Role of 5-HT3 Receptor Antagonists in Treating CINV

Lee S. Schwartzberg, MD: We’ve been talking a lot, in general, about the emetogenic potential of chemotherapy. Let’s hone in, now, on the drugs that we use and how we approach highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC).

We already mentioned that there are several classes of drugs, and the first cornerstone of therapy were the serotonin antagonists, and the specific subtype of serotonin, 5-HT3 (5-hydroxytryptamine), and we have receptor antagonists there. Dawn, can you tell us a little bit about where we are with that and how we got there?

Dawn Dolan, PharmD, BCOP: We’re lucky enough, now, to have a handful of 5-HT3 antagonists, and we now can separate them out into first-generation and second-generation 5-HT3 antagonists: the first-generations being ondansetron, dolasetron, and granisetron; and the second-generations being our new agents, palonosetron and the subcutaneous granisetron. There are some very unique differences. Those early first-generations typically have a shorter half-life. They are pretty good for preventing acute nausea, but not so great in the delayed phase. That is what we’re finding, and we are considering that they probably are not adding a whole lot of value when given in the delayed phase. But, with our new agents, the palonosetron and subcutaneous granisetron, not only have a much longer half-life, but they definitely have some distinct differences that set them apart with regards to receptor binding that make them more potent. They definitely have higher efficacy rates compared to the first-generation 5-HT3 antagonists.

Lee S. Schwartzberg, MD: Do you use palonosetron based on that?

Dawn Dolan, PharmD, BCOP: Yes, we are exclusively using palonosetron right now.

Lee S. Schwartzberg, MD: And you give that when?

Dawn Dolan, PharmD, BCOP: About 30 minutes prior to chemotherapy.

Lee S. Schwartzberg, MD: And you give 1 dose for the entire period because of the receptor binding and the half-life?

Dawn Dolan, PharmD, BCOP: Usually 1 dose. There are some newer data to say that you can probably re-dose palonosetron. So, with our BEP regimen (bleomycin, etoposide, and cisplatin) for testicular patients, we’re actually giving that on day 1, 3, and 5 to give them that extra protection because of the high doses of cisplatin that they’re getting.

Lee S. Schwartzberg, MD: And you mentioned orals; there are intravenous (IV) and oral options. What’s the equivalence that you see between those?

Dawn Dolan, PharmD, BCOP: All of these 5-HT3 antagonists are considered equally efficacious at equal potent doses, whether they’re oral or IV, depending on the dose.

Lee S. Schwartzberg, MD: What kind of toxicities do you see?

Dawn Dolan, PharmD, BCOP: Nicely, they have pretty low toxicities. The big ones, of course, that we see are headache and constipation. Even though we think these are pretty benign drugs, those can be pretty significant side effects for some patients. Some patients come back and say, “Gosh, the constipation, I think, might be worse than the nausea, or might be contributing to the nausea.” So, it is something that we definitely have to have on our radar, despite the percentage being quite low.

Howard Levine, PharmD: We see constipation as being number 1 on the hit parade of side effects with palonosetron, and we use it pretty much as the standard. But the number is relatively small—I’m saying about 3% is a good estimate—so we don’t see too many. But the patients will come in and specifically say that. The headaches, not so much. They’ll deal with the headaches. But constipation, they don’t want to deal with that.

Lee S. Schwartzberg, MD: Do you educate the patients beforehand about those, or are they rare enough that you wait to hear responses?

Howard Levine, PharmD: We wait to hear responses. I don’t think that’s something we throw in as being the biggest problem because we don’t want people to go fishing and look for side effects. But, if they come back and they say, after the first cycle, typically, that they have really bad constipation, we will say, “OK, we’ll adjust your therapy then.”

Dawn Dolan, PharmD, BCOP: That being said, it’s always good to take a quick breeze through the medication list because these are oncology patients. They’re on other drugs that cause constipation, whether it’s a chemotherapy drug like vincristine, or they’re on opioids. So, they’re on concomitant things that can cause constipation. If you’re adding another bonus to that, it could become significant for a patient.

Lee S. Schwartzberg, MD: I think it’s good, as part of your checklist, to ask about that, specifically, because if they’re already on opioids and have constipation, perhaps they would get a little bit more with that. Eric, how do you deal with these complications once you have these side effects? Do you switch your antiemetics? Do you just treat the symptoms? What’s your approach?

Eric Roeland, MD: My experience has been that it’s really a class effect; there isn’t one that’s better than the other with regard to the side effects. It’s really about stopping again, and educating your patients. They’re really quite surprised that they need to be more aggressive about a bowel regimen prior to chemotherapy. Everyone thinks they’re going to have diarrhea. So, I sit down and we review their medication list. If they’re on opioids, I want to ensure that they’re taking a stimulant laxative, which would be senna or bisacodyl, making sure those are at maximum doses. Some people—senna, for example, with opioids—only need 1 tablet a day; and other people need 8. So, it’s important to let people know about stimulant laxatives while they’re on opioids. And then, for 5-HT3-induced constipation, I haven’t found that one particular drug is more helpful than another. If it’s just purely due to that, I think a softener or osmotic such as polyethylene glycol would be fine.

Lee S. Schwartzberg, MD: Good. Does anyone else have any other thoughts on that? Are you changing or just treating?

Dawn Dolan, PharmD, BCOP: If you’re able to, we sometimes will switch it up because that’s an easy thing to do if you have it available to you. There are some rare cases where we’ve taken a patient and switched them from palonosetron to ondansetron, just to see if it made a difference—not so much on the constipation end but the headache. I have had some people report those headaches to be pretty severe, last for several days, and not really respond to traditional things like Tylenol or ibuprofen, which we don’t typically want them to take after chemotherapy because they can mask fevers. But, that adds a whole other layer of complexity to it.

Lee S. Schwartzberg, MD: I think it’s a good point, though, because many patients don’t take anything, or don’t even call because they’ve been instructed not to take any analgesics and antipyretics, and typically in a day or 2 after chemotherapy, that’s not an issue.

Dawn Dolan, PharmD, BCOP: It’s not a big deal.

Lee S. Schwartzberg, MD: But, they come in and say, “I had a headache for 5 days.” We ask, “Did you call?” Their response is, “No, I just thought that was okay.” We ask, “Did you take a Tylenol?” And they say, “No.” So, sometimes it’s, again, about going back to simple, providing education around that, and trying to be proactive.

Beth Eaby-Sandy, CRNP, OCN: As we were talking about the 5-HT3s, I noticed a couple of you said we are exclusively using palonosetron. I’m not afraid to say that, at my institution, palonosetron is our drug of choice for highly emetogenic patients. But, in our moderately emetogenic patients, we’re still using IV ondansetron as the first option. You can delete that and put palonosetron in for any patient, and you’re not going to be questioned on that, necessarily. But, if you’re looking purely at cost, that’s when you have to start deciding about these drugs. How much of this is an issue? You can certainly argue the point that the cost of nausea/vomiting, and the admission rate, and hydration is a higher cost than actually using these drugs, up front. But, that being said, at our institution, we are still using ondansetron at 16 mg, IV, for our moderately emetogenic regimens, with the option of adding an NK1 (neurokinin 1) receptor antagonist.

Eric Roeland, MD: Have you been using subcutaneous granisetron at all?

Beth Eaby-Sandy, CRNP, OCN: We have not used that yet, but I think it’s something that is also an option.

Howard Levine, PharmD: What’s interesting about what you just mentioned is cost is an issue for everybody now, obviously. We’re an OCM practice, as you are, and on our first review, they talked to us about cost of treatment. On the back end is the cost of not treating, and that’s hard to quantify. When we first looked at what we were going to be doing with NK1s, 6 to 7 years ago, we sat down, we looked at it, and we said, “We’re going to add them on, and we’re going to do like you said.” Certainly, the highly emetogenic regimens will get the add-on. In the moderately emetogenic regimens, it’s a choice. It’s not standard but if you choose, it’s there.

So, it made it easy for people to go with that. And when we did that, we looked at outcomes over the next year and we dropped our emergency room rates by 40% for nausea and vomiting just by paying attention. The question, then, is, do we go backwards, in our mind, saying, “We’re going to go back, from palonosetron, to what we used to do.” Is that going to affect the back end again? We’re not willing to do that. It’s a patient issue to start. OCM is a whole other story, and I wonder where it’s going to wind up when looking at baselines and comparing data. Everybody here is the benchmark, and the benchmark may be from people who have tons of admissions to the emergency room. Well, that’s nice, but do we want to drop to that level? That is the benchmark because people weren’t giving optimal therapies in certain regard, and this is one of those. So, I wonder where the dollars fit in, and I understand they do fit in.

One of the concerns you mentioned with the granisetron injection is that it’s really expensive. Does it add a huge advantage? We’re not certain. And the cost, certainly, is an issue there—to change something that’s very expensive, we shy away from it.

Eric Roeland, MD: That’s a new kid on the block that a lot of people are not familiar with. Maybe, Lee, you could tell us more about it?

Lee S. Schwartzberg, MD: We’ve been using it for some time in our AC (anthracycline/cyclophosphamide) patients, which I don’t think we’ve mentioned yet, but they are highly emetogenic and were reclassified as highly emetogenic some years ago. And that’s really for any dose of AC, although, of course, most of the patients who are getting that are in the adjuvant setting and have the additional risk factors of being young females in breast cancer. So, they have those additional factors, but AC is a highly emetogenic regimen. We’ve had good results with it. Cost is definitely an issue, in general, and I think looking at total costs, as you suggest, are really important. We’ve seen very good control with the subcutaneous granisetron. It is a subcutaneous injection, but it really hasn’t proven to be difficult. The way that that works differently—it’s still granisetron—but it’s released in a polymer, so you get a high peak and then a delayed effect, as opposed to having either a continuous amount of release, as with the previous patch form that is still available, as well but has to be started 24 hours in advance of the chemotherapy. So, you get to effective levels or to standard oral or IV granisetron, which is a little different.

But, I think it’s interesting. We could have a healthy debate on using palonosetron in HEC but not MEC, because, actually, the data support its use in doublet therapy. That’s where you see the advantage of palonosetron over the first-generation agents. And, there may not be as much advantage of palonosetron when you add the NK1. We might argue it the other way, but I certainly see how every different institution can come to different conclusions based on the data.

Beth Eaby-Sandy, CRNP, OCN: I think, also, we give much more MEC regimens than we do HEC regimens, anymore, these days. The feeling was, “We’ll give them the strongest possible medication for the HEC regimen.” But, MEC is making up maybe 75% of our treatment regimens. So, in that effect, that would be a lot of dollars to switch from IV ondansetron to IV palonosetron, in our setting, anyway.

Eric Roeland, MD: We’ve merged the 2. In the inpatient setting, we use ondansetron. We use ondansetron in the inpatient setting because we know patients get it. And when we’re worried about compliance with patients, we use palonosetron, mostly in the outpatient setting.