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Management of Chemotherapy-Induced Nausea and Vomiting R E V I E W A R T I C L E Management of Chemotherapy-Induced Nausea and Vomiting POOJA D EWAN, SWATI SINGHAL* AND DEEPIKA HARIT From Department of Pediatrics, UCMS and GTB Hospital, Delhi 110 095; and *Department of Pediatrics, Maulana Azad Medical College, Delhi 110 001; India. Correspondence to: Dr Pooja Dewan, DII/65, Kaka Nagar, Dr Zakir Hussain Marg, New Delhi 110 003, India. [email protected] Context: Chemotherapy-induced nausea and vomiting (CINV) is a significant problem in the treatment of children with cancer. The last decade has seen a variety of newer antiemetics being evaluated for CINV; their efficacy and side-effects need to be assessed in children. This article attempts to highlight this revised management of CINV. Evidence acquisition: Online search; journals. Search period: 6 months. Results: Newer drugs (aprepitant, fosapritant and newer 5HT3 antagonists) have been found to be effective in CINV: both acute and delayed phases. Most of the available literature is, however, based on adult oncology patients, with a few trials on adolescent patients. Conclusion: Every child receiving treatment for cancer should be evaluated for possible CINV. Their treatment should take into account the emetogenic potential of the chemotherapeutic drugs. Newer antiemetic drugs have good efficacy and can be tried in pediatric patients, especially in children > 11 years of age. Keywords: Antiemetics, Cancer, Chemotherapy, Nausea, Vomiting. hemotherapy is a common modality tears, and anxiety, it is imperative to provide for treatment of cancer. Regardless prophylaxis and treatment for CINV. of the fact that chemotherapy improves CLASSIFICATION Csurvival; it has its own toxicity and side- effects, which have a negative impact on the quality Chemotherapy-induced nausea and vomiting of life of children with cancer. Severe side-effects, (CINV) is broadly classified into acute, delayed or and non-compliance because of those side-effects, anticipatory type depending upon the time period of can lead to loss of time at school for the child, loss vomiting(2). Vomiting occurring in the first 24 of time at work for the caregiver, and additional hours of administering chemotherapy is labeled as office visits to the doctor; all of which contribute acute CINV and in the absence of effective both to death and disability, and to the annual costs prophylaxis, it most commonly begins within one to of cancer. It is therefore imperative to optimize two hours of chemotherapy and usually peaks in the chemotherapy and ensure minimum side-effects. first four to six hours. Vomiting occurring later is Nausea and vomiting continue to be significant called delayed CINV. Classically, this phenomenon side-effects of cancer therapy and can affect patient was described with cisplatin. While the frequency compliance(1). To avoid the clinical sequelae of and number of episodes of emesis may be less chemotherapy-induced nausea and vomiting during the delayed period compared to acute (CINV) like malnutrition, dehydration, emesis, the delayed form is less well controlled with dyselectrolytemias, anorexia, stress, esophageal current antiemetic medications. Anticipatory INDIAN PEDIATRICS 149 VOLUME 47__FEBRUARY 17, 2010 DEWAN, et al. CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING emetic episodes are triggered by taste, odor, sight, the chemoreceptor trigger zone (CTZ) in the brain thoughts, or anxiety secondary to a history of poor which leads to vomiting. They can also activate the response to antiemetic agents or inadequate CTZ by causing intestinal obstruction, delayed antiemetic prophylaxis in the previous cycle of gastric emptying, or inflammation. Therefore, chemotherapy. It usually starts 1 to 4 hours before CINV involves coordination of several organs of chemotherapy but can sometimes occur days before the gastrointestinal tract, the peripheral and central chemotherapy(3,4). nervous systems(5). Historically, there were only two neurotransmitter receptors (dopamine D2 and PREDISPOSING FACTORS cannabinoid-1) that were the known targets for antiemetic therapy. Major advances in the Risk factors for CINV include patient gender management of chemotherapy-induced emesis (females >males), age (>3 years), past history of were seen with the introduction of 5- CINV, the emetogenic potential of the drug, and hydroxytryptamine-3 receptor antagonists, which administration schedule of chemotherapy(5). included ondansetron, tropisetron, dolasetron, and The American Society of Clinical Oncology has granisetron. However, these agents offer limited classified the cancer chemotherapeutic drugs in protection in the acute phase of chemotherapy- four categories of high, moderate, low, and minimal induced nausea and vomiting, with little or no effect emetogenecity, depending on their emetogenic over the delayed phase. Recently, selective potential (Table I)(1,2). inhibitors of substance P (Neurokinin1 (NK1) receptor antagonists) and also some newer 5-HT3 PATHOPHYSIOLOGY receptor antagonists have shown promising activity in the management of delayed phase of CINV(6). Chemotherapeutic drugs can cause nausea and Among the NK1 receptor antagonists, aprepitant vomiting by several mechanisms. They act by has been approved for the treatment of CINV. causing irritation of the mucosal lining of the Currently, several other NK1 receptor antagonists, stomach and duodenum, which stimulates certain including casopitant, vestipitant, netupitant, and nerves that activate the vomiting center (VC) and SCH619734 are undergoing clinical evaluation for TABLE I RISK OF EMESIS WITH CHEMOTHERAPEUTIC DRUGS AND RECOMMENDED TREATMENT FOR CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING(1) Emetic Risk Chemotherapeutic Drug Anti-emetic Schedule High (> 90%) Cisplatin, Mechlorethamine, Streptozotocin, 5-HT3 serotonin Dacarbazine, Carmustine, Dactinomycin receptor antagonist: Day 1 Cyclophosphamide (>1500 mg/m2) Dexamethasone: Days 1-4 Aprepitant: Days 1-3 2 Moderate (30 to 90%) Oxaliplatin, Cytarabine (> 1000 mg/m ), Carboplatin, 5-HT3 serotonin Ifosfamide, Cyclophosphamide < 1500 mg/m2, receptor antagonist: Day 1 Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Dexamethasone: Day 1 (2, 3)* Irinotecan (Aprepitant: Days 1, 2, 3) Low (10% to 30%) Paclitaxel, Docetaxel, Mitoxantrone, Topotecan, Dexamethasone: Day 1 Etoposide, Pemetrexed, Methotrexate, Mitomycin, Gemcitabine, Cytarabine (< 1000 mg/m2), Fluorouracil, Bortezomib, Cetuximab, Trastuzumab Minimal (< 10%) Bevacizumab, Bleomycin, Busulfan, Fludarabine, Prescribe as needed Vincristine, Vinorelbine, Vinblastine, 2-Chlorodeoxyadenosine, Rituximab * May omit days 2 and 3 if aprepitant is given; for patients receiving a combination of an anthracycline and cyclophosphamide. INDIAN PEDIATRICS 150 VOLUME 47__FEBRUARY 17, 2010 DEWAN, et al. CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING the prevention of CINV in patients with a variety of Serotonin (5-HT3) Antagonists malignancies. The traditional 5-HT3 antagonist agents are TRADITIONAL DRUGS FOR CINV MANAGEMENT granisetron, ondansetron, and tropisetron. They are highly selective agents sharing the same side-effect The key to effective control of nausea and vomiting pattern, with mild headache, flushing, and is to prevent it before it occurs whenever possible. constipation, being among the most commonly That is why medicines for nausea and vomiting are reported adverse events. In conjunction with started before the chemotherapy is given. Anti- steroids, they have been found to be very useful for emetic drugs may be used alone or in combination. the acute phase of CINV in association with The traditional drugs for management of CINV moderate and high emetogenic schedules. They are have been the dopamine antagonists effective orally as well as parenterally, the effective (metoclopramide); steroids (dexamethasone), the 5- dose being 5 mg/m2 for Ondansetron (maximum HT3 antagonists (ondansetron) and dose: 8 mg). Dolasetron is another effective drug cannabinoids(5-7). though not yet established for pediatric use. Dopamine antagonists Benzodiazepines The prototype of dopamine receptor antagonist Short acting benzodiazepines including lorazepam group of drugs is metoclopramide; other drugs (0.025-0.05 mg/kg) and midazolam (0.1 mg/kg) can being domperidone, haloperidol, chlorpromazine, act as adjuncts to treatment of CINV, especially and prochlorperazine. At higher doses, anticipatory, by reducing anxiety and causing metoclopramide also acts as a serotonin receptor sedation. antagonist. Antiemetic efficacy with metoclopra- mide is slightly less than that seen with the selective Others serotonin receptor antagonists. Side-effects include Cannabinoids, both as plant extracts (dronabinol) acute dystonic reactions, akathisia, and sedation. Domperidone does not cause dystonia as it does not and as semisynthetic agents (nabilone and levonantradol), have been found to have antiemetic cross the blood brain barrier. Haloperidol is rarely used in children for CINV. activity when used alone or in combination with other agents. These agents cause frequent dizziness, Corticosteroids sedation, hypotension, and dysphoria, especially in older adults. Dexamethasone (0.05-0.2 mg/kg) and methylprednisolone (100 mg/m2) have a high In view of limited control of CINV by the therapeutic index when used to prevent traditional group of drugs, there was a need to chemotherapy-induced emesis. They are among the discover newer and better drugs(8). The discovery most frequently used antiemetics. The American of neurokinin 1 receptor antagonists, and also some
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