Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Richard J. Gralla and Dr. Mark T. Holdsworth. This program is available as read only and with accompanying audio.
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Slide 1: Dr. Holdsworth: Welcome to the conference, Chemotherapy Induced Nausea and Vomiting: Advances in Pharmacologic Prevention and Management.
This activity is jointly sponsored by the American Academy of CME and Princeton CME, and is supported by an educational grant from Solvay Pharmaceuticals, Incorporated.
I am Mark Holdsworth, associate professor of pharmacy and pediatrics in the College of Pharmacy at the University of New Mexico in Albuquerque. I will be your presenter, along with Dr. Richard Gralla, president of the New York Lung Cancer Alliance in New York City.
Please note that all faculty disclosures for this activity are included in the front of your activity booklet. Please remember, that to receive continuing education credit following conclusion of this activity, each participant must complete the post-test and evaluation form located in the back of the activity booklet. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Thank you, again, for joining us.
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Slide 5: Now, to begin with our case, a 21 year old female presents with newly diagnosed acute myelogenous leukemia. Following stabilization with transfusions and antibiotics, the patient is enrolled in a multi-center cooperative group chemotherapy study. Chemotherapy is initiated with the following regimen: daunorubicin 50 mg/m2 IV every other day times three doses, cytarabine 100 mg/m2 every 12 hours times 16 doses, and etopiside 100 mg/m2 IV every day times five doses. After she completes this regimen, and following adequate hematologic recovery, she will proceed to additional chemotherapy.
Slide 6: The chemotherapy study that this patient is enrolled on does not allow for the use of corticosteroids as antiemetics. Based upon antiemetic guidelines, design an effective antiemetic plan for this patient for her initial course of chemotherapy.
Slide 7: You come up with the following suggestion for antiemetic therapy – palonosetron 0.25mg IV on day one of chemotherapy, and aprepitant 125mg PO on day one and 80mg PO on days two and day three of chemotherapy.
Slide 8: Despite your antiemetic regimen, the patient develops moderate nausea beginning on day four of chemotherapy. She also has one to three vomiting episodes per day beginning on day five through day eight of chemotherapy. Her next chemotherapy course will consist of the following: cytarabine 1g/m2 IV every 12 hours for five days, plus etoposide 100mg/m2 every day for five doses. Her clinicians would like to give her PRN ondansetron with this course in addition to your anti-emetic regimen.
Slide 9: As you listen to the main presentation, think about what modifications in the antiemetic regimen should be made for this course to improve the patient outcome. Also, do additional doses of serotonin antagonists have a role for this patient?
Slide 10: I would like to now welcome and introduce you to Dr. Gralla for his presentation on advances in pharmacologic prevention and management of chemotherapy induced nausea/vomiting – Dr. Gralla.
Dr. Gralla: Thank you Dr. Holdsworth. Hello to everyone. And today our topic is going to be antiemetics, which remain a very important field in supportive care and oncology, and worthy of our focus.
If you look at the slide that talks about the learning objectives, you can see that we have kind of an ambitious agenda. And that we will look at many areas where there is evidence that supports guidelines, support the kinds of treatment that we give and looking forward at some newer investigations as well as hopefully providing some evidence that helps us all in implementing the most effective antiemetic care.
Slide 11: We can see that on the next slide supportive care in cancer involves so many different areas important to essentially all of our patients. And the area of our focus has to do with gastrointestinal issues, and specifically that of antiemetics.
Slide 12: The next slide shows our goals. And first of all, we must understand that the overall strategy is to prevent emesis in people at risk, rather than to wait to treat it. This in fact is the focus in much of supportive care, but especially in antiemetic treatment. We would like to achieve complete control. We would like to be free of side effects, or minimize side effects as much as possible for these supportive care agents.
We would like our treatment to be as convenient and easy to use in the many different settings in which our patients are treated. And we would like the agents to have value to be worth the expense, and to have costs not be a barrier.
Slide 13: Over much of my presentation, we should look to see how we’re doing and where it is that we can improve results. The first area deals with quality of life in terms of chemotherapy induced nausea and vomiting, or this abbreviation, CINV. Whenever we look at quality of life, we are well advised to use instruments or questionnaires that have been well validated. And that’s true for the FLIE, the results of which are seen on this bar graph from a study that Celeste Lindley from the University of North Carolina presented a number of years ago.
And basically, we see two sets of bars here. And if we look at the left-hand bar in each set, that is the patient reported quality of life level immediately before chemo. And the right-hand bar in each of these two bar sets are the results three days later after chemotherapy.
As you can see, if we look at the two bars to the very far right, that those patients who had no nausea or vomiting rated their quality of life three days after chemo as essentially the same as before they started the chemotherapy. That is in contrast to the bars to the left where there is a one-third fall off in the patient rated quality of life if the patients had any emesis. So clearly, the better we can do in controlling emesis, the complete control of emesis, the more likely we are to preserve quality of life.
Slide 14: You can see that in the next slide as well if we look at this table. There are five major dimensions or domains of quality of life, the physical, functional, psychological, social, and spiritual.
And we can see in the examples, the many, the multidimensional way in which having emesis can affect quality of life. So it should be of no surprise to us, and I am sure it is not that preserving quality of life or improving quality of life means that we have to avoid this very difficult side effect.
And finally, if we conclude on this, we can see that in our studies, probably nothing that we do in the short-term time around the administration of chemotherapy, nothing that we do has a greater impact on quality of life than the complete control of emesis.
Slide 15: The middle bullet on this slide also shows that there are other effects that we have had a bit of a revolution over the last one to two decades in cancer care in that we have been able to give chemotherapy on an ambulatory basis because of the control of emesis. And this further contributes to quality of life by allowing patients to remain in the environment that they would prefer rather than a hospital, and any time we reduce hospitalization, it has a remarkable economic benefit.
So as long as we can further improve the percentage of patients who have complete control of emesis, we should be able to have a greater impact on the short term quality of life. That is quality of life and under chemotherapy administration.
Slide 16: And going to the next slide, to continue to make progress, there are two things we need to really understand. One is the clinical problem of emesis, and then to go forward to understand the physiology and neuropharmacology of the problem.
Slide 17: Looking first at the clinical problem, we can see that there are three major types of emesis that are discussed in terms of giving chemotherapy. Of course there are other issues as well, but these three are the major focus. Acute emesis is defined as that emesis which occurs in the first 24-hours after the administration of chemotherapy.
Delayed emesis is that emesis which begins thereafter. And it may continue for several days. Often the peak is at 48 to 72 hours, and generally after four or five days it diminishes to nearly nothing. Anticipatory emesis, which we will not discuss in detail, but certainly can take up when we go over questions after the presentation, results from conditioned emesis as a failure to control acute and delayed emesis.
So if we can – our best approach is using the best antiemetics that are appropriate for our patients for acute and delayed emesis so that we can avoid the conditioned or anticipatory emesis.
Slide 18: Now the next slide outlines the major clinical risk factors for having emesis associated with chemotherapy. There are more, but these are the major ones. And multi-varied analysis these com out at independent variables. So they are really quite important, and I consider them every time I see a patient who will be receiving chemotherapy.
Number one is the chemotherapy regimen -- the actual chemotherapy that a patient will be receiving. And we’ll go over the four major risk groups there. That is the most important. Next is the fact that it is more difficult using the antiemetics that we have had for many years to control emesis in women than it is in men.
And finally, younger patients are more susceptible to having emesis with the same chemotherapy than are older patients. So it is not that we need to give older patients less good antiemetics, it’s just the fact that we can identify the risk and recognize that we may have more problems with younger patients, female patients. And we need to take steps to be sure that we are monitoring all of our patients well, but especially those at the greatest risk.
For reasons that are not well understood, people who have a long and strong alcohol intake history. Not that they are taking alcohol now. That is not a protection. People who have had a greater alcohol intake history in the past, are easier to control the emesis. Many theories about this, and none of which are absolutely proven. So these are the elements in the way I certainly approach my patients to understand risks.
Slide 19: The next slide shows the four major risk groups associated with chemotherapy. And these have been adopted by most of the major guideline groups -- certainly by MASCC, Multinational Association of Supportive Care in Cancer, by ASCO, American Society Clinical Oncology, and by NCCN.
If you look at the four groups, there is high risk in nearly every one. Moderate is 30-90% of patients have not given effective antiemetics would be likely to have emesis with chemotherapy in that group. And of course that is a very large grab bag there of agents between 30-90%.
Low risk may not seem too low, but 10-30%, so up to about a third of our patients. Then minimal, fewer than 10 percent of patients would be at risk.
Slide 20: The next slide shows some examples of the agents that are embers of each one of these risk groups. So you can see some very commonly used agents here. And see that these agents are very frequently used.
So our biggest problems of course occur among those patients of the high and the moderate risk groups. But we must pay attention to those in the low and minimal. Now if you go to the MASCC web site, which is mascc.org, which is listed here below, you can pull up a paper by Steve Grunberg that is a free download that really goes over 50 different agents and lists them all very closely and also there is a slide presentation there that has tables that show in great detail the specific agents and oral and IV agents as well.
Slide 21: In broad strokes, understanding the physiology and neuropharmacology is also important.
Slide 22: And let’s go to the illustration on the following slide that outlines the fact that the two
key areas are the gut, sort of illustrated in the lower left-hand portion of this illustration, and the brain. To the right on this illustration is the brain stem, which is so important.
So let’s start with the gut. And if we look at the gastrointestinal tract as outlined here in the lower left-hand portion of this slide, we can also see that in the blow-up is an illustration of the enterochromaffin cells which are found in the upper GI tract. Now these enterochromaffin cells contain the majority of the body’s serotonin.
Serotonin is just one important chemical when it comes to emesis, but a very important one. When there is an emetic stimulus, there is some release of serotonin. In some cases it is a very large release. Other cases it may be a relatively small amount. And immediately adjacent to the enterochromaffin cells as seen in this cartoon are the 5-HT3 receptors found on the surface of the vagal nerve afference, they’re immediately adjacent.
Now 5-HT3 means 5-hydroxytriptamine type three, 5-hydroxytriptamine being serotonin. There are at least 12 different serotonin receptors or sub-types of receptors that have been identified, probably more. But only the type three is known to be involved with emesis. So it is a very specific type of serotonin receptor. It is not the same type that are involved in other areas that we think of for different medical problems. It is the only one that is a gated ion channel as an example. So if we get stimulation of these receptors, then we get the message transmitted up the vagal afferent to the brain stem. You can see to the right there the CTZ or the chemo receptor triggers.
This is an area that is rich in neurotransmitter receptors. Not blocked by the blood brain barrier. So it can sense both cerebral spinal fluid in blood, and the relevant receptors are well represented there. If it is stimulated, it can transmit the message deeper into the medulla or to the emetic or vomiting areas or centers. And that leads to the area, this type action of emesis, so this is the brain and the gut together.
Agents such as serotonin antagonists do not have to penetrate directly into the brain, whereas neurokinin type 1 antagonists, such as aprepitant, must get into the brain to be active. So if we can block the receptors at any one of these areas, including receptors in the brain, including receptors in the gut, we can block emesis.
Slide 23: The next slide shows neurotransmitter receptors in an illustration that are of important as far as emesis is concerned. If we look at the dopamine receptors, blocking these receptors still can be useful, but it was really through more knowledge of metoclopramide when given in very high doses that its primary antiemetic action was no longer as a dopamine type two receptor antagonist, but in very high doses, it was actually a serotonin 5-HT3 antagonist.
And, that led to the development of the selective serotonin antagonist. You can see the four agents that are available in the U.S. that make up that list. And that really helped us in moving forward. You can see also the Substance P receptors, or NK1 receptors. The NK1 receptors have Substance P as their natural lygand, and aprepitant is the only agent that is available there and works rather independently.
Now the other receptors are of some interest. But it may be that further work, especially into the GABA and cannabinoid receptors may end up leading to new pathways that can be of interest in the future as well.
Slide 24: So if we look at the next slide, we can see that these are the three main classes of a agents, corticosteroids, Serotonin antagonists, and NK1 antagonists that are important, used in combination to prevent emesis in highly and moderately emetic settings.
So no matter which guideline we use, these agents used in combination are there. Certainly corticosteroids and serotonin antagonists are used in all these settings, and NK1 antagonists are added always and highly emetic and in special circumstances in moderately emetic emesis that are greatly important as well.
Slide 25: The next slide illustrates the three main guideline groups. Again, I am not saying these are the only ones. But these are perhaps the ones that are looked at the most frequently, and the ones that have updated their data as well.
But let me just historically mention that if you look at the guidelines today from all three of these groups, you can see that their conclusions and their recommendations are really very similar.
And historically, the reason for that is that in the second round of guidelines, which were really started in 2004 and 2005, MASCC, Multinational Association for Supportive Care in Cancer gathered together nearly 25 experts from around the world, representing many different oncologic organizations, and said let’s deliberate all of the evidence that we have together, and that this should form the basis for the guidelines of each of our organizations.
And that really is why these are so similar. So you can go to the web sites, which are listed below here. You can go to various publications and you can find a great deal of more evidence also dealing with special emetic problems.
Slide 26: If we look at first dexamethasone as the corticosteroid, why do we talk about dexamethasone? Do other corticosteroids work? They do, but dexamethasone, which is available inexpensively as a generic in many different dosing forms is the one that has been looked at the most and the one for which there is the most information.
There is less information for other corticosteroids. But there is no doubt that they work. So if we look at these, we can see that the dexamethasone dose that is advised is generally between 12 and 20mg for acute emesis. And for either highly or moderately emetic, although for moderately emetic, it is usually the 8mg area for highly emetic 12 to 20 for acute emesis. And for delayed emesis, we’re less sure of the dosing. But it is typically about 8mg.
Now we find that often people do not give dexamethasone for delayed emesis. And this is too bad, because it is a very valuable agent there. Dr. Holdsworth had mentioned some of the reasons people don’t give it, and they look at some of the negatives about corticosteroids, but in fact, when corticosteroids are given over the short period of time of just a few days, they do not have the chronic toxicities.
And minor problems such as GI upset or sleep disturbance can be controlled with very simple medications. And the benefits greatly, greatly outweigh the risks. Hyperglycemia is one that people consider. But in fact this occurs very unusually. And one should identify those patients at greater risk with simple screening for diabetes, which is something very important in any case.
Slide 27: Now going to the next slide, we can see that 5-HT3 receptor antagonists available in the U.S. plus tropisetron, which is not available in the U.S. but is available in many countries. These are the standard doses. It is my belief that the IV and oral doses probably can be the same for almost any of these. There are some studies that show that granisetron at one milligram orally is as good as two and some that show that ondansetron can be given at even lower doses in the 16 milligrams given orally.
But nonetheless, these are appropriate doses of these agents. And the concept is to saturate all the 5-HT3 receptors so the dose of the serotonin antagonist should be the same for moderately emetic as it is for highly emetic to get the best control possible.
Slide 28: If we look at a aprepitant on the next slide, all the guidelines really are extremely similar here. And one of the reasons for that is the truly mature studies using this NK1 antagonist, all use the same dosing scheme. 125mg orally once immediately before chemotherapy, followed by the next two days by 80mg orally each day. And these have been very effective doses. There are many reasons to believe that these are good doses.
But we don’t have too many demonstrations of using other dosing schemes. Dexamethasone is always called for on day one. But there is less investigation about its use for instance, NCCN says lets go ahead and use the dex for delayed emesis, although there is not so much evidence of this – they say well there is so much evidence behind it, benefit of dexamethasone we should look at it that way and develop the evidence later.
I think that in this case makes some degree of sense.
Slide 29: The next slide looks at secondary antiemetics -- antiemetics that are used for other reasons. Antiemetics that are used if people don’t do well before. NCCN goes through these as do the other groups. But unfortunately there is surprising little data to support these agents.
If we look at the anxiolytics such as lorazepam, I typically give a milligram orally. I don’t use an IV very much anymore. And it is not much of an antiemetic on its own. But there is so much anxiety around chemotherapy that it really does support the antiemetics in that way. Cannabinoids and Navalone and Delta-9 THC, dronabinol, are available. These are indicated for second line use.
Butyrophenones and phenothiazines are a little old fashioned these days. They do bind to D2 Dopamine type two receptors. They have some use. But they have more side effects than the other agents that are useful. Not on this list is Metoclopramide which I do use on occasion either in 10mg tablets or when necessary at higher doses IV.
But these again are not agents that I find myself using all that often, except in some of these circumstances.
Slide 30: Now looking at low risk and minimal risk, low risk again being 10 to 30%. There the guidelines advise a single agent to be used for acute emesis. And you can see the asterisks this is typically either dexamethasone or a serotonin antagonist.
I would say that most experts probably use dexamethasone as a single agent. Although we find more use generally as of the serotonin antagonist. And minimal risk is the use of antiemetics for those patients at less than ten percent risk. And here, no agent is advised for prevention either for acute or delayed emesis.
Now we must recognize the guidelines are just that. They are to guide us. They are not laws. And for patients who don’t do well the first time, then most of us jump up a category. So if it was a person receiving say bleomycin and they did have emesis, then we would jump up to the low risk category the next time. Or somebody in the low risk category, if they had a problem, we would jump up to moderate risk.
So that is kind of the way most people look at how guidelines can help in those circumstances. And of course again, I use the patient characteristics to look at risk. And many of us would send home a patient with a simple, single agent to be used PRN in case they have a problem. Here, I typically use metoclopramide.
Slide 31: Do corticosteroids really work? The next graph is a forest plot that is a way of looking at all 11 studies together. If the large rectangle falls to the left of the midline marked one, then there is benefit in adding dexamethasone to a serotonin antagonist. These are all based on randomized trials.
If the opposite occurs, which it didn’t occur in even a single one of these studies, then just the single agent serotonin antagonist would be better. So you can see that consistently the single dose of a corticosteroid adds for the control of acute emesis and that diamond at that bottom is the total effect of combining all of these studies. And you can see there is a relative, almost 50% reduction in the risk of emesis if we add a corticosteroid which is a highly significant finding.
Slide 32: Next slide is kind of interesting. It is the result of a meta-analysis published a couple of years ago in the “Journal of Clinical Oncology” on the top part. And at the very bottom another analysis of the role of corticosteroids in delayed emesis. So in the row that is marked 5-HT3 antagonist versus placebo, there in eight percent absolute benefit, which was significant was found that the addition of the serotonin antagonist rather than nothing for delayed emesis was useful.
And this looks again at serotonin antagonist in light of dexamethasone or not. And here there was benefit shown. But if we add a serotonin antagonist, the next row below that, plus dex vs dexamethasone, we see that there was only a little over a two percent effect of adding the serotonin antagonist in delayed emesis. This was not significant. And the authors concluded that dexamethasone alone was probably a better choice. The article in support of caring cancer, which really was a guideline discussion, concluded the same thing. So there is an effect of serotonin antagonists in delayed emesis, but dexamethasone minimizes that.
Slide 33: We have the interesting results on the next slide of two studies involving nearly 1,000 patients where palonosetron was compared against in one study ondansetron, and against alosetron in another study. And patients receiving moderately meta-chemotherapy such as that used for breast cancer. These would be agents such as anthracyclines plus cyclophosphamide.
And overall, this study is revealing and controversial. It’s controversial because it doesn’t answer every study as no studies really can, but in that it’s only the single agent serotonin antagonist, either palo or ondansetron or dolasetron, is the only antiemetic that patients received, and they received only a single dose of it.
You can see that there is benefit to the palonosetron that is significant in the first 24 hours. And even in delayed emesis as well, and that these are significant results. Really there were three arms of these studies. The third arm was palonosetron at three times the dosage. But since it was no better than palo at .25 that’s only the FDA approved dose of palo shown here.
People have criticized this by saying gosh, if only they would use the guideline to prove which would have been dex plus palo or dex plus ondansetron. Would we still get the same result? Maybe so. Maybe not. And that hasn’t been done. And then the next question would be well, you know, I tend to continue ondansetron or dolasetron. Well here, again, it said, well that’s quite a convenience thing that your patient doesn’t have to be bothered to continue it. So in any case, you can see these comparisons done with the strengths and weaknesses of this kind of study design
Slide 34: The next table shows the very excellent safety profile seen with palo vs palo and ondansetron. The same is true to Dolasetron in that these agents have a very fine side effect profile. Headache is the most commonly reported side effect. Generally this is well treated if necessary by just something like acetaminophen. And patients need to be educated in that.
These are the percentage of patients who reported constipation. But if you ask about it, it occurs far more often. I always talk with my patients about constipation, that a simple dose of milk of magnesia or use of senna can avoid this. And I ask patients if they have the slightest problem to go ahead and use this.
Now some chemotherapy can cause diarrhea so therefore I ask patients to wait a few hours to be sure that that is not a problem. So again, even at the very high doses of palo, not the recommended doses you can see that the side effects hardly go up.
Slide 35: So we know that serotonin antagonists remain an important central component in our antiemetic strategy, especially for patients with moderate risk of emesis or high risk. There is some controversy about the use of the newer serotonin antagonist, although the results have been rather favorable, but the guideline groups who would like to see the studies that I mentioned using comparing current guiding combinations of the older and newer agents corticosteroids to see whether they would continue to recommend a specific agent.
And so if we had those, that might very well change the guidelines if the results were positive.
Slide 36: The next slide is a basic science slide looking at molecular studies, but it is kind of interesting. It turns out that there are two sub-units, A and B or Alpha and Beta to the 5-HT3 receptor. And the genes have been cloned that code for these different receptors.
It turns out that there are a lot of genetic polymorphisms around that B sub-unit to the 5-HT3 receptor. And if we have mutations in that gene, it can make a difference in the antiemetic control. Now this affects only a relatively small percentage of our patients. But it’s perhaps a large percentage of those patients who have trouble with emesis.
So if we look at these bar graphs we can see that those patients who are homozygous for the wild type, WT, the wild type, that from both parents they receive the typical gene, they have the best control, the least emesis. But the middle bar looks at those patients who have one allele with a mutation in it from one parent, and they have about half the rate of control. And that those unusual people who have a mutated allele from each parent, or are homozygous for the mutation, those patients have the least control
Slide 37: So this tells us a little something about those patients with the greatest risk. And it also tells us that we need to use, perhaps, agents that effect different receptors. And that then walks into the neurokinin-1 receptor. And which is the receptor for Substance P. And we know that Substance P is elaborated in a number of emetic settings, and that this is important. You can see some of the background here.
Slide 38: But does it really work? And the next slide shows two phase three studies, very large studies that we have combined them here. Each one had about the same results. About 1,000 patients altogether. And you can see that the left-hand bar for acute emesis, there was a highly significant improvement in the complete control of emesis, and in delayed emesis an even bigger effect.
Slide 39: So this really led to the registration of aprepitant. The aprepitant regimen here is three drug regimen combining ondansetron and dexamethasone compared with just the two drugs without aprepitant.
Slide 40: Now an interesting effect occurred that if we look at the next slide, we can see that it was easier to control emesis in men than women who received, ondansetron, dexamethasone in the control arm of these studies. This was not a surprise. But when we look at the next slides, we can see that when the aprepitant was given, that men received a modest benefit in the complete control of emesis and women received a large benefit. And for the first time, we had equal control when aprepitant was added to ondansetron and dexamethasone. That’s for acute emesis on this slide
Slide 41: And, the next slide shows basically the same effect in delayed emesis, a fairly large benefit for men, and a very large effect for women. And so for whatever reason, the aprepitant helps the group that needs it the most, women, but it also helps men as well, but to a slightly lesser extent.
Slide 42: We look at this next slide, and we look at side effects, we can see that there is a slight increase in side effects for the aprepitant group, but there’s no specific side effect that can be found that is only in the aprepitant group, and that maybe there is more hiccoughs and a few other things, but basically these are well tolerated oral agents.
Slide 43: The next two slides were surprising when these results came about. So looking at these studies, this looks at the complete control of emesis in women. The left-hand bar is the complete control in those receiving AC (anthracycline cyclophosphamide) the right-hand bar is the complete control in women receiving cisplatin.
Here the antiemetic is dexamethasone and ondansetron. And what we can see is that the control was just about the same. And that means that women receiving A plus C chemotherapy, so commonly used for breast cancer and many other malignancies, actually have no better control than those women receiving cisplatin. And this was a surprising finding and kind of a disappointment because AC is considered to be moderately emetic, but in fact, it has the same risk as highly emetic setting cisplatin.
That’s acute emesis.
Slide 44: (This) next slide is delayed. And we can see for delayed emesis at least half of our patients who are women are still having delayed emesis. So, there is work to do, and that’s why we need better control than just the serotonin antagonist and dexamethasone as such.
Slide 45: The next slide is an interesting one. This is based on the WARR, W-A-R-R reference, which is on the prior slide. And this looks at the addition of aprepitant. So the aprepitant regimen here is aprepitant plus dex plus ondansetron, the standard regimen since ondansetron and dex.
In the WARR study they looked at the first cycle. And that means in the upper curve, the three drug regimen there was 76% of women had no emesis and no vomiting at all in the first cycle, as opposed to 59% who received only ondansetron and dex.
But what this study and Dr. Herrstedt did was looked at all four cycles of AC chemotherapy that these women received. And this is again a large study as you can see from the numbers over 800 patients. And that after four cycles of chemotherapy, nearly two thirds of the women receiving the aprepitant regimen, the 63% there, never had any vomiting whatsoever, as opposed to fewer than 40% had that accumulative complete control throughout their chemotherapy experience who received the ondansetron and dex.
And, I think this is a very important finding from that study.
Slide 46: We also see in the next slide something that may be important to us as healthcare providers, and that is that if we look at the left-hand bar in each one of these four sets, that is what the doctors and nurses predicted would be the emesis that their patients would be having.
The right-hand bar in each set is what the patient actually experienced. So you can see for acute nausea and vomiting, the control is pretty good. The prediction by the doctors, nurses pretty good. But, on the other hand delayed emesis when the patients are not available is not really so good, and that basically the prediction is only half of that of what really occurred.
Slide 47: So we need to be aware of this and that we are underestimating control. So we know that we achieve complete control in many settings, that we get better control of acute emesis than delayed, therefore leaving some populations still at risk. We have better control of vomiting than of nausea. And that efficacy, that is what we observe in clinical trials, continues to exceed effectiveness that which really happens.
And part of the reasons for this is we need to adhere to guidelines. We need to recognize the value economically of de-hospitalization and being able to avoid other problems that good antiemetics can provide for us. We need to understand that while corticosteroids have a few side effects, we can control those. And that these are very valuable agents and they are often underused.
And we need to be sure we educate our patients about taking medicines for delayed emesis even if they are feeling well.
Slide 48: So let’s look at some of the under addressed issues. And we have some new research that helps with this, even though it may not be definitive.
Slide 49: The next slide shows a phase two study in multiple day chemotherapy. Here, cisplatin is given a 20mg daily times five days. This was presented by Ms. Brames, who works with Dr. Einhorn at Indiana where they treat a lot of patients for germ-cell malignancies. And what they did was saying if palonosetron, the newer serotonin antagonist has this much longer half-life and better binding to the 5-HT3 receptor, can we get away with giving it just every other day? And then they also looked at giving them corticosteroids only on day one and day two even though cisplatin’s given for all five days.
And what you can see is, the complete control is fairly good here. But it does diminish later on in the five-day cycle. But at day-two when no serotonin antagonist is given, they still do well, thus indicating that the palonosetron really continues to have an effect for acute emesis as well. Now, you may wonder when the control rate falls down to two thirds et cetera, could they have done better if they continued the corticosteroids. Would adding aprepitant be useful? All good questions that one could, because we have this study, one could look at in the future to try to see if we can raise this rate. But so far, this is really the – I think the best study we have for multiple day emesis.
Slide 50: The next one, next slide looks at a small study, but it’s in high-dose chemotherapy or transplant type chemotherapy. And you can see that there is a three-drug regimen, the upper box on the left compared with just the two-drug regimen is adding aprepitant. You can see the conditioning regimens and that they did pharmacokinetics on the series of patients.
The good news was that they saw no effect of aprepitant on pharmacokinetics which is an important consideration based on its elimination through the 3A4 pathway. And if you look at the results you can see the no emesis rate always favored the three-drug regimen.
Now in a phase two study I don’t really like to look at the P values. But you can see that there is a really dramatic improvement in the control of nemesis here that indicates that there can be real benefit to using aprepitant. Obviously, a larger study would be useful. But I think this is some of the best evidence that we have.
Slide 51: And the third slide here in this little set looks at pediatrics where we have really a dearth of good studies, and here there were 60 patients. This was presented at ASCO this past spring, and they looked at very young children from 25 days to teenagers. And they gave the adult dose on a milligram per kilogram basis, not total, but microgram per kilogram basis, .3 micrograms per kilo.
And they found that when they gave it that way, there may be a slight shortening of the half-life. But that the half-life was still rather long. But that the control was relatively good, and that there can be confidence in using this dosage in pediatrics. So that was, I think, important as well.
Slide 52: When we go forward, we are looking at greater convenience. We are looking at investigation of newer agents and new classes.
Slide 53: If we look at the next slide that looks at greater convenience, we can see newer dosage forms such as patches, sub-cue injections to last a longer time, even oral sprays, and the interesting concept of looking at canabanoids given by inhalant formulations to increase the Cmax to hopefully have greater efficacy. These are all interesting approaches.
Slide 54: When we look at newer agents, there are newer classes, or looking at newer agents in our existing classes, there is not too much interest in the serotonin antagonist.
Slide 55: But there is a lot of research going on looking at the NK1 antagonist. And the next slide shows many new agents. Aprepitant is the only one that is approved, but we will see more studies with casopitant and the other agents going forward even as early as 2008. It will be interesting to see if they can provide benefit.
Slide 56: I do want to go over one study quickly with you that is a small study. Only 41 patients reported at ASCO this year. But I think it is interesting. Here, they looked at palo, the new serotonin antagonist plus aprepitant, plus dexamethasone, but they gave all the drug in a single dose all on the first day.
This is highly investigational. Giving all the aprepitant up front, the patient went home with no drug. And everything was given immediately before chemo. It’s a high risk group of women, 98% of them women, all but one, and all getting AC chemotherapy.
But if you look at the results, the most accurate no vomiting rate is astounding at 100% complete control of acute emesis and very excellent delayed emesis of 95%. There is nausea here. But if these results can be duplicated, so far the toxicity have been good, this might predict a change in how we approach emesis in this group.
Slide 57: So there are certainly reasons to look at new classes of agents to meet our unmet needs as shown in the next slide.
Slide 58: And here, looking at the slide after that, we can see that there is some concentration on the look at GABA receptors and cannabinoids receptors. Olanzapine involves many different receptors, gabapentin, as well, but also GABA.
With this result, there are phase two studies that are promising. But will that result actually in better control especially for our unmet needs, we will have to see. I talked before about the inhalant Delta-9 THC to try to raise that to higher levels and could be available through other dosage forms and new classes of agents that bind to cannabinoid receptors that aren’t themselves cannabinoids. So we will have to stay tuned to see where that goes.
Slide 59: The next slide outlines, quickly, that we have newer approaches to advanced carcinomas. We are trying to target specific patients, target specific problems. And as we look at that in the small rectangles, you can see new supportive care areas that we need. But we must remember the classical areas of emesis and infection remain very, very important.
Slide 60: And finally to conclude, antiemetics continue to be crucial in so many patients who are receiving chemotherapy, which remains the cornerstone of our care in patients with advanced disease. And, we have more patients being treated with chemotherapy in terms of adjunctive settings as well.
This helps us preserve quality of life, keep patients in their own environments which they prefer, reduce other symptoms and side effects, and allows us to use the best antineoplastic drugs. The newer antiemetics clearly have been beneficial. And that it is very important that we maintain our knowledge base to use the very best treatments for our patients.
Been a pleasure being with you. And let me turn the microphone back to Dr. Holdsworth.
Slide 61: Dr. Holdsworth: Thank you, Dr. Gralla. Let's revisit the case now.
Some current chemotherapy protocols are now excluding dextomethisone. Reasons including fears of increased risk of fungal infections and wanting to avoid other agents that could impact chemotherapy activity. Since the antiemetics are an important component of standard care, protocol coordinators should be contacted in this situation.
Slide 62: It should be stressed that the patient has failed to respond adequately to alternative anti-emetic agents and that corticosteroids are indicated for adequate patient care. If protocol coordinators do not allow for dexamethisone in this situation, options would include addition of metaclopramide with appropriate anti-cholinergic agent protection or removing the patient from the study in order to provide appropriate antiemetic protection.
Slide 63: There is no evidence in this case that additional doses of serotonin antagonists would benefit this patient, and alternate serotonin antagonists may be employed, but it should be given as a standard daily prophylactic dose, and additional PRN doses should be discouraged.
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