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Published on 8 June 2010

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Chemotherapy induced emesis: pathophysiology and prevention

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Prevention of emesis is a prioritry point and efforts should be made to ensure that optimal treatments designed into guidelines are applied in clinical practice

Audrey Mailliez
MD

Breast Cancer Dept
Centre Oscar Lambret
3 rue Frederic Combemale
59020 Lille
France

Nausea and emesis are two of the most feared side effects of chemotherapy. More effective anti-emetic treatments have been developed after the introduction of cisplatin, a cytotoxic with the highest emetic potential. Chemotherapy-induced nausea and vomiting have been classified into acute, delayed and anticipatory based on the time of onset. According to the percentage of patients with nausea and vomiting without any anti-emetic treatment, chemotherapy is divided into 3 groups according to the risk of emesis: high, moderate, low and very low. The discovery of emetics stimuli neurotransmitters and their receptors has led to the introduction of new molecules which, associated with steroids, have prevented chemotherapy-induced nausea and vomiting in 70 to 80% of the patients receiving chemotherapy with high emetic potential. Numerous studies have evaluated the various anti-emetics and recommendations were issued by Oncology Societies in US and Europe.

We will discuss the physiopathology of nausea and vomiting, the development of anti-emetics with emphasis on the newest ones. Finally, a summary of the recommendations developed by the Multinational Association of Supportive Care in Cancer, the American Society of Clinical Oncology, the National Comprehensive Cancer Network and the European Society For Medical Oncology is presented.

Anticancer drugs have been used for more than 50 years but the real development of anti-emetic therapy began only 20 years ago. With the introduction of Cisplatin, nausea and vomiting became two of the most severe side-effects of chemotherapy imposing refusal of curative treatment for 20 % of the patients.[1] Nausea and vomiting are the most feared and distressing side-effects according patients.[2]

Pathophysiology
Pathophysiology of chemotherapy-induced nausea and vomiting is only partially known. The most likely mechanism is the release of emetics transmitters (dopamine, serotonin and substance P) that bind to different receptors located in areas of the gut and the central nervous system. Anti-emetics prevent the emetic stimuli by binding to these receptors as antagonists.

Classification of chemotherapy-induced nausea and vomiting (CINV)
CINV are classified into three categories:[3] acute (within 24 h of the administration of chemotherapy), delayed (24-120 h) and anticipated.

Some risk factors have been identified:[4] young age, females, motion sickness, vomiting during pregnancy, anxiety and poor quality of life are risk factors. Conversely, heavy drinkers do not experience chemotherapy induced emesis.

Classification of the emetic risk
The emetic potential of each drug is the main risk factor for CINV. Anticancer drugs have been classified into four groups according to the emesis risk without anti-emetics: high (emesis risk >90 % without anti-emetics), moderate (30–90 %), low (10–30 %) and minimal (<10 %).

Emetics transmitters
Serotonin has been discovered by Rapport in 1948.[5] Its receptors have been identified and classified into three groups: 5 HT (5-hydroxytryptamine) 1, 5HT2, 5HT3.

Substance P was isolated in 1931[6] but purified and sequenced only in 1970.[7] Substance P belongs to tachykinines whose receptors are neurokinines (NK) especially NK1 for the substance P.

Other transmitters involved in the emetic stimuli are histamine, acetylcholine, endorphins, gamma-aminobutyric acid and cannabinoids.

Antiemetic therapy
With new anti-emetics, CINV are actually prevented in 70–80% of patients.[8]

Steroids
The mechanism of action is not completely known but they might affect the brain activity of prostaglandins, modify the blood-cerebro-spinal fluid barrier and inhibit cortical input to the vomiting centre.

No study supports the superiority of one corticosteroid over another in terms of efficacy.[9] Dexamethasone is the most extensively investigated.

Studies prove that steroids alone exert an anti-emetic effect in moderately emetic drugs but less effective against nausea and vomiting induced by cisplatin.[10,11,12]

Steroids increase the effectiveness of other anti-emetics therapies.

Dexamethasone administered within 24 hours prevents acute nausea and vomiting and allows a complete response (any vomiting, any rescue treatment) for 80 to 90% of patients receiving moderately emetic chemotherapy and 60 to 70% of patients receiving cisplatin-based chemotherapy.[13,14]

For delayed CINV, steroids remain very important and a meta-analysis shows the superiority of dexamethasone over the 5HT3 receptor antagonists.[15]

In association with Neurokinin[1] receptors antagonists, the dose of steroids should be reduced by 50% because of the inhibition of CYP3A4 by NK1 Receptors antagonists.[16]
Guidelines recommend 12mg of dexamethasone in case of high emesis risk and 8mg for moderate emesis risk.

5HT3 receptor antagonists (RA)
Five serotonin antagonists are available: ondansetron, granisetron, tropisetron, dolasetron and palonosetron. Many trials have compared two or more of the first four serotonin antagonists and no clinically significant differences were found.[17,18]

Studies have also shown that the lowest fully effective dose should be used. In fact, higher doses don’t increase efficiency because of receptor saturation. Oral and intravenous administrations are similarly effective. Single dose regimens are as effective as multiple dose regimens. Adverse effects of these agents are comparable.

On the basis of two meta-analyses which pooled five trials (serotonin antagonists versus placebo, 1716 patients) and five trials (dexamethasone + serotonin antagonists versus dexamethasone alone, 2240 patients), the Multinational Association for Supportive Care in Cancer (MASCC) and ASCO guidelines no longer recommend 5HT3-RAs for the prevention of delayed CINV in highly emetogenic chemotherapy. MASCC and ASCO guidelines recommend that dexamethasone should be the agent of choice and that 5HT3-RAs can be used as an alternative agent in the prevention of delayed nausea and vomiting induced by moderate emetogenic chemotherapy.

Palonosetron is a recent, strong and selective antagonist of 5HT3 receptors. Three main trials have compared palonosetron to others 5HT3-RAs.[19,20,21] These trials have shown at least equal efficiency and even superiority of palonesetron. But the results of these trials must be accepted with caution since the population was heterogeneous and patients did not receive the optimal anti-emetic treatment (only 0%, 5% and 63% of patients received dexamethasone in each study). Palonosetron was approved by US FDA for the prevention of both acute and delayed nausea and vomiting in patients treated with moderately emetogenic chemotherapy and for the prevention of acute emesis in patients treated with highly emetogenic chemotherapy but only for the prevention of acute symptoms by the European Agency for the Evaluation of Medicinal Products.

Neurokinin-1-receptor antagonists (RA) Aprepitant
Aprepitant is the first NK-1-RA. It is a potent selective, oral non-peptide antagonist of the NK1 receptor. It has been shown to cross the blood brain barrier.

The first trials evaluated the efficiency of aprepitant in prevention of nausea and vomiting induced by highly emetogenic chemotherapy. The results proved that aprepitant alone or in association with dexamethasone was inferior to 5HT3-RAs.[22,23,24] Thus, aprepitant cannot replace 5HT3-RAs in the prevention of acute NV induced by highly emetogenic chemotherapy. Conversely, aprepitant increases the efficiency of the association dexamethasone and 5HT3-RAs.[16,24,25] Furthermore, in these studies, aprepitant shows a very important activity against delayed CINV.

Subsequent studies have shown an increase of 9 to 21% of complete response rate in the prevention of acute and delayed nausea and vomiting induced by highly emetogenic chemotherapy and anthracyclin + cyclophosphamide-based regimens.[10,26,27,28] Studies from Poli-Bigelli and Hesketh justify aprepitant in prevention of CINV with high emesis risk while Warr shows its activity against CINV with moderate emesis risk.

The optimal dose and scheme was determined by Chawla[16] at 125mg for J1 and 80mg at J2 and J3 even if two phases II don’t shown any differences between unique administration of aprepitant the first day and administration from J1 to J5.

Aprepitant is a CYP3A4 substrate and an inducer of CYP2C9. So the effect of aprepitant on other drugs have been investigated.[29,30] When it is combined with aprepitant, a 2-fold increase in the area under concentration curve (AUC) of dexamethasone has been found.[16] Thus, the dose of dexamethasone should be reduced by approximately 50% with aprepitant. Some drugs (pimozid, tergenadin, astemizole, cisaprid) must not be associated because of prolongation of QT interval. Toxicity from ergoline derivates and irinotecan could be increased. The concentration of some molecules like warfarin, acetocoumarol or oral contraceptive pill might decrease in association with aprepitant so INR should be closely monitored and other contraceptives methods than the pill had to be discussed until two months after the last dose of aprepitant. Inhibitors of CYP3A4 (ritonavir, ketoconazole, clarithromycine, thelitromycine) might increase the concentration of aprepitant while inducer of CYP3A4 (rifampicin, phenytoin, carbamazepin, phenobarbital) might decrease it. About anticancer drugs, aprepitant doesn’t have any effect on Docetaxel[31] and intravenous Vinorelbine.[32]

Casopitant
Casopitant is a potent and selective NK-1-RA. Several trials have shown its efficacy against acute and delayed CINV with high and moderate emesis risk.[33,34] Recently its development has been stopped until additional data on its safety are known.

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Dopamine receptor antagonists

Dopamine receptor antagonists were among the first anti-emetic therapy but their efficacy as single agents is quite low.

Metoclopramide
Metoclopramide is a D2-antagonist with a central and peripheric action. At high doses, it is a serotonin antagonist.[35] Since the introduction of 5HT3-RAs, metoclopramide is no longer recommended in the prevention of delayed CINV. The role of metoclopramide is reserved for patients intolerant of or refractory to 5-HT3-RAs, dexamethasone and aprepitant and for the National Comprehensive Cancer Network it could be an option in the prevention of acute NVCI with low emesis risk. The usual recommended doses are 20–40 mg po q 4–6h or 2–3 mg/kg (high dose).

Metopimazine
Metopimazine is a phenothiazine derivate with antidopaminergic activity. It should be reserved for patients intolerant of 5-HT3-RAs, dexamethasone and aprepitant.[36]

Neuroleptics
The role of butyrophenones is limited to the treatment of breakthrough NVCI.[36]

Olanzapine is an atypical antipsychotic drug with potential anti-emetic properties due to its action at multiple receptor sites involved in the emesis control.[37] Olanzapine is efficacious and well tolerated in the treatment of chronic nausea related to opioids for pain in advanced cancer patients.[38] The combination of olanzapine + palonosetron + dexamethasone seems to be highly effective in the prevention of acute and delayed CINV.[39,40]

Benzodiazepines
Benzodiazepines can be useful for reduce anxiety and anticipatory nausea. It could be adjunct to anti-emetic prophylaxis especially in patients with refractory emesis in spite of optimal standard anti-emetic prophylaxis and treatment.[41]

Cannabinoids
Reports of decreased CINV in younger patients using marijuana support anti-emetic activity of cannabinoids. However their use is limited by side effects (dizziness, dysphoria).

Antihistamines
Antihistamines exert an effect against nausea mediated the vestibular system but they don’t have a role in the prevention of CINV.[42]

Herbs[43]
Ginger

The results of studies done with ginger in patients receiving chemotherapy are controversial. Any convincing efficacy has been shown but ginger might be an optional therapy for intractable nausea.

Peppermint
Peppermint acts as an internal calcium channel-blocking agent. Peppermint doesn’t have been evaluated in CINV.

Guidelines
MASCC,[44] ASCO,[18] NCCN[45] and ESMO[46] established guidelines for the prevention and treatment of CINV. In most cases, these recommendations are consistent and can be summarised in Table 1.

Combination of several anti-emetic agents becomes a standard in the prevention of CINV. With the association of NK-1-receptor antagonist, 5-HT3-RAs and dexamethasone vomiting can be prevented in 70 to 80 % of patients receiving highly emetogenic therapy. Prevention of emesis is a prioritry point and efforts should be made to ensure that optimal treatments designed into guidelines are applied in clinical practice.

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