Expert Addresses Difficulties in Controlling Chemotherapy-Induced Nausea and Vomiting

Even with approved drugs, controlling chemotherapy-induced nausea and vomiting (CINV) is not always an easy task, says Richard Gralla, M.D., professor of medicine at Albert Einstein College of Medicine in New York.

In an interview with CURE, Gralla discussed current management success using cisplatin and AC— anthracycline cyclophosphamide chemotherapy, followed by a discussion of how management improved with the addition of neurokinin 1 (NK-1) receptor antagonists, which boosted the control rate to 75 percent or 85 percent from approximately 55 percent.

Although that was clearly a success, practitioners know that it is still much harder to control nausea than vomiting. In addition, more needs to be known about managing these conditions in the pediatric setting, as well as the need for more knowledge about the various agents.

How does Zyprexa (olanzapine) come into play?

With regard to drugs approved over the last two years, Gralla talked about the tablet combination of netupitant and Akynzeo (palanosetron), which is commercially available in an oral fixed-dose combination. He also discuss Varubi (rolapitant), which is a new NK-1 receptor antagonist that is metabolized differently than currently available agents—netupitant or Emend (aprepitant).He also discussed Zyprexa, an old drug with fresh promise.There are new studies with that, including one published in the New England Journal of Medicine in July. We do know, without any doubt, that Zyprexa is active. The question is, where should we use it? The way it was used in the NEJM study was as a fourth drug—instead of giving three drugs (a corticosteroid plus the other two). Do we give it as a fourth drug, as they did? Do we give it as a replacement for an NK-1?

It is not as highly selective as all the other drugs we’ve talked about, and it has different side effects— particularly, sedation, which is something that we had gotten away from. So, do we reserve it for those who haven’t done well on the first cycle? Or do we look at individual risk factors. We know CINV is toughest, for example, on young women getting highly emetic chemo. Should we use it first line for that particularly high-risk group? I can only ask questions about that.

Now, what do we know about pediatrics? We know that Emend, the longest-used NK-1 receptor antagonist, is safe and very useful in kids, based on a 2015 publication in Lancet Oncology.

Nowadays, there are a lot more data on whether we should use three drugs—that is, add an NK-1, in patients receiving carboplatin. The answer is yes, we ought to, and some of the guideline groups have already started emphasizing that.

You put a lot of stress on guidelines. Why is that?

If you get nausea and vomiting from chemo, there’s a one-third falloff in your quality of life. So, patients take a big hit. If you’re vomiting, you’re not going to be a very social person. You’re not going to go to work. By controlling emesis, you can reduce the number of urgent care visits. You cut them by more than 50 percent—if you follow a guideline. Often, we find that guidelines are not followed. We want to prevent drug over-usage and under-usage. You don’t need four drugs to control emesis in somebody getting fluorouracil. That’s where evidence-based guidelines are particularly beneficial.

What new agents are in development for nausea?

By no means are as many people getting medication as ought to be the case. Across medicine, it’s a
 big issue—why is it that doctors often don’t follow guidelines? They say there are often two kinds of learning styles: one is evidence-based and the other is experience-based. People say, “Well, I know that’s what I read in the literature, but that’s not what’s true in my practice.” That leads to false economies. If you’re going to end up with more clinic visits and more people returning because they’re miserable, that’s pretty expensive—not to mention the hit on quality of life that patients are unnecessarily taking.There is no new pathway that people are really interested in right now. Perhaps the interesting thing about Zyprexa is that, unlike the research of the last quarter century, this is the first time looking at a drug that is not selective. Zyprexa is a shotgun that affects a whole variety of transmitters, and maybe that’s what you need for nausea.

Do you have any further thoughts on treatment of nausea versus vomiting?

Perhaps, a look at other pathways will be interesting in nausea. One question I have is, since the NK-1 receptor antagonists are so safe, should we be looking at higher doses of these? And might that continue to be safe and have more of an effect on nausea? We don’t know the answer to that—that’s speculation.What we know is there is a strong correlation—the better you do in treating vomiting, the better you do in controlling nausea, but it’s not one-for-one. The first step is to completely control vomiting. And then, do we need to add on other things to control nausea?

I have theories why nausea is necessarily more [challenging to treat] than vomiting. Do we need other neurotransmitter receptors for the control of nausea rather than vomiting—maybe yes, maybe no. One of my theories is that our drugs are actually anti-nausea drugs—they’re not anti-vomiting drugs. There are certain physiologic things that occur that can be measured before you perceive nausea—meaning the feeling that you might vomit. You get gastric stasis, you may get sweaty and all the rest, but you don’t perceive the feeling that you might vomit.

However, if the stimulus continues above what I’ll call a nausea threshold, then you feel nauseated. And that’s a miserable unpleasant feeling. And then that continues. If the stimulus goes even higher, you go over the vomiting threshold. So, you have nausea leading to vomiting. Now, if our drugs are successful, they lower that stimulus below the vomiting threshold, so you don’t have vomiting, but then the stimulus is still in the nausea threshold. Sometimes people describe vomiting without nausea. I believe that’s because the stimulus rose so fast, that you didn’t have time to experience nausea.

I think prevention, rather than treatment, is important. That’s why using the guidelines is a good idea. The guidelines, if they’re evidence-based, should prevent over-usage and help prevent under-usage. That’s a big deal.

How well are patients and health care providers communicating when it comes to CINV?

It’s a shame to have drugs that work and then not use them. We have lots of problems in oncology where we don’t have treatments that work, but it’s a real shame that we don’t use the ones that do work.Studies have shown that especially for delayed nausea and vomiting, medical oncologists and oncology nurses underestimate the risk of emesis. Patients have twice as much delayed nausea and delayed vomiting as their doctors and nurses believe. I believe this is a real reason—this lack of communication—why we have treatment under-usage and over-usage.

Communicating what’s really happening is important. There are practice tools available, including an anti-emesis tool called the MAT, which is available as a free download at the Multinational Association of Supportive Care In Cancer website. It’s an easy way for patients, caregivers, and healthcare professionals to communicate, and there’s an even an app.