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(5).

The American Society of Clinical Oncology has classified the cancer chemotherapeutic drugs in four categories of high, moderate, low, and minimal emetogenecity, depending on their emetogenic potential (Table I)(1,2).

Table I



Risk of Emesis with Chemotherapeutic Drugs and Recommended Treatment for Chemotherapy-induced 

Nausea and Vomiting(1)

Chemotherapeutic drugs can cause nausea and vomiting by several mechanisms. They act by causing irritation of the mucosal lining of the stomach and duodenum, which stimulates certain nerves that activate the vomiting center (VC) and the chemoreceptor trigger zone (CTZ) in the brain which leads to vomiting. They can also activate the CTZ by causing intestinal obstruction, delayed gastric emptying, or inflammation. Therefore, CINV involves coordination of several organs of the gastrointestinal tract, the peripheral and central nervous systems(5). Historically, there were only two neurotransmitter receptors (dopamine D2 and cannabinoid-1) that were the known targets for antiemetic therapy. Major advances in the management of chemotherapy-induced emesis were seen with the introduction of 5-hydroxytryptamine-3 receptor antagonists, which included ondansetron, tropisetron, dolasetron, and granisetron. However, these agents offer limited protection in the acute phase of chemotherapy-induced nausea and vomiting, with little or no effect over the delayed phase. Recently, selective inhibitors of substance P (Neurokinin1 (NK1) receptor antagonists) and also some newer 5-HT3 receptor antagonists have shown promising activity in the management of delayed phase of CINV(6). Among the NK1 receptor antagonists, aprepitant has been approved for the treatment of CINV. Currently, several other NK1 receptor antagonists, including casopitant, vestipitant, netupitant, and SCH619734 are undergoing clinical evaluation for the prevention of CINV in patients with a variety of malignancies.

The key to effective control of nausea and vomiting is to prevent it before it occurs whenever possible. That is why medicines for nausea and vomiting are started before the chemotherapy is given. Anti-emetic drugs may be used alone or in combination. The traditional drugs for management of CINV have been the dopamine antagonists (metoclopramide); steroids (dexamethasone), the 5-HT3 antagonists (ondansetron) and cannabinoids(5-7).

Short acting benzodiazepines including lorazepam (0.025-0.05 mg/kg) and midazolam (0.1 mg/kg) can act as adjuncts to treatment of CINV, especially anticipatory, by reducing anxiety and causing sedation.

In view of limited control of CINV by the traditional group of drugs, there was a need to discover newer and better drugs(8). The discovery of neurokinin 1 receptor antagonists, and also some newer 5-HT3 antagonists has led to a better control of CINV. This review highlights some of these drugs.

Aprepitant is the most widely studied and the most commonly used drug of all the NK1 receptor antagonists(8). Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic such as cisplatin by blocking substance P landing on receptors in the neurons. It was first approved by the FDA in 2003 as an oral antiemetic drug.

Pharmacokinetics: Aprepitant has an average bioavailability of 60-65% when consumed orally, with 95% of the drug being bound to plasma proteins. Its peak plasma concentration is achieved about 4 hours after administration and is mainly eliminated from body by phase I metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. The half-life ranged from approximately 9 to 13 hours. No dose adjustment is needed in renal disease or mild to moderate hepatic insufficiency (Child-Pugh score 5-9)(8,9).

Regimens and efficacy: It is mainly used as a preventive add-on drug for CINV. Many case series are available that prove the efficacy of aprepitant in the delayed phase of CINV, especially of the highly emetogenic chemotherapeutic group. Aprepitant is available commercially as capsules in bottles or blister pack (Emend, Merck, 125 mg and 80 mg capsules, INR 1150 for a pack of 3 capsules). It is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of Aprepitant is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg once daily in the morning on Days 2 and 3. Capsules can be stored at 20-25°C. Most of the aprepitant studies have been conducted in adult patients(10-15). A pilot, single-institution, randomized, double-blind, placebo-controlled trial by Herrington, et al.(15) found that in patients who were receiving palonosetron, aprepitant, and dexamethasone for highly emetogenic chemotherapy, a single dose of aprepitant displayed similar effectiveness compared with 3-day aprepitant. Only a few adolescent studies are available(16,17). A clinical regimen tried effectively in adolescents by Gore, et al.(17) is shown in Table II. Pediatric studies are required to establish the role of this drug in management of CINV.

Table II



Newer Regimen using Combination of Anti-emetic Drugs for CINV

Side effects and drug interactions: The main reported side effects of aprepitant are constipation, fatigue and diarrhea. In view of its induction of various enzymes, there is a possibility of drug interactions. Aprepitant may interfere with the metabolism of ifosfamide as it inhibits CYP3A4. A retrospective study of 45 patients conducted by Howell, et al.(18) has shown an increase in the incidence of neurotoxicity of ifosfamide with the concomitant use of aprepitant. It should not be used with cisapride and pimozide.

Fosaprepitant dimeglumine (MK-0517 or L-758,298), a prodrug of aprepitant, was developed to provide a parenteral alternative to the orally administered aprepitant(19, 20). Fosaprepitant is rapidly converted to aprepitant via the action of ubiquitous phosphatases. Based on equivalence studies, 115 mg fosaprepitant seems to be the substitute for 125 mg orally administrated aprepitant. Tolerability of the prodrug is no different from the active drug. In phase I and II trials, fosaprepitant shows efficacy, but most of the large randomized efficacy studies have utilized aprepitant. Fosaprepitant has recently been approved by FDA and EMEA as an intravenous substitute for oral aprepitant on day 1 of the standard 3-day CINV prevention regimen, which also includes dexamethasone and a 5-HT3 antagonist. 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 NK1 antagonist which is scheduled to be marketed having completed phase II and phase III trials(5). It can be administered orally or intravenously.

Palonosetron is different from conventional serotonin receptor antagonists as it has a longer half-life (40 hours) and also a higher affinity for serotonin receptors(21). It is the first agent in the class which is approved for preventing both delayed and acute emesis induced by moderately emetogenic chemotherapy.

In a study by Grunberg, et al.(22), 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. In another study by Grote, et al.(23) patients received a single intravenous dose of palonosetron (0.25 mg on day 1 of chemotherapy), along with 3 daily oral doses of aprepitant (125 mg on day 1, 80 mg on days 2 and 3) and dexamethasone (12 mg on day 1, 8 mg on days 2 and 3). The proportion of patients with complete response (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 5 days post chemotherapy. Multiple-day dosing of palonosetron plus dexamethasone was safe and effective for prevention of emesis induced by 5-day cisplatin-based chemotherapy. There was no evidence of cumulative toxicity when palonosetron was given three times over 5 days.

Palonosetron represents a useful addition to the therapeutic armamentarium for the management of chemotherapy-induced nausea and vomiting. Further studies are needed to assess the effectiveness of palonosetron in combination with dexamethasone compared with that of older serotonin receptor antagonists combined with dexamethasone, However, palonosetron may offer advantages of convenience over the short-acting older antagonists due to its ability to be given as a single intravenous dose prior to chemotherapy.

The choice of antiemetic drug to be used in a chemotherapy regimen should include not only the chemotherapeutic drug being used but also the possible patient characteristics and etiology of emesis. Emphasis should be on the primary prevention of CINV rather than its treatment. Further, 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, 24-48 hours of parenteral drugs may help to attain good control till such time that oral treatment can be instituted. Recommended antiemetic regimens for highly emetogenic chemotherapy include a 5-HT3 antagonist, and dexamethasone. (Table III). Moderately emetogenic chemotherapy requires a 5-HT3 antagonist or corticosteroid and the various drugs and their dose schedule is depicted in Table III. Options for treatment of refractory CINV include aprepitant, olanzapine, dronabinol, nabilone, gabapentin, and casopitant; however, their efficacy and safety needs to be established in pediatric cancer patients.

Table III



Dose and Schedule of Antiemetics used to Prevent Emesis Induced by Antineoplastic Therapy 

of High Emetic Risk (2)

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