The CINV Primer You Were Never Taught

Nothing puts fear into the heart of pharmacy students like the subject of Oncology. It’s easy to understand why. In most programs, students have a 2 - 5 week module where they go through the entirety of what is arguably the most complex subject in medicine.

Luckily, tl;dr pharmacy has your back. There are plenty of good reasons why you need to level up your chemo game:

  • It's on the NAPLEX
  • It's where the majority of pharmaceutical research dollars are going
  • Most practitioners avoid it like the plague, so you can give yourself a useful (read: profitable) skill set
  • Because you're interested in your profession and you like learning more about it (you ARE interested in your profession, right?)

As part of a series on topics in oncology, today we’ll be focusing on chemo-induced nausea and vomiting (CINV). Alright, buckle up and get ready. 

 

General Principles

Kawaii Overdose

For starters, let's establish: chemotherapy can induce nausea and vomiting. There are a number of proposed mechanisms for how this occurs, and it’s probably due a combination of any/all of them.

The neurotransmitters of concern here are serotonin, dopamine, neurokinin, and histamine. These little guys get released from cells that have been damaged or killed by chemotherapy--and once released, they stimulate certain nerves or areas of the brain to induce nausea.

Serotonin released from cells in the GI tract can stimulate the vagal nerve. This runs up and hits the chemoreceptor trigger zone (CTZ), located in the fourth ventricle of the brain. Chemotherapy can also directly stimulate the CTZ all on its own. The CTZ sends a message to the vomiting center in the medula. This (spoiler alert) makes you vomit. Some chemotherapy disrupts your vestibular apparatus directly, creating a sensation of motion sickness.

Understand that this is a defense mechanism of the body. Over the course of our evolution, our body developed ways to sense that you just ate something you shouldn’t have (like Taco Bell or Jack in the Box). So it created a way to quickly rid itself of the bad stuff while deterring you from eating it again. This is vomiting, and nausea respectively.  

When it comes to CINV, prevention is key. It’s much easier to prevent nausea and vomiting than it is to correct once it’s started. Our anti-nausea regimen is selected based on how likely the chemotherapy is to make someone vomit (emetogenic potential). We also account for acute, delayed, and anticipatory nausea when selecting a anti-nausea regimen. 
 

Enter: The Regimens

As a disclaimer, this section is grossly oversimplified. But there's a good reason for that. Using even a little of the google magic will give you handy summaries and practice guidelines. You'll find complete lists of low, moderate, and high emetogenic potential regimens as well as suggested CINV prophylaxis. Also, most institutions you work at will have their own set of policies to guide your decisions.

However, you have to prepare for your upcoming oncology test, so we're going to give you some pointers.  Here are a couple of general rules:

  1. If you see cisplatin or dacarbazine, it is a highly emetogenic regimen
  2. Monocolonal antibodies (end in--mab) are minimal emetogenic potential. You won't normally use prophylaxis for nausea, but you may pre-treat for infusion-related reactions (think tylenol, benadryl, +/- a steroid)
  3. Almost everything else falls somewhere in between. Higher doses equal more potential for emesis (ex. cyclophosphamide)
  4. The more chemotherapeutic agents in a regimen, the more potential for CINV. 

The backbone of most CINV regimen is the serotonin (5-HT3) antagonists. These are your drugs that end in --setron. Ondansetron, granisetron, dolasetron, and palonosetron. Of note here, palonosetron [Aloxi] is typically given as a single dose. It’s got a very long half-life so we administer it once and once only (per cycle) for high/moderate emetogenic chemo for acute and delayed prophylaxis. On a test, if you ever see palonosetron with a dosing schedule, it’s probably wrong.

For regimens that need a little extra oomph, a steroid is added. In oncology, it’s usually dexamethasone. Why add a steroid for nausea, you ask? I dunno. There are several theories of the steroid's mechanism in CINV, but if there is a consensus on which is correct I am unaware of it.  

Dexamethasone is also used for patients getting radiation therapy or during chemo that can cause infusion-related reactions (I’m looking at you, Taxol). Also, certain drugs (docetaxel) can cause fluid accumulation in the lower extremities and typically require dexamethasone. Remember that dexamethasone is an incredibly potent anti-inflammatory agent and it makes sense why it'd be used in these ways.  In these cases, you may actually use it FIRST, and then add a 5-HT3 antag for additional nausea coverage if needed. To be clear, dexamethasone does have some benefit in nausea, but it is much better as an anti-inflammatory.

Finally, for those nasty highly emetogenic chemo regimens, we will add an NK-1 antagonist. There are just two of these at the time of this writing. The original (and still most popular) goes by the trade name of Emend and is available as IV (fosaprepitant) and PO (aprepitant). I used to have a comically difficult time pronouncing this, so allow me to save any of you with the same affliction: ah-prep-ih-tant. The newer kid on the block is called Varubi (rolapitant). 

Regarding Emend, when using the IV, a SINGLE dose is given (150mg) for the regimen. When using PO, it's a 3-day course (125mg, 80mg, 80mg). You don’t mix and match here. It’s either IV x 1, or PO x 3. Not both. One additional note to look out for is that Emend is a moderate CYP3A4 inhibitor; so you must be wary of many potential drug interactions. A common adjustment you'll make in oncology is reducing the dose of dexamethasone if a patient is also receiving Emend.

Varubi is similar. It's only dosed once (180mg PO taken 2 - 3 hours before chemo). There is only a PO version of Varubi, no IV. An additional benefit is there is no drug interaction with dexamethasone.

These three classes (5-HT3 antag, steroid, NK-1 antag) in some combination form the foundation of your CINV regimens. Take note that they are added in a stepwise manner. You are not likely to see a regimen containing Emend by itself without a 5-HT3 antag + dexamethasone. If that shows up on a test it deserves a pretty bright red flag.

All of the Rest

The above "backbone" is far from all of the agents we use in CINV. We also need to account for anticipatory and breakthrough nausea.

For anticipatory nausea, (which is exactly what it sounds like) we use benzodiazepines. Lorazepam is most common here, but you may also see diazepam or clonazepam. This is similar to how we use benzos before you have a dental surgery or other procedure. Patients are often anxious before receiving chemo, especially if they've had a bad prior experience with it. The anticipation alone of receiving another cycle is enough to induce nausea. Benzos are the agents of choice here.

For breakthrough nausea (which is also exactly what it sounds like) we start adding in other drug classes. Here you will start to see dopamine antagonists, antihistamines, and more. These are considered your "prn" agents. You would want your patients to start taking these as soon as they felt nauseous. Again, it's much easier to prevent CINV than it is to treat it. You might use any of the following:

  • Metoclopramide
  • Olanzapine
  • Haloperidol
  • Prochlorperazine
  • Promethazine
  • Dronabinol

In a (very small) nutshell, that’s how we prevent and treat CINV. As always, patient-specific factors are going to play a role in what agents are selected (and in what order). For example, for patients with QT prolongation you should be wary of using haloperidol and any of the 5-HT3 antagonists. It's not that you won't use them, but caution should be exercised. These are also the sort of questions that have a habit of showing up on tests just so you can recognize the drug interaction--so be on the lookout.

Do you want an Oncology Cheat Sheet? 

It's got all you need to know for the NAPLEX. It's a great way to prepare for an APPE rotation. Keep it on hand when you're practicing and you'll know what to monitor. 

It packs a ton of information in a single page. Dose limiting toxicities, renal and hepatic dosage adjustments, emetogenic potential, likelihood of hair loss, infusion reactions, and much more. 

 

 

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