Antiemesis Management in Cancer Therapy - Part 1

Antiemesis Management in Cancer Therapy - Part 1 Dr. Leiva é Main culprits are radiation therapy (XRT) and traditional chemotherapy agents (oral and parenteral). Estimated that 70-80% of the patients receiving chemotherapy are at risk for N/V Mechanisms are not completely understood, but we know chemo induced nausea better than XRT induced nausea Targeted and biologic therapies less prone but individual patients may vary. Cancer Therapies and Emesis Eyal Location, Location, Location breathing autonomic u Several areas of the brain implicated u onto a Vomiting Center located in the medulla u Final common pathway for initiating emesis (still a subject of debate) u Area Postrema (AP) aka the chemoreceptor trigger zone (CTZ) u Higher brainstem and cortical structures interact with vagus and splanchnic nerves from GI tract u Vestibular-labyrinthine apparatus of the inner ear CTZ Dps Neurotransmitters Involved (The usual suspects?) u Dopamine t u Serotonin u Substance P u AOE BlockedbyAfab u Neurokinin u Neurons in the CNS and PNS Others u Prostaglandins serotonin dexamethasone Blockit http://www.drugabuse.gov/ PATHOPHYSIOLOGY OF CINV A Earl 5473releasedbyEntrochromaffin 5 a soul BBB i iontains 3 http://pharmacologycorner.com/drugs-cinv-prophylaxis-treatment/ Definition of Nausea and Vomiting Grade 1 Nausea Loss of appetite w/out alteration of eating habits 2 Oral Intake decreased w/out significant wt loss, dehydration or malnutrition weights 711th your 3 Inadequate oral caloric or fluid intake; tube feedings, TPN, or hospitalization indicated Vomiting 1 to 2 episodes (separated by 5 minutes) in 24 hours 3 to 5 episodes (separated by 5 minutes) in 24 hours >6 episodes (separated by 5 minutes) in 24 hours; tube feeding, TPN, or hospitalization indicated NA Life threatening consequences; urgent intervention indicate 4 NA Death 5 National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, 2017, National Institutes of Health, N ational Cancer Institute Types of CINV know tf definitions u Acute emesis u u < 24 hours during or post chemo Delayed emesis u >24 hours after chemo on at I after experience emesis u Complicated conditioned response u Incidence ranges from 18% to 57%, and nausea >vomiting u 3 Anticipatory u u aBreakthrough emesis u u Younger patients more susceptible, more aggressive chemo, anxiety, and poorer emesis control It Occurs within 5 days of treatment despite prophylactic treatment and/or requires rescue with antiemetic agents 5Refractory PE Emesis u Nausea and/or vomiting occurring during subsequent treatment cycles when antiemetic prophylaxis and/or rescue has not been effective in earlier cycles Patient Risk Factors Eton A Patient’s age and sex assigned at birth • >Younger women 2 Environment in which chemo administered • Chaotic, stressful, other sick patients 3 History of Motion sickness U Anxiety (History or Current issue) S Previous episodes of N/V 6 Dosage of emetogenic agent 7 Efficacy of antiemetic regimen 8 Concurrent chemotherapy/radiation likely to happen for people who regularly consume alcohol 9 Less N Engl J Med 2008;358:2482-94 Risk Factors u u Benzo or NOT antifeties Acute Emesis u Often drug dependent/specific, dose related u Anxiety may play role u Carmustine, etc Delayed-onset CINV u Complicated and often missed by providers u Cisplatin, carboplatin, oxaliplatin, irinotecan, cyclophosphamide and/or doxorubicin u Carboplatin  Day 2-3, up to 5 days post chemo u Cisplatin  maximal intensity 48-72 hours post administration; can last up to 7 days Risk Factors u I can’t escape feeling sick… Anticipatory CINV u Typically after a negative chemo experience. u Incidence ranges from 18% to 57% u Nausea>Vomiting u Younger patients I’m not going to be able to continue my chemo.. http://painconsortium.nih.gov/symptomresearch/chapter_11/sec4/cgms4pg4.htm Emetogenicity of Antineoplastic Agents prophylatticmed Abilityofchemodiginggey u Classified ptnotsivenary Eton by Four Distinct Levels u High frequency of emesis u Moderate u30-90% frequency of emesis u Low u10-30% frequency of emesis u Minimal u<10% frequency of emesis High u>90% Moderate Low Minimal NCCN Guidelines (High and Moderate Emetic Risk-Parenteral Agents) As a reminder please make sure that you know the level for all of the parenteral and oral agents we cover!! Ego NCCN Guidelines (Low and Minimal Emetic Risk-Parenteral Agents) As a reminder please make sure that you know the level for all of the parenteral and oral agents we cover!! Fyi oralauto Anti-emetic Administration Timing u Generally oral antiemetic premeds are given 40 to 60 minutes prior to chemotherapy u u Adherence and insurance can sometimes be barriers for compliance yo Oregon They Better IV antiemetic premeds given generally 20 to 30 minutes prior to chemotherapy, however increased bioavalibility of IV formulations allows for decreased wait time prior to chemo 1V 230 Treatment and Prophylaxis Backbone Fteleasedby CINV Treatment and Prophylaxis enterpochrmin g 5-HT3 Antagonists Dolasetron Granisetron Ondansetron Palonosetron 3 Corticosteroids Dexamethasone NK-1 Blocker Aprepitant Fosaprepitant Rolapitant Netupitant Fosnetupitant Olanzapine b GN Salvage or Adjunct Dopamine Antagonists -Antipsychotics -Metoclopramide Holistic - Acupuncture - Massage -Acupressure - Relaxation thfmetics Benzodiazepines Cannabinoids - Nabilone - Dronabinol - Marijuana/CBDs Location Agent(s) Emetic Center Antihistamines, Scopalamine, 5HT3 Antagonists, Olanzapine CTZ Metoclopramide, Haloperidol, Phenothiazines, Olanzapine Cerebral Cortex Antihistamines, Benzos, Cannabinoids, Corticosteroids, NK-1 Receptor Antagonists, Olanzapine Peripheral Metoclopramide, NK-1 Receptor Antagonists, 5HT3 Antagonists, Olanzapine Unknown Corticosteroids Site of Action of Antiemetic Agents Dolasetron (Anzemet) 5-HT3 Antagonists Granisetron (Kytril) Ondansetron (Zofran) Palonosetron (Aloxi) 5-HT3 Antagonists u Pharmacology u Selective to 5-HT3 receptors u Single dose prior to chemo therapeutically equivalent to a multiple dose schedule u Plateau effect at a definable dose for each drug; increasing dose does not increase the drug’s effect u Oral formulations are as effective as IV formulations 5HT3 Antagonists u pGranisetron (Kytril, Sancuso - Patch) u u u Administration: u Patch 3.1 mg/24 hrs to upper outer arm 24-48 hrs before chemo, worn up to 7 days u PO formulation Best without food Dosing: u 10 mcg/kg IV w/in 30 min before chemo or u 1 mg PO BID z Dolasetron (Anzemet) u u Administration: u MUST BE PO for CINV IV is contraindicated in CINV u Without regard to meals Dosing: u u 100 mg PO 1 hr before chemo moPOIprolongation Drug Interactions: CYP3A4 and CYP2D6 5HT3 Antagonists u 3Ondansetron (Zofran) u Administration: u u u 0.15 mg/kg administered every 4 hrs up to 3 doses or 16 mg u Few Patients above 80 kg have been studied Max PO dose 24 mg/day u Dosing: 8 mg PO BID-TID for breakthrough/delayed u Drug Interactions: u u *Max IV single dose 16 mg CYP3A4 substrate Dronedarone is contraindicated w/ ondansetron Warnings u **Prolongation of the QT interval of the ECG can lead to an abnormal and potentially fatal heart rhythm (including Torsade de Pointes) u Patients at risk: u Congenital long QT syndrome (men >450 ms, Women >470 ms) u Hypokalemia and hypomagnesemia (vomiting/diarrhea/etc) u Taking other medications that lead to QT prolongation http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm 5HT3 Antagonists Clash of the Titans u uPalonosetron (Aloxi®) u Administration: u u IV only Dosing: u 0.25 mg IVPush over 30 seconds single dose 30 min prior to chemo u Preferred for delayed nausea > ondansetron (Controversial) u More expensive > ondansetron u Benefits – does not cause QTc prolongation u Counseling – do NOT take Ondansetron within 3 days of Palonosetron administration Figure 2. Proportion of patients with no emetic episodes during the acute, delayed and overall time periods. *P ≤0.05 compared with ondansetron (χ2 test; intention-to-treat cohort, n = 563) Gralla R et al. Ann Oncol 2003;14:1570-1577 5-HT3 Antagonists ADRS Common: • • • • Headache (~42.5%) Sleepiness GI: Constipation, diarrhea, dry mouth Hepatic: increased ALT, AST Serious: • Cardiovascular: A fib, dysrhythmia, EKG abnormalities, Prolonged QT, 2nd degree AV block, Torsades de pointes (Not Palonosetron) • Hepatic: Hepatic necrosis, hepatitis, liver failure • Neurologic: Oculogyric crisis NK 1 Receptor Antagonists and Combinations u O Aprepitant (Emend - PO, Cinvanti - Injection) u PO Formulation u Tri-pak and 40 mg capsules u Aprepitant emulsion injection 130 mg aFosaprepitant (Emend IV) u con'tgiveAloxin Single 150 mg IV dose in 150 mL NS over 20-30 min thismed u NOT COMPATIBLE WITH PALONOSETRON FOR ADMIXTURE u u u 3 Rolapitant (Varubi) u 180 mg PO u 166.5 mg/92.5 mL injectable emulsion – CI in patients with ALL to soybean oil – Infuse straight from vial over 30 min (Fos)Netupitant/palonosetron (Ankyzeo) u Available PO (300 mg/0.5 mg) or u IV (235 mg/0.25 mg) in 50 mL D5W or NS over 30 min NK 1 Receptor Antagonists t u u greatforprevention Pharmacology u u DonottreatNI Selective high affinity antagonist of substance P/Neurokinin 1 Receptor u Half-Life 9 to 13 hours for Emend, ~7 days for Varubi, ~88 hours for Netupitant u Shown significant efficacy with delayed nausea Common ADRS: u Common: Constipation, Diarrhea, tinnitus, headache, insomnia, hiccups* u Serious: Neutropenia, tinnitus, allergic reaction, hypotension, bradycardia, and disorientation, transient elevation in LFTs Serious Drug Interactions: u Rolapitant - moderate inhibitor of CYP2D6 – Thioridazine is CONTRAINDICATED!!!!!!! u (Fos)Aprepitant, (Fos)Netupitant Common Drug interactions: CYP3A4 Inhibitor/CYP2C9 Inducer u Decreases therapeutic efficacy of Warfarin u Increases plasma concentrations of Dexamethasone Corticosteroids breakfast wi morning Takein u Dexamethasone (Decadron®) uPharmacology: uMay decrease prostaglandin activity in the brain uADRS uInsomnia, adrenal axis suppression, increased appetite, increased thirst, hypertension, irritability, increased blood sugar, heartburn, delayed wound healing/skin thinning/easy bruising or tearing of the skin Dopamine Receptor Antagonists u *Olanzapine prevention and no treatment (Zyprexa) u Metoclopramide u Promethazine (Phenergan) u Prochloperazine u Haloperidol (Reglan) (Compazine) longation (Haldol)or Ispr So mostlyforptutreftoryNIV Olanzapine (Zyprexa) u MOA: Atypical antipsychotic works on D2 in the mesolimbic as an antagonist and antagonizes serotonin u PK: t ½ ~30 hours u Dosing: u DDIs: u ADRs: 2.5 – 10 mg Inducers/inhibitors of CYP1A2 and CYP2D6 drowsiness, postural hypotension, constipation, dizziness, dry mouth, QTc prolongation not likely based on the literature Wrap Up and Recap u u u u u u Part 1 Part 2 What is chemo induced nausea and u What kinds of drugs do we use for vomiting? salvage or adjunct therapies? How does it happen? u How do we apply the guidelines to a patient case? How do we define it and identify patients at risk of CINV? u What are some clinical pearls the guidelines give us when using these What categories of chemo tend to drugs for prophylaxis and dealing cause N/V? with patients who have breakthrough or refractory What are the various types of drugs we nausea/vomiting? use to prevent CINV? What are some important safety considerations we should think about for patients receiving these drug?