CINV dr salah mabrouk khallaf
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This document discusses the management of chemotherapy-induced nausea and vomiting (CINV). It defines different types of CINV including acute, delayed, and anticipatory. The pathophysiology involves serotonin, substance P, and dopamine pathways in the brain and gut. Risk factors include the emetogenic potential of chemotherapy agents as well as patient factors. Common antiemetic agents discussed are 5-HT3 receptor antagonists such as palonosetron, dolasetron, ondansetron, and granisetron which are effective for acute CINV. Guidelines for their use and dosing are provided.
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CINV dr salah mabrouk khallaf
- 1. Management of CINVManagement of CINV By Salah Mabruok Khalaf South Egypt Cancer Institute 2017 Course of Medical Oncology Medical Oncology department
- 2. AgendaAgenda • DefinitionsDefinitions • Types of CINVTypes of CINV • PathophysiologyPathophysiology • Risk Factors of CINVRisk Factors of CINV • Therapeutic AgentsTherapeutic Agents • NCCN GuidelinesNCCN Guidelines • SECI Guidelines in ArabicSECI Guidelines in Arabic • Patient Information in ArabicPatient Information in Arabic
- 3. Definitions • Nausea: • The unpleasant sensation of the imminent need to vomit, usually referred to the throat or epigastrium; a sensation that may or may not ultimately lead to the act of vomiting. • Vomiting: • Forceful oral expulsion of gastric contents associated with contraction of the abdominal and chest wall musculature. • Regurgitation: • The act by which food or gastric juice is brought back into the mouth without the abdominal and diaphragmatic muscular activity that characterizes vomiting.
- 4. Types of CINV • Anticipatory • Learned or conditioned response from poorly controlled nausea and vomiting associated with previous chemotherapy. • Emetic episodes are triggered by taste, odor, sight, thoughts, or anxiety secondary to a poor response to antiemetic agents. • Acute (post-treatment) • Occurs within first 24 hours after administration of cancer chemotherapy • Mainly caused by serotonin release from enterochromaffin cells • Delayed • CINV that begins after first 24 hours to several days after initiation of chemotherapy. • Multifactorial but mainly caused by substance P, disruption of the blood– brain barrier, disruption of the gastrointestinal motility, or adrenal hormones • Breakthrough • CINV that occurs despite prophylaxis and requires rescue • Refractory • Occurs during subsequent treatment cycles when prophylaxis and/or rescue has failed in previous cycles.
- 5. Pathophysiology of CINVPathophysiology of CINV Chemotherapy administrationChemotherapy administration Chemotherapy leads to free radicals generation Enterochromaffin cell of small intestine Stimulation Release of Serotonin Exocytosis 5-HT3 receptors of on vagal afferent terminals in the wall of the bowel Stimulation Afferent vagal impulses Dorsal vagal complex (nucleus tractus solitaries and CTZ in area postrema) Substance P for neurokinin-1 (NK-1) receptor Serotonin for 5-HT3 receptor Dopamine for dopamine D2 receptor Neurotransmitor Receptor interaction Vomiting center efferent impulses Efferent vagal impulses Pharyngeal, GI, abdominal muscular contractions Vomiting
- 7. •Serotonin (5-hydroxytryptamine) • 90% of the body’s stores are in the enterochromaffin cells • It plays the most important role in the process of acute CINV • It acts through binding to 5-HT3 receptor • 5-HT3 receptors in the brain are mainly located in the area postrema, nucleus tractus solitarius, and dorsal vagal motor nucleus. •Substance P • It involved in the transmission of unpleasant stimuli, such as pain, mood disorders, anxiety, stress, and nausea and vomiting. • It acts through binding to NK-1 receptor. • It plays the most important role in the process of delayed CINV •Dopamine • Dopamine interacts with dopamine D1 and D2 receptors. • The dopamine D2 receptor, located in the chemoreceptor trigger zone. Pathophysiology of CINVPathophysiology of CINV
- 9. Risk factors •Chemotherapy related factors • The emetogenic potential of a chemotherapy agent is the most important risk factor for determining the degree of CINV, and is classified into four risk groups HIGHHIGH Risk in nearly all patients (> 90%)Risk in nearly all patients (> 90%) MODERATEMODERATE Risk in 30% to 90% of patientsRisk in 30% to 90% of patients LOWLOW Risk in 10% to 30% of patientsRisk in 10% to 30% of patients MINIMALMINIMAL Fewer than 10% at riskFewer than 10% at risk
- 10. Chemotherapy related factors • High risk > 90% for IV agents • AC combination (Adria 60 mg/m2 and Cyclophosphamide 600 mg/m2) • Anthracyclines • Adriamycin ≥ 60mg/m2 • Epirubicin > 90 mg/m2 • Nitrogen mustards • Cyclophosphamide > 1500 mg/m2 • Ifosfamide > 2 gm/m2 per dose • Mechlorethamine • Platinum • Cisplatin • Carboplatin AUC ≥ 4 • Nitrosureas • Carmustine > 250 mg/m2 • Zanosar (streptozocin) • Triazenes • Dacarbazine
- 11. Chemotherapy related factors • Anthracyclines • Adriamycin < 60mg/m2 • Epirubicin ≤ 90 mg/m2 • Idarubicin • Daunorubicin • Nitrogen mustards • Cyclophosphamide ≤ 1500 mg/m2 • Ifosfamide < 2 gm/m2 per dose • Bendamustine hydrochloride • Melphalan • Platinum • Carboplatin AUC < 4 • Oxaloplatin • Nitrosureas • Carmustine ≤ 250 mg/m2 • Lomustine • Semustine • Triazenes • Temozolomide • Purine analogues • Clofarabine • Pyrimidine analogues • Azacitidine • Cytarabine > 200 mg/m2 • Folate anatagonist • Methotrexate ≥ 250 mg/m2 • Topoisomerase I inhibitors • Irinotecan • Differentiating agents • Arsenic trioxide • DNA binding • Trabectedin Moderate emetic risk (>30%- 90% frequency of emesis) for IV agents
- 12. Chemotherapy related factors • Nitrogen mustards: no agents • Platinum: no agents • Nitrosureas: no agents • Triazenes: no agents • Purine analogues • Pentostatin • Pyrimidine analogues • Cytarabine 100-200 mg/m2 • 5-fluorouracil (5-FU) • Floxuridine • Gemcitabine • Folate anatagonist • Methotrexate >50mg/m2 - < 250 mg/m2 • Pemetrexed • Pralatrexate • Topoisomerase inhibitors • Irinotecan • Teniposide • Topotecan • Differentiating agents • Arsenic trioxide • DNA binding • Trabectedin Low emetic risk (10%-30% frequency of emesis) for IV agents • Anthracyclines • Liposomal doxorubicin • Anthracyclines analogue • Mitoxantrone • Taxanes • Cabazitaxel • Docetaxel • Paclitaxel • Paclitaxel, Protein-bound • Non-taxane mitotic inhibitors • Eribulin mesylate • Epothilones: • Ixabepilone
- 13. Chemotherapy related factors • No agents of the following • Platinum • Nitrosureas • Triazenes • Topoisomerase inhibitors • Anthracycline • Taxane • NonTaxanes mitotic inhibitors • Epothilones • Nitrogen mustards • Purine analogues • Cladribine • Fludarabine • Nelarabine • Pyrimidine analogues • Cytarabine < 100 mg/m2 • Decitabine • Folate anatagonist • Methotrexate ≤ 50mg/m2 • Enzymes • Asparaginase • Pegaspargase • Vinca alkaloids • Vinblastine • Vincristine • Vinorelbine • Vindesine • Most of IV target therapy agents Minimal emetic risk ( < 10% frequency of emesis) for IV agents • Anthracyclines • valrubicin • Anthracyclines analogue • Mitoxantrone
- 14. Patient-related risk factors • Sex: Females are more predisposed to CINV than males • Age: younger patients (<50 years) experience more severe CINV than older patients (>65 years). • Past history of CINV: The more control of emesis to previous CTR, the more control to subsequent CTR. • History of motion sickness: Patients susceptible to motion sickness report a greater frequency, severity, and duration of CINV following treatment. • Other risk factors • Anxiety • Fatigue • Chemotherapy as outpatient • Impaired quality of life • Vomiting during pregnancy
- 16. 5-HT5-HT33 antagonitsantagonits • Primary mechanism of action appears to be peripheral. • Block release of serotonin release from enterochromaffin cells in GI tract • Effective in acute vomiting; very limited efficacy for delayed events • Best given as a start dose pre-chemotherapy • Oral and IV equally effective • Members • Palonosteron • Dolasteron • Ondanosteron • Granisteron 1. Berger AM, Clark-Snow RA. In: DeVita VT Jr et al. 7th ed. Cancer: Principles & Practice of Oncology. Lippincott Williams & Wilkins; 2005:2515–2523. 2. Hesketh PJ et al. Eur J Cancer. 2003;39(8):1074–1080.
- 17. Palonosteron:Palonosteron: Aloxi ® • MOA • Selective 5-HT3 receptor antagonist • Metabolism • Hepatic • Elimination • Renal • Dosage • 0.25 mg administered as a single dose approximately 30 minutes before the start of chemotherapy. • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Administration • IV over 30 seconds • Do not mix with other drugs • Venous flushing before and after administration • Contraindication • Hypersensitivity • Pregnancy. Teratogenic Effects: Category B • SE • Headache (9%) • Constipation (5%) • Diarrhea (1%) • Dizziness (1%)
- 18. Dolasetron:Dolasetron: ANZEMET ® • MOA • Selective 5-HT3 receptor antagonist • Metabolism • Hepatic • Elimination • Renal mainly • Dosage • 100 mg PO 1 hour before the start of chemotherapy. • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Contraindication • Hypersensitivity • Pregnancy. Teratogenic Effects: Category B • SE • Headache (17%) • Bradycardia (5%), tachycardia (3%) • Diarrhea (2%) • Dizziness (1%) • Precaution: • Patients with any risk factors for QT prolongation • Hypokalemia • Hypomagnesaemia • Congenital QT syndrome • Taking anti-arrhythmic causing QT prolongation • High cumulative anthracycline dose • Elderly
- 19. Ondanosteron oral tablet: ZofranOndanosteron oral tablet: Zofran • MOA • Selective 5-HT3 receptor antagonist • Metabolism • Hepatic • Elimination • Hepatic • Dosage • 24 mg/d (3 tab 8 mg) • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: reduced to 8 mg/day in Child-Pugh class C hepatic impairment • Administration • Three 8 mg tablets administered orally 1 hour before the start of single-day highly emetogenic chemotherapy • Take without regard to meals. • Contraindication • Hypersensitivity • Concomitant use of apomorphine • Pregnancy: Category B • SE • Headache (24%) • Constipation (9%) • Diarrhea (6%) • Dizziness (5%) • Strengths • Ondansetron tablets USP, 8 mg
- 20. Ondanosteron Injection: ZofranOndanosteron Injection: Zofran • MOA • Selective 5-HT3 receptor antagonist • Metabolism • Hepatic • Elimination • Renal • Dosage • 0.15 mg/kg per dose for 3 doses (maximum of 16 mg per dose). • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Strengths • Ampoule 4 mg and 8 mg • Administration • Diluted in 10-50 ml NaCl 0.9% or D5W • First dose given 30 minutes before chemotherapy then every 8 hours if required • Do not mix with other drugs • Contraindication • Hypersensitivity • Concomitant use of apomorphine • SE and precautions • Headache (17%) • Dizziness (8%) • Injection site reaction (4%) • QT prolongation • Serotonin Syndrome • It may mask a progressive ileus and gastric distention so, it should not be used instead of nasogastric suction. • Pregnancy: Can be used
- 21. Serotonin Syndrome • Etiology • Overdose of Selective 5-HT3 receptor antagonist • Ordinary dose of Selective 5-HT3 receptor antagonist but with concomitant use of serotonergic drugs • Selective serotonin reuptake inhibitors (SSRIs) • Serotonin and norepinephrine reuptake inhibitors (SNRIs) • Monoamine oxidase inhibitors • Lithium • Fentanyl • Tramadol • Intravenous methylene blue • Clinical manifestations • Mental status changes (e.g., agitation, hallucinations, delirium, and coma) • Autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia) • Neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination, seizures) • Gastrointestinal symptoms(e.g., nausea, vomiting, diarrhea) • Management • Discontinue Granisetron and initiate supportive treatment.
- 22. Granisteron oral tabletGranisteron oral tablet • MOA • Selective 5-HT3 receptor antagonist • Metabolism • Hepatic • Elimination • Hepatic • Dosage • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Administration • Take without regard to meals • Contraindication • Hypersensitivity • Pregnancy. Teratogenic Effects: Category B • SE • Serotonin Syndrome • Headache (9%) • Constipation (5%) • Diarrhea (1%) • Dizziness (1%)
- 23. Granisteron oral tablet:Granisteron oral tablet: EMEX ® • MOA • Selective 5-HT3 receptor antagonist • Metabolism • Hepatic • Elimination • Hepatic • Dosage: 2mg/d • 2 mg once daily • 2 tablets 1mg 1 hour before chemotherapy once • 1 mg twice daily • One tablet 1mg 1 hour before chemotherapy • One tablet 1mg 12 hours after the first tablet • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Administration • Take orally without regard to meals • Contraindication • Hypersensitivity • Pregnancy. Teratogenic Effects: Category B • SE • Serotonin Syndrome • QT prolongation • Headache (21%) • Constipation (18%) • Dizziness (14%) • Diarrhea (8%)
- 24. Granisteron Injection:Granisteron Injection: EMEX ® • MOA • Selective 5-HT3 receptor antagonist • Metabolism • Hepatic • Elimination • Renal • Dosage • 10 mcg/kg • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Administration • Direct IV over 30 seconds or diluted in 50 ml saline over 5 min given 30 minutes before chemotherapy • Do not mix with other drugs • Contraindication • Hypersensitivity • Pregnancy. Teratogenic Effects: Category B • SE • Headache (9%) • Constipation (5%), Diarrhea (1%) • Dizziness (1%) • QT prolongation • Serotonin Syndrome • Strengths • Single-Use Vial: 1 mg/mL • Multiple-Dose Vials: 4 mg/4 mL
- 25. NKNK11 receptor antagonistreceptor antagonist • Primary mechanism of action appears to be central • NK1 receptor blockade effective for delayed vomiting: - Less effective for acute vomiting: needs a 5HT3 antagonist - Less effective for nausea: needs dexamethasone • Members – NNeupitant – FFosaprepitant – AAprepitant – RRolapitant
- 26. Neupitant:Neupitant: (Available in combination with palonosetron in one(Available in combination with palonosetron in one capsule)capsule) Akynzeo®Akynzeo® • MOA • Selective human substance P/neurokinin 1 (NK1) receptors antagonist • Metabolism and Elimination • Hepatic • Dosage: • One capsule 1 hour before chemotherapy once • Taken with dexamethasone • Dose adjustment • Geriatrics: no adjustment but with caution. • Renal Impairment: • Avoid in severe RI or end-stage renal disease • Hepatic Impairment: • no adjustment in child-Pugh class A & B • Avoid in class C • Administration • Take orally without regard to meals • Contraindication • Pregnancy Category C • SE • Headache (9%) • Dyspepsia (4%) • Fatigue (4%) • Constipation (3%) • Erythema (3%) • Strengths • AkynzeoAkynzeo (300 mg netupitant/0.5 mg palonosetron) capsule
- 27. Fosaprepitant:Fosaprepitant: IVEMEND®IVEMEND® • MOA • Selective human substance P/NK1 receptors antagonist • Metabolism • Hepatic • Elimination • Hepatic and renal • Dosage: • One amp 150mg 30 min before chemotherapy once • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Administration • Reconstitute vial with 5 mL of NS with slowly directing diluent down side of vial then add to 145 mL NS, gentlly invert bag 2 to 3 times to mix. • Infuse over 20 to 30 minutes • Indication • Prevention of CINV • Highly & moderate • Acute& delayed • Not studies for existed CINV • Contraindication • Hypersensitivity • SE • Headache (9%) Dyspepsia (2%) • Fatigue (15%) Constipation (2%) • Peripheral neuropathy (3%) • Neutropenia (8%), anemia (3%), leukopenia (2%) • Strengths • IVEmend:IVEmend: 115 mg and 150mg solution
- 28. AprepitantAprepitant: EMEND® • MOA • Selective human substance P/neurokinin 1 (NK1) receptors antagonist • Metabolism and Elimination • Hepatic • Dosage: • One capsule 1 hour before chemotherapy • If chemotherapy D2, D3, give one capsules 1 hour before • If no, give one capsule at morning • Dose adjustment • Geriatrics: no adjustment • Renal Impairment: no adjustment • Hepatic Impairment: no adjustment • Administration • One capsule 1 hour before chemotherapy • Take orally without regard to meals • Indication • Prevention of CINV • highly & moderate • Acute & delayed • Not studies for existed CINV • Not studies for Chronic continuous use • Contraindication • Pregnancy Category C • SE • Dyspepsia (7%) • Fatigue (13%) • Diarrhea (9%) • Leucopenia (3%) • Precaution • Reduced Efficacy of Hormonal Contraceptives • Avoid concomitant use with moderate to Strong CYP3A4 Inhibitors • Strengths • Emend Capsules, 3-day pack (125-mg/80- mg/80-mg)
- 29. DexamethasoneDexamethasone •M.O.A not fully understood. •Very effective for nausea, acute and delayed vomiting •Acute: pre-dose before chemotherapy •Delayed: 2-4 days of chemotherapy •Side effects: heartburn/indigestion, agitation, hiccups, abnormal BM’s (all manageable in most instances) HIGH 20 mg (12 mg with aprepitant) 8 mg bd 3-4 d (8 mg od 3-4d with aprepitant) MODERATE 8 mg (12 mg with aprepitant) 8 mg od 2-3 d LOW 4-8 mg N/A MINIMAL N/A N/A
- 30. Antianxiety and anti-depressant agentAntianxiety and anti-depressant agent • It is effective treatment of anticipatoryanticipatory Nausea and vomiting – Caution if elderly and frail- increased risk of falls. If necessary- lowest dose. – Useful for anxiety issues, smells and taste of food problematic. • Members – Antianxiety:Antianxiety: Lorazepam (Ativan) is 0.5-1mg bd. (oral/SL/IV) for anticipatory Nausea and vomiting – anti-depressant:anti-depressant: Olanzapine (Zyprexa) 10 mg PO once D1, 2 ,3 , 4 for prevention of acute and delayed CINV
- 31. NCCN Guidelines V2.2017NCCN Guidelines V2.2017
- 34. High Emetic Risk ChemotherapyHigh Emetic Risk Chemotherapy • Day 1: choose one out of 6 options (NCCN V 2.2017): Option NK1 RA 5-HT3 RA (choose one) Dexamethason e Others A Aprepitant 125 mg PO once Palonosteron or Granisteron or Ondanosteron or Dolasteron 12mg PO/IV Once B Fosaprepitant 150 mg IV once As option A As option A C Rolapitant 180 mg PO once As option A As option A D Neupitant 300 mg PO once Palonosteron 0.5 mg PO once As option A E ---- Palonosteron 0.25 mg PO once 20 mg IV Once Olanzapine 10 mg PO once F As option A or Option B As option A As option A Olanzapine 10 mg PO once
- 35. High Emetic Risk ChemotherapyHigh Emetic Risk Chemotherapy • Day 2, 3, 4: choose one out of 6 options (NCCN V 2.2017): Option NK1 RA 5-HT3 RA Dexamethasone Others A Aprepitant 80 mg PO D2, 3 8 mg PO/IV Once D2 ,3 , 4 B 8 mg PO/IV Once D2 Twice D3, 4 C 8 mg PO/IV Twice D2 ,3 , 4 D 8 mg PO Once D2 ,3 , 4 E Olanzapine 10 mg PO once D2 ,3 , 4 F Aprepitant 80 mg PO D2, 3 8 mg PO/IV Once D2 ,3 , 4 Olanzapine 10 mg PO once D2 ,3 , 4
- 36. Moderate Emetic Risk ChemotherapyModerate Emetic Risk Chemotherapy • Day 1: choose one out of 6 options (NCCN V 2.2017): Option NK1 RA 5-HT3 RA (choose one) Dexamethasone Others A Aprepitant 125 mg PO once Palonosteron or Granisteron or Ondanosteron or Dolasteron 12mg PO/IV Once B Fosaprepitant 150 mg IV once As option A As option A C Rolapitant 180 mg PO once As option A As option A D Neupitant 300 mg PO once Palonosteron 0.5 mg PO once As option A E ------ As option A but Palonosteron is preferred As option A F ------ Palonosteron 0.5 mg PO once 20 mg IV Once Olanzapine 10mg PO once
- 37. Moderate Emetic Risk ChemotherapyModerate Emetic Risk Chemotherapy • Day 2, 3, 4: choose one out of 6 options (NCCN V 2.2017): Option NK1 RA 5-HT3 RA Dexamethasone Others A Aprepitant 80 mg PO D2, 3 (±) 8 mg PO/IV Once D2 ,3 B As option A C As option A D As option A E Granisteron or Ondanosteron or Dolasteron (+) 8 mg PO/IV Once D2 ,3 F Olanzapine 10 mg PO once D2 ,3 , 4
- 38. Breakthrough symptoms- which anti-emetic?Breakthrough symptoms- which anti-emetic? • Diagnosis of the cause of nausea and vomiting is crucial for deciding on which anti-emetic to use. • Key questions- when did symptoms start? when was last dose of chemo/XRT? When did steroid course stop? Nausea related to smells/taste of food? How many vomiting episodes? VAS to assess nausea? Appetite/food and fluid intake? • The only evidence available to rescue patients who have CINV is with the use of a D2 antagonist e.g. metoclopramide or a 5HT3 antagonist such as oondansetron. • Domperidone is supplied at a dose of 20mg qds with the majority of chemotherapy regimens..
- 39. SECI Guidelines based onSECI Guidelines based on NCCN guidelines andNCCN guidelines and availability of agentsavailability of agents
- 40. Brand names in SECIBrand names in SECI • 5HT3 antagonists • Palonosteron: Aloxi ® • Dolasteron: not available • Ondanosteron: Zofran ® • Granisteron: EMEX ® • Substance P/neurokinin 1 (NK1) receptors antagonists • Neupitant: not available • Fosaprepitant: not available • Aprepitant: EMEND • Rolapitant: not available
Editor's Notes
- Two sites in the brainstem—the vomiting center and the chemoreceptor trigger zone—are important to emesis control. The vomiting center consists of an intertwined neural network in the nucleus tractus solitarius that controls patterns of motor activity. The chemoreceptor trigger zone, located in the area postrema, is the entry point for emetogenic stimuli. Enterochromaffin cells in the gastrointestinal tract respond to chemotherapy by releasing serotonin. Serotonin binds to 5-HT3 receptors, which are located not only in the gastrointestinal tract, but also on vagal afferent neurons and in the nucleus tractus solitarius and the area postrema. The activated 5-HT3 receptors signal the chemoreceptor trigger zone via pathways thatmay include the afferent fibers of the vagus nerve. Serotonin also may bind with 5-HT3 receptors in the brainstem. Other neurotransmitters, including dopamine and substance P, also influence the chemoreceptor trigger zone. Afferent impulses from the chemoreceptor trigger zone stimulate the vomiting center, which initiates emesis.1 1. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med. 1993;329:1790-1796.