Managing Toxicities of Colorectal Cancer Drugs / Systemic Therapy – Dr. Rona Yaeger

Hello and welcome back to another episode of The Oncology Brothers. I'm Rohit Gossane, alongside my brother and co-host Rahul Gossane. This is the third episode of three part series on colorectal cancer. For the first episode, we talked about a broad overview of treatment landscape of colorectal cancer. Then in the second episode, we talked about one of the most important studies in colorectal cancers. That was breakwater for B-raftly 600 E-mutation. And today, the third episode, which is the talk-se cheque portion of the agents that we utilize in colorectal space. For this, we are excited to have Dr. Roni Yeager, a medical oncologist from the Memorial Sloan-Kettering Cancer Center, joining us. Roni, welcome. Thank you for having me. It's a pleasure to join. Roni, thank you so much for joining us. Over the next 20 minutes or so, let's talk through how to manage some of these common side effects we see with our systemic treatment options. Let's start here with 5FU. This has been the backbone for colorectal cancer now for decades. And recently, we see a FDA label update for this and Cape Cytobene to test for a Dpy demutation up front. This should now be the case for all comers whenever we're using 5FU or Cape Cytobene. Also, we tend to avoid 5FU bolus in metastatic settings. Roni, with all that in mind, what are some of the side effects we see with 5FU infusion and some clinical pearls around this? So for 5FU, this is a traditional chemotherapy. So we see effects on the counts. As you see here, we see cytopenia. You can see neutropenia in general. 5FU, the IV form will have more myelus suppression than the oral Cape Cytobene. We can also see effects on the bowel. So mucocytis and diarrhea can occur as well. Again, mouth sores are more common with the IV form than with the oral Cape. And foot is less common, usually, with the IV form than we see with Cape Cytobene. And then there are some important but less common side effects like you have marched here. The potential for cardiac toxicity or coronary vasospasm, particularly if you have a patient with known significant coronary artery disease, I often talk about, you know, if you have chest pain, you know, we want you to take a nitrate, come in immediately. We want to take it seriously. Generally, the 5FU is not highly immunogenic. So if you're giving it alone, patients may not need medications for nausea. Well, thanks for covering that. We're all sorry, go on. Yeah, one of a few things here, I started off by saying we're not using 5FU bolus and metastatic settings. Do you for go 5FU bolus, even in adjuvant settings? And when you're not using bolus, do you let go lukewarm as well? So I generally give the bolus unless there's a reason I'm trying to modify the dose. So if a patient is frail, I drop the bolus. If the patient has mild suppression, they drop the bolus. So I have a very low threshold to drop the bolus. But if someone is well, I don't see an issue to start with full dose, full fox or some similar combination regimen, I often do include the bolus. I agree with you the data supporting the bolus is not there at the same time. You know, we don't have the gavanna mice trial. So the standard regimen does include it. So it's kind of the first thing I drop. And similarly, like you mentioned, the data is also not clear that we actually need the lukewarm with the infusion of 5FU result. But I also usually start with it. I think you asked about the adjuvant setting. In the adjuvant setting, we've shifted much more based on the idea study to use capesite of AIDS. So it's a little bit less of an issue. So the idea study was looking at the duration of adjuvant therapy and was really a summer period, multiple studies. And then the studies, there was a three month versus six month and different studies, different centers used either capesite or being or 5 floor urs. So and it wasn't anticipated to have a difference. But if you look at the data by the floor permitting news with the three month versus six months, the capesite and containing regimen had seem to do well with three months and all that. So because of that, we've shifted much more using capox in the adjuvant setting. Again, I kind of follow a similar rule. If I think someone is frail and they're going to struggle with treatment, especially if I think their frail might be easier to give the IV 5 floor urs. Then I have a very low threshold to drop the bullies. But if someone looks well and there's some reason, there's some renal dysfunction that I feel like is better to give IV 5FU over capesite. I mean, then I often will actually start with the bullies. And then if there's any toxicity like we are saying low accounts, quickly I would drop it. And then it's just the right way. Right. I think the practice varies quite a bit. When you talk to Dr. Kathy Ang, she'll be skipping the bullies in lukewarm or in even in adjuvant setting. In my settings, I do skip out on 5FU bullies and lukewarm or in in metastatic space. But I tend to give that in adjuvant space. Royal, you and I have talked about this. That's your practice as well, I believe. Yeah. And I agree. With regards to the coronary vasospasm, I just wanted to bring that up because that is more tied to continuous aspect of it. When you dose this weekly, that's a solution that you can battle through the coronary vasospasm as opposed to giving that continuously. All right, moving along into the next agent, Oxali Platin. This is an effective agent, but yet one has to deal with the most dreaded complication here, which is neuropathy. And because of this side effect, one has to stop this agent early, whether that's for adjuvant setting or in metastatic space. Roana, any clinical pearls here with regards to neuropathy, any role of oral cryotherapy or any data around cold compressions. So please, any tips and tricks with this agent at all? So we unfortunately don't have as many tips as we want, right? There's not much that you can really do to prevent it. I think if the neuropathy can be like numb or can be kind of painful, if it has a painful component, I think that medications that can help with neuropathic pain, like the gabapentin can be more effective if it's numb and maybe less so. I think just being in touch with patients every time, like, do you have symptoms? Because as you know, here, the symptoms escalate when we stop the Oxali Platin. So you don't really want to get to the point that the neuropathy is affecting like daily tasks when you stop. I don't know of a way to truly prevent it, kind of help recovery, speed up the recovery for the kind of icing and cooling. Maybe that helps with the more immediate effect, the cold, the dysthesias, more than the kind of longer term peripheral neuropathy that takes longer to reverse. I don't think there's data to show that it actually prevents the longer term kind of that numbness than rather than that cold sensitivity. As MSK's institution actually doesn't do the cooling and we, if patients who want to do it have to bring in their own supplies. I personally am very comfortable with it. And so I usually just will put in order patient, you know, patient okay to proceed with cooling, but it's not our standard. I think it's just being proactive in informing these patients whenever they experience the prolonged neuropathy to inform us so we can get rid of this therapy, especially in adjuvant setting and again in metastatic settings because this all impacts the quality of life. Which regards to Oxali Platin. We have a small study of oral cryotherapy that is chewing ice chips and there has been some hint of benefit that is tied with utilization of this. All right, moving along into the next agent here, Irina T. Can, Rona, your thoughts here. You know, in the adjuvant setting, you kind of want to get the treatment in, right? That's the balance. So in the palliative metastatic setting, for sure you don't want to push so hard that you're having all this toxicity, but in the adjuvant setting, you want to make sure you're giving that. So that's the nice thing about the three month treatment that the very small portion of those patients really had significant neuropathy. And it's the reason, a reason to think about that K-Box, but we really don't know why K-Box was better. And one theory is maybe getting that Oxali Platin at the higher dose soon, get a little bit more in sooner, maybe has some benefits. I don't know. Yeah. And quickly, I want to reiterate that that's the benefit of that three month because Oxali Platin neuropathy is dose dependent. So a lot of us are leaning into that three month dosing so that we're not exposing our patients for that longer Oxali Platin. All right, moving along into the Irina T. Can space where diarrhea tends to be an issue, Rona, clinical pearls inside effects we keep in mind here. One of the key things about Irina T. Can is potential hair loss as we think about selecting first line treatment. We have similar efficacy for combination floor permeating like full fox, full per eggs, aloe plant and full fury. So I usually discuss with patients. One has neuropathy, one has potential for aloe piecia. Again, diarrhea, like you mentioned, not everyone has diarrhea, but definitely some need to discuss with patients ahead of time and have a plan what to do. And we have in our treatment plans, we have the atropine as a dose and a PRN as needed, a second dose too, can help with the kind of media cramping colonergic effects. We don't do a MSK UGTY1 testing and right now we dose and modify as needed based on toxicity. Absolutely. And again, this diarrhea that we tend to see is colonergic and that's the reason why that atropine is working right away with full fox or full fury. Rona, we're often using Babysysmab or anti-UGFR. Let's start with Bab, here we have to worry about hypertension, progenuria, perforation, increased risk of bleeding, even blood clots. Though overall with these side effects in mind, we often lean into this because we've been using this agent for so long and there's that comfort. Can you touch on some clinical pearls here? Should we stop or alter those if a patient was to have a blood clot while on Babysysmab or just add anti-coagulation and continue with Bab? What about that progenuria still? Yeah, I mean, so, bevacism has a survival benefit. So if patients are appropriate and can receive it, is worth giving in the MEPSAC setting, I should say. In patients who have clot, I have traditionally held the bevacism out, but I recently spoke to hematology and they suggested to me that you should give three to six months of anticoagulation if the clot is stable, okay, to resume the bev. So probably that I was being too careful there. Similarly, in patients who have a history, like you have pointed out here, either a fistula radiation that you're worried about, a fistula, based on kind of complications, I'm very careful and I don't usually give the bevacism app. I don't follow, I don't track for the protein area. We follow the blood pressure and we treat blood pressure and then you just have to be aware of the patient might have a procedure and we have to hold it and be kind of on top of it for that. With the gore2 bevacism app, Brahu, was wondering, do you use anticoagulation with prior history of clots? I have not utilized in my practice. I've not used it as a prophylactic, but while someone is on bevacism app and was to have a blood clot, I give anticoagulation and continue coming back to that risk. There's a risk of bleeding. Now they're on anticoagulation, you have to keep in mind, but there's also increased risk of hypercraglable state. So it's just that balance where you have to be mindful about. And then Rona, you also touched on planning for that procedure, especially for those oligomets. If you are leading into bev, stopping that appropriately prior to that surgery and keeping your surgeons on board with this is important. Now onto our anti-EGFR drugs, Cytoxamab or Pantitumamab. We're using these for Raswild-Top tumor or Cytoxamab with Enchiraphinib for B-Raph-V600 E-Metated Disease. With these anti-EGFRs, rash, nail changes, infusion reactions, common side effects. Rona, clinical pearls around these agents. I always talk to patients about sun exposure. So sun exposure makes the rash more likely. And I emphasize that the skin is dry. So even though the rash may look like acne, it's actually dry rash and I have patients from moisturized. The patient can be very sensitive even. Sometimes the lips can get burned. So we kind of think about that. I give prophylaxis. I give an antibiotic prophylaxis that give toxic cycling. I don't think it's necessarily needed in patients who have a bev, V600 E-Colon cancer, again, enchiraphinib as well. But when you give the Cytoxamab unopposed without the bev, inhibitor, your Pantitumab, your transor rash is higher. So I usually will give antibiotic prophylaxis to try to kind of modulate and limit the rash when it's severe. We involve dermatology. And then if it's severe, I usually hold rather than dose reduced. We hold and give a little chance for the skin to recover and then resume more commonly than not. You can then resume once the skin is improved. And with the gorge to Cytoxamab, one can see infusion reactions, which is not the case with Pantitumab. And Rona, when utilizing Cytoxamab with enchiraphinib here, if the infusion reaction was to occur, do you usually switch from Cytoxamab to Pantitumab or rather fight through that infusion reaction and reintroduce Cytoxamab? I think you can switch. There's no, I mean, they were developed together. A lot of it is that the drugs are owned by different companies and you need to have an agreement, I think, in the NCCN guidelines they have either. So if someone has a real reaction that you're worried, we premedicate for the first treatment. So try to minimize reactions and then patients do well. We stop the premedication. You can slow the infusion rate if someone has a reaction. So if the reaction is mild, you could just go ahead next time at a slower rate. If they have no problem, you can slowly start bringing the rate back to the full rate. So if the reaction is mild, I would try to continue with this atoxamab. But if you feel like the patient has severe reaction, you don't want, you can't easily or safely treat with this atoxamab again. I don't say any reason not to give the Pantitumab. And if you can't give either, you could continue with enchiraphinib. Enchiraphinib has activity alone. Adding the EGFR antibody can help you inhibit the pathway better and kind of overcome that reactivation. But I wouldn't give the EGFR inhibitor alone for someone who is a Bureffi-Saxon-Rykohlen cancer. But the Bureff inhibitor you definitely could give alone. So in patients who can't tolerate the EGFR inhibitor, I would just give the incorrect. And actually before we run away from the rash story, quickly here with anti-EGFR's Rona, if it's facial or scalp rash, high-dose steroids we are often a little cautious around topical low-dose steroids or swing away from steroids completely zinc-based cream. What are you doing in your clinical practice? I use topical steroids if it's severe. I don't use systemic steroids at all for the rash. I usually will involve dermatology, especially if the scalp is severely affected. Sometimes it becomes infected and they can culture it. That's the main issue. This one is also just holding and giving a patient a chance to recover. And then in those moments usually it's good to involve dermatology to have kind of another person with expertise help manage. Absolutely. Well moving along into our second half where we will be talking about the oral agents. We just briefly touched on Encoreffinib. This was initially approved in second line settings, but now with breakwater where we have doubling of overall survival in front line settings, which is from 15 months to 30 months with either full fox or full fury combined with Encoreffinib and Cetoximab. Andcoreffinib does cause anemia and rash which can also be seen with Cetoximab. But withincoreffinib we can also see low grade pyrexia. Rona, can you touch on some of the clinical pearls that we tie in with Encoreffinib and management with regards to that? So the rash with the stroke is different on the rash with the EGFR inhibitors. Carraffinib activates signaling and skin, so you actually activate it. And the EGFR inhibitors will inhibit it. So they actually oppose each other. So the rash is generally quite mild in the patients who have a B-Raffi 600E mutant tumor and again in combination treatment. So I don't usually give doxocycline here. The rash is not usually a big issue. I tell the patients again to avoid the sun. Both agents cause photosensitivity. So even more so they are sensitive. The rash tends not to be so significant. There is a risk of secondary malignancies. Again it's lower because we have the EGFR antibody on board. So you are limiting that activation of ARC in the normal tissues. It can happen and I've seen squamous cells, lesions. They're usually small and excised. So usually if someone who has a new lesion while on these treatments should see dermatology and it should be excised and usually they can continue. The astralogis can be a difficult side effect that not everyone has astralogis myelogis. Maybe 20% of patients. I used to in the days of B again, I used to be able to give a macchenthypidrate. I used to give a macchenthypidrate for it or talking to the malignoma. My malignoma colleagues, I give a friend who has about 5 milligrams with it. But sometimes it's not so easy. It's very hard for me to get the macchenthypidrate now. I cannot get it. Even though it could ameliorate those toxicities. The myelus suppression tends to be mild. You're right. You can get neutropenia. But it's not as common as it would be with the key. So if someone's getting the breakwater regimen at first thing, I think are they on the bolus, drop the bolus, should you dose modify the chemo before I would rush to change the end-corrafinib. Similarly, you can get out lupesia but not so common. I don't refer them to epistemology. I have a little threshold if they have any eye complaints to send them to opt-throw, but I don't do a baseline unless there's some issue. Similarly, I'm kind of alert to medications. You have a QTC prolongation. But I, and it's common to get a baseline EQG, but I don't follow. Maybe I should. I don't follow the time on treatment. I mean, I think those are the main items. You know, out in community, we have some comfort around this. You touched that you're leaning into your melanoma colleagues. We've been using this for melanoma now for quite some time. We're using this for lung cancer. And now here we are using it frontline settings for colorectal cancer as well. But coming back, even though the rash or that low-grade arthralgia or your neutropenia, you briefly touched on this. There are some overlapping side effects here. Rona, if that is what you're running into. Let's say mild rash, let's say that anemia. Are you jumping on decreasing the dose for end-corrafinib or saying, hey, rash is likely from cetoxamab. Let's address that or let's drop the chemotherapy or dose adjust that. How are you maneuvering through when you have these overlapping side effects? If I see that there are multiple counts, it looks like there's significant mild suppression. I suspect it's the chemo part and I will modify that. Like I said, the rash is not usually so much an issue if it is. The first question is, does it look like a cetoxamab, panatema rash or does it look like a. You probably see it much more because in melanoma, there was much more experience with the berofinibral alone of the kind of proliferative rash. So does it look like one or the other and that can guide you? You can definitely dose reduce the end-corrafinib, the next dose levels to 25, but as you note here, our dose is different. So there's a historical reason. So the trial that was done in colorectal combined the end-corrafinib with alpellisib. And alpellisib has a drug-drug interaction with end-corrafinib. So because of that, the absolute dose would be higher. So they. Sorry, I had lowered. And so that's how the 300 came to be, but because of that, I don't usually do more than one dose level dose reduction. I'll go down to 25, particularly for ethyralogias, or if someone tells me they have joint pains and I'm not really sure it's related, I'll nice and hold for a few days. Let's just see the joint pain goes away. And then if it doesn't change, I'm like, okay, it's not drug. Let's keep going. Absolutely. Right, Rhona, onto another oral agent here. That is Cape Cytopean. One has to tie in the hand foot syndrome, which we touched on it briefly when talking about five FU. We tend to see that more with capesitabine and what helps essentially is Volteranjil, so something to utilize in clinical practice. And diarrhea is another complication that we see with this agent. Rona, when prescribing this agent, I tend to be a bit conservative, though this is supposed to be body surface area, but I never usually go beyond 2,000 milligrams twice a day dosing. Is that your approach? How do you dose this regimen? I calculate the dose and I kind of think is this a reasonable dose? Does it fit okay with the patient or is there a reason that I can't give the calculated dose? And then I use that to kind of guide myself. I generally try to stick with the dose and if there are reasons like you're saying, this is a big patient. The dose is really high or a frail patient or then I will kind of make those modifications after I do the calculation, but I don't have a set rule here. I mean, the advantage here is like this is the ultimate continuous, they're right. So we have the five, five view, but that's a two day continuous. Here we like stretch it out. So that helps in that sense with the toxicity, just like you said, the hand foot is probably the most bothersome dose limiting toxicity. But you can usually get away with a list of beginning and make sure they're doing okay with it. All right, before we run away from Cape Sytebian, we have FDA label update here as well. We brought this up initially. DpyD testing should now be standard of care when using Cape Sytebian or five FU. Okay, two clothes. We have TAS 102 and two TKI's, Regaraphneb and Frequitneb. For Regaraphneb, it is important to have that step up dosing based off of redo study, starting low and then up titrating for TAS 102. We have data that every other week dosing is better tolerated and we might not be compromising any efficacy. Rona, thoughts here and any tricks and managing side effects for TAS 102, Rago or Frequitneb. Do you also do step up dosing for Frequitneb? I have it. I do it for just as you said. I do this dosing modifications. I like the every other week that the TAS 102 and I do the step up dosing. You might not need to go all the way up for the Regaraphneb for the effect. But what about Frequitneb when we're starting, do you start with that idea as well? I have followed the FDA label, started at five, but I've learned you have to follow the TSH as you have here pretty closely. But I don't have experience with step up dosing, but that's a good idea. It's interesting. Because it is associated with hypothyroidism and other things that Frequitneb can cause is hypertension. One has to keep that in mind. Well, the theme generally with any of the side effects is to educate the staff, educate the patient, so they can inform us so we can act on it at the end of the day. So the patients can safely stay on these medications for a longer period of time while preserving the quality of life. Rona, thank you so much for taking the time to walk us through these available treatment options and clinical pearls around them with regards to managing side effects. For our listeners, let us go over a quick recap from today's discussion. In our talkstack discussion today, we focused on managing side effects that come along with our systemic treatment options here in Colorado Cancer Space. A few things that I'm walking away with are omitting five-fu bolus in metastatic space. But when skipping that, also skipping out the lucho-warren. And testing for DpyD mutation testing, that's for five-fu as well as Cape Cytobene should be rather the standard of care. For Bevis-Zumab, we have to worry about hypertension, for wound healing, and increased risk of bleeding when tying in anti-ETFR, including Cytoxamab and Penitumab, we have to keep in mind the rash, nail changes, and hair changes on our radar. For rash, up from doxycycline can be very helpful. Rahul, your thoughts? Roll ahead, in our second half, we touched on our oral agents here. And KuraFNAB is now approved in frontline settings for BRAF-R600E, with Cytoxamab and chemotherapy. With this combination, yes, we see rash, but it's actually lower than what you see with Cytoxamab alone. Like you said, up front antibiotics can help. Then for RegarrafNAB, starting slow and then uptight trading, with that dose is important. When it comes to TAS-102, I do tend to use this every other week, given better telepobility. Thanks for tuning in. We look forward to seeing you in our next episode. We are the oncology brothers.