Chemotherapy- and radiotherapy- induced nausea and vomiting

Nausea and vomiting is one of the most severe side-effects associated with cancer therapy, and can result from chemotherapy - Chemotherapy-induced nausea and vomiting (CINV) and radiotherapy (radiotherapy-induced nausea and vomiting).  The effects of nausea and vomiting can be more distressing to a patient than future concerns of life expectancy, sometimes resulting in the patient choosing to discontinue potentially curative therapy^[1]. 

The medical complications of nausea and vomiting include dehydration, electrolyte imbalance and a risk of aspiration pneumonia.  However much of cancer therapy has a palliative intent and quality of life is important.  Therefore the effective management of nausea and vomiting associated with cancer therapy is one of the primary goals.

The aetiology and risk factors for CINV and radiotherapy-induced nausea and vomiting

Not all patients receiving chemotherapy or radiotherapy will experience nausea and vomiting but it has been estimated that (untreated) it occurs in up to 70% of patients receiving cancer chemotherapy^[2]. 

There are three types of nausea and vomiting associated with chemotherapy and radiotherapy, each with different aetiologies^[3],[4],[5]:

• Acute nausea and vomiting. This lasts for 12-24 hours.
• Delayed nausea and vomiting. This may occur up to 5 days after chemotherapy. It is less apparent in the case of radiotherapy.
• Anticipatory nausea and vomiting. This conditioned response results from the patient's expectation (anticipation) of nausea and vomiting.

There are a number of predictive factors to take into account^[2],[6], and these can be divided into patient risk factors, drug risk factors and procedural risk factors.

Patient risk factors

• Age.  Children are more likely to develop nausea and vomiting than adults
• Gender.  The prevalence of nausea and vomiting is higher in women
• History of nausea and vomiting.  Patients with a history of motion sickness may have a lower threshold to nausea and vomiting than the rest of the population.  This can be exacerbated by patient anxiety and by a prior history of nausea and vomiting associated with chemotherapy or radiation therapy
• History of heavy alcohol use. This is associated with a lower risk of nausea and vomiting.

Drug risk factors

This is by far the most important risk factor for CINV.  There is a wide range of emetic potential in chemotherapeutic drugs.  This ranges from highly emetogenic agents such as cisplatin to weak emetogens such as fluorouracil, though individuals vary in their response (table 3).

The dose, duration of infusion and number of cycles of chemotherapy are important factors for CINV, with shorter infusion cycles generally increasing the risk.  Combination drug regimes can increase the risk of CINV.

Patients on chemotherapy or radiotherapy may be in significant pain, and undergoing treatment with opioid analgesics.  The opioids in turn will add to the emetic risk.

Procedural risk factors

With radiotherapy-induced nausea and vomiting the site irradiated is important.  Radiotherapy to the brain, skull and spine, upper abdomen, stomach, bowel or close to the liver is more likely to induce nausea and vomiting than treatment of other sites.  Higher doses of radiation, longer duration of treatment and a larger treatment field will also increase the emetic risk. 

The causes of CINV and radiotherapy-induced nausea and vomiting

As described in more detail elsewhere numerous neuronal pathways converge on the vomiting centre in the medulla (part of the hind brain) where the vomiting reflex is initiated.  These include vagal sensory pathways from the gastrointestinal tract and neuronal pathways from the labyrinths, higher centres of the cortex, intracranial pressure receptors and the Chemoreceptor Trigger Zone (CTZ). 

The exact involvement of each of these pathways in CINV and radiotherapy-induced nausea and vomiting is not known.   However, it is thought that stimulation of vagal sensory pathways results from agents released due to cell damage.  For example serotonin (5HT) is released from enterochromaffin cells in the gastrointestinal tract^[7].  Also activation of the CTZ is thought to be caused either by the treatment itself or by agents released from cells damaged by the treatment. 

The factors involved in radiotherapy- or chemotherapy-induced nausea and vomiting are shown in Figure 9.

Figure 9 The factors involved with CINV and radiotherapy-induced nausea and vomiting

The consequences of CINV and radiotherapy-induced nausea and vomiting

As with other forms of nausea and vomiting, CINV and radiotherapy-induced nausea and vomiting can be very distressing and result in practical consequences for patients and carers, it can lead to medical complications and impose an economic burden.

Practical consequences

Nausea and vomiting can be very distressing for patients when they are already feeling uncomfortable and anxious as a result of an underlying cancer.  Carers or medical personnel will also have to clear up after patients.

Medical complications

There is the possibility of the regurgitation of stomach contents, leading to risks of respiratory obstruction, pulmonary inflammation and aspiration pneumonia.  Electrolyte imbalance, dehydration and weight loss can occur if nausea and vomiting is severe, which can be a particular issue with already frail patients.  Finally the delayed ability to take oral therapy for patients who are likely to be undergoing treatment with a number of other drugs can be a concern.

The distress caused by the nausea and vomiting can lead to some patients choosing to discontinue potentially curative therapy^[1].

Economic burden

The economic burden of nausea and vomiting includes personnel time in clearing up and material costs of disposable products, laundry, caring for patients, delayed discharge and unplanned admission leading to bed blocking.

The management of CINV and radiotherapy-induced nausea and vomiting

The management of nausea and vomiting associated with cancer chemotherapy and radiotherapy is especially important since the distress caused by the nausea and vomiting can lead to some patients choosing to discontinue potentially curative therapy^[1].  However much of cancer therapy has a palliative intent and quality of life is important.  Therefore the effective management of nausea and vomiting associated with cancer therapy is one of the primary goals.

It is also important to distinguish between the different types of nausea and vomiting, with some drugs being effective against acute nausea and vomiting, whilst not having an effect on delayed or anticipatory nausea and vomiting.   Also different drugs have been shown to be effective against either CINV or radiotherapy-induced nausea and vomiting.

As with other treatment regimes for nausea and vomiting, combination therapy using drugs of different classes is widespread.  See for example the Palliative Care Formulary ^[8].

Acute emesis

Various classes of drugs have efficacy against acute mild-to-moderate emetogenic therapy.  These include dopamine receptor antagonists, cannabinoids, corticosteroids and the serotonin (5-HT₃) receptor antagonists.  The most effective agents against acute emesis resulting from mild- moderate- and highly-emetogenic chemotherapy are the 5-HT₃ receptor antagonists^[9].  A wider range of agents, including dopamine antagonists and anti-histamines is effective against nausea and vomiting resulting from radiotherapy.

Delayed emesis

Anti-emetics, including 5-HT₃ receptor antagonists, have little efficacy against the delayed emesis that occurs 2-5 days after administration of agents such as cisplatin.  Clinical trials indicate that neurokinin NK₁ receptor antagonists can effectively prevent delayed emesis^[10] but none are yet commercially available. 

Anticipatory emesis

The best treatment for anticipatory emesis is the effective control of acute and delayed emesis, although benzodiazepines are sometimes used for their anxiolytic and amnesic effects when anticipatory emesis is established^[3].

The drug treatment of nausea and vomiting is summarised in Figure 10.

Figure 10 The drug treatment of CINV and radiotherapy-induced nausea and vomiting

Summary

• Nausea and vomiting is a major problem in cancer therapy that can lead to some patients refusing further, potentially curative treatment
• Chemotherapy-induced nausea and vomiting and radiotherapy-induced nausea and vomiting result from a complex interaction between various neurotransmitters and receptors in the CNS and gastrointestinal tract.
• There are three types of emesis resulting from chemotherapy and radiotherapy; acute, delayed and anticipatory. Each has a different aetiology, and should be treated differently.
• 5-HT₃ receptor antagonists are the most effective treatment for acute emesis resulting from cancer chemotherapy.
• A wider range of agents, including anti-histamines and dopamine antagonists is effective against nausea and vomiting resulting from radiotherapy.
• 5-HT₃ receptor antagonists are less effective against delayed emesis resulting from treatment with agents such as cisplatin.
• The best treatment of anticipatory emesis is effective control of acute and delayed emesis.

References