Chemo-induced vomiting mechanisms

Vomiting is a fundamental protective reflex mediated by the central nervous system to prevent the harmful consequences of ingested, potentially toxic substances.
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Vomiting (known medically as emesis and informally as throwing up and by a number of other terms) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can occur due to a wide variety of conditions; it may present as a specific response to ailments like gastritis or poisoning, or as a non-specific sequela of disorders ranging from brain tumors and elevated intracranial pressure to overexposure to ionizing radiation. The feeling that one is about to vomit is called nausea, which usually precedes, but does not always lead to, vomiting. Antiemetics are sometimes necessary to suppress nausea and vomiting. In severe cases, where dehydration develops, intravenous fluid may be required.

The vomiting reflex is mediated by several distinct brainstem nuclei which integrate afferent inputs from diverse sources, including: the area postrema (a medullary site which contains the chemoreceptor trigger zone); the vestibular system; the pharynx and gastrointestinal and cardiovascular systems; and higher brainstem or cortical sites.

The peripheral afferent input from the gastrointestinal tract is mediated predominantly by the vagus nerve.
Afferent inputs to the vomiting centre are coordinated by the brainstem neuronal network of the dorsal vagal complex which includes the nucleus tractus solitarius (NTS). The NTS is a site for convergence of afferent input into the neuronal common efferent pathway, via the dorsal motor nucleus of the vagus, that produces the various visceral and skeletal muscular contractions necessary to produce oral expulsion of gastrointestinal contents, as well as changes in gut motility.
 
Many neurotransmitters have been implicated in the pathogenesis of vomiting, including dopamine, acetylcholine, histamine, opiates, serotonin and substance P. A more refined understanding of the relative importance of these neurotransmitters and their interrelationships in the regulation of vomiting is necessary for the development of more effective approaches for the treatment or prevention of vomiting.

Clinical aspects of chemotherapy induced vomiting

In addition to its continued importance as a clinical problem, vomiting induced by cancer chemotherapy may serve as an important model for understanding the physiology of vomiting in general.

Cisplatin is the single most emetogenic chemotherapeutic agent currently in use and may be considered the benchmark for evaluation of preventive strategies for CIV. At doses >50 mg/m² and in the absence of prophylactic therapy, cisplatin causes vomiting in virtually all patients. This vomiting typically follows a biphasic time course.

In the setting of clinical studies of cisplatin-induced emesis, chemotherapy induced vomiting has historically been described as occurring in two arbitrarily defined phases: the acute phase (from 0 to 24 h following the initiation of chemotherapy) and the delayed phase (from 24 h onwards).

Following initiation of the cisplatin infusion there is a latency period of 1–3 h before the onset of vomiting. The peak frequency of vomiting tends to occur at 6–8 h post-initiation of the cisplatin infusion, and this first phase of vomiting diminishes at approximately 12 h.

There follows a tendency for less emesis over approximately 4 h, after which the second phase of vomiting begins (approximately 16 h post-initiation of cisplatin). This second phase peaks between 24 and 72 h, although vomiting frequently occurs for several more days.

Many neurotransmitters exist which stimulate either directly or through other stimulation the chemoreceptor trigger zone (CTZ) situated in area postrema. During chemotherapy, most of the vomiting effect is produced by serotonin (5HT3) and Substance P (NK1). However, anticipatory vomiting also exist which might be related to stimulation of CTZ by other brain structures. The nucleus tractus solitarius (NTS) is the coordinator of the various visceral and skeletal muscular contractions necessary to vomit.

Role of serotonin

The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) has been shown to be an important mediator of the early (‘‘acute’’) phase of CIV. Cisplatin causes a calcium-dependent exocytic release of serotonin from enterochromaffin cells in the gastrointestinal tract, possibly as a result of free radical generation. In patients receiving cisplatin, a large increase in the urinary output of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) is observed within 24 h, indicating the release of intracellular serotonin.

The released serotonin activates receptors on vagal afferent fibres, which stimulates the CNS centres that mediate the emetic response. 5-HT3 receptors have been shown to exist in the area postrema, nucleus tractis solitaris, subnucleus gelatinosus and in lower densities in the dorsal motor nucleus of the vagus and the spinal trigeminal tract.

These receptors are known to be of the 5-HT3 subtype, as 5-HT3 receptor antagonists (RAs) inhibit the acute emetic effect of cisplatin.

Although important in the acute phase, serotonin is not believed to be a significant mediator of emesis occurring more than 24 h after chemotherapy. Delayed CIV responds poorly to 5-HT3 antagonists, and it is therefore highly likely that other neurotransmitters are involved in the pathogenesis of delayed-phase symptoms.

Role of substance P

Substance P (Neurokinin 1 or NK1) is a member of the tachykinin family of neuropeptides. It is co-localised with serotonin in enterochromaffin cells in the gastrointestinal tract, and substance P levels in the peripheral circulation are elevated following cisplatin administration. Substance P crosses the blood-brain barrier, which raises the possibility that substance P of peripheral origin may act centrally to induce emesis.

Central nervous system penetration by the NK1 Receptor Anatagonitss has been shown to be essential for the prevention of vomiting in the first 4 hours following cisplatin-based chemotherapy, which suggests that the antiemetic effect these antagonists is mediated centrally, probably in region of the nucleus tractis
solitaris.

A better effect is observed on delayed events (after 8 hours).

Plasticity of the emetogenic reflex

The effects of 5-HT3 antagonists are not simple to interprete even in experimental animal models. All patients do not react in a simlar way to antimetic treatments. These observations suggest that emetic reflex pathways may have some plasticity which should be further explored.

Acute vomiting

Vomiting is often present but is of varying intensity according to the chemotherapy drug, some being highly emetic such as cisplatin, dacarbazine or adriamycin.

Vomiting is one of patients’ major fears and is a frequent reason for stopping treatment.
The prevention of vomiting has been greatly improved with the arrival of the new antiemetic drugs which are 5-HT3 receptor antagonists: ondansetron, granisetron and tropisetron.

Mechanism of action

For patients and the general public, one of chemotherapy’s most feared side effects is vomiting. Significant progress has been made with the use of antiserotonin drugs (anti-5-hydroxtryptamine or anti-5HT3).

Serotonin receptors are present in great quantities in the lower brain stem, from the area postrema to the solitary tractus nucleus. Less dense receptors are also observed in the middle cortex and in limbic areas (especially hippocampus). At the periphery, receptors are found on pre- and postganglionic neurons as well as in the nervous system of the small intestine.

Vomiting is most often related to a stimulation of the central nervous system (target zone at the lower brain stem which provokes cholinergic, dopaminergic and serotoninergic stimulation).

The effect of increased chemo-induced serotonin secretion may be countered by administering anti-5HT3 drugs.

Chemical formulae

Ondansetron	Granisetron	Tropisetron

Indications

Three powerful drugs against vomiting are currently available: their efficiency is more or less identical. They act essentially on acute vomiting. In order for them to be active, they should be administered before any anticancer drug.

In contradiction to common practice which has unfortunately been approved by health authorities, the prescription of setrons for preventing delayed emesis and persisting nausea is no more efficient than simple corticosteroid administration, as demonstrated in double blind studies. In reality there is a placebo effect. Apepritant (see corresponding page) is far more efficient in these cases.

These drugs are also useful for the prevention of nausea and vomiting induced by radiotherapy (in particular brain or abdominal radiotherapy). They can also be used to prevent post-operative vomiting.

Dosing

Dosage varies; no ideal dosage has been established via rigorous studies.

Granisetron (Kytril™) is prescribed at the IV dose of 3 mg or the oral dose of 1 mg before chemotherapy. It is also prescribed by certain teams at the dose of 1 mg twice a day for 5 days, without any clinical proof of efficiency.

Ondansetron (Zophran™) is prescribed at the IV dose of 8 mg or orally before chemotherapy. The pharmaceutical company obtained, without clinical justification, the authorisation to administer 8 mg tablets, twice a day for 5 days for the prevention of delayed emesis.

Tropisetron (Navoban™) is prescribed at the IV or oral dose of 5 mg before chemotherapy. This dose is pursued for 5 days without any particular justification.

Side effects

The side effects of these drugs are minimal but should be acknowledged:

headaches are very common,
as well as constipation,
rarer side effects, whose aetiology is uncertain, include arterial hypotension or hypertension, diarrhoea, somnolence, asthenia, transaminase increase.

5-HT3 drugs represent a genuine revolution in chemotherapy tolerance.

The study of chemotherapy induced vomiting shows that various components are involved in the process with varying kinetics: firstly, serotonine metabolites are involved, intestinal motility is then disturbed and finally cancer cell lysis with the appearance of necrotic substances in patient serum.

When such treatment fails to give a positive result, neuroleptic drugs associated with corticosteroids can still be used, however they induce severe drowsiness, a situation which is not very comfortable for the patient if he/she needs to vomit.

The prevention of vomiting through such drugs should also avoid the occurrence of anticipated vomiting (patients vomiting before the administration of chemotherapy) and the constant anxiety at the prospect of returning to the day unit for chemotherapy, as well the occurrence of psychogenic vomiting.

The first cycle is the most important: everything possible effort should be made to prevent vomiting and even nausea. These drugs are sometimes so powerful that patients do not suffer any nausea at all. On the contrary, for a few patients, they seem to be totally inefficient and certain patients refuse further curative or adjuvant chemotherapy, when confronted with such painful situations.

Highly emetic chemotherapy	Moderately emetic chemotherapy	Slightly emetic chemohterapy
Cisplatin> 50 mg/m2 Cytoxan >1g /m2 Anthracycline > 50 mg/m2 Cariolysine Déticène	Cytoxan(<1g/m2) New Anthracyclines Cisplatin (< 50 mg/m2) Carboplatin Ifosfamide Taxanes Topotecan	Fluoro-Uracile Methotrexate Vepeside Oncovin Chloraminophene Purinethol Hydrea
Classification of chemotherapy drugs according to their emetic power

Delayed vomiting - Anorexia

Delayed vomiting is related to another relatively unknown mechanism which is different from acute vomiting and does not respond to new medicines. Delayed vomiting is generally more important if acute vomiting has been poorly controlled, but there is no absolute correlation.

Delayed vomiting is treated by metoclopramide, metoprimazine or alizapride in association with corticosteroids per os.

There is a new and very interesting class of drugs: anti-NK1 which act on neurokinin 1 (NK1) receptors and has a long-lasting emetic effect. Only one product is currently available: aprepitant (Emend™)

Delayed nausea is very unpleasant for patients and prevents the speedy return to a normal diet. Cooking smells are intolerable. Anorexia is very frequent, and is axacerbated when families force patients to rapidly return to normal eating habits (the general opinion being that a patient who doesn’t eat is very sick!). It is much healthier to ensure correct hydration than to fill the patient up with unwanted food.
With a three week cycle, it is most common to have only fluid diet during the first week, light food during the second and proper meals during the third. If the patient’s weight remains stable between the cycles, there is no particular risk. The physician should appease any family drama and reassure the relatives