Clinical Pearls for CINV

Imagine vomiting 7 to 10 times per day for about a week. You feel nauseous the entire time and you can’t keep anything down. It finally passes and you get a few days of rest. Unfortunately, now it’s time to go back and get another cycle of chemotherapy.

Before improvements in antiemetic therapy, that’s what it was like to receive cisplatin. For some patients, that’s still what it’s like.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most unpleasant adverse effects of receiving chemo. It contributes to morbidity, and it limits our ability to treat the underlying cancer.

We’ve made some improvements in recent years to CINV management. Although we haven’t conquered it completely, many chemo regimens are now much more tolerable for patients.

This article offers some clinical pearls for helping patients through CINV. Even if you don’t work in oncology, you’ll find a lot of overlap with general nausea and vomiting management.

CINV Pathophysiology

Although there are several proposed mechanisms for CINV, there isn’t a consensus on the exact one. It’s probably a combination of several pathways.

The process involves several neurotransmitters—specifically, serotonin, dopamine, histamine, and neurokinin. These neurotransmitters are released by cells damaged from chemotherapy, and they stimulate certain nerves or areas of the brain to induce nausea.

Serotonin released from cells in the gastrointestinal tract can stimulate the vagal nerve, which runs up to the fourth ventricle of the brain, where it stimulates the chemoreceptor trigger zone (CTZ). Chemotherapy can also directly stimulate the CTZ without using the vagal nerve.

The CTZ sends a message to the vomiting center in the medula, which causes emesis. Additionally, chemotherapy can disrupt the vestibular apparatus, creating a sensation of motion sickness.

When it comes to CINV, it’s much easier to prevent than it is to treat. To select an antinausea regimen, we must consider the following:

• The emetogenic potential of the chemotherapy regimen.
• The risk of delayed emesis (vomiting that initiates or continues 24 hours after treatment).
• Anticipatory nausea (nausea that occurs in anticipation of chemotherapy administration).

The American Society of Clinical Oncology and the National Comprehensive Cancer Network both have CINV guidelines. They’re your best resources for more information on CINV and other cancer-related topics.

Here’s a quick summary of current CINV practices (stratified by emetogenic risk):

• Minimal emetogenic risk (<10%): no prophylaxis necessary.
• Low emetogenic risk (10—30%): dexamethasone 8 mg or any first-generation 5HT3 antagonist.
• Moderate emetogenic risk (30—90%): 5HT3 antagonist + dexamethasone. If the patient developed severe/refractory emesis after previous cycle(s), add an NK1 antagonist to future cycles. If there’s a risk of delayed emesis, continue dexamethasone daily until day 4 or give palonosetron as the 5HT3 antagonist.
• Severe emetogenic risk (>90%): NK1 antagonist + 5HT3 antagonist + dexamethasone.
• For anticipatory nausea/vomiting: benzodiazepines (usually lorazepam because it won’t accumulate in the liver or cause renal failure).
• For breakthrough nausea/vomiting: There’s no consensus on treatment. Use what works best for your patient based on prior experience or other clinical factors. Common options include prochlorperazine, promethazine, olanzapine, metoclopramide, haloperidol, and dronbinol.

Now that we’ve covered the treatment basics, here are a few CINV clinical pearls, organized by drug class.

NK1 Antagonists

The recently approved combination pill Akynzeo contains netupitant (an NK1 antagonist) and palonosetron (a second-generation, long-acting 5HT3 antagonist). It’s dosed only once per cycle, and it covers both severe emetogenic risk and delayed CINV. Dexamethasone must still be used with Akynzeo, but other NK1 or 5HT3 antagonists aren’t necessary.

Aprepitant (Emend) was the first NK1 antagonist to market. It can be given intravenously (as fosaprepitant) for a single 150 mg dose per cycle. It’s also given orally as a 3-day regimen (120 mg, 80 mg, 80mg). Aprepitant is a moderate CYP3A4 inhibitor, which has a notable drug interaction with dexamethasone. This interaction is compensated for by decreasing the dexamethasone dose by approximately 50%.

Another NK1 antagonist, rolapitant (Varubi) has been approved within the past year. It’s only available single, oral dose, and there’s no drug interaction with dexamethasone.

Otherwise, all NK1 antagonists (aprepitant, rolapitant, netupitant) are considered equally efficacious.

5HT3 Antagonists

All first-generation 5HT3 antagonists (ondansetron, granisetron, dolasetron) are considered equally efficacious. They’re usually selected based on formulary preference and dosing convenience. For example, ondansetron has an ODT formulation available, whereas granisetron has a transdermal patch. Formulations that don’t require the patient to swallow a tablet are useful for patients already experiencing nausea or having difficulty swallowing. A long-acting formulation of granisetron (Sustol) has also recently been approved, but it’s not yet available.

First-generation 5HT3 antagonists are also associated with QT prolongation. These agents should be used cautiously in patients with heart rhythm abnormalities.

Palonosetron (Aloxi) is a second-generation 5HT3 antagonist. It’s not associated with QT prolongation. Aloxi also has a long half-life and only requires one dose per cycle. It’s role in therapy is usually for patients at risk for delayed CINV or QT prolongation.

Dexamethasone (And Other Glucocorticoids)

All glucocorticoids are similarly effective for CINV. Dexamethasone is most frequently used because it’s been studied the most. Additionally, it has no mineralocorticoid activity; high doses are unlikely to result in fluid retention. In fact, dexamethasone is specifically used to prevent fluid retention seen with chemotherapy like docetaxel. Dexamethasone is also used for patients receiving radiation therapy, or for chemotherapy that’s prone to causing infusion reactions, like paclitaxel.

These 3 classes (5-HT3 antag, steroid, NK-1 antag) in combination form the foundation of CINV regimens. Notice they’re added in a stepwise manner. It’s unlikely to see an antinausea regimen containing only an NK1 antagonist, for example.

The last clinical pearl for CINV is to be flexible and patient-centered. A particular chemo regimen may only have a “moderate” risk of emesis, but if the patient develops uncontrollable nausea during a cycle, the antiemetic regimen should be escalated in future cycles. This may mean adding an NK1 antagonist or trying different medications for breakthrough nausea.