I will be talking first just about the challenges of chemotherapy-induced nausea and vomiting.

Transcription

1 The Role of Pharmacists in Improving the Care of Patients With Chemotherapy-Induced Nausea and Vomiting Sally Yowell Barbour, PharmD, BCOP, CPP Susan Urba, MD John M. Valgus, PharmD, MHA, BCOP, CPP SALLY YOWELL BARBOUR, PHARMD, BCOP, CPP: This is a CPE-accredited satellite symposium, The Role of Pharmacists in Improving the Care of Patients with Chemotherapy-Induced Nausea and Vomiting. My name is Sally Barbour. I m an oncology pharmacist at Duke. I am the director of Oncology Pharmacy Programs and have a practice in the outpatient clinics and I m also our oncology residency director. My copresenters this evening are Dr Susan Urba and Dr John Valgus. Dr Urba is professor of internal medicine in the Division of Hem-Onc and the medical director of the Symptom Management and Supportive Care Program at the University of Michigan Comprehensive Cancer Center in Ann Arbor. She and I serve together on the NCCN Antiemetic Committee. Dr Valgus is a hematology/oncology clinical pharmacist practitioner and the director of the Hem-Onc Residency at UNC; he is also a clinical assistant professor at UNC Eshelman School of Pharmacy and a member of the Center for Pharmacogenomics and Individualized Therapy. The program has been planned and sponsored by Continuing Education Alliance for 1.5 contact hours, and the program is supported by an unrestricted educational grant from Eisai. Here are the learning objectives. We ll be talking about implementing guideline-based strategies, delineating emetogenicity of various chemotherapeutic regimens, and evaluating the data that is available to support the use of these antiemetic agents and combinations for patients receiving moderately-emetogenic and highly-emetogenic chemotherapy. And we will also talk about some emerging agents. I will be talking first just about the challenges of chemotherapy-induced nausea and vomiting. I don t have anything to disclose. I m going to try to set the stage a little bit about why we re still talking about nausea and vomiting in this era. What you see on this graph is a series of rankings that have really gone back to the early 80s and we can see where nausea and vomiting has fallen out. Obviously we have made a lot of progress in managing chemotherapy-induced nausea and vomiting, but as evident by this slide, there is still room for improvement. You go back to the 80s where we really didn t have a lot of effective agents and clearly vomiting was the number 1 symptom that really was most feared by patients who were receiving chemotherapy, with nausea following up second. Then, you can see that we had the first serotonin antagonist introduced between that first and second set of data. So, in 1993, you see vomiting really falling down from its top spot and nausea taking over that number 1 spot, where it really has pretty much remained over the last 20 or 30 years. The last time any kind 1

2 of survey like this was done was 2004, but I would bet that if we did this today, nausea would still really rank up there as something that is most concerning to patients receiving chemotherapy. Another study, just to continue to drive home this point in the evidence, is a study that was done in 2005 where the investigators had GYN patients rank and perform symptom assessments of side effects from chemotherapy. I don t know how well you can actually read the side effects that are along the bottom, but suffice it to say that these ones at the end which are chemotherapy-induced nausea and vomiting, both acute and delayed were the ones that were ranked the most concerning and the only side effect that they beat out was death. And then another study, the ANCHOR Study, also looked at the effects of chemotherapy-induced nausea and vomiting and how it affected patients quality of life. I m sure none of us need a study to convince us that throwing up is going to reduce someone s quality of life, but this is continued data to support that regardless of whether it s nausea or vomiting, that patients quality of life was negatively impacted. And again, not surprising, for those of us who practice, today we see nausea really is more of a concern and decreases patients quality of life because it seems to continue. You vomit and you re done and you feel better. You re nauseated for days with chemotherapy and also, not surprisingly, what they found in this was that highly-emetogenic chemotherapy more negatively affected patients quality of life than did moderately-emetogenic chemotherapy. So, what are the definitions? If we re going to talk about nausea and vomiting, it s important to understand what makes up chemotherapy-induced nausea and vomiting in terms of timing. Just to briefly review, acute nausea and vomiting is nausea and vomiting that occurs within minutes to hours after a patient has received chemotherapy. It typically has resolved within the first 24 hours after receiving chemotherapy. Delayed nausea and vomiting is referring to the nausea and vomiting that starts to occur that next day; not that 24 hours is a magic cut-off, but that s where, in studies, you see that cut-off and we re talking about typically, nausea and vomiting occurring within those first several days after a patient has received chemotherapy. Typically, we see that this resolves within a couple of days. It can last longer, but certainly when patients are complaining about nausea and vomiting really beyond that, you start to think about perhaps other causes of nausea and vomiting. Delayed nausea and vomiting can be fairly frequent, and is fairly frequent in highly-emetogenic chemotherapy, but it also can be a problem with certain moderately-emetogenic chemotherapy agents. And then breakthrough nausea and vomiting is fairly self-explanatory. Despite appropriate prophylaxis, patients can still have nausea and vomiting that breaks through that requires some sort of rescue medication. Anticipatory nausea and vomiting there are patients that will do that if they have had poor control in prior chemotherapy or just the thought of coming to get chemotherapy because they ve talked to their friends and they know it s going to be bad. They are already nauseous before you ve even given them any chemotherapy. 2

3 And then the last is refractory nausea and vomiting, which you have done everything, you have given appropriate prophylactic antiemetics, you ve given breakthrough antiemetics, and they are continuing to have problems and nothing seems to be working for those patients. What are the consequences of all of this? If patients don t have their nausea and vomiting controlled, they can become dehydrated. They can have electrolyte imbalances, as we ve talked about; their quality of life is impaired. They get admitted to the hospital. They can have other consequences that can negatively affect their outcomes. We ve had patients that, if their nausea and vomiting isn t controlled, they just don t even want to get chemotherapy anymore. And in a patient who s receiving curative chemotherapy, that really shouldn t be happening today. So again, how are we doing? I think, as practitioners, we seem to think that we re doing great, but the perception vs the reality is something that is important to take a look at. What this study shows is that physicians and nurses think that they re doing pretty good, but when you look at their perception vs the reality in a patient, you see that patients are actually having a worse experience than we think that they are having. Again, reinforcing the need to talk to patients and get patients feedback so that you can make adjustments. Our understanding of the model of acute and delayed nausea and vomiting is that we know that in that first 24 hours, that acute phase, that nausea and vomiting is sensitive to the serotonin receptor antagonist sensitive phase, which is why we see those drugs being so effective in that acute first 24-hour setting. Then, starting not really in that first 24 hours, but later, we start to see the NK1-sensitive phase, where we ve seen aprepitant and fosaprepitant really have a role. I love steroids; steroids are very effective and we can see, based on this, that all throughout both in the acute and the delayed setting, nausea and vomiting is really receptive to steroids. Just a brief overview of the physiology of nausea and vomiting. Nausea and vomiting is there for a reason. It is there to protect us. When we ingest things that are not good, that are toxins, nausea and vomiting is our body s protective mechanism to get rid of it. So, it is a good thing to have. Because it is a good thing to have and it is how we were made, it makes it sometimes difficult to control. What are the key components of this emetic reflex and how it relates to chemotherapy-induced nausea and vomiting? There are really 2 key players: the central nervous system and the GI tract. The emetic center is really the center that coordinates all the various input and causes us to actually throw up. The area postrema, which is also referred to as the chemoreceptor trigger zone, is another key player in causing nausea and vomiting. And in our GI tract, enterochromaffin cells contain serotonin and when they are disrupted, either from radiation or chemotherapy, they release serotonin, which binds to those receptors and causes triggering of that emetic center. This is just a schematic of the chemoreceptor trigger zone, which the reason that it is located outside of the blood-brain barrier, so it is exposed to those toxins in circulation. The cerebral 3

4 cortex its role is in that anticipatory nausea and vomiting and the role of the periphery is in the GI tract, where that serotonin is released from enterochromaffin cells. The key receptors that play a role in emesis are dopamine, serotonin, and substance P, which are the NK1 receptors. Those are really the key neurotransmitters that we target with our drugs. Risk factors: there are 2 key types of risk factors. We have patient-specific risk factors and treatment-specific risk factors. Patients that are older tend to do better with nausea and vomiting management as opposed to younger patients. It could potentially be because younger patients, we tend to give more aggressive regimens to. Women tend to have more problems with nausea and vomiting than do men; men tolerate it better. Patients who have a significant alcohol history, that s actually a positive risk factor. The more you drink, or have drunk, the better you do with nausea and vomiting. It s important to talk to patients. Have they had emesis with prior chemotherapy? Do they have a history of nausea with riding in cars or while they were pregnant? Talking to patients and seeing if they have any additional patient risk factors is important. And then there is the potential for polymorphisms in the metabolism of antiemetics that can also play a role in how they might respond. And then our treatment-specific risk factors: the most important, obviously, is the chemotherapy drugs themselves. What is the emetogenicity of the single drug or what is the emetogenicity of that single regimen? Also, how drugs are given some drugs are more or less emetogenic based on how they re given, whether they re given as an IV push as opposed to a continuous infusion. Also, are they getting concurrent radiation along with their chemotherapy? And if they ve had surgery, has their gut been affected or are there other things that are not part of their chemotherapy treatment, but are part of their overall cancer treatment that might also contribute to them being more at risk? When we look specifically at the chemotherapy drugs, and they are ranked, and the regimens are all ranked high, moderate, low, or minimal. In patients receiving highly-emetogenic chemotherapy, if we don t give them anything, we know that greater than 90% of those patients are going to throw up. This helps guide our choice of antiemetics. Most regimens and drugs fall in that middle category, which is quite wide-ranging, from 30% to 90% risk of having emesis if we didn t do anything. And then low is 10% to 30%, and then agents that have a less than 10% risk are considered minimal. This slide summarizes the most recent versions of the guidelines. The ASCO guidelines, NCCN guidelines, and the MASCC guidelines are really all fairly similar. They have become more similar over the years. The ASCO guidelines haven t been updated since NCCN guidelines, we update those every year, and the MASCC guidelines have also not been updated in the past couple years. But again, they re very similar. Patients receiving a highly-emetogenic regimen, they all agree that patients should be receiving a serotonin antagonist, an NK1 antagonist, and dexamethasone. The NCCN guidelines do list 4

5 palonosetron as preferred in that highly-emetogenic setting, whereas the other 2 guidelines do not have a preferred serotonin antagonist. And then, for moderately-emetogenic chemotherapy, again it s pretty standard across all 3 regimens that a serotonin antagonist and a dexamethasone should be given to those patients. And the NCCN guidelines and the ASCO guidelines do recognize that there might be some patients who are receiving a moderately-emetogenic regimen but have other risk factors that might make them more high risk where you would want to add an NK1 antagonist. NCCN, within the last year, has added an olanzapine-based regimen as an option for patients receiving moderately- or highly-emetogenic chemotherapy. And then patients who are receiving a low-emetogenic agent or regimen really don t need a lot of powerful or expensive antiemetics, and as recommended by the guidelines, treat them with dexamethasone or metoclopramide or something along those lines. So not just acute, also thinking about delayed. Again, the guidelines are fairly comparable in terms of what is recommended, and you really see dexamethasone being a key player in the delayed emesis setting. For highly-emetogenic regimens, dexamethasone is all that is recommended with the assumption that they ve gotten fosaprepitant on day 1. Obviously, if you re using the oral regimen, you re going to continue that aprepitant for the additional 2 days. And then it s important also for those moderate regimens, to make sure that patients have a scheduled antiemetic for those 2 days to make sure that we re preventing any nausea in those patients. And patients that have received a low regimen, you don t need to schedule anything for those 2 days. Everybody, regardless of what chemotherapy they re getting, should always have something as needed. A lot of progress has been made, but we obviously still have challenges. As seen by that first graph, while vomiting has pretty much fallen off in the last survey, nausea really does continue to remain a problem, and part of that is because while we have a good understanding of the cause of vomiting, we don t really have a great understanding of the cause of nausea, and probably because there are so many different things that go into causing nausea. Guidelines, we have these great guidelines. Do we all follow them? Some maybe better than others. Why is that? Some of it might be that practitioners just aren t aware of the guidelines. Over the years, the recommendations have differed. Some of it is cost and financial issues, and I know that we ll talk about that some perhaps in our discussions. Some, it s an institutional issue. Your own institution has guidelines. And sometimes there are just not good outcomes on them. So, what are the things that are not addressed and what are the things that maybe we, as pharmacists, can help provide data for? Right now, the guidelines are really based on the emetogenicity of the regimen and the pattern of nausea and vomiting, meaning acute or delayed. It doesn t really take into consideration any of the patient and individual risk factors. If you talk to a patient and they have 3 of those other risk factors, what do you do? Does that make a low a moderate? Does it make a low a high? We don t really know. You just kind of have to make your best educated guess and go on. There s also a lot of data that s lacking and this is where I think we, as pharmacists, can perhaps do some research and look into this. There s not a lot of great data on multiday chemotherapy. There s 5

6 not a lot of great data on nausea and vomiting in the stem cell transplant population. The NCCN guidelines have attempted to provide some guidance on managing nausea and vomiting in patients receiving oral chemotherapy, but there s not a real lot of data out there on that. And pediatric patients, there s not a lot of data in managing emesis in those patients as well. And then, as I alluded to, how do you incorporate all these patient risk factors into the guidelines? We re going to have our first faculty discussion. So, our first case, we would like to introduce you to Jeanne. Jeanne is a 48-year-old woman who has stage III HER2-positive breast cancer with incomplete control of her nausea and vomiting. She started her adjuvant therapy; she received docetaxel, carboplatin, and trastuzumab after her surgery. Her past medical history is really nonsignificant. She has not smoked at all and she doesn t drink any alcohol. For prophylaxis of her nausea and vomiting, she received ondansetron and dexamethasone. She got that before chemotherapy, but that night she went home and had nausea and vomiting. She did have a prescription for prochlorperazine, which did relieve the emesis, but was just nauseated continually for 3 days after her chemotherapy and relatively miserable. Despite this misery, she did not call the oncology team, but when she went back for her 1-week follow-up visit, she did tell them that she had been miserable and was nauseated for days after her chemotherapy. The faculty is going to discuss this case. I ll start with John. So you re in clinic, Jeanne has come back to clinic, and Dr Urba has come to you and said, John, what do you think? What can I do? What happened? What went wrong? What questions might you ask Jeanne? JOHN M. VALGUS, PHARMD, MHA, BCOP, CPP: I think things that clearly stand out here, you know, patient-specific factors. She s female, she s a younger female, no history of alcohol consumption, all those are things that put her at a little bit higher risk and then, sort of turning over and looking at the chemotherapy she s receiving, you have 3 different drugs in that combination, but the highest would probably put you in the moderate category. So, that s most likely how we would treat her, as a moderate risk. BARBOUR: Do you have any concerns about the antiemetic regimen that she was prescribed? Do you think that what she was prescribed followed guidelines and was appropriate, or do you have concerns, Dr Urba? SUSAN URBA, MD: Well, certainly she got a serotonin antagonist and dexamethasone and, in general, for moderately emetogenic, that s okay. When you look at the drugs, there s a little bit of a gray zone when we re adding 2 drugs together. The carboplatin is in the moderate category. The docetaxel is in a lower category, but see then when you re combining things, does that bring it up a category? Are you still in the moderate category? I think a lot of times people will just try it with a moderate regimen, which is not necessarily with aprepitant. I would say, Well if the next day, if that s when she started getting nauseated, did we cover her for day 2, 3, 4? Did we send her home 6

7 with some dexamethasone or something like that? Number 1, did we do it and then, number 2, did she take it or not? Because, you know, sometimes people don t realize, they think it s prn as opposed to just scheduled and taking it in that way. There s also some discussion, and we ll talk a little more about the NCCN guidelines, the drugs that are in the moderate category and therefore don t necessarily need aprepitant, but the NCCN guideline panel thinks that some of those moderate drugs can be in the higher end of moderate, so you might want to consider treating them more like highly emetogenic and adding an aprepitant. Carboplatin and a few other drugs kind of fall in that category. We can always rethink what we should ve done. I don t think what was done was wrong in any way as long as there was some coverage for the next couple of days. Sometimes thinking, well, this is a woman, she s young, she s not a drinker, she s already got a few strikes against her, she s getting carboplatin and then another thing, maybe that might ve pushed me to start by treating her almost as a highly emetogenic. BARBOUR: So, what might you recommend for her cycle 2 of chemotherapy? URBA: Knowing that she struggled so much, would really go up with everything. Number 1, if she was sick, if she s going to perseverate on that, I might send her home with a little lorazepam or call in some lorazepam or something. Maybe she could take it the day she s coming, if she s starting to get anxious about it. I might up that ondansetron to the palonosetron. If you go according to the NCCN guidelines, that is considered preferred. In some studies, it s looked a little bit better. I probably would add in aprepitant. I realize I m also jacking up the price of all this, but on the other hand, it s a very tough thing to go through this for the patient and I think it was the adjuvant therapy, if I m not mistaken, so we really want to get her through it, we re really going for cure here. And then I d just make sure she had something, and I d make sure that we d say, Look, call us the day you re uncomfortable, don t wait a week, because we could ve probably helped you earlier. And getting on top of it sooner is easier than just waiting and then trying to play catch-up. VALGUS: I agree. I think the way that I usually process it is up-front, first cycle, we don t know how a patient s going to respond and so we often have to use those guides to help predict for us how a patient s going to respond. But when you have patient-specific information, the patient has received that regimen in the past, she did not tolerate it well. If you were to put the percentages all over again for that individual patient, I d probably say if we did everything the same for cycle 2, there s a greater than 90% chance she s going to have emesis and she s going to have nausea. And so I think, for me, that s what is a rational approach is to bump up and give her something that will cover her for a highly-emetogenic chemotherapy regimen. BARBOUR: I d like to bring up Dr Urba to continue our program and she will be looking at the progress that we have made in antiemetic therapy. URBA: Thank you. Here are my disclosures. 7

8 Again, we ve got to cover and prevent nausea and vomiting maybe a little bit longer for the highly emetogenic, at least out through 3 days or so; for moderately emetogenic, about 2 days. Now, here also, oral and IV are actually equivalent efficacy with the correct dose. It doesn t mean the dose is the same. We ll talk a little bit about palonosetron. You give that IV, you give it 25 mg. There s a new oral formulation in a combination product, we ll talk about for a couple of minutes and there, it s 50 mg. But if you use the correct dosing, it should be the same whether it s IV or not. Having said that, if someone s vomiting a lot, a lot of times we ll switch them to IV to at least get it into them if they can t get a pill down. And then certainly, some of the agents that we use have various toxicities. Now, it wouldn t necessarily, I mean if I have to give a serotonin antagonist, I ve got to give one no matter what, and it s hard to say if ondansetron or palonosetron is causing more of one thing than the other, but things to think about are constipation, headaches, and dizziness. I think the constipation and headaches are really the big ones that we do see a fair amount of time. For the NK1 antagonists, there s a whole long laundry list. Personally, it doesn t seem to me that that s clinically relevant, but if you look at the prescribing information, they say that that list occurs about 10% of the time or more. So, I guess if someone gets hiccups or whatever, you have to at least consider that might be the cause of it. Corticosteroids, I think we re all aware of all the issues with that. Insomnia, sometimes they re agitated, up at night. And then some of the dopamine antagonists can cause some extrapyramidal symptoms. So, we really base our choices on the emetic risk of the therapy. While we think about the patient factors, it s really the drug list that we look at, how the patient has done before, and of course we have to think of other causes. You know, every now and then, just because we re so focused on chemotherapy, we all of a sudden realize that the patient s off-kilter a little bit and maybe we d better be doing a head CT. So here s the list of which of these are available kind of anywhere, but I think there s a copy just like this in the NCCN guidelines. And interestingly, nowadays we hardly have to think about this because I think a lot of us are on electronic records, electronic ordering, so that once the template is made, along with it you get the nausea drugs. For HEC, which is the highly emetogenic, the thing to point out, I think we may know by now, AC, the adriamycin/cytoxan regimen for breast cancer patients used to be considered moderately emetogenic. Over time, we ve realized it s really highly emetogenic. So, that s the category it s in and then also, I just highlighted a few I wanted to make some comments on. The cisplatin, because that s the one against which a lot of the new nausea drugs are tested because if you can control cisplatin, you can control anything. The doxorubicin, if it s greater than 60 mg, it s highly emetogenic. If it s less than 60, it s moderately. So, for some of the drugs, it s really dose-dependent. For other drugs, no matter what it is, it s in that category. 8

9 9 For the moderately emetogenic, I highlighted a few. The ones I highlighted are the ones that, for whatever reason, the NCCN guideline panel has said, if you re equivocating, if you should kind of bump a regimen up to highly emetogenic vs moderately emetogenic, they said if some of these drugs, like carboplatin or doxorubicin, epirubicin, ifosfamide are involved in the regimen, those might be a little more emetogenic and so, if you re kind of on the border of where to go, you may want to err on the side of overdoing rather than underdoing. After I highlighted paclitaxel and docetaxel, for some reason, I think those are combined with other things a lot and because the other things are nauseating, I always think of them as having a fair amount of nausea. But actually, on their own, they re really in the low category. And then, in the minimal category, there s a whole lot of stuff there, all the mabs, all the antibodies are that category for the most part. And then there s a whole separate list for the oral chemotherapy. As you can see, the majority of them are minimal and low. Some of the more commonly used ones, I think capecitabine is used for just about everything. If given on its own, it s really in the minimal to low category. Let s talk a little bit now, one by one, about the different drugs in these categories: serotonin antagonists, the NK1 receptor antagonists, the new combination product that was just approved, steroids, olanzapine, benzodiazepine, dopamine receptor antagonists, and cannabinoids. Serotonin antagonists. Here s some pictures of it, of the serotonin on the left and, of course, all the antagonists have that similar sort of indole ring setup so that it can sort of fool the receptor and antagonize it and keep the serotonin from hooking up with the receptor and causing the stimulation. Here s a picture of that. On your left, you can see that the big blue thing is the serotonin receptor and it goes through the membrane and then the little T-shaped thing is the serotonin itself when it hooks up with it. The channel is opened, the sodium, the cations can go through and really cause and lead to the nausea and vomiting when stimulated by the serotonin. However, if you have the antagonist there blocking it, that channel stays closed and therefore this cuts down on the stimulation and the nausea. Some of the pharmacokinetic properties of these drugs: half-life is the difference between some of them, the palonosetron being much longer half-life; it should really be good for about 2 to 3 days or so of coverage. Renal elimination, you have to think about that a little bit more with the palonosetron than with the others, and with all of them, you ve got to think about that CYP3A system of metabolism, thinking of other drugs that may go along that same system because those drugs may be a little bit higher in the system. And we ll talk a little bit about some of the things that we need to worry about or not worry about regarding those drug interactions.

10 The palonosetron being a little more effective in preventing both acute and delayed emesis. While the NCCN kind of emphasizes that, the other 2 sets of guidelines don t. It doesn t mean the other drugs aren t good, and as a matter of fact in my own institution, because of cost considerations, we are asked to try to use ondansetron first because they buy it in bulk and really have to consider costs of it. However, we are allowed, even in our preprinted template, to override that. So, for whatever reason, I think for this patient I need a little bit stronger drug, palonosetron, or the patient is already queasy just thinking about it and I don t want to risk them getting sick, then I can override it because guidelines are just guidelines and then common sense has to prevail. And it s the effectiveness isn t so much, just because of its longer half-life. I mean, you could re-dose the other serotonin antagonists over and over, but it s a little bit hard to duplicate just by spreading out how long you give it. Now, we re talking about the NK1 receptor antagonists. Substance P is the stimulus, the tachykinin family of the peptides. Its action is primarily on the NK1 receptor, which when the substance P combines with the NK1, that s what induces the nausea and vomiting. It s primarily in the central nervous system, but not necessarily completely. We sort of talk about these as if they have 1 set place in the whole episode of nausea and vomiting. It s really a continuum and some overlap, but certain things seem to have a little more predominance in 1 category than the other. The NK1 receptor is also membrane-bound protein and, while it can help in acute and delayed, really the primary benefit that was really first noticed to be very helpful is more in the delayed nausea and vomiting. This is just kind of a schematic of levels of substance P showing that they do tend to correlate. If you look at that white line in the middle that separates the people on the left, down below they had emesis with chemotherapy. The people on the right, down below it says they didn t. And then it also talks acute and delayed, by that 24-hour mark. And those who had emesis, above the line means their substance P levels were higher, so you could certainly see more is above the line going along with the fact that they were vomiting and then the others below the line or at the line, they had less substance P, less vomiting. As far as the NK1 receptor antagonists, for whatever reason, it seems like for a lot of patients, just to give them an IV infusion, if you give them the palonosetron and the aprepitant and then you re really pretty good for both of those for about 3 days or so. It has a pretty good safety profile. And again, all of these, all the data we see, it s always better with complete response or control of emesis, and nausea is still the thing that s not as good as it should be, so there still is room to improve. The consensus guidelines do say use this for sure for HEC, which is highly emetogenic, including the adriamycin/cytoxan combination for breast cancer. Other potential uses are MEC, the moderately emetogenic. Again, I ve already shown you a list of some of the drugs in that moderate category that NCCN thinks might be a little bit higher. That moderate category is so big, it says 30% to 90% of the time you might get nauseated. Well, that s a big range, you know, so some of those that are a little closer to the 90% might be the ones where you d consider using the aprepitant. 10

11 11 Keeping in mind also that there s a lot of influence on the CYP34A, it s a substrate for it, it s also a moderate inhibitor of it, and it can induce it. So, just if other medications are going along this pathway, like some of the chemotherapy drugs, some of the taxanes, like the vincristine and Velban and whatnot, their toxicities might be a little stronger if administered with this. There isn t a lot of data, but it s something to keep in mind. The ones that we do act on, as far as the drug interaction, so to speak, would be the corticosteroids. When you give it with an NK1 receptor antagonist, you do have to bring it down. Instead of the typical 20 or so that we usually give as part of the chemo regimen, we bring it down to about 12, and then it s just as effective there. Oral contraceptives, in the prescribing information for the aprepitant, they say there s quite a bit of a decrease in the plasma concentration and they do recommend actually secondary alternate form of birth control for young women of childbearing potential who are on aprepitant. And their recommendation is to continue about 28 days after the last dose of aprepitant because it might continue to have some effect on the birth control pills. And, even though at first there was a lot of concern about warfarin because it s metabolized along the same way, clinically it doesn t seem that that s been a big issue. They do recommend watching it a little more carefully and even for a couple of weeks afterwards to make sure that the patients aren t getting over-anticoagulated. But in general, it hasn t been a big clinical problem or as long as people know, even if they ve been on their warfarin and they re getting checked once a month now, maybe now because I ve given them this drug, maybe I should check it every couple of weeks or so and make sure that they re not having some reaction with it. The use of the NK1 receptor is a recommended option, possibility through NCCN, and then not so much for the other 2 groups. They say there s sort of limited or mixed information. Now there s a new combination product that was just approved, so we ll spend a few slides talking about that. Since the guidelines these aren t really included in any guidelines yet there s an oral fixed-dose combination of a new NK1 receptor, netupitant, and it s in combination with oral palonosetron. It s kind of a big capsule. You have to take it an hour before chemotherapy. The reason it s a big capsule is when you open it up, out come 4 little capsules in there, 1 of which is the oral palonosetron and 3 of which are the netupitant, 100 mg each. For some of my esophageal cancer patients who struggle to get pills down, this might not be ideal. But, on the other hand, for other patients, it might be just fine. It was just approved October 10, 2014, and indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of chemo, including but not limited to HEC, which for the FDA is a little bit of ambiguous wording, I think. Maybe it gives us a little

12 more leeway as far as when we could use it or not, and I ll show you a little bit of the data of how it got approved and we ll go from there. This slide shows 2 studies. The light blue top says AC MEC study. Now, I know that just a few slides ago, I told you that AC, the adria-cytoxan, is a highly-emetogenic regimen, but a while back, when these studies were started, because these studies involve like 1000 patients each, it was considered to be more moderately emetogenic. That s sort of where the data comes from, no matter what you want to call it. And they did compare this combination plus dexamethasone to oral palonosetron and dexamethasone. So, the thing that was missing in the right-hand arm is the NK1 receptor antagonist. But that s the way the FDA mandates these trials be done. It was a significant difference to the benefit of NEPA vs oral palo; the P value was less than.01. Then another study was reported with multiple cycle, non-ac MEC and also HEC. They were really just trying to see, okay, most of these studies were done in the first cycle, 1 dose, how did you do, and then they report their data. But does it hold over second cycle, third cycle, fourth cycle? And overall, the ratings there were 81% vs 76%. Now, what I do have to point out, it wasn t truly a randomized trial. In case there was some unusual safety data that came up, they wanted to have the more standard arm there just for comparison. It did look effective and safe over cycle after cycle. Now this one is another study that was presented at ASCO, looking at NEPA and dex vs oral palo and dex in AC-based MEC. And again, the AC because this study was started when it was thought to be moderately emetogenic. The blue is the NEPA and over cycle 1, 2, 3, and 4, it continued to be effective and it continued to be more effective than just the palo. Let s cut to the chase on the bottom, which is the most common treatment-related adverse events. For both palo and NEPA, it is constipation and headache. And constipation, very little bit, 2% or so. Half my patients who are on morphine, that always trumps the chemotherapy nausea agent. But it s good to at least think about it. Okay, corticosteroids. What do they contribute? Mechanism of action a little bit uncertain but can certainly be effective as a single agent, and it can potentiate the other antiemetics. This is a summary, a forest plot, of about 12 or 13 different studies and this is when, on the left-hand side, these are all randomized trials of 5-HT3 and dexamethasone and/or vs the 5-HT3 receptor antagonist alone. And as you can see, all the purple dots, which means that group did better, is to the left if they got the dex with the serotonin antagonist. If we were trying to figure out how a patient went wrong, number 1, I always say, okay, was dex prescribed? And number 2, did the patient take the dexamethasone, because that s really a big one and an easy way to correct the nausea, if it hasn t been done. Nowadays with our electronic ordering, almost always we order it, but whether or not they get it filled is another thing. Olanzapine. We mentioned that that s kind of a new use for this drug. It s an atypical antipsychotic, all kinds of possibilities really for its best mechanism of action. It says use in 12

13 caution with elderly patients. If you really look at that black box warning, it says patients with dementia-related psychosis who are treated with this medication might have an increased risk of suicide. But I m thinking, if you ve got dementia-related psychosis, with any luck, nobody s giving you chemotherapy, and therefore having the need to give you olanzapine as an antiemetic. But it can be used for prophylaxis for acute and delayed nausea and vomiting and it s really an alternative now to aprepitant. The regimen, if you re going to use it, is just as you would with anything else: palonosetron, dexamethasone, and it would usually be aprepitant. But a study was done comparing olanzapine to aprepitant, and here it is. This shows the results for complete response. So, no vomiting and no need for rescue medication; 251 patients, either treated with the big 3, serotonin antagonist, dexamethasone, and either olanzapine or aprepitant, and how did they do? If you look down below in the acute setting, 97% for the olanzapine group, 87% for the aprepitant group, and then delayed was pretty similar. So, certainly, at least equal if not even a little better. And then, how about nausea? Again, very similar kind of results in the acute setting, very well, but if you look in the delayed setting, it looks like the olanzapine group did quite a bit better, 69% vs 38%. Certainly a reasonable alternative, and the NCCN did recently add it into the guidelines as an alternative regimen to using the aprepitant. Benzodiazepines. Probably the most common one we use, I think, is lorazepam. We can certainly add it in. It can be used as a rescue. It can be used for anticipatory nausea and vomiting, that sort of thing. And also every now and then, if someone gets some extrapyramidal symptoms from some other medication we ve given, it can be very helpful for helping control those symptoms. The dopamine receptor antagonist, metoclopramide, can be used really as a good adjunct in some cases, sometimes maybe 20 mg or so at a dose. It increases the trigger zone threshold; kind of a low therapeutic index, only because it does have some of these sort of dystonic side effects. But again, for breakthrough, when you ve given the things that are recommended and then you re stuck and the patient s nauseated or vomiting, then you really just go through your laundry list of what haven t I tried from a different category and then kind of go down the list and see. The cannabinoids can be used for either nausea or appetite. In some patients, it can be very effective. I always start at a very low dose, probably 2.5 mg twice a day. Then you can go up to 5 mg and I think even 10 mg twice a day. Personal experience tells me that maybe at least half the patients don t like the way they feel on it, but a fair amount, maybe a quarter, seem to really benefit from it. Never as a first agent really, but on top of other things if they re really struggling. To summarize principles for managing breakthrough chemo-induced nausea and vomiting: give an agent from a different class, something you haven t used before; consider around-the-clock rather than as-needed, particularly if they say, a lot of times, if they have nausea and vomiting. I always say, When did it happen? You know, did it happen the third or fourth day after the chemo? 13

14 Because if I treated them for that delayed nausea and vomiting and then they started acting up, then maybe they re one of those people who just has to get the delayed nausea and vomiting treated for maybe a full week or so. Every now and then I run into someone we just keep it going, right through if they really, really struggle. IV or rectal administration might be required. Again, if you give the right dosing, either oral or IV, a lot of times if it s really tough nausea and vomiting, then we either give IV, sometimes I bring them in for that and hydration. There s a patch granisetron comes in a patch. You can slap it on for 7 days; you don t have to worry about them remembering it or throwing it back up. New directions. Just a couple quick things that might be coming down the line. Rolapitant: there s a couple of studies that were just reported at MASCC randomized, phase 3 for patients with MEC, and they looked at rolapitant vs placebo. Everybody got granisetron and dex, but then either you got rolapitant or not. The overall, and the delayed in particular, was statistically significant. And then also kind of a similar trial in highly-emetogenic chemotherapy and again, the results were the same, with some benefit to the rolapitant. In the future we may very well be seeing more about that. Okay, so now we ll move on to our next case and faculty discussion. Thank you. BARBOUR: So we have another case for our panel to discuss. George is a 65-year-old man with egfr- and ALK-negative adenocarcinoma of the lung. He also has type 2 diabetes and uncontrolled nausea and vomiting. He had his staging and workup done and this workup revealed that George had contralateral hilar lymph nodes and liver mets. Therapy was initiated with cisplatin and pemetrexed. For his antiemetic regimen, he received palo, aprepitant, and dexamethasone. And he did well initially, but 24 hours later he had nausea and vomiting and decided to check his blood sugar and saw that it had increased to almost 300, despite the fact that because of the nausea and vomiting, he really hadn t eaten a whole lot. He took his as-needed Compazine as instructed, but it really did not provide him any relief, so he called the team the next day and notified them of his symptoms. I guess the first question I d like to ask is, what are your thoughts about the fact that he has diabetes and his blood sugar was high? That s one I think that we get brought up to us frequently. So, any comments about George and his case? VALGUS: I think, from oncology, you look at it from a little bit of a different perspective. I think you definitely need to take into consideration the diabetes and pay attention to that. I don t know if it would alter everyone s decision to actually use dexamethasone, just because it is so effective at preventing emesis and especially in somebody who is having issues already, the risks of taking that away. There s obviously also risks inherent with someone having significant nausea and vomiting for a prolonged period of time, so I think it s a really tough call. There have been situations where we ve held the steroid in some of these patients and other times where we just try to sort of power 14

15 through and try and maintain a nondangerous glucose level and continue to give them dexamethasone. URBA: I would agree with that, because even sometimes if people come in, they re already insulin-dependent diabetics, it just feels like the dexamethasone can be useful enough, so I wouldn t avoid it necessarily. Having said that, sometimes patients themselves, if they re worried about it or they don t like the way they feel on it, sometimes they just stop it themselves and then they tell me about it later on. But otherwise, I mean really, if we check it closer, if it s in the 500s, we give them insulin. If they have an endocrinologist, we have them get in touch and make sure that they know they ll be getting steroids at least intermittently. Maybe they can change their sliding scale or their baseline on those days, and having said that, every now and then, if someone doesn t have a tough time with nausea and vomiting, they drop it out of their regimen. But this guy had it in and was already having a tough time. As far as what to add, go down the list and think what you haven t added. You ve already had a serotonin antagonist, aprepitant, and dexamethasone, so Ativan is always a good one, probably one of the first ones I add on, and actually olanzapine. I was checking his age, he s 65, and even as patients are elderly I d probably certainly consider it, maybe a little lower dose. But I think that could certainly be helpful. BARBOUR: I would probably also consider switching him to fosaprepitant just to simplify his regimen so that we could give it once so that we re simplifying his regimen and I guess, also, just thinking of the low-hanging fruit, was he taking his delayed antiemetics appropriately, to think about those types of things. And he s somebody who might be at obviously higher risk in his subsequent cycles because he wasn t well-controlled. Steroids are great, so we would probably try to manage the diabetes and keep the steroids onboard because they are so effective. I d like to ask Dr Valgus to come up and to talk about the role of the pharmacist and how our involvement can improve patient care. VALGUS: No disclosures to report. What is the role of the pharmacist in medication management? There s a lot of different things that we re involved with, both on the clinical side and the operational side. I m just going to highlight a couple of things I think are pertinent specifically to this presentation. One is selection. We are the drug content experts. We are the experts at individualizing therapy and trying to optimize patient therapy when it comes to medications. This fits right into our role. Also, prescribing and dosing. There are several states throughout the US that allow pharmacists actually to prescribe and adjust doses through either collaborative practice agreements or in-house protocols, and so definitely that s a big role where the pharmacists can be involved in CINV. The final piece I ll highlight is the monitoring and the evaluation. I think this is very key. I think that very first case that we had talked about, where we found out the patient didn t tolerate cycle 1 very well, I think we very rarely get that information, and I think pharmacists are in a perfect location within the clinics, in the hospitals, to follow up after these initial cycles of chemotherapy 15

16 to see how patients did and make sure that information gets back to the provider so that we can alter their antiemetics if we need to. Other roles that we have, and these are a little bit out of the direct patient care role, but some of them where we fill a role may be institutional IRB, things like that. But participate in the development or implementation of institution-specific guidelines, and I think the institution-specific piece is very important. Translating what are in some of the national/international guidelines and really applying that to your individual scenario wherever you re practicing is very important. The gatekeeper, the drug police. Maybe not the most fun part of our job, but definitely a very important part of our job. Development of medication management protocols, ongoing assessment, improve adherence with patients through patient education, making sure patients actually can get the drugs that we re prescribing, that s a very important role for us as well. Let s talk a little bit about CINV guideline development. What is the purpose of developing these guidelines? Well, I would say the number 1 purpose of developing these guidelines is to optimize patient care. That s what it s all about. All those clinical outcomes that Dr Urba talked about in terms of preventing CINV, really that total control is what our goal should be for these patients. But there s a lot of other things that guidelines can help us with. They can help us on the operation side, with standardizing ordering and preparation. For me, it s a great educational tool for staff. We have a lot of new staff coming on board at UNC on a constant basis. Giving them access to our in-house guidelines is a perfect way to get them up to speed in terms of what we do very quickly. Provide a systematic method of assessment and adjustment of treatment, very important there. Definitely containing costs. Think about all the ways that people look at the value of the pharmacist, and definitely containing costs is a big one. But there s also data that actually speaks to the importance of adhering to these guidelines. This is one study that looked at guideline-consistent care and compared that to guideline-inconsistent care. And I ll highlight a couple of things on here. First is the incidence of, or the rates of complete response in these patients. Here you have the guideline-consistent care at about 60% vs about 50% for guideline-inconsistent care. So definitely when we adhere to the guidelines, we are improving these patient outcomes. It was interesting. This study also looked at some of the resource utilization of these patients that may be related to CINV. Some of the numbers here, including GP visits, specialist visits, ER visits, you can see some statistical significance in some of those numbers. I think you could argue if they look clinically significant, but definitely the study wasn t powered to show some of these differences. But definitely, I think it s important to think about these because these are some of the big-picture things we re trying to prevent patients from having to do, come back specifically to the clinics to help manage these problematic symptoms. Much better to prevent it up front. And where did we sort of fall off when it came to some of the guideline-inconsistent care? Well, in here, they divided it between the different emetogenic categories. So you can see HEC there where, in the purple for the acute phase, only about 43% of the time did we do guideline-consistent 16