Dr Pooja Dewan MBBS MD
Lecturer – Department of Pediatrics
University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India
Dr Preeti Dewan MBBS MD
Specialist Trainee Anaesthesia Frimley Park NHS Trust
Chemotherapy-induced nausea and vomiting (CINV) remain two of the most dreaded effects of cancer treatment. The consequences of not controlling the nausea and vomiting induced by cancer treatment in children not only leads to failure of compliance with treatment but also is distressing for parents and caregivers. It is therefore imperative to optimise chemotherapy, ensure minimum side effects and effectively prevent and treat CINV.1 Most of the published literature on CINV pertains to adults and standard recommendations on the use of anti-emetic therapy for CINV is hampered by the lack of robust evidence.
Pathophysiology of CINV2
Chemotherapeutic drugs trigger nausea and vomiting by multiple mechanisms. The most common is activation of the chemoreceptor trigger zone (CTZ) in the area postrema of the brain. Other mechanisms include peripheral stimulation of the gastrointestinal tract, vestibular mechanisms, cortical stimulation or alteration of taste and smell. Chemotherapeutic drugs induce the release of various neurotransmitters, namely dopamine, serotonin, histamine, norepinephrine, apomorphine, neurotensin, angiotensin-II, vasoactive intestinal peptide, gastrin, vasopressin, thyrotropin-releasing hormone, leucine, encephalin and substance P, whose receptors are located in the CTZ. Of these, 5HT and neurokinin receptors are particularly involved in chemotherapy-induced emesis.
CINV is broadly classified into five types – acute, delayed, breakthrough, refractory and anticipatory, depending upon the occurrence of vomiting in relation to the time of administration of chemotherapy.3 Vomiting occurring in the first 24 hours of administering chemotherapy is labelled as acute CINV. In the absence of effective prophylaxis, it usually begins within one to two hours of chemotherapy and peaks in the first four to six hours. Vomiting occurring later is called delayed CINV. Classically, this phenomenon was described with cisplatin. Nausea and vomiting occurring despite preventive therapy is termed breakthrough emesis. Rescue therapy is offered to such patients. Refractory emesis occurs when antiemetic prophylaxis or rescues both fail. Anticipatory emetic episodes are conditioned responses that can occur before, during or after the administration of chemotherapy, and may be triggered by taste, odour, sight, thoughts or anxiety secondary to a history of poor response to antiemetic agents, or inadequate antiemetic prophylaxis in the previous cycle of chemotherapy. It usually starts one to four hours before chemotherapy but can sometimes occur days before chemotherapy. An optimal anti-emetic regimen during the initial course of chemotherapy decreases the likelihood of anticipatory emesis with subsequent cycles.
Risk factors for CINV include patient gender (females >males), age (>3 years), past history of CINV, the emetogenic potential of the drug and administration schedule of chemotherapy. The acute emetogenicity of various chemotherapeutic drugs is categorised into five levels, as shown in Table 1.
Drugs for CINV4, 5
Historically, there were only two neurotransmitter receptors (dopamine D2 and cannabinoid-1) that were the known targets for antiemetic therapy. Until the mid-1970s, phenothiazines were the most commonly used anti-emetic agents for CINV. Major advances in the management of chemotherapy-induced emesis were seen with the introduction of 5-hydroxytryptamine-3 receptor antagonists (ondansetron, tropisetron, dolasetron, granisetron). Recently, selective inhibitors of substance P (neurokinin-1 [NK-1] receptor antagonists) and also some newer 5-HT3 receptor antagonists have shown promising activity in the management of the delayed phase of CINV. Among the NK-1 receptor antagonists, aprepitant has been approved for the treatment of CINV. Currently, several other NK-1 receptor antagonists, including casopitant, vestipitant, netupitant and SCH619734, are undergoing clinical evaluation for the prevention of CINV in patients with a variety of malignancies. Other emerging modalities include metopimazine, nabilone, olanzepine, diphenhydramine-lorazepam-dexamethasone combination and acupressure.
The prototype of dopamine receptor antagonist (D2 blocker) group of drugs is metoclopramide – other drugs being domperidone, haloperidol, chlorpromazine and prochlorperazine. At higher doses metoclopramide also acts as a serotonin receptor antagonist. Antiemetic efficacy with metoclopramide is slightly less than that seen with the selective serotonin receptor antagonists. Side effects include acute dystonic reactions, akathisia and sedation. Their current use is out of favour due to a tendency to cause extra pyramidal side effects. Domperidone may be preferred as it does not cross the blood–brain barrier and has a lesser risk of causing dystonias. Haloperidol is rarely used in children for CINV.
The early 1990s saw the emergence of serotonin 5-HT3 antagonists as a promising treatment for acute CINV. The first generation 5-HT3 antagonist agents are granisetron, ondansetron, dolasetron and tropisetron. They are highly selective agents sharing the same side-effect pattern, with mild headache, flushing and constipation being among the most commonly reported adverse events. In conjunction with steroids, they have been found to be very useful for the acute phase of CINV in moderate and high emetogenic schedules. They are effective orally as well as parenterally, the effective dose being 5mg/m2 or 0.15mg/kg for ondansetron (maximum dose: 8mg); 1.8mg/kg or 45mg/m2 for dolasetron; 0.2mg/kg or 5mg/m2 for tropisetron; and 30–40mg/kg/day IV or oral for granisetron. A single-dose schedule is recommended. Oral doses are believed to be as effective as parenteral doses, although schedules have been established based upon intravenous administration. Several trials evaluating 5-HT3 receptor antagonists in children have been done, however it is not clear if any one of these agents provides superior antiemetic control in children compared with other drugs in the same class. Paediatric experience is highest with ondansetron and granisetron.
Berrak et al. reported granisetron when administered in two different doses – 10mg/kg and 40mg/kg intravenously to have a comparable efficacy in controlling carboplatin-induced acute and delayed nausea/emesis in children and young adults.6 Granisetron is also reported to be safer and more efficient than metoclopramide plus dimenhydrinate for controlling chemotherapy-induced emesis and nausea in children with osteosarcoma.7
Tropisetron has been used orally or intravenously in children receiving in a dose of 0.2mg/kg (5mg/m2). When used as monotherapy in children receiving highly emetogenic chemotherapy, tropisetron was found to be less effective in controlling nausea and vomiting compared to granisetron or ondansetron.8
Dolasetron can be given orally or intravenously in a dose of 1.8mg/kg (45mg/m2).9,10 It is not clearly established whether a single daily dose is better than divided doses, or if the oral route is as effective as intravenous administration in children. When used in conjunction with dexamethasone in children receiving highly emetic chemotherapy, no single first-generation 5-HT3 receptor antagonist has proven superior to the other. Thus, the choice of first-generation 5-HT3 receptor antagonist should be based upon the cost and availability of the drug.
Palonosetron is a second-generation 5-HT3 receptor antagonist and has a longer half-life (40 hours) compared to the other first-generation 5-HT3 receptor antagonists. It is more effective for both acute and delayed emesis resulting from chemotherapy when compared with ondansetron or granisetron. A single daily dose of 3mg/kg as well as 10mg/kg has been found to be effective and well tolerated in children for CINV in two separate clinical trials in children receiving highly emetogenicy chemotherapy.11 Palonosetron in paediatric cancer patients was found to be safer, more effective and more cost effective than ondansetron.12
Palonosetron has been used extensively in adults and adolescents. A single-dose regimen of palonosetron in combination with dexamethasone and aprepitant was found highly effective in preventing acute and delayed emesis following administration of moderately emetogenic chemotherapy. Patients received a single intravenous dose of palonosetron (0.25mg on day 1 of chemotherapy), along with three daily oral doses of aprepitant (125mg on day 1, 80mg on days 2 and 3) and dexamethasone (12mg on day 1, 8mg on days 2 and 3). The proportion of patients with complete response (CR; no emesis and no rescue medication) was 88% during the acute (0–24 hours) interval, 78% during the delayed (>24–120 hours) interval and 78% during the overall (0–120 hours post chemotherapy) interval. More than 90% of patients during all time intervals had no emetic episodes, and between 57% and 71% of patients reported no nausea during each of the five days post chemotherapy. Multiple-day dosing of palonosetron plus dexamethasone was safe and effective for prevention of emesis induced by five-day cisplatin-based chemotherapy. There was no evidence of cumulative toxicity when palonosetron was given three times over five days.13
According to the Cochrane review on the efficacy of different serotonin receptor antagonists in the control of acute and delayed emesis induced by highly emetogenic chemotherapy in adults, ondansetron and granisetron appear to be equivalent drugs.14 According to one single trial, the combination of palonosetron and dexamethasone was superior to granisetron and dexamethasone in controlling delayed emesis. However, more evidence is needed before palonosetron could become the candidate 5-HT3 RA for the control of delayed emesis induced by highly emetogenic chemotherapy.14
Corticosteroids have a high therapeutic index when used to prevent chemotherapy-induced emesis. They are among the most frequently used antiemetics. The American Society of Clinical Oncology has proposed its single-agent use in patients receiving chemotherapies of low-emetic potential. They are given in combination with serotonin receptor antagonists in patients receiving highly emetogenic chemotherapy.15 Single doses of corticosteroids, dexamethasone (0.05mg/kg–0.2mg/kg or 12mg/m2) and methylprednisolone (100mg/m2), are recommended for acute emesis and for delayed emesis they may be given 12-hourly for two to three days. Corticosteroids act by decreasing inflammatory effects on intestinal mucosa, blocking 5-HT3 release and by decreasing the permeability of the blood–brain barrier. Adverse effects of single dexamethasone doses are rare, although elevations of serum glucose levels, epigastric burning, physical and verbal aggression, prolonged periods of inconsolability and insomnia have been reported. There are also concerns over the use of dexamethasone as an antiemetic in paediatric brain tumour patients as corticosteroids may reduce penetration of chemotherapeutic drugs by repairing the blood–brain barrier.
Neurokinin-1 receptor (substance P) antagonists
Among the drugs in this category, aprepitant and its intravenous counterpart fosaprepitant are the only ones currently being marketed. Currently, the recommendations of their use in children are lacking due to the paucity of studies documenting their use in children. However, in adults receiving highly emetic chemotherapy, their use is recommended in conjunction with 5-HT3 antagonists and dexamethasone.
Aprepitant is the most widely studied and the most commonly used drug of all the NK-1 receptor antagonists. Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutics such as cisplatin by blocking substance P landing on receptors in the brain’s neurons. It was first approved by the FDA in 2003 as an oral antiemetic drug.
Aprepitant has an average bioavailability of 60%–65% when consumed orally, with 95% of the drug being bound to plasma proteins. Its peak plasma concentrations are achieved about four hours after administration and is mainly eliminated from the body by phase I metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4, with minor metabolism by CYP1A2 and CYP2C19. The apparent terminal half-life ranged from approximately nine to 13 hours. No dose adjustment is needed in renal disease or mild to moderate hepatic insufficiency (Child-pugh grade 5–9).
It is given for three days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of aprepitant is 125mg orally one hour prior to chemotherapy treatment (day 1) and 80mg once-daily in the morning on days 2 and 3. Capsules can be stored at 20°C–25°C. Most of the aprepitant studies have been confined to adult patients. Only a few adolescent studies are available. In a study, adolescents receiving emetogenic chemotherapy were randomised into two groups such that one group received aprepitant triple therapy (aprepitant [A] 125mg po, dexamethasone [D] 8mg po and ondansetron [O] 0.15mg/kg IV tid day 1; A 80mg, D 4mg and O 0.15mg/kg tid day 2; A 80mg and D 4mg day 3; and D 4mg day 4) or the other group received (D 16mg and O 0.15mg/kg tid day 1; D 8mg and O 0.15mg/kg tid day 2; and D 8mg days 3 and 4). Febrile neutropenia was more frequent in the aprepitant group (25% vs 11.1%). CR rates were 35.7% for aprepitant triple therapy versus 5.6% for the control group.13 Paediatric studies are required to establish the role of this drug in management of CINV.
The main reported side effects of aprepitant are constipation, fatigue and diarrheoa. In view of its induction of various enzymes, there is a possibility of a drug reaction taking place. Aprepitant may interfere with the metabolism of ifosfamide as it inhibits CYP3A4, thereby increasing the incidence of neurotoxicity of ifosfamide. It should not be used with cisapride and pimozide. Since the trials of aprepitant in children are lacking, most oncologists reserve its use to children older than 12 years or weighing ≥40kg, receiving highly emetic chemotherapy. It should be administered in conjunction with a 5-HT3 receptor antagonist and dexamethasone.
Fosaprepitant dimeglumine (MK-0517 or L-758,298), a prodrug of aprepitant, is an intravenous substitute for oral aprepitant on day 1 of the standard three-day CINV prevention regimen, which also includes dexamethasone and a 5-HT3 antagonist. Based on equivalence studies, 115mg fosaprepitant seems to be the substitute for 125mg orally administered aprepitant. Side effects are similar to aprepitant with the addition of mild venous irritation and headache. Further studies are needed to clarify the utility of fosaprepitant in the prevention of CINV and to clarify optimal dosing regimens that may be appropriate substitutes for oral aprepitant. It is not yet available commercially.
It is a novel NK-1 antagonist which is scheduled to be marketed, having completed phase II and phase III trials. It may be administered orally or intravenously.
Quick- and short-acting benzodiazepines like lorazepam (0.025mg/kg–0.05mg/kg) and midazolam (0.1mg/kg) are valuable adjuncts to treatment of CINV, especially anticipatory, by reducing anxiety and causing sedation.
Studies on the use of cannabinoids both as plant extracts (dronabinol) and as semisynthetic agents (nabilone and levonantradol) for CINV in children are limited. They have weak to modest antiemetic efficacy, which is generally superior to metochlopramide or prochlorperazine, and they have been tried effectively for anticipatory emesis. Their use is associated with unpleasant side effects including dizziness, drowsiness and mood alteration. Nabilone is a newer antiemetic tried in adolescents and older children who are receiving refractory to standard therapy with a 5-HT3 receptor antagonist and a corticosteroid. Nabilone is typically given twice-daily owing to its long duration of action (eight–12 hours). The usual daily dosage of nabilone is 1mg–2mg bid, with the first dose given one to three hours before administration of chemotherapy – the maximum recommended daily dosage is 6mg daily divided bid or tid. Similar to several medications, there is a therapeutic window for nabilone, at which maximum benefit is obtained without intolerable side effects. Thus, treatment should be initiated with the lowest starting dose, and the dose should be increased based on patient response to minimise side effects. Patients often benefit from one dose the evening before chemotherapy, and another dose one to three hours pre-chemotherapy.
Cyclizine is antihistaminic and anticholinergic and is used as an adjunct to 5-HT3 receptor blockers. Its use in breakthrough CINV is limited by its eight-hour dosage interval. Side effects include dizziness and sedation. It should not be prescribed along with a prokinetic drug like metoclopramide.
Phenothiazines like prochlorperazine, chlorpromazine and levomepromazine are effective antiemetics with antagonist effects on dopamine (D1), histamine (H1), cholinergic and dopamine (5-HT2) receptors. Of these levomepromazine is promising due to its wide spectrum of effects and may be used where CINV has not responded to other drugs.
Some other drugs being used in adults for CINV but not yet used in children include olanzapine, gabapentin, midazolam and mirtazapine. Further research is needed before trials in children can begin.
Despite the advances in the pharmacological armamentarium for CINV, traditional therapies like acupressure and acupuncture continue to remain popular. The P6 acupressure point above the wrist has been a component of traditional Chinese medicine. Cochrane systematic reviews assessing P6 stimulation for chemotherapy-induced nausea and vomiting showed 11 trials and more than 1,200 patients.16 Electroacupuncture, but not manual acupuncture, was beneficial for first-day vomiting. Acupressure was effective for first-day nausea but not vomiting. Wristwatch-like electrical devices were not effective for any outcome. Studies in children are lacking due to poor acceptance of this method in children.
Recommendations for preventing CINV
The choice of antiemetic drug to be used in a chemotherapy regimen should include not only the chemotherapeutic drug being used but also consideration of the possible patient characteristics and aetiology of emesis. Emphasis should be given to the primary prevention of CINV rather than its treatment. Furthermore, the selection of the route of administration needs to be proper, as oral drugs may be ineffective in a child who is vomiting actively. Therefore, 24 to 48 hours of parenteral drugs may help to attain good control until such time that oral treatment can be instituted. Recommended antiemetic regimens for highly emetogenic chemotherapy include a 5-HT3 antagonist and dexamethasone. Moderately emetogenic chemotherapy requires a 5-HT3 antagonist or corticosteroid and the various drugs and their dose schedule is shown in Table 2. Options for treatment of refractory CINV include aprepitant, olanzapine, dronabinol, nabilone, gabapentin and casopitant but their efficacy and safety needs to be established in paediatric cancer patients. Until more such studies are done and further evidence on their efficacy and safety in children becomes available, paediatric oncologists will have to rely on results available from studies in adult cancer patients.
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