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Chemotherapy-Induced Nausea and Vomiting: A review on Antiemetics Used for Treatment and Prevention

26 Sep 2019 1:46 PM | Deleted user

Authors: Betsy Abraham, PharmD: PGY-1 Pharmacy Resident, NorthShore University HealthSystem
Katie Lentz, PharmD, BCOP: Oncology Clinical Pharmacy Specialist, Barnes-Jewish Hospital

Nausea and vomiting are common in patients who are on chemotherapy. A recent analysis of 991 patients receiving chemotherapy showed an incidence of anticipatory nausea of 8 to 14%, with rates increasing with each subsequent cycle.1  Patients beginning a cancer treatment consistently list chemotherapy-induced nausea and vomiting (CINV) as one of their greatest fears.2 Patient factors which increase the risk of nausea and vomiting include: female gender, age less than 50 years, dehydration, history of motion sickness, prior history of nausea and vomiting with chemotherapeutic agents, receiving chemotherapy outpatient, dose and emetogenicity of chemotherapy, no history of alcohol consumption and radiation (whole body or upper abdomen). Inadequately controlled emesis decreases the quality of life for patients, increases the use of healthcare resources, and can impair a patient from completing chemotherapy.3-4 However, new insights into the pathophysiology of CINV and a better understanding of the risk for these effects have helped clinicians better treat and prevent CINV. 

There are three subtypes of CINV which include: acute, delayed and anticipatory (see Table 1 for list of available agents). Acute CINV occurs within 24 hours after chemotherapy. Patients who are at greater risk for anticipatory CINV include those who have any of the patient factors which increase the risk of nausea and vomiting. The neurotransmitter responsible for anticipatory CINV is serotonin (5HT3). Therefore, treatment of CINV is with 5HT3 receptor antagonists (5HT3-RA) such as ondansetron (Zofran®). On the other hand, delayed CINV occurs 1 to 7 days after chemotherapy. The chemotherapeutic classes/agents which increase the risk for delayed CINV are ones of high emetic risk (> 90% of patients experience CINV without appropriate prophylaxis) which include, but are not limited to: anthracyclines, platinum analogs, cyclophosphamide (Cytoxan®), and ifosfamide (Ifex®).5 The neurotransmitter believed to primarily be responsible for delayed CINV is Substance P. However, delayed CINV is treated with a combination of antiemetics which include Neurokinin-1 receptor antagonists (NK1-RA) such as aprepitant (Emend®) and fosaprepitant intravenous (Emend®), corticosteroids, and the 5HT3-RA palonosetron (Aloxi®) (see Table 2 for list of combinations).6-7 Finally, anticipatory CINV happens prior to receiving a chemotherapeutic agent and is seen in patients with a history of CINV with prior use of chemotherapeutic agents. Treatment of anticipatory CINV is with benzodiazepines, specifically lorazepam (Ativan®).

Despite receiving antiemetic prophylaxis for acute and/or delayed CINV, some patients may experience breakthrough nausea and vomiting. Various antiemetics may be used during this time, including 5HT3-RAs, dopamine receptor antagonists, and cannabinoids. 5HT3-RAs such as ondansetron, palonosetron, granisetron (Kytril®) and dolasetron (Anzemet®) are usually well-tolerated by most patients and have constipation and migraine-like headaches as its side effects. Dopamine receptor antagonists such as prochlorperazine (Compazine®), promethazine (Phenergan®), and metoclopramide (Reglan®) are commonly prescribed; however, these agents carry unpleasant side effects such as extrapyramidal symptoms such as acute dystonia as well as sedation.6-7 Patients who develop acute dystonic reactions are treated with anticholinergics: benztropine (Cogentin®) and diphenhydramine (Benadryl®). Furthermore, cannabinoids, like dronabinol (Marinol®) and nabilone (Cesamet®) can be used second line for breakthrough CINV. These are synthetic analogs of delta-9-tetrahydrocannabinol, a naturally occurring component of Cannabis sativa. Cannabinoids carry side effects such as increased appetite, sedation, dysphoria, or euphoria. Therefore, these agents are prescribed only when patients have CINV with the preferred agents.6-8

Additionally, one agent that has recently come to prominence for CINV is the second-generation anti-psychotic olanzapine (Zyprexa®) typically used for the treatment of bipolar I disorder and schizophrenia. A randomized, double-blind phase 3 trial compared olanzapine with placebo in combination with dexamethasone (Decadron®), aprepitant or fosaprepitant, and a 5HT3-RA. The study revealed that the anti-emetic combination with olanzapine, as compared with placebo, had a lower proportion of patients with no CINV in the first 24 hours (74% vs. 45%, p = 0.002), the period from 25 to

120 hours after chemotherapy (42% vs. 25%, p = 0.002), and the overall 120-hour period (37% vs. 22%, P=0.002).9 Moreover, complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (p < 0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001).9 Dosed at 5-10 mg by mouth daily, olanzapine has become a novel agent used in combination with dexamethasone and palonosetron in patients with moderate to high emetogenic potential.

The goal for each patient is to prevent CINV and to start antiemetics prior to chemotherapy. The risk of nausea and vomiting can persist for up to 3 days after receiving the last dose of high emetic potential agents and for up to 2 days with moderate emetic potential agents.  CINV is a fear of patients who are starting chemotherapy or already receiving chemotherapy. Over the past two decades, more effective and better tolerated pharmacologic agents have been developed to prevent CINV. Currently, 5HT3-RAs, NK1-RAs, and corticosteroids are the most effective therapeutic agents to help prevent and control CINV. Despite the use of these therapeutic agents, uncontrolled vomiting and inadequately controlled nausea remain a problem in patients. Nevertheless, complete remission from CINV should be a goal for each patient with the hopes that patients can receive chemotherapy without having the fear of CINV.

References

  1. Aapro M. CINV: still troubling patients after all these years. Supportive Care in Cancer. 2018;26(1):55-59.
  2. de Boer-Dennert M, de Wit R, Scmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer 1997;76:1055-1061.
  3. Bloechl-Daum B, Deuson RR, Mavros P, et al. Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol 2006;24:4472-4478.
  4. Farrell C, Brearley SG, Pilling M, et al. The impact of chemotherapy-related nausea on patients' nutritional status, psychological distress and quality of life. Support Care Cancer 2013;21(1): 59-66.
  5. National Comprehensive Cancer Network/ Anti-Emesis Guidelines. Version 2.2017. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf
  6. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2492.
  7. Navari R, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;374:1356-1367.
  8. Hesketh PJ, Kris GM, Basch E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017;35:3240-3261.
  9. Navari R, Qin R, Ruddy JK, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375(2):137-142.


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