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Published on 29 September 2009

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Chemotherapy induced nausea and vomiting

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The prevention of chemotherapy induced nausea and vomiting (CINV) can be achieved in the majority of patients using standard antiemetic regimens

Anna McNicholas
Clinical pharmacist

Geoff Saunders
Consultant oncology pharmacist

Chemotherapy induced nausea and vomiting (CINV) has a major influence on a patient’s quality of life, with it being named as the most distressing side-effect of chemotherapy by patients.[1],[2] Untreated CINV has an estimated incidence of about 70%. The likelihood is dependent on a number a factors including the drug or combination of drugs in the regimen, the gender and age of the patient and factors such as alcohol consumption and previous experiences.[3]

The severity of nausea and vomiting varies with the chemotherapy agent in use: agents such as the platinum compounds for instance cisplatin are highly emetogenic as opposed to agents such as oral busulphan which rarely causes nausea or vomiting.[4]

The susceptibility to the emetogenic effects of chemotherapy varies between patients with females being more susceptible than males and previous experience for example morning sickness in pregnancy, motion sickness and anxiety influencing response to chemotherapy. Patients who are younger are more susceptible. Additional anti-emetics should be considered in patients with three or more risk factors. For example a 28 year old female with previous experience of emesis would require enhanced treatment.

Patients who drink moderate amounts of alcohol are less likely to be at risk of significant nausea and vomiting induced by chemotherapy as it has been shown to have a protective effect.[5]

Nausea and vomiting induced by cancer chemotherapy has three main causes. Firstly, the release of serotonin in the gut stimulating serotonin receptors and vagal afferents resulting in gastric atony and inhibition of peristalsis.[6] Secondly, the stimulation of receptors in the chemotherapy trigger zone (CTZ) within the substantia nigra. Thirdly anticipatory nausea a psychological effect resulting in a conditioned response to external stimuli.[7]

When selecting appropriate anti-emetics all factors should be considered. Anti-emetics should be administered regularly, prophylactically, and orally. Intravenous and rectal routes can also be considered although caution should be used in patients with thrombocytopaenia. CINV can also be classified as either acute, delayed or anticipatory. Acute nausea and vomiting occurs within 24 hours of chemotherapy administration whereas delayed nausea and vomiting occurs at least 24 hours after chemotherapy administration and may persist 4-5 days later. Anticipatory nausea and vomiting can begin days or hours prior to the administration of chemotherapy.[8]

Chemotherapeutic agents have been classified by Hesketh based on their degree of emetogenicity.[9] In the Hesketh model there are four categories of agents, ranging from those most likely to cause emesis through to those least likely to cause emesis. Where agents are combined together an antiemetic regimen should be chosen according to the highest level of emetogenicity. Two or more agents from the same category would push the emetogenicity of the regimen into the next higher category. The American Society of Clinical Oncology have issued recommendations for the use of antiemetics based on the Hesketh model.[10] These guidelines are available through their website and are reviewed at regular intervals. These evidence based, peer reviewed guidelines form the basis for locally agreed guidelines available across many UK Cancer networks, resulting in patients being offered consistent, high quality treatment that is also cost-effective.[11]

This approach has been criticised because although the risk of emesis associated with individual agents is clearly defined, the risk of emesis for combinations of chemotherapy is far less obvious. There is a tendency to categorise all combination treatments at the same level of risk as the agent within it with the highest level of risk without considering any additive effect. Potentially patients may not be offered the best level of protection from chemotherapy induced nausea and vomiting. Response to antiemetic therapy should be monitored at each cycle with any adjustments made to take into account individual patients needs.[4]

A variety of anti-emetic agents are available for the prevention and treatment of CINV
5-HT3 antagonists act by preventing the release of serotonin the gut. Examples of such agents areondansetron, granisetron and palonosetron. Ondansetron and granisetron have been shown to be therapeutically equivalent and to be of little use in delayed CINV. It has been demonstrated that palonosetron has a pro-longed half-life. This tends to be used second line in patients who have experienced delayed severe nausea or vomiting due to ondansetron failure.

Dexamethasone is used in combination with other anti-emetics. It is effective in acute and delayed CINV. Metoclopramide is a prokinetic agent and is used in combination with other anti-emetics and to treat breakthrough CINV. Domperidone should be substituted for metoclopramide for the treatment of breakthrough CINV if the patient cannot tolerate it or the patient is a young female. Domperidone does not penetrate the blood brain barrier so does not exibit the central effects of metoclopramide. Cyclizine is another agent used to treat breakthrough CINV. This tends to be used second-line.

Levomepromazine is a very effective second or third line agent. It is available as 6 mg tablets, although they are unlicensed in the UK. Large doses of this agent are associated with sedation.

Neurokinin-1-receptor antagonists, such as aprepitant, are a new class of anti-emetic agents for the prevention of CINV. Aprepitant is licensed for use in acute and delayed CINV associated with cisplatin-based treatment (>50 mg/m2) and CINV associated with moderately emetogenic chemotherapy. It is administered over three days (125 mg an hour prior to treatment on day 1 and 80 mg on day 2 and 3) and in combination with a corticosteroid and 5-HT3 antagonist. When using such agents the dexamethasone dose should not exceed 8 mg daily. Casopitant mesylate, another neurokinin-1-receptor antagonist, is currently being trialled in various countries including parts of Europe and the United States. So far, it has been suggested that aprepitant and casopitant do not differ in efficacy.[12]

Anticipatory nausea and vomiting can be treated with benzodiazepines such as lorazepam. A thorough explanation of the treatment can also help.

Despite using standardised antiemetic regimens corresponding to the expected level of emetogenicity, a proportion of patients will experience nausea and or vomiting. If this is significant and the patient has adhered to the treatment regimen then the antiemetic regimen should be changed for the one corresponding to the next higher level of emetogenicity. For patients already receiving antiemetic regimens corresponding to the highest level of risk, other strategies should be employed, for instance use of one of the newer 5HT3 antagonists with a longer half life for example palonosetron may improve emetic control both in the acute and delayed phases.[11] Another approach would be to use increased doses of agents already being prescribed. Although the dose of ondansetron commonly recommended is 8 mg bd, doses as high as 32 mg per 24 hours have been administered in US studies. This dose is not licensed in the UK but could be recommended in exceptional circumstances although the patient would be exposed to increased risk of side effects, particularly constipation.[4]

Other strategies in the acute setting could include the additional use of the NK1 inhibitor aprepitant which has been shown to be particularly effective against cisplatin induced nausea and vomiting. Alternative therapeutic strategies in the delayed phase include prolonged courses of corticosteroids, increasing the use of 5HT3 receptor antagonists beyond the first 48 hours or increasing the dose of second line antiemetics.[4] All these strategies will put the patient at increased risk of side effects with an increased need for monitoring.

The prevention of CINV can be achieved in the majority of patients using standard antiemetic regimens. Patients should always be assessed at each cycle for the efficacy of the therapy being prescribed as control of CINV can deteriorate with successive cycles of chemotherapy.

References
1. Cohen L, de Moor, CA, Eisenberg P, Ming EE, & Hu
H (2007). Chemotherapy-induced nausea and vomiting:
Incidence and impact on patient quality of life at
community oncology settings. Supportive Care in Cancer:
MASCC 15(5),497-503.
2. Griffin AM, Butow PN, Coates AS, Childs AM, Ellis
PM, Dunn SM, Tattersall MH (1996). On the receiving
end. V. Patient perceptions of the side effects of cancer
chemotherapy in 1993. Ann Oncol 7:189-195.
3. Jenns K. (1994). Importance of nausea. Cancer Nurs
17:488-493.
4. Mays T. (2007) Oncology Pharmacy Speciality
Certification On-Line Review Course. American Society of
Health System Pharmacists.
5. Finley R. (1998) Concepts in Oncology Therapeutics.
American Society of Health-System Pharmacists.
6. Wickhman R. Nausea and Vomiting. In CH Yarbro,
MH Frogge & M Goodman (Ed). Can Symp Mgmt
Third Edition, (2004). Sudbury, MA: Jones and Bartlett
Publishers.
7. Koda-Kimble. Applied Therapeutics, The Clinical use of
Drugs, Fifth Edition. (1992) Appl Therap Vancouver.
8. Berger AM, Clarke-Snow RA. Adverse effects of
treatment. Principles of Oncol Philadelphia: Lippincott,
Williams & Wilkins. (2001) 2869-2880.
9. Hesketh PJ, Kris MG, Grunberg SM et al. (1997)
Proposal for classifiying the acute emetogenicity of
cancer chemotherapy. J Clin Oncol 15:103-109.
10. Kris M, Hesketh PJ, Somerfield MR et al. American
Society of Clinical Oncology Guideline for Antiemetics in
Oncology: Update. J Clin Oncol 2006;24:2932-2947.
11. (GM&CCN) Greater Manchester and Cheshire Cancer
Network Guidelines for the use of Antiemetics 2005.
Accessed at www.gmccn.nhs.uk 30.01.2009
12. Ruhlman C and Herrstedt Jorn. (2009) Casopitant:
a novel NK1-receptor antagonist in the prevention of
chemotherapy-induced nausea and vomiting. Ther Clin
Risk Manag 5;375-384.



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