An overall study may show that antiemetic drugs have similar effectiveness in a particular population. However, individual patients might respond differently and thus, when selecting an antiemetic regimen to accompany a patient’s chemotherapy journey, it is important to consider:
- Therapy goals;
- Patient’s medical condition(s);
- Medication access;
- Possible drug interaction(s);
- Counselling on proper use;
- Adherence and discussion with patients on their expectations;
- Side effect management; and
- Patient’s experience.
This article will discuss some common antiemetic agents used in chemotherapy.
Neurokin-1-Receptor (Nk1) Antagonists
These agents selectively block binding of substance P at NK1 receptors in the central nervous system, which predominantly causes delayed CINV. Hence, they are most beneficially used for prevention instead of treating nausea and vomiting.
It may also be worthwhile to note that aprepitant, fosaprepitant and netupitant inhibit dexamethasone’s metabolism and can increase serum dexamethasone levels when administered concurrently.
A randomised phase 3 trial consisting 521 patients compared the addition of aprepitant with ondansetron 32mg IV and oral dexamethasone in patients administered high dose cisplatin against patients who were only given ondansetron and dexamethasone. It was found that introducing aprepitant was significantly more effective in controlling both acute and delayed emesis. Another similar trial with 523 patients has also demonstrated the benefits of adding aprepitant. Moreover, the benefits of aprepitant have been consistent in other studies where it has been administered with palonosetron, granisetron or ondansetron. Collectively, these studies show aprepitant regimens help improve emesis and quality of life for patients on moderate to highly emetogenic chemotherapy.
In addition, a meta-analysis of 17 randomised trials reported that introducing aprepitant has improved outcomes for both acute and delayed CINV with no emetic episodes and no rescue medication required between zero to 120 hours after moderate to high-risk emesis chemotherapy.
In terms of safety, data from three trials did not find an increased risk of severe infections, febrile neutropenia or other haematologic toxicities. Constipation was the most common side effect experienced by 39% of patients.
Aprepitant is a substrate, moderate inducer and moderate inhibitor of CYP3A4, and is a CYP2C9 inducer. Hence, it can alter the metabolism of certain drugs and change plasma concentrations. This effect may be especially pronounced with orally administered drugs compared with intravenous medications due to first-pass metabolism. Aprepitant decreases plasma concentrations of oral contraceptives. Thus patients are recommended to use other birth control methods during treatment and for one month after the last dose. Other CYP3A4 inhibitors (ketoconazole, erythromycin) can increase aprepitant concentration whereas concomitant administration with CYP3A4 inducers (carbamazepine, phenytoin, rifampin) can decrease aprepitant levels.
As a prodrug and intravenous form of aprepitant, fosaprepitant has similar efficacy to aprepitant. A phase 3 trial of patients having highly emetogenic treatments were given ondansetron, dexamethasone, and either a three-day oral schedule of aprepitant or a single dose of fosaprepitant. It was shown that fosaprepitant was non-inferior.
Netupitant (300mg) is available as a fixed oral product, with palonosetron (0.5mg). A randomised trial demonstrated that this combination together with dexamethasone could decrease acute, delayed, and overall nausea and vomiting in patients compared with just administering palonosetron and dexamethasone. The clinical efficacy was maintained over multiple chemotherapy cycles. Furthermore, based on several other randomised trials, netupitant and palonosetron has been approved to treat the effects of moderate to high-risk emetogenic chemotherapy.
Netupitant has a half-life of 90 hours and a high binding affinity. Similar to aprepitant, it can also affect CYP3A4 enzymes.
Generally, 5-HT3-receptor antagonists reduce or prevent 50% of emesis cases. When used with dexamethasone, this figure increases to 70%. If an NK1-receptor antagonist is added, the benefits increase to about 84%. All agents (palonosetron, ondansetron, and granisetron) have been shown to be effective in controlling acute CINV. However, a recent meta-analysis of randomised controlled trials reported that palonosetron was significantly more effective in preventing both acute and delayed nausea and vomiting in moderate to high-risk emetogenic treatments, compared to ondansetron and granisetron. On the other hand, ondansetron and granisetron are effective in preventing acute emesis but seem to be less effective in delayed emesis.
It is important to note that 5-HT3-receptor antagonists have pharmacokinetic and pharmacodynamic differences that can influence safety and efficacy in different populations. Ondansetron and granisetron are associated with increasing the risk of developing abnormal electrical activity of the heart through PR or QT prolongation. This warning is yet to be available for palonosetron, but caution is advised. Although this effect is reversible and asymptomatic, it can result in cardiac arrhythmias including torsade de pointes in some cases. The risk is further increased in patients with underlying cardiac issues like congestive heart failure, bradycardia, congenital long QT syndrome, patients already taking medications which affects the QT interval, and any electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia).
As the first 5-HT3-receptor antagonist to be introduced, ondansetron added to dexamethasone offers more effective protection from CINV compared to high dose metoclopramide combined with dexamethasone. This regimen also has an improved side effect profile.
Palonosetron has a 100 times higher binding affinity for 5-HT3-receptors compared to ondansetron and granisetron. It has a half-life of about 40 hours, which is significantly longer than other 5-HT3-receptor antagonists. A study of 563 patients found that a single dose of 0.25mg intravenous (IV) palonosetron was superior compared to a single dose of 32mg ondansetron in preventing acute and delayed emesis where no corticosteroid was given concomitantly.
Another phase 3 trial consisting of 667 patients undergoing high-risk emesis chemotherapy were administered dexamethasone, and either 0.25mg IV palonosetron or 32mg IV ondansetron. Both regimens appear to be similar in preventing acute emesis. However, palonosetron was better at preventing delayed emesis. In addition, a study with patients undergoing doxorubicin plus cyclophosphamide treatment reported that having palonosetron with dexamethasone on day 1 of treatment allowed cessation of the steroid on subsequent days after chemotherapy. Moreover, antiemetic control or patients’ function was not significantly affected over a five-day post-chemotherapy timeframe.
On the other hand, after intravenous palonosetron administration, using a 5-HT3-receptor antagonist for breakthrough emesis has a limited role, and a different drug class should be considered.
Steroids are commonly used during chemotherapy treatments for various reasons including infusion-type reactions. For the purpose of this article, dexamethasone will be the main focus.
The Italian Group for Antiemetic Research conducted two randomised, double-blind studies.Evidently, 20mg dexamethasone was more effective against acute emesis compared to either 4mg or 8mg doses. However, the 12mg and 20mg doses are equivalent in protecting against acute emesis. Moreover, 20mg dexamethasone was not significantly different from the other doses for protection against acute nausea. Adverse effects and control of delayed CINV were similar among the four groups of different dosings. A second study compared the effect of three different dexamethasone dosing regimens in patients on day 1 treated with anthracyclines, cyclophosphamide, or carboplatin (either alone or combined with chemotherapy agents considered moderately emetogenic). It was concluded that 8mg dexamethasone IV is the best dose for antiemetic regimens for patients receiving chemotherapy with these agents.
In another phase 3 trial, two regimens were compared in women having moderate risk chemotherapy. One group had dexamethasone combined with palonosetron on day 1 of treatment only. The second group had palonosetron and dexamethasone on day 1 and also continued with dexamethasone on day 2 and 3. It was found that there was no clinically significant difference between the two regimens during the acute (zero to 24 hours) and delayed (days two to five) phases of treatment.
Therefore, based on patient characteristics, doses of dexamethasone may be individualised and can vary. In some instances, a lower dose or frequency or even omission of dexamethasone on subsequent days may be acceptable. Limiting dexamethasone to day 1 only in moderate risk emetogenic treatment may be appropriate if the patient has few CINV risk factors or is intolerant to steroids.
A common side effect of dexamethasone is insomnia, and thus, it is recommended to be taken in the morning. If dexamethasone is required for prolonged periods, there needs to be careful consideration of its side effects. It can cause dyspepsia and an H2-antagonist or proton pump inhibitor may be needed. Furthermore, dexamethasone can increase serum glucose and needs to be cautiously used for diabetic patients.
Although there are general recommendations to prevent and treat breakthrough CINV, a patient may not be sufficiently protected in some instances and require an adjustment to their regimen. Some suggested alternatives can include:
- Adding a neurokinin-1-receptor (NK1) antagonist if not already included;
- Adding other concomitant antiemetics (e.g. a dopamine antagonist like metoclopramide);
- Adjusting the dose and/or frequency of serotonin 5-HT3 receptor antagonist. A different serotonin 5-HT3 receptor antagonist can also be used. This option may not be effective but anecdotal studies and limited trial data suggest it can be useful for certain patients;
- If the chemotherapy goal is not for an absolute cure, another less emetogenic treatment may be more ideal;
- An anxiolytic may be beneficial; and
- If dyspepsia is suspected, treat with an antacid.
Editor’s note: For more information on the presentation of nausea and vomiting in patients receiving chemotherapy, please refer to Chemotherapy-Induced Nausea and Vomiting.
- Ettinger DS, Berger MJ, Aston J, Barbour S, Bergsbaken J, Bierman PJ, et al. NCCN Clinical Practice Guidelines in Oncology: Antiemesis [version 2.2017]. Fort Washington: National Comprehensive Cancer Network; 2017.
- Longo DL, Navari RM, & Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016; 374(14): 1356-67.
- Rossi S, editor. Immunomodulators and antineoplastics. In: Australian Medicines Handbook 2018 [online]. Adelaide: Australian Medicines Handbook Pty Ltd; 2018.