Subchapter list

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14.1 Antiemetic prophylaxis and therapy

14.1.1 Approaching a patient with nausea and vomiting

Nausea and vomiting are natural defense mechanisms that protect the body after consuming a potentially toxic substance. These mechanisms are mediated through central receptors in the chemoreceptor trigger zone, which is located in the area postrema, where the blood-brain barrier is absent. The absence of the blood-brain barrier allows easy interaction even between large polar molecules and chemoreceptors localized in the area postrema. If the chemoreceptors intercept the molecule, the so-called emetogenic center is activated, which then sends stimuli to other structures of the brainstem, thus inducing the vomiting itself. The emetogenic center does not only receive signals from the chemoreceptor trigger zone, but also from a number of other receptors located peripherally (mechanoreceptors and chemoreceptors of the gastro-intestinal tract (GIT), vestibular organs...) and from the limbic system. Therefore, vomiting can be triggered by a number of stimuli (e.g. GIT distension during ileus, kinetosis, stress-induced vomiting) and for this reason, the choice of antiemetic therapy must be approached rationally, with the aim of identifying the triggering cause and selecting the appropriate drug

It should be mentioned that vomiting as such is a symptom, not the disease itself, which we can influence quite successfully. On the other hand, successful control of emesis should not discourage us from active treatment of the underlying diagnosis that triggered the vomiting.

The most crucial factors for the correct choice of antiemetic drug in acute vomiting are, of course, a well-taken anamnesis, physical examination and basic biochemical (ions, CRP) and hematological examination, abdominal ultrasound and/or radiography. In cases where we have ruled out mechanical obstruction, gastrointestinal perforation and gastrointestinal bleeding, prokinetics may be the first-line of treatment:

• Metoclopramide (single dose 10 mg, maximum daily dose 30 mg) – we choose mainly for the possibility of parenteral administration in the form of a slow bolus intravenously. In order to avoid side effects, the time between two doses should be at least 6 hours. The total duration of therapy should be as short as possible, max. 5 days. Similarly, bear in mind the contraindications to metoclopramide due to its permeation through the blood-brain barrier (e.g. Parkinson's disease, epilepsy). Patients with renal and hepatic impairment should have their dose reduced by 50–75% depending on the degree of organ dysfunction.
• Itopride (single dose 50 mg, usual daily dose 150mg) – in the case when metoclopramide is contraindicated. The disadvantage in acute vomiting is the availability of the oral form only. On the other hand, the advantage of itopride may be the possibility of its long-term administration. It is one of the relatively safe agents and if side effects such as diarrhoea or constipation develop, the dose can be adjusted depending on the severity. In contrast, if gynaecomastia, galactorrhoea or abnormal blood counts (leukopenia) occur, treatment should be discontinued. Patients with hepatic and renal impairment should be monitored and doses should be reduced or treatment should be discontinued if adverse effects occur.

If prokinetic therapy is not sufficient in acute vomiting, either a drug group switch is made and setrones (5-HT₃ antagonists) are given in monotherapy or in combination with prokinetics as add-on therapy. If prokinetic therapy is contraindicated, setrons are the drug of choice for acute vomiting. In the case of acute vomiting, we primarily administer setrons with a shorter half-life. Setrons as a large group will be discussed in detail later in this chapter.

If setrones or setrone in combination with prokinetic fail, it is possible to extend the existing therapy with NK₁ antagonists or corticosteroids in parenteral form.

 In cases where the triggering cause originates from the vestibular organs, H₁-histamine antagonists (e.g. moxastine or bisulepin, which has the advantage of availability in both oral and parenteral forms) may be the drug of choice. The advantage of treating acute emesis through monotherapy or combination with H₁-histamine antagonists is the concomitant side effect of sedating and calming the patient. Cannabinoids also have strong antiemetic effects. Analgesics (e.g. for headache or abdominal pain) or benzodiazepines to relieve anxiety and nausea may also have some additive effect.

Symptomatic treatment includes mainly rehydration (oral replacement of water, glucose and ions, or parenteral rehydration with correction of ion losses: solutions with glucose, sodium and potassium) and modification of the diet.

Ideally, we try to prevent the onset of acute vomiting by administering antiemetics before the development of emesis. It should be remembered that prophylaxis of nausea and vomiting is always more effective than treatment of the developed symptoms.

14.1.2 Chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common side effects accompanying cytostatic therapy. It is an adverse effect that significantly affects patient tolerability, adherence to treatment and overall quality of life. In this case, it is appropriate to intervene prophylactically. The importance of prophylaxis does not only lie in protecting the patient from unnecessary stressful situations, but is also important for the effectiveness of antiemetic therapy as such. In fact, the effect of antiemetics is higher when administered prophylactically than when administered on demand. Previous episodes of CINV are a source of anticipatory nausea and vomiting.

The emetogenicity of cancer treatment depends on the emetogenic potential of individual drugs (Table 14.1) and on personal risk factors. In combination chemotherapy, emetogenicity is usually determined by the most emetogenic agent, and is usually higher than in monotherapy. The patient's individual risk factors should be included in the decision-making process for setting up antiemetic therapy. Factors that increase the risk of CINV include:

• age (<50 years),
• female sex,
• previous vomiting (kinetosis, drug-induced, ...),
• anxious patient, vomiting after previous cycles of treatment,
• metastatic cancer.

In contrast, older patients, men and those who regularly consume alcohol are at lower risk.

Table 14.1: Emetogenicity of selected anticancer drugs according to MASCC/ESMO 2016

High emetogenicity	Moderate emetogenicity	Low emetogenicity	Minimal emetogenicity
AC combination	Cyclophosphamide (<1500 mg/m2)	Etoposide	Asparaginase
Cisplatin	Doxorubicin	Gemcitabine	Bevacizumab
Cyclophosphamide (>1500 mg/m2)	Oxaliplatin	Fluorouracil	Bleomycin
Ifosfamide (>2 mg/m2)	Epirubicin	Paclitaxel	Rituximab
Carboplatin (AUC >4 mg/ml×min)	Irinotecan	Trastuzumab-emtansine	Vinblastine

AC – doxorubicin + cyclophosphamide, AUC – Area Under the Curve

CINV is divided into acute, delayed, anticipatory, breakthrough and refractory (Table 14.2).

Table 14.2: Types of nausea and vomiting after anticancer treatment

Vomiting type	Description
Acute	within 24 hrs from the beginning of therapy
Delayed	day 2–5 after beginning chemotherapy
Anticipatory	before the next cycle starts
Breakthrough	occurring despite optimal prophylaxis
Refractory	persisting after rescue antiemetic treatment

Acute emesis is caused not only by the detection of the chemotherapeutic drug or its metabolite in the chemoreceptor trigger zone, but also by the release of serotonin and substance P from enterochromaffin cells of the gastrointestinal mucosa, which stimulate vagal afferent nerve fibres and thus the information is transmitted to the emetogenic center. Delayed emesis is stimulated mainly by substance P released from the gastrointestinal mucosa, but the information is transmitted through less myelinated fibres and thus more slowly. Anticipatory emesis is not yet sufficiently explained. It is assumed that the limbic system is involved based on the previous negative experience of nausea and vomiting. Each type of vomiting therefore has a different therapeutic approach.

14.1.3 Antiemetic therapy in oncological treatment

The spectrum of antiemetics in CINV prophylaxis is based on the above-mentioned pathophysiology; serotonin antagonists at 5-HT₃ receptors (setrons) and NK₁ inhibitors blocking the action of substance P combined with dexamethasone as a representative of glucocorticoids are mainly used.

Setrones are standard prophylaxis during chemotherapy and can be given enterally (oral, dispersible tablet in the mouth) or parenterally (intravenously). Setrones act mainly on acute forms of CINV, except palonosetron, which also acts on delayed vomiting. The dose of setrones does not need to be adjusted in liver and kidney dysfunction.

• Ondansetron is recommended at a dose of 8–16 mg every 12 hours. Intravenous administration is possible by a slow bolus at a dose of 8 mg, at higher doses an infusion with a minimum of 15 minutes is recommended (risk of prolongation of the QT interval). Ondansetron, unlike other setrones, has a significant interaction potential – mainly on CYP 3A4.
• Another agent is granisetron at a dose of 1–3 mg per day administered intravenously in a short infusion. The longer biological half-life of granisetron provides some advantage over ondansetron. When compared with ondansetron, granisetron shows comparable efficacy.
• A newer agent is palonosetron, which has a high affinity for 5-HT₃-receptors and induces their internalization, therefore its effect persists for up to 5 days. Unlike ondansetron and granisetron, palonosetron does not cause significant prolongation of the QT interval.

In addition to QT interval prolongation, side effects of setrones include constipation and headaches. These side effects are usually transient and should not lead to discontinuation from premedication.

Administration of setrones in monotherapy for CINV prophylaxis is effective in only 50% of patients, and therefore not adequate treatment regimens in high or moderate emetogenic risk. Therefore, we use combinations of antiemetics with different mechanisms of action, e.g. NK₁-inhibitors, glucocorticoids, in more emetogenic regimens.

NK₁-inhibitors are part of prophylaxis in highly emetogenic chemotherapy or as a boosting medication in case of previously documented CINV. NK₁-inhibitors are never given as monotherapy but always in combination with other antiemetics.

• Aprepitant is administered orally in a 3-day regimen with an initial dose of 125 mg on day 1 and a dose of 80 mg on days 2 and 3.
• An intravenous alternative is the prodrug fosaprepitant, which is administered as a single 150 mg dose in a slow infusion.
• Netupitant (in a single dose of 300 mg) with palonosetron (0.5 mg) is a fixed combination. Both agents have a long biological half-life – one capsule is given for the entire chemotherapy cycle, but it must be given 1 hour beforehand and the maximum plasma concentration of both drugs is reached after 5 hours. NK₁-inhibitors are CYP3A4 inhibitors – this is not significant in the context of cytostatic doses, but a 40% dose reduction is recommended for dexamethasone dose when they are co-administered.

In moderate and high emetogenic regimens, it is recommended to potentiate the anti-emetic effect of setrones and NK-1 antagonists by the administration of glucocorticoids:

• The mechanism of action of dexamethasone in the indication of CINV prophylaxis has not yet been explained. However, it improves the response to antiemetic therapy and reduces the risk of delayed vomiting. Both oral and intravenous forms are available, and the dose should be chosen according to the emetogenicity of the chemotherapy. The usual dosage for prophylaxis of acute CINV is between 8–20 mg in a single dose (depending on patient emetogenic factors, additional premedication, etc.). In the case of prophylaxis of delayed CINV, we choose lower doses. Dexamethasone is basically a drug with a safe profile, especially for short-term administration. In prediabetic and diabetic patients, emphasis should be placed on monitoring glycemia by means of a glycemic profile during chemotherapy in which dexamethasone is given in premedication.

It is also possible to extend the treatment of CINV with H₁-histamine antagonists (see above) or proton pump inhibitors (Table 14.3).

Therapy of breakthrough and anticipatory vomiting is beyond the scope of this chapter and will be discussed in the lecture together with the use of the olanzapine antiemetic regimen.

Table 14.3: Possible scheme of antiemetic prophylaxis in high emetogenicity regimen

Group	Drug	Acute phase (day 1 – before chemo)	Delayed phase  (day 2–3)
5HT3 inhibitors	granisteron	1–3 mg i.v./p.o.	–
corticosteroid	dexamethasone	12–16 mg i.v./p.o.	8 mg i.v./p.o.
± NK1 antagonists	aprepitant	125 mg p.o.	80 mg p.o.
± proton pump inhibitor/ H2 antihistamine	pantoprazole famotidine	40 mg i.v./p.o. 20 mg i.v./40 mg p.o.	40 mg i.v./p.o. 20 mg i.v./40 mg p.o.

Application exercise:

A 30-year-old female patient with locally advanced triple-negative breast cancer is planned for neoadjuvant chemotherapy using the AC regimen (doxorubicin, cyclophosphamide). During medical interview, she reports a diagnosed anxiety disorder and denies other diseases.

• What other factors should you consider when deciding on the appropriate antiemetic prophylaxis?

  Risk factors are female sex, age and anxiety disorder. Further questions should therefore be directed at least to alcohol abuse and a history of nausea and vomiting.

• What should be the optimal antiemetic prophylaxis in this patient?

  The AC regime is a high risk regime for developing CINV. Thus, premedication with setron, dexamethasone should be chosen with use of aprepitant from the first cycle. Given the diagnosis of anxiety disorder, benzodiazepines can be added to the premedication, but in this case we should know the patient's chronic medication.

• What dosage of antiemetic prophylaxis would you choose?

  Given the number of risk factors, higher doses of antiemetic prophylaxis should be chosen. For example, granisetron 3 mg i.v., dexamethasone 20 mg i.v. or 12 mg i.v. if aprepitant 125 mg p.o. is used. Prophylaxis of delayed vomiting should definitely not be missed: dexamethasone 8 mg p.o./i.v. and aprepitant 80 mg p.o. day 2–3.