Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 155 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is oncology. 911, tumor lysis syndrome as an oncologic emergency. We actually have a very special guest with us today, Dr. Amir Ali, welcome to the podcast. Speaker 1 00:49 Thank you, Dr. Kane and Dr. Patel for having me on for this important topic today. So why Dr. Sean Kane 00:54 don't we go ahead and get started with kind of the nature of today's episode is tumor lysis syndrome. But before we get into that. Dr. Lee, maybe you could just tell the audience a little bit about yourself and why you you are on today's episode. Absolutely. Speaker 1 01:07 Dr. Kane, so I went to school at University of California, San Francisco, UCSF in the Bay Area, completed my first year residency with Kaiser Permanente, and my second year residency in hematology oncology at USC, University of Southern California, and stayed on there and practiced so my role is pretty unique down there. So I don't work in a in a pharmacy. I work in the clinics with patients. I deal with mostly hematology and bone marrow transplants down there. And on the side, I'm also a adjunct assistant professor. A lot of involvements with P and T policies, and also the Residency Program Coordinator at USC for our oncology program there. Dr. Khyati Patel 01:48 Well, that sounds great. And you know, a person like me who has nothing to do with oncology will ask, why do people who are not Oncology Specialists need to be familiar with the tumor lysis syndrome. So what do you have to say? Speaker 1 02:03 Yeah, so most of us have been touched by cancer, so whether it's a family member or one of our patients that we endear so it's important for pharmacists in any practice setting to be familiar with the risks and symptoms associated with tumor lysis syndrome, or TLS and and some understanding of the basic management's associated with that. But nonetheless, oncology pharmacists do play a key role in managing TLS and preventing it from occurring in the first place, and are also involved in creating policies in many practice settings, Dr. Sean Kane 02:37 and I would say even in my practice, and I'm absolutely not an oncology specialist by any stretch of the imagination. I've seen plenty of patients with TLS in the ICU, because they come in either they already have, you know, an oncologic diagnosis, or this is like their initial presenting problem, right? So this is going to happen and be seen by people who are not Oncology Specialists too. In addition to that, there are other oncologic quote, unquote emergencies. These are kind of acute complications of cancer or the treatment of cancer. Dr. Lee, can you just run through a couple other typical emergencies that fall under the umbrella of oncologic emergencies? Besides TLS, Speaker 1 03:17 yeah, there are certainly many of them. Dr. Kane, so you know, the most commonly seen ones that we see often in the clinics and in the inpatient setting, include febrile neutropenia, so when your ANC is low, below 500 and you develop an infection there hypercalcemia of malignancy, cord compressions from tumors. You know, there's many more that can occur, but one of the most common oncologic emergencies is tumor lysis syndrome. So hence today's podcast episode, Dr. Sean Kane 03:45 and then maybe you could just package it up in kind of two or three sentences if you had to explain TLS to a p2 student. What exactly is tumor lysis syndrome at the very 30,000 foot view? Yeah. Speaker 1 03:57 So it's essentially a result of cancer cells that are dying too quickly, right? So whether they're dying spontaneously from a high tumor burden or we're using chemotherapy to destroy those cancer cells, that's essentially the big understanding of tumor lysis syndrome. So what happens is, when you're lysing these cells, the intracellular contents are spilling out, releasing DNA electrolytes that can lead to a whole host of complications known collectively as tumor lysis syndrome. Dr. Khyati Patel 04:30 So I would love to dive more into the nitty gritty of what happens when the burst happens. And you know, all these content are spilled out. So one thing you mentioned, Dr. Ali was DNA spills out. So what do you have more DNA floating in the blood? Speaker 1 04:45 Yeah, so let's dive into the pathophysiology. So again, it has to do all with the lysis of these cells. So when you mentioned the DNA, you know it's being released into the plasma. This DNA is catabolized. It's metabolized by. Body, and one of the metabolites of DNA is actually uric acid. So you see large increases in uric acid from the DNA. So really, it's a similar concept to what you see in gout, right? So you see increases in uric acid, and you see it in gout, for example, expect affecting a specific joint, right? For example, a big toe. So it's a similar concept. In TLS, you're seeing increases in uric acid, but it's really not affecting a specific joint. And I will say that the uric acid levels you see in tumor lysis syndrome are typically much higher than you would see in in gout, for example. Dr. Sean Kane 05:37 And then you know other things that get spilled from those cells would be things like protein, right? Your cells have proteins to do all of their functions. What ends up happening to those proteins in the body? Speaker 1 05:48 Yeah, so proteins from inside of the cells, you know, those are released as well, and those are degraded into urea, and that results in increases in bun Dr. Khyati Patel 05:57 and then we have intracellular ions that also get released into the blood, mainly potassium, that leads to hyperkalemia, and phosphate that can lead to hyperphosphatemia. And interesting thing about hyperphosphatemia is it's going to try to bind up all the calcium in the blood, and will lead to lower levels of calcium hypocalcemia. So these electrolyte herb now abnormalities are real, but then there is something else that causes physiological complications, right? So, too much uric acid. It doesn't cause gout, but what could it cause in patients like who have TLS? Speaker 1 06:37 Yes, exactly. Thank you. Dr. Patel, so as a result of these increases in uric acid bu when and these electrolytes that can lead to a whole host of complications that really are as the mainstay of the the issues that we see with TLS. So for example, you mentioned uric acid increasing. So when you have really high values of uric acid that can actually crystallize. It can precipitate out and affect the kidney function and cause issues, including Aki, for example, similar situation with calcium phosphate. You see those high numbers and precipitation from high levels of phosphate and calcium. Those can precipitate in the kidneys as well and cause the same exact problem. You also have increases in potassium that you mentioned. So increases in potassium, we know that it can cause arrhythmias in a lot of our patients, and then changes also with low calcium, high fast those can cause some seizures, tetany and some of our patients. So you know, as I mentioned, these complications, you can see this is why we categorize these as oncological emergencies, because you can see a lot of these issues occur. Dr. Sean Kane 07:44 Dr. Lee, I know that, for example, potassium is renally eliminated, so I'd assume then that if you have these crystals that form that knock out your kidneys, it becomes this kind of death spiral, if you will, of impaired renal function. Means that you're going to hold on to that uric acid and not pee it out, and hold on to that potassium, not pee it out, and then those levels go higher. Is that kind of what ends up happening in these patients, if they do knock out their kidneys early on, exactly. Speaker 1 08:09 So one of the risk factors we have for patients for developing severe tumor lysis syndrome is depressed renal function to begin with, so you know? And this is the case, right? So when you're having patients that are having precipitates of uric acid or calcium-phosphate in the kidneys that in turn worsens renal function and can worsen the whole cycle, so even higher levels of these electrolytes. Dr. Sean Kane 08:31 Now, from a diagnostic standpoint, is it enough to just say you have cancer and your uric acid level is high? Is it a clinical diagnosis, are there very specific criteria that patients have to meet? Speaker 1 08:43 Yeah, so one of the most commonly used criteria is actually the Cairo-Bishop criteria. That's the one that most pharmacists will employ in diagnosing tumor lysis syndrome. The way that the Chiro Bishop criteria is used is that we look at patients and they need to at least have two or more of the following criteria that I'll mention that occur within either three days before their chemotherapy or seven days after their chemotherapy. And the main criteria we use is really electrolyte levels, including also uric acid. So if the uric acid, for example, is above eight potassium, above six, phosphate, greater than 4.5 and lower calcium levels less than seven. Most commonly what we see in clinic, though, we don't usually hold those values and memorize them, but we look at the patient's baseline electrolytes, and if we see a 25% increase from their baseline for some of these electrolytes, or, for example, for calcium, if we see it dropped by 25% we consider that if they meet two or more of those criteria as laboratory TLS. But at the same time, you have to think about your differential diagnosis here, and you have to make sure that these electrolytes are not being affected by other things besides the cancer. So for example, confirming that. The patients are not on any supplements that are increasing these levels, also meds that can potentially cause hypercalcemia. We know many of those as well, so we need to check for these interactions that may be clouding the diagnostic picture. Dr. Khyati Patel 10:14 So since you mentioned the name laboratory TLS, I'm thinking there is another type of TLS. We're going to call it clinical TLS. And so what is the criteria for diagnosing that a patient actually has clinical TLS? Exactly. Speaker 1 10:29 So laboratory TLS is based on the electrolytes, the uric acid. Clinical TLS is if you're actually symptomatic from these changes, right? So a lot of patients can tolerate these changes in their electrolytes, but as soon as they have, for example, Aki, we mentioned arrhythmias from the calcium or seizures, that shifts the picture towards clinical TLS. Dr. Khyati Patel 10:54 Dr. Kane, you used an example of patient who have maybe poor renal function, who might be at a higher risk of having this condition. Dr. Ali question for you as to what patients are outside of who have Aki or poor renal function are at risk for tumor lysis syndrome, and how do Is there a baby stratify their risk levels? Speaker 1 11:17 Yeah, so there's a couple ways we can stratify these patients. We again use the Cairo Bishop criteria, and a lot of hospitals actually employ their own protocols and guidelines for the treatment and prevention of tumor lysis syndrome. So the main way we approach these patients is by stratifying them on their risks, whether they're low risk, intermediate risk or high risk patients, and once we stratify these patients, that will tell us how we can prevent or treat their tumor lysis syndrome. Now there's two main ways we can stratify these patients. One is by their disease state itself, and the other is by patient specific factors outside of the disease state. So I'll start off with the disease state itself. So you know, for the most part, patients are considered low risk. Usually have, like, a solid malignancy. So when we talk about solids in cancer, so things like prostate cancer, breast cancer, lung cancer, you know, unless these are very bulky diseases, they're, for the most part, considered low risk tumors, then you have your hematologic malignancies, so your leukemias and lymphomas, for the most part, those hover between intermediate and high risk, and the way that we usually determine them is by looking at the patient's white blood cell count, looking at the patient's LDH. These are markers of, you know, how plorific The cells are in the body, the cancer cells, and that will give us a better picture of how likely the patient is to experience tumor lysis syndrome. Dr. Sean Kane 12:50 So, Dr. Lee, you mentioned that leukemias and lymphomas are kind of hovering intermediate and high risk. Can you just give us an example of, let's say, a very, very, very high risk type of leukemia or lymphoma that is always considered a high risk based on the kind of leukemia or lymphoma that it is, Speaker 1 13:07 yeah, burkitt's lymphoma, that is notoriously known for being high risk for for tumor license syndrome. You also have chronic lymphocytic leukemia, so those ones are considered high risk as well. In fact, one of the main treatments we use for CLL and sometimes CML as well is the use of a medication called Venetoclax. And I remember in pharmacy school, you know, we often learn about this med. It's very useful. But you know, when you're targeting this malignancy, there's actually a black box warning for tumor lysis syndrome, and they notice in the clinical trials that many patients actually passed away from tumor lysis syndrome in the clinical trial for the treatment of clo so one of the warnings is for TLS as a result of Venetoclax. So in the package insert. It tells you exactly what to monitor for in terms of tumor lysis syndrome and how to appropriately ramp up the dose to prevent severe tumor lysis syndrome in these patients. So you know, those are some of the higher risk lymphomas that we have out there. Dr. Sean Kane 14:15 And in terms of risk, we talked about the kind of cancer that a patient has. What about patient specific factors? We kind of covered acute kidney injury or just renal impairment would be a risk factor. Are there any other patient specific factors that we consider? Speaker 1 14:27 Yeah, and I think this is actually the most important part when you're stratifying a patient's risk of tumor license syndrome, right? So for example, let's say their tumor is classified as high risk, or the leukemia or lymphoma is classified at high risk, but if they're not having these specific factors, then most likely, they can be easily managed. So for example, patients with predisposed dehydration are currently dehydrated, patients with already worsened renal function or receiving nephrotoxic medications at the time. Um, patients with already elevated uric acid levels, potentially patients that are coming in with gout before even having a tumor lysis syndrome, patients that are on medications that increase potassium in their blood. So a lot of these patients actually, you can change their risk stratifications based on these patient specific factors, right? What is their white blood cell count to begin with? What is their LDH? What is their creatinine, and if these things are already elevated that can push someone from an intermediate risk to a higher risk or vice versa? Dr. Khyati Patel 15:35 So Dr. Ali, you know, we talked about some of the diagnostic criteria for which we had lab thresholds, and we also talked about stratification. And I feel like, you know, both of these together could be used for preventative purposes as well. Can you tell us, in clinical scenario, how is TLS monitored? And you know, what can we do to prevent it? Speaker 1 15:57 You know, one of the best things that we can do is to prevent tumor license syndrome rather than treat it itself. So lab monitoring is key for a lot of these patients. So we're monitoring uric acid. We're monitoring these electrolytes, along with their renal function, their ins and outs, very important to take a look at when you're looking at dealing with these patients, and depending on their risk, you can change the frequency of how, how often you're monitoring, so let's say minimal risk. You know, you can monitor daily or less than that. If they're intermediate risk, maybe twice a day or so, and if they're very high risk, you're measuring this every four to eight hours, right, trying to catch these cases, because we mentioned earlier, once you have that Aki and the electrolytes are starting to increase, these things can quickly spiral out of control within hours, Dr. Sean Kane 16:49 and we'll certainly go into more specific details, but kind of starting at the 30,000 foot blueprint view of how we prevent TLS in these patients. What is our typical strategy for that low, medium or intermediate and high risk patient? Speaker 1 17:04 Yeah, and it's actually pretty straightforward. So if they're low risk, oftentimes, we can just get away with rigorous hydration for these patients, whether it's by mouth or IV, in your immediate risk, probably have to use IV for a lot of these patients to keep them hydrated. We also employ a medication called allopurinol, which is very common, and many pharmacists will able be able to distinguish Allopurinol in the outpatient setting, whether it's being used for gout or prevention of tumor license syndrome, and for high risk patients, use the whole shebang. So you can use a combination of hydration allopurinol and a medication that was approved after allopurinol, called raspberry case, which is highly effective in the treatment and prevention of tumor lysis syndrome. Well, let's Dr. Sean Kane 17:50 start with the hydration. So it makes sense to me that you want to avoid getting too dehydrated, because you want to get really good perfusion to that kidney, potentially you're going to be able to excrete more potassium, uric acid, phosphate, reduce the formation of crystals in the kidney. Walk us through like, Agent selection, you mentioned IV and po and like, how much are you asking these patients to either intake or give IV in terms of dosing? Sure. Speaker 1 18:18 So in my opinion, hydration is really the most important thing that we can do for these patients, and I think it's probably one of the most effective things in prevention. So keeping these patients hydrated, helping their kidneys excrete a lot of these electrolytes and uric acid. But in terms of fluids specific amounts, you know, for the most part, you're you're targeting about 150 to 200 milliliters per hour, a lot of these patients, and three liters a day would be great if a patient's able to tolerate that amount of volume. So for the most part, you know, you'll it is patient specific in terms of the amount of fluids that you're giving. But you do have to keep in mind, if a patient's fluid restricted, Dr. Sean Kane 18:58 and then what kind of fluid are you typically using, yeah, Speaker 1 19:02 so for the most part, it's either normal saline or saline in free water combination d5, and s or so. And we try to avoid lactated ringers due to the presence of some electrolytes in there. The one thing I will share is conventionally or historically, rather, there was often a use of sodium bicarb based fluids with the idea of alkonizing the urine with the intent of really increasing some secretion of some of these electrolytes. So we found that bicarb actually is able to increase uric acid solubility, right? But at the same time, it was also found to decrease calcium phosphate solubility, so when these precipitates form, you're not able to excrete those as much. So you know, there's not a lot of evidence that shows that patients have improved function and improved clearance of these electrolytes with the use of sodium bicarb or in terms of prevention of tree. Mint of TLS. So it's really no longer recommended in the guidelines to use sodium bicarb fluids. So then the Dr. Sean Kane 20:06 next medication you mentioned was allopurinol, that I think most people are going to be fairly familiar with, and it's used for gout. Is this dosed differently or used differently when we're using it as a preventative measure for TLS? Yeah. Speaker 1 20:20 So dosing can differ depending on if you're using it for gout or tumor lysis syndrome. I always love mentioning the mechanism here, because, you know, I enjoy the mechanisms with regards to getting rid of uric acid. So it's actually a xanthine oxidase inhibitor, so it prevents the conversion of Xanthine, one of the byproducts of DNA, breakdown into uric acid, so you're able to prevent that from happening. And Xanthine is actually more water soluble, so, you know, you can excrete it a little more easily than than uric acid. Dr. Khyati Patel 20:50 What situations would you say you would go for all puranol Use versus go for a different medication? Because the way it works, for example, Speaker 1 21:02 you know, there's some nuances when it comes to Allopurinol. So, you know, I mentioned it, it's preventing the new formation of uric acid, but Allopurinol is not doing anything to get rid of the existing uric acid in the body, right? So if the uric acid is already elevated, it's not going to have much of an effect there. So it may take a couple days for your body to be able to decrease the amount of uric acid via excretion in the kidneys. So it's not going to work right away. And if you have a patient with severe TLS and you're having a lot of these complications, you often can't afford waiting that long for the uric acid to start going down, but, but again, it's it's very useful in preventing the the new formation. Dr. Sean Kane 21:42 Dr. Lee, I kind of read that there are some drug interactions as it relates to chemotherapy with Allopurinol. Could you just briefly Speaker 1 21:48 comment on that? Yeah, certainly. So when we look at drug interactions, there are certain drug interactions, for example, six mercaptapurin that need to be dose reduced when you combine them with Allopurinol. So it's important to look out for these cases. There's also renal dose modifications associated with Allopurinol as well. There's also a point that we often educate our students on, which has to do with the adverse effects associated with allopurinol, one being the skin rashes and hypersensitivity reactions that we can sometimes see. So there's some pharmacogenomics here. So it's found that patients that have the HLA B 5801 allele, unfortunately, have an increased risk for these skin reactions and these hypersensitivity it's more common in Asian patients. But screening is not routinely done, but it's important to keep in mind, Dr. Khyati Patel 22:39 and then I like to talk about the heavy duty in our preventative resources that we have here is, I love to mention the name of this drug, raspberry. Case sounds like raspberries, but allotac is the brand name, and this is a unique drug where it's a recombinant urine oxidase. Can you explain, like you said you loved talking about mechanism of action? Dr. Ali, how does this work? Speaker 1 23:02 This works slightly differently. So this works in a different cascade. So we talked about all up here now preventing the formation of uric acid, but if the uric acid is already there, the question becomes, how do we get rid of this uric acid? So here comes rasibura, case or brand name, elatech. So it employs the use of recombinant urate oxidase, which is able to convert the uric acid into allantoin, which is a more soluble substance we're able to excrete that in the kidneys. So it's fascinating. So you're, you're in you use this IV medication to give patients this recombinant enzyme table to be able to clear the uric acid. And Dr. Kane actually taught me something about this, that most mammals actually have this enzyme, but humans do not, which I found that fascinating. So unfortunately, we don't have that, so we have to give the recombinant version to get rid of that uric acid that starts building up. But how great would it be if we can make that as well? Dr. Sean Kane 24:02 I'm guessing this is pretty effective because we use it. So in your experience, dr, Ali, when you've given this, what kind of effect on the uric acid do you typically see? Speaker 1 24:12 Yeah, so you see the levels fall fast. So you know, within hours of giving it usually the median time for you start seeing effects, it's within four hours or so, and that's the amount of times that you will start pulling levels again for those high risk patients. And it works extremely fast, and so it's a recombinant enzyme. So a fun fact about this actually, is, you know, when you're pulling a patient's uric acid level, right? And you just gave them raspberry case, the recommendation is actually to put the sample on ice, the blood on ice, but the reason is the enzyme is still working in the blood, and so if you wait a while to check the uric acid levels, it can be artificially deflated, right? So you put that on ice, you slow down the enzymatic activity. So you can get a better picture of how the uric acid level is doing. Dr. Sean Kane 25:05 So Dr. Lee, anytime I think of a protein based drug that works really, really well, that seems like a game changer. I think, wow. That must be really expensive, right? Not necessarily commenting on how much it is per dose, because it depends on how many milligrams you give. But is it an expensive drug still, and then if so, does the cost outweigh the benefits or not? Speaker 1 25:27 So it is certainly more expensive than the use of Allopurinol. But I will say this, if the patient is having severe TLS, or is at high risk of TLS, it's certainly important and warranted to use raspberry case. You know, there's often times in many case reports out there, and if you look at pharmacoeconomic studies where, you know, there's many institutions that try to avoid the use of raspberry case as a cost saving measure, and it's found that a lot of these patients, unfortunately have to be transferred to the ICU for management or start on dialysis, just because we properly did not start the use of raspberry case either for prevention or treatment. So yes, it is more expensive than allopurinol, but certainly warranted if needed. Dr. Khyati Patel 26:14 Seemingly, it's used for emergency purposes. How and dosing needs to be something that comes to mind right away that you can quickly calculate and dose. It is dosing complicated? Is it relatively easy? Can you shed some light on that? Dr. Ali, sure. Speaker 1 26:30 So for the package insert, it's actually weight based dosing, but I'll let you know that that's not often used in the real world setting. So often, what happens is we use fixed doses for most patients, and the way we come up with the fixed doses by a lot of peer reviewed articles and trials that gave us an idea of how much to administer for a lot of these patients. So the basic picture is this, oftentimes you can use three milligrams for TLS prophylaxis or six milligrams for TLS treatments, and you can see at many different institutions also, they'll stratify it depending on their uric acid. For example, if it's above eight, they'll use three milligrams. Or if it's a uric acids below above 12, you'll use six milligrams. So I will say that these fixed doses are often just as effective and certainly more cost effective than using the weight based dosing, which would have you use, likely a higher dose, Dr. Sean Kane 27:27 and then just to put a number to it, you know, in the FDA package insert, we're looking at something like 16 milligrams for an 80 kilo patient, versus, like you said, three, six, maybe sometimes a Repeat dose, but still way lower than the weight based dose that we typically have seen in the package insert, then Speaker 1 27:47 certainly so you're using much, much less drug. And we found that, you know, it's certainly more cost effective, even if you use more doses for prevention or treatment of TLS and Dr. Sean Kane 27:59 Dr. Italy, I believe that the original weight based dosing came from pediatric data, and then it kind of got extrapolated to adult data, which is usually not how things work in medicine, where we have the adult data and then we extrapolate it to pediatric so I guess it's not that surprising that we have a different way to dose it. I did want to ask you, though, so we talked about this like fixed dose. You give a dose and then presumably you re evaluate within four hours. At that four hour mark, what thing are you looking at to decide, are you going to give them another dose, or hold off and keep, you know, checking every four hours Speaker 1 28:35 so you want to see at least a decent drop in their uric acid. Oftentimes, you're not going to see a clinical improvement right away, but you want to see at least an improvement, if possible, for a lot of these patients. So you know you do have to often keep a close eye on these labs, checking every four hours or so. And you know you do want, for the most part, you're the goal is to decrease the uric acid below eight, right? But if you're still seeing a worsening in their renal function, and the uric acids being a little more stubborn and starting to increase again or not decreasing as much as you'd like, oftentimes you would use another dose for these patients. Dr. Khyati Patel 29:17 So Dr. Ali, you mentioned about the cool way of monitoring the levels of uric acid whether the drug is working or not, by putting a sample on ice. Are there any other things that we need to monitor with the use of raspberry case, Speaker 1 29:32 yeah, so one of the side effects that is important for anyone to know is the actual increase in risk of hemolysis and methemoglobinemia for patients who are g6 PD deficient. So I will share that g6 PD deficiency is more common in African Americans, Mediterraneans or patients with Asian descent, Southeast Asian descent, but routinely in the clinical setting, g6 PD deficiency is. Not often screened for it, or we will screen for it, but we won't wait until the results come back to start using raspberry case for these patients. Dr. Sean Kane 30:10 And Dr. Lee, I just wanted to comment, so we had Allopurinol with the HLA B 5801 allele, and then we just talked about g6 PD deficiency with raspberry case in both settings. You said that routine checking of those risk factors for a reaction is not commonly done. Is it because it's so rare, it's not worth it, or because this is such an acute condition you just don't have the time? Or kind of a mix of both? Yeah. Speaker 1 30:38 So it is a mixture of different factors. So one is they are rare, so you're not going to see it that often. The second is, if these adverse effects occur, they are manageable, right? So we can manage these adverse effects if they do occur, it's very unfortunate when they do occur, but they are manageable. And third is they do take a while to return, and there is certainly costs associated with them. So, you know, in certain cases, we will send it out, but oftentimes we won't wait for the results to commence therapy. Dr. Khyati Patel 31:11 And so that's where we talked about, you know, agents that we use in prophylaxis. And in case of raspberry case, we even got to talk about the treatment dose versus the prophylaxis dose. But you know, in a general picture, when patient you mentioned, prevention is the key. We're going to use these tools to prevent a TLS to occur. But what if it already occurred? How does the approach or therapy changes if patient already has a TLS? Speaker 1 31:39 A lot of our prophylactic measures do not change much in terms of when we're actually treating a patient for TLS. So again I mentioned Hydration is key for both prevention and treatment of tumor lysis syndrome. So we will you know in the case of of treatment of TLS, hydration still becomes a key point for for management of tumor lysis syndrome. So again, using either normal saline or a mixture of free water with normal saline is very important. They're keeping the volume as high as possible for these patients, as much as they can tolerate. And oftentimes these patients will become fluid overload. So we do have to pair it with some diuretics, for example, Lasix, to be able to treat this fluor overload and be able to hydrate these patients more. You know, the lasix is able to enhance the elimination of a lot of these electrolytes, but at the same time, actually, lasix can increase uric acid, right? So it's important to weigh out the pros and cons of using lasix in a lot of these patients, and Dr. Sean Kane 32:48 I just want to highlight that for a second, because one, fascinating, right? Because you have a drug like lasix or any loop diuretic, that's going to make one thing better, another thing a little bit worse. But two, almost never Is it okay to give IV fluids with a loop diuretic, and it actually happens more often than you think, at least in the ICU setting, because people think that's how you get people to pee better and perfuse their kidneys better. That doesn't do anything in acute kidney injury, but in this one circumstance where you're trying to literally just get rid of electrolytes, this is like a really effective way to do that. As you said, though you do have to worry about that uric acid going up too well. What about Allopurinol? So I'm guessing, because you said that once the uric acid level is high, and that's our criteria for TLS, it probably doesn't have a huge role here. Do you still give it? And if so, why would you give it? Speaker 1 33:37 Yeah, certainly. So you know, raspberry case will be the mainstay of treatment for tumor lysis syndrome, but Allopurinol can certainly be used in certain ways. So you did mention so once the uric acid is already high, you know you need to bring it down with uric acid, but at the same time, you can still use Allopurinol. Often. When it's used is after raspberry case. So you'll use raspberry case to get rid of the existing uric acid, but then you can then add on Allopurinol to prevent the formation of new uric acid. Dr. Khyati Patel 34:10 And we kind of spoke about the dosing of raspberry case at its extent. I wanted to bring that back up again, because you mentioned we continue to monitor the uric acid levels and and then redose it. And this particular thing I noted in the FDA label, that it's a single course treatment for up to five days. Is it how it's clinically used, where you know all the lysis of the tumor cell has done, and you're not producing any new uric acid, and so you kind of maximum five days and then don't use it thereafter. Yeah. Speaker 1 34:45 So there's really, you know, that's correct in the package insert, but there is no specific amount of time that we typically use in the real world setting, so we base it on the patient's response, right? So oftentimes we can get away with. One or two doses of raspberry case, but if the patient's continuing to deteriorate, you're seeing the res uric acid just take up after every use of raspberry case. Like, for example, they'll depress the level for a bit, but within hours, it'll just start going back up again. So you know, that would be, you know, the ideal situation where you would use more doses of raspberry case. So again, you know, pairing it with the use of Allopurinol to prevent the formation of near uric acid, keeping the patient hydrated is very important for the treatment here. And I Dr. Sean Kane 35:34 just want to highlight this for one more second, because I think it's so fascinating and interesting. So in the package insert for TLS treatment with raspberry case, it's this weight based dose. A typical adult person might get 1516, milligrams, and they're going to get it every day for five days per the package insert. But based on kind of data that is definitely not done by the drug company, we could potentially get away with like a three or six or maybe nine milligrams over the entire course of therapy. For a patient, I feel like this is like a Buzzfeed article of like, what the maker of raspberry case doesn't want you to know, or something, that's a huge difference between 16 milligrams for five days and, like, six once. How did this happen? Dr. Lee that we went from crazy dosing lots of cost to a profound cost savings measure. Speaker 1 36:24 Well, it's a result of some smart pharmacists that initiated this study and found these results. So you know you're right. So you know you can get away with using these small doses, but sometimes patients will require more over for over a time frame. But you know, when you extrapolate this data for adults and vice versa, oftentimes, you know, we've noticed with a lot of treatments in oncology, where you can get away with flat dosing and as a cost saving measure, this was done and it was found to be effective as well. Dr. Khyati Patel 36:57 I think this also raises the case for in a professional practice, because, you know, anybody, any physician or non pharmacist practitioner, can pick up PDR and say, That's the dose we're gonna go, you know, we're gonna use up all five days. And the PMT gods would come down and say, Nope, you're not doing that. Right. That's because there was a smart pharmacist involved in making the dosing recommendations. Speaker 1 37:20 Yeah, you're right. So pharmacists play a key role in this setting. So you know, we often deal with the complications and the supportive care associated with cancer and malignancies, and they'll often look to an oncology pharmacist to manage that themselves. So we'll provide these recommendations and and treat the patient holistically and get them through this. Dr. Sean Kane 37:43 Dr. Lee, we don't have time in this podcast to talk about basically the non uric acid components of TLS. So for example, hyperkalemia. We're not going to talk about all of it, but suffice it to say that there's a number of medications that we give in hyperkalemia, because this is a life threatening emergency. If you had one clinical pro about hyperkalemia, the most common pitfall or the most important thing for that new practitioner to remember, what is it for you about hyperkalemia? Speaker 1 38:11 Biggest thing to notice if you're seeing very high levels of potassium is looking for those EKG changes, and if the patient is having those EKG changes, to administer calcium in those patients, but you know, at the same time, you'll have more of that precipitation with with phosphate, so you can worsen things. So that's one of the nuances. Specifically with TLS, we also mentioned the use of loop diuretics that can increase the risk of uric acid buildup, right? So that's a nuance that's different than treating general hyperkalemia. So you know, you do want to pair it with, you know, insulin and dextrose, if the patient is isn't diabetic, the use of albuterol is key and binders, if at all possible. Dr. Khyati Patel 38:57 And I'm going to direct our audience's attention to our recorded episode number 107, on acute as well as chronic hyperkalemia, which seems like a lot of pearls, can be extrapolated to treat these patients as well. Dr. Sean Kane 39:09 And then in terms of hyperphosphatemia, I know that we have oral phosphate binders that will bind new phosphate in your diet. Do those play a huge role in TLS, when you see that really high phosphate level? Do you still give them, even though it's not going to drive that? Drive that level down from the blood? Speaker 1 39:24 Yeah, you know, if the patient's still eating a healthy diet, then you can potentially give a phosphate binder to a lot of these patients, but oftentimes not much you can do for these patients for the phosphate level, unless you know you start correcting the underlying malignancy itself, or hope that the raspberry case and Allopurinol is able to cure the uric acid, increase the renal function, and hopefully the body will start getting rid of Dr. Sean Kane 39:50 the phosphate itself. Then our last one was the low calcium, and this is one that I think students frequently forget as we think about high levels of all these ions. But this. Case and say, low calcium. Do you reach for that calcium gluconate and give it to them to help with their low calcium level? You mentioned earlier that we're not super excited to give it for hyperkalemia, which is like one of the cornerstones of hyperkalemia management to kind of stabilize myocardium and prevent arrhythmias. When and if? Do we go with a calcium supplement for these patients. Speaker 1 40:21 Yeah, so for the most part, you're only administering calcium if the patient's very symptomatic. You don't want to just administer it if the patient just has low calcium levels, because we did mention that precipitation can worsen. And at the same time, when you're improving the uric acid and hopefully the renal function, you'll be able to get rid of the phosphate more, and as the phosphate is able to decrease, the potassium should start increasing again. So oftentimes, you're not going to really need to supplement any of these patients. Now I do want to mention that this as this last point. So for all of these electrolytes, for example, the potassium and the phosphate, in severe cases, dialysis can be warranted. So if these patients having severe Aki and is not able to clear any of these electrolytes and fluids are going and they're starting to get fluid overload, we can often target these electrolytes and these electrolyte abnormalities with the use of hemodialysis, if warranted. Dr. Sean Kane 41:21 So Dr. Lee, first of all, thank you so much for your expertise today. We really appreciate you coming on to the show today. What are kind of some key points or pearls that you would like the audience to take away from today's episode? Speaker 1 41:33 Absolutely thank you. Dr. Kane, and I think this was a very important episode, not trying to be biased here, but really enjoyed it, and I think it's tremendously helpful for our pharmacists here. So some key points, you know, I'll mention that tumor lysis syndrome, or TLS, is certainly an oncologic emergency that results from a high tumor burden from cancer cells or a result of treating the cancer itself. And what you're seeing is apoptosis, or cell death from the chemotherapy that's able to lyse these cells and extrude the DNA and all the electrolytes that are in these cells into the bloodstream. And what you're seeing is increases in uric acid, potassium phosphate and low calcium. And you might be wondering, why is that a big deal? The issue is these changes in electrolytes and uric acid can lead to a whole host of issues, including the acute kidney injury from Crystal formations, seizures from electrolyte changes, and arrhythmias from changes in the potassium. So certainly an important disease state to focus on. Dr. Khyati Patel 42:43 And as we talked about, you know, stratifying the risk of patients who would get TLS, and kind of preventing from TLS to occurring is the key in the holistic treatment. And the patients who are typically at higher risk for TLS are those with hematologic malignancies like lymphomas or leukemias or whatever, the white counts or LDH levels are very, very high, Dr. Sean Kane 43:09 and Dr. Patel, as you mentioned, prevention is the key, right? So our preventative approach mainly involves really good hydration, po for the low risk IV, for the higher risk patients, allopurinol, and sometimes we'll even give a lower dose of raspberry case as a preventative measure. If a patient does have TLS, then we're going to try to aggressively hydrate as much as can be tolerated. And then definitely, raspberry case is one of our go to therapies to get that uric acid level down very quickly. We're going to keep monitoring to see if we need to give more doses or deal with any of the other, typically electrolyte complications of TLS. I think that wraps up today's episode quite nicely. We do have show notes at HelixTalk.com Again, this is episode 155 we've included some guidelines on TLS prevention and management. So do check those out at our website. We're also on Twitter at HelixTalk. We still love the five star reviews, so keep those coming on iTunes, and then Dr. Ali, thank you so much for your time. We really appreciate your expertise. Thanks for having me on with that. I'm Dr. Kane. Dr. Khyati Patel 44:11 I'm Dr. Patel. And thank you, Dr. Ali, for coming and educating our audience. Thank you and study hard. Narrator - Dr. Abel 44:18 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store, search for HelixTalk and place your review there to Narrator - ? 44:29 suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.