Management of Chemotherapy Induced Nausea and Vomiting

Amongst the many toxicities associated with chemotherapy, nausea and vomiting remain among the most feared adverse effects for cancer patients during their treatment. With the development of a number of effective and well tolerated antiemetics, significant progress has been made in the management of chemotherapy induced nausea and vomiting (CINV).

If not effectively controlled, CINV can significantly impact quality of life for cancer patients, adding to the morbidity and cost of treatment.

Several guidelines have been developed and recently updated, with recommendations for antiemetic use in the prevention of CINV; these include the American Society of Clinical Oncology (ASCO) Antiemetic Guidelines, the National Comprehensive Cancer Network (NCCN) Antiemetic Guidelines and the Multinational Association of Supportive Care in Cancer (MASCC) Antiemetic Guidelines.

Vomiting occurs due to the stimulation of a multistep pathway which is regulated in the brain. This involves stimulation of the vomiting centre (located in the medulla) by the chemoreceptor trigger zone (CTZ), gastrointestinal (GI) tract, vestibular system, psychological mechanisms, and intracranial activity. The neurotransmitters dopamine, serotonin (5HT3), histamine, acetylcholine, corticosteroids and neurokinin-1 mediate this stimulation, and are each found in varied proportions in the GI tract, the vestibular system and the CTZ. Chemotherapy, or its metabolites, can activate these neurotransmitters, leading to emesis.

Nausea and vomiting may also be associated with anxiety, or can be a learned response. As chemotherapy has the potential to cause nausea and vomiting in a number of ways rather than through one specific pathway, there is no single antiemetic agent that can be used to prevent all CINV.

CINV can be classified as either acute, delayed, anticipatory, breakthrough, or refractory. Acute onset emesis occurs within the first 24 hours of chemotherapy, with the intensity usually peaking at five to six hours after drug administration. Delayed nausea and vomiting occurs more than 24 hours after chemotherapy. Anticipatory emesis occurs before a patient receives their treatment, and is a conditioned response which occurs in those who have had significant nausea and vomiting with previous chemotherapy.

Breakthrough emesis is that which occurs even if prophylactic antiemetics have been given. In these cases, rescue antiemetics are required. Refractory emesis refers to emesis that occurs after treatment cycles where patients no longer respond to first-line prophylactic and rescue antiemetics.

Chemotherapeutic agents vary significantly in their ability to cause emesis. Intravenous and oral chemotherapy drugs are classified as either high (occurring in more than 90% of patients), moderate (30-90%), low (10-30%) or minimal (<10%) emetic risk. Other factors which may increase the risk of CINV include: female gender, previous chemotherapy, previous chemotherapy associated emesis, being younger than 50 years of age, and no history of alcohol consumption.

Commonly used antiemetics for CINV include serotonin (5HT3) receptor antagonists, neurokinin-1 receptor antagonists, corticosteroids, dopamine receptor antagonists and benzodiazepines. 5HT3 receptor antagonists include palonosetron, tropisetron, ondansetron, granisetron and dolasetron. These are most effective in the prevention of acute CINV.

Palonosetron is a potent second generation 5HT3 receptor inhibitor, which can be given as a single dose prior to chemotherapy because it has a long half-life (approximately 40 hours). It is now the preferred 5HT3 antagonist. Neurokinin-1 receptor antagonists include aprepitant and fosaprepitant (the IV formulation).

When combined with 5HT3 receptor antagonists and dexamethasone, aprepitant can provide significant additional antiemetic effects for both acute and delayed nausea and vomiting.

Dexamethasone is the most commonly used corticosteroid in CINV management. It is used synergistically with other agents and can help manage delayed emesis. Dopamine receptor antagonists, including metoclopramide, domperidone, and prochlorperazine, are generally used for breakthrough and refractory emesis, while benzodiazepines are reserved for anticipatory nausea and vomiting. Antihistamines like promethazine and cyclizine are also used in the management of acute, delayed and refractory CINV.

The aim of antiemetic treatment is to prevent nausea and vomiting; with optimal management of the acute phase required to prevent emesis in the delayed phase of treatment. To prevent acute CINV, antiemetics should begin prior to administration of chemotherapy and should cover the first 24 hours of treatment.

Antiemetics chosen should be based on the chemotherapy drug with the highest emetogenic risk in the patients’ treatment regime, as well as any patient specific risk factors, and previous experiences. Patients may also modify their eating habits to reduce CINV, such as eating smaller, more frequent meals and avoiding foods that make them feel nauseous. A summary of the antiemetic guidelines for the prevention and management of CINV can be found in Table 1.

Table 1. Antiemetic Guidelines According to Emetic Risk

* During May 2013, Aprepitant 165mg as a single dose one hour prior to chemotherapy on day one, was made available on the PBS to replace the current three day dosing schedule.

Managing breakthrough emesis can be challenging as it is easier to prevent than to treat CINV. Treating breakthrough emesis requires giving an additional antiemetic agent from a different drug class with a different mechanism of action. There may be a need for regular dosing rather than as required, or to change antiemetic therapy to a higher level, such as from moderate emetic risk to high emetic risk.

Anticipatory emesis is ideally controlled by optimal prevention of acute and delayed CINV. Psychological and behavioural techniques should first be used to help prevent further anticipatory nausea and vomiting. In some cases benzodiazepines may be used as an alternative or additional treatment, such as lorazepam 0.5mg to 2mg the night before and the morning of treatment.

Chemotherapy administered over multiple days does not have a specific antiemetic regimen, and recommendations are difficult as acute and delayed CINV can potentially overlap. Recommendations vary depending on the types of protocols used, as the degree of acute and delayed CINV depends on the emetogenicity of the individual drugs and the sequence of administration.

The MASCC and NCCN Guidelines recommend a 5HT3 antagonist and dexamethasone be given before doses of moderately or highly emetogenic chemotherapy on each day, and with dexamethasone continuing for two to three days after for protocols likely to cause delayed CINV. Aprepitant may also be used in protocols with high emetic risk that have delayed CINV.