map, in that the center gets the most dose. The center got 64.8 Gray, and then less and less dose as you go out. So SBRT does afford a very sharp drop off. So, like the rest of the lung is getting very little dose. And we, by design, make it so the center actually gets more than the prescription dose. We think that sometimes the center the tumor is poorly oxygenated and may not respond as well to radiation. So we actually, by design, give it a much higher dose, especially if it’s in a safe location like this. So this is one of the spots, and then the second spot that we treated.

Dr. Nina Sanford 23:00
So this is a great example of a follow up scan for lung radiation. So the two spots that we treated are here. You can see that the actual tumor, there’s no solid mass there anymore, which is good. It means that the radiation worked. However, there is development of these opacities in the area that we treated. And that’s just consistent with radiographic radiation pneumonitis, which is inflammation of the lung in the area that we treated. Sometimes, patients will get scans, and they may not know that the patient had radiation before, and they may be concerned about an infection such as pneumonia in the area. But the way to confirm that this is radiation change is that they really correspond exactly to the spots that were radiated. All the rest of the lung looks, looks fine. Usually this is just something we see on the scans, and then if you follow them, it just goes away. So this is grade one radiation pneumonitis, meaning you just see it on the scans, and it’s asymptomatic. If this were to present with symptoms, which can occur if this is happening in a lot, lots of areas, the lungs have been treated several areas. The most common symptoms would be fever, dry cough and some shortness of breath, this can be managed with steroids with a slow taper, so it’s treatable, but something I still warn my patients about. I don’t believe I’ve seen this patient in follow up yet. He got his liver surgery, and is planning for surgery, basically to the pelvis, hopefully in the next couple of months.

Dr. Nina Sanford 24:41
Again, when we sequence how we treat several sites of metastatic disease, we usually do sort of the lesser operation or treatment first. Make sure that they are able to do that. So the lung was the easiest to treat with sbrt. Liver surgery was a little bit more involved. And then the primary surgery will be a little bit of a bigger surgery. We do that also because this whole time the patient is not on chemotherapy. So we also give them sort of the test of time to show that they are not spreading in other areas, in which case we would not want to do a more aggressive treatment.

Dr. Nina Sanford 25:19
So other sites that we treat. And again, we can treat with an ablative dose to really any site, depending on the exact location of the tumor– is a bone, is an area that we treat. Traditionally, we did palliative radiation in this site. But if it’s really the only site of disease, we can do sort of ablative SBRT doses. The brain is not a common area for colorectal cancer to spread to, but I have seen it in a couple of patients. It’s unfortunately, carries a poor prognosis if the patient has brain metastases. But we can also treat that area. If they have many, we do whole brain radiation. If they have just a couple, we tend to do SRS– stereotactic radiosurgery to spare the rest of the brain any side effects from radiation.

Dr. Nina Sanford 26:09
So this is a trial that I just want to briefly mention. It’s not specific to colorectal cancer, but kind of the elephant in the room is that okay, you can technically treat these spots, but what are you accomplishing? Those lung spots aren’t causing symptoms. The lung spots aren’t causing symptoms, the liver spots aren’t causing symptoms. Yes, it’s not very toxic, but how are you actually helping the patient, by putting them through treatment, and that is obviously a very important question. Not only are we subjecting patients to toxicity, we’re taking away time from them, and our treatments cost money. So to really prove that these types of aggressive therapies have ultimately improved patient outcomes, we need trials. So Dr David Palma is a radiation oncologist in in Canada. I think he’s in Toronto, but I could be mistaken about that, but he’s in Canada. And he’s really been a pioneer of SABR or SBRT to oligometastatic disease.

Dr. Nina Sanford 27:18
So this was a phase two trial of 99 patients, so modest size, they had one to five metastases, and they were randomized to either ablative radiation to all sites of disease, versus standard of care, which would be chemotherapy and no radiation. And then the patient characteristics are on the right. They’re randomized two to one to SABR, meaning more patients got the radiation treatment. And in this study, radiation was associated with a survival benefit. So the addition of aggressive therapy, prolonged survival from 20 to 41 months, which was significant, obviously, again, this is 99 patients. A lot of heterogeneity in not only the tumor type, but the extent of disease. So a lot of these have to be parsed out in terms of, does it work for five metastases or one metastases? Does it work for this histology versus that histology? And obviously that’s a very important question to answer. Just because we have a technology, doesn’t mean we should always use it, unless we know it’s ultimately improving patient outcomes. So just, I think, a couple more slide, one more slide.

Dr. Nina Sanford 28:34
So, and I don’t want to say that this is much less important, and I’m happy to talk about this more, but radiation is very effective for palliation of symptoms, so palliative radiation therapy, I tell patients, it means we’re not trying to get rid of every last cancer cell, but we’re trying to stop the growth of the tumor to help your symptoms. And what could those symptoms be? So pain is a big one, and that can be pain from the primary tumor site, if that’s left in place. That can be pain in the liver from liver metastases, pain in the bone. Usually lung metastases don’t cause pain unless they’re invading into a rib, but basically anywhere where these tumorscan grow can be painful. Bleeding is another big reason why we do radiation– bleeding from the primary tumor. If a lung tumor is going into an airway or bleeding from a liver met, radiation is very, very effective for bleeding. It’s probably one of the more effective treatments, and I’ve seen bleeding stop with as little as one treatment. And the third one is obstruction. And obstruction, I would say radiation is probably not the best treatment for a primary colorectal tumor obstruction. These patients really need to be diverted, because we don’t expect as much shrinkage from the radiation quickly to help with obstruction. But if a patient is completely adamant against diversion, which I have some patients who just do not want to, we have tried radiation with them with some success. Lung tumors can also cause obstruction–if they’re obstructing airway, causing lung collapse, and radiation can be helpful for that. The standard palliative treatment is 30 gray and 10 fractions. But we do a lot more fewer treatments, acknowledging that these patients maybe have limited time left and or be just not very mobile and be very uncomfortable. So we really want to limit the number of times you’re coming to our department. So 20 gray in five fractions, five treatments every day, is probably what I do the most. And then eight gray in one fraction, which is as a single treatment, is something that I do as well. So radiation can be effective for palliation, and I think that is all I have for slides. But I am happy to talk more, and I know there are a lot more other issues, so I wanted to save plenty of time for questions.

Manju George 31:05
Thank you, Dr. Nina, thank you so much for being with us. So we have one question in chat. when people say they’re following the COMET SABR protocol, how different is that from just SABR?

Dr. Nina Sanford 31:16
That is a good question. I would assume, when they’re saying they’re following the SABR COMET protocol. They’re using criteria for eligibility on that protocol, which is basically five or fewer sites of disease. I don’t know if it means or maybe the dosing on the protocol, but I think the gestalt of that is they’re using that data to support treatment of oligo metastatic disease, rather than like a specific part of the protocol. But sometimes insurance companies or even other providers want data for something. So I think radiation oncologists are referring to that protocol, as following the protocol as sort of evidence that this is a meaningful treatment to try.

Dr. Nina Sanford 32:03
[Question from Natalia–] When to consider chemo sensitization like capecitabine prior to radiation. Can this increase the chances of the abscopal of effect? So generally, chemo sensitization means doing radiation and chemotherapy at the same time. With either 5FU or Cape are the most common ones in colorectal cancer to make the radiation work better. Generally, we don’t give chemotherapy during SBRT. We do that with the long courses of chemo radiation. So we’re generally not giving it during the SBRT. However, the question of when todo chemo, before or after local therapy, I think that is an open question that we do case by case, depending on what prior chemotherapy the patient has gotten, how long since their prior no evidence of disease that they knew before they developed metastatic disease. So it’s basically looking at the whole picture of how much we want to add chemotherapy to the local therapy. We know that a lot of these patients eventually will get chemotherapy, because unfortunately, with our best treatments, they still have a high risk of developing additional sites of metastases in the future. Sometimes our medical oncologists want to spare them the toxicity now and save it for later, knowing that there may not be evidence to giving it now versus later. I think there was a, I can’t remember the details, but a study presented at ASCO looking at the benefit of maintenance capecitabine in metastatic colorectal cancer. And I think that it showed that it had progression free survival benefit, which is obvious because you’re giving that treatment up front, that you’re staving off disease, but it did not have an overall survival benefit. So, you can hold these treatments for later, sort of sparetoxicity, versus giving them right away to try to prevent progression. And a lot of that is both the sort of recommendation of the oncologist, but also what the patient prefers as well. Sometimes patients just want all the treatments there. They have the cancer, and they want the radiation, then the chemotherapy after and some kind of want to wait to do the chemo later.

Dr. Nina Sanford 34:25
I have to say something about the abscopal effect. So the abscopal effect is very rare. What is the abscopal effect? Abscopal effect is basically that you treat one area with radiation, like I have a lung met. I treat that lung met just along with radiation, and then a liver met goes away. So there’s some distant effect from the radiation in the lung that’s in some way helped the liver met go away either. I would say that we don’t do chemotherapy to increase the chance it’s abscopal effects, it’s so rare. We would usually do chemotherapy to either potentially make the radiation more effective or to prevent further sites of disease.

Dr. Nina Sanford 35:12
Do you have familiarity with View Ray radiation and its relative benefits on better targeting? So View Ray is MRI based, right? Right? Yes. So we do. So we recently started doing MRI–diagnostic MRIs for radiation treatment planning, and also we will soon have an MRI linear accelerator which actually uses an MRI imaging during the delivery of treatment. So this is definitely an advantage for certain areas of tumors, such as a liver, such as a pancreas, that we didn’t talk about here, but it depends on the area that you’re treating. So a lung tumor, a CT scan is actually the better scan for it. You don’t need View Ray, you don’t need an MRI, but pelvic tumors and liver tumors are areas that are better seen on an MRI. So View Ray or MRI, either simulation or treatment planning, is definitely potentially beneficial, if for all the reasons that I talked about before, seeing the target better decreasing margins. So that is something that is an area of, certainly, of investigation.

Dr. Nina Sanford 36:28
I would say radiation oncology, is very– we’re a technology driven field. We have to prove that even though the technology looks better and the images look better, that that offers a clinical benefit for patients. So that’s something that we’re working on as well. Follow up Natalia question, what about abscopal effect with immunotherapy? So I’m glad you asked that. So there is a lot, there has been a lot of excitement about combining radiation therapy with immunotherapy. And the thought is that the radiation can prime the immunesystem better to be attacked by the immunotherapy. I would say this is definitely an area of an investigation that people are excited about. I would say, similar to Natalia. I think our hypothesis is that radiation can prime immunotherapy to both make radiation the area we’re treating better and potentially other areas of the body. So potentially both areas.

Dr. Nina Sanford 37:29
Could you please comment about radiation therapy for retro peritoneal lymph nodes? So that is another good question. I have treated isolated nodal recurrences with SBRT. These are, generally, these can be areas that are tough to resect because they’re near a major blood vessel. When a patient has nodal disease, I always worry that the one node that we see maybe just one of the several nodes involved. So that might be a reason to do some chemotherapy after radiation. Another potential concern is that for patients who had rectal cancer, sometimes their initial radiation field treats some of the pelvic nodes and it can go to basically to the top of the sacrum. So there could be some overlap with the prior radiation field. That being said, if the patient has isolated retroperitoneal nodal recurrence, and the area is not super close to bowel, we don’t care about vessel as much, because those areas vessels can tolerate higher doses of radiation. But if it’s not close to bowel, I have treated those areas with SBRT, and it’s been very effective.

Dr. Nina Sanford 38:44
Following Manju’s question, is there a limitation in terms of node location when considering SBRT? Very good question. And it totally depends on if it’s near the bowel or not, is and the prior radiation. So if the node was in the prior radiation field, we can probably still do it, because SBRT is so localized. But if it’s really near bowel, like a butting bowel, then it’s a little bit harder to treat in that we can’t get the full dose that we want to get to it. We can do different tricks. Sometimes we have the patient eat or not eat before, and their stomach moves and their bowel moves. And the good thing about SBRT is, every day, you’re actually matching the patient’s anatomy that day to your treatment plan. So you can actually see their real time bowel, and that allows you to put on a smaller margin, but it totally depends on how close a node is to bowel. If they have an isolated nodal recurrence, it also very usable to first ask, Hey, can this area be resected too? Because then they can potentially explore other nodes as well. Sometimes, as I was saying, if it’s really close to a vessel, it’s hard to get up there. But definitely a multidisciplinary discussion.

Dr. Nina Sanford 40:11
Woerner: how long do you need to watch a patient with oligomets? For you to have confidence that more Mets are not popping up and that you’ll proceed with local radiation.That is a very good question It depends on a couple of things. One is, How long since they had their prior cancer? So if this is a patient that just finished chemotherapy for their colon cancer three months ago and then popped up with a new met three months later, our index of suspicion that that met is a harbinger of more widespread disease is pretty high just because they just finished the chemotherapy. If it’s a patient who– and I’ve had this– that finished their definitive therapy many years ago, and then come up with one spot, and then we always do a PET scan to make sure nothing else is there. Then I’m a little bit more confident that this was just sort of a rogue one or a few rogue cells in that area that grew over time. Like I was saying, we also like to do more than one scan, so sometimes, if they just come up with one met, we may watch and do another short interval scan, just to give them a test of time and two intervals to see not only if there are new mets, but how that one metastasis is changing. Sometimes we’ll start the patients on chemotherapy see how they respond, maybe even give them abreak off of chemotherapy to see if they don’t develop disease off chemotherapy. So it really depends our decision about radiation is also how big that spot is, how likely radiation is to be successful, and what are the potential side effects of radiation? So, and then also, we’re looking at the biology of the tumor too. So there are some mutations in colorectal cancer, like a BRAF mutation, that really portend a poor prognosis. Metastatic disease– we’re definitely less likely to treat those tumors or rectal cancer with a higher grade neuroendocrine component. Those are tumors that are really likely to have distant progression. We may be less likely to treat those.

Dr. Nina Sanford 42:28
Julia: SBRT seems to be an unsung hero of local treatments. I agree with that. Even in cases where it’s an option, it seems to be under-recommended by other disciplines like oncologists and surgeons seem to be more likely to recommend ablation. Any thoughts on this? I think this is very institutionally driven. I think they’re just, when there are different potential treatments for the same tumor, they’re just going to be different voices in the room and different people who are louder or not. But I think a benefit of SBRT is that it’s usually very safe and it can be very effective, but it’s up to us to provide evidence that it has long term benefits for the patient.Surgery has been traditionally and still is the gold standard. And to really–one difficulty has been that randomized trials between two modalities are very hard to run. So it’s very hard, understandably, to randomize patients between surgery and SBRT. Those studies are being done, but those are, there’s lack of equipoise in the patient, lack of equipoise in the doctor. So those studies are hard to do, even though they’re the best studies to show that certain treatment may be better. So that certainly hindered active investigation in seeing what is a better treatment?

Dr. Nina Sanford 44:06
Size of mets that qualify for radiation in liver and lung, and how are they different? That’s a very good question. So I would say that it has to do with the size, the number and the location of them, so like the real estate of them, if they’re together or far away. Generally, I guess this is from the SABR COMET trial, five or more mets– I’m less likely to treat with radiation. Certainly, if they’re in all different areas of an organ, but even if they’re in the same area, just because, I think if someone has five or more that is really a sign that there’s probably more occult disease. In the liver what we look for when designing our liver radiation plan is how much remnant liver can be left below a certain dose. So we basically want 700 cc’s, or 700 milliliters of liver, to be under a certain gray– a certain dose for radiation. That is what’s deemed safe. And that number, the 700 cc’s, is totally taken from the surgery literature that when they resect a liver, they want 700 cc’s of healthy liver left. And then the other part for the liver is that, as they’re saying, the size of the actual tumor correlates with how likely it is to be successful. So if it’s really a big tumor– big, usually is more than five centimeters, I usually tell patients that radiation can control it, but it’s probably not going to eradicate every last cell. At that size, ablation also is not helpful. Surgery can be the best treatment for larger tumorsf that’s an area that’s easy to resect without compromising blood supply. So it really depends on, I would say remnant liver, size correlating to local control. Then also, as I was saying, the location of the tumor. So if it’s close to stomach or esophagus or bowel, I’m less likely to be able to give those an ablative dose. Lung is similar. Again, bilateral metastasis, if there are a lot, I’m definitely less likely to treat. And if it’s close to central airways like the trachea or the carina [cartilegenous ridge at the lower end of the trachea], those areas can be a little bit trickier to treat as well.

Dr. Nina Sanford 46:41
Julie Clouer: what are you most excited about in the upcoming evolution of radiation treatments for metastatic colorectal cancer? That is a very good question. So I think that we, as I was saying, our field is very technologically driven, but the studies showing the benefit of the technology has lagged behind the technology. And I think people are realizing that appropriately– patients, payers, providers. So I am excited about, I know Dr Palma has, like, a second iteration of the SABR COMET study, and we have some trials of oligo metastatic disease. So I’m excited about really critically looking to see the benefits of these treatments, and then also optimizing patient selection, so figuring out what patients may best benefit from these treatments. I think, obviously our treatments can always be improved, but we have a lot of really exciting technologies that I think it’s really finding the right patient and the right timing to do them. And I think right now, there are some exciting trials in that space.

Dr. Nina Sanford 47:49
If a rectal cancer patient has one to two lung mets that appear over a few months, would you recommend ablation to take care of the individual mets, then go for a chemo? Do you mean like one appears, then a couple months later, another one appears, yeah, yeah, like that. Okay, so I guess that Okay, so one appears, we don’t do anything. We see another one appear after so that would qualify as sort of just progressive disease. So in that situation, we might recommend chemotherapy first. If we’re looking at the big picture that that patient is progressing, I think before recommending SBRT or any local therapy, we want to sense that the disease is at least stable or responding.

Dr. Nina Sanford 48:38
There are new, quite aggressive protocols to treat isolated mets in retroperitoneal nodes, involving chemo, SBRT + intraoperative radiation while doing resection of the spot. What is the advantage of doing IRT or intra operativeradiation if the spot is going to be removed? That is a very good question. So we do IORT intraoperative radiation at our institution. That is often done, not always, but in recurrent colorectal primary cancer cases, because those tumors tend to be very infiltrative. And after the patient has had surgery before, the tumor may not respect the meso rectum or natural boundary, so they tend to be very sticky against like the pelvic sidewall or the sacrum. So we do intraoperative radiation whenever there’s a concern that surgery is going to result in positive margins, and when the patient has gotten radiation therapy before. The benefit of intraoperative radiation is that you’re literally going in during the surgery and just treating that area, so there’s no like external beam dose, so you can really avoid the bowel or areas that have gotten radiation before. There are different ways to do IORT. What we do is we actually put a ham applicator. Actually don’t know what ham stands for. It’s obviously not the meat ham, but it’s basically like a piece of flab with wires that the radiation goes through, and we actually lay it on the area that we’re concerned about. The patient is left in the room with that applicator, and we create a plan, and they’re in that room for about 45 minutes while the radiation is working. So I would say to answer your question, if there is an area of recurrence, a nodal recurrence, where there is a concern that that node is sticking to something, whether it’s a bone, whether it’s another part of the body, and that it can’t be taken out cleanly, they may recommend intraoperative radiation at the time of surgery, depending on with the surgeon sees. A limitation of IORT is that we can never put that applicator on bowel. So if it’s sticking towards bowel, that’s an area that we’re not going to put IORT on. Or ureter. We know these are areas that we avoid. It’s really safest against bone. So again, it’s a location question. If there’s a concern for positive margins, we may add IORT.

Dr. Nina Sanford 51:19
Okay, can sbrt or conventional radiation interfere with future surgery? I’ve heard GI surgeon saying they don’t want radiation prior to surgery because they have to deal with problems and scar from radiation that may complicate surgery. So yes, radiation can cause fibrosis. And a couple points to that– one, you’re always weighing the pros and cons, right? So yes, the surgeries after radiation can take longer because there’s just a lot more fibrosis, and it can take longer to kind of dissect things, but you’re potentially weighing the benefit of radiation in eradicating microscopic disease. So you’re kind of weighing the pros and cons of that, and the second part is timing. So for example, for pancreas cancer, you don’t want to wait longer than eight to 10 weeks after SBRT to do the resection, because that’s when the fibrosis develops. So fibrosis takes time to develop. So if you want to plan your surgery, I would say we usually plan, like six to eight weeks after, so that it hasn’t been years after the radiation.

Dr. Nina Sanford 52:32
When do you prioritize hot, cold ablation instead of SBRT? That is a good question. That is again, this is one of those things that it’s sort of institutional dependent, who has the louder voice at tumor board. Sometimes I say both of these are effective treatments for small tumors. When we’re looking at specifics of the tumor, sometimes, if the tumor is near a blood vessel, that’s not a great area for ablation because of the heat sink effect. If the tumor is near stomach or bowel, it’s not a great location for SBRT because of dose to those areas. So it’s just a discussion about the location the tumor. But a lot of that, to be honest, is sort of just institutional experience. There are certainly tumors that can be effectively treated with both, which is a good thing, but sometimes it’s just based on what the workflow is at an institution in addition to the anatomical considerations.

Dr. Nina Sanford 53:34
How many times can lungs be irradiated before scarring affects lung function if the patient only has lung mets and doesn’t want chemo and is asymptomatic. So this is a question I get asked a lot. Basically, can radiation be repeated? And that is a good question. So a couple things to consider. If you radiate one spot and you give it an ablative dose and then it grows after, it kind of tells you that that tumor is not very sensitive to radiation for whatever reason. So we usually don’t radiate the exact same spot over. But usually what happens..fortunately, usually that doesn’t happen, but unfortunately, often the patients develop a new spot. And the good thing with SBRT is that it is a very small area we’re usually treating with a sharp fall off. So I have treated patients like three or four times when we’re doing that, to make a composite plan that shows all the prior radiation, because in addition to the lungs, the esophagus and the spinal cord get radiation, and those are areas that you don’t want to over radiate. So even though each plan may be safe for the esophagus, sometimes when you actually add up all the plans, you’re kind of surprised that, hey, actually the spinal cord in three plans got a pretty high dose, so you always have to make a composite plan to make sure that you’re being safe.

Dr. Nina Sanford 55:06
How widespread are SBRT program? So they are pretty widespread, certainly at most academic centers, and becoming more more frequently used. A lot of the QA and the technical issues are different from center to center. So okay, I’m gonna head out.

Manju George 55:24
Yeah, thank you so much, Dr. Nina.

Dr. Nina Sanford 55:25
You’re welcome.

Manju George 55:27
Take care. Thanks a lot.

Dr. Nina Sanford 55:28
Bye, bye, everyone.

Manju George 55:30
Bye.