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. Speaker 1 00:11 This podcast is 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. And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 59 I'm your co host, Dr. Kane, and today we actually have a very special guest with us today. Dr. Megan Hartranft, do you want to tell the audience about yourself and your practice site? Certainly. Speaker 1 00:43 Thank you for welcoming me back to the podcast. I'm so happy to be here. So I'm on faculty at Rosalind Franklin University, and my specialty is hematology oncology. I have a practice site at Rush University Medical Center in downtown Chicago, where I run our oral chemotherapy clinic. So I get to meet with patients starting new oral chemotherapies, talk to them and their families about side effects monitoring and just generally, what to expect from their treatment. Awesome. Dr. Sean Kane 01:08 Well, Megan, I invited you here today because I know that students are starting to think about NAPLEX and as part of that, clearly, oncology is a huge portion, and one that, at least in my experience, many students are less comfortable with. So I thought that today would be a great time to go through. We're going to title this episode as the five oncology drugs every pharmacist should know about. Really. The intent here is to kind of briefly overview five very common chemotherapy classes, what we should know about them, and, you know, kind of a brief review of some of these really important drugs. Speaker 1 01:40 Great. I'm really excited about this topic. I think people find chemotherapy pretty daunting sometimes, but as you'll see, chemotherapy are they're drugs, just like any other drugs, we need to take the same safety precautions as you would with any prescription that you're dispensing. There's been a lot of news the last few years about great advances in the care of cancer patients, but still, the backbone of most of our chemotherapy regimens are these cytotoxic drugs. So I went back and I pulled five drugs that I think are really common and that every pharmacist, no matter where you practice, you should know about these drugs and how to manage some of the toxicities that come along with them. So why Dr. Sean Kane 02:16 don't we start with the first drug class or drug category that you selected, which are the alkylating agents and cytokine cyclophosphamide is the one that you picked. But how about you tell us a little bit about this drug category and why you picked it as our number one need to know drug Speaker 1 02:30 definitely so alkylating agents, especially drugs like cyclophosphamide, are incredibly common. We use them in all sorts of different regimens, lymphomas, breast cancer, other solid tumor types, I think most folks will be familiar with Cytoxan. Will probably have heard of it. We've been using these drugs for decades. In fact, the alkylating agents were first discovered back in World War One after physicians noticed that soldiers who'd been exposed to mustard gas attacks had shrinkage of their lymph nodes, and that's why we started treating lymphomas with these types of drugs. Dr. Sean Kane 03:04 So you're saying that this was actually used as a chemical warfare agent, and it kind of got put into the category of a therapeutic agent for Speaker 1 03:11 Exactly. So we're repurposing some of those chemical warfare agents for a much better cause. Dr. Sean Kane 03:17 Awesome. Okay, well, how does it work, then? Speaker 1 03:19 So these drugs work by binding the nitrogens in our DNA bases, usually the nitrogen and guanine. And what they can do is they can bind at just one nitrogen, and that's called mono alkylation for one alkylation. And in that case, it kind of creates this very bulky side group on the DNA, and it interrupts the replication and transcription process, or alkylating agents, can bind to two different nitrogens. So we can actually bind two different DNA groups together. If this happens on the same strand, we call it intra strand cross linking. And if it happens across the DNA strand, so between the complementary DNA strands, then that's inter strand cross linking. And either way, it's very problematic for cells because they can't replicate or transcribe their DNA if it's caught up in these cross links. So the cell actually has to cut out that portion that has the alkylating agent attached and then replace it with new DNA. Dr. Sean Kane 04:19 So can cyclophosphamide do both of these kinds of cross-links, or do other agents tend to produce only one form? Speaker 1 04:26 They can do both, actually. So we'll find that most of the alkylating agents can cause both inter and intra cross linking. Some will cause different ratios of inter to intra strand cross linking, it really depends on the size of the drug. So you would imagine that smaller drugs, we see more of the intra where it's along the same strand, and larger molecules are able to cross over, and so we get more of that inter strand cross linking. Dr. Sean Kane 04:52 So I'm pretty familiar with Cytoxan or cyclophosphamide. Every once in a while, we'll see it in the ICU, but not very often. Are there other drugs in this kind of category that you. Would say would be pretty common. Speaker 1 05:02 Yeah, so we're going to look at another group of alkylating agents. There are quite a few of different sub classes, but within the specific nitrogen mustard class, there's one other sister to cyclophosphamide, and that is ifosfamide. Dr. Sean Kane 05:16 And are there any big difference between cyclophosphamide and iphosomide Speaker 1 05:20 for the most part, no, the big difference is where we use them. So cyclophosphamide has been around a lot longer. It's studied in many, many disease states. Ifosfamide hasn't been around quite as long, so it has a little bit more limited use. We mostly see iphosphemide in sarcomas, whereas we see cyclophosphamide in so many different disease states, Dr. Sean Kane 05:40 and a sarcoma would be cancer of the bone, a Speaker 1 05:43 cancer of the bone or other connective tissue. So we might also have cancer of the muscle, or cancer, perhaps even of tendons. That's very unusual. Dr. Sean Kane 05:51 Okay, clearly these are going to have some side effects, given that their alkylating agents impair, you know, the DNA structure itself. We used to use these as mustard gas agent. So what are some of the common toxicities that we see with either Cytoxan or with iphosphonate? Right? Speaker 1 06:08 So when we think about chemotherapy side effects, I think everybody thinks about common things like hair loss, nausea, vomiting and myelosuppression and the reduced cell counts and risk of infection that go along with it, cyclophosphamide, Cytoxan is a very typical chemotherapy drug, so of course, we definitely see those side effects, so be prepared to counsel patients about hair loss, about nausea, vomiting, and about taking appropriate precautions when their blood counts drop low. Dr. Sean Kane 06:35 Now I know that there's different degrees of emetic potential. Is this on at the high list at the low list, or where does this kind of fall within our spectrum of emetic potential? Speaker 1 06:45 That's a really great question. Cyclophosphamide doesn't fall into a neat category. It depends on both the dose and what drugs you're using. With higher doses of Cytoxan, or Cytoxan in combination with an anthracycline, it is categorized as a highly emetogenic agent, but lower doses of cyclophosphamide, or cyclophosphamide used on its own, are categorized as moderately emetogenic and require less prophylaxis. So it really depends on the setting you're using it in. Dr. Sean Kane 07:14 Then in terms of like high doses and low doses, is there kind of a prototype indication for the really high dose, or prototype for the really low dose? Speaker 1 07:22 Yeah. So really high doses, we would think about our patients who are getting bone marrow transplants. So cyclophosphamide can be used in combination with other agents to prepare patients for their bone marrow transplant. So it completely wipes out the cells in the bone marrow, creating space for new cells to come in. So that would definitely be a very high dose. The other great example is our breast cancer patients who are on the regimen AC, followed by T, where A stands for Adriamycin, which is doxorubicin, and that C is cyclophosphamide. So anyone who's getting AC in combination will require prophylaxis for highly amatogenic chemotherapy. Dr. Sean Kane 08:01 That's awesome. So Megan, if there's one thing that the students preparing for NAPLEX should know about cyclophosphamide, what would you say it is Speaker 1 08:10 the one key word or phrase that I want everyone to think about as soon as they hear cyclophosphamide? Is the phrase hemorrhagic cystitis that sounds severe. It does, doesn't it? It basically means pain, bleeding and inflammation from the bladder. So as the body gets rid of cyclophosphamide, it's excreted through the renal tubules and collects in the bladder, and it can cause a lot of irritation to the cells lining the bladder. This is very problematic for patients, because it puts them at risk of infection. It causes them a lot of pain, and it may cause us to have to decrease their dose of the drug, and we hate having to decrease chemotherapy doses. There is one thing we can do. We can administer a drug called Mesna in combination with cyclophosphamide, Mesna protects those bladder cancer cells. So for pharmacy students, when you're administering iphosphemide or cyclophosphamide, definitely be prepared to counsel your patients about this side effect, that they can report any signs or symptoms of hemorrhagic cystitis, and so that you can double check to see if their regimen requires co administration with Mesna. Dr. Sean Kane 09:17 So just to be clear, Mesna is an IV drug. It is, it can Speaker 1 09:20 also be administered orally, but I think most institutions are using IV Mesna. Dr. Sean Kane 09:25 And then is it only sometimes that you'll use Mesna with cyclophosphamide, or is it all of the time? It will be part of your regimen? Speaker 1 09:31 it's most of the time with cyclophosphamide, although there are some exceptions for lower doses, and it's 100% of the time with ifosfamide. Dr. Sean Kane 09:39 Great tip. Okay, why don't we move on to our second drug category, another alkylating agent. But this time, it is the Platinums, and the prototype that you selected was cisplatin, or platinum? Excellent. Speaker 1 09:51 Cisplatin is one of the drugs that I find most interesting in the chemotherapy class. As you mentioned, it's another alkylating agent. So once again, we see that it works through. To inter and intra strand cross linking, so it gums up the machinery of that DNA replication and transcription process, and the cell can really only fix that by taking out those base pairs that have been linked up irreversibly by the cisplatin. Cisplatin is an interesting drug because it was actually discovered by accident by researchers in a chemistry lab who wanted to see the effect of electrical currents on bacterial growth patterns. They picked platinum electrodes because they thought it was biologically inert. Turns out that's not the case. Dr. Sean Kane 10:34 So I'm guessing the bacteria did not do so well. Then, when they were exposed to this cisplatin, Speaker 1 10:39 yeah, the bacteria could no longer divide, so they kept growing, but they wouldn't actually divide. So they had bacterial they had E coli that was 300 times longer than a normal E coli. Fascinating, yeah. So they shelved it for a while, but eventually someone picked up the bottle again and started thinking about, how can we repurpose this? And turned their attention to curing cancer. Thanks to cisplatin, we had the first cures of testicular cancer. Dr. Sean Kane 11:06 So what are some of the other agents in this drug category? Speaker 1 11:10 There are three Platinums available. Cisplatin was the first. It was followed by carbo platinum and the newest, oxaliplatin. Dr. Sean Kane 11:18 Then are there any differences between the three? There are. Speaker 1 11:21 So we'll find that cisplatin tends to have the most severe side effects and requires the most dose adjustments, but it's been around the longest and has the best data behind it. Carboplatin, in some cases, although not all, can be used in place of cisplatin, carboplatin tends to be a little bit more tolerable. One thing pharmacy students really need to remember about carboplatin is that the only drug dosed by AUC or area under the curve, so it has its own special equation, oxaliplatin, the new one, is also pretty well tolerated, but only studied in a few disease states, and oxaliplatin tends to have more neuropathy side effects than The other two Dr. Sean Kane 12:01 and then I know you mentioned testicular cancer. Are there other cancers that we're going to be using these platinums in? Speaker 1 12:07 I think cisplatin has been tested in just about every disease state there is. But the ones you'll see it in most these days are solid tumors. So it has a lot of use in lung cancer. We also see it in ovarian cancer, bladder cancer, and head and neck cancer, and it's commonly used as an adjunct for radiation therapy. So if patients are receiving both cisplatin and radiation at the same time, it makes the radiation much more effective. Dr. Sean Kane 12:35 So with the cisplatin or any of the platens, what are the main side effects that we should be concerned about with these agents. Speaker 1 12:41 So once again, when we think about alkylating agents, we think about our classic cytotoxic chemotherapy side effects. So be prepared to talk to patients about hair loss, about nausea, vomiting, about myelo suppression, bleeding, those side effects, specifically with cisplatin, there's a high rate of renal toxicity. So it's really important that we talk to patients about staying hydrated. The other thing to remember about cisplatin is that it's highly emetogenic. Oxaliplatin and carboplatin are only moderately emetogenic. In the days before we had the wonderful antiemetic drugs that we have now, the rate of nausea and vomiting with cisplatin was over 90%, so definitely we need to be talking to our patients and making sure that they are on an optimal antiemetic regimen before they start this drug. Dr. Sean Kane 13:34 Now, in terms of the renal toxicity with cisplatin, is it because the drug is causing dehydration, or does it have an actual like toxic effect on the kidney itself? Speaker 1 13:43 It's actually very toxic to the kidneys, and cisplatin is the worst of the three by far. Carboplatin has some renal toxicity as well, but it's more easily dose adjusted versus the cisplatin that we don't have as much data behind dose adjusting and renal impairment. Yeah, cisplatin can be very problematic for patients who have renal problems. Dr. Sean Kane 14:04 So let's say that you had 30 seconds right before the NAPLEX for a pharmacy student, what do they need to know for sure about cisplatin? Speaker 1 14:12 Yeah, two quick things on cisplatin. First is hearing problems, so make sure your patients get a hearing test before they start. And second, absolutely positively, remember that renal impairment every time you check an order for cisplatin, patients need to get IV fluids before and after their drug, and they need to go home and drink tons of fluids. Dr. Sean Kane 14:30 And as you said, they may need a dose adjustment if they do have renal impairment, correct? Excellent. Okay, well, why don't we move on to our third drug class, and this was anti metabolites, with the kind of prototype being methotrexate. Speaker 1 14:42 So methotrexate is another drug that has a long history. We've been using methotrexate since the 1940s and it was one of the this class, I should say, was one of the first to induce remissions in kids with leukemia. It was discovered by researchers who were working on some. Studying the effects of B vitamins. So methotrexate actually looks a lot like folic acid. So how Dr. Sean Kane 15:05 does it actually work? Then I would assume if it looks like folic acid, it must be doing something along that pathway, Right exactly. Speaker 1 15:12 So where folic acid is helpful to our body in producing thymidine nucleotides, methotrexate goes in and interrupts that cycle, so the body is no longer able to continue the cycle of turning uridine nucleotides into thymidine nucleotides. If the body can't make thymidine nucleotides, then it can't produce DNA. And if the cell can no longer produce DNA, it eventually starts the apoptotic signaling pathway and the cell will self destruct. Dr. Sean Kane 15:39 Cool, okay, so methotrexate. I've definitely heard of that one. Are there other drugs in this category that maybe aren't as Speaker 1 15:44 common there are? So there's two newer drugs in this category, and you'll find that they also have that same kind of trexate root in their name. So we have pralotrexate and pemetrexed. Dr. Sean Kane 15:55 And are there any big differences in considering these three different agents? Speaker 1 16:00 No, they all tend to work pretty much the same way, and we see very similar side effects that we'll talk about in a minute. One thing to remember about the this class of drugs is that sometimes patients will require supplementation with B vitamins. Since we're interfering with that cycle, it can actually cause depletion of B vitamins in other cells, not only cancer cells. So with some of the newer drugs, the pralotrexate and the pemetrexed, the package labeling per the FDA does actually recommend that patients start on B vitamin supplementation. Dr. Sean Kane 16:31 And I would assume, though, that that supplementation of B vitamins doesn't reverse the effect of the methotrexate and allow the cancer cells to proliferate. Then Right, correct. Speaker 1 16:41 So we do have to be careful that patients aren't taking too much supplementation, because we want to make sure our chemo is effective. But oftentimes cancer cells lose the ability to pick up those B vitamins, and so we're able to administer supplementation to our patients, knowing that healthy cells can take it up, but the cancer cells cannot. Dr. Sean Kane 16:59 Okay. So what are kind of the classic indications for these anti metabolites, right? Speaker 1 17:04 So if we think about methotrexate specifically, the classic use of methotrexate is in leukemias, especially childhood leukemias, like acute lymphoblastic leukemia. We see it in other disease states. We also see it used in sarcomas, and there's been plenty of research into breast cancer and other solid tumors, but I would say the use of methotrexate in those disease states has been replaced by newer agents. Dr. Sean Kane 17:28 And this clearly goes without saying, but just so that we cover it, methotrexate is sometimes used in something like gout, for example, where you take, let's say, seven and a half or 15 milligrams once a week. What kind of doses, or how does that regimen differ when we're using it for more chemotherapy based indications? Right? Speaker 1 17:45 So your patients who are taking methotrexate for gout or for arthritis are going to take small milligram level doses, 510, milligrams. My patients, we measure their dose in grams. So for example, in sarcoma regimens, they might get 1212, grams per meter squared. Wow. So you may have a dose of methotrexate that's 20 grams. Dr. Sean Kane 18:09 That's amazing. Okay, so with these gram level doses, what are some of the side effects that we're going to observe that we clearly would not see with these minuscule doses? For gout, absolutely. Speaker 1 18:20 So methotrexate, like any chemotherapy, is not without its side effects. The number one thing that I think about when I think about side effects of any of my anti metalloids and my anti folates is mucositis, sometimes called stomatitis, and that's when you have peeling of the mucous membranes in the mouth or all throughout the GI tract. We always think about it being in the mouth, because that's what we can see when we examine a patient. But you do need to think about the fact that this mucositis and stomachitis will go throughout the entire length of the GI tract. So your patients will have pain in their mouth. They'll have trouble swallowing, but they're also going to experience symptoms like nausea, heartburn, diarrhea, and maybe even blood in their stool. So we need to be monitoring patients very closely, because this can be a serious site of bleeding or of infection. Dr. Sean Kane 19:11 I would imagine then that that's happening because clearly, our methotrexate is causing damage to the GI tract. Is it just because those cells are turning over enough that they're taking in that methotrexate, or what's kind of the etiology Speaker 1 19:23 of that? Oh, excellent question. So most of our traditional cytotoxic chemotherapies, including our alkylating agents and our anti metabolites, work by targeting cells that are dividing very rapidly, because cancer cells are growing and dividing all the time. But unfortunately, we have other cells that grow and divide quickly as well, and that can include our skin mucous membranes and the cells in our blood and bone marrow. And that's why we see those side effects commonly. Dr. Sean Kane 19:48 Okay, what are some of the other side effects that we can see with methotrexate? Speaker 1 19:51 So methotrexate, just like any other chemotherapy, can cause some myelosuppression, so we'll see lowering of blood counts. It can also cause renal toxicity. So again. And be thinking very carefully about keeping your patients hydrated. And methotrexate is one of the few drugs that we can administer through the intrathecal route, so we can put it directly into the CSF. So if patients have cancer in their brain or in their central nervous system, we can target that directly with this chemotherapy. But of course, if you're administering chemotherapy into someone's intrathecal space, you're going to have some CNS side effects, so patients may report headaches, dizziness, sleepiness, things like that. Okay? Dr. Sean Kane 20:30 And just to touch on that, renal toxicity again, is that again, due to some direct toxic effect on the kidney, and do we have to dose adjust it? Speaker 1 20:38 We can dose adjust it. Another thing for pharmacists to think about with the renal toxicity is that methotrexate has some drug drug interactions. So when you're administering this to a patient, you should always double check that it's not going to be interacting with other medications that would perhaps impair its renal excretion. Dr. Sean Kane 20:54 So for the NAPLEX studies, what would be one or two of those big drug interactions that would be red flag, absolute. Big Deal interactions, Speaker 1 21:02 absolutely so I would think about things like NSAIDs. They would certainly impair excretion of our methotrexate. And another one that comes up commonly in the Leukemia population is Allopurinol. And another one that pops up every once in a while are interactions with PPIs. Dr. Sean Kane 21:20 Okay, so again, kind of in the same format, you have 30 seconds for that NAPLEX student. What's the one or two things that they absolutely have to know about methotrexate before they walk into that exam room? Definitely. Speaker 1 21:31 So if you're going to be administering 20 grams of a drug to a patient, you want to have something in your back pocket to fix any side effects that you might be causing. And the good news is that methotrexate has an antidote. So we often will, quote, rescue our patients with the drug leucovorin. Leucovorin is another drug that looks a lot like a B vitamin, and in this case, it actually does the job of the B vitamin, and it will restart that pathway to help the cell make thymidine nucleotides again. So usually for patients, we're getting very high doses of methotrexate, we will wait a few hours after their chemotherapy dose, and then we will start giving them IV infusions of leucovorin. Sometimes leucovorin goes on shortage, and we might use its sister drug, levoleucovorin. Dr. Sean Kane 22:19 So what you're saying is that we're actually rescuing the healthy cells, and then, as you said, the leucovorin is not taken up by the cancer cells, and they'll continue to get the toxicity from the methotrexate Exactly. Speaker 1 22:31 So most of our normal body cells possess a receptor that helps them to pick up that leucovorin, but a lot of blood cells, especially leukemia cells, have lost that receptor. Dr. Sean Kane 22:41 Are there any types of cancer where you would not do that rescue, because the cells can uptake the leucovorin? Speaker 1 22:47 There's actually one cancer where we take advantage of that mechanism for our patients who have colorectal cancer and get the drug 5-FU (5-fluorouracil); those colon cancer cells still can take up leucovorin, and the leucovorin in that case actually extends the period of activity of 5-FU, giving extended efficacy and some increased toxicity. Dr. Sean Kane 23:11 Yeah. All right, so if we move on to our fourth drug class, the anthracyclines, with the kind of prototype being doxorubicin or Adriamycin, why did you pick this one? And what can you tell us Speaker 1 23:21 about it? So anthracyclines are a very common drug class, especially for patients with breast cancer. And almost all of us know someone who's experienced breast cancer. I also think that the anthracyclines are a really interesting drug class. So they were discovered a few decades ago by Italian researchers, and out of a sense of hometown pride. They named the brand name of doxorubicin, Adriamycin after the Adriatic Sea. Dr. Sean Kane 23:47 So nice. All right. So how does it work? Speaker 1 23:50 Then, anthracyclines are pretty cool. They don't have one mechanism. They have three. So the first way they work is that they inhibit the topoisomerase enzyme. And if you remember, topoisomerase is responsible for unzipping DNA, and so it will create a break in the DNA and unwind it. But if you inhibit topoisomerase, you can still create that break in the DNA, but you can't fix it again. So that's the first way they work. The second is that they intercalate between DNA base pairs. So if we think of DNA like a ladder, the anthracyclines will just fit in between some of those steps in the ladder, and it blocks the DNA machinery from being able to progress up the strand. The third way that they work is they produce oxygen free radicals. And for anyone who's big fan of drinking pomegranate juice, you know, we want to fight free radicals. And so by creating these free radicals, the anthracyclines can actually cause a lot of damage to proteins and DNA within the cancer cell. Dr. Sean Kane 24:51 So I'm definitely familiar with doxorubicin because I remember one specific thing that I'm sure we'll talk about with doxorubicin. But what are some of the other anthracyclines that are on the market? Speaker 1 25:00 It definitely so there are a handful of them in the class. There's also daunorubicin, idarubicin and epirubicin. And you'll notice they all have the same ending — they all end in "-rubicin." And this comes from the Latin word rubor, meaning red. And if you hold up a vial of any of the anthracyclines, you'll see that it's bright red. Dr. Sean Kane 25:21 So with you know several of these different anthracyclines, is there a big difference between any of these in terms of indications or side effects or anything special to know about them, Speaker 1 25:31 some differences in indication, we'll find that doxorubicin mostly gets used for breast cancer, whereas daunerubicin is more commonly used in heme malignancies. But most of what we'll talk about in terms of side effects and monitoring holds true for all of these. The other important thing to remember is that they're considered equivalent when we look at patient's lifetime usage. So we'll talk about the fact that there is actually a lifetime limit on the dose of anthracyclines that one patient can receive, and that includes all anthracycline exposure, so you can't use up your lifetime doxorubicin and then switch to epirubicin. Dr. Sean Kane 26:07 It all counts. So then in terms of some of the side effects, what are the main ones that come to your mind? Speaker 1 26:12 So the one, what we'll dive into most is going to be the cardiotoxicity. But in addition to that, you'll find that these cause problems with myelo suppression, hair loss and a pretty unique toxicity where patients will actually have red coloring of their sweat, tears and urine, and that's because the drugs are red. Dr. Sean Kane 26:32 Now, will that actually stain clothes, or is it washable? Speaker 1 26:35 It can actually stain clothes, and it can be pretty nerve wracking, especially since we talked about the fact that doxorubicin is frequently used with cyclophosphamide for breast cancer. Imagine, I've just counseled a patient all about hemorrhagic cystitis with their cyclophosphamide, and the next time they pee, they realize their urine is sort of reddish pink. It can make patients very nervous, so it's important to make sure that they know when they go home that they shouldn't be wearing their favorite clothes, and that they will notice that all their fluids are going to be stained kind of a pinkish orange color. Great. Dr. Sean Kane 27:08 Let's dive in a little bit more to the cardio toxicity, because that's the one thing I remember about doxorubicin. So what can you tell us about the Speaker 1 27:16 cardiac toxicity? So these drugs can cause a lot of problems with the cardiac muscle, both short term and long term. For our patients, the mechanism isn't very well understood for a long time. It was theorized that most of the cardiotoxicity was due to the generation of those oxygen free radicals, but now it seems like it might actually have a lot more to do with the topoisomerase inhibition, but either way, it's a problem for our patients. So right away, within the first few hours to days of anthracycline administration, we can see problems like arrhythmias. And then long term, we see a cumulative damage to the heart muscle, and many patients, 1020, years out from their anthracycline will end up with heart failure. So we can cure a lot of people from leukemia or from breast cancer, but we might be setting them up for cardiotoxicity on down the road. So for pharmacy students, definitely remember that these patients need to get an echo and an EKG at baseline and when they finished their treatment to assess for any changes, and some patients may even require closer monitoring during their therapy with the anthracycline. Dr. Sean Kane 28:28 Is there anything that can be done? I said, from monitoring, especially if the patient is at high risk for some of these cardiac problems, definitely. Speaker 1 28:35 So if patients already have cardiotoxicity, if they come into us with heart failure, we're going to be hesitant to give them these drugs to begin with, although I will tell you we go pretty low on the echoes. So I think I've had patients who had EFs below 50%, and we still started it. Depending on what other options we have available, we can also limit their total lifetime exposure to anthracyclines and the number that you need to remember for that is 550 mg/m2. That's for most patients. There is an exception for patients who have any radiation to their chest. Those patients can only get 450 mg/m2 of anthracycline over the course of their lifetime. The other thing we can do for our patients who are at high risk or are getting up toward that lifetime dose limit, we can give them another drug called dexrazoxane, which has been shown to decrease the risk of cardiotoxicity with doxorubicin and other anthracyclines. It seems to work mostly through scavenging those free radicals. We don't use it in all cases, but in certain high-risk patients, we can Dr. Sean Kane 29:45 add that on. Now, is there a reason it's not given all of the time? Speaker 1 29:49 Partly it's that dexrazoxane isn't used routinely, but also because there is a concern that if you are inhibiting one of the mechanisms through which the chemotherapy is effective. That is by its generation of free radicals, you might impact the efficacy of that chemotherapy. Dr. Sean Kane 30:06 Just to be clear, in terms of the heart failure that patients can progress into, is it always systolic heart failure, where they'll end up having a low ejection fraction Speaker 1 30:14 for the most part? Yes, it seems to impact the ejection fraction. It really can impact the contractility of the heart. Okay? And so we have a cardiac oncologist at the hospital I work at who takes care of a lot of these patients, and she loves to look at the stress on the heart. Dr. Sean Kane 30:34 Okay, wonderful. Well, why don't we kind of wrap up with the fifth drug category that you picked? This is the antimicrotubules — the Vinca alkaloids — with the prototype being vincristine (Oncovin). Great. Speaker 1 30:46 There's a couple of different sub categories of anti microtubules, and our audience might even be more familiar with the other category, called the Taxanes. But I wanted to pull out the vincas because there's some really important information that those of you who are studying for the NAPLEX are going to want to keep in mind so vincristine, or oncovin, and the other medications in this class are one of our chemotherapy categories that's derived from natural products. These drugs actually come from flowers. So anyone who's a gardener, if you have Impatiens out in your yard — that's where we get the vincas from. Dr. Sean Kane 31:23 So if they're natural and come from flowers, clearly these are not toxic Speaker 1 31:27 ages, right? Yeah, well, we'll get into that. Dr. Sean Kane 31:31 So how does a Vinca alkaloid actually work? Speaker 1 31:33 Then all right. So within our microtubule class, as I say, we have a couple of different categories. The vincas are assembly inhibitors. So that is to say that they stop the microtubules from being able to stack up. So when we think about the process of mitosis, when our cells are dividing During metaphase, the microtubules work their way toward the center of the cell and allow the chromosomes to be divided, but the Vinca Alkaloids stop the microtubules from being able to be built up, so we never have that attachment to the chromosomes. We never have appropriate Division during mitosis. Dr. Sean Kane 32:14 Okay, and then what are some of the other Vinca Alkaloids out there, besides vincristine? Speaker 1 32:18 Yeah, there's three in the class. Vinblastine and vinorelbine are the other two Dr. Sean Kane 32:22 two that are available, then any big differences between the three? Actually, there are some Speaker 1 32:26 differences in this one. So we'll talk about vincristine side effects. It has a pretty mild side effect profile for chemotherapy. It has very little myelosuppression. But the other two in the class, especially the Vinblastine, do have a lot of myelosuppression that go along with their use. Dr. Sean Kane 32:43 Okay, what are some of the other side effects that we see with the ven Christina? Speaker 1 32:48 Anytime you see an anti microtubule drug, you definitely need to think about peripheral neuropathy. It's usually reversible if caught early, but if it's allowed to go untreated, or patients get more and more cycles of chemotherapy, it can be harder to reverse it, and so patients may still have neuropathy, months to years after finishing their chemotherapy, some other side effects we see with Van Christine, as I mentioned, very mild myelo suppression, but also constipation. So much like you think about having a bowel regimen on board for your patients who are on opioids, you probably want to have a bowel regimen on patients who are going to get vincristine. Dr. Sean Kane 33:25 All right, so kind of wrapping that up, what is your 32nd kind of pow wow with that student before they walk into NAPLEX regarding vincristine, Speaker 1 33:34 the number one thing I want students to know about the Vinca is absolute number one. Can't forget this ever, never, ever administer the Vinca Alkaloids through the intrathecal route. Any CNS administration of the Vinca Alkaloids is 100% fatal. There have been a lot of very tragic medication errors where these meds were administered through the it route. So the number one thing for a student taking the NAPLEX is knowing that you cannot ever give vincas through the intrathecal route. Dr. Sean Kane 34:10 So it seems like that's a fairly simple recommendation, or fairly simple thing to remember when this does happen in clinical practice. Is it being mixed up with another agent like methotrexate, or is it that they don't know any better? How does this actually happen? Speaker 1 34:25 What happens, sadly, is patients who have leukemia often on the same day are scheduled to receive a small dose of vincristine and a small dose of intrathecal methotrexate. If both of those doses are mixed in syringes and put in the same chemotherapy bag, it's very easy to grab the vincristine syringe instead of the methotrexate syringe when you're doing the IT administration. So most institutions now will not mix them at the same time. Because they will not be administered in the same place. Usually, your intrathecal methotrexate is given in a radiology suite, so we will give that one at a separate time from the intravenous vincristine. The other thing that we do is vincristine, for the most part, is no longer administered in syringes. Even though it's a small dose, it usually is only about 10 milliliters or less. When you mix the dose up, we will dilute it and put it in a 25 ml mini piggyback bag, because you would never accidentally administer a bag into the CNS Dr. Sean Kane 35:36 got it okay? Well, Dr. Megan Hartranft, I really appreciate your time. I think that for the benefit of the listeners, if we could just run through kind of your 32nd pow wow. The first agent we talked about was cyclophosphamide, which was an alkylating agent. What was the main thing with that one? Speaker 1 35:50 Definitely remember hemorrhagic cystitis with that one. And we can prevent that hemorrhagic cystitis by giving Mesna with our cyclophosphamide, okay? Dr. Sean Kane 35:59 And then our second one was the Platinums like cisplatin, which are is another alkylating agent. What was your go to for that? Speaker 1 36:06 One always think about the renal toxicity with our cisplatin, and the fact that those patients will need IV fluids before and after their infusion of cisplatin. Okay? Dr. Sean Kane 36:16 And then we moved on to the methotrexate anti metabolites. What was your go to with methotrexate. Speaker 1 36:21 So with methotrexate, again, we're thinking about, how can we prevent side effects? And in this case, we want to give our patients doses of leucovorin, an antidote to the methotrexate after they finish any high dose infusion of methotrexate, perfect. Dr. Sean Kane 36:36 So the number four was our anthracyclines, like doxorubicin. What was our main thing with that one, doxorubicin. Speaker 1 36:42 Always think about cardio toxicity, and think about the fact that we have some ways to prevent it, including limiting patient's lifetime dose to 550 mix per meter squared, and giving antidotes like dexrazoxane. Okay? Dr. Sean Kane 36:55 And then our final drug category was the anti microtubules, specifically the vanca alkaloids like Van Christine, Speaker 1 37:01 and when it comes to Van Christine and the other Vinca Alkaloids, just remember that they cannot be administered through the intrathecal route. Outstanding. Dr. Sean Kane 37:09 Well, again, thank you so much for your time and for the listeners. If you would like to visit us online, we're at HelixTalk.com, on Twitter, at HelixTalk. We love five star reviews, and Dr. Schuman and Dr. Patel should be back on the episode shortly. With that I'm Dr. Kane and I'm Dr. Megan Hartranft. Study hard. 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