Chemotherapy-Induced Nausea and Vomiting: Current Guidelines and Emerging Evidence

Transcription

1 Chemotherapy-Induced Nausea and Vomiting: Current Guidelines and Learning Objectives Identify risk and severity of CINV for each patient on chemotherapy Evaluate the data supporting the use of individual antiemetic agents and combinations Implement guideline-based strategies to ensure that every patient is prescribed evidence-based antiemetic therapy 2 CINV = chemotherapy-induced nausea and vomiting. Case Study 1: Linda Linda is a 48-year-old woman recently diagnosed with stage IV non small-cell lung cancer Linda has a history of morning sickness with all 3 pregnancies She is a lifelong nonsmoker and does not drink alcohol She is starting chemotherapy with cisplatin/paclitaxel 3 1

2 Which of the following increase(s) Linda s risk for CINV? (Select all that apply)?decision POINT 1. Age 2. Female gender 3. History of morning sickness 4. Type of chemotherapy Use your keypad to vote now! 4 Case Study 2: Dan Dan is a 74-year-old man with stage III colon cancer He smoked 2 packs/day for 30 years, but quit smoking 25 years ago He is a heavy consumer of alcohol Dan underwent resection and is now receiving adjuvant therapy with FOLFOX 5 FOLFOX = folinic acid, fluorouracil, oxaliplatin. Which of the following increase(s) Dan s risk for CINV??DECISION POINT 1. History of smoking 2. Male gender 3. Heavy alcohol consumption 4. Type of chemotherapy Use your keypad to vote now! 6 2

3 Complications of CINV Dehydration and electrolyte imbalance Decline of performance status and mental status Hospitalization Poor nutrition Weight loss Impaired health-related quality of life Negative impact on activities of daily living 7 Craver C, et al. J Med Econ. 2011;14:87-98; Burke TA, et al. Support Care Cancer. 2011;19: Risk Factors: Patient-Specific Age Younger age (also, younger patients may get more aggressive regimens) Gender Occurs in women more frequently than it occurs in men Low alcohol consumption Emesis with prior chemotherapy History of motion sickness or morning sickness Polymorphisms in metabolism of antiemetics and neurotransmitter receptors 8 National Cancer Institute. HealthProfessional/page3. Accessed May 4, Risk Factors: Treatment-Specific Emetogenicity of chemotherapy regimen Chemotherapy dose, schedule, combination, rate Type of radiation therapy Administration schedule Fractionated vs not fractionated Area of radiation field Type and location of surgery 9 3

4 Case 1: Linda (cont d) Linda received prophylaxis for CINV with granisetron and dexamethasone administered before chemotherapy The evening after chemotherapy she experienced N/V, which continued for 3 days postchemotherapy She did not call her oncology nurse practitioner at the time, but told her about the nausea at her next visit 10 N/V = nausea/vomiting. Which of the following best describes Linda s CINV??DECISION POINT 1. Acute 2. Anticipatory 3. Breakthrough 4. Delayed Use your keypad to vote now! 11 Definitions Acute N/V: onset within minutes to hours after administration of chemotherapy Resolves within 24 hours Delayed N/V: occurs 24 hours or later after administration of chemotherapy Typically resolves within 3 days Occurs in 50%-90% of patients treated with HEC; 35%-70% of patients treated with MEC Breakthrough N/V: occurs despite appropriate prophylaxis, requires rescue medication Anticipatory N/V: occurs before subsequent chemotherapy cycles Associated with poor control of CINV in a previous cycle Refractory N/V: repeated need for rescue when prior rescue efforts have failed 12 HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy. 4

5 Conceptual Model of Acute and Delayed CINV 5-HT 3 sensitive phase Prokinetic-sensitive phase Intensity of Emesis 5-HT 5-HT NK 1 -sensitive phase Steroid-sensitive phase Disrupted gut motility Cell breakdown products Time (days) 13 5-HT = 5-hydroxytryptamine; NK 1 = neurokinin-1. Adapted from Andrews PL, Davis CJ. In: Andrews PL, Sanger GJ. Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. London, UK: Chapman and Hall Medical; 1993: Case 2: Dan (cont d) Dan underwent resection and is now receiving adjuvant therapy with FOLFOX He is given APD for CINV prophylaxis He does well initially, but experiences N/V 24 hours later and prochlorperazine gives no relief He takes the lorazepam he was given in the clinic, but still gets no relief Dan calls the oncology care team after a day with continued symptoms 14 APD = aprepitant, palonosetron, and dexamethasone. Which of the following best describes Dan s CINV??DECISION POINT 1. Acute 2. Anticipatory 3. Breakthrough 4. Delayed Use your keypad to vote now! 15 5

6 Physiology of N/V N/V serve as important mechanisms to protect an animal from ingested toxins Redundancy and plasticity in emetic pathways make control more difficult 16 Hesketh PJ. N Engl J Med. 2008;358: Pathways by Which Chemotherapy May Produce Emesis 17 Hesketh PJ. N Engl J Med. 2008;358: Neurotransmitters in Emesis Dopamine (D2) Histamine Cannabinoids Endorphins Emetic Reflex Serotonin (5-HT 3 ) Acetylcholine Substance P (NK 1 ) Gammaaminobutyric acid 18 Slide courtesy of Paul Hesketh, MD. 6

7 Emetogenic Potential of Single Antineoplastic Agents High >90% of patients at risk Moderate 30%-90% of patients at risk Low 10%-30% of patients at risk Minimal <10% of patients at risk 19 NCCN. Accessed May 4, Emetogenic Potential of IV Antineoplastic Agents Level HEC AC combination, defined as doxorubicin or epirubicin with cyclophosphamide Carmustine >250 mg/m 2 Cisplatin MEC Aldesleukin >12-15 million IU/m 2 Amifostine >300 mg/m 2 Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin Carmustine 250 mg/m 2 Agent Cyclophosphamide >1500 mg/m 2 Dacarbazine Doxorubicin 60 mg/m 2 Clofarabine Cyclophosphamide 1500 mg/m 2 Cytarabine >200 mg/m 2 Dactinomycin Daunorubicin Doxorubicin <60 mg/m 2 Epirubicin 90 mg/m 2 Idarubicin Epirubicin >90 mg/m 2 Ifosfamide 2 g/m 2 per dose Mechlorethamine Streptozocin Ifosfamide <2 g/m 2 per dose Interferon alfa 10 million IU/m 2 Irinotecan Melphalan Methotrexate 250 mg/m 2 Oxaliplatin Temozolomide 20 AC = anthracycline + cyclophosphamide; IV = intravenous. Adapted from NCCN. Accessed May 4, Emetogenic Potential of IV Antineoplastic Agents (cont d) Level Agent Low Ado-trastuzumab emtansine Aldesleukin 12 million IU/m 2 Amifostine 300 mg/m 2 Belinostat Brentuximab vedotin Cabazitaxel Carfilzomib Cytarabine (low dose) Docetaxel Doxorubicin (liposomal) Eribulin Etoposide 5-fluorouracil Floxuridine Gemcitabine Interferon alfa >5<10 million IU/m 2 Ixabepilone Methotrexate >50 mg/m 2 <250 mg/m 2 Mitomycin Mitoxantrone Omacetaxine Paclitaxel Paclitaxel-albumin Pemetrexed Pentostatin Pralatrexate Romidepsin Thiotepa Topotecan Ziv-aflibercept Minimal Alemtuzumab Asparaginase Bevacizumab Bleomycin Bortezomib Cetuximab Cladribine Cytarabine <100 mg/m 2 Decitabine Denileukin diftitox Dexrazoxane Fludarabine Interferon alfa 5 million IU/m 2 Ipilimumab Methotrexate 50 mg/m 2 Nelarabine Obinutuzumab Ofatumumab Panitumumab Pegaspargase Peginterferon Pembrolizumab Pertuzumab Ramucirumab Rituximab Siltuximab Temsirolimus Trastuzumab Valrubicin Vinblastine Vincristine Vincristine (liposomal) Vinorelbine 21 Adapted from NCCN. Accessed May 4,

8 Emetogenic Potential of Oral Antineoplastic Agents Level Agent Moderatehigh Altretamine Busulfan ( 4 mg/d) Crizotinib Cyclophosphamide ( 100 mg/m 2 /d) Estramustine Etoposide Lomustine (single day) Mitotane Procarbazine Temozolomide (>75 mg/m 2 /d) Vismodegib Minimallow Axitinib Bexarotene Bosutinib Busulfan (<4 mg/d) Cabozantinib Capecitabine Chlorambucil Cyclophosphamide (<100 mg/m 2 /d) Dabrafenib Dasatinib Erlotinib Everolimus Fludarabine Gefitinib Hydroxyurea Imatinib Lapatinib Lenalidomide Melphalan Mercaptopurine Methotrexate Nilotinib Pazopanib Pomalidomide Ponatinib Regorafenib Ruxolitinib Sorafenib Sunitinib Temozolomide ( 75 mg/m 2 /d) Thalidomide Thioguanine Topotecan Trametinib Tretinoin Vandetanib Vemurafenib Vorinostat 22 Adapted from NCCN. Accessed May 4, Which of the following best describes the emetogenic potential of Linda s chemotherapy (cisplatin/paclitaxel)??decision POINT 1. High 2. Moderate 3. Low 4. Minimal Use your keypad to vote now! 23 Emetogenic Potential of IV Antineoplastic Agents Level Agent HEC AC combination, defined as doxorubicin or epirubicin with cyclophosphamide Carmustine >250 mg/m 2 Cisplatin MEC Aldesleukin >12-15 million IU/m 2 Amifostine >300 mg/m 2 Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin Carmustine 250 mg/m 2 Cyclophosphamide >1500 mg/m 2 Dacarbazine Doxorubicin 60 mg/m 2 Clofarabine Cyclophosphamide 1500 mg/m 2 Cytarabine >200 mg/m 2 Dactinomycin Daunorubicin Doxorubicin <60 mg/m 2 Epirubicin 90 mg/m 2 Idarubicin Epirubicin >90 mg/m 2 Ifosfamide 2 g/m 2 per dose Mechlorethamine Streptozocin Ifosfamide <2 g/m 2 per dose Interferon alfa 10 million IU/m 2 Irinotecan Melphalan Methotrexate 250 mg/m 2 Oxaliplatin Temozolomide 24 Adapted from NCCN. Accessed May 4,

9 Emetogenic Potential of IV Antineoplastic Agents (cont d) Level Agent Low Ado-trastuzumab emtansine Amifostine 300 mg/m 2 Aldesleukin 12 million IU/m 2 Belinostat Brentuximab vedotin Cabazitaxel Carfilzomib Cytarabine (low dose) Docetaxel Doxorubicin (liposomal) Eribulin Etoposide 5-fluorouracil Floxuridine Gemcitabine Interferon alfa >5 <10 million IU/m 2 Ixabepilone Methotrexate >50 mg/m 2 <250 mg/m 2 Mitomycin Mitoxantrone Omacetaxine Paclitaxel Paclitaxel-albumin Pemetrexed Pentostatin Pralatrexate Romidepsin Thiotepa Topotecan Ziv-aflibercept Minimal Alemtuzumab Asparaginase Bevacizumab Bleomycin Bortezomib Cetuximab Cladribine Cytarabine <100 mg/m 2 Decitabine Denileukin diftitox Dexrazoxane Fludarabine Interferon alfa 5 million IU/m 2 Ipilimumab Methotrexate 50 mg/m 2 Nelarabine Obinutuzumab Ofatumumab Panitumumab Pegaspargase Peginterferon Pembrolizumab Pertuzumab Ramucirumab Rituximab Siltuximab Temsirolimus Trastuzumab Valrubicin Vinblastine Vincristine Vincristine (liposomal) Vinorelbine 25 Adapted from NCCN. Accessed May 4, What is the emetogenic risk associated with Dan s chemotherapy (FOLFOX)??DECISION POINT 1. High 2. Moderate 3. Low 4. Minimal Use your keypad to vote now! 26 Emetogenic Potential of IV Antineoplastic Agents Level HEC AC combination, defined as doxorubicin or epirubicin with cyclophosphamide Carmustine >250 mg/m 2 Cisplatin MEC Aldesleukin >12-15 million IU/m 2 Amifostine >300 mg/m 2 Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin Carmustine 250 mg/m 2 Agent Cyclophosphamide >1500 mg/m 2 Dacarbazine Doxorubicin 60 mg/m 2 Clofarabine Cyclophosphamide 1500 mg/m 2 Cytarabine >200 mg/m 2 Dactinomycin Daunorubicin Doxorubicin <60 mg/m 2 Epirubicin 90 mg/m 2 Idarubicin Epirubicin >90 mg/m 2 Ifosfamide 2 g/m 2 per dose Mechlorethamine Streptozocin Ifosfamide <2 g/m 2 per dose Interferon alfa 10 million IU/m 2 Irinotecan Melphalan Methotrexate 250 mg/m 2 Oxaliplatin Temozolomide 27 Adapted from NCCN. Accessed May 4,

10 Emetogenic Potential of IV Antineoplastic Agents (cont d) Level Agent Low Ado-trastuzumab emtansine Amifostine 300 mg/m 2 Aldesleukin 12 million IU/m 2 Belinostat Brentuximab vedotin Cabazitaxel Carfilzomib Cytarabine (low dose) Docetaxel Doxorubicin (liposomal) Eribulin Etoposide 5-fluorouracil Floxuridine Gemcitabine Interferon alfa >5 <10 million IU/m 2 Ixabepilone Methotrexate >50 mg/m 2 <250 mg/m 2 Mitomycin Mitoxantrone Omacetaxine Paclitaxel Paclitaxel-albumin Pemetrexed Pentostatin Pralatrexate Romidepsin Thiotepa Topotecan Ziv-aflibercept Minimal Alemtuzumab Asparaginase Bevacizumab Bleomycin Bortezomib Cetuximab Cladribine Cytarabine <100 mg/m 2 Decitabine Denileukin diftitox Dexrazoxane Fludarabine Interferon alfa 5 million IU/m 2 Ipilimumab Methotrexate 50 mg/m 2 Nelarabine Obinutuzumab Ofatumumab Panitumumab Pegaspargase Peginterferon Pembrolizumab Pertuzumab Ramucirumab Rituximab Siltuximab Temsirolimus Trastuzumab Valrubicin Vinblastine Vincristine Vincristine (liposomal) Vinorelbine 28 Adapted from NCCN. Accessed May 4, NCCN Treatment Guidelines NCCN Guidelines for Acute/Delayed CINV Highly emetogenic Acute Aprepitant-containing regimen NK 1 antagonist Aprepitant 125 mg PO, or Fosaprepitant 150 mg IV once AND Serotonin (5-HT 3) antagonist Dolasetron 100 mg PO once Granisetron 2 mg PO once, or 1 mg PO twice per day, or 0.01 mg/kg (max 1 mg) IV once, or 3.1 mg/24 h transdermal patch applied h before chemotherapy Ondansetron mg PO once or 8-16 mg IV once Palonosetron 0.25 mg IV once AND Steroid: dexamethasone 12 mg PO/IV once Netupitant-containing regimen Netupitant 300 mg/palonosetron 0.5 mg PO once Dexamethasone 12 mg PO/IV once Olanzapine-containing regimen Olanzapine 10 mg PO once Palonosetron 0.25 mg IV once Dexamethasone 20 mg IV once Delayed If aprepitant PO given on day 1, aprepitant 80 mg PO daily on days 2 and 3 If fosaprepitant IV given on day 1, no further aprepitant needed on days 2 and 3 AND If aprepitant PO given on day 1, dexamethasone 8 mg PO/IV daily on days 2, 3, and 4 If fosaprepitant IV given on day 1, dexamethasone 8 mg PO/IV once on day 2, then 8 mg PO/IV on days 3 and 4 Dexamethasone 8 mg PO/IV on days 2, 3, and 4 Olanzapine 10 mg PO on days 2, 3, and 4 30 PO = by mouth. 10

11 According to the NCCN guidelines, what would be the best option to prevent CINV for cycle 2 of Linda s chemotherapy (cisplatin/paclitaxel)??decision POINT 1. Prescribe a higher dose of granisetron 2. 5-HT 3 receptor antagonist (RA) + dexamethasone 3. 5-HT 3 RA + dexamethasone + NK 1 RA 4. Prochlorperazine Use your keypad to vote now! 31 NCCN Guidelines for Acute/Delayed CINV (cont d) Moderately emetogenic Acute Serotonin (5-HT 3) antagonist + steroid ± NK 1 antagonist Serotonin antagonist Dolasetron 100 mg PO once Granisetron 2 mg PO once, or 1 mg PO twice a day, or 0.01 mg/kg (max 1 mg) IV once, or 3.1 mg/24 h transdermal patch applied h prior to first dose of chemotherapy Ondansetron mg PO once or 8-16 mg IV once Palonosetron 0.25 mg IV once (preferred) AND Steroid Dexamethasone 12 mg PO/IV once WITH/WITHOUT NK 1 antagonist Aprepitant 125 mg PO once Fosaprepitant 150 mg IV once Netupitant-containing regimen Netupitant 300 mg/palonosetron 0.5 mg PO once Dexamethasone 12 mg PO/IV once Olanzapine-containing regimen Olanzapine 10 mg PO once Palonosetron 0.25 mg IV once Dexamethasone 20 mg IV once Delayed Serotonin antagonist monotherapy Dolasetron 100 mg PO on days 2 and 3 Granisetron 1-2 mg PO daily or 1 mg PO twice a day or 0.01 mg/kg (maximum 1 mg) IV daily on days 2 and 3 Ondansetron 8 mg PO twice a day or 16 mg PO daily or 8-16 mg IV daily on days 2 and 3 OR Steroid monotherapy Dexamethasone 8 mg PO/IV on days 2 and 3 OR NK 1 antagonist ± steroid Aprepitant used day 1: aprepitant 80 mg PO daily on days 2 and 3 ± dexamethasone 8 mg PO/IV daily on days 2 and 3 Fosaprepitant used day 1: ± dexamethasone 8 mg PO or IV daily on days 2 and 3 ± Dexamethasone 8 mg PO/IV days 2 and 3 Olanzapine 10 mg PO daily days 2 and 3 32 NCCN Guidelines for Acute/Delayed CINV (cont d) Emetogenicity Low Begin before chemotherapy; repeat daily for multiday doses of chemotherapy Dexamethasone 12 mg PO/IV daily OR Metoclopramide mg PO/IV and then either every 4 or every 6 hours as needed OR Prochlorperazine OR Serotonin (5-HT 3 ) antagonist Minimal No routine prophylaxis 33 NCCN. Accessed May 4,

12 Chemotherapy-Induced Nausea and Vomiting: Current Guidelines and Pharmacologic Agents for CINV 5-HT 3 RAs NK 1 RAs 5-HT 3 RA/NK 1 RA combination Corticosteroids Olanzapine Benzodiazepines Dopamine RAs Cannabinoids 34 Clinical Studies Comparing 5-HT 3 RAs: Efficacy Differences in CINV Prevention Palonosetron is more effective in preventing both acute and delayed emesis 1-4 Not accounted for by longer half-life of palonosetron or binding affinities to the receptor 5,6 Higher doses of ondansetron and administration of ondansetron >24 hours does not mimic improved efficacy of palonosetron on delayed emesis Aapro MS, et al. Ann Oncol. 2006;14: ; 2. Eisenberg P, et al. Cancer. 2003;98: ; 3. Gralla R, et al. Ann Oncol. 2003;14: ; 4. Saito M, et al. Lancet Oncol. 2009;10: ; 5. Rojas C, et al. Anesth Analg. 2008;107: ; 6. Geling O, et al. J Clin Oncol. 2005;23: Current Status of NK 1 RAs in CINV 36 FDA-approved agents Aprepitant: 125 mg PO day 1; 80 mg PO days 2 and 3 Fosaprepitant: 150 mg IV day 1 NEPA Good safety profile and significantly enhanced CINV control when combined with a 5-HT 3 RA + dexamethasone More effective in emesis vs nausea control Consensus guideline-recommended use: Single-day HEC (including AC) Other potential uses MEC Multiday HEC; high-dose chemotherapy with autologous stem cell transplant FDA = Food and Drug Administration; NEPA = netupitant 300 mg/palonosetron 0.5 mg. 12

13 Aprepitant: Potential for Drug Interactions Aprepitant is: Substrate for CYP3A4 Extensively metabolized by CYP3A4 Moderate inhibitor of CYP3A4 Inducer of CYP3A4 and CYP2C9 Exposure to agents also subject to CYP3A4 and/or CYP2C9 metabolism might be altered when coadministered with aprepitant (and vice versa) 37 Aapro MS, et al. Ann Oncol. 2010;21: ; Emend (aprepitant) [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc.; NEPA: A New Option Combining an NK 1 RA With a 5-HT 3 RA Oral, fixed-dose combination of novel NK 1 RA netupitant (300 mg) + 5-HT 3 RA palonosetron (0.5 mg) in 1 capsule Taken 1 hour before start of chemotherapy FDA approved on October 10, 2014 Indicated for prevention of acute and delayed N/V associated with initial and repeat courses of chemotherapy, including, but not limited to, HEC 38 NEPA: Efficacy Results From 2 Randomized Phase 3 Clinical Trials: Cycle 1 Overall (0-120 hours) CR a AC MEC Study 1 NEPA + dexamethasone Oral palonosetron + dexamethasone CR 74% (n = 724) b 67% (n = 725) Multiple-Cycle Non-AC MEC + HEC Study 2,c NEPA + dexamethasone Aprepitant + palonosetron + dexamethasone d (no formal efficacy comparisons) CR 81% (n = 309) 76% (n = 104) 39 a All patients were chemotherapy-naïve with solid tumors; b P <.01 vs oral palonosetron; c Primary end point delayed ( hours) phase: NEPA 77% vs oral palonosetron 70% (P <.001); d No formal (efficacy) comparisons APD; included as exploratory and to help interpret results. CR = complete response. 1. Aapro M, et al. Ann Oncol. 2014;25: ; 2. Gralla RJ, et al. Ann Oncol. 2014;25:

14 NK 1 RA in Development: Rolapitant Application for FDA approval filed September 8, 2014 Prescription Drug User Fee Act (decision required by FDA) by September 4, 2015 No induction of CYP3A4 180-hour half-life >90% receptor occupancy rate for 5 days 40 Rolapitant: 2 Randomized Trials in HEC Chemotherapy CR rate is superior in rolapitant vs the control arm in the delayed, acute, and overall phase CR rate is superior in rolapitant vs the control arm in the delayed phase CR rate is numerically greater in rolapitant vs the control arm in the acute and overall phases, but it is not significant HEC1 (Modified Intention-to-Treat Population, n = 526) CR Rate Rolapitant (%) Control (%) P Value Delayed phase (> hours) <.001 Acute phase (0-24 hours) Overall phase (0-120 hours) HEC2 (Modified Intention-to-Treat Population, n = 544) CR Rate Rolapitant (%) Control (%) P Value Delayed phase (> hours) Acute (0-24 hours) Overall (0-120 hours) Rapoport BL, et al Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium. Abstract NK 1 RA in Development: Rolapitant for MEC Randomized phase 3 trial 1369 patients receiving MEC Granisetron + dexamethasone Rolapitant 200 mg or placebo CR Rolapitant Placebo P (%) (%) Overall <.001 Acute Delayed Schnadig I, et al Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium. Abstract

15 Corticosteroids Uncertain mechanism of action May involve prostaglandin synthesis inhibition in hypothalamus Effective as single agent or in combination therapy Potentiate effects of other antiemetics Effective for acute and delayed CINV 43 de Jong FA, et al. J Clin Oncol. 2005;23: ; Hesketh PJ. N Engl J Med. 2008;358: ; Jantunen IT, et al. Eur J Cancer. 1997;33:66-74; Perwitasari DA, et al. Int J Clin Pharm. 2011;33: Effect of Adding Dexamethasone to 5-HT 3 RAs for Acute Emesis No. of Patients Vomiting/No. of Patients Evaluable Author Hesketh Smith Roila Joss Smyth Heron Latreille Italian group Carmichael Sorbe Adams Total 0 5-HT 3 + Dexamethasone Better Treatment effect P < HT 3 2 Better 51 Jantunen IT, et al. Eur J Cancer. 1997;33: Olanzapine Olanzapine (atypical antipsychotic) Mechanism of action in CINV: unknown Possible neurotransmitter receptors blocked include dopaminergic, serotonergic, catecholamine alpha 1 adrenergic, acetylcholine muscarinic, histamine Use with caution in elderly patients Prophylaxis for acute and delayed CINV; a new alternative to aprepitant Also effective for breakthrough CINV 45 15

16 Olanzapine vs Aprepitant for Prevention of CINV in Patients Receiving HEC CR (No Emesis No Rescue) (%) Acute Delayed Overall OPD (n = 121) APD (n = 120) No Nausea (%) OPD (n = 121) APD (n = 120) OPD = olanzapine, palonosetron, dexamethasone. Navari RM, et al. J Support Oncol. 2011;9: Benzodiazepines Benzodiazepines (anxiolytics) Examples: lorazepam, alprazolam, midazolam Drugs of choice for anticipatory CINV May decrease severity of extrapyramidal symptoms associated with dopamine RAs 47 National Cancer Institute. nausea/healthprofessional/page6#section_171. Accessed May 4, 2015; Wang XF, et al. Sci Rep. 2014;4:4813. Dopamine RAs Examples: metoclopramide, prochlorperazine, haloperidol Blockade in the area postrema Increase chemoreceptor trigger zone threshold Decrease sensitivity of vagal afferent nerves from gastrointestinal tract to central nervous system Low therapeutic index as antiemetics May be useful for breakthrough emesis 48 de Jong FA, et al. J Clin Oncol. 2005;23: ; Hesketh PJ. N Engl J Med. 2008;358: ; Perwitasari DA, et al. Int J Clin Pharm. 2011;33:33-43; NCCN. Accessed May 4,

17 Cannabinoids Examples: dronabinol, nabilone Agonist antiemetic effect on enterochromaffin cells Anticholinergic effect on cholinergic terminals and Auerbach plexus Low therapeutic index as an antiemetic 49 de Jong FA, et al. J Clin Oncol. 2005;23: ; Hesketh PJ. N Engl J Med. 2008;358: ; Perwitasari DA, et al. Int J Clin Pharm. 2011;33:33-43; NCCN. Accessed May 4, Which of the following treatment strategies would you choose to manage Dan s breakthrough CINV? (Dan was previously given APD, prochlorperazine, and lorazepam.)?decision POINT 1. Prescribe a different 5-HT 3 RA 2. Increase the dose of lorazepam 3. Prescribe a 5-HT 3 RA/NK 1 RA combination 4. Olanzapine Use your keypad to vote now! 50 Principles for Managing Breakthrough CINV Give additional agent from a different class of antiemetic Consider around-the-clock rather than as-needed administration of antiemetic If patient is vomiting, IV or rectal administration may be required Before next cycle of chemotherapy, reassess response in both acute and delayed setting Consider an alternative regimen if needed Add aprepitant if not previously used 51 NCCN. Accessed May 4,

18 Much Progress Has Been Made, but Challenges Remain Prevention of nausea remains a challenge Adherence to guidelines is poor due to: Lack of knowledge by healthcare providers Differing recommendations Cost/financial issues Lack of institutional enforcement Inadequate measurement of quality of care and outcomes 52 Grunberg SM. J Natl Compr Cancer Netw. 2009;7: Challenges Not Addressed in Current Antiemetic Guidelines Current guidelines based primarily on 2 factors: Emetogenicity of single-dose chemotherapy Pattern of CINV (eg, acute, delayed) Lack of data on: How to incorporate additional patient-specific emetic risk factors Female gender Younger age (<50 years) No/low alcohol consumption (<1 drink/day) History of nausea with stress History of motion sickness or hyperemesis in pregnancy Stem cell transplant Pediatric patients 53 Principles of Antiemetic Therapy Goal: prevent CINV throughout the period of risk 3 days in patients receiving HEC 2 days in those receiving MEC Oral vs IV 5-HT 3 RAs: equivalent efficacy with correct dose Consider toxicity of the specific antiemetic classes 5-HT 3 RAs: constipation, headache, dizziness NK 1 RAs: alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups, nausea Corticosteroids: insomnia, epigastric discomfort, agitation, weight gain, hyperglycemia Dopamine RAs: extrapyramidal symptoms, dystonia, drowsiness 54 NCCN. Accessed May 4, 2015; National Cancer Institute. HealthProfessional/page6. Accessed May 4, 2015; Wickham R. Cancer Control. 2012;19(2 suppl):

19 Principles of Antiemetic Therapy (cont d) Choice should be based on: Emetic risk of therapy (based on drug with highest level of emetogenicity) Patient experience with antiemetics Patient factors Consider other potential causes of emesis Bowel obstruction, hypercalcemia, brain metastases, electrolyte imbalance, uremia, other drugs 55 NCCN. Accessed May 4, PCE ACTION PLAN PCE Action Plan Consider both patient- and treatment-specific risk factors when choosing prophylactic agents for CINV Consider the NCCN guidelines when selecting agents to manage acute and delayed CINV Consider a different class of medication or around-theclock rather than as-needed administration for breakthrough CINV PCE Promotes Practice Change 57 19