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CHEMOTHERAPY-INDUCED NAUSE and VOMITING

CHEMOTHERAPY-INDUCED NAUSE and VOMITING. Doç. Dr. AHMET SELİM YURDAKUL Gazi University Faculty of Medicine Department of Pulmonary Medicine. CHEMOTHERAPY-INDUCED NAUSE and VOMITING. Importance of control of nause and vomiting Pathophysiology of nause and vomiting

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CHEMOTHERAPY-INDUCED NAUSE and VOMITING

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  1. CHEMOTHERAPY-INDUCED NAUSE and VOMITING Doç. Dr. AHMET SELİM YURDAKUL Gazi University Faculty of Medicine Department of Pulmonary Medicine

  2. CHEMOTHERAPY-INDUCED NAUSE and VOMITING • Importance of control of nause and vomiting • Pathophysiology of nause and vomiting • Clinical features of nause and vomiting • Treatment approach of nause and vomiting • Future treatments of nause and vomiting

  3. Nause and vomiting are common side effects for patients treated systemic chemotherapy (70-80 %). • Approximately, half of patients refuse of systemic chemotherapy because of side effects. • 10-44% of these patients are “Anticipatory emesis”. • Patients treated systemic chemotherapy are risked for 5 days. Morrow GR. Chemotherapy-related nausea and vomiting:etiology and management. Cancer J Clin 1989;39:89-104. Morran C, Smith DC, Anderson DA, et al. Incidence of nausea and vomiting with cytotoxic chemotherapy: A prospective random­ized trial of antiemetics. Br Med J 1979;1:1323-4. Jenns K. Importance of nause. Cancer Nurs 1994;17:488-93.

  4. Acute vomiting Delayed vomiting

  5. Importance of control of nause and vomiting • It effects patients’ quality of life. • The compliance of treatment was decreased. • It causes metabolic changes. • It effects functional and intelligence capacity of patients. • It causes anorexia and nutritional deficiency. • Aspiration pneumonia and oesophagus damage might be seen. • Effective chemotherapy treatments were discontinued because of this side effect.

  6. Pathophysiology of nause and vomiting

  7. Higher central nervous system centers 5-HT Amygdala 5-HT3 receptor Medulla Third route Vagus nerve Second route AP NTS CTZ Chemotherapy VC First route Enterochromaffin cells Small Intestine Vagal afferents

  8. Receptors stimulated by chemotherepy drugs and their metabolities Dopamine Serotonin Histamine Emetic Reflex Substance P acetylcholine GABA Cannabinoids Norepinephrine, Apomorphine Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43. Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

  9. Higher central nervous system centers 5-HT Amygdala 5-HT3 receptor Medulla Third route Vagus nerve Second route • CTZ • 5-HT3 receptors • NK1 receptors • Dopamine receptors AP NTS CTZ • VC • 5-HT3 receptors • NK1 receptors • Dopamin ereceptors Chemotherapy VC First route Enterochromaffin cells Small Intestine Vagal afferents

  10. Carpenter DO. Neural mechanisms of emesis. Can J Physiol Pharmacol 1990;68:230-6. Miller AD, Nonaka S, Jakus J.Brain areas essential or non-essential for emesis. Brain Res1994;647:255-64. Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43. Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

  11. Etiologies of nause and vomiting • Chemotherapy • Radiotherapy • Cranial metastasis • Drugs (Opiates etc.) • Metabolic disorders (hypercalcemia, hyperglycemia, hyponatremia) • Uremia • Psychogenic causes (Anxiete, anticipatory emesis) • Intestinal obstruction • Vestibular function disorders Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

  12. CHEMOTHERAPY-INDUCED EMESIS • Acute emesis • Delayed emesis • Anticipatory emesis • Breakthrough emesis • Refractory emesis Herrstedt J. Antiemetics:an update andthe MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43.

  13. Type of Emesis Acute emesis Acute emesis occurs within 0-24 hours after chemotherapy administration Delayed emesis Delayed emesis occurs 24 or more hours after chemotherapy administration Anticipatory emesis Anticipatory emesis (conditioned emesis) occurs before chemotherapy administration Breakthrough emesis Breakthrough emesis occurs despite of prophylactic treatment and we must provide additional therapy. Refractory emesis Refractory emesis occurs among patients who have experienced unsuccessful control of emesis during previous courses of chemotherapy

  14. CHEMOTHERAPY-INDUCED NAUSE and VOMITINGPrognostic Factors • Chemotherapy related • Route/rate/frequency of administration • Dose • Drug combination emetogenicity Patient related • Effects of prior exposure to chemotherapy • Pretreatment anxiety • Depression • Female gender • Motion sickness • Low alcohol intake • Age (<30years old) • Various tastes and odors HainsworthJD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

  15. Emetic Risk of Chemotherapeutic Agents • High risk > 90% • Moderate risk 30-90% • Low risk 10-30% • Minimal risk < 10% incidence of emesis Hesketh PJ, Kris MG, Grunberg SM. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103-9. NCCN antiemesis guidline-2008

  16. Cisplatin ≥ 50 mg/m2 Carmustine >250 mg/m2 Cyclophosphamide >1500 mg/m2 Dacarbazine Mechlorethamine Procarbazine (oral) Streptozotocin Altretamine High Emetic Risk (>90%) of Chemotherapeutic Agents NCCN antiemesis guidline-2008

  17. - - - - Chclophosphamide/Carpoplatine • Cisplatin Severity of emesis 1 2 3 4 5 DAYS

  18. Carboplatin Cisplatin< 50mg/m2 Cyclophosphamide ≤ 1500 mg/m2 Cyclophosphamide (oral) Doxorubicine Etoposide (oral) İfosfamide İrinotecan Methotrexate 250-1000 mg/m2 Oxaliplatin > 75 mg/m2 Vinorelbine (oral) Moderate Emetic Risk (30-90%) of Chemotherapeutic Agents NCCN antiemesis guidline-2008

  19. Docetaxel Doxorubicine (lipozomal) Etoposide 5-Fluorouracil Gemcitabine Mitomycin Paclitaxel Pemetrexed Topotecan Methotrexate 50-250 Low Emetic Risk (10-30%) of Chemotherapeutic Agents NCCN antiemesis guidline-2008

  20. Bevacizumab Bleomycin Cetuximab Vinblastine Vincristine Vinorelbine Erlotinib Gefitinib Fludarabine Talidomid Rituximab Minimal Emetic Risk (<10%) of Chemotherapeutic Agents NCCN antiemesis guidline-2008

  21. Treatment of chemotherapy-induced nause and vomitting • Antiemetic drugs prevent nause and vomiting by blocking different neural networks and preventing emetic stimuli on different points. • There is no single agent preventing all stages of chemotherapy-induced nause and vomiting. • Antiemetic drugs block the different receptors when they are used properly doses. • Combination of antiemetic drugs is more effective than single agent.

  22. Treatment of chemotherapy-induced nause and vomitting Highest therapeutic index 5-HT3 receptor antagonists NK-1 (neurokinin-1) receptor antagonists Corticosteroids Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73. Kris MG, Hesketh PJ, Herrstedt J, et al. Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic risk chemotherapy. Support Care Cancer 2005;13:85-96.

  23. Treatment of chemotherapy-induced nause and vomitting Lower therapeutic index • Metoclopramide • Phenothiazines (Proclorperazine, promethazine) • Butyrophenones (Haloperidol, droperidol) • Cannabinoids (Dronabinol, Nabilone) Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73. Kris MG, Hesketh PJ, Herrstedt J, et al. Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic risk chemotherapy. Support Care Cancer 2005;13:85-96.

  24. Treatment of chemotherapy-induced nause and vomitting Adjunctive Drugs • Benzodiazepines (Lorazepam) • Antihistamines Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73. Kris MG, Hesketh PJ, Herrstedt J, et al. Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic risk chemotherapy. Support Care Cancer 2005;13:85-96.

  25. (5-HT3) Serotonin receptor antagonists Single dose before chemotherapy • Ondansetron → oral 16-24 mg İV 8 mg or 0.15 mg/kg • Granisetron → oral 2 mg İV 1 mg or 0.01 mg/kg • Dolasetron → oral 100 mg İV 100 mg or 1.8 mg/kg • Tropisetron → oral or İV: 5 mg • Palonosetron → İV: 0.25 mg Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43. Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

  26. (5-HT3) Serotonin receptor antagonists • (5-HT3) serotonin receptor antagonists have equivalent efficacy and safety. • Oral or IV form of (5-HT3) serotonin receptor antagonists have equivalent efficacy. • Side effects -Mild headache -Transient elevation serum aminotreansferases -Constipation • Combination with corticosteroids increased their efficacy. • (5-HT3) serotonin receptor antagonists are not effective for preventing delayed emesis (except palonosetron) Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43. Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

  27. (5-HT3) Serotonin receptor antagonists Palonosetron • Second generation (5-HT3) serotonin receptor antagonist • It is longer serum half-life (40 hour) and higher binding affinity to the (5-HT3) serotonin receptor. • It is effective for the prevention delayed emesis Gralla RJ et alAnn Oncol 14:1570-77, 2003 Eisenberg P et al.Ann Oncol 15: 330-337, 2004 Aapro MS et al.Ann Oncol 17:1441-449, 2006

  28. Pathophysiology of nause and vomiting • PET studies in humans demonstrated that substance P (SP) and neurokinin-1 (NK1) receptor were located in the central of brainstem and substance P (SP) is a neurotransmitter and neuromodulator that mediates vomitting reflex in the brain predominantly via the neurokinin-1 receptors (NK1Rs). Hargreaves R. Imaging substance Preceptors (NK1) in the living human brain using positron emission tomography. J Clin Psyc 2002;63:18-24.

  29. NK1 (neurokinin-1) receptor antagonist Aprepitant • The effect of aprepitant is blockade of NK1 receptors. • Aprepitant is effective for the prevention acute and delayed emesis. • Aprepitant increased the antiemetic effect of seratonin receptor antagonist and steroids. Jardon K, et al. The Oncologist 12:1143–50, 2007

  30. NK1 (neurokinin-1) receptor antagonist Aprepitant • Drugs interaction! (cytochrome p450 enzyme CYP3A4) • Terfenadine, astemizole and cisapride are not used with aprepitant. • Aprepitant inhibits the effect of coumadin and oral contraceptive and induces the effect of steroids. NCCN Clinical Practice Guidelines in Oncology: Antiemesis, 2008

  31. NK1 (neurokinin-1) receptor antagonists • Aprepitant (Emend): 125 mg PO before chemotherapy, 80 mg PO second and third days. • Fosaprepitant (Emend):İV dose: 115 mg before chemotherapy.

  32. Before Chemotherapy With Aprepitant İV dose: 12 mg, PO dose: 12 mg b) WithoutAprepitant İV dose: 20 mg, PO dose: 20 mg After Chemotherapy With Aprepitant PO dose: 8 mg 2th-4th days b) WithoutAprepitant PO dose: 8 mg 2x1 2th-4th days Corticosteroids

  33. Recommendation for antineoplastic therapy of high emetic risk (> 90%) MASCC: Multinational Association of Supportive Care in Cancer ASCO: American Society of Clinical Oncology NCCN: National Comprehensive Cancer Network

  34. Recommendation for antineoplastic therapy of moderate emetic risk (30%-90%) MASCC: Multinational Association of Supportive Care in Cancer ASCO: American Society of Clinical Oncology NCCN: National Comprehensive Cancer Network

  35. Recommendation for antineoplastic therapy of low emetic risk (10%-30%) MASCC: Multinational Association of Supportive Care in Cancer ASCO: American Society of Clinical Oncology NCCN: National Comprehensive Cancer Network

  36. Recommendation for antineoplastic therapy of minimal emetic risk (<10%) MASCC: Multinational Association of Supportive Care in Cancer ASCO: American Society of Clinical Oncology NCCN: National Comprehensive Cancer Network

  37. Anticipatory Emesis • Anticipatory emesis occurs in patients who have had poor control of vomitting with prior chemotherapy and a history of motion sickness predisposes patients to anticipatory emesis. • The most effective method for preventing anticipatory emesis was to apply optimal effective antiemetic therapy during the chemotherapy treatment • Behavioral therapy • Relaxation, Hypnoz • Music therapy, Acupuncture • Alprazolam 0.5-2 mg before treatment • Lorazepam 0.5-2 mg before treatment Laszlo J, ClarkRA, Hanson DC, Tyson L, Crumpler L, Gralla R. Lorazepam in cancer patients treated with cisplatin: A drug with antiemetic amnesic, and anxiolytic effects . J Clin Oncol 1985;3:864-9. Morrow GR. Prevalence and correlates of anticipatory nausea and vomiting in chemotherapy patients. J Natl Cancer Inst 1982;68:585-8.

  38. Refractory Emesis • Evaluate antiemetic agents, chemotherapy drugs, tumour status, risk factors, concurrent disease, other drugs. • Check the antiemetic therapy whether the best regimen is being administered for the emetic setting, or not. • Consider adding lorazepam to the regimen. • Consider treating the patients with dopamine antagonist (Metoclopramide) instead of 5-HT3 receptor antagonist therapy. • Evaluate the antiemetic therapy carefully for the patients treated with chemotherapy and radiotherapy, because the risk of emesis is increased in these patients.

  39. “New” Antiemetic drugs • CASOPITANT • OLANZAPINE • GABAPENTIN Arpornwirat W, et al. ASCO 24:471s (ab.8512) 2006 Navari RM, et al. Support Care Cancer 13:529-34,2005 Guttuso T, et al. Lancet 361:1703-05, 2003 Rudd JA et al. Neuroscience Letters 92:79-85, 2006

  40. Non-Pharmacologic Treatment • Eat the foods smaller and more frequent. • Eat the foods served at room temperature or cold. • Eat the fruits, ice-cream, sandwich, white cheese and oderless foods. • Drink the liquids one hour before or after meals. • Eat the cracker, toast, salty biscuit, haricot foods if the emesis occur in the morning.

  41. Non-Pharmacologic Treatment • Walking short distance outdoors and inhale air deeply and slowly. • Keep away from odors of foods, perfüme and fume. • Put on comfortable clothes. • Do not sleep immediately after dinner. • Begin eating light foods (soup, yoghurt, puree) after control nause and vomitting.

  42. In the first systemic chemotherapy treatment True and effective antiemetic treatment Control the symptoms of nause and vomitting Success of continuation of chemotherapy treatment and complet the chemotherapy treatment of patients It is very important point.

  43. Çalışmadan, öğrenmeden, yorulmadan rahat yaşamanın yollarını aramayı alışkanlık haline getirmiş milletler, evvele haysiyetlerini, sonra hürriyetlerini ve daha sonra da istikballerini kaybetmeye mahkumdurlar. M. Kemal ATATÜRK

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