vomiting in cancer and mecanism

Nausea and vomiting in advanced cancer

Dylan G. Harris*

Department of Palliative Care, Cwm Taf Health Board, Merthyr Tydfil, South Wales, UK

Nausea and vomiting are distinct symptoms, commonly occurring together but

which should be assessed separately. Both are prevalent in patients with advanced

cancer. Data are taken from The Cochrane Library (2010) and Ovid MEDLINE

(1966–2010). Most current guidelines advocate an aetiology-based approach to

the management of nausea and vomiting. Choice of anti-emetic is based on a

clinical assessment of the likely pathophysiological component of the emetogenic

pathway that is being triggered and selecting an anti-emetic drug that blocks the

key receptors involved. Some authors propose a more empirical approach. The

limited available evidence would suggest that both an empirical or aetiology-

based approach may have similar overall efficacy. There are no published studies

directly comparing the two. Standardized assessment and outcome tools are

needed to enable well-designed studies to establish efficacy for conventional

agents and also compare efficacy with the newer, more expensive ones.

Keywords: nausea/vomiting/cancer/emesis

Accepted: August 22, 2010

Introduction

Nausea and vomiting is common in advanced disease. The prevalencein patients with advanced cancer is up to 70% and up to 50% in non-malignant advanced disease such as heart failure, chronic obstructivepulmonary disease and renal failure.1–8 Nausea and vomiting appearto increase in prevalence as disease progresses.9

Nausea may be defined as an unpleasant feeling of the need to vomit,often accompanied by autonomic symptoms such as pallor, cold sweat,salivation, tachycardia and diarrhoea,5,7,10 whereas vomiting is the for-ceful expulsion of gastric contents through the mouth through acomplex reflex involving coordinated activities of the gastrointestinaltract, diaphragm and abdominal muscles.5,7,10

Although the two symptoms are often clinically associated, theyshould be assessed separately.1,5 Patients may use the term ‘vomiting’to describe a variety of problems including expectoration and regurgi-tation and a careful history is therefore important.

British Medical Bulletin 2010; 96: 175–185

DOI:10.1093/bmb/ldq031

& The Author 2010. Published by Oxford University Press. All rights reserved.

For permissions, please e-mail: [email protected]

*Correspondence address.

Palliative Medicine,

Prince Charles Hospital,

Merthyr Tydfil CF47 9DT,

UK. E-mail: dgharris@

doctors.org.uk

Published Online September 30, 2010

by guest on April 11, 2014

http://bmb.oxfordjournals.org/

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Physiology of the emetogenic pathway

The current approach to managing nausea and vomiting in advancedcancer is largely based on physiological principles, an understanding ofwhich is therefore required to appreciate the rationale behind currentrecommendations.

The afferent and efferent reflexes that result in nausea and vomitingare thought to be integrated by two distinct centres at brainstem level(Fig. 1):

(i) The ‘chemoreceptor trigger zone (CTZ)’ is located in the floor of thefourth ventricle and is outside the blood–brain barrier.5,10–12 Rather thanbeing a specific anatomical area, the CTZ is likely to exist as interconnect-ing neural networks penetrating into the nucleus of the tractus solitarius.12

The CTZ is stimulated by chemicals in cerebrospinal fluid and blood aswell as vestibular and vagal afferents.1,5,10 It contains receptors for dopa-mine (D2), serotonin (5HT3), acetylcholine (ACH) and opioids (MU2).5

(ii) The ‘vomiting centre (VC)’ is situated in the medulla oblongata and has ablood–brain barrier.5,10 The VC, again a diffuse interconnecting neuralnetwork rather than a distinct anatomical structure, receives afferent inputfrom the CTZ; the glossopharyngeal and splanchnic nerves; cerebralcortex; thalamus; hypothalamus; and, the vagus nerve through the stimu-lation of stretch of mechanoreceptors and activation of 5HT3 receptors inthe gastrointestinal (GI) tract.1

Fig. 1 The emetogenic pathway.1,7,9,10,13

D. G. Harris

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The end result of the above pathways is the vomiting reflex, whichresults in peristalsis of the upper GI tract, relaxation of the pylorus andoesophagus and contraction of the intercostal muscles, diaphragm andabdominal wall culminating in forced expulsion of gastric contentsthrough the mouth past a closed glottis. It is postulated that stimuliinsufficient to trigger vomiting may nevertheless produce nauseathrough the same pathway.1

At least 17 potential neurotransmitters or receptors have been ident-ified in the CTZ and nucleus of the tractus solitariu.8,13 Numerousreceptors have been identified at the CTZ and VC and many more mayexist (Fig. 1). Furthermore, there is some evidence that the efficacy ofan anti-emetic drug is directly related to its binding affinity for aspecific receptor.14,15

There are now five known dopamine receptors (D1–D5); historicallyonly D2 receptors were associated with the emetogenic pathway (antag-onized by drugs such as haloperidol and metoclopramide) but D3 recep-tors are also now felt to be involved on the basis of animal studies.12

There are several groups of serotonin receptors of which 5HT3 hashad the most interest since metoclopramide was found to be a weak5HT3 receptor antagonist. Selective 5HT3 receptor antagonists weresubsequently developed with ondansetron being one of the first drugsin this category.8,12

Other important receptors involved in the emetogenic pathwayinclude histamine, ACH, endorphins, gamma-aminobutyric acid andcannabinoids.12 In contrast to other anti-emetics, cannabinoids appearto exert their effect by agonism at the cannabinoid (CB1) receptor.12

The above pathophysiological process forms the basis of most currentguidelines: choice of anti-emetic is based on a clinical assessment ofwhich component of the emetogenic pathway is being triggered, whichreceptors are involved and selecting an anti-emetic drug which there-fore blocks those specific receptors (Table 1 and Fig. 1).1,4

Clinical application

On the above basis, current recommendations advocate a structuredapproach to choosing an anti-emetic in clinical practice.1,3,4,7,9–11,13

(i) Clinical assessment to ascertain the most likely cause of the symptoms(history, examination and appropriate investigations).

(ii) Identify the pathway by which each cause triggers the emetogenicpathway and vomiting reflex.

(iii) Treat any reversible cause, e.g. hypercalcaemia.


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(iv) Identify the likely neurotransmitter receptor(s) involved in eachpathway.

(v) Choose an anti-emetic that antagonizes the receptor(s) identified.

(vi) Give each anti-emetic by a route that ensures absorption (therefore unli-kely to be oral in the frequently vomiting patient).

(vii) Give regularly, titrate the dose and reassess the patients symptoms.

(viii) Use non-pharmacological measures in combination with the selectedpharmacological agents.

Common mechanisms in advanced cancer are delayed gastric emptying(prevalence of 35–44% in case series3,16), chemical (prevalence of30–33% in case series3,16) and gastrointestinal causes such as bowelobstruction and constipation (prevalence of 31–32% in caseseries3,16).

Clearly the effectiveness of aetiology-based guidelines depends on theability to identify the underlying cause of the nausea/vomiting. It issuggested that this can be done clinically in 90% of cases.4,16,17 Thisfigure can obviously only be an estimate as there is no gold standarddiagnostic test for nausea–vomiting aetiology against which it can betested. Furthermore, many patients (up to 25% in some studies) mayhave multiple causes.3,16,18

Table 1 Aetiology-based classification of nausea and vomiting.7–10,16

Aetiology Examples Appropriate first-line antiemetic and

typical starting dose

Chemical Drugs, e.g. opioids, digoxin, antibiotics,

cytotoxics; toxins, e.g. ischaemic bowel,

infection; metabolic, e.g. hypercalcaemia

Haloperidol, 1.5 mg bd or 5 mg

subcutaneously over 24 h

Delayed gastric

emptying

Drugs, e.g. opioids, tricyclic

antidepressants; ascites

Metoclopramide, 10 mg qds or 40 mg


Hepatomegaly; autonomic dysfunction Domperidone, 10 mg qds

Gastrointestinal Bowel obstruction Hyoscine butylbromide, 60 mg

subcutaneously over 24 h or cyclizine,

150 mg subcutaneously over 24 h.

Consider adding haloperidol and/or

dexamethasone. If partial obstruction

and/or abdominal colic consider

metoclopramide instead

Radiation colitis, post-chemotherapy Ondansetron, 8 mg bd-tds

Cranial Raised intracranial pressure, e.g. from

tumour or intracranial bleed; meningeal

infiltration

Cyclizine, 50 mg tds or 150 mg

subcutaneously over 24 h (in conjunction

with dexamethasone)

Vestibular Drugs, e.g. opioids; vestibular neuritis

and labyrinthitis

Cyclizine, 50 mg tds or 150 mg


Cortical Anxiety, anticipatory nausea, pain Benzodiazepines, e.g. oral lorazepam,

0.5 mg as required

Bd, twice daily; tds, three times daily; qds, four times daily.

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Specific anti-emetics

Metoclopramide

Metoclopramide is a pro-kinetic anti-emetic (through agonism of5HT4 receptors, antagonism of peripheral D2 receptors and possibleantagonism of 5HT3 receptors) and therefore useful in nausea andvomiting related to gastric stasis.3,7 There are a few small placebo-controlled trials to support its efficacy.4 Pro-kinetic agents which actthrough 5HT4 receptors require ACH as a mediator at the myentericplexus and so are, in theory, antagonized by anticholingeric medication(cyclizine may potentially therefore antagonize the pro-kinetic effect ofmetoclopramide).5,7 Domperidone is an alternative pro-kinetic to meto-clopramide: it does not cross the blood-brain barrier and extrapyrami-dal side effects are therefore less likely.7

Haloperidol

Haloperidol is an anti-emetic principally acting in the area postrema.3

It is a very potent D2 antagonist.1 It is widely used in palliative care,usually in the context of chemical causes of nausea and vomiting.19 Asystematic review of its efficacy in the management of nausea andvomiting found that evidence of use is limited to case reports and caseseries with no controlled studies.19 Consensus-based recommendationsadvocate use in chemical or metabolic causes of nausea andvomiting.6,7

Cyclizine

Cyclizine is classified as an H1-antihistaminic anticholinergicanti-emetic and principally acts by decreasing excitability of the innerear labyrinth and blocking conduction in the vestibular–cerebellar path-ways as well as acting directly at the vomiting centre in the brain-stem.3,9 It is particularly advocated for nausea and vomiting where theunderlying aetiology is felt to be increased intracranial pressure, motionsickness, pharyngeal stimulation or mechanical bowel obstruction.5,20

Current recommendations for use are largely based on ‘consensus’(based on clinical experience).9 As mentioned above, pro-kinetic agentssuch as metoclopramide are potentially antagonized by anticholinergicmedication such as cyclizine and should not in theory be used together.

Levomepromazine

Levomepromazine is a phenothiazine which antagonizes 5HT2, hista-mine, alpha-adrenergic receptors, D2 and muscarinic cholinergic





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receptors.7 It is a broad-spectrum anti-emetic often used where first-line options have failed, particularly for nausea and vomiting of mul-tiple or indeterminate cause.13,21,22 There are no randomized con-trolled trials to support its use in this context but there is someevidence from open label studies.6,22 Typical starting doses are 6.25 mgonce daily. Drowsiness can be the main dose limiting side effect.21

Steroids

Steroids are used as a prophylactic anti-emetic for chemotherapy andmay have a wider adjuvant role in the management of nausea andvomiting.5 In the context of chemotherapy, studies have demonstratedthat dexamethasone improves the effect of other anti-emetics (metoclo-pramide and more recently 5HT3 and NK1 receptor antagonists) inpreventing chemotherapy-induced nausea and vomiting.6,12 It has alsobeen shown to have a beneficial effect over placebo when used alone inthis context.6 Dexamethasone (and possibly other corticosteroids) poss-ibly act by reducing the permeability of the area postrema (where thechemoreceptor trigger zone is located) and the blood–brain barrier toemetogenic substances.7,21 Alternatively, its action may also relate todepleting the inhibitory amine gamma-aminobutyric acid.7,13 In symp-tomatic bowel obstruction there is some evidence that corticosteroids(e.g. 6–16 mg daily) may help resolve the obstruction with a numberneeded to treat of six (but confidence interval 3 to infinity).13,23 Thereis some anecdotal evidence of benefit in nausea due to other causes interminal cancer (e.g. liver metastases).7,13 Dexamethasone has a half-life of up to 36 h which allows once-daily dosing.5

Benzodiazepines

Anticipatory nausea and vomiting can be a learned response, e.g. fol-lowing previous chemotherapy, but can also occur without priorspecific experiences depending on patient emotional distress and expec-tations of the patient. Benzodiazepines have been documented to helpin adult patients in combination with psychological techniques.24

5HT3 receptor antagonists

5HT3 receptor antagonists, e.g. ondansetron, granisetron, tropisetron,dolasetron and palonosetron. 5HT3 receptors are implicated in theemetogenic pathway in relation to massive release of 5HT from entero-chromaffin cells in the bowel wall, immediately following

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chemotherapy for example (and block the amplifying effect of 5HT onthe vagal nerve).9,10 Serotonin antagonists appear to exert theiranti-emetic effect via 5HT3 receptors both peripherally (enterochro-maffin cells of the enteric nervous system) and centrally (nucleustractus solitaries and CTZ).7 There is good evidence of efficacy in redu-cing acute vomiting in patients receiving chemotherapy compared withmetoclopramide-based regimes (particularly cisplatin-based chemother-apy).6–8 Previously there has been limited use in palliative care practiceoutside the context of chemotherapy-related nausea and vomiting andconcern about side effects, particularly constipation. There is someargument, and a small amount of evidence, that these agents may be atleast as effective, or possibly even more effective, than anti-emetics tra-ditionally used.4,6,25,26 Current consensus guidelines advocates use forchemical causes of nausea and vomiting refractory to haloperidol andlevomepromazine or when clinically it is felt that the cause of thesymptoms may relate to massive release of 5HT/serotonin from entero-chromaffin cells, e.g. bowel obstruction and renal failure, as well as themore recognized indications related to chemotherapy andradiotherapy.7,9

Olanzapine

Olanzapine is an atypical antipsychotic agent which blocks multiplereceptors including dopaminergic (D1–D4), serotonergic (5HT2,5HT3), histaminic (H1) and muscarinic.7,9,12 This mode of action atmultiple receptors has therefore led to its experimental use as a second-line anti-emetic in patients with refractory nausea.18,27 Small uncon-trolled studies have shown efficacy in this context.18,27

Substance P antagonists (NK1 receptor antagonists)

Substance P is a neuropeptide found in the gut and central nervoussystem and may induce nausea by binding the specific neuroreceptorneurokinin1 (NK1). Several NK1 receptor antagonists have beendeveloped in the context of chemotherapy-induced nausea andvomiting and post-operative nausea and vomiting.5,8,28 Aprepitantdoes not appear to be superior to ondansetron or granisetron in thecontext of chemotherapy-induced vomiting (and to a lesser extentnausea) but may increase their efficacy when used together withdexamethasone.8,12,13,20





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Cannabinoids

Initially reports of a lower incidence of chemotherapy-induced nauseaand vomiting amongst marijuana smokers led to exploration of canna-binoids in the treatment of nausea and vomiting.13 A brainstem canna-binoid receptor has now been identified but as some of the anti-emeticeffects of synthetic cannabinoids are reversed by naloxone part of theiraction may be at the opioid mu receptor.13 A systematic review foundthat the cannabinoids oral nabilone, oral dronabinol and intramuscularlevonantradol were more effective in reducing nausea and vomiting inpatients receiving chemotherapy than prochlorperazine, metoclopra-mide, chlorpromazine, haloperidol, domperidone and alizapride.20

They were however also associated with significant greater side effectssuch as sedation, euphoria, dizziness, depression, hallucinations andparanoia and a significantly higher patient withdrawal rate fromstudies because of adverse effects.20 As yet cannabinoids are not widelyused in this context in clinical practice, particularly as they oftenappear to be associated with a high burden of side effects.9,20

Non-pharmacological strategies

Non-pharmacological strategies are very important in the overall man-agement of the patient. Examples include avoiding food with strongtastes and smells; small but frequent meals; control of malodour fromwounds or ulcers, behavioural approaches (e.g. distraction, relaxation)and acupuncture/acupressure.7,8,10,11,13 There are positive Cochranereviews for acupuncture in the prevention of post-operative nausea andvomiting29 and chemotherapy-induced nausea.21

Evidence base

A previous systematic review of the efficacy of anti-emetics in advancedcancer found 21 appropriate published studies, which included two sys-tematic reviews, seven randomized controlled trials and 12 uncon-trolled studies.4 A more recent systematic review of nausea andvomiting in people with cancer and other chronic diseases found ninestudies that met the inclusion criteria.6 Difficulties encountered in thequality of these studies included small sample sizes; high attrition rates;difficulty controlling for confounding variables (patients with‘advanced cancer’ are a very heterogeneous population); and, differingoutcome measures. These problems in methodology are common instudies in palliative care.30

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Evidence for individual anti-emetics is weak or non-existent.4,8,19

However, little or no evidence does not mean they are ineffective:‘absence of evidence is not evidence of absence’.31 There are somesmall placebo-controlled trials for some anti-emetics such as metoclo-pramide.6,32,33 A systematic review of the efficacy of haloperidol wasunable to find enough studies of sufficient quality to draw any specificconclusions but it is advocated by consensus-based guidelines.6,19

There is however a greater evidence base for treatment-related causesof nausea and vomiting (radiotherapy and chemotherapy).6 The latterseems to be an area that has attracted more interest from the pharma-ceutical industry and hence drug development (such as the 5HT3antagonists).

Whilst the above aetiology-based approach to treating nausea andvomiting is widely endorsed in palliative care guidelines it should benoted that there is limited evidence to support the recommendations(through a paucity of evidence rather than negative studies). In practiceit may sometimes be difficult to clinically ascertain the specific emeto-genic pathway and therefore receptors involved.

The few studies and retrospective audits that have been conductedhave shown generally favourable outcomes through use of the aboveapproach with improvement in nausea in 56–82% of patients andvomiting in 84–93%.3,13,16,17 These studies have largely been uncon-trolled, and the few randomized controlled studies that have beenperformed have shown lower response rates. Of note, similar responserates have been found when an ‘empirical’ drug selection method hasbeen used.13,16,17,25,32–35 There has been no direct comparisonbetween the two approaches.11

Conclusion

The aetiological-based approach to choice of anti-emetic is a usefuloverall framework and remains the recommended practice in mostcurrent guidelines. As with many areas of palliative care, the lack ofevidence for current practice is due to an absence of evidence ratherthan evidence of absence (i.e. lack of robust clinical studies rather thana collection of negative ones).

However, considering the multifactorial nature of nausea and vomit-ing in many patients with advanced cancer; the multidimensionalaspects to nausea and vomiting (with anxiety and other psychologicalfactors playing an important role); and, the fact that many anti-emeticdrugs are known to affect multiple receptors, it is important to thinkoutside a mono-mechanistic treatment approach when facing a patientwith nausea and vomiting.





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Future research in this area should include randomized controlledtrials of the empirical versus aetiology-based approaches, as well asdirect comparisons of the newer anti-emetic agents with thosehistorically used in a wider context than trials of chemotherapy-induced emesis alone. On-going basic science research to enhance ourunderstanding of the neurophysiology of the emetogenic pathway isalso fundamental to identify new potential mechanisms of anti-emeticdrug action.

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vomiting in cancer and mecanism

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